PMID- 18443134 TI - Omega-3 fatty acids-supplemented parenteral nutrition decreases hyperinflammatory response and attenuates systemic disease sequelae in severe acute pancreatitis: a randomized and controlled study. AB - BACKGROUND: The objective of this study was to investigate whether altering the fatty acid (FA) profile by omega-3 FA supplementation affects inflammatory response and systemic disease sequelae in severe acute pancreatitis. METHODS: Forty severe acute pancreatitis patients were enrolled and randomly assigned to receive parenteral nutrition (PN) for 5 days in a double-blind manner. Patients received PN with identical amounts of amino acids (1.25 g/kg/d), glucose (3 g/kg/d), and fat (1 g/kg/d) but different lipid compositions: the control group received a soybean oil (SO; Lipovenos 20%; Fresenius, Germany)-based fat solution and the omega-3 FA group was supplemented with 0.15 - 0.2 g/kg/d fish oil (FO; Omegaven 10%; Fresenius, Germany). Serum concentrations of eicosapentaenoic acid (EPA), interleukin-6, C-reactive protein (CRP), white blood cell count, and routine respiratory and renal parameters were measured before PN, and again on day 6 after starting PN. Outcomes such as infection morbidity, mortality, intensive care unit time, and length of hospital stay were recorded. RESULTS: Patients treated with FO had a significantly higher EPA concentration (P < .01), lower CRP level (P < .05), and better oxygenation index (P < .05) after 5 days of PN. Moreover, the number of days of continuous renal replacement therapy (CRRT) in the omega-3 FAs group was significantly less than that in the control group (P < .05). CONCLUSIONS: PN supplemented with omega-3 FAs diminishes the hyperinflammatory response by the EPA increase and the proinflammatory cytokine decrease in severe acute pancreatitis. This, together with improved respiratory function and shortened CRRT time, suggests that the systemic response to pancreatic and organ injury is attenuated. PMID- 18443135 TI - Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation. AB - BACKGROUND: Aluminum toxicity can cause serious central nervous system and bone toxicities. Aluminum is a contaminant of parenteral nutrition (PN) solution components. Premature neonates requiring high doses of calcium and phosphate to mineralize their bones, children with impaired renal function, and children on PN therapy for prolonged duration are at the highest risk. Effective in July 2004, the U.S. Food and Drug Administration (FDA) mandated labeling requirements for aluminum content in all PN solution components. To assess the aluminum exposure in neonatal and pediatric populations, this study aims to determine patients' daily aluminum load (mug/kg/d) delivered from PN solutions. METHODS: The study included all inpatients who received PN during calendar year 2006 (13,384 PN patient days). The calculated parameters of mug/kg/d and mug/L of parentally administered aluminum were stratified according to patient age and weight. Aluminum content by product and manufacturer were tabulated. RESULTS: Forty-nine percent of the PN patient days were in patients weighing < 3 kg. These patients also received the largest amounts of aluminum (range, 30-60 mug/kg/d). Meeting the FDA regulation was possible only in patients weighing > 50 kg. CONCLUSIONS: Currently available parenteral products used to make PN solutions contain amounts of aluminum that make it impossible to meet the new FDA rule of <5 mug/kg/d of aluminum exposure. Manufacturers must identify, develop, and adopt new methods to reduce the aluminum contamination in their products. Health care professionals should calculate aluminum loads in patients and make informed decisions when choosing PN products. PMID- 18443136 TI - Carbohydrate supplementation before operation retains intestinal barrier function and lowers bacterial translocation in a rat model of major abdominal surgery. AB - BACKGROUND: Overnight fasting of rats augments the susceptibility of the small intestine to ischemia-reperfusion damage. Feeding before surgery may improve injuries to distant organs that were induced by ischemia-reperfusion. The present study tested the hypothesis that one of the food constituents, namely carbohydrates, may be responsible for the protective effect of preoperative feeding on postoperative organ dysfunction. METHODS: Male Wistar rats were fed ad libitum for 5 d and had either free access to water or free access to a carbohydrate drink and water. Then they were fasted for 16 h and access remained to either water or a carbohydrate drink and water. Following this, the arteria mesenterica superior was clamped for 60 min followed by 180 min of reperfusion. Subsequently, the intestinal permeability of stripped ileum was determined by measuring the mucosal to serosal flux in Ussing chambers. For assessment of bacterial content, organs were aseptically removed and assessed for bacterial content by culture under anaerobic conditions. RESULTS: Preoperative supplementation with carbohydrates resulted in a better maintenance of intestinal barrier function when compared with water supplemented animals. Moreover, carbohydrate supplementation resulted in a reduction in the ischemiareperfusion induced increase in bacterial content of the liver, kidney, and mesenteric lymph nodes. CONCLUSIONS: Preoperative intake of carbohydrates by rats retains both the intestinal barrier function and prevents translocation of bacteria to distant organs. PMID- 18443137 TI - Exogenous glucagon-like peptide-2 (GLP-2) augments GLP-2 receptor mRNA and maintains proglucagon mRNA levels in resected rats. AB - BACKGROUND: Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent proglucagon derived hormone that stimulates intestinal adaptive growth. Our aim was to determine whether exogenous GLP-2 increases resection-induced adaptation without diminishing endogenous proglucagon and GLP-2 receptor expression. METHODS: Rats underwent transection or 70% jejunoileal resection +/- GLP-2 infusion (100 microg/kg body weight/d) and were fed a semipurified diet with continuous infusion of GLP-2 or saline by means of jugular catheter. After 7 days, body weight, mucosal cellularity (dry mass, protein and DNA), crypt-villus height, and crypt cell proliferation (by bromodeoxyuridine staining) were determined. Plasma bioactive GLP-2 (by radioimmunoassay), proglucagon and GLP-2 receptor mRNA expression (by Northern blot and real-time reverse transcriptase quantitative polymerase chain reaction) were measured. GLP-2 receptor was colocalized to neuroendocrine markers by immunohistochemistry. RESULTS: Low-dose exogenous GLP-2 increased mucosal cellularity and crypt-villus height in the duodenum, jejunum, and ileum; enterocyte proliferation in the jejunal crypt; and duodenal and jejunal sucrase segmental activity. Plasma bioactive GLP-2 concentration increased 70% upon resection, with an additional 54% increase upon GLP-2 infusion in resected rats (P < .05). Ileal proglucagon mRNA expression increased with resection, and exogenous ileum GLP-2 failed to blunt this response. Exogenous GLP 2 increased ileum GLP-2 receptor expression 3-fold in resected animals and was colocalized to vasoactive intestinal peptide-positive and endothelial nitric oxide synthase-expressing enteric neurons and serotonin-containing enteroendocrine cells in the jejunum and ileum of resected rats. CONCLUSIONS: Exogenous GLP-2 augments adaptive growth and digestive capacity of the residual small intestine in a rat model of mid-small bowel resection by increasing plasma GLP-2 concentrations and GLP-2 receptor expression without diminishing endogenous proglucagon expression. PMID- 18443138 TI - Colostrum supplementation restores insulin-like growth factor -1 levels and alters muscle morphology following massive small bowel resection. AB - BACKGROUND: Colostrum protein concentrate (CPC) contains a high level of insulin like growth factor-1 (IGF-1). IGF-1 and IGF binding protein (IGFBPs) may play an important role during the postresection adaptation response. As smooth muscle is an important site for IGF-1 action in the intestine, this study aims to (1) investigate the effect of CPC supplementation on circulating levels and tissue expression of IGF-1, IGF-1 receptor, and IGFBPs following massive small bowel resection (MSBR), and (2) characterize the effect of CPC on the muscular adaptation response following MSBR. METHODS: Four-week-old piglets underwent either a 75% MSBR or sham operation. Piglets received either a polymeric infant formula (PIF) diet or PIF supplemented with CPC for 8 weeks. Serum was analyzed by enzyme-linked immunosorbent assay, and ileal tissue assessed by molecular and histological analysis. RESULTS: There was no difference in IGF-1 or IGFBPs mRNA among groups. CPC treatment resulted in significant increases in circulating levels of IGF-1 and IGFBPs and a concurrent increase in muscle width and the number of muscle cells, but did not alter muscle cell size. CONCLUSIONS: Strategies aimed at increasing muscular adaptation may decrease Gl transit and allow greater mucosal contact time for absorption. We have shown that CPC supplementation following resection results in increased levels of circulating IGF-1, IGFBP-2, and IGFBP-3 and muscular hypertrophy. Our results suggest that IGF-1 and its mediators may play a role in the muscular adaptation response and warrant further exploration as a treatment option for short bowel syndrome. PMID- 18443139 TI - Sesame oil does not show accumulatively enhanced protection against oxidative stress-associated hepatic injury in septic rats. AB - BACKGROUND: Sepsis is one of the major causes of death reported in intensive care units. A daily supplement of sesame oil for 1 week significantly attenuates oxidative stress-associated hepatic injury in septic rats. However, the excess intake of sesame oil may be associated with a health risk. This study investigates the effect of accumulative sesame oil on oxidative stress-associated hepatic injury after cecal ligation and puncture in rats. METHODS: Sesame oil was administered daily (4 mL/kg/d, orally) to rats, and the total intake of sesame oil ranged from 0 (control) to 140 mL/kg before cecal ligation and puncture in 9 groups of rats. Oxidative stress was examined by determining the levels of lipid peroxidation and glutathione. Hepatic injury was evaluated by measuring serum levels of aspartate aminotransferase and alkaline phosphatase. RESULTS: Rats that received sesame oil for 4 and 5 weeks had a lower body weight gain compared with those that received saline. Lipid peroxidation was decreased in the 20-mL/kg and 28-mL/kg groups, but it was increased in the 140-mL/kg group compared with the control group. Glutathione levels were increased in the < or =28-mL/kg groups compared with the control group. Serum levels of aspartate aminotransferase and alkaline phosphatase were reduced in the < or =28-mL/kg groups compared with the control group. CONCLUSION: Sesame oil does not demonstrate accumulatively enhanced protection against oxidative stress-associated hepatic injury after cecal ligation and puncture in rats. PMID- 18443140 TI - Severe weight loss and hypermetabolic paroxysmal dysautonomia following hypoxic ischemic brain injury: the role of indirect calorimetry in the intensive care unit. AB - A 14-year-old girl with hypoxic ischemic brain injury developed multiple paroxysms (storms) of dysautonomia. She had a dramatic weight loss of 20 kg over 8 weeks. Resting energy expenditure measured by indirect calorimetry during an autonomic storm was 309% of predicted resting energy expenditure, indicating extreme hypermetabolism. Energy intake and expenditure calculations showed cumulative energy deficits during the period of weight loss. The frequency of her hypermetabolic events increased daily energy needs that were unmatched by her intake, which was calculated from standard equations. Weight stabilized soon after nutrient intake was titrated to account for her heightened energy expenditure. This case illustrates an important nutrition complication of dysautonomic storms in children with brain injury. Regular weight checks during the intensive care course allow detection of weight loss from underfeeding. Measurement of energy needs is prudent when weight loss is unexplained or increased energy expenditure is suspected. In hospitalized patients with metabolic fluctuations, accurate measurement of energy requirements by indirect calorimetry allows serial monitoring of energy balance and may guide nutrition intake to prevent cumulative energy deficits. PMID- 18443141 TI - Necrotizing Candida infection after percutaneous endoscopic gastrostomy: a fatal and rare complication. AB - Gastrostomy site infections following percutaneous endoscopic gastrostomy (PEG) are the most common complication after PEG placement. Recent meta-analyses were able to show that PEG site infections can be reduced significantly with a systemic antimicrobial prophylaxis. This mostly cephalosporin- or penicillin based prophylaxis does not cover fungal infections. Although Candida skin infections after PEG placement are rarely described, a mucosal colonization or infection of the upper GI tract with Candida species is very common, especially in severely ill patients such as those requiring artificial nutrition. The authors report a rare and lethal case of a necrotizing PEG site infection with Candida albicans in a patient with diabetes with multiple comorbidities, presenting like gas gangrene. In patients with probable immunodeficiency or visible candidiasis of the skin, oropharynx, or esophagus, a Candida infection should be considered in case of a gastrostomy site infection. PMID- 18443142 TI - Fasting plasma citrulline concentrations do not reflect intestinal absorption capacity. PMID- 18443144 TI - Religion, risk, and medical decision making at the end of life. AB - OBJECTIVE: The purpose of this study is to present empirical evidence about whether religious patients are more or less willing to undergo the risks associated with potentially life-sustaining treatment. METHODS: At least every 4 months 226 older community-dwelling persons with advanced cancer, congestive heart failure, or chronic obstructive pulmonary disease were asked questions about several dimensions of religiousness and about their willingness to accept potentially life-sustaining treatment. RESULTS: Results were mixed but persons who said that during their illness they grew closer to God (odds ratio [OR] = 1.79; 95% confidence intervals [CI] = 1.15, 2.78) or those grew spiritually (OR = 1.61; 95% CI = 1.03, 2.52) were more willing to accept risk associated with potentially life-sustaining treatment than were persons who did not report such growth. DISCUSSION: Not all dimensions of religiousness have the same association with willingness to undergo potentially life-sustaining treatment. Seriously ill older, religious patients are not especially predisposed to avoid risk and resist treatment. PMID- 18443145 TI - DNA replication timing of the human beta-globin domain is controlled by histone modification at the origin. AB - The human beta-globin genes constitute a large chromosomal domain that is developmentally regulated. In nonerythroid cells, these genes replicate late in S phase, while in erythroid cells, replication is early. The replication origin is packaged with acetylated histones in erythroid cells, yet is associated with deacetylated histones in nonerythroid cells. Recruitment of histone acetylases to this origin brings about a transcription-independent shift to early replication in lymphocytes. In contrast, tethering of a histone deacetylase in erythroblasts causes a shift to late replication. These results suggest that histone modification at the origin serves as a binary switch for controlling replication timing. PMID- 18443146 TI - Degradation of several hypomodified mature tRNA species in Saccharomyces cerevisiae is mediated by Met22 and the 5'-3' exonucleases Rat1 and Xrn1. AB - Mature tRNA is normally extensively modified and extremely stable. Recent evidence suggests that hypomodified mature tRNA in yeast can undergo a quality control check by a rapid tRNA decay (RTD) pathway, since mature tRNA(Val(AAC)) lacking 7-methylguanosine and 5-methylcytidine is rapidly degraded and deacylated at 37 degrees C in a trm8-Delta trm4-Delta strain, resulting in temperature sensitive growth. We show here that components of this RTD pathway include the 5' 3' exonucleases Rat1 and Xrn1, and Met22, which likely acts indirectly through Rat1 and Xrn1. Since deletion of MET22 or mutation of RAT1 and XRN1 prevent both degradation and deacylation of mature tRNA(Val(AAC)) in a trm8-Delta trm4-Delta strain and result in healthy growth at 37 degrees C, hypomodified tRNA(Val(AAC)) is at least partially functional and structurally intact under these conditions. The integrity of multiple mature tRNA species is subject to surveillance by the RTD pathway, since mutations in this pathway also prevent degradation of at least three other mature tRNAs lacking other combinations of modifications. The RTD pathway is the first to be implicated in the turnover of mature RNA species from the class of stable RNAs. These results and the results of others demonstrate that tRNA, like mRNA, is subject to multiple quality control steps. PMID- 18443148 TI - Social information processing, security of attachment, and emotion regulation in children with learning disabilities. AB - This study examined the contribution of attachment security and emotion regulation (ER) to the explanation of social information processing (SIP) in middle childhood boys with learning disabilities (LD) and without LD matched on age and grade level. Children analyzed four social vignettes using Dodge's SIP model and completed the Kerns security scale and the children's self-control scale. Study results demonstrated major difficulties in SIP, lower attachment security, and less ER in children with LD compared to children without LD. Attachment as well as the interaction between attachment and ER emerged as important contributors to most SIP steps, suggesting that children with higher security who also have better ER skills will have better SIP capabilities along the different steps, beyond group inclusion. Results were discussed in terms of practical and clinical implications regarding the importance of mother-child attachment and ER skills for social cognitive capabilities in children with LD. PMID- 18443147 TI - Structural basis of histone H4 recognition by p55. AB - p55 is a common component of many chromatin-modifying complexes and has been shown to bind to histones. Here, we present a crystal structure of Drosophila p55 bound to a histone H4 peptide. p55, a predicted WD40 repeat protein, recognizes the first helix of histone H4 via a binding pocket located on the side of a beta propeller structure. The pocket cannot accommodate the histone fold of H4, which must be altered to allow p55 binding. Reconstitution experiments show that the binding pocket is important to the function of p55-containing complexes. These data demonstrate that WD40 repeat proteins use various surfaces to direct the modification of histones. PMID- 18443149 TI - Outcome status of students with learning disabilities at ages 21 and 24. AB - This study investigated whether the presence of learning disabilities (LD) at age 10 was related to later schooling, employment, income, receipt of public aid, involvement in crime, and feeling of victimization at ages 21 and 24. Confidential self-report data were collected in a prospective, longitudinal panel study from a sample of 571 students, of whom 60 (10.5%) were children with LD. After controlling for gender, ethnicity, and socioeconomic status, the following results were obtained: The highest postsecondary school attainment for young adults with LD was not significantly different from that of their peers without LD, both at age 21 and age 24. The rate of employment and amount of earned income of young adults with LD were not significantly lower than those of their peers without LD both at age 21 and age 24. Young adults with LD were not significantly different from their peers without LD at age 21 and age 24 with respect to having children, but young adults with LD received significantly more public aid (such as food stamps, supplemental security income, and unemployment compensation) at age 21 but not at age 24. Young adults with LD were not significantly different from their peers without LD in committing crimes or feeling victimized at age 21 and age 24. PMID- 18443150 TI - Mental arithmetic in children with mathematics learning disabilities: the adaptive use of approximate calculation in an addition verification task. AB - The adaptive use of approximate calculation was examined using a verification task with 18 third graders with mathematics learning disabilities, 22 typically achieving third graders, and 21 typically achieving second graders. Participants were asked to make true-false decisions on simple and complex addition problems while the distance between the proposed and the correct answer was manipulated. Both typically achieving groups were sensitive to answer plausibility on simple problems, were faster at rejecting extremely incorrect results than at accepting correct answers on complex addition problems, and showed a reduction of the complexity effect on implausible problems, attesting to the use of approximate calculation. Conversely, children with mathematics disabilities were unaffected by answer plausibility on simple addition problems, processed implausible and correct sums with equal speed on complex problems, and exhibited a smaller reduction of the complexity effect on implausible problems. They also made more errors on implausible problems. Different hypotheses are discussed to account for these results. PMID- 18443151 TI - Response to Stenson et al on the review of general mutation databases. PMID- 18443152 TI - We need a detailed phenome in the phenomenon of genetics and congenital heart disease. PMID- 18443153 TI - Provide GPs with spirometry, not spirometers. PMID- 18443154 TI - The evidence based treatment of tuberculosis: where and why are we failing? PMID- 18443155 TI - Short course of antibiotic treatment in acute exacerbations of COPD. PMID- 18443156 TI - Celebrating 25 years of the BTS: the Silver Jubilee Meeting. PMID- 18443157 TI - Perils of fire eating. An acute form of lipoid pneumonia or fire eater's lung. PMID- 18443162 TI - Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: a systematic review. AB - OBJECTIVE: To systematically review the evidence for the medium to long term benefits and risks of montelukast as add-on therapy to inhaled corticosteroids (ICS) in comparison with placebo and active controls in mild to moderate asthma. DATA SOURCES: Medline, Embase, Cochrane Register of Controlled Trials, reference lists of retrieved articles, clinical trial registries and study results databases. REVIEW METHODS: Systematic review of randomised controlled trials (duration > or = 12 weeks) in adolescents and adults comparing montelukast/ICS versus ICS monotherapy or montelukast/ICS versus active control/ICS. Meta analyses were conducted where feasible. The main focus was on clinical outcomes (eg, exacerbations). Adverse events were also assessed. RESULTS: 13 studies meeting all of the inclusion criteria were identified: 7 studies, including constant or tapered doses of ICS, compared montelukast/ICS with ICS monotherapy. Six studies compared add-on montelukast with an add-on active control (salmeterol). Overall, the data indicated that montelukast/ICS was clinically more effective than ICS monotherapy. The ICS sparing potential of montelukast was clearly demonstrated in one study. Montelukast/ICS and ICS monotherapy showed similar safety profiles. In the active controlled studies, montelukast/ICS was clinically less effective than salmeterol/ICS in the 12 week trials (pooled proportion of patients with > or = 1 exacerbation: p = 0.006). However, separate analysis of active controlled 48 week trials showed comparable proportions for patients with > or = 1 exacerbation in both groups. CONCLUSIONS: Montelukast as add-on therapy to ICS improves control of mild to moderate asthma compared with ICS monotherapy. Although the addition of salmeterol to ICS is clinically as effective as or even more effective than the addition of montelukast, montelukast may have a better long term safety profile and offer a treatment alternative for asthma patients. PMID- 18443163 TI - HIV associated pulmonary emphysema: a review of the literature and inquiry into its mechanism. AB - Chronic lung diseases are increasingly recognised complications of the human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). Of these, pulmonary emphysema, characterised by permanent destruction of the lung parenchyma distal to the terminal bronchioles accompanied by various degrees of inflammation, is emerging as a distinct source of morbidity for patients infected with HIV. Similarly, HIV is now frequently cited as a susceptibility factor for the development of emphysema, independent of cigarette smoking status. The presence of common coexistent confounding factors that may predispose patients to chronic lung injury such as drugs, opportunistic infections and malnutrition, limits the scope of studies of direct mechanisms involved in HIV associated emphysematous lung disease. We review the clinical studies supporting a direct association between HIV infection and emphysema. Recent developments in the basic understanding of HIV infection and emphysema are also reviewed, since they may aid in understanding the pathobiology of HIV associated emphysema. The authors emphasise how HIV infection may affect cytotoxic lymphocyte activation, lung capillary endothelial cell injury and apoptosis, sphingolipid imbalance and oxidative stress in the lung. A better understanding of the pathogenesis of HIV associated pulmonary emphysema may provide clues and therapeutic targets that have broader application in this disease, including cigarette smoke induced emphysema. PMID- 18443164 TI - Lymphocytic interstitial pneumonia and pulmonary embolism in a patient with tetralogy of Fallot and common variable immunodeficiency: is there any link? AB - We report the simultaneous occurrence of lymphocytic interstitial pneumonitis and pulmonary embolism in a patient with tetralogy of Fallot and common variable immunodeficiency. An explanation based on the pathogenesis of these diseases is proposed to explain this "unfortunate coincidence". PMID- 18443165 TI - Adalimumab-induced bronchospasm: not a class effect. PMID- 18443166 TI - Serum LDH and exercise capacity in COPD. PMID- 18443167 TI - Is bronchodilation required routinely before diagnostic sputum induction? Evidence from studies with tuberculosis. PMID- 18443168 TI - Renal impairment in cystic fibrosis. PMID- 18443169 TI - Margarine: a supplement may be decisive. PMID- 18443170 TI - Smoking cessation intervention. PMID- 18443171 TI - High effectiveness of short treatment with bupropion for smoking cessation in general care. PMID- 18443172 TI - Oxygen therapy in the breathless patient. PMID- 18443173 TI - Pulmonary cryptococcosis mimicking solitary lung cancer in an immunocompetent patient. PMID- 18443174 TI - Homocysteine and folate status in an era of folic acid fortification: balancing benefits, risks, and B-vitamins. PMID- 18443175 TI - Estimating LDL ApoB: infomania or clinical advance? PMID- 18443176 TI - Estimation of LDL-associated apolipoprotein B from measurements of triglycerides and total apolipoprotein B. AB - BACKGROUND: VLDL and chylomicrons may interfere with measurements of apolipoprotein B (apo B) on LDL particles. Ultracentrifugation of samples enriched in chylomicrons and VLDL and subsequent measurement of apo B in the infranate fraction [density (d) = 1.006] removes this interference. This apo B fraction is called "LDL-apo B." METHODS: We retrospectively analyzed 64 895 measurements of triglycerides, total apo B, and LDL-apo B. Samples were ultracentrifuged, and 3 commercially available immunoassays that use different antibodies were used to measure LDL-apo B in the 1.006 infranate fraction. RESULTS: After adjusting for triglyceride concentration, we found total apo B and LDL-apo B measurements to be strongly correlated. We derived a simple linear equation for calculating LDL-apo B concentration (in milligrams per deciliter) from measurements of total apo B and triglycerides: LDL-apo B = apo B - 10 mg/dL triglycerides/32. This equation accurately predicts LDL-apo B values within +/- 12% of the measured value in 75% of cases. CONCLUSIONS: Our equation provides a convenient means of estimating LDL-apo B from commonly available measurements of total apo B and triglycerides without the need for ultracentrifugation. LDL-apo B measurements were also independent of the different apo B antibodies in the 3 assays used in this study. An equation that predicts LDL-apo B particle number may be useful, regardless of the apo B assay used. PMID- 18443177 TI - A simple assay to measure phagocytosis of live bacteria. AB - BACKGROUND: The phagocytosis of pathogens is essential for fighting infections. No assay is available, however, to measure both engulfment and degradation of bacteria under conditions similar to those in vivo. We sought to develop a flow cytometric assay to measure the engulfment and degradation of live bacteria by human blood monocytes and granulocytes. METHODS: We generated enhanced green fluorescent protein (EGFP)-expressing Eschericha coli by transforming E. coli with the plasmid vector pEGFP. We used these bacteria in a flow cytometric assay to measure both engulfment and degradation of living bacteria by monocytes and granulocytes in human whole blood from fresh, heparinized venous blood samples. To determine whether the test detected differences between healthy individuals and patients with secondary immunodeficiencies, we compared the phagocytosis of monocytes and granulocytes measured in blood samples from immunosuppressed kidney transplantation patients and from patients with postoperative sepsis in immunoparalysis with phagocytosis measured in samples from age-matched healthy individuals. RESULTS: In samples from healthy individuals, we found that in both monocytes and granulocytes bacterial degradation was negatively correlated with the age of the sample donor. Furthermore, we detected decreased bacterial engulfment in granulocytes from septic patients and decreased bacterial degradation in monocytes from immunosuppressed kidney transplantation patients. CONCLUSIONS: This flow cytometric assay measures the engulfment and degradation of live bacteria by human blood monocytes and granulocytes. By means of this assay we detected significant differences between healthy controls and patients with secondary immunodeficiencies that may contribute to the increased incidence of infection complications seen in these patients. PMID- 18443178 TI - Photoinstability of S-nitrosothiols during sampling of whole blood: a likely source of error and variability in S-nitrosothiol measurements. AB - BACKGROUND: The determination of reference intervals for the concentration of total S-nitrosothiols (RSNOs) in blood is a highly controversial topic, likely because of the inherent instability of these species. Most currently available techniques to quantify RSNOs in blood require considerable sample handling and multiple pretreatment steps during which light exposure is difficult to completely eliminate. We investigated the effect of brief light exposure on the stability of RSNO species in blood during the initial sampling process. METHODS: A novel amperometric RSNO sensor, based on an immobilized organoselenium catalyst at the distal tip of an electrochemical nitric oxide detector, was used to determine RSNO species in diluted whole blood without centrifugation or pretreatment. Porcine blood was collected into aluminum foil-wrapped syringes via a 12-inch butterfly needle tube assembly. Two blood samples were collected from the same animal -- one with the butterfly needle tubing wrapped in aluminum foil and one with the tubing exposed to ambient room light. The RSNO concentrations in these sequential blood samples were determined by a standard addition procedure. RESULTS: Eight sets of measurements were made in 6 animals. Samples exposed to light yielded RSNO concentrations only 23.6% (7.2%) [mean (SD)] of the RSNO concentrations determined in samples that were shielded from light and obtained from the same animals. CONCLUSIONS: These results suggest significant photoinstablity of RSNOs in whole blood and indicate the critical importance of proper light protection during sampling and processing of blood samples for the accurate determinations of endogenous RSNO concentrations. PMID- 18443179 TI - Automated time-resolved immunofluorometric assay for progastrin-releasing peptide. AB - BACKGROUND: Small cell lung cancer accounts for approximately 20% of new cases of lung cancer, and advanced disease is prevalent at the time of diagnosis. Neuron specific enolase (NSE) has been the primary tumor marker in small cell lung cancer but it has relatively low sensitivity in early-stage disease. Progastrin releasing peptide (proGRP) is a promising alternative or complementary marker for NSE. We have previously described a time-resolved immunofluorometric assay (TR IFMA) for proGRP that lacked the necessary sensitivity and robustness for use in the routine clinical laboratory. Herein we describe the development of an improved assay using a novel monoclonal antibody pair. METHODS: Mice were immunized with different conjugated proGRP peptides, including residues 31-98, 1 98, and preproGRP(-23-125). Pair combinations of the resulting monoclonal antibodies (mAb) were tested. The improved TR-IFMA was compared with the only other available proGRP assay, the proGRP ELISA (IBL). RESULTS: A panel of 12 high affinity mAbs was produced. The best assay combination was between our original E146 mAb as solid-phase antibody and the new mAb M16 as tracer. The new TR-IFMA had a linear dose-response curve, a wide dynamic range (13-13 500 ng/L), and a limit of detection of 2.8 ng/L. Total CV was <5.6% over the whole measuring range. Bland-Altman difference analysis indicated a significant positive bias between the IFMA and the ELISA. CONCLUSIONS: We describe a sensitive and robust mAb-based TR-IFMA for proGRP. The assay is fully automated and displays high quality performance. PMID- 18443180 TI - High-density lipoproteins: the neglected stepchildren whose importance as a risk factor continues to be defined. PMID- 18443181 TI - Agreement of different immunoassays for urinary albumin measurement. PMID- 18443182 TI - Influence of thyroid hormone autoantibodies on 7 thyroid hormone assays. PMID- 18443183 TI - Analytical quality of calcitonin determination and its effect on the adequacy of screening for medullary carcinoma of the thyroid. PMID- 18443184 TI - Stabilization of glucose in blood specimens: mechanism of delay in fluoride inhibition of glycolysis. PMID- 18443185 TI - Variability of lipoprotein-associated phospholipase A2 measurements. PMID- 18443186 TI - Effect of plasma protein depletion on BNP-32 recovery. PMID- 18443188 TI - An antibody against the surfactant protein A (SP-A)-binding domain of the SP-A receptor inhibits T cell-mediated immune responses to Mycobacterium tuberculosis. AB - Surfactant protein A (SP-A) suppresses lymphocyte proliferation and IL-2 secretion, in part, by binding to its receptor, SP-R210. However, the mechanisms underlying this effect are not well understood. Here, we studied the effect of antibodies against the SP-A-binding (neck) domain (alpha-SP-R210n) or nonbinding C-terminal domain (alpha-SP-R210ct) of SP-R210 on human peripheral blood T cell immune responses against Mycobacterium tuberculosis. We demonstrated that both antibodies bind to more than 90% of monocytes and 5-10% of CD3+ T cells in freshly isolated PBMC. Stimulation of PBMC from healthy tuberculin reactors [purified protein derivative-positive (PPD+)] with heat-killed M. tuberculosis induced increased antibody binding to CD3+ cells. Increased antibody binding suggested enhanced expression of SP-R210, and this was confirmed by Western blotting. The antibodies (alpha-SP-R210n) cross-linking the SP-R210 through the SP-A-binding domain markedly inhibited cell proliferation and IFN-gamma secretion by PBMC from PPD+ donors in response to heat-killed M. tuberculosis, whereas preimmune IgG and antibodies (alpha-SP-R210ct) cross-linking SP-R210 through the non-SP-A-binding, C-terminal domain had no effect. Anti-SP-R210n also decreased M. tuberculosis-induced production of TNF-alpha but increased production of IL 10. Inhibition of IFN-gamma production by alpha-SP-R210n was abrogated by the combination of neutralizing antibodies to IL-10 and TGF-beta1. Together, these findings support the hypothesis that SP-A, via SP-R210, suppresses cell-mediated immunity against M. tuberculosis via a mechanism that up-regulates secretion of IL-10 and TGF-beta1. PMID- 18443189 TI - Calpain-mediated regulation of the distinct signaling pathways and cell migration in human neutrophils. AB - We studied the mechanisms underlying calpain inhibition-mediated human neutrophil migration. MAPKs, including ERK, p38, and JNK, MEK1/2, MAPK kinase 3/6 (MKK3/6), PI-3K/Akt, c-Raf, and p21-activated kinase (PAK; an effector molecule of Rac) were rapidly (within 30 s) activated in neutrophils upon exposure to calpain inhibitors (PD150606 and N-acetyl-Leu-Leu-Nle-CHO) but not PD145305 (inactive analog of PD150606). Following activation of these pathways, neutrophils displayed active migration (chemotaxis), which was sustained for more than 45 min. The studies with pharmacological inhibitors suggest that calpain inhibition mediated neutrophil migration is mediated by activation of MEK/ERK, p38, JNK, PI 3K/Akt, and Rac. NSC23766 (Rac inhibitor) and pertussis toxin (PTX) suppressed calpain inhibitor-induced phosphorylation of distinct signaling molecules (PAK, c Raf, MEK1/2, ERK, MKK3/6, p38, JNK, and Akt) as well as cell migration, suggesting that the PTX-sensitive G protein and Rac axis may be a possible key target of calpain inhibitors. Differentiated neutrophil-like HL-60 cells but not undifferentiated cells displayed cell migration and activation of MAPKs and PI 3K/Akt on calpain inhibition. These findings suggest that constitutively active calpain negatively regulates activation of the distinct signaling pathways and cell migration in resting neutrophils, and this regulatory system develops during differentiation into mature neutrophils. PMID- 18443190 TI - An eosinophil immune response characterizes the inflammatory skin disease observed in Tie-2 transgenic mice. AB - Although mouse models of inflammatory skin diseases such as psoriasis and atopic dermatitis fail to completely phenocopy disease in humans, they provide invaluable tools to examine the molecular and cellular mechanisms responsible for the epidermal hyperplasia, inflammation, and excess angiogenesis observed in human disease. We have previously characterized a tyrosine kinase with immunoglobin-like and epidermal growth factor-like domain-2 (Tie-2) transgenic mouse model of an inflammatory skin disease exhibiting these features. More specifically, we demonstrated that the inflammatory component consisted of increased infiltration of CD3-positive T lymphocytes and mast cells in the skin. Here, we further characterize the inflammatory component in the blood and skin of Tie-2 transgenic mice at cellular and molecular levels. We observed increased numbers of CD3-positive T lymphocytes in the blood and increased infiltration of eosinophils in the skin. Furthermore, we characterized cytokine protein and gene expression in the blood and skin, respectively, and observed the deregulated expression of cytokines associated with Th1 and eosinophil immune responses. Interestingly, treatment of Tie-2 transgenic mice with anti-CD4 antibody appeared to resolve aspects of inflammation but did not resolve epidermal hyperplasia, suggesting an important role for eosinophils in mediating the inflammatory skin disease observed in Tie-2 transgenic mice. PMID- 18443191 TI - Preventing left ventricular hypertrophy by ACE inhibition in hypertensive patients with type 2 diabetes: a prespecified analysis of the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT). AB - OBJECTIVE: In patients with type 2 diabetes, left ventricular hypertrophy (LVH) predicts cardiovascular events, and the prevention of LVH is cardioprotective. We sought to compare the effect of ACE versus non-ACE inhibitor therapy on incident electrocardiographic (ECG) evidence of LVH (ECG-LVH). RESEARCH DESIGN AND METHODS: This prespecified study compared the incidence of ECG-LVH by Sokolow Lyon and Cornell voltage criteria in 816 hypertensive type 2 diabetic patients of the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT), who had no ECG LVH at baseline and were randomly assigned to at least 3 years of blinded ACE inhibition with trandolapril (2 mg/day) or to non-ACE inhibitor therapy. Treatment was titrated to systolic/diastolic blood pressure <130/80 mmHg. ECG readings were centralized and blinded to treatment. RESULTS: Baseline characteristics of the two groups were similar. Over a median (interquartile range) follow-up of 36 (24-48) months, 13 of the 423 patients (3.1%) receiving trandolapril compared with 31 of the 376 patients (8.2%) receiving non-ACE inhibitor therapy developed ECG-LVH (hazard ratio [HR] 0.34 [95% CI 0.18-0.65], P = 0.0012 unadjusted, and 0.35 [0.18-0.68], P = 0.0018 adjusted for predefined baseline covariates). The HR was significant even after adjustment for follow-up blood pressure and blood pressure reduction versus baseline. Compared with baseline, both Sokolow-Lyon and Cornell voltages significantly decreased with trandolapril but did not change with non-ACE inhibitor therapy. CONCLUSIONS: ACE inhibition has a specific protective effect against the development of ECG-LVH that is additional to its blood pressure-lowering effect. Because ECG-LVH is a strong cardiovascular risk factor in people with hypertension and diabetes, early ACE inhibition may be cardioprotective in this population. PMID- 18443192 TI - Risks of nontraumatic lower-extremity amputations in patients with type 1 diabetes: a population-based cohort study in Sweden. AB - OBJECTIVE: The purpose of this study was to estimate the risks of nontraumatic lower-extremity amputations (LEAs) in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We identified 31,354 patients with type 1 diabetes (15,001 women and 16,353 men) in the Swedish Inpatient Register between 1975 and 2004. The incidence of nontraumatic LEAs was followed up until 31 December 2004 by cross-linkage in the Inpatient Register and linkage to the Death and Migration registers. Poisson regression modeling was used to compare the risks of nontraumatic LEAs during different calendar periods of follow-up, with adjustment for both sex and attained age at follow-up. Standardized incidence ratios (SIRs) were used to estimate the relative risks (RRs) with the age-, sex-, and calendar period-matched general Swedish population as reference. The cumulative probability of nontraumatic LEAs was calculated by the Kaplan-Meier method. RESULTS: In total, 465 patients with type 1 diabetes underwent nontraumatic LEAs. The risk was lower during the most recent calendar period (2000-2004) than during the period before 2000 (RR 0.6 [95% CI 0.5-0.8]). However, even in this most recent period, the risk for nontraumatic LEAs among these relatively young patients was 86-fold higher than that in the matched general population (SIR 85.8 [72.9-100.3]). By age 65 years, the cumulative probability of having a nontraumatic LEA was 11.0% for women with type 1 diabetes and 20.7% for men with type 1 diabetes. CONCLUSIONS: Although the risks appeared to have declined in recent years, patients with type 1 diabetes still have a very high risk for nontraumatic LEAs. PMID- 18443193 TI - Dietary patterns and A1C in Japanese men and women. AB - OBJECTIVE: Dietary patterns in Western populations have been linked to type 2 diabetes, but the role of diet in Japanese remains unclear. We investigated the association between major dietary patterns and glucose tolerance status as measured by A1C in Japanese adults. RESEARCH DESIGN AND METHODS: The groups of subjects were comprised of 3,243 men and 4,667 women who participated in the baseline survey of an ongoing cohort study on lifestyle-related diseases in Fukuoka, Japan. Dietary patterns were derived by using principal-component analysis of the consumption of 49 food items, ascertained by a food-frequency questionnaire. Logistic regression analysis was used to estimate sex-specific odds ratios (ORs) of elevated A1C (>or=5.5%), with adjustment for potential confounding variables. RESULTS: The Westernized breakfast pattern characterized by frequent intake of bread but infrequent intake of rice was inversely related to A1C concentrations (P(trend) = 0.02 in both men and women); the multivariate adjusted ORs for the highest versus lowest quintiles were 0.60 (95% CI 0.43-0.84) and 0.64 (0.46-0.90) for men and women, respectively. The seafood dietary pattern was positively associated with A1C concentrations in men only (P(trend) = 0.01). Neither the healthy nor high-fat dietary pattern was related to A1C. CONCLUSIONS: A dietary pattern featuring frequent intake of white rice may deteriorate glucose metabolism in Japanese men and women, and the salty seafood dietary pattern may have a similar effect in men. PMID- 18443194 TI - Differences in the contribution of the CTLA4 gene to susceptibility to fulminant and type 1A diabetes in Japanese patients. AB - OBJECTIVE: To examine the contribution of the CTLA4 gene in the susceptibility to fulminant type 1 diabetes and compare it with classic type 1A diabetes. RESEARCH DESIGN AND METHODS: We genotyped the +49G>A and CT60G>A variants of the CTLA4 gene in fulminant type 1 diabetic patients (n = 55), classic type 1A diabetic patients (n = 91), and healthy control subjects (n = 369). We also assessed serum levels of the soluble form of CTLA4 (sCTLA4). RESULTS: The +49GG and CT60GG genotypes were associated with type 1A diabetes (P < 0.001). In contrast, the CT60AA genotype, but not the +49G>A variation, was associated with fulminant type 1 diabetes (P < 0.05), especially in patients carrying HLA-DR4 (P < 0.01). Serum levels of sCTLA4 were significantly decreased in patients with fulminant type 1 diabetes (P < 0.05). CONCLUSIONS: These results suggest that CTLA4 CT60 affects the genetic susceptibility to fulminant type 1 diabetes. Furthermore, the contribution of CTLA4 to disease susceptibility is distinct between fulminant type 1 diabetes and classic type 1A diabetes. PMID- 18443195 TI - Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the Steno-2 study. AB - OBJECTIVE: To assess the cost-effectiveness of intensive versus conventional therapy for 8 years as applied in the Steno-2 study in patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS: A Markov model was developed to incorporate event and risk data from Steno-2 and account Danish specific costs to project life expectancy, quality-adjusted life expectancy (QALE), and lifetime direct medical costs expressed in year 2005 Euros. Clinical and cost outcomes were projected over patient lifetimes and discounted at 3% annually. Sensitivity analyses were performed. RESULTS: Intensive treatment was associated with increased life expectancy, QALE, and lifetime costs compared with conventional treatment. Mean +/- SD undiscounted life expectancy was 18.1 +/- 7.9 years with intensive treatment and 16.2 +/- 7.3 years with conventional treatment (difference 1.9 years). Discounted life expectancy was 13.4 +/- 4.8 years with intensive treatment and 12.4 +/- 4.5 years with conventional treatment. Lifetime costs (discounted) for intensive and conventional treatment were euro45,521 +/- 19,697 and euro41,319 +/- 27,500, respectively (difference euro4,202). Increased costs with intensive treatment were due to increased pharmacy and consultation costs. Discounted QALE was 1.66 quality-adjusted life-years (QALYs) higher for intensive (10.2 +/- 3.6 QALYs) versus conventional (8.6 +/- 2.7 QALYs) treatment, resulting in an incremental cost-effectiveness ratio of euro2,538 per QALY gained. This is considered a conservative estimate because accounting prescription of generic drugs and capturing indirect costs would further favor intensified therapy. CONCLUSIONS: From a health care payer perspective in Denmark, intensive therapy was more cost-effective than conventional treatment. Assuming that patients in both arms were treated in a primary care setting, intensive therapy became dominant (cost- and lifesaving). PMID- 18443196 TI - Epidermal innervation in type 1 diabetic patients: a 2.5-year prospective study after simultaneous pancreas/kidney transplantation. AB - OBJECTIVE: To assess the effect of normoglycemia following simultaneous pancreas/kidney transplantation (SPK) on neurological function and intraepidermal nerve fiber density (IENFD) in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We performed vibration perception threshold (VPT) testing and autonomic function testing (AFT) and assessed IENFD in skin biopsies from the lower thigh and upper calf in 14 healthy control subjects and 18 patients with type 1 diabetes at the time of and at 21-40 (median 29) months post SPK. RESULTS: At baseline, significantly increased VPTs, pathological AFT results, and severe reduction in IENFD were present in SPK recipients. After SPK, an increase of IENFD in the thigh of more than one epidermal nerve fiber per millimeter was noted in three patients (median 4.1, range 1.9-10.2), but changes were not significant for the group as a whole. CONCLUSIONS: We conclude that either irreversible nerve damage might be present in some SPK recipients or that longer periods of normoglycemia might be needed to allow nerve regeneration. PMID- 18443197 TI - Serum bilirubin and ferritin levels link heme oxygenase-1 gene promoter polymorphism and susceptibility to coronary artery disease in diabetic patients. AB - OBJECTIVE: Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeats in the promoter of human HO-1 gene has been shown to modulate gene transcription. The aim of this study was to assess the association of the length of (GT)(n) repeats in the HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: We screened the allelic frequencies of (GT)(n) repeats in the HO-1 gene promoter in 986 unrelated individuals who underwent coronary angiography. Serum bilirubin and markers of iron status were evaluated. RESULTS: The distribution of numbers of (GT)(n) repeats was divided into two subclasses: class S included shorter (<27) repeats, and class L included longer (>or=27) repeats. Among those with diabetes, subjects with the L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70 +/- 0.22 vs. 0.81 +/- 0.24 mg/dl, P = 0.001) and higher serum ferritin values (4.76 +/- 0.72 vs. 4.28 +/- 1.05 mug/l for log ferritin, P = 0.001). Compared with those carrying the S allele, diabetic subjects with the L/L genotype had an almost threefold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, [95% CI 1.22-6.47], P = 0.015). With adjustment for both serum bilirubin and ferritin, the effect of HO 1 promoter polymorphism on susceptibility to CAD disappeared. CONCLUSIONS: Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients, and this effect might be conveyed through its influence on serum bilirubin and ferritin. PMID- 18443198 TI - Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related kinase 1/2. AB - OBJECTIVE: Chronic activation of the nuclear factor-kappaB (NF-kappaB) in white adipose tissue leads to increased production of pro-inflammatory cytokines, which are involved in the development of insulin resistance. It is presently unknown whether peroxisome proliferator-activated receptor (PPAR) beta/delta activation prevents inflammation in adipocytes. RESEARCH DESIGN AND METHODS AND RESULTS: First, we examined whether the PPARbeta/delta agonist GW501516 prevents lipopolysaccharide (LPS)-induced cytokine production in differentiated 3T3-L1 adipocytes. Treatment with GW501516 blocked LPS-induced IL-6 expression and secretion by adipocytes and the subsequent activation of the signal transducer and activator of transcription 3 (STAT3)-Suppressor of cytokine signaling 3 (SOCS3) pathway. This effect was associated with the capacity of GW501516 to impede LPS-induced NF-kappaB activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPARbeta/delta expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-kappaB DNA-binding activity. Furthermore, IL-6 expression and NF-kappaB DNA-binding activity was higher in white adipose tissue from PPARbeta/delta-null mice than in wild-type mice. Because mitogen-activated protein kinase-extracellular signal-related kinase (ERK)1/2 (MEK1/2) is involved in LPS-induced NF-kappaB activation in adipocytes, we explored whether PPARbeta/delta prevented NF-kappaB activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylation by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-kappaB activity, such as ZDF rats and PPARbeta/delta-null mice, also showed enhanced phospho-ERK1/2 levels. CONCLUSIONS: These findings indicate that activation of PPARbeta/delta inhibits enhanced cytokine production in adipocytes by preventing NF-kappaB activation via ERK1/2, an effect that may help prevent insulin resistance. PMID- 18443199 TI - Autocrine IGF-1 action in adipocytes controls systemic IGF-1 concentrations and growth. AB - OBJECTIVE: IGF-1 and the IGF-1 receptor (IGF-1R) have been implicated in the regulation of adipocyte differentiation and lipid accumulation in vitro. RESEARCH DESIGN AND METHODS: To investigate the role of IGF-1 receptor in vivo, we have inactivated the Igf-1r gene in adipose tissue (IGF-1R(aP2Cre) mice) using conditional gene targeting strategies. RESULTS: Conditional IGF-1R inactivation resulted in increased adipose tissue mass with a predominantly increased lipid accumulation in epigonadal fat pads. However, insulin-stimulated glucose uptake into adipocytes was unaffected by the deletion of the IGF-1R. Surprisingly, IGF 1R(aP2Cre) mice exhibited markedly increased somatic growth in the presence of elevated IGF-1 serum concentrations, and IGF-1 mRNA expression was significantly increased in liver and adipose tissue. IGF-1 stimulation of wild-type adipocytes significantly decreased IGF-1 mRNA expression, whereas the opposite effect was observed in IGF-1R-deficient adipocytes. CONCLUSIONS: IGF-1R signaling in adipocytes does not appear to be crucial for the development and differentiation of adipose tissue in vivo, but we identified a negative IGF-1R-mediated feedback mechanism of IGF-1 on its own gene expression in adipocytes, indicating an unexpected role for adipose tissue IGF-1 signaling in the regulation of IGF-1 serum concentrations in control of somatic growth. PMID- 18443200 TI - Heritability of proliferative diabetic retinopathy. AB - OBJECTIVE: Diabetic nephropathy clusters in families, suggesting that genetic factors play a role in its pathogenesis. We investigated whether similar clustering exists for proliferative retinopathy in families with two or more siblings with type 1 diabetes. RESEARCH DESIGN AND METHODS: The FinnDiane Study has characterized 20% (4,800 patients) of adults with type 1 diabetes in Finland. In 188 families, there were at least two siblings with type 1 diabetes. Ophthalmic records were obtained for 369 of 396 (93%) and fundus photographs for 251 of 369 (68%) patients. Retinopathy was graded based on photographs and/or repeated ophthalmic examinations using the Early Treatment of Diabetic Retinopathy grading scale. RESULTS: Mean age at onset of diabetes was 14.3 +/- 10.2 years, and mean duration was 25.9 +/- 11.8 years. Proliferative retinopathy was found in 115 of 369 patients (31%). The familial risk of proliferative retinopathy was estimated in 168 of 188 sibships, adjusted for A1C, duration, and mean blood pressure. Proliferative retinopathy in the probands (48 of 168) was associated with an increased risk (odds ratio 2.76 [95% CI 1.25- 6.11], P = 0.01) of proliferative retinopathy in the siblings of probands (61 of 182). The heritability of proliferative retinopathy was h(2) = 0.52 +/- 0.31 (P < 0.05). CONCLUSIONS: We found a familial clustering of proliferative retinopathy in patients with type 1 diabetes. The observation cannot be accounted for by conventional risk factors, suggesting a genetic component in the pathogenesis of proliferative retinopathy in type 1 diabetes. PMID- 18443201 TI - Protein kinase C-delta mediates neuronal apoptosis in the retinas of diabetic rats via the Akt signaling pathway. AB - OBJECTIVE: Protein kinase C (PKC)-delta, an upstream regulator of the Akt survival pathway, contributes to cellular dysfunction in the pathogenesis of diabetes. Herein, we examined the role of PKC-delta in neuronal apoptosis through Akt in the retinas of diabetic rats. RESEARCH DESIGN AND METHODS: We used retinas from 24- and 35-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) diabetic and Long-Evans Tokushima Otsuka (LETO) nondiabetic rats. To assess whether PKC delta affects Akt signaling and cell death in OLETF rat retinas, we examined 1) PKC-delta activity and apoptosis; 2) protein levels of phosphatidylinositol 3 kinase (PI 3-kinase) p85, heat shock protein 90 (HSP90), and protein phosphatase 2A (PP2A); 3) Akt phosphorylation; and 4) Akt binding to HSP90 or PP2A in LETO and OLETF retinas in the presence or absence of rottlerin, a highly specific PKC delta inhibitor, or small interfering RNAs (siRNAs) for PKC-delta and HSP90. RESULTS: In OLETF retinas from 35-week-old rats, ganglion cell death, PKC-delta and PP2A activity, and Akt-PP2A binding were significantly increased and Akt phosphorylation and Akt-HSP90 binding were decreased compared with retinas from 24-week-old OLETF and LETO rats. Rottlerin and PKC-delta siRNA abrogated these effects in OLETF retinas from 35-week-old rats. HSP90 siRNA significantly increased ganglion cell death and Akt-PP2A complexes and markedly decreased HSP90 Akt binding and Akt phosphorylation in LETO retinas from 35-week-old rats compared with those from nontreated LETO rats. CONCLUSIONS: PKC-delta activation contributes to neuro-retinal apoptosis in diabetic rats by inhibiting Akt mediated signaling pathways. PMID- 18443202 TI - Association analysis in african americans of European-derived type 2 diabetes single nucleotide polymorphisms from whole-genome association studies. AB - OBJECTIVE: Several whole-genome association studies have reported identification of type 2 diabetes susceptibility genes in various European-derived study populations. Little investigation of these loci has been reported in other ethnic groups, specifically African Americans. Striking differences exist between these populations, suggesting they may not share identical genetic risk factors. Our objective was to examine the influence of type 2 diabetes genes identified in whole-genome association studies in a large African American case-control population. RESEARCH DESIGN AND METHODS: Single nucleotide polymorphisms (SNPs) in 12 loci (e.g., TCF7L2, IDE/KIF11/HHEX, SLC30A8, CDKAL1, PKN2, IGF2BP2, FLJ39370, and EXT2/ALX4) associated with type 2 diabetes in European-derived populations were genotyped in 993 African American type 2 diabetic and 1,054 African American control subjects. Additionally, 68 ancestry-informative markers were genotyped to account for the impact of admixture on association results. RESULTS: Little evidence of association was observed between SNPs, with the exception of those in TCF7L2, and type 2 diabetes in African Americans. One TCF7L2 SNP (rs7903146) showed compelling evidence of association with type 2 diabetes (admixture-adjusted additive P [P(a)] = 1.59 x 10(-6)). Only the intragenic SNP on 11p12 (rs9300039, dominant P [P(d)] = 0.029) was also associated with type 2 diabetes after admixture adjustments. Interestingly, four of the SNPs are monomorphic in the Yoruba population of the HAPMAP project, with only the risk allele from the populations of European descent present. CONCLUSIONS: Results suggest that these variants do not significantly contribute to interindividual susceptibility to type 2 diabetes in African Americans. Consequently, genes contributing to type 2 diabetes in African Americans may, in part, be different from those in European-derived study populations. High frequency of risk alleles in several of these genes may, however, contribute to the increased prevalence of type 2 diabetes in African Americans. PMID- 18443203 TI - Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity, and dyslipidemia in db/db mice. AB - OBJECTIVE: Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by Pck1) catalyzes the first committed step in gluconeogenesis. Extensive evidence demonstrates a direct correlation between PEPCK-C activity and glycemia control. Therefore, we aimed to evaluate the metabolic impact and their underlying mechanisms of knocking down hepatic PEPCK-C in a type 2 diabetic model. RESEARCH DESIGN AND METHODS: PEPCK-C gene targeting was achieved using adenovirus transduced RNAi. The study assessed several clinical symptoms of diabetes and insulin signaling in peripheral tissues, in addition to changes in gene expression, protein, and metabolites in the liver. Liver bioenergetics was also evaluated. RESULTS: Treatment resulted in reduced PEPCK-C mRNA and protein. After treatment, improved glycemia and insulinemia, lower triglyceride, and higher total and HDL cholesterol were measured. Unsterified fatty acid accumulation was observed in the liver, in the absence of de novo lipogenesis. Despite hepatic lipidosis, treatment resulted in improved insulin signaling in the liver, muscle, and adipose tissue. O(2) consumption measurements in isolated hepatocytes demonstrated unaltered mitochondrial function and a consequent increased cellular energy charge. Key regulatory factors (FOXO1, hepatocyte nuclear factor-4alpha, and peroxisome proliferator-activated receptor-gamma coactivator [PGC]-1alpha) and enzymes (G6Pase) implicated in gluconeogenesis were downregulated after treatment. Finally, the levels of Sirt1, a redox-state sensor that modulates gluconeogenesis through PGC-1alpha, were diminished. CONCLUSIONS: Our observations indicate that silencing PEPCK-C has direct impact on glycemia control and energy metabolism and provides new insights into the potential significance of the enzyme as a therapeutic target for the treatment of diabetes. PMID- 18443204 TI - Exposure to maternal diabetes induces salt-sensitive hypertension and impairs renal function in adult rat offspring. AB - OBJECTIVE: Epidemiological and experimental studies have led to the hypothesis of fetal origin of adult diseases, suggesting that some adult diseases might be determined before birth by altered fetal development. We have previously demonstrated in the rat that in utero exposure to maternal diabetes impairs renal development leading to a reduction in nephron number. Little is known on the long term consequences of in utero exposure to maternal diabetes. The aim of the study was to assess, in the rat, long-term effects of in utero exposure to maternal diabetes on blood pressure and renal function in adulthood. RESEARCH DESIGN AND METHODS: Diabetes was induced in Sprague-Dawley pregnant rats by streptozotocin on day 0 of gestation. Systolic blood pressure, plasma renin activity, and renal function were measured in the offspring from 1 to 18 months of age. High-salt diet experiments were performed at the prehypertensive stage, and the abundance of tubular sodium transporters was evaluated by Western blot analysis. Kidney tissues were processed for histopathology and glomerular computer-assisted histomorphometry. RESULTS AND CONCLUSIONS: We demonstrated that in utero exposure to maternal diabetes induces a salt-sensitive hypertension in the offspring associated with a decrease in renal function in adulthood. High-salt diet experiments show an alteration of renal sodium handling that may be explained by a fetal reprogramming of tubular functions in association or as a result of the inborn nephron deficit induced by in utero exposure to maternal diabetes. PMID- 18443205 TI - siRNA-mediated reduction of inhibitor of nuclear factor-kappaB kinase prevents tumor necrosis factor-alpha-induced insulin resistance in human skeletal muscle. AB - OBJECTIVE: Proinflammatory cytokines contribute to systemic low-grade inflammation and insulin resistance. Tumor necrosis factor (TNF)-alpha impedes insulin signaling in insulin target tissues. We determined the role of inhibitor of nuclear factor-kappaB kinase (IKK)beta in TNF-alpha-induced impairments in insulin signaling and glucose metabolism in skeletal muscle. RESEARCH DESIGN AND METHODS: Small interfering RNA (siRNA) was used to silence IKKbeta gene expression in primary human skeletal muscle myotubes from nondiabetic subjects. siRNA gene silencing reduced IKKbeta protein expression 73% (P < 0.05). Myotubes were incubated in the absence or presence of insulin and/or TNF-alpha, and effects of IKKbeta silencing on insulin signaling and glucose metabolism were determined. RESULTS: Insulin increased glucose uptake 1.7-fold (P < 0.05) and glucose incorporation into glycogen 3.8-fold (P < 0.05) in myotubes from nondiabetic subjects. TNF-alpha exposure fully impaired insulin-mediated glucose uptake and metabolism. IKKbeta siRNA protected against TNF-alpha-induced impairments in glucose metabolism, since insulin-induced increases in glucose uptake (1.5-fold; P < 0.05) and glycogen synthesis (3.5-fold; P < 0.05) were restored. Conversely, TNF-alpha-induced increases in insulin receptor substrate-1 serine phosphorylation (Ser(312)), Jun NH(2)-terminal kinase phosphorylation, and extracellular signal-related kinase-1/2 mitogen-activated protein kinase (MAPK) phosphorylation were unaltered by siRNA-mediated IKKbeta reduction. siRNA mediated IKKbeta reduction prevented TNF-alpha-induced insulin resistance on Akt Ser(473) and Thr(308) phosphorylation and phosphorylation of the 160-kDa Akt substrate AS160. IKKbeta silencing had no effect on cell differentiation. Finally, mRNA expression of GLUT1 or GLUT4 and protein expression of MAPK kinase kinase kinase isoform 4 (MAP4K4) was unaltered by IKKbeta siRNA. CONCLUSIONS: IKKbeta silencing prevents TNF-alpha-induced impairments in insulin action on Akt phosphorylation and glucose uptake and metabolism in human skeletal muscle. PMID- 18443206 TI - Cancer screening in the United States, 2008: a review of current American Cancer Society guidelines and cancer screening issues. AB - Each year the American Cancer Society (ACS) publishes a summary of its recommendations for early cancer detection and a summary of the most current data on cancer screening rates and trends in US adults. In 2007, the ACS updated its colorectal cancer screening guidelines in a collaborative effort with the US Multi-Society Task Force and the American College of Radiology. In this issue of the journal, we summarize the current ACS guidelines, provide an update of the most recent data pertaining to participation rates in cancer screening from the Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System and the National Health Interview Survey, and address some issues related to access to care. PMID- 18443207 TI - Correlates of leisure-time physical activity in Korean immigrant women. AB - This study describes the physical activity behavior of Korean immigrant women and examines the relationships among leisure-time physical activity (LTPA) behavior, background, and intrapersonal correlates of behavior in Korean immigrant women in the United States using a cross-sectional survey design. A convenience sample of Midwestern Korean immigrant women completed the long form of the International Physical Activity Questionnaire in Korean. Among the participants, 78% were physically active, meeting the Healthy People 2010 goal for physical activity when all physical activity behaviors were considered, whereas 23% met the goal when only LTPA was considered. Women who were older, did not have a child younger than 5, used environmental resources for physical activity, had lower depressive symptoms, and had higher confidence for overcoming exercise barriers were spent more time in LTPA. Accommodating those with young children, enhancing environmental resource use, and improving exercise self-efficacy are important considerations for interventions aimed at increasing LTPA in Korean immigrant women. PMID- 18443208 TI - Data mining for chinese materia medica and pharmacological research. AB - Chinese materia medica (CMM) is becoming increasingly important in modern health care, with the potential for new or improved clinical protocols and reduction in treatment costs. Conventional approaches to drug discovery are based on knowledge of biological systems and screen phenotypes in the context of a whole organism. It will be valuable to identify the CMM that would induce certain biological responses (such as angiogenesis). The authors have developed a database that they plan to commercialize that contains traditional knowledge of Chinese medicine and pharmacology along with their own experimental data from controlled scientific observations by using the zebrafish as a model of CMM-induced pathology. The database is visualized and functions via the World Wide Web by subscription or license. The authors have also written software for personal digital assistant (PDA) devices that supports multiple users performing screening experiments worldwide. This provides a platform for the study of CMM, and data mining of this resource will help evaluate CMM in the context of experimental observations of biological aberrations. PMID- 18443209 TI - Oral cyclophosphamide for active scleroderma lung disease: a decision analysis. AB - BACKGROUND: Results from the recent Scleroderma Lung Study (SLS) show that oral cyclophosphamide (CYC) is better than placebo in preventing the progression of scleroderma-related interstitial lung disease (SSc-ILD) at 12 mo but is associated with adverse events. Also, the long-term balance of risk and benefit remains unclear. METHODS: The authors evaluate the risk-benefit tradeoffs using a Markov decision analytic model to project the quality-adjusted life years (QALYs) for strategies of CYC versus no CYC in SSc-ILD. The base case examined a 50-y-old woman with SSc of 1.5 y, SSc-ILD with moderate ventilatory restriction. The authors analyze the decision to treat with 1 y of daily CYC versus no SSc-ILD specific therapy. Based on 2-y data from the SLS, the authors assume CYC resulted in no survival benefit and only a transient beneficial impact on pulmonary function. They explore the impact of changes in model parameters through sensitivity analyses, including the efficacy of CYC in preventing progression of lung disease and SSc-ILD- related death. Results. In the base-case analysis, CYC treated patients fared worse, with a small loss of 0.21 QALYs (16.84 v. 17.15). CYC remained inferior across sensitivity analyses for most variables. In analyses assuming a survival benefit with CYC, CYC resulted in a clinically significant gain (18.17 v. 17.15 QALYs). CONCLUSIONS: CYC therapy for 1 y results in a small loss in QALYs compared with no CYC for SSc-ILD. The lack of a beneficial impact on survival and the transience of CYC's impact on decline in pulmonary function drive this conclusion. PMID- 18443210 TI - Polymorphonuclear leukocyte injury by methylglyoxal and hydrogen peroxide: a possible pathological role for enhanced oxidative stress in chronic kidney disease. AB - BACKGROUND: Accelerated burst of polymorphonuclear leukocytes (PMNs) may be involved in the primary pathology of enhanced oxidative stress in patients with chronic kidney disease (CKD); however, the precise mechanism remains unknown. Methylglyoxal (MGO), an alpha-oxoaldehyde reportedly elevated in CKD, could induce apoptosis in several cell lines, and generates radicals by the reaction with hydrogen peroxide (H(2)O(2)). Thus, we tested if a high MGO of uraemic milieu could play a role in PMN injury by interaction with H(2)O(2). METHOD: Cellular viability of PMNs, isolated from healthy volunteers, was tested by ATP chemiluminescence levels under MGO and/or H(2)O(2), or 4-beta phorbol 12-beta myristate 13-alpha-acetate (PMA). Superoxide anion (O(2)(-)) generation and apoptosis were measured by the reduction of ferricytochrome C and fluorocytometric analysis, respectively. Plasma MGO levels were measured by mass spectometry in 29 CKD patients. RESULTS: At low levels of MGO (1-10 microM) and H(2)O(2) (12.5 microM), no differences were found in cellular viability as compared to controls, whereas their combination significantly decreased PMN viability. PMA stimulation enhanced cellular injury of MGO by a function of MGO levels and preincubation with 5,5-dimethyl-1-pyrroline-N-oxide (free radical trap agent) attenuated it. MGO suppressed O(2)(-) generation by PMA, while it accelerated apoptotic ratios in PMNs. Significant increases of plasma MGO and C reactive protein levels were found by a function of CKD stage, and clinical level of MGO could induce PMN injury in combination with H(2)O(2). CONCLUSION: These results indicate the combinatory effect of MGO and H(2)O(2) on PMN oxidative injury, and this pathology may be linked to enhanced oxidative stress in CKD. PMID- 18443211 TI - Relationship between dialysate oxidized protein and peritoneal membrane transport properties in patients on peritoneal dialysis. AB - BACKGROUND: Increased levels of oxidized proteins have been reported in the serum of patients with end-stage renal disease, though little is known regarding the oxidized protein content of the dialysate in patients on peritoneal dialysis (PD) and no information is available as to how this may correlate with important clinical and laboratory variables, including abnormal peritoneal membrane function. In this study we attempted to identify oxidized proteins in the dialysate of patients on PD using western blot analysis, and examined the relationship between these proteins and the function of the peritoneal membrane and other clinical and laboratory variables. METHODS: Peritoneal dialysate and serum samples were obtained from 18 patients on PD, and western blot analysis using an antibody to oxidized protein was carried out with reprobing for albumin. Oxidized protein/albumin ratios were determined and compared with various clinical and laboratory variables including peritoneal equilibration test results. RESULTS: Oxidized protein/albumin ratios were higher in the dialysate of patients who were high/high average transporters compared to low/low average transporters. Oxidized protein ratios were also found to be higher in the dialysate of patients who had diminished urine output as a reflection of loss of residual renal function. Negative correlations were noted between oxidized protein ratios in the dialysate and serum albumin levels and creatinine clearance. CONCLUSIONS: Higher levels of oxidized protein in the dialysate appear to be correlated with high/high average peritoneal membrane transport characteristics and may be related to loss of residual renal function. These preliminary findings suggest that it is plausible that oxidized proteins in the dialysate might play a contributory role in complications including membrane damage and ultrafiltration failure in patients on PD. PMID- 18443212 TI - A genome-wide search for linkage to chronic kidney disease in a community-based sample: the SAFHS. AB - BACKGROUND: Chronic kidney disease (CKD) phenotypes such as albuminuria measured by urinary albumin creatinine ratio (ACR), elevated serum creatinine (SrCr) and/or decreased creatinine clearance (CrCl) and glomerular filtration rate (eGFR) are major risk factors for renal and cardiovascular diseases. Epidemiological studies have reported that CKD phenotypes cluster in families suggesting a genetic predisposition. However, studies reporting chromosomal regions influencing CKD are very limited. Therefore, the purpose of this study is to identify susceptible chromosomal regions for CKD phenotypes in Mexican American families enrolled in the San Antonio Family Heart Study (SAFHS). METHODS: We used the variance components decomposition approach (implemented in the software package SOLAR) to perform linkage analysis on 848 participants from 26 families. A total of 417 microsatellite markers were genotyped at an average interval of 10 cM spanning 22 autosomal chromosomes. RESULTS: All phenotypes were measured by standard procedures. Mean +/- SD values of ACR, SrCr, CrCl and eGFR were 0.06 +/- 0.38, 0.85 +/- 0.72 mg/dl, 129.85 +/- 50.37 ml/min and 99.18 +/- 25.69 ml/min/1.73 m(2) body surface area, respectively. All four CKD phenotypes exhibited significant heritabilities (P < 0.0001). A genome-wide scan showed linkage on chromosome 2p25 for SrCr, CrCl and eGFR. Significant linkage was also detected on chromosome 9q21 for eGFR [logarithm of the odds (LOD) score = 3.87, P = 0.00005] and SrCr (LOD score = 2.6, P = 0.00026). ACR revealed suggestive evidence for linkage to a region on chromosome 20q12 (LOD score = 2.93, P = 0.00020). CONCLUSION: Findings indicate that chromosomal regions 2p25, 9q21 and 20q12 may have functional relevance to CKD phenotypes in Mexican Americans. PMID- 18443213 TI - Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a major cause of steroid resistant nephrotic syndrome in childhood with a central role for the podocytes in the pathogenesis. Mutated proteins expressed in podocytes cause proteinuria. The role of combined gene defects in the development of FSGS is less clear. METHODS: We analysed seven podocyte genes known to cause proteinuria and FSGS in a group of 19 non-familial childhood-onset steroid-resistant FSGS patients. These genes include NPHS1, NPHS2, ACTN4, CD2AP, WT-1, TRPC6 and PLCE1. We also screened for the mitochondrial A3243G DNA transition associated with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), and occasionally FSGS. RESULTS: No mutations were found in the ACTN4 and TRPC6 genes, and no mitochondrial A3243G DNA transition was found in our group of patients. Two patients showed mutations in the CD2AP gene, one combined with an NPHS2 mutation. A tri-allelic hit was found in a patient carrying compound heterozygous NPHS2 mutations and a heterozygous NPHS1 mutation. In another patient a de novo WT-1 mutation was found combined with a heterozygous NPHS1 mutation, and finally two patients showed three heterozygous PLCE1 mutations. CONCLUSIONS: In our rather small group of 19 steroid-resistant FSGS patients, we found 11 mutations in podocyte genes in 6 patients. In four of them the found mutations could explain the pathology. Our data suggest that combined gene defects in podocyte genes may play a role in the development of FSGS. PMID- 18443214 TI - Coiled-coiled domains as a mechanism to stop haemorrhage after renal biopsies. PMID- 18443215 TI - Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. AB - Reporting of myelodysplastic syndromes (MDSs) and chronic myeloproliferative disorders (CMDs) to population-based cancer registries in the United States was initiated in 2001. In this first analysis of data from the North American Association of Central Cancer Registries (NAACCR), encompassing 82% of the US population, we evaluated trends in MDS and CMD incidence, estimated case numbers for the entire United States, and assessed trends in diagnostic recognition and reporting. Based on more than 40 000 observations, average annual age-adjusted incidence rates of MDS and CMD for 2001 through 2003 were 3.3 and 2.1 per 100,000, respectively. Incidence rates increased with age for both MDS and CMD (P < .05) and were highest among whites and non-Hispanics. Based on follow-up data through 2004 from the Surveillance, Epidemiology, and End Results (SEER) Program, overall relative 3-year survival rates for MDS and CMD were 45% and 80%, respectively, with males experiencing poorer survival than females. Applying the observed age-specific incidence rates to US Census population estimates, approximately 9700 patients with MDS and 6300 patients with CMD were estimated for the entire United States in 2004. MDS incidence rates significantly increased with calendar year in 2001 through 2004, and only 4% of patients were reported to registries by physicians' offices. Thus, MDS disease burden in the United States may be underestimated. PMID- 18443216 TI - Impact of impurity on kinetic estimates from transport and inhibition studies. AB - Although in vitro transport/inhibition studies are commonly performed on impure drug candidates to screen for pharmacokinetic properties in early development, quantitative guidelines concerning acceptable impurity levels are lacking. The broad goal was to derive models for the effect of impurity on transport and inhibition studies and identify the maximum allowable impurity level that does not bias assay results. Models were derived, and simulations were performed to assess the impact of impurity on substrate properties K(t) and J(max) and inhibition K(i). Simulation results were experimentally challenged with a known amount of impurity, using the intestinal bile acid transporter as a model system. For substrate uptake studies, glycocholate served as substrate and was contaminated with either a very strong, strong, or moderate impurity (i.e., taurolithocholate, chenodeoxycholate, or ursodeoxycholate, respectively). For inhibition studies, taurocholate and glycocholate together was the substrate/inhibitor pair, where glycocholate was contaminated with taurolithocholate. There was high agreement between simulation results and experimental observations. It is not surprising that, in the inhibition assay, potent impurity caused test compound to appear more potent than the true potency of the test compound (i.e., reduced inhibitory K(i)). However, results in the transport scenario surprisingly indicated that potent impurity did not diminish test compound potency but, rather, increased substrate potency (i.e., reduced Michaelis-Menten substrate K(t)). In general, less than 2.5% impurity is a reasonable target, provided the impurity is less than 10-fold more potent than test compound. Study results indicate that careful consideration of possible impurity effect is needed when quantitative structure-activity relationship analysis cannot explain high compound potency from transport or inhibition studies. PMID- 18443217 TI - Polo-like kinase is required for Golgi and bilobe biogenesis in Trypanosoma brucei. AB - A bilobed structure marked by TbCentrin2 regulates Golgi duplication in the protozoan parasite Trypanosoma brucei. This structure must itself duplicate during the cell cycle for Golgi inheritance to proceed normally. We show here that duplication of the bilobed structure is dependent on the single polo-like kinase (PLK) homologue in T. brucei (TbPLK). Depletion of TbPLK leads to malformed bilobed structures, which is consistent with an inhibition of duplication and an increase in the number of dispersed Golgi structures with associated endoplasmic reticulum exit sites. These data suggest that the bilobe may act as a scaffold for the controlled assembly of the duplicating Golgi. PMID- 18443218 TI - Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes. AB - Telomeres are maintained by three DNA-binding proteins (telomeric repeat binding factor 1 [TRF1], TRF2, and protector of telomeres 1 [POT1]) and several associated factors. One factor, TRF1-interacting protein 2 (TIN2), binds TRF1 and TRF2 directly and POT1 indirectly. Along with two other proteins, TPP1 and hRap1, these form a soluble complex that may be the core telomere maintenance complex. It is not clear whether subcomplexes also exist in vivo. We provide evidence for two TIN2 subcomplexes with distinct functions in human cells. We isolated these two TIN2 subcomplexes from nuclear lysates of unperturbed cells and cells expressing TIN2 mutants TIN2-13 and TIN2-15C, which cannot bind TRF2 or TRF1, respectively. In cells with wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere dysfunction and cell death. Our findings suggest that distinct TIN2 complexes exist and that TIN2-15C-sensitive subcomplexes are particularly important for cell survival in the absence of functional p53. PMID- 18443219 TI - Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. AB - It is well established that misfolded forms of cellular prion protein (PrP [PrP(C)]) are crucial in the genesis and progression of transmissible spongiform encephalitis, whereas the function of native PrP(C) remains incompletely understood. To determine the physiological role of PrP(C), we examine the neurophysiological properties of hippocampal neurons isolated from PrP-null mice. We show that PrP-null mouse neurons exhibit enhanced and drastically prolonged N methyl-d-aspartate (NMDA)-evoked currents as a result of a functional upregulation of NMDA receptors (NMDARs) containing NR2D subunits. These effects are phenocopied by RNA interference and are rescued upon the overexpression of exogenous PrP(C). The enhanced NMDAR activity results in an increase in neuronal excitability as well as enhanced glutamate excitotoxicity both in vitro and in vivo. Thus, native PrP(C) mediates an important neuroprotective role by virtue of its ability to inhibit NR2D subunits. PMID- 18443220 TI - Augmin: a protein complex required for centrosome-independent microtubule generation within the spindle. AB - Since the discovery of gamma-tubulin, attention has focused on its involvement as a microtubule nucleator at the centrosome. However, mislocalization of gamma tubulin away from the centrosome does not inhibit mitotic spindle formation in Drosophila melanogaster, suggesting that a critical function for gamma-tubulin might reside elsewhere. A previous RNA interference (RNAi) screen identified five genes (Dgt2-6) required for localizing gamma-tubulin to spindle microtubules. We show that the Dgt proteins interact, forming a stable complex. We find that spindle microtubule generation is substantially reduced after knockdown of each Dgt protein by RNAi. Thus, the Dgt complex that we name "augmin" functions to increase microtubule number. Reduced spindle microtubule generation after augmin RNAi, particularly in the absence of functional centrosomes, has dramatic consequences on mitotic spindle formation and function, leading to reduced kinetochore fiber formation, chromosome misalignment, and spindle bipolarity defects. We also identify a functional human homologue of Dgt6. Our results suggest that an important mitotic function for gamma-tubulin may lie within the spindle, where augmin and gamma-tubulin function cooperatively to amplify the number of microtubules. PMID- 18443221 TI - FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. AB - Autophagy is a membrane-mediated intracellular degradation system. The serine/threonine kinase Atg1 plays an essential role in autophagosome formation. However, the role of the mammalian Atg1 homologues UNC-51-like kinase (ULK) 1 and 2 are not yet well understood. We found that murine ULK1 and 2 localized to autophagic isolation membrane under starvation conditions. Kinase-dead alleles of ULK1 and 2 exerted a dominant-negative effect on autophagosome formation, suggesting that ULK kinase activity is important for autophagy. We next screened for ULK binding proteins and identified the focal adhesion kinase family interacting protein of 200 kD (FIP200), which regulates diverse cellular functions such as cell size, proliferation, and migration. We found that FIP200 was redistributed from the cytoplasm to the isolation membrane under starvation conditions. In FIP200-deficient cells, autophagy induction by various treatments was abolished, and both stability and phosphorylation of ULK1 were impaired. These results suggest that FIP200 is a novel mammalian autophagy factor that functions together with ULKs. PMID- 18443222 TI - Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division. AB - Rac1 regulates a wide variety of cellular processes. The polybasic region of the Rac1 C terminus functions both as a plasma membrane-targeting motif and a nuclear localization sequence (NLS). We show that a triproline N-terminal to the polybasic region contributes to the NLS, which is cryptic in the sense that it is strongly inhibited by geranylgeranylation of the adjacent cysteine. Subcellular fractionation demonstrated endogenous Rac1 in the nucleus and Triton X-114 partition revealed that this pool is prenylated. Cell cycle-blocking agents, synchronization of cells stably expressing low levels of GFP-Rac1, and time-lapse microscopy of asynchronous cells revealed Rac1 accumulation in the nucleus in late G2 and exclusion in early G1. Although constitutively active Rac1 restricted to the cytoplasm inhibited cell division, activated Rac1 expressed constitutively in the nucleus increased the mitotic rate. These results show that Rac1 cycles in and out of the nucleus during the cell cycle and thereby plays a role in promoting cell division. PMID- 18443223 TI - CENP-E combines a slow, processive motor and a flexible coiled coil to produce an essential motile kinetochore tether. AB - The mitotic kinesin centromere protein E (CENP-E) is an essential kinetochore component that directly contributes to the capture and stabilization of spindle microtubules by kinetochores. Although reduction in CENP-E leads to high rates of whole chromosome missegregation, neither its properties as a microtubule dependent motor nor how it contributes to the dynamic linkage between kinetochores and microtubules is known. Using single-molecule assays, we demonstrate that CENP-E is a very slow, highly processive motor that maintains microtubule attachment for long periods. Direct visualization of full-length Xenopus laevis CENP-E reveals a highly flexible 230-nm coiled coil separating its kinetochore-binding and motor domains. We also show that full-length CENP-E is a slow plus end-directed motor whose activity is essential for metaphase chromosome alignment. We propose that the highly processive microtubule-dependent motor activity of CENP-E serves to power chromosome congression and provides a flexible, motile tether linking kinetochores to dynamic spindle microtubules. PMID- 18443224 TI - All quiet on the neuronal front: NMDA receptor inhibition by prion protein. AB - The normal function of the prion protein (PrP)-the causative agent of mad cow or prion disease-has long remained out of reach. Deciphering PrP's function may help to unravel the complex chain of events triggered by PrP misfolding during prion disease. In this issue of the JCB, an exciting paper (Khosravani, H., Y. Zhang, S. Tsutsui, S. Hameed, C. Altier, J. Hamid, L. Chen, M. Villemaire, Z. Ali, F.R. Jirik, and G.W. Zamponi. 2008. J. Cell Biol. 181:551-565) connects diverse observations regarding PrP into a coherent framework whereby PrP dampens the activity of an N-methyl-d-aspartate (NMDA) receptor (NMDAR) subtype and reduces excitotoxic lesions. The findings of this study suggest that understanding the normal function of proteins associated with neurodegenerative disease may elucidate the molecular pathogenesis. PMID- 18443225 TI - A role for sex chromosome complement in the female bias in autoimmune disease. AB - Most autoimmune diseases are more common in women than in men. This may be caused by differences in sex hormones, sex chromosomes, or both. In this study, we determined if there was a contribution of sex chromosomes to sex differences in susceptibility to two immunologically distinct disease models, experimental autoimmune encephalomyelitis (EAE) and pristane-induced lupus. Transgenic SJL mice were created to permit a comparison between XX and XY within a common gonadal type. Mice of the XX sex chromosome complement, as compared with XY, demonstrated greater susceptibility to both EAE and lupus. This is the first evidence that the XX sex chromosome complement, as compared with XY, confers greater susceptibility to autoimmune disease. PMID- 18443226 TI - T cell receptor-instructed alphabeta versus gammadelta lineage commitment revealed by single-cell analysis. AB - alphabeta and gammadelta T cell lineages develop in the thymus from a common precursor. It is unclear at which stage of development commitment to these lineages takes place and in which way T cell receptor signaling contributes to the process. Recently, it was demonstrated that strong TCR signals favor gammadelta lineage development, whereas weaker TCR signals promote alphabeta lineage fate. Two models have been proposed to explain these results. The first model suggests that commitment occurs after TCR expression and TCR signaling directly instructs lymphocytes to adopt one or the other lineage fate. The second model suggests that commitment occurs before TCR expression and that TCR signaling merely confirms the lineage choice. By tracing the fate of single T cell precursors, this study shows that there is no commitment to either the alphabeta or gammadelta lineage before TCR expression and that modulation of TCR signaling in progeny of a single TCR-expressing cell changes lineage commitment. PMID- 18443227 TI - MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells. AB - Like CD1d-restricted iNKT cells, mucosal-associated invariant T cells (MAITs) are "innate" T cells that express a canonical TCRalpha chain, have a memory phenotype, and rapidly secrete cytokines upon TCR ligation. Unlike iNKT cells, MAIT cells require the class Ib molecule MHC-related protein I (MR1), B cells, and gut flora for development and/or expansion, and they preferentially reside in the gut lamina propria. Evidence strongly suggests that MAIT cell activation is ligand-dependent, but the nature of MR1 ligand is unknown. In this study, we define a mechanism of endogenous antigen presentation by MR1 to MAIT cells. MAIT cell activation was dependent neither on a proteasome-processed ligand nor on the chaperoning by the MHC class I peptide loading complex. However, MAIT cell activation was enhanced by overexpression of MHC class II chaperones Ii and DM and was strikingly diminished by silencing endogenous Ii. Furthermore, inhibiting the acidification of the endocytic compartments reduced MR1 surface expression and ablated MAIT cell activation. The importance of the late endosome for MR1 antigen presentation was further corroborated by the localization of MR1 molecules in the multivesicular endosomes. These findings demonstrate that MR1 traffics through endocytic compartments, thereby allowing MAIT cells to sample both endocytosed and endogenous antigens. PMID- 18443229 TI - Sitagliptin augments sympathetic enhancement of the renovascular effects of angiotensin II in genetic hypertension. AB - Dipeptidyl peptidase IV converts neuropeptide Y(1-36) (Y(1)-receptor agonist released from renal sympathetic nerves) to neuropeptide Y(3-36) (selective Y(2) receptor agonist). Previous studies suggest that Y(1), but not Y(2), receptors enhance renovascular responses to angiotensin II in kidneys from genetically susceptible animals. Therefore, we hypothesized that inhibition of dipeptidyl peptidase IV with sitagliptin (antidiabetic drug) would augment the ability of exogenous and endogenous neuropeptide Y(1-36) to enhance renal vascular responses to angiotensin II in kidneys from spontaneously hypertensive rats. This hypothesis was tested using 3 protocols in isolated perfused kidneys. Results from Protocol 1: Exogenous neuropeptide Y(1-36) enhanced renovascular responses to angiotensin II. This effect of neuropeptide Y(1-36) was blocked by BIBP3226 (selective Y(1) receptor antagonist); Exogenous neuropeptide Y(3-36) did not enhance renovascular responses to angiotensin II. Results from Protocol 2: Sitagliptin augmented the ability of exogenous neuropeptide Y(1-36) to enhance renovascular responses to angiotensin II. This effect of sitagliptin was blocked by BIBP3226. Results from Protocol 3: Renal sympathetic nerve stimulation enhanced renovascular responses to angiotensin II; this enhancement was augmented by sitagliptin and abolished by BIBP3226. Neuropeptide Y(1-36) via Y(1) receptors enhances renovascular responses to angiotensin II in kidneys from genetically hypertensive animals. Sitagliptin, by blocking dipeptidyl peptidase IV, prevents metabolism of neuropeptide Y(1-36) and thereby increases the effects of neuropeptide Y(1-36) released from renal sympathetic nerves on Y(1) receptors leading to augmentation of neuropeptide Y(1-36)-induced enhancement of the renovascular effects of angiotensin II. The renal effects of dipeptidyl peptidase IV inhibitors in hypertensive diabetic patients merit a closer examination. PMID- 18443228 TI - During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain. AB - Apoptosis accompanying negative selection is a central but poorly understood event in T cell development. The Nur77 nuclear steroid receptor and Bim, a proapoptotic BH3-only member of the Bcl-2 family, are two molecules implicated in this process. However, how they relate to each other and how Nur77 induces apoptosis remain unclear. In thymocytes, Nur77 has been shown to induce cell death through a transcriptional-dependent pathway, but in cancer cell lines, Nur77 was reported to induce apoptosis through conversion of Bcl-2 into a killer protein at the mitochondria. Whether this Nur77 transcriptional-independent pathway actually occurs in vivo remains controversial. Using an optimized fractionation protocol for thymocytes, here we report that stimulation of CD4(+)CD8(+) thymocytes results in translocation of Nur77 and its family member Nor-1 to the mitochondria, leading to their association with Bcl-2 and exposure of the Bcl-2 proapoptotic BH3 domain. In two T cell receptor transgenic models of negative selection, F5 and HY, a conformational change of the Bcl-2 molecule in the negatively selected T cell population was similarly observed. Thus, the Nur77 family and Bim pathways converge at mitochondria to mediate negative selection. PMID- 18443230 TI - Environmental smoke exposure: a complex cardiovascular challenge. PMID- 18443231 TI - Peripheral augmentation index and wave reflection in the radial artery. PMID- 18443232 TI - Hepatocyte nuclear factor 1 and hypertensive nephropathy. AB - Hypertension in spontaneously hypertensive rat (SHR) is associated with renal redox stress, and we hypothesized that nephropathy arises in SHR-A3 from altered capacity to mitigate redox stress compared with nephropathy-resistant SHR lines. We measured renal expression of redox genes in distinct lines of the spontaneously hypertensive rat (SHR-A3, SHR-B2, SHR-C) and the normotensive Wistar-Kyoto (WKY) strain. The SHR lines differ in either resisting (SHR-B2, SHR C) or experiencing hypertensive nephropathy (SHR-A3). Immediately before the emergence of hypertensive renal injury expression of redox genes in SHR-A3 was profoundly altered compared with the injury-resistant SHR lines and WKY. This change appeared to arise in antioxidant genes where 16 of 28 were expressed at 34.3% of the level in the reference strain (WKY). No such change was observed in the injury-resistant SHR lines. We analyzed occurrence of transcription factor matrices in the promoters of the downregulated antioxidant genes. In these genes, the hepatocyte nuclear factor 1 (HNF1) transcription factor matrix was found to be nearly twice as likely to be present and the overall frequency of HNF1 sites was nearly 5 times higher, compared with HNF1 transcription factor matrices in antioxidant genes that were not downregulated. We identified 35 other (nonredox) renal genes regulated by HNF1. These were also significantly downregulated in SHR A3, but not in SHR-B2 or SHR-C. Finally, expression of genes that comprise HNF1 (Tcf1, Tcf2, and Dcoh) was also downregulated in SHR-A3. The present experiments uncover a major change in transcriptional control by HNF1 that affects redox and other genes and precedes emergence of hypertensive renal injury. PMID- 18443233 TI - Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1. AB - Atherosclerosis is considered to be a combined disorder of lipid metabolism and chronic inflammation. Recent studies have reported that liver X receptors (LXRs) are involved in lipid metabolism and inflammation and that LXR agonists inhibit atherogenesis. In contrast, angiotensin II is well known to accelerate atherogenesis through activation of the angiotensin II type 1 receptor (AT1R). To better understand the mechanism of LXR on the prevention of atherogenesis, we examined whether activation of LXR affects AT1R expression in vascular smooth muscle cells. T0901317, a synthetic LXR ligand, decreased AT1R mRNA and protein expression with a peak reduction at 6 hours and 12 hours of incubation, respectively. A well-established ligand of LXR, 22-(R)-hydroxycholesterol, also suppressed AT1R expression. The downregulation of AT1R by T0901317 required de novo protein synthesis. AT1R gene promoter activity measured by luciferase assay revealed that the DNA segment between -61 bp and +25 bp was sufficient for downregulation. Luciferase construct with a mutation in Sp1 binding site located in this segment lost its response to T0901317. T0901317 decreased Sp1 serine phosphorylation. Although preincubation of vascular smooth muscle cells with T0901317 for 30 minutes had no effect on angiotensin II-induced extracellular signal-regulated kinase phosphorylation, phosphorylation of extracellular signal regulated kinase by angiotensin II was markedly suppressed after 6 hours of preincubation. These results indicate that the suppression of AT1R may be one of the important mechanisms by which LXR ligands exert antiatherogenic effects. PMID- 18443234 TI - Relation of blood pressure and all-cause mortality in 180,000 Japanese participants: pooled analysis of 13 cohort studies. AB - Hypertension is a leading cause of death because of cardiovascular disease and predominantly affects total mortality. To reduce avoidable deaths from hypertension, we need to collect blood pressure data and assess their impact on total mortality. To examine this issue, a meta-analysis of 13 cohort studies was conducted in Japan. Poisson regression was used for estimating all-cause mortality rates and ratios. In the model, blood pressure data were treated as continuous (10-mm Hg increase) and categorical (every 10 mm Hg) according to recommendations of the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Hypertension. Potential confounders included body mass index, smoking, drinking, and cohort. The impact of hypertension was measured by the population-attributable fraction. After excluding participants with cardiovascular disease history, 176 389 participants were examined in the analysis. Adjusted mortality rates became larger as the blood pressure increased, and these were more distinct in younger men and women. Hazard ratios also showed the same trends, and these trends were more apparent in younger men (hazard ratio [unit: 10-mm Hg increase] aged 40 to 49 years: systolic blood pressure 1.37 (range: 1.15 to 1.62); diastolic blood pressure 1.46 [range: 1.05 to 2.03]) than older ones (hazard ratio: aged 80 to 89 years: systolic blood pressure 1.09 [range: 1.05 to 1.13]and diastolic blood pressure 1.12 [range: 1.03 to 1.22]). Population-attributable fraction of hypertension was approximately 20% when the normal category was used as a reference level and was 10% when we included the prehypertension group in the reference level. In conclusion, high blood pressure raised the risk of total mortality, and this trend was higher in the younger Japanese population. PMID- 18443235 TI - Gender differences in left ventricular hypertrophy regression. PMID- 18443236 TI - Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population. AB - The genes responsible for several monogenic hypertensive and hypotensive disorders have been identified. Our aim was to evaluate whether common variants in these genes affect blood pressure in the general population. We studied 2037 adults from 520 nuclear families characterized for 24-hour ambulatory blood pressure and related cardiovascular traits. We genotyped 298 tagging and putative functional single nucleotide polymorphisms, achieving a median coverage of 82.4% across 11 candidate loci. Five polymorphisms in the KCNJ1 gene coding for the potassium channel, ROMK, showed associations with mean 24-hour systolic or diastolic blood pressure. The strongest association was with an intronic polymorphism, rs2846679, where the minor allele (frequency 16%) was associated with a -1.58 (95% CI -2.47 to -0.69) mm Hg change in mean 24-hour systolic blood pressure, after accounting for age, sex, and familial correlations (P=0.00048). Polymorphisms in the gene were also associated with clinic blood pressure and left ventricular mass as assessed by ECG Sokolow-Lyon voltage (P=0.0081 for rs675759). Associations with mean 24-hour systolic or diastolic blood pressure were also observed for variants in CASR, NR3C2, SCNN1B, and SCNN1G. The findings show that common variants in genes responsible for some Mendelian disorders of hypertension and hypotension affect blood pressure in the general population. Notably, variants in KCNJ1, which causes Bartter syndrome type 2, were strongly associated, potentially providing a novel target for intervention. PMID- 18443237 TI - Both intestinal and hepatic lipoprotein production are stimulated by an acute elevation of plasma free fatty acids in humans. AB - BACKGROUND: Hepatic lipoprotein production has been shown previously to be regulated by free fatty acid (FFA) flux to the liver, whereas intestinal lipoprotein production is stimulated mainly by ingested fat absorbed from the intestinal lumen. Emerging evidence indicates that intestinal lipoprotein production is increased in insulin resistance and type 2 diabetes mellitus, conditions that are associated with increased levels of circulating FFAs. Here we investigated whether short-term elevation of plasma FFAs stimulates intestinal apolipoprotein (apo) B-48- and hepatic apoB-100-containing triglyceride-rich lipoprotein (TRL) production in humans in the fed state. METHODS AND RESULTS: TRL apoB-48 and apoB-100 metabolism were examined in 12 healthy men during a constant fed state. The studies were as follows, respectively: (1) Intralipid/heparin was infused intravenously immediately before and during the kinetics study to induce an approximately 3-fold difference in plasma FFA compared with the saline study; (2) saline was infused intravenously as a control. ApoB-48- and apoB-100 containing TRL production and clearance were determined with a 12-hour primed constant infusion of [D3]L-leucine and multicompartmental kinetic modeling. TRL apoB-48 production rate was 69% higher in the Intralipid/heparin study than in the saline control (5.95+/-1.13 versus 3.53+/-0.58 mg/kg per day; P=0.027), and there was no significant difference in TRL apoB-48 clearance. TRL apoB-100 concentrations were also increased (P<0.001) and TRL apoB-100 production rate was 35% higher in the Intralipid/heparin study compared with saline (28+/-4 versus 21+/-3 mg/kg per day; P=0.020). CONCLUSIONS: This is the first study to demonstrate that intestinal TRL apoB-48 production is increased after short-term elevation of plasma FFAs in humans in the fed state, similar to the well described stimulation of hepatic TRL apoB100-containing particles by FFAs. PMID- 18443238 TI - Prevalence, predictors, and prognostic value of renal dysfunction in adults with congenital heart disease. AB - BACKGROUND: Renal insufficiency in patients with ischemic heart disease and acquired heart failure is associated with higher mortality and morbidity. We studied the prevalence of renal dysfunction in adult patients with congenital heart disease (ACHD) and its relation to outcome. METHODS AND RESULTS: A total of 1102 adult patients with congenital heart disease (age 36.0+/-14.2 years) attending our institution between 1999 and 2006 had creatinine concentration measured. Glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients were divided into groups of normal GFR (> or =90 mL . min(-1) . 1.73 m(-2)), mildly impaired GFR (60 to 89 mL . min( 1) . 1.73 m(-2)), and moderately/severely impaired GFR (<60 mL . min(-1) . 1.73 m(-2)). Survival was compared between GFR groups by Cox regression. Median follow up was 4.1 years, during which 103 patients died. Renal dysfunction was mild in 41% of patients and moderate or severe in 9%. A decrease in GFR was more common among patients with Eisenmenger physiology, of whom 72% had reduced GFR (<90 mL . min(-1) . 1.73 m(-2), P<0.0001 compared with the remainder), and in 18%, this was moderate or severe (P=0.007). Renal dysfunction had a substantial impact on mortality (propensity score-weighted hazard ratio 3.25, 95% CI 1.54 to 6.86, P=0.002 for moderately or severely impaired versus normal GFR). CONCLUSIONS: Deranged physiology in adult patients with congenital heart disease is not limited to the heart but also affects the kidney. Mortality is 3-fold higher than normal in the 1 in 11 patients who have moderate or severe GFR reduction. PMID- 18443239 TI - Regulator of G-protein signaling subtype 4 mediates antihypertrophic effect of locally secreted natriuretic peptides in the heart. AB - BACKGROUND: Mice lacking guanylyl cyclase-A (GC-A), a natriuretic peptide receptor, have pressure-independent cardiac hypertrophy. However, the mechanism underlying GC-A-mediated inhibition of cardiac hypertrophy remains to be elucidated. In the present report, we examined the role of regulator of G-protein signaling subtype 4 (RGS4), a GTPase activating protein for G(q) and G(i), in the antihypertrophic effects of GC-A. METHODS AND RESULTS: In cultured cardiac myocytes, treatment of atrial natriuretic peptide stimulated the binding of guanosine 3',5'-cyclic monophosphate-dependent protein kinase (PKG) I-alpha to RGS4, PKG-dependent phosphorylation of RGS4, and association of RGS4 and Galpha(q). In contrast, blockade of GC-A by an antagonist, HS-142-1, attenuated the phosphorylation of RGS4 and association of RGS4 and Galpha(q). Moreover, overexpressing a dominant negative form of RGS4 diminished the inhibitory effects of atrial natriuretic peptide on endothelin-1-stimulated inositol 1,4,5 triphosphate production, [(3)H]leucine incorporation, and atrial natriuretic peptide gene expression. Furthermore, expression and phosphorylation of RGS4 were significantly reduced in the hearts of GC-A knockout (GC-A-KO) mice compared with wild-type mice. For further investigation, we constructed cardiomyocyte-specific RGS4 transgenic mice and crossbred them with GC-A-KO mice. The cardiac RGS4 overexpression in GC-A-KO mice significantly reduced the ratio of heart to body weight (P<0.001), cardiomyocyte size (P<0.01), and ventricular calcineurin activity (P<0.05) to 80%, 76%, and 67% of nontransgenic GC-A-KO mice, respectively. It also significantly suppressed the augmented cardiac expression of hypertrophy-related genes in GC-A-KO mice. CONCLUSIONS: These results provide evidence that GC-A activates cardiac RGS4, which attenuates Galpha(q) and its downstream hypertrophic signaling, and that RGS4 plays important roles in GC-A mediated inhibition of cardiac hypertrophy. PMID- 18443240 TI - Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. AB - BACKGROUND: The potential biological significance of hydrogen sulfide (H(2)S) has attracted growing interest in recent years. The aim of this study was to characterize a novel, water-soluble, slow-releasing H(2)S compound [morpholin-4 ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137)] and evaluate its use as a tool to investigate the cardiovascular biology of this gas. METHODS AND RESULTS: The acute vasorelaxant effect of drugs was assessed in rat aortic rings and perfused rat kidney in vitro and in the anesthetized rat in vivo. The chronic effect of GYY4137 on blood pressure in normotensive and spontaneously hypertensive rats was determined by tail-cuff plethysmography. GYY4137 released H(2)S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo. GYY4137 caused a slow relaxation of rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle K(ATP) channels. GYY4137 did not affect rat heart rate or force of contraction in vitro. GYY4137 exhibited antihypertensive activity as evidenced by ability to reduce N(G)-nitro-L-arginine methyl ester-evoked hypertension in the anesthetized rat and after chronic (14 day) administration in spontaneously hypertensive rats. CONCLUSIONS: These results identify GYY4137 as a slow-releasing H(2)S compound with vasodilator and antihypertensive activity. GYY4137 is likely to prove useful in the study of the many and varied biological effects of H(2)S. GYY4137 may also prove of therapeutic value in cardiovascular disease. PMID- 18443241 TI - Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. AB - BACKGROUND: Elevated heart rate is associated with increased cardiovascular morbidity. We hypothesized that selective heart rate reduction may influence endothelial function and atherogenesis and tested the effects of the I(f) current inhibitor ivabradine in apolipoprotein E-deficient mice. METHODS AND RESULTS: Male apolipoprotein E-deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg . kg(-1) . d(-1)) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472+/-9 versus 545+/-11 bpm; P<0.01) but did not alter blood pressure or lipid levels. Endothelium-dependent relaxation of aortic rings was significantly improved in ivabradine-fed animals (P<0.01). Ivabradine decreased atherosclerotic plaque size in the aortic root by >40% and in the ascending aorta by >70% (P<0.05). Heart rate reduction by ivabradine had no effect on the number of endothelial progenitor cells and did not alter aortic endothelial nitric oxide synthase, phosphorylated Akt, vascular cell adhesion molecule-1, or intercellular adhesion molecule-1 expression but decreased monocyte chemotactic protein-1 mRNA and exerted potent antioxidative effects. Ivabradine reduced vascular NADPH oxidase activity to 48+/-6% and decreased markers of superoxide production and lipid peroxidation in the aortic wall (P<0.05). The in vivo effects of ivabradine were absent at a dose that did not lower heart rate, in aortic rings treated ex vivo, and in cultured vascular cells. In contrast to ivabradine, treatment with hydralazine (25 mg . kg(-1) . d( 1) for 6 weeks) reduced blood pressure (-15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress. CONCLUSIONS: Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice. PMID- 18443242 TI - Images in cardiovascular medicine. Hypoplastic left heart syndrome with left ventricular myocardial sinusoids: echocardiographic and angiographic findings in the first neonate surviving the Norwood I and II procedure. PMID- 18443243 TI - Cardiology patient pages. Can patients with cardiovascular disease take nonsteroidal antiinflammatory drugs? PMID- 18443244 TI - Letter by Ristagno and Gullo regarding article, "Survival is similar after standard treatment and chest compression only in out-of-hospital bystander cardiopulmonary resuscitation". PMID- 18443246 TI - Metabolic management of acute myocardial infarction comes to the fore and extends beyond control of hyperglycemia. PMID- 18443247 TI - Congenital long-QT syndromes: who's at risk for sudden cardiac death? PMID- 18443248 TI - Can the off-pump coronary artery bypass debate shed light on postoperative right heart dysfunction? PMID- 18443249 TI - Does size matter? Clinical applications of scaling cardiac size and function for body size. AB - Extensive evidence is available that cardiovascular structure and function, along with other biological properties that span the range of organism size and speciation, scale with body size. Although appreciation of such factors is commonplace in pediatrics, cardiovascular measurements in the adult population, with similarly wide variation in body size, are rarely corrected for body size. In this review, we describe the critical role of body size measurements in cardiovascular medicine. Using examples, we illustrate the confounding effects of body size. Current cardiovascular scaling practices are reviewed, as are limitations and alternative relationships between body and cardiovascular dimensions. The experimental evidence, theoretical basis, and clinical application of scaling of various functional parameters are presented. Appropriately scaled parameters aid diagnostic and therapeutic decision making in specific disease states such as hypertrophic cardiomyopathy and congestive heart failure. Large-scale studies in clinical populations are needed to define normative relationships for this purpose. Lack of appropriate consideration of body size in the evaluation of cardiovascular structure and function may adversely affect recognition and treatment of cardiovascular disease states in the adult patient. PMID- 18443250 TI - Endovascular repair of thoracoabdominal aneurysms. AB - BACKGROUND: Morbidity and mortality after conventional repair of thoracoabdominal aneurysms remain high. Alternative techniques have been proposed and are the subject of this report. METHODS AND RESULTS: Endovascular grafts that have a means of incorporating the visceral vessels into the aortic repair were divided into devices with fenestrations and those with formal branches. Hybrid procedures whereby an extra-anatomic bypass procedure is used to provide inflow to the renal and mesenteric arteries followed by aortic relining with stent grafts were reviewed and tabulated. A description of the techniques and review of the current results are provided. Only 4 series with >10 cases of hybrid procedures have been published. The experience with such a procedure suggests feasibility, but most reports describe a persistently high risk of mortality (up to 25%). Larger series of fenestrated stent grafts to treat juxtarenal aneurysms have been published, and intermediate-term results confirm the safety and efficacy of the procedure. A larger multicenter trial is under way. Other pure endovascular methods have been used to treat thoracoabdominal aneurysms with both reinforced fenestrations and directional branches. Without counting small series (<10 cases), 2 series exist with approximately 100 cases that noted perioperative mortality rates between 3% and 6%, without evidence of late ruptures. CONCLUSIONS: Endovascular repair of thoracoabdominal aneurysms is feasible and is associated with relatively low perioperative mortality. Several methods of visceral vessel incorporation have been described. Because of persistently high mortality, hybrid procedures will likely be relegated to nonsurgical and nonendovascular patients with sizable aneurysms. Endografts with branches continue to evolve and will be assessed in the context of clinical trials. PMID- 18443251 TI - Images in cardiovascular medicine. Pseudonormal position of an atrial pacemaker lead associated with a contralateral pneumothorax: where is the atrial lead? PMID- 18443252 TI - Considering competing risks . . . Not all black and white. PMID- 18443253 TI - Mandated diabetes registries will benefit persons with diabetes. PMID- 18443254 TI - Mandated diabetes registries will not benefit persons with diabetes. PMID- 18443255 TI - Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections: a systematic review of the literature. AB - BACKGROUND: Staphylococcus aureus causes severe life-threatening infections and has become increasingly common, particularly methicillin-resistant strains. Rifampin is often used as adjunctive therapy to treat S aureus infections, but there have been no systematic investigations examining the usefulness of such an approach. METHODS: A systematic review of the literature to identify in vitro, animal, and human investigations that compared single antibiotics alone and in combination with rifampin therapy against S aureus. RESULTS: The methods of in vitro studies varied substantially among investigations. The effect of rifampin therapy was often inconsistent, it did not necessarily correlate with in vivo investigations, and findings seemed heavily dependent on the method used. In addition, the quality of data reporting in these investigations was often suboptimal. Animal studies tended to show a microbiologic benefit of adjunctive rifampin use, particularly in osteomyelitis and infected foreign body infection models; however, many studies failed to show a benefit of adjunctive therapy. Few human studies have addressed the role of adjunctive rifampin therapy. Adjunctive therapy seems most promising for the treatment of osteomyelitis and prosthetic device-related infections, although studies were typically underpowered and benefits were not always seen. CONCLUSIONS: In vitro results of interactions between rifampin and other antibiotics are method dependent and often do not correlate with in vivo findings. Adjunctive rifampin use seems promising in the treatment of clinical hardware infections or osteomyelitis, but more definitive data are lacking. Given the increasing incidence of S aureus infections, further adequately powered investigations are needed. PMID- 18443256 TI - Use of thiazolidinediones and fracture risk. AB - BACKGROUND: Thiazolidinediones may adversely affect the skeleton owing to decreased bone formation and accelerated bone loss. METHODS: This study examines the association between the use of thiazolidinediones or other oral antidiabetic drugs and the risk of fracture. This nested case-control analysis uses the UK General Practice Research Database, including case patients with fracture aged 30 to 89 years with an incident fracture diagnosis between January 1994 and December 2005 and control subjects who were matched to case patients on age, sex, calendar time, and general practice attended. We assessed the odds ratios (ORs) of having a fracture associated with the use of rosiglitazone maleate, pioglitazone hydrochloride, other oral antidiabetic agents, or insulin. RESULTS: There were 1020 case patients with an incident low-trauma fracture and 3728 matched controls. After adjustment for age, body mass index, other antidiabetic drugs, comedication, and comorbidities, the ORs for users of 8 or more thiazolidinedione prescriptions (corresponding to approximately 12-18 months of therapy) compared with nonuse was 2.43 (95% confidence interval [CI], 1.49-3.95). Rosiglitazone (OR, 2.38; 95% CI, 1.39-4.09) and pioglitazone (OR, 2.59; 95% CI, 0.96-7.01) were used more frequently by case patients with fracture (predominantly hip and wrist fractures) than by controls. The association was independent of patient age and sex and tended to increase with thiazolidinedione dose. No materially altered relative fracture risk was found in association with the use of other oral antidiabetic drugs. CONCLUSION: This analysis provides further evidence of a possible association between long-term use of thiazolidinediones and fractures, particularly of the hip and wrist, in patients with diabetes mellitus. PMID- 18443257 TI - Use of alendronate and risk of incident atrial fibrillation in women. AB - BACKGROUND: A recent publication from the HORIZON (Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly) trial in women with postmenopausal osteoporosis reported a higher risk of serious atrial fibrillation (AF) in zoledronic acid recipients than in placebo recipients. This adverse effect was unexpected and had not been recognized previously. METHODS: We studied alendronate sodium ever use in relation to the risk of incident AF in women in a clinical practice setting. This population-based case-control study was conducted at Group Health, an integrated health care delivery system in Washington State. We identified 719 women with confirmed incident AF between October 1, 2001, and December 31, 2004, and 966 female control subjects without AF, selected at random from the Group Health enrollment and frequency matched on age, presence or absence of treated hypertension, and calendar year. RESULTS: More AF case patients than controls had ever used alendronate (6.5% [n = 47] vs 4.1% [n = 40]; P = .03). Compared with never use of any bisphosphonate, ever use of alendronate was associated with a higher risk of incident AF (odds ratio, 1.86; 95% confidence interval, 1.09-3.15) after adjustment for the matching variables, a diagnosis of osteoporosis, and a history of cardiovascular disease. Based on the population-attributable fraction, we estimated that 3% of incident AF in this population might be explained by alendronate use. CONCLUSION: Ever use of alendronate was associated with an increased risk of incident AF in clinical practice. PMID- 18443259 TI - Persistent hot flushes in older postmenopausal women. AB - OBJECTIVE: To examine the prevalence, natural history, and predictors of hot flushes in older postmenopausal women. METHODS: Prevalence, severity, and 3-year change in severity of hot flushes were assessed by questionnaire in 3167 older postmenopausal women with osteoporosis. Logistic regression was used to identify characteristics associated with symptoms at baseline and after 3 years of follow up. RESULTS: At baseline, 375 women (11.8%) reported bothersome hot flushes. Women were more likely to have baseline symptoms if they were less educated (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.06-1.53 per 4-year decrease), more recently menopausal (OR, 1.44; 95% CI, 1.34-1.56 per 5-year decrease), had previously used estrogen (OR, 1.57; 95% CI, 1.23-2.00), or had undergone hysterectomy (OR, 1.51; 95% CI, 1.14-1.99). Hot flushes were also associated with higher body mass index (OR, 1.22; 95% CI, 1.08-1.38 per 1 SD), higher follicle stimulating hormone levels (OR, 1.34; 95% CI, 1.20-1.51 per 1 SD), lower high density lipoprotein levels (OR, 1.17; 95% CI, 1.03-1.34 per 1 SD decrease), vaginal dryness (OR, 1.52; 95% CI, 1.19-1.93), and trouble sleeping (OR, 2.48; 95% CI, 1.94-3.16), but not estradiol levels. Of the 375 women with baseline symptoms, 278 contributed 3-year data, and 157 (56.5%) of these women reported persistent symptoms after 3 years. Fewer years since menopause (OR, 1.15; 95% CI, 1.01-1.32 per 5-year decrease) and trouble sleeping (OR, 1.97; 95% CI, 1.19-3.26) were associated with symptom persistence. CONCLUSIONS: For a substantial minority of women, hot flushes are a persistent source of discomfort into the late postmenopausal years. Identification of risk factors for hot flushes may help guide evaluation and treatment in this population. PMID- 18443260 TI - Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. AB - BACKGROUND: Few studies have examined factors identified as contributing to heart failure (HF) hospitalization, and, to our knowledge, none has explored their relationship to length of stay and mortality. This study evaluated the association between precipitating factors identified at the time of HF hospital admission and subsequent clinical outcomes. METHODS: During 2003 to 2004, 259 US hospitals in OPTIMIZE-HF submitted data on 48 612 patients, with a prespecified subgroup of at least 10% providing 60- to 90-day follow-up data. Identifiable factors contributing to HF hospitalization were captured at admission and included ischemia, arrhythmia, nonadherence to diet or medications, pneumonia/respiratory process, hypertension, and worsening renal function. Multivariate analyses were performed for length of stay, in-hospital mortality, 60- to 90-day follow-up mortality, and death/rehospitalization. RESULTS: Mean patient age was 73.1 years, 52% of patients were female, and mean ejection fraction was 39.0%. Of 48 612 patients, 29 814 (61.3%) had 1 or more precipitating factors identified, with pneumonia/respiratory process (15.3%), ischemia (14.7%), and arrhythmia (13.5%) being most frequent. Pneumonia (odds ratio, 1.60), ischemia (1.20), and worsening renal function (1.48) were independently associated with higher in-hospital mortality, whereas uncontrolled hypertension (0.74) was associated with lower in-hospital mortality. Ischemia (1.52) and worsening renal function (1.46) were associated with a higher risk of follow-up mortality. Uncontrolled hypertension as a precipitating factor was associated with lower postdischarge death/rehospitalization (hazard ratio, 0.71). CONCLUSIONS: Precipitating factors are frequently identified in patients hospitalized for HF and are associated with clinical outcomes independent of other predictive variables. Increased attention to these factors, many of which are avoidable, is important in optimizing the management of HF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00344513. PMID- 18443261 TI - Thyrotropin levels and risk of fatal coronary heart disease: the HUNT study. AB - BACKGROUND: Recent studies suggest that relatively low thyroid function within the clinical reference range is positively associated with risk factors for coronary heart disease (CHD), but the association with CHD mortality is not resolved. METHODS: In a Norwegian population-based cohort study, we prospectively studied the association between thyrotropin levels and fatal CHD in 17,311 women and 8002 men without known thyroid or cardiovascular disease or diabetes mellitus at baseline. RESULTS: During median follow-up of 8.3 years, 228 women and 182 men died of CHD. Of these, 192 women and 164 men had thyrotropin levels within the clinical reference range of 0.50 to 3.5 mIU/L. Overall, thyrotropin levels within the reference range were positively associated with CHD mortality (P for trend = .01); the trend was statistically significant in women (P for trend = .005) but not in men. Compared with women in the lower part of the reference range (thyrotropin level, 0.50-1.4 mIU/L), the hazard ratios for coronary death were 1.41 (95% confidence interval [CI], 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher (thyrotropin level, 2.5-3.5 mIU/L) categories, respectively. CONCLUSIONS: Thyrotropin levels within the reference range were positively and linearly associated with CHD mortality in women. The results indicate that relatively low but clinically normal thyroid function may increase the risk of fatal CHD. PMID- 18443258 TI - Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans. AB - BACKGROUND: Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD. METHODS: Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20-65 mL/min/1.73 m2). Following a 3x2-factorial trial (1995-2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and beta-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002-2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death. RESULTS: During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2). CONCLUSION: Despite the benefits of renin-angiotensin system-blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term. PMID- 18443262 TI - Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy. AB - BACKGROUND: We evaluated stroke risk associated with hormone therapy (HT) in younger women, in recently menopausal women, and in older women. METHODS: Prospective, observational analyses were performed in postmenopausal participants of the Nurses' Health Study, from 1976 to 2004, with biennial mailed questionnaires. Proportional hazards models were used to calculate multivariable adjusted relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: We found a significantly increased risk of stroke for women currently taking HT (estrogen alone: RR, 1.39; 95% CI, 1.18-1.63; and estrogen with progestin: RR, 1.27; 95% CI, 1.04-1.56), a finding that is nearly identical to that of the Women's Health Initiative. This increased risk was observed for women initiating HT at young ages or near menopause and at older ages or more than 10 years after menopause. Short-term (<5 years) HT initiated at younger ages was not associated with a clear increase in stroke; however, this apparently null result was based on a small number of cases. The incidence of stroke was relatively low in younger women, and the attributable risk in women aged 50 through 54 years indicated approximately an additional 2 cases of stroke per 10 000 women per year taking hormones. We found a strong relationship between dose of oral conjugated estrogen and stroke, with RRs of 0.93, 1.54, and 1.62 for doses of 0.3, 0.625, and 1.25 mg, respectively (P for trend, <.001). CONCLUSIONS: Hormone therapy is associated with an increased risk of stroke, and this increased risk does not appear to be related to the timing of the initiation of HT. In younger women, with lower stroke risk, the attributable risk of stroke owing to hormone use is modest and might be minimized by lower doses and shorter treatment duration. PMID- 18443264 TI - Assessment of the scientific soundness of clinical performance measures: a field test of the National Committee for Quality Assurance's colorectal cancer screening measure. AB - BACKGROUND: Relatively few studies have evaluated the scientific soundness of widely used performance measures. This study evaluated quality measures by describing a field test of the colorectal cancer screening measure included in the Health Plan Employer Data and Information Set of the National Committee for Quality Assurance. METHODS: We conducted a field test in 5 health care plans that enrolled 189 193 individuals considered eligible for colorectal cancer screening. We assessed measurement bias by calculating the prevalence of colorectal cancer screening while varying the data sources used (administrative data only, a hybrid of administrative data and medical record data, and enrollee survey data only) and the minimum required enrollment period (2-10 years). RESULTS: Across the 5 health care plans, the percentage of health care plan enrollees counted as screened varied according to the data used, ranging from 27.3% to 47.1% with the administrative data, 38.6% to 53.5% with the hybrid data, and 53.2% to 69.7% with the survey data. The relative ranking of plans also varied. One health care plan ranked first based on administrative data, second based on hybrid data, and fourth based on survey data. Survey respondents were more likely than nonrespondents to have evidence of colorectal cancer screening (62.7% vs 46.5%; P < .001). CONCLUSIONS: Administrative data seem to underestimate colorectal cancer screening and survey data seem to overestimate it, suggesting that a hybrid data approach offers the most accurate measure of screening. Implementation of performance measures should include evaluation of their scientific soundness. PMID- 18443265 TI - The joint effects of physical activity and body mass index on coronary heart disease risk in women. AB - BACKGROUND: Physical activity and body mass index (calculated as weight in kilograms divided by height in meters squared) independently alter the risk of coronary heart disease (CHD); however, their combined effect on CHD is not established. Our objective was to study the combined association of physical activity and body mass index on CHD. METHODS: Prospective cohort study of 38,987 women free of cardiovascular disease, cancer, and diabetes at baseline in the Women's Health Study, with 10.9 mean years of follow-up. Weight, height, and recreational activities were reported on entry. Body mass index was categorized as normal weight (<25), overweight (25 to <30), and obese (> or =30). Active was defined as 1000 kilocalories or more expended on recreational activities weekly. Six joint body weight-physical activity categories were defined. The main outcome measure was the occurrence of incident CHD during follow-up, defined as a cardiovascular event including nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or CHD death. RESULTS: A total of 948 cases of incident CHD occurred during follow-up. Higher body mass index and physical inactivity were individual predictors of CHD. In joint analyses, compared with active normal-weight individuals, the multivariate adjusted hazard ratios (95% confidence intervals) were 1.54 (1.14-2.08) for overweight-active; 1.87 (1.29-2.71) for obese-active; 1.08 (0.84-1.39) for normal weight-inactive; 1.88 (1.46-2.42) for overweight-inactive; and 2.53 (1.94-3.30) for obese-inactive. Increasing levels of walking also resulted in significant reductions in CHD risk for overweight and obese individuals. CONCLUSIONS: The risk of CHD associated with elevated body mass index is considerably reduced by increased physical activity levels. However, the risk is not completely eliminated, reinforcing the importance of being lean and physically active. PMID- 18443267 TI - A prospective study of maternal anti-HPA 1a antibody level as a potential predictor of alloimmune thrombocytopenia in the newborn. AB - BACKGROUND: Neonatal alloimmune thrombocytopenia is most commonly due to transplacental passage of maternal anti-HPA 1a antibodies. A prospective study was carried out to evaluate the pattern and quantity of maternal anti-HPA 1a antibodies in order to predict the level of thrombocytopenia in the neonates. DESIGN AND METHODS: A monoclonal antibody immobilization of platelet antigen assay was used to detect antibodies in maternal samples from 1,990 HPA 1bb women. HLA DRB3*0101 typing was performed in all immunized women by sequencing the HLA DRB3 gene when present. RESULTS: Primary immunization more often took place in connection with delivery than during the first pregnancy. There was a strong correlation between maternal antibody levels and the platelet counts in the newborn (R(2) = 0.49, p < 0.001). A maternal antibody level above 3.0 IU/mL measured in gestational week 22 or 34 had a diagnostic sensitivity and specificity of 93% and 63%, respectively, for predicting the grade of neonatal thrombocytopenia. The women who were negative for HLA DRB3*0101 had significantly lower anti-HPA 1a antibody levels than those who were HLA DRB3*0101 positive (p < 0.007). In contrast to primigravida, in whom anti-HPA 1a antibody levels increased during pregnancy, the antibody level decreased in 92 of 147 women who had been pregnant previously (P(92 or more of 147) = 0.003). The anti-HPA 1a antibody level regularly increased after delivery. CONCLUSIONS: Maternal anti-HPA 1a antibody levels in weeks 22 and 34 of pregnancy are good predictors of the degree of thrombocytopenia in the newborn both in the first and subsequent pregnancies. Most mothers became immunized at the time of delivery. PMID- 18443266 TI - Genetic predisposition, nongenetic risk factors, and coronary infarct. AB - BACKGROUND: Using a genetic predisposition score (GPS), additively integrating the associations of 11 polymorphisms with coronary heart disease (CHD), we examined the consequences of the joint presence of a high GPS and nongenetic CHD risk factors. METHODS: Within the European Prospective Investigation Into Cancer and Nutrition, 202 case patients with medically confirmed incident coronary infarct and 197 control subjects were identified in Greece. Each polymorphism contributed 1 unit (high-risk homozygous), one-half unit (heterozygous), or no units (low-risk homozygous) to the GPS. Odds ratios of coronary infarction for those at high risk because of genetic predisposition and simultaneous presence of an established CHD risk factor were estimated, compared with subjects at low risk, for both GPS and each CHD risk factor. RESULTS: The joint presence of a high GPS (> or =3.5) and each studied CHD risk factor was in all instances associated with a significantly increased risk of coronary infarction. The odds ratio (95% confidence interval) was 2.62 (1.14-6.02) for ever smoking, 2.88 (1.33 6.24) for hypertension, 3.50 (1.67-7.33) for low high-density lipoprotein (HDL) level, 3.05 (1.53-6.08) for high non-HDL level, and 3.66 (1.75-7.65) for poor adherence to the Mediterranean diet. The odds ratios were always lower and nonsignificant when the GPS was low. There was suggestive evidence for interaction of a high GPS with hypertension (P = .05) and non-HDL cholesterol level (P = .13). CONCLUSIONS: Genetic predisposition may interact with hypertension and, perhaps, also with the level of non-HDL cholesterol, in the causation of CHD. Genetic predisposition and the other studied exposures seem to have converging effects. Thus, the GPS may identify individuals who could realize disproportional benefits by controlling their hypertension and, possibly, their non-HDL cholesterol level. PMID- 18443268 TI - The functional properties of a truncated form of endothelial cell protein C receptor generated by alternative splicing. AB - BACKGROUND: A soluble form of endothelial cell protein C receptor (sEPCR) is generated by shedding of the cellular form. sEPCR binds to protein C and factor VIIa and inhibits both the activation of protein C and the activity of activated protein C and factor VIIa. High sEPCR levels may increase the risk of thrombosis. We wanted to explore the possibility of detecting soluble endothelial cell protein C receptor forms generated by alternative splicing. DESIGN AND METHODS: Reverse transcriptase polymerase chain reaction was used to look for new forms of endothelial cell protein C receptor. A yeast expression system was used to generate sufficient amounts of the distinct sEPCR forms. Surface plasmon resonance experiments, chromogenic assays, clotting assays and immunoassays were subsequently performed to characterize a new form of sEPCR that was found. RESULTS: We demonstrated, by reverse transcriptase polymerase chain reaction and sequencing, the existence of a new, soluble form of endothelial cell protein C receptor generated by alternative splicing, in which the transmembrane region is replaced by a 56-residue tail (tEPCR). Its cDNA was present in human umbilical vein endothelial cells and in most tissues as well as in lung cancer cells. tEPCR was not located in the membrane of transfected cells. We demonstrated that tEPCR binds to protein C and factor VIIa. tEPCR blocked the generation of activated protein C and inhibited the activity of both activated protein C and factor VIIa. tEPCR was detected, by immunoassays, in the supernatant of lung cancer cells and human umbilical vein endothelial cells. CONCLUSIONS: A truncated form of alternatively spliced endothelial cell protein C receptor was detected in the endothelium and cancer cells. tEPCR behaves as sEPCR generated by shedding of the cellular endothelial cell protein C receptor. PMID- 18443269 TI - Different cut-off values of quantitative D-dimer methods to predict the risk of venous thromboembolism recurrence: a post-hoc analysis of the PROLONG study. AB - BACKGROUND: The PROLONG study showed that patients with venous thromboembolism who had qualitatively abnormal results in a D-dimer assay (Clearview Simplify D dimer) after discontinuation of vitamin K antagonism benefit from resumption of treatment with vitamin K antagonism. The objective of this study was to evaluate the possible advantage of using quantitative D-dimer assays. DESIGN AND METHODS: VIDAS D-dimer Exclusion (bioMerieux), Innovance D-DIMER (Dade Behring), HemosIL D dimer HS (Instrumentation Laboratory) and STA Liatest D-dimer (Diagnostica Stago) assays were performed in plasma aliquots sampled 30+/-10 days after cessation of vitamin K antagonism in 321 patients enrolled in the PROLONG study. RESULTS: During the follow-up without vitamin K antagonism, 25 patients had recurrent venous thromboembolism. The cut-off levels of the quantitative assays giving results most comparable with those of the qualitative test were: VIDAS = 800 ng/mL; Innovance = 800 ng/mL; HemosIL HS = 300 ng/mL; STA Liatest = 700 ng/mL. When the effect of the patients' age (< or = 70 vs. >70 years) was analyzed, it was found that only in younger patients was the rate of recurrence of venous thromboembolism significantly higher in patients with abnormal D-dimer levels. However, using the quantitative assays and age-specific cut-off levels it was possible to determine statistically significant hazard ratios also in elderly patients (VIDAS = 600 and 1200 ng/mL, Innovance = 500 and 900 ng/mL, HemosIL HS = 250 and 450 ng/mL, STA Liatest = 700 and 1000 ng/mL, in patients aged < or = 70 and >70 years, respectively). CONCLUSIONS: Quantitative D-dimer assays may provide information useful for evaluating the individual risk of recurrent venous thromboembolism. They seem particularly advantageous since they allow the selection of different cut-off levels according to the age or other characteristics of the patients. PMID- 18443271 TI - The effect of azacitidine on interleukin-6 signaling and nuclear factor-kappaB activation and its in vitro and in vivo activity against multiple myeloma. AB - BACKGROUND: Azacitidine is a DNA methyltransferase inhibitor and cytotoxic agent known to induce apoptosis of some cancer cells. This study evaluated the pre clinical potential of azacitidine as a therapeutic agent for multiple myeloma. DESIGN AND METHODS: Dose responsiveness to azacitidine was determined utilizing a panel of genetically heterogenous human multiple myeloma cell lines. Azacitidine was also tested against primary multiple myeloma cells and in the 5T33MM murine model of systemic myelomatosis. Mechanistic studies included immunoblotting of key apoptosis signaling proteins, analysis of p16 gene methylation status, and characterization of both the interleukin-6 and nuclear factor-kappaB signaling pathways following azacitidine treatment. RESULTS: Human myeloma cell lines and primary multiple myeloma cells underwent apoptosis following exposure to clinically achievable concentrations of azacitidine (1 microM-20 microM). Similarly, azacitidine prolonged survival from 24.5 days to 32 days (p=0.001, log rank) in the 5T33MM model. At a mechanistic level azacitidine down-regulated two crucial cell survival pathways in multiple myeloma. First, it inhibited the elaboration of both interleukin-6 receptor-alpha and interleukin- 6 resulting in the reduced expression of both phospho-STAT3 and Bcl-xl. Secondly, azacitidine inhibited both nuclear factor-kappaB nuclear translocation and DNA binding in a manner independent of IkappaB. The kinetics of these azacitidine-induced responses was more consistent with protein synthesis inhibition than with either hypomethylation or another DNA-mediated effect. CONCLUSIONS: Azacitidine rapidly induces apoptosis of multiple myeloma cells, is effective in vivo against multiple myeloma and inhibits two crucial cell survival pathways in this disease. We conclude that azacitidine demonstrates novel and highly relevant anti-myeloma effects and warrants further evaluation in a clinical context. PMID- 18443270 TI - Diabetes and the risk of non-Hodgkin's lymphoma and multiple myeloma in the European Prospective Investigation into Cancer and Nutrition. AB - BACKGROUND: Non-Hodgkin's lymphomas are a heterogeneous group of neoplasms arising from the lymphopoietic system including a wide range of subtypes of either B-cell or T-cell lymphomas. The few established risk factors for the development of these neoplasms include viral infections and immunological abnormalities, but their etiology remains largely unknown. Evidence suggests that certain medical conditions may be linked, through immunosuppression, to the risk of non-Hodgkin's lymphoma. Multiple myeloma is a neoplasm of plasma cells that accounts for approximately 15% of lymphopoietic cancers. Increases in the incidence of non-Hodgkin's lymphoma and multiple myeloma in the past implicate environmental factors as potential causal agents. DESIGN AND METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,213 histologically confirmed incident cases of non-Hodgkin's lymphoma and multiple myeloma (594 men; 619 women) were identified during a follow-up of 8.5 years. Cox proportional hazard models were used to explore the association between self reported diabetes, diagnosed after 30 years of age, and the risk of non-Hodgkin's lymphoma overall and multiple myeloma and various lymphoma subtypes. RESULTS: We found no association between a personal history of diabetes and the risk of non Hodgkin's lymphoma overall in men (HR: 1.28, 95% CI: 0.89-1.84), in women (HR: 0.71, 95% CI: 0.41- 1.24), or in men and women combined (HR: 1.09, 95% CI: 0.80 1.47). Among the B-non-Hodgkin's lymphoma subtypes, we observed a statistically significant increased risk of B-cell chronic lymphocytic leukemia (HR: 2.0, 95% CI: 1.04-3.86) in men, but not in women (HR: 1.07, 95% CI: 0.33-3.43). CONCLUSIONS: This prospective study did not provide evidence for a role of self reported diabetes in the etiology of non-Hodgkin's lymphoma overall or multiple myeloma. We found an increased risk of B-cell chronic lymphocytic leukemia among men with diabetes, but not among women. We hypothesize that diabetes may not play a causal role in the etiology of B-cell chronic lymphocytic leukemia, though the underlying pathogenic mechanisms of both disorders may include shared genetic, host and/or environmental susceptibility factors. PMID- 18443272 TI - Expression of c-Kit isoforms in multiple myeloma: differences in signaling and drug sensitivity. AB - BACKGROUND: c-Kit is expressed in the plasma cells from 30% of patients with multiple myeloma. Two different isoforms of c-Kit, characterized by the presence or absence of the tetrapeptide sequence GNNK in the extracellular domain, have been described. However, their expression and function in myeloma cells are unknown. We explored the function and expression of these c-Kit isoforms in myeloma cells. DESIGN AND METHODS: Expression of c-Kit isoforms was investigated by reverse transcriptase polymerase chain reaction in fresh plasma cells from patients and cell lines. The function of these c-Kit isoforms was analyzed upon expression in myeloma cells. Signaling was investigated by western blotting using antibodies specific for activated forms of several signaling proteins. The impact of c-Kit on the action of drugs commonly used in the treatment of multiple myeloma was investigated by MTT proliferation assays. RESULTS: Fresh plasma cells from patients as well as myeloma cell lines expressed the two isoforms of c-Kit. Retroviral infection of myeloma cells with vectors that code for c-Kit-GNNK+ or c Kit-GNNK- forms demonstrated differences in the kinetics of phosphorylation between these isoforms. Stem cell factor-induced activation of the GNNK- form was faster and more pronounced than that of the GNNK+ form, whose activation, however, lasted for longer. The c-Kit receptors weakly activated the Erk1/2 and Erk5 pathways. Both receptors, however, efficiently coupled to the PI3K/Akt pathway, and stimulated p70S6K activation. The latter was sensitive to the mTOR inhibitor, rapamycin. Studies of drug sensitivity indicated that cells expressing the GNNK- form were more resistant to the anti-myeloma action of bortezomib and melphalan. CONCLUSIONS: Our data indicate that c-Kit expression in multiple myeloma cells is functional, and coupled to survival pathways that may modulate cell death in response to therapeutic compounds used in the treatment of this disease. PMID- 18443273 TI - Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy. AB - The Wilms' tumor gene WT1 is a reliable marker for minimal residual disease assessment in acute leukemia patients. The study was designed to demonstrate the potential use of WT1 to establish quality of remission in acute leukemia patients for early identification of patients at high risk of relapse. A prospective study based on a quantitative Real-Time PCR (TaqMan) assay in 562 peripheral blood samples collected from 82 acute leukemia patients at diagnosis and during follow up was established. The evaluation of WT1 in peripheral blood samples after induction chemotherapy can distinguish the continuous complete remission patients from those who obtain only an "apparent" complete remission and who could relapse within a few months. WT1 helps identify patients at high risk of relapse soon after induction chemotherapy allowing post-induction therapy in high risk patients to be intensified. PMID- 18443274 TI - Arthroscopic rotator cuff repair in overhead-throwing athletes. AB - BACKGROUND: When overhead-throwing athletes suffer from a rotator cuff tear, their ability to perform sporting activities is significantly impaired. HYPOTHESIS: Arthroscopic rotator cuff repair allows amateur overhead-throwing athletes to return to their preoperative level of overhead-throwing sports. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Twenty-one overhead-throwing athletes (14 male and 7 female; average age, 58.9 years, range, 46-69 years) were reviewed for clinical outcome with the Constant Score and structural integrity of the repair on magnetic resonance imaging. The average follow-up was 25.7 months (24-29 months). Athletes were asked to retrospectively assess their sporting activity for pain, strength, endurance, and range of motion before onset of symptoms, preoperatively and at follow-up. They also were asked to evaluate their overall performance as a percentage of their original performance (0% to 100%). Retear rates and Constant Scores were compared with those of 32 patients who were not overhead-throwing athletes and who were operated on during the same time span. RESULTS: Patients significantly improved their Constant Score from 54.9 to 84.2 (P < .001). Sporting activity was not significantly influenced by repair integrity; the retear rate was 23.8% (5/21). There was no significant difference for retear rate (25%; 8/32) or clinical outcome (Constant Score 84.5, P = .993) compared with patients who were not involved in overhead-throwing sports or any sports. All patients returned to their overhead-throwing sport an average of 6.3 months (3-12 months) after the surgery. Participation (2.1 per week) and duration (2.3 hours) of overhead-throwing activity postoperatively were not significantly lower than before the patient was injured (2.2 per week, P = .290; and 2.4 hours, P = .285). Patients estimated their overall activity level to be 91.9% of their original, noninjured condition, which was significantly improved from the preoperative condition of 34.8% (P < .001). CONCLUSION: Arthroscopic rotator cuff repair led to good clinical results in this group of overhead-throwing athletes. Patients were able to return to overhead-throwing sports, most of them at the same preoperative level. PMID- 18443263 TI - Circumstances of death in hospitalized patients and nurses' perceptions: French multicenter Mort-a-l'Hopital survey. AB - BACKGROUND: In developed countries at present, death mostly occurs in hospitals, but the circumstances and factors associated with the quality of organization and care surrounding death are not well described. METHODS: We designed a large multicenter cross-sectional study to analyze the setting and clinical course of each patient on the day of death. We included 2750 clinical departments of 294 hospitals. Of these, 1033 departments (37.6%) of 200 hospitals (68.0%) contributed to the Mort-a-l'Hopital survey. Data were collected prospectively by the bedside nurse of each patient within 10 days of the occurrence of death. Main outcome measures included circumstances of death in hospitalized patients; secondary outcomes, nurses' perceptions of quality of end-of-life care. RESULTS: Of the 1033 participating departments, 420 recorded no deaths during the study period and 613 declared at least 1 death. In the 3793 patients who died and were included for assessment, only 925 (24.4%) had loved ones present at the time of death; 70.1% had respiratory distress during the period before death; and only 12.0% were in pain. Written protocols for end-of-life care were available in 12.2% of participating departments. Only 35.1% of nurses judged the quality of dying and death acceptable for themselves. Principal factors significantly associated with this perception were availability of a written protocol for end of-life care, anticipation of death, informing the family, surrogate designation, adequate control of pain, presence of family or friends at the time of death, and staff meeting with the family after the death. CONCLUSIONS: This large prospective study identifies nonoptimal circumstances of death for hospitalized patients and a number of suggestions for improvement. A combination of factors reflected in the nurses' satisfaction may improve the quality of end-of-life care. PMID- 18443275 TI - Arthroscopic and magnetic resonance image appearance and reconstruction of the anterior talofibular ligament in cases of apparent functional ankle instability. AB - BACKGROUND: Many patients report feeling functional ankle instability, despite having no clinically demonstrable lateral instability. HYPOTHESIS: Some patients who experience functional instability of the ankle have substantial abnormalities of the anterior talofibular ligament despite having apparently normal lateral laxity in clinical examination. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Fourteen patients who had functional ankle instability after sprain, despite having no clinically demonstrable lateral instability, were included in this study. All subjects underwent standard stress radiography, magnetic resonance imaging, and ankle arthroscopy. These patients were treated with anatomical reconstruction of the anterior talofibular ligament. RESULTS: Arthroscopic assessment revealed 3 cases with no ligamentous structure with scar tissue, 9 cases with partial ligament tears and scar tissue on the disrupted anterior talofibular ligament fiber, and 2 cases of abnormal course of the ligament at the fibular or talar attachment. Magnetic resonance imaging revealed the following: 5 cases of discontinuity of the anterior talofibular ligament, 2 cases of narrowing of the anterior talofibular ligament, 4 cases of high intensity lesion in the anterior talofibular ligament, and 3 normal cases. The mean American Orthopaedic Foot and Ankle Society Ankle Hindfoot scale score was 66.2 +/- 3.2 points at preoperation and 92.3 +/- 4.4 points 2 years after surgery. CONCLUSION: All patients in this study with functional ankle instability, despite their having no demonstrable abnormal lateral laxity, had morphologic ligamentous abnormality on arthroscopic assessment. PMID- 18443276 TI - Epidemiology of National Football League training camp injuries from 1998 to 2007. AB - BACKGROUND: Football is one of the leading causes of athletic-related injuries. Injury rates and patterns of the training camp period of the National Football League are unknown. HYPOTHESIS: Injury rates will vary with time, and injury patterns will differ between training camp practices and preseason games. STUDY DESIGN: Descriptive epidemiology study. METHODS: From 1998 to 2007, injury data were collected from 1 National Football League team during its training camp period. Injuries were recorded as a strain, sprain, concussion, contusion, fracture/dislocation, or other injury. The injury was further categorized by location on the body. Injury rates were determined based on the exposure of an athlete to a game or practice event. An athlete exposure was defined as 1 athlete participating in 1 practice or game. The injury rate was calculated as the ratio of injuries per 1000 athlete exposures. RESULTS: There were 72.8 (range, 58-109) injuries per year during training camp. Injuries were more common during weeks 1 and 2 than during weeks 3 to 5. The rate of injury was significantly higher during games (64.7/1000 athlete exposures) than practices (12.7/1000 athlete exposures, P < .01). The rate of season-ending injuries was also much higher in games (5.4/1000 athlete exposures) than practices (0.4/1000 athlete exposures). The most common injury during the training camp period was a knee sprain, followed by hamstring strains and contusions. CONCLUSION: Muscle strains are the most common injury type in practices. Contact type injuries are most common during pre-season games, and the number of significant injuries that occur during preseason games is high. PMID- 18443277 TI - Revision surgery for failed elbow medial collateral ligament reconstruction. AB - BACKGROUND: Although excellent results can be achieved in up to 90% of primary elbow medial ulnar collateral ligament reconstructions, retears of the ligament have been reported. As the number of primary reconstructions continues to increase, one could expect a commensurate increase in the number of revision medial collateral ligament reconstructions performed. HYPOTHESIS: Given the difficulty associated with revision procedures, the complication rate relative to primary reconstructions would increase while the percentage of athletes returning to their previous level of play would decrease. STUDY DESIGN: Case series; Level of evidence. 4. METHODS: This was a retrospective review of 15 patients who underwent revision surgery for retear of a reconstructed elbow medial collateral ligament. All patients had undergone previous elbow medial collateral ligament reconstruction and had new history and physical examination findings consistent with medial collateral ligament injury. Twelve subjects were professional baseball players and 3 were college-level players at the time of their revision procedure. Patients were evaluated at a minimum of 2 years after revision surgery. Outcomes were classified using the Conway scale. RESULTS: Average time to revision was 36 months. The technique used in the revision was the Jobe technique in 11 cases, DANE TJ in 3, and primary repair in 1. Thirty-three percent (5/15 excellent) returned to their previous level of play for at least 1 season. Additionally, there were 4 good, 2 fair, and 4 poor results. The ligament repair had a good outcome. Forty percent (6/15) of patients had complications, 1 of whom required a subsequent surgery (lysis of adhesions). One subject experienced a retear of the medial collateral ligament. CONCLUSION: The rate of return to play after revision medial collateral ligament surgery is much lower than after primary reconstruction. As was expected, the complication rate of revision surgery is higher as well. This study should help physicians when counseling baseball players who suffer retears of their medial collateral ligament. PMID- 18443278 TI - The association of a varus hindfoot and fracture of the fifth metatarsal metaphyseal-diaphyseal junction: the Jones fracture. AB - BACKGROUND: Fractures to the fifth metatarsal metaphyseal-diaphyseal junction (Jones fracture) have high nonunion rates. Surgical intramedullary screw fixations have excellent results but a high refracture rate. This has been associated with inadequate screw size and too early return to activity. HYPOTHESIS: Varus hindfoot alignment overloads the lateral column of the foot and acts as a predisposing factor to the development of and failure of treatment of Jones fractures. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty one primary Jones fractures (20 patients) treated surgically with a 4.5-mm cannulated screw were retrospectively reviewed. Detailed clinical and radiographic data and outcomes were recorded, including measurements of hindfoot alignment. RESULTS: A 100% union rate with return to prior activity level and no refractures were found at a mean follow-up of 49 months. Clinical varus was present in 16 feet, whereas radiographic measurements revealed 18 of 21 hindfeet to be in varus. The mean calcaneal pitch angle was 28.5 degrees , and the mean Meary angle was 13 degrees convex upward. Patients with varus alignment were fitted postoperatively with lateral hindfoot and forefoot posted orthotic inserts to correct alignment. CONCLUSION: The majority of patients sustaining Jones fractures have evidence of varus hindfoot alignment. This may be a predisposing factor to developing the fracture or refracture after fixation. Postoperative varus unloading (lateral hindfoot and forefoot posting) orthotic insert appears to be helpful in preventing reinjury or refracture of Jones fractures. PMID- 18443279 TI - Bridging the gap in immobile massive rotator cuff tears: augmentation using the tenotomized biceps. AB - BACKGROUND: Numerous operative techniques have been described for the treatment of massive rotator cuff tears with severe retraction where anatomical repair is impossible. PURPOSE: To evaluate the outcome of massive rotator cuff tears repaired using the biceps interposition technique. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between April 2000 and April 2004, 31 shoulders with irreparable massive rotator cuff tears and associated degenerative lesions of the biceps tendon were included for analysis. Open procedures were performed in 15 cases (open group), while 16 patients underwent arthroscopic procedures (arthroscopic group). The mean follow-up period was 32 months (range, 24-67 months). RESULTS: The overall University of California at Los Angeles score at the last follow-up was 31.1 points (range, 21-35). The clinical outcome was excellent in 15 (48.4%) and good in 13 (41.9%) cases. Three patients (9.7%) had poor outcome. There was 1 case of reoperation in the open group for a retear. The mean preoperative Constant score, which was 44.6 points (range, 8-70) in the open group and 51.8 points (range, 24-70) in the arthroscopic group, improved to 80.7 points (range, 37-88) in the former and 83.5 points (range, 57-96) in the latter. The University of California at Los Angeles score improved from preoperative means of 11.3 points (range, 6-16) and 13.6 points (range, 6-19) to 29.5 points (range, 9-33) and 32.6 points (range, 21-35), respectively. However, the differences between the scores in both the categories were not statistically significant (P = .412 and .198, respectively). According to the postoperative repair integrity analyzed with use of magnetic resonance imaging in 14 of 16 cases with arthroscopic augmentation, 9 (64.3%) presented complete healing. CONCLUSION: The biceps tendon interposition technique for massive rotator cuff tears offers a possible improvement in the clinical outcomes and is comparable to that of conventional repair. As well, the augmentation technique using the tenotomized biceps as potential graft for rotator cuff tears is particularly useful in bridging the gap in immobile massive rotator cuff tears with posterior defects and retraction. PMID- 18443280 TI - Primary repair of ulnar collateral ligament injuries of the elbow in young athletes: a case series of injuries to the proximal and distal ends of the ligament. AB - BACKGROUND: Little data exist regarding the treatment of young high school and college athletes with medial ulnar collateral ligament insufficiency of the elbow. It would be logical to assume that younger patients would have less damage to the ligament, allowing the possibility of repair. HYPOTHESIS: Many young athletes with injuries to the medial ulnar collateral ligament have proximal or distal injuries that may be amenable to repair, indicating that graft reconstruction may not always be necessary to obtain satisfactory results. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Sixty patients who had direct repair of the medial ulnar collateral ligament were retrospectively evaluated using the Andrews and Carson elbow score. All patients had symptomatic instability that precluded them from participation in their desired sports, all failed a nonoperative treatment program, and all had comparative stress radiographs, magnetic resonance images, or computerized tomograms with contrast studies that had positive findings for insufficiency of the ligament. RESULTS: The mean age of the 47 male and 13 female patients was 17.2 years. The mean follow-up was 59.2 months. All patients underwent medial ulnar collateral ligament repair by one of the following procedures: suture plication with repair to bone drill holes (n = 9) or suture repair to bone using anchors (n = 51). The mean overall preoperative Andrews-Carson outcome score of 132 improved to 188 postoperatively (P < .0001). Good-to-excellent overall results were obtained in 93% of patients. Fifty-eight of the 60 patients were able to return to sports within 6 months of the surgery at the same or higher level as before the injury. There were 4 failures, 2 early and 2 late (after return to play for 5 and 6 years of unrestricted play, respectively). Three patients sustained a complication of transient postoperative ulnar neuropathy symptoms that resolved spontaneously. CONCLUSION: Primary repair of proximal and distal injuries of the medial ulnar collateral ligament is a viable alternative in the non-professional athlete. Graft reconstructions may not be necessary to obtain favorable outcomes and rapid return to sports in non-professional athletes who require surgical intervention for medial elbow instability. PMID- 18443281 TI - Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance. AB - In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE(-/-)) and compared with wild-type littermates. Compared with wild type littermates, ACE(-/-) mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE(-/-) mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE( /-) mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE(-/-) mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance. PMID- 18443282 TI - Modular patterning of structure and function of the striatum by retinoid receptor signaling. AB - Retinoid signaling plays a crucial role in patterning rhombomeres in the hindbrain and motor neurons in the spinal cord during development. A fundamentally interesting question is whether retinoids can pattern functional organization in the forebrain that generates a high order of cognitive behavior. The striatum contains a compartmental structure of striosome (or "patch") and intervening matrix. How this highly complex mosaic design is patterned by the genetic programs during development remains elusive. We report a developmental mechanism by which retinoid receptor signaling controls compartmental formation in the striatum. We analyzed RARbeta(-/-) mutant mice and found a selective loss of striosomal compartmentalization in the rostral mutant striatum. The loss of RARbeta signaling in the mutant mice resulted in reduction of cyclin E2, a cell cycle protein regulating transition from G(1) to S phase, and also reduction of the proneural gene Mash1, which led to defective neurogenesis of late-born striosomal cells. Importantly, during striatal neurogenesis, endogenous levels of retinoic acid were spatiotemporally regulated such that transduction of high levels of retinoic acid through RARbeta selectively expanded the population of late-born striosomal progenitors, which evolved into a highly elaborate compartment in the rostral striatum. RARbeta(-/-) mutant mice, which lacked such enlarged compartment, displayed complex alternations of dopamine agonist-induced stereotypic motor behavior, including exaggeration of head bobbing movement and reduction of rearing activity. RARbeta signaling thus plays a crucial role in setting up striatal compartments that may engage in neural circuits of psychomotor control. PMID- 18443283 TI - Improving fluid intelligence with training on working memory. AB - Fluid intelligence (Gf) refers to the ability to reason and to solve new problems independently of previously acquired knowledge. Gf is critical for a wide variety of cognitive tasks, and it is considered one of the most important factors in learning. Moreover, Gf is closely related to professional and educational success, especially in complex and demanding environments. Although performance on tests of Gf can be improved through direct practice on the tests themselves, there is no evidence that training on any other regimen yields increased Gf in adults. Furthermore, there is a long history of research into cognitive training showing that, although performance on trained tasks can increase dramatically, transfer of this learning to other tasks remains poor. Here, we present evidence for transfer from training on a demanding working memory task to measures of Gf. This transfer results even though the trained task is entirely different from the intelligence test itself. Furthermore, we demonstrate that the extent of gain in intelligence critically depends on the amount of training: the more training, the more improvement in Gf. That is, the training effect is dosage-dependent. Thus, in contrast to many previous studies, we conclude that it is possible to improve Gf without practicing the testing tasks themselves, opening a wide range of applications. PMID- 18443284 TI - Nuclear translocation of Gln3 in response to nutrient signals requires Golgi-to endosome trafficking in Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae has developed specialized mechanisms that enable growth on suboptimal nitrogen sources. Exposure of yeast cells to poor nitrogen sources or treatment with the Tor kinase inhibitor rapamycin elicits activation of Gln3 and transcription of nitrogen catabolite-repressed (NCR) genes whose products function in scavenging and metabolizing nitrogen. Here, we show that mutations in class C and D Vps components, which mediate Golgi-to-endosome vesicle transport, impair nuclear translocation of Gln3, NCR gene activation, and growth in poor nitrogen sources. In nutrient-replete conditions, a significant fraction of Gln3 is peripherally associated with light membranes and partially colocalizes with Vps10-containing foci. These results reveal a role for Golgi-to endosome vesicular trafficking in TORC1-controlled nuclear translocation of Gln3 and support a model in which Tor-mediated signaling in response to nutrient cues occurs in these compartments. These findings have important implications for nutrient sensing and growth control via mTor pathways in metazoans. PMID- 18443285 TI - Mutations in topoisomerase I as a self-resistance mechanism coevolved with the production of the anticancer alkaloid camptothecin in plants. AB - Plants produce a variety of toxic compounds, which are often used as anticancer drugs. The self-resistance mechanism to these toxic metabolites in the producing plants, however, remains unclear. The plant-derived anticancer alkaloid camptothecin (CPT) induces cell death by targeting DNA topoisomerase I (Top1), the enzyme that catalyzes changes in DNA topology. We found that CPT-producing plants, including Camptotheca acuminata, Ophiorrhiza pumila, and Ophiorrhiza liukiuensis, have Top1s with point mutations that confer resistance to CPT, suggesting the effect of an endogenous toxic metabolite on the evolution of the target cellular component. Three amino acid substitutions that contribute to CPT resistance were identified: Asn421Lys, Leu530Ile, and Asn722Ser (numbered according to human Top1). The substitution at position 722 is identical to that found in CPT-resistant human cancer cells. The other mutations have not been found to date in CPT-resistant human cancer cells; this predicts the possibility of occurrence of these mutations in CPT-resistant human cancer patients in the future. Furthermore, comparative analysis of Top1s of CPT-producing and nonproducing plants suggested that the former were partially primed for CPT resistance before CPT biosynthesis evolved. Our results demonstrate the molecular mechanism of self-resistance to endogenously produced toxic compounds and the possibility of adaptive coevolution between the CPT production system and its target Top1 in the producing plants. PMID- 18443286 TI - Molecular mechanism of pH sensing in KcsA potassium channels. AB - The bacterial potassium channel KcsA is gated by high concentrations of intracellular protons, allowing the channel to open at pH < 5.5. Despite prior attempts to determine the mechanism responsible for pH gating, the proton sensor has remained elusive. We have constructed a KcsA channel mutant that remains open up to pH 9.0 by replacing key ionizable residues from the N and C termini of KcsA with residues mimicking their protonated counterparts with respect to charge. A series of individual and combined mutations were investigated by using single channel recordings in lipid bilayers. We propose that these residues are the proton-binding sites and at neutral pH they form a complex network of inter- and intrasubunit salt bridges and hydrogen bonds near the bundle crossing that greatly stabilize the closed state. In our model, these residues change their ionization state at acidic pH, thereby disrupting this network, modifying the electrostatic landscape near the channel gate, and favoring channel opening. PMID- 18443287 TI - Ghrelin octanoylation mediated by an orphan lipid transferase. AB - The peptide hormone ghrelin is the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue. This modification is crucial for ghrelin's physiological effects including regulation of feeding, adiposity, and insulin secretion. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification has remained unknown. Here we report the identification and characterization of human GOAT, the ghrelin O-acyl transferase. GOAT is a conserved orphan membrane-bound O-acyl transferase (MBOAT) that specifically octanoylates serine-3 of the ghrelin peptide. Transcripts for both GOAT and ghrelin occur predominantly in stomach and pancreas. GOAT is conserved across vertebrates, and genetic disruption of the GOAT gene in mice leads to complete absence of acylated ghrelin in circulation. The occurrence of ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of ghrelin and further implicates acylated ghrelin in pancreatic function. PMID- 18443288 TI - Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. AB - Mitochondria form dynamic tubular networks that undergo frequent morphological changes through fission and fusion, the imbalance of which can affect cell survival in general and impact synaptic transmission and plasticity in neurons in particular. Some core components of the mitochondrial fission/fusion machinery, including the dynamin-like GTPases Drp1, Mitofusin, Opa1, and the Drp1 interacting protein Fis1, have been identified. How the fission and fusion processes are regulated under normal conditions and the extent to which defects in mitochondrial fission/fusion are involved in various disease conditions are poorly understood. Mitochondrial malfunction tends to cause diseases with brain and skeletal muscle manifestations and has been implicated in neurodegenerative diseases such as Parkinson's disease (PD). Whether abnormal mitochondrial fission or fusion plays a role in PD pathogenesis has not been shown. Here, we show that Pink1, a mitochondria-targeted Ser/Thr kinase linked to familial PD, genetically interacts with the mitochondrial fission/fusion machinery and modulates mitochondrial dynamics. Genetic manipulations that promote mitochondrial fission suppress Drosophila Pink1 mutant phenotypes in indirect flight muscle and dopamine neurons, whereas decreased fission has opposite effects. In Drosophila and mammalian cells, overexpression of Pink1 promotes mitochondrial fission, whereas inhibition of Pink1 leads to excessive fusion. Our genetic interaction results suggest that Fis1 may act in-between Pink1 and Drp1 in controlling mitochondrial fission. These results reveal a cell biological role for Pink1 and establish mitochondrial fission/fusion as a paradigm for PD research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in PD intervention. PMID- 18443289 TI - Sunflower (Helianthus annuus L.) as a pre-Columbian domesticate in Mexico. AB - Mexico has long been recognized as one of the world's cradles of domestication with evidence for squash (Cucurbita pepo) cultivation appearing as early as 8,000 cal B.C. followed by many other plants, such as maize (Zea mays), peppers (Capsicum annuum), common beans (Phaseolus vulgaris), and cotton (Gossypium hirsutum). We present archaeological, linguistic, ethnographic, and ethnohistoric data demonstrating that sunflower (Helianthus annuus) had entered the repertoire of Mexican domesticates by ca. 2600 cal B.C., that its cultivation was widespread in Mexico and extended as far south as El Salvador by the first millennium B.C., that it was well known to the Aztecs, and that it is still in use by traditional Mesoamerican cultures today. The sunflower's association with indigenous solar religion and warfare in Mexico may have led to its suppression after the Spanish Conquest. The discovery of ancient sunflower in Mexico refines our knowledge of domesticated Mesoamerican plants and adds complexity to our understanding of cultural evolution. PMID- 18443290 TI - Outer membrane protein G: Engineering a quiet pore for biosensing. AB - Bacterial outer membrane porins have a robust beta-barrel structure and therefore show potential for use as stochastic sensors based on single-molecule detection. The monomeric porin OmpG is especially attractive compared with multisubunit proteins because appropriate modifications of the pore can be easily achieved by mutagenesis. However, the gating of OmpG causes transient current blockades in single-channel recordings that would interfere with analyte detection. To eliminate this spontaneous gating activity, we used molecular dynamics simulations to identify regions of OmpG implicated in the gating. Based on our findings, two approaches were used to enhance the stability of the open conformation by site-directed mutagenesis. First, the mobility of loop 6 was reduced by introducing a disulfide bond between the extracellular ends of strands beta12 and beta13. Second, the interstrand hydrogen bonding between strands beta11 and beta12 was optimized by deletion of residue D215. The OmpG porin with both stabilizing mutations exhibited a 95% reduction in gating activity. We used this mutant for the detection of adenosine diphosphate at the single-molecule level, after equipping the porin with a cyclodextrin molecular adapter, thereby demonstrating its potential for use in stochastic sensing applications. PMID- 18443291 TI - Structural and mechanistic insight into the basis of mucopolysaccharidosis IIIB. AB - Mucopolysaccharidosis III (MPS III) has four forms (A-D) that result from buildup of an improperly degraded glycosaminoglycan in lysosomes. MPS IIIB is attributable to the decreased activity of a lysosomal alpha-N acetylglucosaminidase (NAGLU). Here, we describe the structure, catalytic mechanism, and inhibition of CpGH89 from Clostridium perfringens, a close bacterial homolog of NAGLU. The structure enables the generation of a homology model of NAGLU, an enzyme that has resisted structural studies despite having been studied for >20 years. This model reveals which mutations giving rise to MPS IIIB map to the active site and which map to regions distant from the active site. The identification of potent inhibitors of CpGH89 and the structures of these inhibitors in complex with the enzyme suggest small-molecule candidates for use as chemical chaperones. These studies therefore illuminate the genetic basis of MPS IIIB, provide a clear biochemical rationale for the necessary sequential action of heparan-degrading enzymes, and open the door to the design and optimization of chemical chaperones for treating MPS IIIB. PMID- 18443292 TI - The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. AB - Women with germ-line mutations of the BRCA1 tumor suppressor gene are highly susceptible to breast and ovarian cancer. The protein product of BRCA1 is involved in a broad spectrum of biological processes and interacts with many diverse proteins. One of these, BARD1, associates with BRCA1 to form a heterodimeric complex that is enzymatically active as an ubiquitin E3 ligase. Although the BRCA1/BARD1 heterodimer has been implicated in several aspects of BRCA1 function, its role in tumor suppression has not been evaluated. To address this question, we generated mouse strains carrying conditional alleles of either Bard1 or Brca1 and used Cre recombination to inactivate these genes in mammary epithelial cells. Significantly, the conditional Bard1- and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional Bard1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features. Reminiscent of the basal-like breast carcinomas seen in human BRCA1 mutation carriers, these tumors are "triple negative" for estrogen and progesterone receptor expression and HER2/neu amplification. They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability. The remarkable similarities between the mammary carcinomas of Bard1 , Brca1-, and Bard1/Brca1-mutant mice indicate that the tumor suppressor activities of both genes are mediated through the BRCA1/BARD1 heterodimer. PMID- 18443293 TI - Tightly coupled brain activity and cerebral ATP metabolic rate. AB - A majority of ATP in the brain is formed in the mitochondria through oxidative phosphorylation of ADP with the F(1)F(0)-ATP (ATPase) enzyme. This ATP production rate plays central roles in brain bioenergetics, function and neurodegeneration. In vivo (31)P magnetic resonance spectroscopy combined with magnetization transfer (MT) is the sole approach able to noninvasively determine this ATP metabolic rate via measuring the forward ATPase reaction flux (F(f,ATPase)). However, previous studies indicate lack of quantitative agreement between F(f,ATPase) and oxidative metabolic rate in heart and liver. In contrast, recent work has shown that F(f,ATPase) might reflect oxidative phosphorylation rate in resting human brains. We have conducted an animal study, using rats under varied brain activity levels from light anesthesia to isoelectric state, to examine whether the in vivo (31)P MT approach is suitable for measuring the oxidative phosphorylation rate and its change associated with varied brain activity. Our results conclude that the measured F(f,ATPase) reflects the oxidative phosphorylation rate in resting rat brains, that this flux is tightly correlated to the change of energy demand under varied brain activity levels, and that a significant amount of ATP energy is required for "housekeeping" under the isoelectric state. These findings reveal distinguishable characteristics of ATP metabolism between the brain and heart, and they highlight the importance of in vivo (31)P MT approach to potentially provide a unique and powerful neuroimaging modality for noninvasively studying the cerebral ATP metabolic network and its central role in bioenergetics associated with brain function, activation, and diseases. PMID- 18443295 TI - Mathematical modeling identifies Smad nucleocytoplasmic shuttling as a dynamic signal-interpreting system. AB - TGF-beta-induced Smad signal transduction from the membrane into the nucleus is not linear and unidirectional, but rather a dynamic network that couples Smad phosphorylation and dephosphorylation through continuous nucleocytoplasmic shuttling of Smads. To understand the quantitative behavior of this network, we have developed a tightly constrained computational model, exploiting the interplay between mathematical modeling and experimental strategies. The model simultaneously reproduces four distinct datasets with excellent accuracy and provides mechanistic insights into how the network operates. We use the model to make predictions about the outcome of fluorescence recovery after photobleaching experiments and the behavior of a functionally impaired Smad2 mutant, which we then verify experimentally. Successful model performance strongly supports the hypothesis of a dynamic maintenance of Smad nuclear accumulation during active signaling. The presented work establishes Smad nucleocytoplasmic shuttling as a dynamic network that flexibly transmits quantitative features of the extracellular TGF-beta signal, such as its duration and intensity, into the nucleus. PMID- 18443294 TI - Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. AB - The mechanisms by which bone marrow (BM)-derived stem cells might contribute to angiogenesis and the origin of neovascular endothelial cells (ECs) are controversial. Neovascular ECs have been proposed to originate from VEGF receptor 2-expressing (VEGFR-2+) stem cells mobilized from the BM by VEGF or tumors, and it is thought that angiogenesis and tumor growth may depend on such endothelial precursors or progenitors. We studied the mobilization of BM cells to circulation by inoculating mice with VEGF polypeptides, adenoviral vectors expressing VEGF, or tumors. We induced angiogenesis by syngeneic melanomas, APCmin adenomas, adenoviral VEGF delivery, or matrigel plugs in four different genetically tagged universal or endothelial cell-specific chimeric mouse models, and subsequently analyzed the contribution of BM-derived cells to endothelium in a wide range of time points. To study the existence of circulating ECs in a nonmyeloablative setting, pairs of genetically marked parabiotic mice with a shared anastomosed circulatory system were created. We did not observe specific mobilization of VEGFR-2+ cells to circulation by VEGF or tumors. During angiogenesis, abundant BM derived perivascular cells were recruited close to blood vessel wall ECs but did not form part of the endothelium. No circulation-derived vascular ECs were observed in the parabiosis experiments. Our results show that no BM-derived VEGFR 2+ or other EC precursors contribute to vascular endothelium and that cancer growth does not require BM-derived endothelial progenitors. Endothelial differentiation is not a typical in vivo function of normal BM-derived stem cells in adults, and it has to be an extremely rare event if it occurs at all. PMID- 18443296 TI - Selective targeting of ITK blocks multiple steps of HIV replication. AB - Treatment for HIV has relied on the use of antiretroviral agents that can be subject to the development of resistant viruses. The study of inhibitors directed against cellular proteins required for HIV replication is therefore of growing interest. Inducible T cell kinase (ITK) is a Tec family tyrosine kinase that regulates T cell receptor (TCR)-induced activation of PLCgamma-1, Ca(2+) mobilization and transcription factor activation, and actin rearrangement downstream of both TCR and chemokine receptors. Because productive infection of T cells with HIV requires T cell activation, chemokine receptors and actin reorganization, we asked whether ITK affects HIV infection using ITK-specific siRNA, a kinase-inactive ITK mutant or an ITK inhibitor. We demonstrate that loss of ITK function resulted in marked reductions in intracellular p24 levels upon HIV infection. Loss of ITK function after establishment of HIV infection also decreased virus spread within the culture. Inhibition of ITK did not affect expression of the HIV coreceptors CD4 or CXCR4 but partially blocked HIV viral entry, an effect that correlated with decreased actin polarization to gp120. Additionally, ITK was required for efficient HIV transcription, and overexpression of ITK increased both viral transcription and virus-like particle formation. Our data suggest that inhibition of ITK blocks HIV infection by affecting multiple steps of HIV replication. PMID- 18443297 TI - Anemia and splenomegaly in cGKI-deficient mice. AB - To explore the functional significance of cGMP-dependent protein kinase type I (cGKI) in the regulation of erythrocyte survival, gene-targeted mice lacking cGKI were compared with their control littermates. By the age of 10 weeks, cGKI deficient mice exhibited pronounced anemia and splenomegaly. Compared with control mice, the cGKI mutants had significantly lower red blood cell count, packed cell volume, and hemoglobin concentration. Anemia was associated with a higher reticulocyte number and an increase of plasma erythropoietin concentration. The spleens of cGKI mutant mice were massively enlarged and contained a higher fraction of Ter119(+) erythroid cells, whereas the relative proportion of leukocyte subpopulations was not changed. The Ter119(+) cGKI deficient splenocytes showed a marked increase in annexin V binding, pointing to phosphatidylserine (PS) exposure at the outer membrane leaflet, a hallmark of suicidal erythrocyte death or eryptosis. Compared with control erythrocytes, cGKI deficient erythrocytes exhibited in vitro a higher cytosolic Ca(2+) concentration, a known trigger of eryptosis, and showed increased PS exposure, which was paralleled by a faster clearance in vivo. Together, these results identify a role of cGKI as mediator of erythrocyte survival and extend the emerging concept that cGMP/cGKI signaling has an antiapoptotic/prosurvival function in a number of cell types in vivo. PMID- 18443298 TI - Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet-Biedl syndrome. AB - Facial recognition is central to the diagnosis of many syndromes, and craniofacial patterns may reflect common etiologies. In the pleiotropic Bardet Biedl syndrome (BBS), a primary ciliopathy with intraflagellar transport dysfunction, patients have a characteristic facial "gestalt" that dysmorphologists have found difficult to characterize. Here, we use dense surface modeling (DSM) to reveal that BBS patients and mouse mutants have mid-facial defects involving homologous neural crest-derived structures shared by zebrafish morphants. These defects of the craniofacial (CF) skeleton arise from aberrant cranial neural crest cell (NCC) migration. These effects are not confined to the craniofacial region, but vagal-derived NCCs fail to populate the enteric nervous system, culminating in disordered gut motility. Furthermore, morphants display hallmarks of disrupted Sonic Hedgehog (Shh) signaling from which NCCs take positional cues. We propose a model whereby Bbs proteins modulate NCC migration, contributing to craniofacial morphogenesis and development of the enteric nervous system. These migration defects also explain the association of Hirschsprung's disease (HD) with BBS. Moreover, this is a previously undescribed method of using characterization of facial dysmorphology as a basis for investigating the pathomechanism of CF development in dysmorphic syndromes. PMID- 18443299 TI - Gastric O-acyl transferase activates hunger signal to the brain. PMID- 18443300 TI - Engineering channels: atomic biology. PMID- 18443301 TI - Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase. AB - Flavin-containing monooxygenases (FMOs) are, after cytochromes P450, the most important monooxygenase system in humans and are involved in xenobiotics metabolism and variability in drug response. The x-ray structure of a soluble prokaryotic FMO from Methylophaga sp. strain SK1 has been solved at 2.6-A resolution and is now the protein of known structure with the highest sequence similarity to human FMOs. The structure possesses a two-domain architecture, with both FAD and NADP(+) well defined by the electron density maps. Biochemical analysis shows that the prokaryotic enzyme shares many functional properties with mammalian FMOs, including substrate specificity and the ability to stabilize the hydroperoxyflavin intermediate that is crucial in substrate oxygenation. On the basis of their location in the structure, the nicotinamide ring and the adjacent ribose of NADP(+) turn out to be an integral part of the catalytic site being actively engaged in the stabilization of the oxygenating intermediate. This feature suggests that NADP(H) has a moonlighting role, in that it adopts two binding modes that allow it to function in both flavin reduction and oxygen reactivity modulation, respectively. We hypothesize that a relative domain rotation is needed to bring NADP(H) to these distinct positions inside the active site. Localization of mutations in human FMO3 that are known to cause trimethylaminuria (fish-odor syndrome) in the elucidated FMO structure provides a structural explanation for their biological effects. PMID- 18443302 TI - Giant saltation on Mars. AB - Saltation, the motion of sand grains in a sequence of ballistic trajectories close to the ground, is a major factor for surface erosion, dune formation, and triggering of dust storms on Mars. Although this mode of sand transport has been matter of research for decades through both simulations and wind tunnel experiments under Earth and Mars conditions, it has not been possible to provide accurate measurements of particle trajectories in fully developed turbulent flow. Here we calculate the motion of saltating grains by directly solving the turbulent wind field and its interaction with the particles. Our calculations show that the minimal wind velocity required to sustain saltation on Mars may be surprisingly lower than the aerodynamic minimal threshold measurable in wind tunnels. Indeed, Mars grains saltate in 100 times higher and longer trajectories and reach 5-10 times higher velocities than Earth grains do. On the basis of our results, we arrive at general expressions that can be applied to calculate the length and height of saltation trajectories and the flux of grains in saltation under various physical conditions, when the wind velocity is close to the minimal threshold for saltation. PMID- 18443303 TI - Emerging subspecialties in neurology: neurocritical care. PMID- 18443304 TI - Video NeuroImage: Generalized tetanus in a 70-year-old woman. PMID- 18443305 TI - Bone health. PMID- 18443307 TI - Tackling neuropathic pain: different perspectives of clinicians and investigators. PMID- 18443308 TI - Propofol for stiff-person syndrome: learning new tricks from an old dog. PMID- 18443310 TI - Neuroimaging correlates of subjective memory deficits in a community population. AB - BACKGROUND: Subjective memory deficit (SMD) is one of few potential presenting symptoms for people with early cognitive impairment. However, associations with underlying brain changes are unclear. METHODS: In a community sample of 1,779 people without dementia, and with neuroimaging (MRI) data, associations were investigated for SMD with white matter lesion volume and with the following volumetric measures: gray and white matter, CSF, hippocampal, parahippocampal, and amygdalar. Covariates included depressive symptoms (Center for Epidemiologic Studies Depression Scale), a battery of cognitive tests, physical health, and social activity. RESULTS: SMD was present in 26.4% of the sample. Of the neuroimaging measures analyzed, SMD was most strongly associated with temporal WML (OR for highest quintile compared to the remainder 1.44, 95% CI 1.12-1.85), and lower hippocampal volume (OR per decreasing quintile 1.22, 1.11-1.35). These associations were independent of all other covariates, including cognitive function. CONCLUSIONS: Subjective memory deficit (SMD) was associated with neuroimaging characteristics in the temporal and hippocampal regions, suggesting that SMD may, at least in some cases, represent a realistic appraisal of underlying brain function independent of measured cognition. However, further research is required for volumetric measures and SMD to establish whether the association reflects lifelong structure or neurodegenerative changes. PMID- 18443309 TI - Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. AB - OBJECTIVE: Antiepileptic drugs (AEDs) may have adverse effects on bone mineral density (BMD) and metabolism. We previously reported biochemical evidence of increased bone turnover in premenopausal women with epilepsy on phenytoin monotherapy compared with those on carbamazepine, lamotrigine, and valproate. We therefore hypothesized that rates of bone loss would be higher in young women treated with phenytoin. METHODS: Ninety-three premenopausal women with epilepsy receiving a single AED (carbamazepine, lamotrigine, phenytoin, or valproate) participated. Subjects completed nutritional and physical activity questionnaires. Biochemical indices of bone and mineral metabolism and BMD of the proximal femur and lumbar spine were measured at baseline and 1 year. RESULTS: Participants reported high calcium intake (>1,000 mg/day) and were physically active. Significant loss (2.6%) was seen at the femoral neck in the phenytoin group. BMD remained stable in the other AED groups. Bone turnover markers and calciotropic hormones were unchanged after 1 year in all groups except for a significant decline in urine N-telopeptide in the phenytoin group. In women receiving phenytoin, lower serum 25-hydroxyvitamin D concentrations were associated with higher parathyroid hormone, bone alkaline phosphatase, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling. CONCLUSION: In this study, young women treated with phenytoin had significant femoral neck bone loss over 1 year. In contrast, those treated with carbamazepine, lamotrigine, and valproate did not have detectable adverse effects on bone turnover or bone mineral density. These results raise concerns about the long-term effects of phenytoin monotherapy on bone in young women with epilepsy. PMID- 18443311 TI - Guillain-Barre syndrome: incidence and mortality rates in US hospitals. AB - OBJECTIVE: To determine the incidence, in-hospital mortality, and predictors of death in Guillain-Barre syndrome (GBS) in a large US cohort. METHODS: Our cohort was identified from the Nationwide Inpatient Sample database, 2000 through 2004. We excluded patients younger than 18 years and those who presented with rapidly paralyzing conditions due to other causes. GBS patients who were transferred between hospitals were counted once. The incidence rate adjusted for 20% of the US census reported by the Census Bureau. A logistic regression model was used to identify predictors of death. RESULTS: After data cleansing, 4,954 patients were identified with a primary diagnosis of GBS. The adjusted incidence rate varied between 1.65 and 1.79 per 100,000 during the years included in this study. The in hospital mortality rate was 2.58% (128/4,954) and did not change significantly over the study period. Eleven percent had variable pulmonary complications, and 9.1% received endotracheal intubation, which was a predictor of mortality (adjusted odds ratio 5.09, 95% CI 3.21-8.05). Other predictors of mortality included older age, composite comorbidity index, cardiac complications, and sepsis. CONCLUSION: The mortality rate in Guillain-Barre syndrome is low, and predictors of death are similar to those predicting poor disability outcome. The disease incidence was stable over the 5 years included in this study. PMID- 18443312 TI - T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. AB - BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) defines a group of genetic disorders characterized by brain iron deposition and associated with neuronal death. The known causes of NBIA include pantothenate kinase-associated neurodegeneration (PKAN), neuroferritinopathy, infantile neuroaxonal dystrophy (INAD), and aceruloplasminemia. OBJECTIVE: To define the radiologic features of each NBIA subtype. METHODS: Brain MRIs from patients with molecularly confirmed PKAN (26 cases), neuroferritinopathy (21 cases), INAD (four cases), and aceruloplasminemia (10 cases) were analyzed blindly to delineate patterns of iron deposition and neurodegeneration. RESULTS: In most cases of PKAN, abnormalities were restricted to globus pallidus and substantia nigra, with 100% having an eye of the tiger sign. In a minority of PKAN cases there was hypointensity of the dentate nuclei (1/5 on T2* sequences, 2/26 on fast spin echo [FSE]). In INAD, globus pallidus and substantia nigra were involved on T2* and FSE scans, with dentate involvement only seen on T2*. By contrast, neuroferritinopathy had consistent involvement of the dentate nuclei, globus pallidus, and putamen, with confluent areas of hyperintensity due to probable cavitation, involving the pallida and putamen in 52%, and a subset having lesions in caudate nuclei and thalami. More uniform involvement of all basal ganglia and the thalami was typical in aceruloplasminemia, but without cavitation. CONCLUSIONS: In the majority of cases, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2* and T2 fast spin echo brain MRI, leading to accurate clinical and subsequent molecular diagnosis. PMID- 18443313 TI - Low-dose hydrocortisone in the evening modulates symptom severity in restless legs syndrome. AB - BACKGROUND: Circadian symptom manifestation in the evening and night is one of the main characteristics of restless legs syndrome (RLS). Although the inverse temporal course of corticosteroid rhythm and RLS symptom severity is obvious, this relationship has yet to be studied. We investigated the effect of late evening application of exogenous cortisol (hydrocortisone) on sensory leg discomfort (SLD), one of the main complaints of patients with RLS. METHODS: Ten untreated patients with idiopathic RLS participated in the study. Change of SLD was rated on a visual analogue scale during the 60 minutes resting period of the so-called Suggested Immobilization Test. Patients received either hydrocortisone 40 mg or placebo (saline) IV in random order in a double-blind crossover design, with 1 week between the experiments. RESULTS: Severity of SLD was lower during hydrocortisone infusion than during placebo (p = 0.032). Though blind to the experimental condition, 5 of the 10 patients experienced improvement in symptoms during hydrocortisone administration, but no patient felt an amelioration during the placebo condition. CONCLUSIONS: Our data indicate a probable physiologic relationship between evening and early night hour restless legs syndrome symptom increase and low cortisol level. PMID- 18443314 TI - Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). AB - BACKGROUND: Neurodegeneration associated with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders in which disruption of cellular mechanisms leads to accumulation of iron in the basal ganglia. This group includes patients with recently discovered mutations in the PLA2G6 gene encoding a calcium-independent phospholipase A2 enzyme that catalyzes the hydrolysis of glycerophospholipids. Previously, children with PLA2G6 mutations have been diagnosed with several different disorders and we wished to better define the phenotype of PLA2G6- associated neurodegeneration. METHODS: Detailed review of the clinical and genetic features of 14 and radiologic features of 13 of these patients with PLA2G6 mutations was undertaken. RESULTS: Median age of symptom presentation was 14 months. One third of the cohort presented following an intercurrent illness. The children had progressive cognitive and motor skill regression, with evidence of axial hypotonia, four limb spasticity, bulbar dysfunction, and strabismus. All patients developed cerebellar ataxia and dystonia. Most patients had optic atrophy. Brain imaging demonstrated cerebellar cortical atrophy and gliosis in all patients. Changes consistent with increased iron deposition were identified in the globus pallidus and substantia nigra. Novel corpus callosum changes are also reported. CONCLUSION: We describe a cohort of patients with PLA2G6-associated neurodegeneration (PLAN). Although patients with PLAN have previously been diagnosed with infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome, they display a characteristic clinical and radiologic phenotype. PLA2G6 mutational analysis will negate the need for more invasive diagnostic procedures such as tissue biopsy. PMID- 18443315 TI - Invited article: Neurology and quality improvement: an introduction. PMID- 18443316 TI - Cardiac manifestations in a child with a novel mutation in creatine transporter gene SLC6A8. PMID- 18443317 TI - A test of the mechanisms of sensory extinction to simultaneous stimulation. PMID- 18443319 TI - New spasticity from cervical spine pathology in a patient with athetoid cerebral palsy. PMID- 18443320 TI - Re: CNS lupus: a study of 41 patients. PMID- 18443321 TI - Imaging beta-amyloid burden in aging and dementia. PMID- 18443322 TI - Preface: novel features of the physiology and pathology of human reproduction. PMID- 18443323 TI - The ovary: anatomy and function throughout human life. AB - A prerequisite to the understanding of the ovarian diseases and infertility is a thorough understanding of normal embryology and physiology of the ovary. Therefore, the objective of this review article is to provide brief and updated information on the molecular basis of the events that control gonadal development, germ cell formation, folliculogenesis, and ovulation. PMID- 18443324 TI - Pharmacogenetics in ovarian stimulation--current concepts. AB - Ovarian response to follicle-stimulating hormone (FSH) action differs considerably among women; this has prompted researchers to determine which factors modify this response. The challenge is to identify the genes that affect the response to FSH stimulation by the application of pharmacogenetics to assisted reproduction techniques (ARTs). Recently, new insights have been gained in the investigation of the variability in the gene that encodes the FSH receptor (FSHR) gene or genes of the estrogen pathway. Several polymorphisms of the FSHR gene have been discovered, but Ser680Asn and Thr307Ala are the two most studied. The Ser680Asn polymorphism of the FSHR gene has been found to influence the ovarian response to FSH stimulation in women undergoing in vitro fertilization (IVF), and in women with the genotype Ser/Ser, the FSHR appears to be more resistant to FSH action. The clinical implications of this finding are highly important; the ultimate goal is to apply genetic markers as routine diagnostic tests before ovarian stimulation to predict ovarian response, determine the required FSH dose, and avoid the possible complications related to FSH stimulation. PMID- 18443325 TI - Stem cells: a perspective on oocytes. AB - Stem cells, with their unlimited self-renewal feature and their ability to differentiate into almost every mature cell type in the body, have enormous potential for research and therapeutic application. In this article, we review the formation of primordial germ cells, the precursors of adult gametocytes, from their specification to their migration to prospective gonads. We discuss recent studies that obtained germ cells from stem cells in vitro. We place special emphasis on studies that challenge the current dogma in reproductive biology that female mammals are born with a set number of nonrenewable germ cells in the ovary by showing germ cell renewal in the adult ovary. PMID- 18443326 TI - Ovarian reserve. AB - As a result of temporary social trends, many women elect to postpone their first pregnancy to a later stage in life. A large part of this population will be infertile by the time they opt to conceive, mainly because of a decreasing ovarian reserve and low oocyte quality resulting from age. Aging oocytes have been widely suggested to be the major cause for the decline in fertility. In a subfertile population, the availability of an accurate screening test of ovarian reserve would provide a valuable means of predicting the chances of pregnancy and live birth with or without treatment and selecting an optimal dose of ovarian stimulation where treatment using ovarian stimulation is planned. The following hormonal markers and ultrasound parameters have been used to attempt to estimate ovarian reserve and predict those with a poor chance of success in assisted reproductive techniques: age; concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, inhibin, anti-Mullerian hormone; ovarian volume, ovarian antral follicle count; and ovarian biopsy. Further studies have introduced the use of dynamic tests-using gonadotropin-releasing hormone agonist, FSH, or clomiphene citrate-to assess ovarian function. The use of a wide range of tests suggests that no single test provides a sufficiently accurate result. But the simultaneous evaluation of a combination of tests could be used as a marker of diminished ovarian reserve and a sensitive predictor of response to ovarian stimulation in patients undergoing in vitro fertilization treatment. PMID- 18443327 TI - Pretreatments before the induction of ovulation in assisted reproduction technologies: evidence-based medicine in 2007. AB - Many pretreatment modalities used prior to ovulation induction have been proposed to increase the success rate in women undergoing assisted reproductive technologies. However, no clear evidence from well-designed clinical trials has shown a benefit of these treatments. We conducted a systematic review to explore the effect of different pretreatment therapies on outcomes of in vitro fertilization (IVF) cycles. Studies were limited to women treated prior to undergoing controlled ovarian hyperstimulation in IVF cycles with low-dose aspirin, metformin, growth hormone, oral contraceptives, or corticosteroid supplementation versus placebo or no supplementation. Searches were conducted in the Cochrane Library, MEDLINE, EMBASE, and ISI Proceedings, and all randomized controlled trials that evaluated the effectiveness of those therapies compared with placebo or no treatment in women before IVF were included. The main outcome measures considered were clinical pregnancy and live birth rates, miscarriage rate, number of oocytes retrieved, cycle cancellations, and the incidence of ovarian hyperstimulation syndrome. We conclude that, currently, no clear evidence indicates that using any of these pretreatment modalities is superior to no treatment in IVF cycles. Even when the studies are pooled, small sample size and low power preclude a complete assessment of adjuvant treatment modalities before ovulation stimulation in IVF cycles. PMID- 18443328 TI - An update of assisted reproductive technologies results in the United States. AB - The etiology of compromised spermatogenesis is often genetic. Because male subfertility has been associated with a higher incidence of genomic defects, ranging from aneuploidy to Yq microdeletions, concerns have been raised as to the risk of transmitting genetic defects to the offspring. Thus, screening for such defects can be important for appropriate counseling prior to intracytoplasmic sperm injection (ICSI) treatment. However, only a few reports of father-son cohorts have evaluated the heritability of mutations associated with male factor infertility, as well as the well-being of the children. Because of their invasiveness and their ability to treat severely infertile men known to carry genetic defects, assisted reproductive technologies (ARTs), and ICSI in particular, have generated concerns as to the normality of the offspring. Although early studies on neonatal outcomes failed to reveal any differences between ICSI and in vitro fertilization babies, some recent reports claim a greater incidence of abnormalities in ART children compared with those conceived normally. Anxieties have been voiced also in regard to rare imprinting disorders, as well as cancer following ART. Here we assess the genetic profiles of infertile men treated by ICSI and the profiles of the pregnancies they generated, including obstetrical and perinatal outcomes and developmental milestones in children born from ART. These children were also subjected to genetic and epigenetic analysis as well as to pediatric and psychological examinations. PMID- 18443329 TI - Clinical efficiency of oocyte and embryo cryopreservation. AB - The assessment of the standard for success of in vitro fertilization (IVF) treatment is an arduous task. Clinical efficiency and safety of a given procedure should represent fundamental tools for objective comparison. However, differences in patient populations, laboratory protocols, and expression of clinical data make the analysis of different studies and strategies very difficult. Formulation of the standard for success through the cumulative delivery rate per cycle of stimulation is a very attractive option because it includes the essential contribution of frozen embryos, which can represent 30-40% of all deliveries, while taking into account the need to minimize the proportion of pharmacological and surgical treatments. Embryo cryopreservation may be applied at different postinsemination stages. Larger and more detailed sets of data are available for day 2 embryo freezing, which allows cumulative delivery rates of 50-60% in good prognosis patients. In the last few years, novel freezing methods have improved the overall efficiency of oocyte cryopreservation. Especially in contexts afflicted by legal restrictions to embryo cryo- preservation, this form of preservation has started to have an impact on the IVF standard of success, generating cumulative pregnancy rates approaching 50%. Despite having been applied systematically by some IVF programs for only a few years, oocyte freezing already competes in efficiency with pronuclear-stage cryopreservation, and it does not appear unrealistic to predict that in the future it will challenge the dominance of embryo cryopreservation as the preferred form of conservation. PMID- 18443330 TI - Modern andrology: from semen analysis to postgenomic studies of the male gametes. AB - A male factor is implicated in about 50% of couples treated with advanced assisted reproductive techniques (in vitro fertilization [IVF] or intracytoplasmic sperm injection [ICSI]). An important function of spermatozoa is to deliver the paternal genome to the oocyte. However, neither the routine testing of male fertility potential, nor its treatment, addresses the specific mechanisms by which spermatozoal factors may impact reproductive outcome. Recently, a number of screening tests for DNA integrity have been proposed to assess sperm chromatin abnormalities. These include nonspecific DNA strand breaks, numerical abnormalities in spermatozoal chromosome content, and alterations in the epigenetic regulation of the paternal genome. This minireview discusses methods to assess the influence of the paternal genome on reproduction beyond that which can be appreciated by simple quantitative and morphologic evaluation of spermatozoa. Finally, new data on how to select the "best fit" sperm for ICSI will be presented. PMID- 18443331 TI - Male gamete empowerment. AB - The degree of spermatogenesis varies among infertile men from a barely compromised sperm number in the ejaculate to their complete absence-the condition known as azoospermia. The scarcity of gametes often represents a major hindrance to overcoming spermatogenic failure through the use of assisted fertilization techniques. This induced us to attempt replication of the spermatozoon by "male genome cloning." We then investigated whether it is possible to induce human spermatogenesis in host testes by transplanting germ cells obtained from human testicular biopsy specimens into mouse seminiferous tubules. After plating the sorted germ cells on a feeder layer, one putative spermatogonial stem cell colony proliferated up to day 9 of culture. The production of male gametes by ooplasmic somatic cell haploidization has been tested in our laboratory. Attempts to induce neogametogenesis from embryonic stem cells has yielded mouse offspring following fertilization with sperm-like cells. PMID- 18443332 TI - Decidual cell-expressed tissue factor in human pregnancy and its involvement in hemostasis and preeclampsia-related angiogenesis. AB - During extravascular trophoblast (EVT) invasion of the decidua, thrombin generated from decidual cell-expressed tissue factor (TF) forms a "hemostatic envelope" that protects against hemorrhage during the initial breaching of capillaries by EVTs and subsequent invasion and remodeling of the spiral arteries and arterioles. Preeclampsia, the world's leading cause of fetal and maternal morbidity and mortality, stems from shallow trophoblast invasion leading to incomplete vascular remodeling that impairs uteroplacental blood flow. A considerable subset of cases of preeclampsia is associated with decidual hemorrhage and maternal thrombophilias, which form excess thrombin from decidual cell-expressed TF. Thrombin affects several cell functions by binding to protease activated receptors. In first-trimester decidual cells, thrombin enhances expression of sFlt-1, which can block the angiogenic effects of vascular endothelial growth factor (VEGF) and placental growth factor. By contrast, thrombin does not affect decidual cell VEGF expression. Thrombin-enhanced sFlt-1 expression by decidual cells, the predominant cell type encountered by invading cytotrophoblasts, could promote preeclampsia by interfering with angiogenesis dependent vascular remodeling to reduce uteroplacental blood flow. PMID- 18443333 TI - Pelvic factor infertility: diagnosis and prognosis of various procedures. AB - Infertile women are examined to exclude tubal occlusion or a pelvic factor through indirect tests, such as hysterosalpingography (HSG), sonohysterosalpingography/hysterosalpingosonography (SH), and/or laparoscopy (Lps). Assisted reproductive technologies (ART) are proposed to resolve infertility according to the results of the above-mentioned diagnostic procedures. Today, Lps still represents the second option after several failures of in vivo attempts and before moving to conceive in vitro. The aim of this study was to establish the diagnostic power of HSG and SH compared with that of Lps and the efficacy of ART when each single test is used as an inclusion criterion. We recruited 2560 infertile women (aged 20 to 35) to undergo diagnostic and therapeutic procedures to address their infertility in our clinical theatre. Of these, 1080 women underwent Lps and hysteroscopy (Group 1), 525 underwent HSG (Group 2), and 955 underwent SH (Group 3). The positive and negative predictive values of sonosalpingosonography were 75.8% and 91.2% and those of hysterosalpingography were 71.8% and 88.2%, respectively. Endometriosis (stage II IV of the revised American Society for Reproductive Medicine [ASRM] classification) was diagnosed laparoscopically in 344 out of 1080 women (32%). Only 44 women (13%) with endometriosis showed bilateral tubal occlusion. Pelvic factors other than tubal occlusions are neither diagnosed nor treated in a timely manner by indirect tubal patency tests. The conventional use of HSG and/or SH may increase the time required to find an adequate treatment by which to achieve a successful pregnancy. PMID- 18443334 TI - Uterus transplant: evidence and ethics. AB - Absolute uterine infertility affects millions of women in the United States and more throughout the world. For instance, each year in the United States about 5,000 hysterectomies are performed in women under the age of 24. In total, nearly 9 million women of reproductive age have had a hysterectomy. Based on fecundity rates, thousands of these women may be candidates for uterus transplantation. An ongoing study enrolling some of these potential recipients onto a uterus transplant "waiting list" has revealed that most of these women have Rokitansky syndrome, hysterectomy secondary to endometriosis, cervical cancer, or compelling personal accounts justifying their candidacy. Fertility restoration by uterus transplantation was derived from fertility preservation research, including the development of the radical trachelectomy, oxygenation and perfusion of the in situ uterus, and work with organ donor networks. A decade of modern animal research set the foundation for this human work. Ongoing experiments include stable, long-term large animal allografts for investigating immunosuppression regimens and other transplantation details. Each of the animal models has contributed to the current knowledge base. Recently, nonhuman primates have been used to further investigate the possibility of human uterus transplantation. Nonhuman primate anatomy is analogous to that of humans with notable exceptions. The first human uterus transplant surgery took place in 2000, but it did not result in a pregnancy. However, taken in total, the magnitude of the intervening work from multiple groups throughout the world has made uterus transplantation a topic for discussion. It may also soon be a reality. PMID- 18443335 TI - Endometriosis and infertility: epidemiology and evidence-based treatments. AB - Endometriosis is an estrogen-dependent disorder defined as the presence of endometrial tissue outside of the uterine cavity. A leading cause of infertility, endometriosis has a prevalence of 0.5-5% in fertile and 25-40% in infertile women. The optimal choice of management for endometriosis-associated infertility remains obscure. Removal or suppression of endometrial deposits by medical or surgical means constitutes the basis of endometriosis management. Current evidence indicates that suppressive medical treatment of endometriosis does not benefit fertility and should not be used for this indication alone. Surgery is probably efficacious for all stages of the disease. Controlled ovarian hyperstimulation with intrauterine insemination is recommended in early-stage and surgically corrected endometriosis when pelvic anatomy is normal. In advanced cases, in vitro fertilization is a treatment of choice, and its success may be augmented with prolonged gonadotropin-releasing hormone analog treatment. Further randomized clinical trials focusing on diverse etiopathogenic mechanisms and therapeutic innovation are necessary to find more conclusive, evidence-based answers regarding this enigmatic disease. PMID- 18443338 TI - Bioinformatics and transcriptomics studies of early implantation. AB - Little is known of the genes that mediate cell interactions at implantation. A combined transcriptomics/bioinformatics protocol is described that identifies cell surface glycoproteins in endometrium with potential involvement in implantation. This is linked to an in vitro model in which functional assays of candidate gene products can be carried out. PMID- 18443336 TI - Endometriosis and tissue factor. AB - Tissue factor (TF), is a cellular receptor that binds the ligand factor VII/VIIa to initiate the blood coagulation cascade. In addition to its role as the initiator of the hemostatic cascade, TF is known to be involved in angiogenesis via an interaction with factor VIIa and protease-activated receptor-2 (PAR-2). In this article we review previous studies from our laboratory demonstrating that the pattern and level of TF expression is altered in multiple cell types derived from eutopic and ectopic endometrium from women with endometriosis compared with normal endometrium. We posit that the inflammatory environment that occurs in ectopic and eutopic endometrium from patients with disease results in high TF expression that in turn, signals via PAR-2 to further produce inflammatory cytokine or chemokine production and macrophage recruitment. Thus, our studies suggest that TF might be an ideal target for therapeutic intervention in endometriosis. PMID- 18443337 TI - Stem cells and the pathogenesis of endometriosis. AB - Endometriosis is a common gynecological disorder that is defined by the presence of endometrial tissue outside the uterine cavity. This disease often results in extensive morbidity, including chronic pelvic pain and infertility. The pathogenesis of endometriosis is likely multifactorial, and extensive investigation has explored the role of genetics, environmental factors, and the immune system in predisposing patients to developing endometriosis. A series of recent publications have described the identification of endometrial stem/progenitor cells. Such cells have long been speculated to function in the cyclic regeneration of the endometrium during the menstrual cycle and in the pathogenesis of several gynecological disorders. This narrative review will (i) examine the evidence for endometrial stem cells, (ii) examine their potential role in the pathogenesis of endometriosis, and (iii) identify important unanswered questions with suggestions for future investigation. PMID- 18443339 TI - Inflammation and pregnancy: the role of toll-like receptors in trophoblast-immune interaction. AB - During normal pregnancy, the decidua is populated by a variety of leucocytes; however, cells of the innate immune system seem to dominate this tissue. Their presence suggests that the innate immune system is not indifferent to the fetus and has been associated with a response of the maternal immune system to the "semi-allograft fetus." New evidences, however, indicates that these immune cells are critical for decidual and trophoblast development, rather than induction of tolerance. We hypothesized that, during implantation, an inflammatory environment is necessary for the attachment and invasion of the blastocyst. Therefore, we propose the existence of an "inflammatory-mediated embryo implantation" condition that is dependent on the proper "education" of the innate immune system by the trophoblast. Here we postulate that trophoblast cells successfully orchestrate their inflammatory environment and regulate immune cell differentiation and activation. PMID- 18443340 TI - The placental syncytium and the pathophysiology of preeclampsia and intrauterine growth restriction: a novel assay to assess syncytial protein expression. AB - Preeclampsia is associated with an increased release of factors from the placental syncytium into maternal blood, including the antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin, the antifibrinolytic factor plasminogen activator inhibitor-1, prostanoids, lipoperoxides, cytokines, and microparticles. These factors are suggested to promote maternal endothelium dysfunction and are associated with placental damage in pregnancies also complicated with intrauterine growth restriction (IUGR). In this report, we briefly describe the interaction of syncytial factors with hypoxia, reactive oxygen species, and apoptosis in the pathophysiology of preeclampsia and IUGR. Given the critical role of the syncytium in these complications of pregnancy, we also present a novel methodology in which laser capture microdissection followed by Western blotting is used to assess levels of syncytial Fas ligand, a key protein in the apoptotic cascade. PMID- 18443341 TI - The medical management of menopause: to treat or not to treat? AB - The evidence concerning the effects of hormone therapy (HT) has been greatly expanded by the publication of very large randomized controlled trials. A consequence has been concern among women about the risks of HT such that the number of menopausal women using HT for relief of menopausal symptoms has declined. It is now appropriate to look at the best evidence available and to consider current policies. Women in the early postmenopausal phase, generally younger than 60 years of age, who are troubled by menopausal symptoms should be reassured that, for their circumstances, medical management of menopause in the form of HT is appropriate. If they go on to use HT for several years, it is possible that they will experience skeletal and coronary health benefits, but the evidence for such benefits is a matter of ongoing debate. PMID- 18443342 TI - Reproductive endocrinology and clinical aspects of obesity in women. AB - Obesity is a growing worldwide problem and is associated with a wide range of adverse effects on the female reproductive system. The endocrinological changes in obesity that may cause these adverse effects are complex and include changes in circulating adipokines and sex steroids as well as insulin resistance. Considerable evidence suggests an adverse effect of obesity on the risk of miscarriage and other maternal and fetal complications. Obese patients are also more prone to infertility. The most important single method to improve reproductive performance in obese women is weight loss that can be achieved with lifestyle changes and diet. Antiobesity drugs may also be used and, in severe cases, bariatric surgery. PMID- 18443343 TI - The analgesic effect of betamethasone administered to outpatients before conscious sedation in gynecologic and obstetric surgery. AB - Conscious sedation, used with or without peripheral or central blocks, is an elective anesthetic technique used for many outpatient procedures. The aim of this study was to evaluate the effects of a single pre-anesthetic dose of betamethasone (4 mg) on intraoperative and postoperative pain in 380 women, 18 to 75 years old, undergoing gynecologic and obstetric surgery (diagnostic curettage, operative and diagnostic hysteroscopy, conization, minilaparoscopy, cone biopsy, endometrial ablation, assisted reproduction techniques, and induced and therapeutic abortion) in a outpatient service. In this randomized, double-blind, placebo-controlled study, the patients were divided into two equal groups according to a computer-generated randomized list. One group received 4 mg of betamethasone i.v. as a premedication (group B), whereas the placebo group (group P) received only saline. All patients underwent the same sedation, associated with a peripheral block. Pain was evaluated using a 5-point verbal rating scale during surgery, after 2 h, and on discharge. In group B, intraoperative and postoperative pain was significantly less frequent than in group P (P < 0.001). Consequently, fewer women belonging to group B requested additional analgesic drugs during and after surgery (P < 0.01). Patients in group B also experienced a greater degree of satisfaction (P < 0.01). Briefly, a single dose of betamethasone seemed to reduce the incidence and severity of perioperative pain after gynecologic outpatient surgery. PMID- 18443344 TI - Introducing new treatments and technologies into the clinic. PMID- 18443345 TI - Should randomized clinical trials be required for proton radiotherapy? An alternative view. PMID- 18443346 TI - Protons and parachutes. PMID- 18443348 TI - A patient's perspective on randomized clinical trials for proton radiotherapy. PMID- 18443349 TI - Proton therapy should be tested in randomized trials. PMID- 18443350 TI - On equipoise and emerging technologies. PMID- 18443351 TI - Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer. AB - PURPOSE: To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen. PATIENTS AND METHODS: Five hundred twenty-two patients estrogen receptor-positive metastatic breast cancer were randomly assigned to receive first-line hormone therapy with letrozole or tamoxifen. Serum tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Pretreatment serum TIMP-1 was elevated in 120 (23%) of 522 patients. Patients with elevated serum TIMP-1 had a significantly reduced objective response rate (19.2% v 30.6%; odds ratio, 0.54; P = .01), duration of response (median, 15.5 v 26.2 months; P = .001), time to treatment progression (TTP; median, 4.5 v 9.2 months; HR, 1.78; P = .0001), time to treatment failure (median, 3.5 v 9.0 months; HR, 1.77; P = .0001), and overall survival (median, 20.3 v 35.8 months; HR, 1.77; P = .0001) compared with patients with normal pretreatment TIMP-1 levels. Letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (median TTP, 11.8 v 8.6 months; P = .003) and in the elevated serum TIMP-1 group (median, 6.1 v 3.2 months; P = .03) In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both shorter TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict significantly different clinical outcomes compared to using either biomarker alone. CONCLUSION: Patients with elevated pretreatment serum TIMP-1 had a significantly reduced response and survival. Serum TIMP-1 was an independent predictive and prognostic factor. Blockade of TIMP-1 and HER-2/neu activity may be beneficial in a subset of patients with breast cancer. PMID- 18443352 TI - Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy. AB - PURPOSE: To analyze the prognostic impact of immunophenotyping in patients with multiple myeloma (MM). PATIENTS AND METHODS: We have prospectively analyzed the prognostic impact of antigenic markers, assessed by multiparametric flow cytometry, in a series of 685 newly diagnosed MM patients that were uniformly treated according to the GEM 2000 protocol. RESULTS: Our results show that expression of both CD19 and CD28 as well as the absence of CD117 were associated with a significantly shorter progression free-survival (PFS) and overall survival (OS). Interestingly, the CD28 expression correlated with t(14;16) and del(17p), while CD117-negative patients were associated with t(4;14) and del(13q). Simultaneous assessment of CD28 and CD117 antigens allowed stratification of patients with MM into three risk categories: poor risk (CD28 positive CD117 negative), intermediate (either both markers negative or both positive), and good risk (CD28 negative CD117 positive), with PFS rates of 30, 37, and 45 months, respectively (P = .01), and OS rates of 45, 68, and not reached, respectively (P = .0001). CONCLUSION: To the best of our knowledge, this is the first prospective analysis in which the prognostic impact of a relatively high number of antigenic markers has been simultaneously analyzed in a large series of uniformly treated patients, showing that the expression of several antigens (particularly CD28 and CD117) on bone marrow plasma cells from patients with MM can help to identify patients at high risk of progression. PMID- 18443353 TI - Leukocytosis and risk stratification assessment in essential thrombocythemia. AB - PURPOSE: Established risk factors for thrombosis in essential thrombocythemia (ET) include age and previous vascular events. We aimed to refine this risk stratification by adding baseline leukocytosis. PATIENTS AND METHODS: We enrolled 657 patients with ET followed for a median of 4.5 years who developed 72 major thrombosis. Cox proportional hazard model was performed to analyze the thrombotic risk and to discriminate ET patients with or without thrombosis, multivariable C statistic index was used. We searched for leukocytes cutoff with the best sensitivity and specificity by a receiver operating characteristic curve. RESULTS: Results confirmed that age and prior events are independent risk factors for thrombosis and showed a gradient between baseline leukocytosis and thrombosis. On the contrary, no significant association was found either for JAK2(V617F) allele burden and for other laboratory parameters, including platelet number. In the model with conventional risk factors alone, C statistic ratio for total thrombosis was 0.63 and when leukocytosis was added, the change was small (C = 0.67). In contrast, in younger and asymptomatic patients (low-risk category), C statistic value indicated an high risk for thrombosis in patients with leukocytosis, similar to that calculated in conventionally defined high-risk group (C = 0.65). The best leukocyte cutoff values for predicting the events was found to be 9.4 (x 10(9)/L). CONCLUSION: We suggest to include baseline leukocytosis in the risk stratification of ET patients enrolled in clinical trials. PMID- 18443354 TI - HIV-1 upregulates VEGF in podocytes. AB - HIV-associated nephropathy (HIVAN) is characterized by collapsing FSGS. Because transgenic mice with podocyte-specific overexpression of the vascular endothelial growth factor 164 (VEGF164) isoform also develop collapsing FSGS, we sought to determine whether VEGF plays a role in HIVAN. Compared with controls, immunohistochemistry revealed that kidneys from HIV-1-transgenic mice (Tg26) and from patients with HIVAN had greater expression of both VEGF and its transcriptional regulator, hypoxia-inducible factor 2alpha (HIF-2alpha). Similarly, mRNA and protein levels of VEGF and HIF-2alpha were increased in HIV infected podocytes in vitro, and this transcriptional upregulation was found to be stimulated by the HIV viral protein Nef in a Src kinase-and Stat3-dependent manner. HIV-1 also upregulated VEGFR2 and its co-receptor neuropilin-1 and suppressed the expression of semaphorin 3a in the podocyte. Exogenous VEGF stimulated proliferation and de-differentiation of podocytes, which are features of collapsing FSGS, and VEGFR2 neutralizing antibodies reversed these features in podocytes infected with HIV-1 or isolated from Tg26 mice. In conclusion, HIV-1 induces VEGF and VEGFR2 expression in podocytes, and this may be a critical step in the pathogenesis of HIVAN. PMID- 18443355 TI - The role of osteopontin in the development of albuminuria. AB - Several gene array studies have suggested that osteopontin (Opn) expression strongly correlates with albuminuria and glomerular disease. Urinary Opn concentration and kidney Opn immunoreactivity were found to be increased in patients with steroid-sensitive nephrotic syndrome. In addition, renal Opn mRNA was increased in the Ins2(Akita) mouse model of type 1 diabetic nephropathy, in the LPS-induced albuminuria model, and in glomeruli of puromycin aminonucleotide induced nephrotic rats. Opn knockout mice did not develop albuminuria in response to LPS injection, and Opn knockout mice were protected from diabetes-induced albuminuria and mesangial expansion. In the glomerulus, Opn immunostaining was increased specifically in podocytes. Treatment of podocytes with recombinant Opn activated the NF-kappaB pathway, increased expression of urokinase plasminogen activator and matrix metalloproteinases 2 and 9, and increased podocyte motility. Taken together, these results indicate that Opn plays an important role in the development of albuminuria, possibly by modulating podocyte signaling and motility. PMID- 18443356 TI - IP3 sensitizes TRPV4 channel to the mechano- and osmotransducing messenger 5'-6' epoxyeicosatrienoic acid. AB - Mechanical and osmotic sensitivity of the transient receptor potential vanilloid 4 (TRPV4) channel depends on phospholipase A2 (PLA2) activation and the subsequent production of the arachidonic acid metabolites, epoxyeicosatrienoic acid (EET). We show that both high viscous loading and hypotonicity stimuli in native ciliated epithelial cells use PLA2-EET as the primary pathway to activate TRPV4. Under conditions of low PLA2 activation, both also use extracellular ATP mediated activation of phospholipase C (PLC)-inositol trisphosphate (IP3) signaling to support TRPV4 gating. IP3, without being an agonist itself, sensitizes TRPV4 to EET in epithelial ciliated cells and cells heterologously expressing TRPV4, an effect inhibited by the IP3 receptor antagonist xestospongin C. Coimmunoprecipitation assays indicated a physical interaction between TRPV4 and IP3 receptor 3. Collectively, our study suggests a functional coupling between plasma membrane TRPV4 channels and intracellular store Ca2+ channels required to initiate and maintain the oscillatory Ca2+ signal triggered by high viscosity and hypotonic stimuli that do not reach a threshold level of PLA2 activation. PMID- 18443358 TI - Zebrafish--topical, transparent, and tractable for ultrastructural studies. PMID- 18443359 TI - Structure and function of skeletal muscle in zebrafish early larvae. AB - Zebrafish muscles were examined at an early developmental stage (larvae 5-7 d). Using aluminum clips, preparations (approximately 1.5 mm length, 150 microm diameter) were mounted for force registration and small angle x-ray diffraction. Sarcomeres were oriented mainly in parallel with the preparation long axis. Electrical stimulation elicited fast and reproducible single twitch contractions. Length-force relations showed an optimal sarcomere length of 2.15 microm. X-ray diffraction revealed clear equatorial 1.1/1.0 reflections, showing that myofilaments are predominantly arranged along the preparation long axis. In contrast, reflections from older (2 mo) zebrafish showed two main filament orientations each at an approximately 25 degrees angle relative to the preparation long axis. Electrical stimulation of larvae muscles increased the 1.1/1.0 intensity ratio, reflecting mass transfer to thin filaments during contraction. The apparent lattice volume was 3.42 x 10(-3) microm(3), which is smaller than that of mammalian striated muscle and more similar to that of frog muscles. The relation between force and stimulation frequency showed fusion of responses at a comparatively high frequency (approximately 186 Hz), reflecting a fast muscle phenotype. Inhibition of fast myosin with N-benzyl-p-toluene sulphonamide (BTS) showed that the later phase of the tetanus was less affected than the initial peak. This suggests that, although the main contractile phenotype is fast, slow twitch fibers can contribute to sustained contraction. A fatigue stimulation protocol with repeated 220 ms/186 Hz tetani showed that tetanic force decreased to 50% at a train rate of 0.1 s(-1). In conclusion, zebrafish larvae muscles can be examined in vitro using mechanical and x-ray methods. The muscles and myofilaments are mainly orientated in parallel with the larvae long axis and exhibit a significant fast contractile component. Sustained contractions can also involve a small contribution from slower muscle types. PMID- 18443360 TI - An extracellular Cu2+ binding site in the voltage sensor of BK and Shaker potassium channels. AB - Copper is an essential trace element that may serve as a signaling molecule in the nervous system. Here we show that extracellular Cu2+ is a potent inhibitor of BK and Shaker K+ channels. At low micromolar concentrations, Cu2+ rapidly and reversibly reduces macrosocopic K+ conductance (G(K)) evoked from mSlo1 BK channels by membrane depolarization. GK is reduced in a dose-dependent manner with an IC50 and Hill coefficient of 2 microM and 1.0, respectively. Saturating 100 microM Cu2+ shifts the GK-V relation by +74 mV and reduces G(Kmax) by 27% without affecting single channel conductance. However, 100 microM Cu2+ fails to inhibit GK when applied during membrane depolarization, suggesting that Cu2+ interacts poorly with the activated channel. Of other transition metal ions tested, only Zn2+ and Cd2+ had significant effects at 100 microM with IC(50)s > 0.5 mM, suggesting the binding site is Cu2+ selective. Mutation of external Cys or His residues did not alter Cu2+ sensitivity. However, four putative Cu2+ coordinating residues were identified (D133, Q151, D153, and R207) in transmembrane segments S1, S2, and S4 of the mSlo1 voltage sensor, based on the ability of substitutions at these positions to alter Cu2+ and/or Cd2+ sensitivity. Consistent with the presence of acidic residues in the binding site, Cu2+ sensitivity was reduced at low extracellular pH. The three charged positions in S1, S2, and S4 are highly conserved among voltage-gated channels and could play a general role in metal sensitivity. We demonstrate that Shaker, like mSlo1, is much more sensitive to Cu2+ than Zn2+ and that sensitivity to these metals is altered by mutating the conserved positions in S1 or S4 or reducing pH. Our results suggest that the voltage sensor forms a state- and pH-dependent, metal selective binding pocket that may be occupied by Cu2+ at physiologically relevant concentrations to inhibit activation of BK and other channels. PMID- 18443361 TI - Cholesterol promotes hemifusion and pore widening in membrane fusion induced by influenza hemagglutinin. AB - Cholesterol-specific interactions that affect membrane fusion were tested for using insect cells; cells that have naturally low cholesterol levels (< 4 mol %). Sf9 cells were engineered (HAS cells) to express the hemagglutinin (HA) of the influenza virus X-31 strain. Enrichment of HAS cells with cholesterol reduced the delay between triggering and lipid dye transfer between HAS cells and human red blood cells (RBC), indicating that cholesterol facilitates membrane lipid mixing prior to fusion pore opening. Increased cholesterol also increased aqueous content transfer between HAS cells and RBC over a broad range of HA expression levels, suggesting that cholesterol also favors fusion pore expansion. This interpretation was tested using both trans-cell dye diffusion and fusion pore conductivity measurements in cholesterol-enriched cells. The results of this study support the hypothesis that host cell cholesterol acts at two stages in membrane fusion: (1) early, prior to fusion pore opening, and (2) late, during fusion pore expansion. PMID- 18443362 TI - Periostin is expressed in pericryptal fibroblasts and cancer-associated fibroblasts in the colon. AB - Periostin is a unique extracellular matrix protein, deposition of which is enhanced by mechanical stress and the tissue repair process. Its significance in normal and neoplastic colon has not been fully clarified yet. Using immunohistochemistry and immunoelectron microscopy with a highly specific monoclonal antibody, periostin deposition was observed in close proximity to pericryptal fibroblasts of colonic crypts. The pericryptal pattern of periostin deposition was decreased in adenoma and adenocarcinoma, preceding the decrease of the number of pericryptal fibroblasts. Periostin immunoreactivity appeared again at the invasive front of the carcinoma and increased along the appearance of cancer-associated fibroblasts. ISH showed periostin signals in cancer-associated fibroblasts but not in cancer cells. Ki-67-positive epithelial cells were significantly decreased in the colonic crypts of periostin-/- mice (approximately 0.6-fold) compared with periostin+/+ mice. In three-dimensional co-culture within type I collagen gel, both colony size and number of human colon cancer cell line HCT116 cells were significantly larger ( approximately 1.5-fold) when cultured with fibroblasts derived from periostin+/+ mice or periostin-transfected NIH3T3 cells than with those from periostin-/- mice or periostin-non-producing NIH3T3 cells, respectively. Periostin is secreted by pericryptal and cancer-associated fibroblasts in the colon, both of which support the growth of epithelial components. PMID- 18443363 TI - Expression of somatostatin and somatostatin receptor subtypes 1-5 in human normal and diseased kidney. AB - Somatostatin mediates inhibitory functions through five G protein-coupled somatostatin receptors (sst1-5). We used immunohistochemistry, immunofluorescence, and RT-PCR to determine the presence of somatostatin receptors sst1, sst2A, sst2B, sst3, sst4, and sst5 in normal and IgA nephropathy human kidney. All somatostatin receptors were detected in the thin tubules (distal convoluted tubules and loops of Henle) and thick tubules (proximal convoluted tubules) in the tissue sections from nephrectomy and biopsy samples. Immunopositive sst1 and sst4 staining was more condensed in the cytoplasm of tubular epithelial cells. In normal kidney tissue sections, podocytes and mesangial cells in the glomeruli stained for sst1, sst2B, sst4 and sst5, and stained weakly for sst3. In IgA kidney tissue, the expression of somatostatin receptors was significantly increased with particular immmunopositive staining for sst1, sst2B, sst4, and sst5 within glomeruli. In the epithelial cells, the staining for sst2B and sst4 in proximal tubules and sst1, sst2B, and sst5 in distal tubules was increased. The mRNA expression of sst1-5 was also detected by RT-PCR. Somatostatin and all five receptor subtypes were ubiquitously distributed in normal kidney and IgA nephropathy. The increased expression of somatostatin receptors in IgA nephropathy kidney might be the potential pathogenesis of inflammatory renal disease. PMID- 18443364 TI - Diabetes reduces aortic endothelial gap junctions in ApoE-deficient mice: simvastatin exacerbates the reduction. AB - We examined the endothelial gap junctions in diabetic hyperlipidemic mice. Male apolipoprotein E (apoE)-deficient mice were made diabetic by streptozotocin. Three weeks later, the animals were treated with simvastatin for 2 weeks. The expression of aortic gap junctions in the non-diabetic (n=10), untreated diabetic (n=10), and simvastatin-treated diabetic animals (n=6) was analyzed. There was a >4-fold increase in serum cholesterol level and >50% increase in plaque areas in the diabetic mice, regardless of simvastatin treatment. Western blotting of aortae showed reduced expression of connexin37 (Cx37) and Cx40 in the diabetic mice, which were further decreased in the simvastatin-treated diabetic mice. Immunoconfocal microscopy showed that endothelial gap junctions made of Cx37 and Cx40 were both reduced in the untreated diabetic mice compared with the non diabetic mice (decrease: Cx37, 41%; Cx40, 42%; both p<0.01). The reduction was greater in the simvastatin-treated mice (decrease in treated diabetic vs non diabetic: Cx37, 61%; Cx40, 79%; both p<0.01; decrease in treated diabetic vs untreated diabetic: Cx37, 34%; Cx40, 63%; both p<0.01). Cx37 and Cx40 were decreased in the endothelium of plaque surface. Cx43 appeared in the medial layer and inner layer of the intima. All three connexins were rarely expressed in monocytes/macrophages inside the plaques. In conclusion, in apoE-deficient mice, streptozotocin-induced diabetes is associated with downregulation of endothelial Cx37 and Cx40 gap junctions. Short-term treatment with simvastatin exacerbates the downregulation. PMID- 18443365 TI - Expression of calcyclin-binding protein/Siah-1 interacting protein in normal and malignant human tissues: an immunohistochemical survey. AB - Calcyclin-binding protein (CacyBP)/Siah-1 interacting protein (SIP), a component of ubiquitin-mediated proteolysis, could bind the Skp1-Cul1-F box protein complex. Although CacyBP/SIP was implicated in p53-induced beta-catenin degradation, its exact function was still unknown. Our previous studies showed that CacyBP/SIP could modulate the multidrug-resistant phenotype of gastric cancer cells and was highly expressed in gastric cancer tissues compared with that in non-cancerous tissues. In this study, CacyBP/SIP protein expression profile in a broad range of human normal tissues and carcinomas was analyzed by immunohistochemistry staining with anti-CacyBP/SIP monoclonal antibody first produced in our laboratory. CacyBP/SIP was generally localized in the cytoplasm/nucleus. Positive staining of CacyBP/SIP was found in brain, heart, lymph node, and esophagus. Weak staining was shown in the rectum and kidney. No CacyBP/SIP was detected in other normal tissues. However, CacyBP/SIP was ubiquitously detected in all kinds of tumor tissues and was highly expressed in nasopharyngeal carcinoma, osteogenic sarcoma, and pancreatic cancer. To our knowledge, this is the first study on the CacyBP/SIP expression pattern in a broad range of human normal and tumor tissues. The data presented should serve as a useful reference for other investigators in future studies of CacyBP/SIP functions. Hopefully, this knowledge will lead to discovery of more roles of CacyBP/SIP in tumorigenesis. PMID- 18443366 TI - AP-2alpha and AP-2gamma regulate tumor progression via specific genetic programs. AB - The events occurring during tumor formation and progression display similarities to some of the steps in embryonic morphogenesis. The family of AP-2 proteins consists of five different transcription factors (alpha, beta, gamma, delta, and epsilon) that play relevant roles in embryonic development, as demonstrated by the phenotypes of the corresponding knockout mice. Here, we show that AP-2alpha and AP-2gamma proteins play an essential role in tumorigenesis. Down-modulation of AP-2 expression in tumor cells by RNA interference (RNAi) led to enhanced tumor growth and reduced chemotherapy-induced cell death, as well as migration and invasion. Most of these biological modulations were rescued by AP-2 overexpression. We observed that increased xenotransplant growth was mostly due to highly enhanced proliferation of the tumor cells together with reduced innate immune cell recruitment. Moreover, we showed that migration impairment was mediated, at least in part, by secreted factors. To identify the genetic programs involved in tumorigenesis, we performed whole genome microarray analysis of AP 2alpha knockdown cells and observed that AP-2alpha regulates specific genes involved in cell cycle, cell death, adhesion, and migration. In particular, we showed that ESDN, EREG, and CXCL2 play a major role in AP-2 controlled migration, as ablation of any of these genes severely altered migration. PMID- 18443367 TI - Comment on: DiChiara et al. (2007) The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin induced platelet effect (ASPECT) study: Diabetes 56:3014-3019, 2007. PMID- 18443369 TI - Comment on: Edghill et al. (2008) Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood: Diabetes 57:1034-1042, 2008. PMID- 18443370 TI - Abdominal adiposity and diabetes risk: the importance of precise measures and longitudinal studies. PMID- 18443371 TI - Islet autoreactive CD8 T-cells in type 1 diabetes: licensed to kill? PMID- 18443372 TI - Central versus peripheral glucose sensing and the response to hypoglycemia. PMID- 18443373 TI - Genetic similarities between latent autoimmune diabetes and type 1 and type 2 diabetes. PMID- 18443374 TI - Intensive glycemic control and cardiovascular disease observations from the ACCORD study: now what can a clinician possibly think? PMID- 18443375 TI - Interaction of memantine and ketamine in morphine- and pentazocine-induced antinociception in mice. AB - The interaction between uncompetitive NMDA receptor antagonists (memantine and ketamine), and morphine (mu-opioid receptor agonist) and pentazocine (kappa opioid receptor agonist) was studied in the writhing test in mice. Memantine and ketamine, administered at subthreshold doses, potentiated antinociceptive effect of the threshold (1 mg/kg) dose of morphine. The effects of the threshold (6 mg/kg) dose of pentazocine were not significantly changed by ketamine, and were significantly enhanced by the higher dose of memantine (15 mg/kg). Simultaneously performed experiments in the chimney test have shown that combination of morphine or pentazocine with an NMDA receptor antagonist did not induce significant alterations in the motor coordination of mice. The obtained results have shown that NMDA receptor antagonists (ketamine, memantine) are able to enhance the antinociceptive activity of opioids (morphine, pentazocine). It is necessary to underline that this effect was more apparent for morphine (mu-opioid receptor agonist) + NMDA antagonists than for pentazocine (kappa-opioid receptor agonist). These results may have some importance for clinical practice. PMID- 18443376 TI - NSAID loxoprofen inhibits high threshold or wide dynamic range neuronal responses in the rat at different time-courses. AB - The onset of the antinociceptive effect with loxoprofen sodium (LOX), a non steroidal anti-inflammatory drug, was examined electrophysiologically during carrageenan-induced hindpaw inflammation in the rat. Extracellular recordings were made from either wide dynamic range (WDR) or high threshold (HT) neurons in the dorsal horn. Recordings from the same neuron were continued for at least 3 h after the injection of carrageenan. Three hours after the induction of inflammation, either a fresh solution of LOX (1 mg/kg) or distilled water was directly administered into the stomach through PE 50 tubing. LOX significantly reduced inflammation-increased background activity and noxious heat-evoked responses in both HT and WDR neurons, whereas distilled water did not produce any change. Asignificant difference in the onset of the inhibitory effect of LOX was observed between HT and WDR neurons. The results show that WDR neurons precede HT neurons regarding inhibition of nociceptive processing in the dorsal horn after administration of LOX. PMID- 18443377 TI - Effects of short-term garlic supplementation on lipid metabolism and antioxidant status in hypertensive adults. AB - This prospective and uncontrolled clinical study attempted to evaluate the effects of short-term supplementation with oily garlic formulation on lipid metabolism, glucose level and antioxidant status in patients suffering from primary arterial hypertension. Seventy subjects aged 30 to 60 years with primary arterial hypertension, including 38 females (mean age: 52.0 +/- 8.3 years) and 32 males (mean age: 48.6 +/- 8.2 years), took part in the study. In addition to receiving a standard antihypertensive pharmacotherapy they took 6 capsules of garlic preparation daily for 30 days. Before and after phytotherapy blood samples were collected to assay total cholesterol, HDL, LDL, triglycerides, lipid peroxidation products (TBARS) and vitamin A, C and E, beta-carotene, glutathione and glutathione peroxidase activity, and arterial blood pressure was measured. The analyzed garlic preparation was found to significantly lower lipid level and the level of lipid peroxidation products in the blood. It markedly increased vitamin E concentration in the serum, whereas the increases in the levels of other antioxidant vitamins and glutathione peroxidase activity proved insignificant. The product did not affect arterial blood pressure in the study subjects. The results of this study suggest that the investigated garlic preparation may be tentatively used as an adjunct agent in treatment of arterial hypertension because of its hypolipemic and antioxidant properties. PMID- 18443378 TI - Proline-linked nitrosoureas as prolidase-convertible prodrugs in human breast cancer cells. AB - A number of novel proline-linked nitrosoureas (1-4) were synthesized and examined for cytotoxicity and influence on DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. Evaluation of the cytotoxicity of these compounds employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that compound 2, the most active of the series, proved to be only slightly less potent than carmustine. It has also been found that carmustine did not inhibit MCF&-7 cells prolidase activity, while compounds 1-4 significantly increased its activity, when used at 50-250 microM concentrations. Proline-linked nitrosoureas (1-4) also had lower ability to inhibit collagen biosynthesis in MCF-7 cells, compared to carmustine. The expression of beta(1)-integrin receptor and phosphorylated MAPK, ERK(1) and ERK(2) was significantly decreased in MCF-7 cells incubated for 24 h with 60 microM of compounds 2 and 4 compared to the control, untreated cells, whereas under the same conditions carmustine did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the proline-linked nitrosoureas (1 4), represent multifunctional inhibitors of breast cancer cell growth and metabolism. PMID- 18443379 TI - RM-11, an isoxazole derivative, accelerates restoration of the immune function in mice treated with cyclophosphamide. AB - The aim of this study was to evaluate efficacy of an isoxazole derivative RM11 to accelerate reconstitution of selected immune activities in cyclophosphamide (CP) immunocompromised mice. We demonstrated that administration of fifteen 10 mug intraperitoneal doses of RM11, following a sublethal (200 mug/kg) dose of CP, significantly stimulated the number of antibody-forming cells (AFC) to sheep erythrocytes (SRBC) as determined 35 days after the CP treatment. Similarly, treatment of the CP-injected mice with 7 doses of RM11 significantly enhanced generation of delayed type hypersensitivity (DTH) to ovalbumin (OVA). Moreover, in that model, the treatment of mice with RM11 accelerated the process of myelopoiesis. RM11 also counteracted the suppressive action of methotrexate (MTX) in the in vitro model of the humoral immune response to SRBC. The phenotypic studies with fluorocytometer revealed that intraperitoneal 10 mug dose of RM11 significantly elevated the percentage of mature (CD3(+), CD4(+) and CD8(+)) T cells in the spleen and down-regulated the content of CD19(+) cells. We conclude that RM11 may be of potential therapeutic value in restoration of the immune status in patients undergoing chemotherapy. PMID- 18443380 TI - Molecular assessment of the potential combination therapy of cytokines with biphalin and AZT for Friend leukemia virus infection in vitro. AB - Biphalin, a dimeric enkephalin analog, is under investigation as a potential, long-lasting medication of pain associated with chronic diseases, like cancer or AIDS. The role of cytokines, and splenocytes in anti-Friend leukemia virus (FLV) activity of biphalin, a synthetic opioid, and AZT was investigated in vitro. Mouse splenocytes inhibited FLV replication in Mus dunni (Dunni) cells when they were added to the cell culture. This inhibitory effect of splenocytes also was evident when cells were combined with biphalin and AZT as measured using a focus forming assay. Under cell-free conditions, recombinant interferon gamma (IFNgamma), interleukin 2 (IL-2) and IL-4 directly inhibited the FLV reverse transcriptase (RT) activity by 27% to 36%. IFNgamma at 0.005 pg to 500 ng inhibited FLVRT activity by 61% to 80%. Acombination of 250 ng IFNgamma and 50 mug biphalin resulted in a 94% reduction of FLVRT activity, as compared with 61% inhibition by IFNgamma alone. The combination of AZT and IFNgamma, IL-2 or IL-4 also induced a stronger suppression of FLV RT activity than either cytokine or AZT used alone. In addition, cloned RT from Moloney murine leukemia virus (MMLV) was directly sensitive to inhibition by biphalin. Thus, the anti-FLV effects of splenocytes in combination with biphalin and AZT in cell culture are likely mediated to a large degree by the direct effect of cytokines. This antiviral activity of splenocytes or cytokines combined with chemotherapy, biphalin, and/or AZT, could be used as a complementary therapy to current approaches for retroviral infection and benefit acquired immunodeficiency syndrome (AIDS) patients. In conclusion, biphalin applied primarily as a new medicine for chronic pain treatment in AIDS patients may play a significant beneficial role as a component of antiviral HIV multidrug therapies. PMID- 18443381 TI - Comparative evaluation of the protective effect of selenium and garlic against liver and kidney damage induced by mercury chloride in the rats. AB - The present study was designed to compare the protective effect of selenium and garlic against liver and kidney damage induced by (ip) injection of 0.5 mg/kg mercury chloride (HgCl(2)) in rats. Thirty-six Sprague-Dawley rats were used in the present experiment and divided into six groups: one group was orally given (1 ml) saline and served as a control group; two groups of rats were given either selenium (0.1 mg/kg) or garlic (63 mg/kg) alone, once daily an oral dose for 30 successive days; other two groups of rats were given either selenium or garlic alone, once daily a dose for 15 successive days prior to HgCl(2) injection and on the next 15 successive days simultaneously with HgCl(2) injection; and the last group of rats was injected ip with HgCl(2) for 15 days and at the end of the experiment (which lasted 30 days), blood samples for the biochemical analysis were obtained from all rats after being lightly anesthetized with ether, and specimens of kidney and liver were removed and prepared for histochemical study. Computer image analysis was applied to liver and kidney tissues to evaluate the DNA density and DNA ploidy pattern in different groups. The results revealed that the rats injected with HgCl(2) showed a significant increase in levels of blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) by 29.3%, 62.5%, 29.46% and 30.61%, respectively, while alkaline phosphatase (ALP) showed a significant decrease by 22.6% as compared with saline control group. Rats that were given selenium in combination with the HgCl(2) injection showed a significant decrease in BUN, Serum creatinine, ALT and AST levels, while ALP was significantly increased as compared with HgCl(2) group. Also rats that were given garlic in combination with HgCl(2) injection showed a significant decrease in BUN, Serum creatinine, ALT and AST levels, although serum ALP level showed an increase as compared to HgCl(2) group. Rats that had been orally administered selenium or garlic alone did not show any significant changes in the serum level of BUN, Serum creatinine, ALT and AST but there was a significant decrease in ALP level as compared with saline control group. The cytometric results revealed that injection of HgCl(2) induced an increase in the DNA density in kidney tissues with an increase in aneuploid cells and decrease in diploid cells. However, DNA density decreased in liver tissues with mild decrease in diploid cells and little percentage of aneuploid cells. We can conclude that oral administration of either selenium or garlic produces a significant protection against liver and kidney damage induced by the HgCl(2) injection, but garlic appears to be more protective. PMID- 18443382 TI - Effects of midazolam and buspirone on in vivo concentration of amino acids and monoamine metabolites in the rat hippocampus. AB - The effects of anxiolytic doses of buspirone and midazolam (established in the conditioned fear test) on extracellular concentrations of glutamate, GABA, serotonin and dopamine metabolites in the hippocampus were examined in vivo, in freely moving rats. Buspirone at a dose of 1.5 mg/kg ip disinhibited rat behavior in the conditioned fear test (a freezing response) much stronger than 1.0 mg/kg of midazolam. Both drugs enhanced the local concentration of glutamate to the similar extent, and decreased the concentration of 5-hydroxyindole acetic acid (5 HIAA). Buspirone increased also the extracellular levels of dopamine metabolites: homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). It is suggested that the changes in hippocampal glutamate probably are not directly associated with modification of rat emotional behavior after benzodiazepines and azapirones. The present results provide more arguments for the role of hippocampal 5-HT in the effects of anxiolytic drugs. PMID- 18443383 TI - Central effect of histamine in a rat model of acute trigeminal pain. AB - In conscious rats implanted with an intracerebroventricular (icv) cannula, effect of icv injections of histamine, chlorpheniramine (H(1)-receptor antagonist) and ranitidine (H(2)-receptor blocker) was investigated in a rat model of acute trigeminal pain. Acute trigeminal pain was induced by putting a drop of 5 M NaCl solution on the corneal surface of the eye and the numbers of eye wipes were counted during the first 30 s. Histamine (20, 40 microg) and chlorpheniramine (80 microg) significantly decreased the numbers of eye wipes. Ranitidine alone had no effect. Pretreatment with chlorpheniramine did not change the histamine-induced analgesia, whereas the histamine effect on pain was inhibited with ranitidine pretreatment. These results indicate that the brain histamine, through central H(2) receptors, may be involved in the modulation of the acute trigeminal pain in rats. PMID- 18443384 TI - Biological actions of lipoic acid associated with sulfane sulfur metabolism. AB - This work aimed to investigate the effect of lipoic acid (LA) on sulfane sulfur (S(*)) level and rhodanese activity in rat tissues. In vitro studies conduced so far have indicated that dihydrolipoic acid serves as an S(*) acceptor in the rhodanese-catalyzed S(*) transfer. This study revealed a significant increase in S(*) level and rhodanese activity in the heart, liver and kidney homogenates from rats that had previously been treated intraperitoneally with LA. It demonstrated for the first time in vivo that biological activity of lipoate might be connected with anaerobic cysteine metabolism to S(*) and with rhodanese activity. PMID- 18443385 TI - Effects of etoricoxib on the pharmacokinetics of phenytoin. AB - Etoricoxib is presently the most commonly prescribed cyclooxygenase-2 (Cox-2) inhibitor for chronic pain and inflammatory conditions. In clinical practice, phenytoin and etoricoxib are used in chronic conditions of generalized seizure with concomitant chronic pain. Hence, there are chances of drug-drug interaction because modulations of isoenzymes involved in metabolism CYP2C9/10 and CYP2C19 which partially inhibited by etoricoxib. It is important to maintain the therapeutic level of phenytoin in plasma for effective control of seizure. So, the aim of the study was to determine the effect of etoricoxib on the pharmacokinetics of phenytoin in rabbits. In a parallel design study, phenytoin (30 mg/kg/day) was given daily for seven days. On day 7, blood samples were taken at various time intervals between 0-24 h. In etoricoxib group, phenytoin was administered for seven days as above. On day 8, etoricoxib (5.6 mg/kg) along with phenytoin (30 mg/kg/day) was administered and blood samples were drawn as above. Plasma phenytoin levels were assayed by HPLC and pharmacokinetic parameters were calculated. In etoricoxib group, there was a decrease in t(1/2)a phenytoin and t(1/2)el decreased significantly as compared to phenytoin group. Significant changes were observed in the pharmacokinetic parameters in etoricoxib-treated group. These results suggest that etoricoxib alters the pharmacokinetics of phenytoin. Confirmation of these results in human studies will warrant changes in phenytoin dose or frequency when etoricoxib is co-administered with it. PMID- 18443386 TI - 5-Fluorouracil toxicity-attributable IVS14 + 1G > A mutation of the dihydropyrimidine dehydrogenase gene in Polish colorectal cancer patients. AB - DPYD gene encodes dihydropyrimidine dehydrogenase which is the initial and rate limiting enzyme in the metabolism of 5-fluorouracil (5-FU). The aim of our study was PCR-RFLP based-genetic testing for the most common 5-FU toxicity-attributable IVS14 + 1G > A DPYD mutation (DPYD(*)2A) in 252 Polish colorectal cancer (CRC) patients treated with this adjuvant chemotherapeutic regimen after surgery. The DPYD(*)2A allele was identified only in one patient: a male who was one of 4 CRC patients suffering from grades 3-4 myelotoxicity upon 5-FU chemotherapy. We conclude that IVS14 + 1G > A DPYD (DPYD(*)2A) variant occurs in the Polish population and is responsible for a significant proportion of life-threatening toxicity of 5-FU. PMID- 18443387 TI - Experimental detection of iron overload in liver through neutron stimulated emission spectroscopy. AB - Iron overload disorders have been the focus of several quantification studies involving non-invasive imaging modalities. Neutron spectroscopic techniques have demonstrated great potential in detecting iron concentrations within biological tissue. We are developing a neutron spectroscopic technique called neutron stimulated emission computed tomography (NSECT), which has the potential to diagnose iron overload in the liver at clinically acceptable patient dose levels through a non-invasive scan. The technique uses inelastic scatter interactions between atomic nuclei in the sample and incoming fast neutrons to non-invasively determine the concentration of elements in the sample. This paper discusses a non tomographic application of NSECT investigating the feasibility of detecting elevated iron concentrations in the liver. A model of iron overload in the human body was created using bovine liver tissue housed inside a human torso phantom and was scanned with a 5 MeV pulsed beam using single-position spectroscopy. Spectra were reconstructed and analyzed with algorithms designed specifically for NSECT. Results from spectroscopic quantification indicate that NSECT can currently detect liver iron concentrations of 6 mg g(-1) or higher and has the potential to detect lower concentrations by optimizing the acquisition geometry to scan a larger volume of tissue. The experiment described in this paper has two important outcomes: (i) it demonstrates that NSECT has the potential to detect clinically relevant concentrations of iron in the human body through a non invasive scan and (ii) it provides a comparative standard to guide the design of iron overload phantoms for future NSECT liver iron quantification studies. PMID- 18443388 TI - Real-time 3D motion tracking for small animal brain PET. AB - High-resolution positron emission tomography (PET) imaging of conscious, unrestrained laboratory animals presents many challenges. Some form of motion correction will normally be necessary to avoid motion artefacts in the reconstruction. The aim of the current work was to develop and evaluate a motion tracking system potentially suitable for use in small animal PET. This system is based on the commercially available stereo-optical MicronTracker S60 which we have integrated with a Siemens Focus-220 microPET scanner. We present measured performance limits of the tracker and the technical details of our implementation, including calibration and synchronization of the system. A phantom study demonstrating motion tracking and correction was also performed. The system can be calibrated with sub-millimetre accuracy, and small lightweight markers can be constructed to provide accurate 3D motion data. A marked reduction in motion artefacts was demonstrated in the phantom study. The techniques and results described here represent a step towards a practical method for rigid-body motion correction in small animal PET. There is scope to achieve further improvements in the accuracy of synchronization and pose measurements in future work. PMID- 18443389 TI - Depth-kymography: high-speed calibrated 3D imaging of human vocal fold vibration dynamics. AB - We designed and developed a laser line-triangulation endoscope compatible with any standard high-speed camera for a complete three-dimensional profiling of human vocal fold vibration dynamics. With this novel device we are able to measure absolute values of vertical and horizontal vibration amplitudes, length and width of vocal folds as well as the opening and closing velocities from a single in vivo measurement. We have studied, for the first time, the generation and propagation of mucosal waves by locating the position of its maximum vertical position and the propagation velocity. Precise knowledge about the absolute dimensions of human vocal folds and their vibration parameters has significant importance in clinical diagnosis and treatment as well as in fundamental research in voice. The new device can be used to investigate different kinds of pathological conditions including periodic or aperiodic vibrations. Consequently, the new device has significant importance in investigating vocal fold paralysis and in phonosurgical applications. PMID- 18443390 TI - Randomized controlled comparison of two cognitive behavioral therapies for obese children: mother versus mother-child cognitive behavioral therapy. AB - BACKGROUND: Parent-child treatments have been shown to be superior to child focused treatments of childhood obesity. Yet until now, the comparative effectiveness of parent-only and parent-child approaches has been little studied. METHOD: Fifty-six obese children and their families were randomly assigned to a 16-session cognitive behavioral therapy (CBT) for the parents only or for a combined treatment of parents and children. Children's percent overweight, the body mass index of their mothers, and behavioral and psychological problems of children and mothers were assessed. RESULTS: Both treatments reduced children's percent overweight significantly and equally by 6-month follow-up. Also both treatments provided similar results in reducing general behavior problems (externalizing and internalizing behavior problems), global and social anxiety, and depression. CONCLUSIONS: Our results point to a comparable efficacy of the two treatments. Further, psychological well-being of both mothers and children can be improved in a CBT for obese children and their parents. Future studies should focus on finding ways to improve the adherence of families to long-term treatment of obesity in childhood. PMID- 18443392 TI - Hypnosis upregulates the expression of immune-related genes in lymphocytes. PMID- 18443391 TI - Effects of a multifaceted psychiatric intervention targeted for the complex medically ill: a randomized controlled trial. AB - BACKGROUND: This study evaluated a multifaceted psychiatric intervention targeted at the complex medically ill identified by means of the INTERMED, an instrument to assess case complexity. METHODS: Of 885 rheumatology inpatients and diabetes outpatients who were assessed for eligibility, 247 were identified as complex (INTERMED score >20) and randomized to the intervention (n = 125, 84 rheumatology and 41 diabetes patients) or care as usual (n = 122, 78 rheumatology and 44 diabetes patients). For the majority of the cases the multifaceted intervention consisted of an intervention conducted by a psychiatric liaison nurse and/or of referral to a liaison psychiatrist, followed by advice to the treating physician or organization of a multidisciplinary case conference. Baseline and follow-up at months 3, 6, 9 and 12 measured prevalence of major depression (Mini-International Neuropsychiatric Interview), depressive symptoms (Center for Epidemiological Studies Depression Rating Scale), physical and mental health (SF-36), quality of life (EuroQol), health care utilization and HbA(1c) levels (diabetic patients). RESULTS: Prevalence of major depression was reduced from 61% (T0) to 28% (T4) in the intervention group and remained stable in care as usual (57% at T0 to 50% at T4). Compared to care as usual, significant improvement over time was observed in the intervention group with regard to depressive symptoms (F = 11.9; p = 0.001), perception of physical (F = 5.7; p = 0.018) and mental health (F = 3.9; p = 0.047) and quality of life (F = 21.8; p < 0.001). Effects tended to be stronger in diabetes patients, in patients with baseline major depression and in patients with moderate INTERMED scores. Finally, hospital admissions occurred less often in the intervention group, reaching statistical significance for the period between 6 and 9 months of follow-up (p = 0.02). CONCLUSIONS: The results suggest that a psychiatric intervention targeted for complex medical patients can improve health outcomes. PMID- 18443393 TI - A pilot group therapy for functional memory disorder. PMID- 18443394 TI - Impact of severe childhood sexual abuse on the development of alexithymia in adulthood. PMID- 18443395 TI - Comparison of the efficacy of nasal drop and nasal spray applications of fluticasone propionate in nasal polyps. AB - OBJECTIVES: We assessed the efficacy of different forms of fluticasone propionate in the treatment of bilateral nasal polyposis in adult patients. PATIENTS AND METHODS: This double-blind, randomized, parallel group study included 34 patients, aged 16 years or over, with a diagnosis of bilateral nasal polyposis. The patients were randomized to three groups to receive fluticasone propionate in the form of aqueous nasal spray 100 microg twice daily, or nasal drop preparation 400 microg once or twice daily for 12 weeks. Once every four weeks, nasal volumes were measured by acoustic rhinometry and polyp size was assessed by a 4-mm rigid endoscope. Clinical symptom scores were assessed once a week. RESULTS: The mean nasal polyp scores decreased significantly in all the groups (p<0.005). Total nasal volume did not improve significantly with the nasal spray. Although single daily nasal drop application increased total nasal volume significantly only at the end of treatment (p<0.05), increases with twice daily application were significant at 4, 8, and 12 weeks, compared to the baseline values and corresponding values of the other two groups (p<0.005). Nasal blockage and rhinitis symptom scores improved in all the groups (p<0.05), but the difference from the baseline was highest with twice daily nasal drop application. Smelling showed a significant improvement only with twice daily nasal drop application (p<0.05). In none of the groups did nasal discomfort scores differ significantly from the baseline at the end of treatment. CONCLUSION: Nasal drop preparation of fluticasone propionate given twice daily showed the highest efficacy in increasing total nasal volume, decreasing nasal polyp size, and improving smelling and nasal blockage. PMID- 18443396 TI - [The relationship between lymph node size and metastasis and extracapsular spread in squamous cell carcinoma of the larynx, orohypopharynx, and oral cavity]. AB - OBJECTIVES: We examined the relationship between lymph node size and metastasis and extracapsular spread (ECS) in patients who underwent neck dissection for squamous cell carcinoma of the larynx, orohypopharynx, or oral cavity. PATIENTS AND METHODS: We retrospectively evaluated a total of 200 neck dissections performed in 128 patients (107 males, 21 females; mean age 56+/-11 years; range 26 to 81 years) with squamous cell carcinoma of the larynx, orohypopharynx, or oral cavity, and having complete clinical and pathologic data. Along with 442 metastatic lymph nodes (139 with ECS), the greatest axial diameter of the biggest benign lymph node obtained from each patient was measured. Lymph nodes were classified according to the neck zone and size, and the relationship of lymph node size with metastasis and ECS was examined. RESULTS: Lymph nodes with metastasis and ECS were often 11 to 30 mm in size and the highest rates of metastasis and ECS were seen in lymph nodes measuring 31 to 60 mm. However, approximately 40% and 25% of lymph nodes with metastasis and ECS, respectively, were in the range of 1 to 10 mm, which is not clinically accepted as pathologic. CONCLUSION: In larynx, orohypopharynx, and oral cavity squamous cell carcinomas, the clinical assessment of the size of neck lymph nodes is usually not a predictor for lymph node metastasis or ECS. Thus, until methods like sentinel lymph node biopsy become standard to determine occult metastasis, the importance of elective neck dissections is still valid in clinically N0 necks. PMID- 18443397 TI - The effect of naproxen sodium on experimental otitis media. AB - OBJECTIVES: We evaluated the effect of naproxen sodium on propylene glycol induced otitis media in guinea pig ears. MATERIALS AND METHODS: Twenty adult guinea pigs were randomized to the study and control groups equal in number. A single dose of propylene glycol (0.2 ml, 60%) was applied to the left ears of the control group and to both ears of the study group. Saline solution was applied to the right ears of the control group. After propylene glycol application, the study group received naproxen sodium (oral, 10 mg/kg daily) for 15 days, whereas the control ears were left untreated. At the end of four weeks, the animals were decapitated under anesthesia. Otoscopic examination was performed and temporal bones were removed for histologic examination under light microscopy. RESULTS: Nine animals were alive in each group at the end of four weeks. In the control group, all the right ears receiving saline solution were normal, whereas otitis media and inflammatory changes were observed in six of the left ears receiving propylene glycol. In the study animals treated with naproxen sodium, otitis media and tympanic membrane perforation were seen in 14 ears. Of these, three ears had purulent, 11 ears had serous effusion. Epithelial hyperplasia (n=10), keratinizing epithelium and cholesteatoma formation (n=4) were also observed. CONCLUSION: Our results suggest that the administered dose of systemic naproxen sodium has no inhibitory effect on the development of inflammation and otitis media. PMID- 18443398 TI - [Evaluation of high frequency hearing thresholds in smokers]. AB - OBJECTIVES: We investigated whether high frequency hearing thresholds differed between smokers and nonsmokers. SUBJECTS AND METHODS: The study was carried out in 50 individuals including 20 nonsmokers (mean age 29 years; range 25 to 37 years) and 30 smokers (mean age 34 years; range 25 to 50 years). The smokers group was comprised of individuals who had been smoking at least a pack a day for more than 10 years. High frequency hearing thresholds (8-18 kHz) were compared between the two groups. RESULTS: The mean hearing thresholds of smokers at 16 kHz were 50.66 dB HL and 49.50 dB HL in the left and right ears, respectively; the corresponding figures for nonsmokers were 31.00 dB HL and 33.25 dB HL, respectively (p=0.005). The mean hearing thresholds of smokers and nonsmokers at 18 kHz were 57.33 dB HL and 41.25 dB HL for the left ears, and 59.33 dB HL and 42.52 dB HL for the right ears, respectively (p=0.005). Analyses between the two groups after exclusion of subjects over 40 years of age showed significant differences at 16 kHz and at 18 kHz for the left ears, and at 18 kHz for the right ears (p=0.005). CONCLUSION: Our results suggest that smoking can be considered one of the factors that plays a role in high frequency hearing loss. PMID- 18443399 TI - [Comparison between bipolar cautery dissection and classic dissection techniques in tonsillectomy]. AB - OBJECTIVES: We compared the results of tonsillectomy performed by classical dissection and bipolar cautery dissection in pediatric patients. PATIENTS AND METHODS: A total of 201 pediatric patients were randomly assigned to two tonsillectomy groups. Ninety-five patients (62 boys, 33 girls; mean age 7+/-3 years) underwent bipolar cautery tonsillectomy, and 106 patients (58 boys, 48 girls; mean age 8+/-3 years) underwent classical dissection tonsillectomy. Patients were compared with respect to bleeding during tonsillectomy, operation time, tonsil volumes, primary and secondary bleeding, severity of pain at the first hour and on the tenth day, and time to first solid food intake. RESULTS: With bipolar cautery tonsillectomy, the mean operation time, amount of perioperative bleeding, and pain score at the first hour were significantly lower (p<0.001). However, the mean pain score on the tenth day was significantly higher with cautery tonsillectomy, which significantly prolonged initiation of solid food intake (p<0.001). There were no significant differences between the two groups with respect to tonsil volumes and initiation of cold fluid nutrition at the third postoperative hour (p>0.05). In the late postoperative period, one patient in each group required intervention under general anesthesia to control bleeding. CONCLUSION: Merits and demerits of both techniques should be taken into consideration for appropriate patient selection for the two tonsillectomy methods. PMID- 18443400 TI - [Use of dehydrated temporal fascia in chronic otitis media surgery and tympanoplasty]. AB - OBJECTIVES: We evaluated the use of homograft dehydrated temporal fascia (Tutoplast) in repair of tympanic membrane perforations secondary to chronic otitis media. PATIENTS AND METHODS: Dehydrated temporal fascia was used during tympanoplasty in 17 patients (10 females, 7 males; mean age 34 years; range 15 to 53 years) with chronic otitis media. Operations were type 1 tympanoplasty in six patients, tympanoplasty and mastoidectomy in three patients, and revision tympanoplasty and/or mastoidectomy in the remaining patients. The patients were followed-up for at least two years. RESULTS: Complete wound healing was achieved without complications, and the material used was well tolerated in all the patients. Only one patient had a small perforation. The tympanic membranes were anatomically intact in 16 patients (94%). CONCLUSION: The use of dehydrated temporal fascia provides maximum microsurgical comfort due to its soft, flexible feature and maintenance of its delicacy even in contact with blood. Thus, dehydrated temporal fascia should be considered for selected cases for its ease of use and anatomical success. PMID- 18443401 TI - [The effect of suturing technique and nasal packing on oxidative stress in septoplasty operations]. AB - OBJECTIVES: We investigated the effect of nasal packing or suturing of the nasal septum after septoplasty on oxidative stress. PATIENTS AND METHODS: The study included 37 patients who underwent septoplasty for isolated septal deviation. At the end of the operation, intranasal packing was used in 18 patients (5 women, 13 men; mean age 30+/-10 years; range 18 to 47 years), and nasal septal suturing was used in 19 patients (5 women, 14 men; mean age 31+/-12 years; range 18 to 54 years). Nasal packs were removed after 48 hours. Plasma levels of malondialdehyde (MDH), total sulphydryl content (SH), and nitric oxide (NO) were measured at four sequential times to evaluate oxidative stress. RESULTS: There were no significant changes in plasma levels of MDH, SH, and NO in both treatment groups (p>0.05). Levels of MDH and NO did not differ significantly at four sequential times between the two treatment groups, whereas postoperative SH levels were always significantly higher following septal suturing (p<0.05). CONCLUSION: High levels of SH observed in the suturing group favor this technique over nasal packing application in terms of antioxidant systems and oxidative stress. PMID- 18443402 TI - [A case of herpetic facial paralysis in which cochleovestibular symptoms outweigh facial nerve symptoms]. AB - A 42-year-old man presented with sensorineural hearing loss of acute onset, tinnitus, and vertigo. Physical examination revealed slight asymmetry in facial nerve functions and spontaneous nystagmus. Magnetic resonance imaging of the internal acoustic canal showed contrast enhancement consistent with edema inflammation, being notable and diffuse in the seventh and eighth cranial nerve complex, and minimal in the cochlea. Non-hydropic cochleovestibular syndrome was considered and the patient was treated with antiviral and corticosteroid medications. A week later, facial paralysis improved and the acute hearing loss reversed. On the twelfth day of presentation, he had no complaints other than mild imbalance on abrupt changes in movement. In this type of herpetic facial paralysis in which cochleovestibular symptoms outweigh facial nerve symptoms, it might be argued that varicella zoster virus reactivation occurs in the spiral and/or vestibular ganglion. PMID- 18443403 TI - Treatment of mucoepidermoid carcinoma of the parotid gland and successful repair of iatrogenic facial nerve paralysis. AB - A 15-year-old female patient developed facial nerve paralysis following surgical excision of a right parotid mass at another center. The histopathologic diagnosis of the lesion was mucoepidermoid carcinoma. On admission to our clinic, she underwent extended total parotidectomy and functional neck dissection. For facial nerve reanimation, cervical plexus nerve grafting was performed for frontal and buccal branches, and ansa hypoglossi anastomosis for the marginal mandibular branch. Postoperative radiotherapy was administered. Facial nerve functions returned to normal in the postoperative sixth month (House-Brackmann grade II). No locoregional recurrence or distant metastasis occurred in the follow-up period. PMID- 18443404 TI - [A case of severe rhinophyma]. AB - Rhinophyma is a benign disease of the nasal skin causing cosmetic and functional disturbances. Its etiology remains uncertain. Surgery is the most common treatment of choice. A 55-year-old man with severe rhinophyma was treated with total excision of the involved tissue and sebaceous glands, and the defect was reconstructed with full-thickness skin graft. No recurrence was seen during a two year follow-up period, and cosmetic and functional outcome was satisfactory. PMID- 18443405 TI - [A case of isolated aspergillosis of the maxillary sinus]. AB - Aspergillosis of the maxillary sinus is rarely seen in nonimmunocompromised patients. Among paranasal sinus infections associated with aspergillosis, the most common subtype is Aspergillus fumigatus. A 41-year-old woman presented with facial pain. She had a five-year history of root canal filling in the right upper molar teeth. Paranasal sinus tomography showed fungal sinusitis of radiopaque appearance, giving the impression of a foreign body in the maxillary sinus. The patient underwent endoscopic sinus surgery to purge infection of the maxillary sinus. Pathological examination revealed aspergillosis of the maxillary sinus. PMID- 18443406 TI - [Treatment of olfactory neuroblastoma via subfrontal and midfacial degloving approaches: a case report]. AB - A 12-year-old girl presented with complaints of nasal obstruction and a right infraorbital swelling. A biopsy obtained from the right nasal passage revealed olfactory neuroblastoma. The tumor was completely excised via subfrontal craniofacial and midfacial degloving approaches. No recurrence was observed during a three-year follow-up. PMID- 18443407 TI - Two genetic lineages of sea slaters, Ligia (Crustacea: Isopoda) in South Korea: a population genetic approach. AB - In this study, the species composition and population genetic properties of the sea slater, Ligia, in South Korea were investigated using mitochondrial and nuclear gene sequences. Two groups of sea slaters, genetically isolated from each other, a Western Group (WG) and an Eastern Group (EG) were identified. These groups exhibited considerable genetic divergence from Ligia exotica, previously recorded as a species inhabiting this country. These results indicate that there may be two species of Ligia in South Korea, but there is a small probability that both groups are L. exotica. A comparison of their genetic properties indicates that WG has a higher effective population size than EG, and that EG may have experienced a recent expansion, implying that it has a shorter history in South Korea than WG. These findings suggest that the South Korean sea slater populations may have been established as a result of several colonization events that can be traced on a continental scale by phylogeographic studies of sea slaters. PMID- 18443408 TI - Glyco-engineering of biotherapeutic proteins in plants. AB - Many therapeutic glycoproteins have been successfully generated in plants. Plants have advantages regarding practical and economic concerns, and safety of protein production over other existing systems. However, plants are not ideal expression systems for the production of biopharmaceutical proteins, due to the fact that they are incapable of the authentic human N-glycosylation process. The majority of therapeutic proteins are glycoproteins which harbor N-glycans, which are often essential for their stability, folding, and biological activity. Thus, several glyco-engineering strategies have emerged for the tailor-making of N glycosylation in plants, including glycoprotein subcellular targeting, the inhibition of plant specific glycosyltranferases, or the addition of human specific glycosyltransferases. This article focuses on plant N-glycosylation structure, glycosylation variation in plant cell, plant expression system of glycoproteins, and impact of glycosylation on immunological function. Furthermore, plant glyco-engineering techniques currently being developed to overcome the limitations of plant expression systems in the production of therapeutic glycoproteins will be discussed in this review. PMID- 18443409 TI - New players in the BRCA1-mediated DNA damage responsive pathway. AB - DNA damage checkpoint is an important self-defense mechanism for the maintenance of genome stability. Defects in DNA damage signaling and repair lead to various disorders and increase tumor incidence in humans. In the past 10 years, we have identified many components involved in the DNA damage-signaling pathway, including the product of breast cancer susceptibility gene 1 (BRCA1). Mutations in BRCA1 are associated with increased risk of breast and ovarian cancers, highlighting the importance of this DNA damage-signaling pathway in tumor suppression. While it becomes clear that BRCA1 plays a crucial role in the DNA damage responsive pathway, exactly how BRCA1 receives DNA damage signals and exerts its checkpoint function has not been fully addressed. A series of recent studies reported the discovery of many novel components involved in DNA damage signaling pathway. These newly identified checkpoint proteins, including RNF8, RAP80 and CCDC98, work in concern in recruiting BRCA1 to DNA damage sites and thus regulate BRCA1 function in G2/M checkpoint control. This review will summarize these recent findings and provide an updated view of the regulation of BRCA1 in response to DNA damage. PMID- 18443410 TI - Upregulation by KCl treatment of eukaryotic translation elongation factor 1A (eEF1A) mRNA in the dendrites of cultured rat hippocampal neurons. AB - Activity-dependent local translation in the dendrites of brain neurons plays an important role in the synapse-specific provision of proteins necessary for strengthening synaptic connections. In this study we carried out combined fluorescence in situ hybridization (FISH) and immunocytochemistry (IC) and showed that more than half of the eukaryotic elongation factor 1A (eEF1A) mRNA clusters overlapped with or were immediately adjacent to clusters of PSD-95, a postsynaptic marker, in the dendrites of cultured rat hippocampal neurons. Treatment of the neurons with KCl increased the density of the dendritic eEF1A mRNA clusters more than two-fold. FISH combined with IC revealed that the KCl treatment increased the density of eEF1A mRNA clusters that overlapped with or were immediately adjacent to PSD-95 clusters. These results indicate that KCl treatment increases both the density of eEF1A mRNA clusters and their synaptic association in dendrites of cultured neurons. PMID- 18443411 TI - Cyclic mechanical stretch stimulates the proliferation of C2C12 myoblasts and inhibits their differentiation via prolonged activation of p38 MAPK. AB - Mitogen-activated protein kinases (MAPKs) play an indispensable role in activation of the myogenic program, which is responsive to mechanical stimulation. Although there is accumulating evidence of mechanical force-mediated cellular responses, the role of MAPK in regulating the myogenic process in myoblasts exposed to cyclic stretch is unclear. Cyclic stretch induced the proliferation of C2C12 myoblasts and inhibited their differentiation into myotubes. In particular, it induced persistent phosphorylation of p38 kinase, and decreased the level of phosphorylation of extracellular-signal regulated kinase (ERK). Partial inhibition of p38 phosphorylation increased cellular levels of MyoD and p-ERK in stretched C2C12 cells, along with increased myotube formation. Treatment with 10 microM PD98059 prevented myogenin expression in response to a low dose of SB203580 (3 microM) in the stretched cells, suggesting that adequate ERK activation is also needed to allow the cells to differentiate into myotubes. These results suggest that cyclic stretch inhibits the myogenic differentiation of C2C12 cells by activating p38-mediated signaling and inhibiting ERK phosphorylation. We conclude that p38 kinase, not ERK, is the upstream signal transducer regulating cellular responses to mechanical stretch in skeletal muscle cells. PMID- 18443412 TI - Development of near-isogenic Japonica rice lines with enhanced resistance to Magnaporthe grisea. AB - Thirteen near-isogenic lines (NILs) of japonica rice were developed via a backcross method using the recurrent parent Chucheong, which is of good eating quality but is susceptible to Magnaporthe grisea, and three blast resistant japonica donors, Seolak, Daeseong and Bongkwang. The agro-morphological traits of these NILs, such as heading date, culm length, and panicle length, were similar to those of Chucheong. In a genome-wide scan using 158 SSR markers, chromosome segments of Chucheong were identified in most polymorphic regions of the 13 NIL plants, and only a few chromosome segments were found to have been substituted by donor alleles. The genetic similarities of the 13 NILs to the recurrent parent Chucheong averaged 0.961, with a range of 0.932-0.984. Analysis of 13 major blast resistance (R) genes in these lines using specific DNA markers showed that each NIL appeared to contain some combination of the four R genes, Pib, Pii, Pik-m and Pita-2, with the first three genes being present in each line. Screening of nine M. grisea isolates revealed that one NIL M7 was resistant to all nine isolates; the remaining NILs were each resistant to between three and seven isolates, except for NIL M106, which was resistant to only two isolates. In a blast nursery experiment, all the NILs proved to be more resistant than Chucheong. These newly developed NILs have potential as commercial rice varieties because of their increased resistance to M. grisea combined with the desirable agronomic traits of Chucheong. They also provide material for studying the genetic basis of blast resistance. PMID- 18443413 TI - Regulation of leaf senescence by NTL9-mediated osmotic stress signaling in Arabidopsis. AB - Leaf senescence is a highly regulated genetic process that constitutes the last stage of plant development and provides adaptive fitness by relocating metabolites from senescing leaves to reproducing seeds. Characterization of various senescence mutants, mostly in Arabidopsis, and genome-wide analyses of gene expression, have identified a wide array of regulatory components, including transcription factors and enzymes as well as signaling molecules mediating growth hormones and environmental stress responses. In this work we demonstrate that a membrane-associated NAC transcription factor, NTL9, mediates osmotic stress signaling in leaf senescence. The NTL9 gene is induced by osmotic stress. Furthermore, activation of the dormant, membrane-associated NTL9 is elevated under the same conditions. A series of senescence-associated genes (SAGs) were upregulated in transgenic plants overexpressing an activated form of NTL9, and some of them were slightly but reproducibly downregulated in a T-DNA insertional NTL9 knockout mutant. These observations indicate that NTL9 mediates osmotic stress responses that affect leaf senescence, providing a genetic link between intrinsic genetic programs and external signals in the control of leaf senescence. PMID- 18443414 TI - Comparison of molecular linkage maps and QTLs for morphological traits in two reciprocal backcross populations of rice. AB - Comparison of maps and QTLs between populations may provide us with a better understanding of molecular maps and the inheritance of traits. We developed and used two reciprocal BC1F1 populations, IP/DS//IP and IP/DS//DS, for QTL analysis. DS (Dasanbyeo) is a Korean tongil-type cultivar (derived from an indica x japonica cross and similar to indica in its genetic make-up) and IP (Ilpumbyeo) is a Korean japonica cultivar. We constructed two molecular linkage maps corresponding to each backcross population using 196 markers for each map. The length of each chromosome was longer in the IP/DS//IP population than in the IP/DS//DS population, indicating that more recombinants were produced in the IP/DS//IP population. Distorted segregation was observed for 44 and 19 marker loci for the IP/DS//IP and IP/DS//DS populations, respectively; these were mostly skewed in favor of the indica alleles. A total of 36 main effect QTLs (M-QTLs) and 15 digenic epistatic interactions (E-QTLs) were detected for the seven traits investigated. The phenotypic variation explained (PVE) by M-QTLs ranged from 3.4% to 88.2%. Total PVE of the M-QTLs for each trait was significantly higher than that of the E-QTLs. The total number of M-QTLs identified in the IP/DS//IP population was higher than in the IP/DS//DS population. However, the total PVE by the M-QTLs and E-QTLs together for each trait was similar in the two populations, suggesting that the two BC1F1 populations are equally useful for QTL analysis. Maps and QTLs in the two populations were compared. Eleven new QTLs were identified for SN, SF, GL, and GW in this study, and they will be valuable in marker-assisted selection, particularly for improving grain traits in tongil-type varieties. PMID- 18443415 TI - Enhanced calreticulin expression promotes calcium-dependent apoptosis in postnatal cardiomyocytes. AB - Calreticulin (CRT) is one of the major Ca2+ binding chaperone proteins of the endoplasmic reticulum (ER) and an unusual luminal ER protein. Postnatally elevated expression of CRT leads to impaired development of the cardiac conductive system and may be responsible for the pathology of complete heart block. In this study, the molecular mechanisms that affect Ca2+-dependent signal cascades were investigated using CRT-overexpressing cardiomyocytes. In particular, we asked whether calreticulin plays a critical role in the activation of Ca2+-dependent apoptosis. In the cells overexpressing CRT, the intracellular calcium concentration was significantly increased and the activity of PKC and level of SECAR2a mRNA were reduced. Phosphorylation of Akt and ERKs decreased compared to control. In addition the activity of the anti-apoptotic factor, Bcl 2, was decreased and the activities of pro-apoptotic factor, Bax, p53 and caspase 8 were increased, leading to a dramatic augmentation of caspase 3 activity. Our results suggest that enhanced CRT expression in mature cardiomyocytes disrupts intracellular calcium regulation, leading to calcium-dependent apoptosis. PMID- 18443416 TI - Characterization of beef transcripts correlated with tenderness and moisture. AB - To identify transcriptional markers for beef traits related to meat tenderness and moisture, we measured the transcriptome of the Longissimus dorsi skeletal muscle in 10 Korean native cattle (KNC). We analyzed the correlation between the beef transcriptome and measurements of four different beef traits, shear force (SF), water holding capacity (WHC), cooking loss (CL), and loin eye area (LEA). We obtained non-overlapping and unique panels of genes showing strong correlations (|r|>0.8) with SF, WHC, CL, and LEA, respectively. Functional studies of these genes indicated that SF was mainly related to energy metabolism, and LEA to rRNA processing. Interestingly, our data suggested that WHC is influenced by protein metabolism. Overall, the skeletal muscle transcriptome pointed to the importance of energy and protein metabolism in determining meat quality after the aging process. The panels of transcripts for beef traits may be useful for predicting meat tenderness and moisture. PMID- 18443417 TI - Glial fibrillary acidic protein splice variants in hepatic stellate cells- expression and regulation. AB - The glial fibrillary acidic protein (GFAP) is traditionally used as a marker for astrocytes of the brain, and more recently for the hepatic stellate cells (HSCs) of the liver. Several GFAP splice variants have been previously reported in the astrocytes of the CNS and in the non-myelinating Schwann cells of the PNS. In this study, we investigate whether GFAP splice variants are present in the HSCs and their expression as a function of HSCs activation. Furthermore, the regulation of these transcripts upon treatment with interferon gamma (IFN-gamma) will be explored. Using semi-quantitative RT-PCR and real-time PCR, we examine the expression and regulation of GFAP splice variants in HSCs as well as their respective half-life. We discover that most of the GFAP splice variants (GFAPalpha, beta, delta, epsilon, and kappa) found in the neural system are also expressed in quiescent and culture-activated primary HSCs. Interestingly, GFAPalpha is the predominant form in quiescent and culture-activated primary HSCs, while GFAPbeta predominates in the SV40-immortalized activated HSC-T6. GFAP delta, epsilon, and kappa have similar half-lives of 10 hours, while GFAPbeta has a half-life of 17 hours. Treatment of HSC-T6 with IFN-gamma results in a significant 1.29-fold up-regulation of GFAPalpha; whereas the level of the other transcripts remains unchanged. In summary, GFAPalpha, beta, delta, epsilon, and kappa are present in HSCs. They are differentially regulated on the transcription level, implying a role of the 5' and 3' untranslated regions. PMID- 18443418 TI - Comparisons of recombinant protein expression in diverse natural isolates of Escherichia coli. AB - We assessed heterologous protein expression in 64 strains obtained from the Escherichia coli Reference (ECOR) collection, a collection representing diverse natural E. coli populations. A plasmid generating a glutathione S-transferase and plant carbonic anhydrase fusion protein (GST-CA) under the control of the tac promoter was introduced into the ECOR strains, and the quantity of the fusion protein was determined by SDS-PAGE. The foreign protein was generated at various levels, from very high (40 strains, high producers) to very low (six strains, low producers). Immunoblotting showed that the high producers expressed approximately 250-500 times more GST-CA protein than the low producers. The results of semi quantitative RT-PCR showed that the low producers generated mRNA levels comparable to those of the high producers, thereby suggesting that, at least in this case, inefficient translation is a major cause of the low production. We introduced a different plasmid, which expressed a maltose binding protein and plant guanylate kinase fusion protein (MBP-GK) into the six low producers. Interestingly, five of these expressed MBP-GK at very high levels. Thus, we conclude that the production of a particular protein from an expression vector can vary considerably, depending on the host strain. Strains in the ECOR collection could function as useful alternative hosts when a desired level of protein expression is not obtained from commonly used strains, such as E. coli K12 or B derivatives. PMID- 18443419 TI - Monocyte attachment and migration through collagen IV in diabetes mellitus. AB - The interactions between monocytes and extracellular matrix proteins have been implicated in atherosclerosis pathophysiology. In the present study we evaluated monocyte attachment and migration through oxidized and non-oxidized collagen IV. Monocyte attachment was tested on microwells coated with either native or oxidized collagen IV. Monocyte migration through collagen IV was examined on transwells. Monocytes derived from patients with diabetes mellitus showed an increased ability to attach and migrate through collagen IV as compared to those derived from healthy volunteers. Moreover, control monocytes attached to oxidized collagen at a higher degree, while they migrated through oxidized collagen at a lower degree, as compared to the native protein. Our results also showed the involvement of the alpha2 integrin subunit in the above phenomena suggesting a modified interaction between monocytes and collagen IV in diabetes mellitus. PMID- 18443420 TI - Kinetic analysis of the MAPK and PI3K/Akt signaling pathways. AB - Computational modeling of signal transduction is currently attracting much attention as it can promote the understanding of complex signal transduction mechanisms. Although several mathematical models have been used to examine signaling pathways, little attention has been given to crosstalk mechanisms. In this study, an attempt was made to develop a computational model for the pathways involving growth-factor-mediated mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase/protein kinase B (PI3K/Akt). In addition, the dynamics of the protein activities were analyzed based on a set of kinetic data. The simulation approach integrates the information on several levels and predicts systems behavior. The in-silico analysis conducted revealed that the Raf and Akt pathways act independently. PMID- 18443421 TI - GTP binding is required for SEPT12 to form filaments and to interact with SEPT11. AB - Septins are a family of filament-forming GTP-binding proteins involved in a variety of cellular process such as cytokinesis, exocytosis, and membrane dynamics. Here we report the biochemical and immunocytochemical characterization of a recently identified mammalian septin, SEPT12. SEPT12 binds GTP in vitro, and a mutation (Gly56 to Asn) in the GTP-binding motif abolished binding. Immunocytochemical analysis revealed that wild-type SEPT12 formed filamentous structures when transiently expressed in Hela cells whereas SEPT12G56A generated large aggregates. In addition, wild-type SEPT12 failed to form filaments when coexpressed with SEPT12G56A. We also observed that GTP-binding by SEPT12 is required for interaction with SEPT11 but not with itself. PMID- 18443422 TI - Improved resistance to oxidative stress by a loss-of-function mutation in the Arabidopsis UGT71C1 gene. AB - Approximately 120 UDP-glycosyltransferases (UGTs), which are classified into 14 distinct groups (A to N), have been annotated in the Arabidopsis genome. UGTs catalyze the transfer of sugars to various acceptor molecules including flavonoids. Previously, UGT71C1 was shown to glycosylate the 3-OH of hydroxycinnamates and flavonoids in vitro. Such secondary metabolites are known to play important roles in plant growth and development. To help define the role of UGT71C1 in planta, we investigated its expression patterns, and isolated and characterized a loss-of-function mutation in the UGT71C1 gene (named ugt71c1-1). Our analyses by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), microarray data mining, and histochemical detection of GUS activity driven by the UGT71C1 promoter region, revealed the tissue-specific expression patterns of UGT71C1 with highest expression in roots. Interestingly, upon treatment with methyl viologen (MV, paraquat), ugt71c1-1 plants displayed enhanced resistance to oxidative stress, and ROS scavenging activity was higher than normal. Metabolite profiling revealed that the levels of two major glycosides of quercetin and kaempferol were reduced in ugt71c1-1 plants. In addition, when exposed to MV-induced oxidative stress, eight representative ROS response genes were expressed at lower levels in ugt71c1-1 plants, indicating that ugt71c1-1 probably has higher non-enzymatic antioxidant activity. Taken together, our results indicate that ugt71c1-1 has increased resistance to oxidative stress, suggesting that UGT71C1 plays a role in some glycosylation pathways affecting secondary metabolites such as flavonoids in response to oxidative stress. PMID- 18443423 TI - Derivation of embryonic germ cells from post migratory primordial germ cells, and methylation analysis of their imprinted genes by bisulfite genomic sequencing. AB - The embryonic germ cell (EGCs) of mice is a kind of pluripotent stem cell that can be generated from pre- and post-migratory primordial germ cells (PGCs). Most previous studies on DNA methylation of EGCs were restricted to 12.5 days post coitum (dpc). This study was designed to establish and characterize murine EGC lines from migrated PGCs as late as 13.5 dpc and to estimate the degrees of methylation of their imprinted genes as well as of the non-imprinted locus, Oct4, using an accurate and quantitative method of measurement. We established five independent EGC lines from post migratory PGCs of 11.5-13.5 dpc from C57BL/6xDBA/2 F1 hybrid mouse fetuses. All the EGCs exhibited the typical features of pluripotent cells including hypomethylation of the Oct4 regulatory region. We examined the methylation status of three imprinted genes; Igf2, Igf2r and H19 in the five EGC lines using bisulfite genomic sequencing analysis. Igf2r was almost unmethylated in all the EGC lines irrespective of the their sex and stage of isolation; Igf2 and H19 were more methylated than Igf2r, especially in male EGCs. Moreover, EGCs derived at 13.5 dpc exhibited higher levels of DNA methylation than those from earlier stages. These results suggest that in vitro derived EGCs acquire different epigenotypes from their parental in vivo migratory PGCs, and that sex-specific de novo methylation occurs in the Igf2 and H19 genes of EGCs. PMID- 18443424 TI - Structure-function of the TNF receptor-like cysteine-rich domain of osteoprotegerin. AB - Osteoprotegerin (OPG) is a soluble decoy receptor that inhibits osteoclastogenesis and is closely associated with bone resorption processes. We have designed and determined the solution structures of potent OPG analogue peptides, derived from sequences of the cysteine-rich domain of OPG. The inhibitory effects of the peptides on osteoclastogenesis are dose-dependent (10( 6) M-10(-4) M), and the activity of the linear peptide at 10(-4) M is ten-fold higher than that of the cyclic OPG peptide. Both linear and cyclic peptides have a beta-turn-like conformation and the cyclic peptide has a rigid conformation, suggesting that structural flexibility is an important factor for receptor binding. Based on structural and biochemical information about RANKL and the OPG peptides, we suggest that complex formation between the peptide and RANKL is mediated by both hydrophobic and hydrogen bonding interactions. These results provide structural insights that should aid in the design of peptidyl-mimetic inhibitors for treating metabolic bone diseases caused by abnormal osteoclast recruitment. PMID- 18443425 TI - Novel linear DNA vaccines induce protective immune responses against lethal infection with influenza virus type A/H5N1. AB - Vaccine development for possible influenza pandemics has been challenging. Conventional vaccines such as inactivated and live attenuated virus preparations are limited in terms of production speed and capacity. DNA vaccination has emerged as a potential alternative to conventional vaccines against influenza pandemics. In this study, we use a novel, cell-free DNA manufacturing process (synDNA) to produce prototype linear DNA vaccines against the influenza virus type A/H5N1. This synDNA process does not require bacterial fermentation, so it avoids the use of antibiotic resistance genes and other nucleic acid sequences unrelated to the antigen gene expression in the actual therapeutic DNA construct. The efficacy of various vaccines expressing the hemagglutinin and neuraminidase proteins (H5N1 synDNA), hemagglutinin alone (H5 synDNA) or neuraminidase alone (N1 synDNA) was evaluated in mice. Two of the constructs (H5 synDNA and H5N1 synDNA) induced a robust protective immune response with up to 93% of treated mice surviving a lethal challenge of a virulent influenza A/Vietnam/1203/04 H5N1 isolate. In combination with a potent biological activity and simplified production footprint, these characteristics make DNA vaccines prepared with our synDNA process highly suitable as alternatives to other vaccine preparations. PMID- 18443426 TI - Targeting the hallmarks of cancer. PMID- 18443427 TI - Immunogenicity of DNA vaccines in humans: it takes two to tango. AB - Two recently completed phase I clinical trials with candidate HIV-1 vaccines demonstrated that DNA vaccines are, indeed, immunogenic in humans, even when administered through routine needle injections. However, the best use of this evolving technology lies in its potential to prime the host's immune system. Since the discovery of DNA immunization as a new method of vaccination in the early 1990s, the real value of this technology for human vaccine development was questioned due to the apparent poor immunogenicity in repeated early phase clinical studies when DNA plasmids were injected into humans by conventional needle injections. New results indicate that DNA vaccination can provide excellent priming effects to the human immune system, and high level, antigen specific antibody and T cell immune responses are elicited upon further stimulation through the employment of a different form of vaccine which contains antigens that match those included in the original priming DNA vaccine formulation. These findings in no way will reduce the value of DNA vaccines, instead, the roles of DNA vaccines should be redefined. It is very likely that DNA vaccine can be most useful by providing an antigen-specific immunologic help to other types of vaccines that are known to have low immunogenicity, including inactivated or recombinant protein-based subunit vaccines. PMID- 18443428 TI - Neither antibody to a group B streptococcal conjugate vaccine nor the vaccine itself is teratogenic in rabbits. AB - Group B Streptococcus (GBS) is a leading cause of human neonatal bacterial disease, resulting in pneumonia, sepsis, meningitis and sometimes, death. Supportive preclinical studies of GBS capsular polysaccharide (CPS)-protein conjugate vaccines have led to several phase 1 and phase 2 trials in healthy, non pregnant adults, which demonstrated that the vaccines, produced at the Channing Laboratory, were safe and immunogenic. However, evaluation of the safety and immunogenicity of a GBS conjugate vaccine administered to pregnant women demanded that it be manufactured under current good manufacturing practices (cGMP) and that it undergo developmental toxicity evaluation. In this report, we describe a GBS type III CPS-tetanus toxoid (III-TT) vaccine lot 3-1-96 manufactured and vialed under cGMP and our evaluation of the effect of this vaccine and of GBS type III CPS-specific antibody on conception and early- and late-stage fetal development in rabbits. III-TT lot 3-1-96 was compositionally similar to prototype III-TT lot 91-1, produced under non-GMP, and was potent in a mouse maternal vaccination-neonatal pup challenge model of GBS disease. Four groups of 30 female rabbits each were randomized to receive III-TT lot 3-1-96 vaccine, saline-alum, or combinations of these treatments before and after insemination. The dose of conjugated CPS on a weight basis was 1 microg/kg, mimicking the anticipated actual human dose. Based on the weight of the rabbits, this was 20- to 100-fold greater than the expected human dose. Does were pre-assigned to deliver litters naturally or have their kits delivered by Caesarean-section at gestation day 29, to assess late fetal development. Sera from does and kits were collected, and the presence of type III CPS-specific IgG was confirmed by quantitative ELISA. Based on all assessments, GBS type III-TT lot 3-1-96, nor antibody to it did not affect embryo fetal viability, sex ratio, growth or cause malformations (i.e., it was non-teratogenic). In addition, that III-TT lot 3-1-96 was found to be safe and immunogenic in two clinical studies involving healthy non-pregnant adults supports a clinical evaluation of this vaccine in pregnant women. PMID- 18443429 TI - Anti-ERBb4 targeted therapy combined with radiation therapy in prostate cancer. Results of in vitro and in vivo studies. AB - PURPOSE: To evaluate the efficiency of anti ErbB4 targeted therapy combined with irradiation (XRT) over each modality alone in prostate cancer. RESULTS: Clones with high ErbB4 expression grew faster than those with low ErbB4 expression. XRT inhibited the growth of both expressive and non-expressive ErbB4 cells, while mAb inhibited only high ErbB4-expressing cells. The combination of XRT and mAb resulted in a 30% reduction of the survival of high ErbB4 expressing cells over XRT alone (p = 0.013). In tumor bearing mice the tumor size in the combined arm was 1 mm at 4 weeks compared to 2-3 mm and 4-5 mm in the radiation and mAb arms (p' value of 0.02 and 0.087 respectively). METHODS: Clones with low and high expression of ErbB4 isolated by a limited dilution technique from an androgen independent Cl-1 cell line were used. The cells from these clones were exposed to XRT (single dose of 2-6 Gy) and to anti-ErbB4 monoclonal antibody (mAb). The XTT test was used to measure cell survival. In addition, tumor-bearing nude mice were treated either by XRT, mAb or by a combined treatment. Tumor sizes were recorded at given time points. CONCLUSION: Anti ErbB4 combined with XRT is possibly more effective than each modality alone in prostate cancer. PMID- 18443430 TI - Remarkable enhancement of cytotoxicity of onconase and cepharanthine when used in combination on various tumor cell lines. AB - Onconase (Onc), a ribonuclease from oocytes or early embryos of Northern Leopard frog (Rana pipiens), is cytostatic and cytotoxic to a variety of tumor lines in vitro, inhibits growth of tumors in animal in vivo models and is currently in Phase IIIb clinical trials for malignant mesothelioma where it displays antitumor activity with minor overall toxicity to the patient. One of the characteristic features of Onc is a synergism with a variety of other antitumor modalities. Cepharanthine (Cep), a biscoclaurine alkaloid from Stephania cepharantha Hayata, is widely used in Japan to treat variety of ailments. It also shows low toxicity to patients. The aim of the present study was to assess the interaction of these two drugs on different tumor cell lines. When human promyelocytic leukemia HL-60, histiomonocytic lymphoma U937, multiple myeloma RPMI-8228, prostate carcinoma DU 145 and prostate adenocarcinoma LNCaP cells were exposed to relatively low concentrations of Onc or Cep their growth rates were somewhat suppressed but the cells were still able to proliferate. Cell growth, however, was totally abolished in each of these cell lines when treated with Onc and Cep combined. The frequency of apoptosis was also many-fold higher in cultures treated with a combination of Onc and Cep than in respective cultures treated with Onc or Cep alone. The mechanism of the observed synergism is unclear but it may be associated with the Onc activity in targeting microRNAs and/or NFkappaB and Cep activity also targeting NFkappaB. The data suggest that the combination of these two drugs, that individually express a low toxic profile, may have strong antitumor potential. PMID- 18443431 TI - EphA2 overexpression promotes ovarian cancer growth. AB - BACKGROUND: Silencing EphA2 has been shown to result in anti-tumor efficacy. However, it is not known whether increasing EphA2 expression specifically results in increased tumor growth and progression. We examined the effects of stable EphA2 transfection into poorly invasive ovarian cancer cells with regard to in vitro invasive and in vivo metastatic potential. RESULTS: In low cell density, EphA2-overexpressing A2780 cells (A2780-EphA2) displayed less cell-cell contact, increased cell-extracellular matrix (ECM) attachment and anchorage-independent cell growth compared to empty vector controls. There was no significant effect on anchorage-dependent cell proliferation, migration or invasion. Increased expression of EphA2 promoted tumor growth and enhanced the metastatic potential in A2780-EphA2 human ovarian cancer xenografts. The overexpression of EphA2 resulted in enhanced microvessel density (MVD), but had no effect on tumor cell proliferation. METHODS: EphA2 gene was introduced into A2780 cells by retroviral infection. The effects of increased EphA2 expression were examined on cellular morphology, and anchorage-dependent and independent cell growth. Furthermore, the effect of EphA2 overexpression on metastatic ability was determined using an orthotopic nude mouse model of ovarian carcinoma. CONCLUSIONS: EphA2 promotes tumor growth by enhancing cell-ECM adhesion, increasing anchorage-independent growth and promoting angiogenesis. PMID- 18443432 TI - Sustained ERK activation is involved in the kaempferol-induced apoptosis of breast cancer cells and is more evident under 3-D culture condition. AB - In order to determine the effects of a variety of flavonoids, we applied differing amounts of several flavonoids to human breast cancer cells. Kaempferol treatment resulted in significant reduction of cell viability in the MCF-7 cells, although it exerted only minor effect on the cell viability of MDA-MB-231 or mammary epithelial HC-11 cells. Kaempferol was demonstrated to induce sustained ERK activation concomitantly with MEK1 and ELK1 activation, and this kaempferol induced apoptosis was suppressed by treatment with PD98059, the overexpression of a kinase-inactive ERK mutant, or ERK siRNA. Kaempferol treatment was shown to profoundly induce the generation of fluorescent DCF in the MCF-7 cells, and treatment with N-acetyl cysteine suppressed kaempferol-induced PARP cleavage. Moreover, because breast cancer is associated with increased collagen synthesis and accumulation, we utilized a collagen-based 3D culture method. Under the 3 dimensional culture condition employed herein, kaempferol treatment was shown to result in a significant reduction in cell viability, an effect which occurred in a dose-dependent manner. Compared with what was observed under conventional 2D culture condition, we observed more evident apoptotic cell death and ERK activation as the result of kaempferol treatment in a collagen-based 3D culture environment. Similar to the case of conventional 2D cultured cells, the addition of PD98059 significantly suppressed intracellular ROS production. Collectively, these results show that the sustained activation of the ERK signaling pathway is markedly involved in kaempferol-induced apoptosis of breast cancer MCF-7 cells, and that this effect is more evident under 3D culture condition. PMID- 18443473 TI - Dear sepsis trials, why do you like playing tricks on us? PMID- 18443474 TI - Targeting the lipopolysaccharides: still a matter of debate? AB - PURPOSE OF REVIEW: The intention of this article is to review endotoxin, host response to endotoxin, clinical significance of endotoxemia, past failed therapies targeting endotoxin, current therapeutic efforts in this area and the authors' opinion on the future of such therapy. RECENT FINDINGS: Endotoxin or lipopolysaccharide is implicated in the activation of cytokine release with the potential to lead to severe sepsis. Therapies targeting endotoxin are very appealing and remain a matter of study and debate. Antiendotoxin antibody studies did not show consistent benefit to warrant its approval for use. Lipid A analog, phospholipid emulsion, and ethyl pyruvate are currently being evaluated for potential clinical use. Polymyxin B as an antiendotoxin strategy has an unacceptable toxicity profile for routine use as an intravenous agent and its use in plasmapheris is too cumbersome. Curcumin and lipopolysaccharide binding peptides, although having a potentially desirable effect on ameliorating endotoxin toxicity, remain to be shown effective in clinical trials. The development of a vaccine against endotoxin carries promise. SUMMARY: The benefits of therapies targeting endotoxin remain to be elucidated. Clinical trials targeting populations with documented endotoxemia are more likely to provide an adequate test of this therapeutic approach. Prophylaxis of high-risk populations should also be considered. PMID- 18443433 TI - Evaluating the drug-target relationship between thymidylate synthase expression and tumor response to 5-fluorouracil. Is it time to move forward? AB - Thymidylate synthase is a target of 5-fluoruracil, a pyrimidine analog used to treat gastrointestinal and other cancers. The 5-fluorouracil metabolite, fluoro deoxyuridine monophosphate, forms a ternary complex with thymidylate synthase and 5,10-methylene tetrahydrofolate. The purpose of this study was to evaluate the time-honored connection between thymidylate synthase and 5-fluorouracil. From our literature search spanning reports from 1995 to 2007 published in journals having an impact factor greater than 2, we stratified the tumors within each article, according to low versus high thymidylate synthase expression. These groups were subdivided into responders, stable disease or disease progression. The relationship between thymidylate synthase expression and 5-fluorouracil response was analyzed for the overall group, as well as for subsets. Overall, the literature supported an approximately 2-fold inverse relationship between thymidylate synthase expression and response to 5-fluoruracil. We found no change in the trend for a relationship between thymidylate synthase and 5-fluorouracil when the literature was stratified by date of publication, impact factor of the journal in which the report was published, or substrate (mRNA versus protein) for measuring thymidylate synthase expression. Of note, there is no significant change in the trend when comparing 5-fluorouracil treatment alone or in combination with leucovorin. We found a decline of this trend when certain chemotherapeutics were used in combination with 5-fluorouracil. In sum, the connection between thymidylate synthase expression and patient response to 5 fluorouracil does not satisfy expectations for an effective drug-target relationship; and thus, studies of the thymidylate synthase tandem repeat status might only be clinically valuable in regards to patient toxicity. Thus, we question the reliability of thymidylate synthase expression as a clinical predictor of 5-fluorouracil response. Future research could perhaps be directed towards alternate targets and metabolites of 5-fluorouracil, in an effort to find a clinically relevant biomarker panel for response and to optimize fluoropyrimidine-based therapy. PMID- 18443475 TI - Inhibition of potassium channels in critical illness. AB - PURPOSE OF REVIEW: The development of refractory arterial hypotension represents a significant problem in the treatment of critically ill patients, especially during sepsis. Increased activation of ATP-sensitive potassium channels in vascular smooth muscle cells is critically implicated in the pathophysiology of sepsis-induced vasodilation and vascular hyporesponsiveness to catecholamines. Pharmacological blockade of ATP-sensitive potassium channels has been proposed as a goal-directed therapeutic approach to stabilize hemodynamics in septic patients. RECENT FINDINGS: In different animal models of sepsis, ATP-sensitive potassium channel inhibition with intravenously infused sulfonylureas effectively reversed sepsis-induced systemic vasodilation and hypotension. Two recent clinical trials, however, failed to demonstrate beneficial effects of enterally administered glibenclamide on norepinephrine requirements and blood pressure in septic shock patients. Relevant problems related to ATP-sensitive potassium channel blockade with sulfonylureas in human septic shock include the route of administration (enteral versus intravenous) and the dose itself (benefit-risk relationship). In addition, significant adverse events may result from unspecific inhibition of nonvascular ATP-sensitive potassium channels. SUMMARY: Inhibition of ATP-sensitive potassium channels remains an attractive option to treat excessive vasodilation in the presence of systemic inflammation. Before this knowledge can be translated into clinical practice, however, future research is needed to define the role of ATP-sensitive potassium channels in critical illness and their specific inhibition in different tissues in more detail. PMID- 18443476 TI - Poly(ADP-ribose) polymerase: a new therapeutic target? AB - PURPOSE OF REVIEW: To overview the emerging data in the literature showing the role of poly(ADP-ribose) polymerase (PARP) in the pathogenesis of critical illness. RECENT FINDINGS: PARP, an abundant nuclear enzyme involved in DNA repair and transcriptional regulation, is now recognized as a key regulator of cell survival and cell death in response to noxious stimuli in various forms of cardiovascular collapse. PARP becomes activated in response to oxidative DNA damage and depletes cellular energy pools, thus leading to cellular dysfunction in various tissues. The activation of PARP may also induce various cell death processes, and promotes an inflammatory response. In circulatory shock PARP plays a crucial role both in the development of early cardiovascular dysfunction and in the delayed systemic inflammatory response syndrome with associated multiple organ failure. Inhibition of PARP activity is protective in various models of circulatory shock. SUMMARY: A solid body of literature supports the view that PARP is an important target for therapeutic intervention in critical illness. PMID- 18443477 TI - Arginine vasopressin in vasodilatory shock: effects on metabolism and beyond. AB - PURPOSE OF REVIEW: To describe the effects of arginine vasopressin other than its vasoconstrictive and antidiuretic potential in vasodilatory shock. RECENT FINDINGS: Arginine vasopressin influences substrate metabolism by stimulation of hepatic glucose release, gluconeogenesis, ureogenesis and fatty acid esterification. Although arginine vasopressin is a secretagogue of different hormones, only prolactin increases during arginine vasopressin therapy. Plasmatic and cellular coagulation are affected by arginine vasopressin, resulting in thrombocyte aggregation. Therefore, platelet count typically decreases following arginine vasopressin infusion in critically ill patients. In addition, arginine vasopressin reduces bile flow and may increase bilirubin concentrations. Despite its potential to decrease serum sodium, no change in electrolytes was observed in critically ill patients receiving arginine vasopressin. Although arginine vasopressin is an endogenous antipyretic, body temperature is not decreased by central venous arginine vasopressin infusion. In addition, arginine vasopressin modulates immune function through V1 receptors. Compared with norepinephrine, arginine vasopressin may have protective effects on endothelial function. Net arginine vasopressin effects on gastrointestinal motility seem to be inhibitory and are dose dependent. SUMMARY: Except for its antidiuretic and vasoconstrictive actions, the effects of arginine vasopressin in patients with vasodilatory shock have so far only been partially examined. Potential influences of arginine vasopressin on metabolism and immune, liver and mitochondrial function remain to be assessed in future studies. PMID- 18443478 TI - Early goal-directed therapy in severe sepsis and septic shock: a contemporary review of the literature. AB - PURPOSE OF REVIEW: Aggressive approaches to acute diseases such as acute myocardial infarction, trauma, and stroke have improved outcomes. Early goal directed therapy for severe sepsis and septic shock represents a similar approach. An analysis of the literature assessing external validity and generalizability of this intervention is lacking. RECENT FINDINGS: Eleven peer reviewed publications (1569 patients) and 28 abstracts (4429 patients) after the original early goal-directed therapy study were identified from academic, community and international settings. These publications total 5998 patients (3042 before and 2956 after early goal-directed therapy). The mean age, sex, APACHE II scores and mortality were similar across all studies. The mean relative and absolute risk reduction was 0.46 +/- 26% and 20.3 +/- 12.7%, respectively. These findings are superior to the original early goal-directed therapy trial which showed figures of 34% and 16%, respectively. A consistent and similar decrease in healthcare resource consumption was also found. SUMMARY: Early goal directed therapy modulates systemic inflammation and results in significant reductions in morbidity, mortality, and healthcare resource consumption. Early goal-directed therapy has been externally validated and is generalizable across multiple healthcare settings. Because of these robust findings, further emphasis should be placed on overcoming logistical, institutional, and professional barriers to implementation which can save the life of one of every six patients presenting with severe sepsis and septic shock. PMID- 18443479 TI - Vasopressor use in septic shock: an update. AB - PURPOSE OF REVIEW: This article reviews new findings on the use of vasopressor agents in septic shock. RECENT FINDINGS: Several recent large randomized clinical trials have compared vasopressor agents in patients with septic shock. Briefly, the survival of patients treated with norepinephrine alone or a combination of norepinephrine and dobutamine did not significantly differ from that of patients treated with epinephrine. In observational studies, dopamine use was associated with poor outcome. The results of a clinical trial comparing dopamine and norepinephrine as a first-line agent in septic shock are pending. The addition of low-dose vasopressin to norepinephrine did not significantly improve the survival of patients with septic shock. A positive effect on survival was observed in a predetermined (norepinephrine dose <15 microg/kg/min) subgroup of patients with moderate shock. There is no large randomized clinical trial on the use of terlipressin. In contrast, nitric oxide inhibitors were associated with increased mortality in patients with septic shock. SUMMARY: The use of norepinephrine or epinephrine can be left to the discretion of the treating physician. Low-dose vasopressin administration remains an option for catecholamine-refractory septic shock. The potential benefit of early use in combination with a moderate dose of norepinephrine remains to be determined. PMID- 18443480 TI - Critically elucidating the role of selenium. AB - PURPOSE OF REVIEW: To assess the current role of selenium supplementation in critically ill patients. RECENT FINDINGS: Studies consistently demonstrate decreased selenium concentration in plasma and whole blood in some critically ill patients, especially those with septic shock, and have suggested that persistent low concentrations may be associated with worse outcomes. However, clinical trials of selenium administration have not consistently or convincingly demonstrated improved outcomes. SUMMARY: Despite the low selenium content in the body (20-40 mg), selenoenzymes play an important role in antioxidant defense in humans. Selenium administration may be associated with improved outcomes, but further studies are needed to determine the precise mechanism of action. Studies are also needed to determine optimal dosing regimens, and to identify those patients in whom this approach is likely to be most effective. Currently, doses below the tolerable upper intake level (400 microg) may be used in supplementation. Higher doses (up to the level of no adverse effect, 800 microg) may be of interest and need to be studied further. The pro-oxidant effects of selenocompounds, especially sodium selenite, which vary depending on the compound, dose, and concentration, also need to be assessed further for their toxicity and potential therapeutic use in patients with septic shock. PMID- 18443481 TI - Role of glutamine supplementation in critically ill patients. AB - PURPOSE OF REVIEW: To update the documentation concerning the clinical use of glutamine supplementation in critically ill patients. Outcome, patient safety and future plans are examined. RECENT FINDINGS: In terms of outcome studies, the last 2 years have added little to our knowledge. A number of multi-centre studies are under way, however, which can be expected to give better evidence for the use of glutamine in the near future. In terms of patient safety, several new studies have demonstrated metabolic tolerance, vascular tolerance, losses in conjunction with continuous renal replacement therapy and the relation to intracerebral glutamate in head trauma. Glutamine losses in continuous renal replacement therapy are not negligible, and are actually a further argument for exogenous glutamine supplementation. Losses of supplemented glutamine into the dialysate are not a problem. SUMMARY: The use of intravenous glutamine supplementation in critically ill patients on total parenteral nutrition is currently the standard of care. The use of exogenous glutamine supplementation in critically ill patients on enteral nutrition is still not supported by sufficient evidence. The use of plasma glutamine concentration as an indicator for glutamine deficiency and a possible indicator for supplementation is suggested. PMID- 18443482 TI - Ethyl pyruvate. AB - PURPOSE OF REVIEW: Ethyl pyruvate is a simple derivative of the endogenous metabolite, pyruvic acid. Ethyl pyruvate was shown to ameliorate some of the structural and functional changes associated with mesenteric ischemia and reperfusion in rats. RECENT FINDINGS: Treatment with ethyl pyruvate has been shown to improve survival and ameliorate organ dysfunction in a wide variety of preclinical models of critical illnesses, such as severe sepsis, acute respiratory distress syndrome, burn injury, acute pancreatitis and stroke. Ethyl pyruvate has been shown to improve cardiac function after coronary ischemia and reperfusion. This ester was originally regarded as a way to administer pyruvate, while avoiding some of the problems associated with the instability of pyruvate in aqueous solutions. Increasingly, however, it is becoming apparent that certain pyruvate esters, including ethyl pyruvate, have pharmacological effects, such as suppression of inflammation, which are distinct from those exerted by pyruvate anion. Ethyl pyruvate has been tested in human volunteers and shown to be safe at clinically relevant doses. SUMMARY: Ethyl pyruvate is a simple molecule that has been shown to have salutary effects in numerous large and small animal models of critical illness. It remains to be determined whether this ester can be used successfully to treat human diseases. PMID- 18443483 TI - Role of levosimendan in sepsis and septic shock. AB - PURPOSE OF REVIEW: To present the pharmacologic and biologic profile of levosimendan and discuss potential indications in the treatment of sepsis and septic shock, with a special focus on myocardial and pulmonary dysfunction. RECENT FINDINGS: In animal models of endotoxic shock, levosimendan improved both left ventricular systolic and diastolic dysfunction, as well as ventriculovascular coupling. In addition, positive effects have been reported on right ventricular performance and pulmonary circulation. Two randomized, controlled trials in patients with septic shock revealed levosimendan provided consistent beneficial effects on cardiopulmonary performance, global oxygen transport, splanchnic perfusion and renal function. These effects have been reported as superior to placebo and the classic inotropic agent dobutamine. Due to its vasodilatory effects, combination with vasoconstrictor agents may be crucial in the presence of arterial hypotension. SUMMARY: There is increasing evidence that levosimendan exerts beneficial effects in the treatment of sepsis induced myocardial and pulmonary dysfunction. Future large-scale multicenter clinical trials are now needed to clarify whether levosimendan improves the overall outcome of patients with sepsis and septic shock. PMID- 18443484 TI - Teamwork and the legal and ethical responsibility of the anaesthetist. AB - PURPOSE OF REVIEW: Anaesthetists are members of the operating team. Although the surgeons usually consider themselves to be the leaders of the team, all members, including the anaesthetist, have their own legal, ethical and professional responsibilities. RECENT FINDINGS: Good communication and sharing responsibility are characteristics of teamwork. Many factors can affect team functioning: training differences, social status, differences in responsibility, gender, age and culture, among others. An increasing number of individuals are involved in modern treatment due to limited working hours and increasing subspecialization, which complicates collaboration. Not all participants have the same perception of the team structure and its operation. Multidisciplinary, well designed training programmes are needed. SUMMARY: Anaesthetists have to be more aware of their position in the care team and pay more attention to their legal, ethical and professional responsibilities. PMID- 18443485 TI - Critical incident monitoring in anaesthesia. AB - PURPOSE OF REVIEW: Updates on developments in critical incident monitoring in anaesthesia, and assesses its role in improving patient safety. RECENT FINDINGS: Critical incident reporting has become more widely accepted as an effective way to improve anaesthetic safety, and has continued to highlight the importance of human errors and system failures. The establishment of an international database also improves critical incident reporting. Experiences from the national reporting and learning system in the UK have provided some solutions to the many problems and criticisms faced by the critical incident reporting technique. Direct observations to detect errors are more accurate than voluntary reporting of critical incidents, and may be a promising new approach. SUMMARY: Critical incident monitoring is a valuable tool in ensuring patient safety due to its low cost and the ability to provide a comprehensive body of detailed qualitative information. The qualitative information gathered can be used to develop strategies to prevent and manage existing problems, as well as to plan further initiatives for patient safety. Novel approaches should complement existing methods to achieve better results. The development of a culture which emphasises safety should go hand in hand with current audit activities. PMID- 18443486 TI - Multimodal multidisciplinary standardization of perioperative care: still a long way to go. AB - PURPOSE OF REVIEW: The complexity of the perioperative care process has resulted in a suboptimal use of resources, quality problems and a relatively high incidence of errors. In an attempt to optimize resources, patient safety, and quality, multimodal, multidisciplinary standardization of the care process has become an increasingly recognized goal. RECENT FINDINGS: The anaesthesiologist as perioperative clinician plays a pivotal role in the development and implementation of standardized perioperative care. Historically, however, a significant portion of perioperative care has relied upon anecdotal information that represents an amalgam of any individual anaesthesiologist's collective influences and experiences. Current status of standardized perioperative care and different factors that influence successful implementation of guidelines, fast track surgery programs and clinical pathways are described. SUMMARY: Although recent literature indicates that standardization of perioperative care improves efficiency, quality, and patient satisfaction, implementation of standardized care is difficult since resistance is still enormous. PMID- 18443487 TI - Doing a few things right. PMID- 18443488 TI - Basic life support. AB - PURPOSE OF REVIEW: Bystander cardiopulmonary resuscitation increases the chances of survival after out-of-hospital cardiac arrest. Existing bystander cardiopulmonary resuscitation rates are poor. There are several strategies for increasing the frequency and effectiveness of bystander cardiopulmonary resuscitation. These include simplifying the technique for basic life support, emphasizing the importance of compressions over ventilation, reducing the length of training by using video-based self-instruction and widening the range of those trained to include school children. RECENT FINDINGS: A change in compression ventilation ratio from 15: 2 to 30: 2 increases the number of compressions delivered. There is some evidence that compression-only cardiopulmonary resuscitation may increase survival rates from out-of-hospital cardiac arrest. Video-based self-instruction enables laypeople to be trained in basic life support in a fraction of the time of traditional courses. School children can be taught basic life support and can be used to help disseminate the skill. SUMMARY: The optimal basic life support technique that will generate the highest survival rates from out-of-hospital cardiac arrest has not been determined, but there is increasing evidence that the existing technique needs to be simplified. Bystander cardiopulmonary resuscitation increases survival but it needs to be undertaken more frequently if overall survival rates are to be improved significantly. PMID- 18443489 TI - Feedback during cardiopulmonary resuscitation. AB - PURPOSE OF REVIEW: Current cardiopulmonary resuscitation guidelines emphasize that providing high-quality basic life support is the single most important contribution to successful resuscitation. Efficiency of advanced cardiac life support depends on sufficient cardiopulmonary resuscitation performance leading to continuous bloodflow and oxygenation. Existing data show that the quality of cardiopulmonary resuscitation performance is poor. Feedback technologies claim to improve cardiopulmonary resuscitation quality by supporting rescuers in their efforts. RECENT FINDINGS: Rescuers regularly fail to achieve chest compressions at sufficient frequency and depth. Interruption of chest compression whilst the patient is in cardiac arrest results in reduced chances for successful defibrillation and survival. ECG interpretation in cardiac arrest challenges rescuers and results in nonindicated defibrillations. In several simulator studies and clinical trails cardiopulmonary resuscitation performance was improved by introducing feedback elements. It remains unclear, however, to what extent feedback is needed and useful. SUMMARY: Since effective basic life support is crucial for victims of cardiac arrest, recent findings that cardiopulmonary resuscitation quality provided by professionals fails to achieve recommended levels is not acceptable. Efforts need to be made in order to improve cardiopulmonary resuscitation quality and to support rescuers by real-time feedback. The technical elements of cardiopulmonary resuscitation feedback need to be carefully studied before being introduced into practice. PMID- 18443490 TI - Pediatric resuscitation. AB - PURPOSE OF REVIEW: The new International Liaison Committee on Resuscitation documents, published in 2005, include important changes in pediatric resuscitation. Some issues that were left pending have since been supplemented with new studies. Their impact will be discussed here. RECENT FINDINGS: Studies on oxygen use for neonatal resuscitation have consistently found room air to be superior to 100% oxygen. Prospective studies indicate that intubation by first responders in preclinical resuscitation of children is dangerous and should probably be avoided. New studies point to a better neurological outcome with hypothermia in neurologically depressed neonates after perinatal asphyxia. SUMMARY: Resuscitation of 'depressed' near-term neonates should be started with an oxygen content of less than 100%, and only change to 100% if the child remains bradycardic and cyanotic. A neonate who can be resuscitated with room air will receive no benefit from 100% oxygen and may even have a worse outcome. If the first responder in a pediatric emergency is out of training with pediatric intubation he or she should feel reassured that resuscitation without an attempt at endotracheal intubation is acceptable. Presently, hypothermia in neonates after birth asphyxia should be used within controlled studies, or at least follow the protocols of published studies and be performed in specialized centers. PMID- 18443491 TI - Therapeutic hypothermia after out-of hospital cardiac arrest: how to secure worldwide implementation. AB - PURPOSE OF REVIEW: Despite the scientific evidence, therapeutic hypothermia in comatose out-of-hospital cardiac arrest survivors is still not widely used. It is unlikely that technical, logistical and financial barriers alone can explain the geographically large differences in its application. Our review focuses on how generic knowledge on implementation may help speed up the transfer of therapeutic hypothermia into daily practice. RECENT FINDINGS: In countries like Finland and Norway, rapid nationwide implementation has been obtained. Surveys from larger countries like the US, UK and Germany, however, show an overall low implementation rate of therapeutic hypothermia. Recent comparisons of outcome before and after implementation of therapeutic hypothermia in unselected groups of patients (effectiveness studies) show the same benefit as that found in previous randomized controlled trials (efficacy studies). New studies show that logistical, financial, technical and safety aspects cannot be considered barriers to the implementation of therapeutic hypothermia into daily practice. SUMMARY: More than 40 years after the late Peter Safar first suggested therapeutic hypothermia as standard therapy during postresuscitation care, worldwide implementation of this treatment seems possible. To secure this, however, hospitals and health systems must institute well defined implementation plans taking local cultural and organizational barriers into account. PMID- 18443492 TI - Preoperative resuscitation of the trauma patient. AB - PURPOSE OF REVIEW: The traditional approach to trauma patients with presumed internal hemorrhage has been immediate, aggressive intravenous fluid resuscitation. Recent experimental and clinical data, however, suggest a more discriminating approach that first considers concurrent head injury, hemodynamic stability and the presence of potentially uncontrollable hemorrhage (e.g. deep truncal injury) versus a controllable source (e.g. distal extremity wound) as well as the use of new techniques to inhibit bleeding and better ways to monitor the patient's condition. RECENT FINDINGS: Evolving data suggest that while aggressive fluid infusions could be used for patients with isolated extremity, thermal or head injury, they should be limited in conditions with potentially uncontrollable internal hemorrhage, and particularly in patients with penetrating truncal injury being transported immediately to a trauma center. Likewise, the minute volume of positive pressure ventilatory support should be limited with potential severe hemorrhage due to the secondary reductions in venous return. For trauma patients with severe bleeding there is growing evidence for the increased use of plasma and factor VIIa, as well as tourniquets, intraosseus devices and evolving monitoring techniques. SUMMARY: Owing to the growing societal threat of trauma, further research, including studies already under way, will be critical to delineate the timing and technique of infusing advantageous resuscitative fluids such as hypertonic saline and hemoglobin-based oxygen carriers as well as the use of hemostatic agents and special blood products. PMID- 18443493 TI - Paramedic versus emergency physician emergency medical service: role of the anaesthesiologist and the European versus the Anglo-American concept. AB - PURPOSE OF REVIEW: Much controversy exists about who can provide the best medical care for critically ill patients in the prehospital setting. The Anglo-American concept is on the whole to provide well trained paramedics to fulfil this task, whereas in some European countries emergency medical service physicians, particularly anaesthesiologists, are responsible for the safety of these patients. RECENT FINDINGS: Currently there are no convincing level I studies showing that an emergency physician-based emergency medical service leads to a decrease in overall mortality or morbidity of prehospital treated patients, but many methodical, legal and ethical issues make such studies difficult. Looking at specific aspects of prehospital care, differences in short-term survival and outcome have been reported when patients require cardiopulmonary resuscitation, advanced airway management or other invasive procedures, well directed fluid management and pharmacotherapy as well as fast diagnostic-based decisions. SUMMARY: Evidence suggests that some critically ill patients benefit from the care provided by an emergency physician-based emergency medical service, but further studies are needed to identify the characteristics and early recognition of these patients. PMID- 18443494 TI - The anesthesiologist in prehospital and hospital emergency medicine. AB - PURPOSE OF REVIEW: The German emergency medical system is different from the Anglo-American system. Emergency medicine is no distinct specialty in Germany. Physicians are involved in prehospital emergency medicine. This review highlights the historic development of prehospital and hospital emergency medicine in Germany and describes future trends. RECENT FINDINGS: Studies have shown that involvement of specially trained prehospital emergency physicians can result in reduced patient mortality. The in-hospital emergency medicine structure is important for the 'chain of survival' for patients with life-threatening medical conditions. In-hospital emergency medicine has been reorganized in many hospitals during the last few years. New qualification criteria for physicians in emergency departments, therefore, need to be developed. SUMMARY: Economic and quality arguments have initiated the development of departments for emergency medicine in Germany. In the future, this will lead to new qualification criteria for physicians working in these departments. PMID- 18443495 TI - Quality management and benchmarking in emergency medicine. AB - PURPOSE OF REVIEW: Being critical in terms of time and complexity, emergency medicine is exposed to an emerging imperative for quality improvement strategies. We review current concepts and recent advances in the management of quality in emergency medicine. RECENT FINDINGS: There is a strong interdependence between quality of emergency healthcare provision and the education of emergency healthcare providers. Introduction of emergency medical residencies and highly qualified triage liaison physicians helps prevent the overcrowding of emergency departments, accelerate access to emergency medical care and improve patient satisfaction. New advances in detecting and reducing patient management errors include the collection of healthcare provider complaints and the classification of unpreventable and preventable deaths of patients within 1 week of admission via the emergency department. Medical record review and video recording have revealed that frequent patient management problems relate to shortcomings in the diagnostic process, clinical tasks, patient factors, and poor teamwork. Communication skills and patient data/documentation systems may effectively resolve these problems. SUMMARY: According to the available evidence, more performance improvement strategies need to be tested to delineate which process changes would be most effective in improving patient outcome in emergency medicine. PMID- 18443496 TI - Critical incident reporting system in emergency medicine. AB - PURPOSE OF REVIEW: This review summarizes the knowledge of error and of critical incident reporting systems in general and especially in emergency medicine. RECENT FINDINGS: Medicine is a high-risk area and emergency medicine in particular needs consequent use of critical incident reporting systems. We need a safety culture to learn from our mistakes and we need to discuss all mistakes regardless of hierarchical structures in medicine. SUMMARY: The first step in avoiding fatalities in emergency medicine is to accept that errors do occur. The next question is how to prevent errors in medicine and not to search for personal mistakes. We need a culture of error and not a culture of blame. Critical incidents occur in all ranges of medical hierarchical structures. We have to accept the presence of mistakes and we need to recognize them every day to protect our patients. PMID- 18443499 TI - Standing near the right people. PMID- 18443500 TI - Self-reported outcome after diode laser hair removal. AB - BACKGROUND: Laser-assisted photoepilation has become the procedure of choice for permanent hair reduction. Our purpose was to evaluate patient satisfaction with the procedure using a diode-laser system. METHOD: A self-administered survey was mailed to 220 patients who underwent treatment between 2000 and 2004. These questions addressed the area treated, number of treatments received, postprocedure hair density, and overall satisfaction. RESULTS: Of 220 patients, 114 (52%) completed the survey. Eighty percent of patients were either "very satisfied" or "somewhat satisfied." Forty percent of patients felt they achieved 75% hair reduction and 38% reported 50% hair reduction. The majority of patients required 5-6 treatments over 13-18 months for maximum improvement. Multiple treatments over this prolonged time were a significant deterrent to treatment completion. The majority of patients (91%) experienced no long-term side effects. CONCLUSION: Diode-laser hair removal is a safe, well-tolerated procedure. Our patient satisfaction is comparable to hair-count studies in the literature. PMID- 18443501 TI - A useful tool for intraoperative photography: underwater camera case. AB - The use of cameras in the operating room is increasing. However, there is not always a free person or an assistant who is familiar with your camera. In order to take faster and high quality photographs in the operating room, we use under water camera cases. These cases are produced for each type of camera and can be gas sterilized prior to operation. PMID- 18443502 TI - The rib-sparing technique for internal mammary vessel exposure in microsurgical breast reconstruction. AB - The internal mammary vessels are frequently used for free flap breast reconstruction and are typically dissected via resection of an entire rib cartilage. Resection of rib cartilage may cause increased postoperative pain or a depressed thoracic contour deformity. We have used a new, less invasive technique that does not resect rib cartilage and exposes the vessels within the rib interspace. Over a 3-year period, all breast free flaps performed with the rib sparing technique were reviewed and compared with a group of flaps performed with the standard rib resection technique. The rib-sparing technique was performed for 74 flaps, with no significant increase in complications, including revision of anastomosis (3%), fat necrosis (11%), or flap loss (1%), when compared with a group of 125 flaps undergoing rib resection. This less invasive technique is reviewed in detail and may prove beneficial in regard to postoperative pain and incidence of chest wall deformities. PMID- 18443503 TI - The impact of breast reconstruction on the oncologic efficacy of radiation therapy: a retrospective analysis. AB - Current indications for radiation therapy in women with breast cancer are controversial and continue to be modified. Current indications for breast reconstruction in the setting of radiation therapy are also controversial and poorly defined. The purpose of this study is to analyze oncologic outcomes following various methods of breast reconstruction in the setting of radiation therapy. A retrospective review of 676 women who had breast reconstruction following mastectomy was completed. A total of 146 women had breast reconstruction either before or after radiation therapy and were analyzed. Response variables included tumor recurrence and patient demise for patients having autologous and prosthetic reconstruction. Explanatory variables included patient age, cancer stage, radiation therapy, diabetes mellitus, and tobacco use. Recurrence of tumor occurred in 29 of 146 women (19.8%), of which 27% was when radiation followed reconstruction and 14.9% was when radiation preceded reconstruction. Patient demise occurred in 8.9%, of which 11.9% was when radiation followed reconstruction and 6.9% was when radiation preceded reconstruction. The difference in tumor recurrence in the setting of radiation therapy before or after breast reconstruction was significant for autologous (P = 0.0146) and prosthetic (P = 0.0424) reconstruction. The difference in patient demise was significant for autologous reconstruction (P = 0.0380) but not for prosthetic reconstruction (P = 0.2827). These results imply that tumor recurrence and patient demise may be increased when radiation therapy is performed following breast reconstruction. The need for a prospective inquiry is validated. PMID- 18443504 TI - A new method in tendon repair: angular technique of interlocking (ATIK). AB - BACKGROUND: The risk of adhesion following flexor tendon repair, despite provision of rehabilitation by mobilization of the tendon with passive exercises without the risk of rupture, is not negligible. Active mobilization of tendons has recently been more frequently recommended to prevent adhesions of tendons. The tendon repair zone, which should withstand active traction forces, should maintain its strength until complete recovery of the tendon. For this purpose, a new treatment method named angular technique of interlocking (ATIK) has been developed. This method was compared with the Modified Kessler method, in vivo and in vitro. MATERIALS AND METHODS: In four groups, each consisting of 10 chickens, severed flexor tendons repaired with the Modified Kessler and ATIK techniques were compared for biomechanical properties. RESULTS: Although there were no differences between these techniques in vitro, this new technique's superiority was statistically significant in in vivo studies. CONCLUSIONS: The second and third postoperative weeks are periods during which the number of fibroblasts and the amount of collagen are the highest. In these periods, edema resolves and sutures begin to loosen. In this situation, the force withstanding the active movements is the support of the suture materials and the degree of recovery of the tendon. Following this recommended suture technique and active movements, the healing potential of the tendon increases and the risk of tendon rupture owing to decrease in the force exerted per unit area decreases. PMID- 18443505 TI - Free digital artery flap: an ideal flap for large finger defects in situations where local flaps are precluded. AB - The heterodigital arterialized flap is increasingly accepted as a flap of choice for reconstruction of large finger wounds. However, in situations where the adjacent fingers sustained concomitant injuries, the use of this flap as a local flap is precluded. This paper describes our experience with the free digital artery flap as an evolution of the heterodigital arterialized flap. Four patients with large finger wounds were reconstructed with free digital artery flap. Our indications for digital artery free flap were concomitant injuries to adjacent fingers that precluded their use as donor sites. The arterial supply of the flap was from the digital artery and the venous drainage was from the dominant dorsal vein of the finger. The flap was harvested from the ulnar side of the finger. The digital nerve was left in situ to minimize donor morbidity. The donor site was covered with a full-thickness skin graft and secured with bolster dressings. Early intensive mobilization was implemented for all patients. All flaps survived. No venous congestion was noted and primary healing was achieved in all flaps. In addition to providing well-vascularized tissue for coverage of vital structures, the digital artery was also used as a flow-through flap for finger revascularization in one patient. Donor-site morbidity was minimal, with all fingers retaining protective pulp sensation and the distal and proximal interphalangeal joints retaining full ranges of motion. In conclusion, the free digital artery flap is a versatile flap that is ideal for coverage of large-sized finger defects in situations where local flaps are unavailable. Donor-site morbidity can be minimized by preservation of the digital nerve, firmly securing the skin graft with bolster dressings, and early mobilization of the donor finger. PMID- 18443506 TI - Fourteen cases of free thenar flap: a rare indication in digital reconstruction. AB - BACKGROUND: The thenar area was first used for a free vascularized transfer by Tsai who, in 1991, resurfaced and vascularized a traumatized index finger basing the dissection on the radial digital artery of the thumb. Later, Kamei and Omokawa described a similar flap in finger reconstruction, which was supplied either by the radial artery or its volar branch. METHODS: Between 1997 and 2005 14 free thenar flaps were performed at Chang Gung Memorial Hospital for thumb (3 cases) and digital reconstruction (11 cases). In 6 cases, the pulp was involved whereas in the remaining 8 cases, the lesion was either in the volar (6 cases) or in the dorsal surface (2 cases) of the fingers. In 7 patients, a perforating branch rising about 3 cm proximal to the wrist crease was the main vascular source of the flap. In 8 cases, the volar radial artery provided adequate blood supply to the flap. No sensory nerve was included in the flap dissection. RESULTS: Two patients underwent reexploration for arterial thrombosis and venous congestion, respectively, which resulted in complete survival in this series. Donor site morbidity was inconspicuous and, in all cases, the thenar flap provided a well-padded tissue with glabrous skin. In the 7 patients who came back for a final evaluation, 2PD showed poor recover. CONCLUSION: The free thenar flap offers a thick skin of similar glabrous texture to that of the digits. This flap is especially indicated in those cases of multiple digital injuries or wide skin defects where homodigital or heterodigital island flaps are unsuitable. PMID- 18443507 TI - Split second- and third-toe transplantation in mutilating-hand-injury reconstruction. AB - Although bilateral second-toe transplantation has offered a satisfactory solution for multiple toe transplantation when the neighboring amputation stumps present an intact web space, exceptions exist. To provide an alternative and adapt the experience from the established methods, we propose split second- and third-toe transplantation in a 1-stage hand-function reconstruction. Three male patients underwent 4 split second- and third-toe transplantations for fingers amputated distal to the preserved or recreated web space. The average age was 22 years old, and all patients were reconstructed secondarily. No failure of transplantation occurred. All patients achieved restored hand functions for daily and occupational activities. In situations in which multiple lesser toe transplantations are required and harvesting toes from the bilateral foot may be needed, a split second- and third-toe transplantation with a healthy contralateral foot for allowing another toe transfer proves to have a satisfactory functional result and affords an opportunity for simultaneous or staged great toe transplantation. PMID- 18443508 TI - Carbon dioxide laser vaporization of facial siliconomas: flash in the pan or way of the future? AB - In 1988, Becker first described the "laser silicone flash" encountered while using the CO2 laser to remove breast siliconosis, but no subsequent use of the CO2 laser to remove siliconomas has been reported since. To our knowledge, lasers have not been described to treat facial silicone granulomas. Three cases of facial silicone granuloma (cheek, upper eyelids, and chin) were treated using the technique of CO2 laser vaporization.We describe a novel and effective method to remove facial siliconomas. This technique could avoid the need for radical resection of functional facial tissues such as nerves. Tiny globules of injected silicone in the face were vaporized without any untoward effects. Whether larger siliconomas can be treated in the same way remains to be seen and is an area of potential study. PMID- 18443510 TI - An 18-year experience in the management of congenital nevomelanocytic nevi. AB - BACKGROUND: Children with giant congenital nevomelanocytic nevi (CNN) are referred to our pediatric burn center for the surgical management of this disfiguring and potentially malignant skin disorder. Use of tissue expanders has contributed significantly in limiting donor site morbidity associated with treatment of giant CNN. Cultured skin substitutes (CSS) have also shown promise as an alternative wound coverage. With recent controversy regarding the effectiveness of excision in preventing melanoma risk, we wished to review our surgical management of giant CNN and to determine the incidence of malignancy in these patients. METHODS: A retrospective chart review of patients with giant CNN was performed from 1985 to 2003. Charts were reviewed for age, sex, percentage total body surface area (TBSA) involved, age at initiation and completion of treatment, surgical treatment, complications, histopathology, and length of follow-up. RESULTS: Of the 40 patients treated at our facility, the mean extent of skin involvement was 10% TBSA (range: 0.5%-75%). The mean age at initial operation was 5.1 years, and the majority of surgical interventions were completed within a mean of 1.3 years. Twenty-two patients (55%) required more than 1 surgical procedure. Excision and split-thickness skin grafting was the most common surgical procedure (n = 22) followed by excision with primary closure (n = 18). Ten patients were treated with tissue expansion, while 4 received cultured skin replacements. One patient died of extracutaneous melanoma during the course of surgical treatment. Three patients demonstrated histopathologic evidence of cytoatypia but remained clinically free of malignancy during a mean follow-up of 11 years. CONCLUSIONS: Giant CNN are both important cosmetic and medical problems. With an associated lifetime risk of melanoma in 4%-10% of patients, excision of CNN is recommended despite the fact that 50% of melanomas arise extracutaneously. Depending on the extent of body surface area involvement, wound closure can be obtained with conventional split- or full-thickness skin grafts, tissue expansion, and/or cultured autologous cultured skin substitutes. The latter 2 modalities provide improved cosmetic results, with minimal donor site morbidity. PMID- 18443509 TI - Postburn head and neck reconstruction in children with the fasciocutaneous supraclavicular artery island flap. AB - Postburn deformities or scar contractures in the head and neck region of children represent a challenge with unique problems compared with the rest of the body. Fourteen children suffered from neck contractures following burns, and 4 children required reconstruction following panfacial burn deformities. The experience of late-phase secondary burn reconstruction in the head and neck region of 18 pediatric patients (age range, 9-17 years) with 22 fasciocutaneous supraclavicular island flaps, including 5 preexpanded flaps, is reported. Clinical follow-up was performed between 10 and 29 months postoperatively. High functional and esthetic requirements could be fulfilled in all patients. Flap complications occurred in 9%, with low donor site morbidity (9%). The fasciocutaneous supraclavicular artery island flap is reliable and safe for immediate or late resurfacing of facial defects and to release cervical contractures. Customized flap design with tissue expansion without the need for microsurgery allows extended indications and optimized skin utilization, while good texture and color match is generally difficult to achieve in the head and neck region of severely burned children. PMID- 18443511 TI - Surgical treatment for dermatofibrosarcoma protuberans: the Dartmouth experience and literature review. AB - INTRODUCTION: Dermatofibrosarcoma protuberans (DFSP) is an invasive soft tissue tumor with asymmetric pattern of growth and propensity for recurrences, thus warranting systematic treatment planning at onset. We conducted a retrospective analysis of 25 patients with DFSP that received either wide excision, modified wide excision (with horizontal processing), Mohs micrographic surgery (MMS), or combination surgery. Follow-up ranged from 15-133 months, with a median of 68 months. RESULTS/CONCLUSIONS: Fourteen patients were treated with wide excision, 4 with modified wide excision, 6 with MMS followed by modified wide excision, and 1 with MMS. No recurrences were reported. Patients with lesions arising from "cosmetically sensitive" areas (head and neck) most often underwent MMS or modified wide excision. Our study supports that all 4 surgical treatment methods were successful in achieving recurrence-free survival, but emphasis on presurgical planning and patient selection for each surgical approach is key to allow for the least complicated repair while maximizing tissue preservation. PMID- 18443512 TI - Management of chronic postoperative groin pain. AB - Postoperative groin pain is a common complaint following surgery of the abdomen and groin. Although this pain usually resolves in the early postoperative period, some experience prolonged, debilitating pain lasting months to years. There is currently a lack of consensus as to the appropriate transition from medical to surgical management of these patients. A retrospective review of 19 consecutive patients with postoperative pain symptoms suspicious for neuropathic origin was undertaken. Neuromas or entrapment of 1 or more nerves was identified in all patients. Improvement of pain and quality of life was reported in 84%, with a minimum 1 year's follow-up. Average preoperative and postoperative pain was 7.6 and 1.2, respectively, a statistically significant reduction. This study confirms high success rates for patients surgically treated for chronic postoperative groin pain when proper selection criteria and appropriate surgical techniques are applied. A management approach is proposed and the surgical technique is described for treatment of these patients. PMID- 18443513 TI - Effect of heparin on production of transforming growth factor (TGF)-beta1 and TGF beta1 mRNA expression by human normal skin and hyperplastic scar fibroblasts. AB - Heparin affects both dermal fibroblast proliferation and collagen and may mediate these effects by altering the levels of transforming growth factor-beta1 (TGF beta1) production and TGF-beta1 mRNA expression as a wound healing modulator. The purpose of this study is to probe the effect of heparin on TGF-beta1 and TGF beta1 mRNA production by human normal skin and hyperplastic scar fibroblasts. This research investigates the effect of heparin on TGF-beta1 and TGF-beta1 mRNA production by human normal skin and hyperplastic scar fibroblasts with exposure to 0 microg/mL, 100 microg/mL, 300 microg/mL, or 600 microg/mL heparin for 24, 48, 72, or 96 hours in a serum-free in vitro model. Levels of TGF-beta1 in the supernatants and TGF-beta1 mRNA expression of fibroblasts were determined by enzyme-linked immunosorbent assay (ELISA) and real time RT-PCR, respectively. Heparin (300 microg/mL and 600 microg/mL) stimulated TGF-beta1 production by normal skin (26% to 83%) and hyperplastic scar fibroblasts (63% to 85%), with statistical significance (P < 0.05) at various time points. Heparin (300 microg/mL and 600 microg/mL) also stimulated TGF-beta1 mRNA expression by normal skin (12% to 53%) and hyperplastic scar fibroblasts (33% to 52%), with statistical significance (P < 0.05) at various time points. These effects of heparin on normal skin and hyperplastic scar fibroblasts may have implications for hyperplastic scar formation and wound healing in vivo. PMID- 18443514 TI - Role of gender and anatomical region on induction of osteogenic differentiation of human adipose-derived stem cells. AB - Adipose-derived stem cells (ASCs) display multilineage plasticity and, under appropriate conditions, can mineralize their extracellular matrix and undergo osteogenesis. The aims of this study are to examine in vitro osteogenic differentiation properties of ASCs to assess the role of gender, fat depot, and optimal duration as variables for differentiation. Human ASCs were isolated from superficial and deep adipose layers of the abdominoplasty specimens obtained from patients undergoing elective surgeries. ASCs were cultured in osteogenic media (OM). After 1, 2, and 4 weeks of differentiation, cultures were assessed for markers of osteogenesis. Alkaline phosphatase (AP), alizarin red (AR) and Masson trichrome (MT) stainings for osteoblastic transformation, matrix mineralization, and collagen production; enzyme-linked immunosorbent assay (ELISA) for Gla osteocalcin; and Western blot analysis for osteonectin protein expression were performed. Osteogenic differentiation began as early as 1 week. Cells exhibited a vertical growth pattern, lacunae formed in the cultures, matrix volume increased, and mineralization was observed. Differences in AP staining were most evident during the first week. AR activity progressively increased over 4 weeks, and collagen was secreted only by differentiated ASCs. There was no significant difference in the degree of osteogenic differentiation between the ASCs from both depots in the female. In the male, the superficial depot ASCs differentiated faster and more efficiently than those of the deep depot. Male ASCs from both depots differentiated more effectively than female ASCs from both depots. We describe a hierarchy of osteogenic differentiation potential based on gender and anatomic harvest site by layering adipose tissues of the abdominal wall. ASCs derived from male superficial layer were most efficient in achieving osteogenesis. In future clinical applications using stem cells for osseous healing, these gender and depot differences will guide our clinical methods. PMID- 18443515 TI - Plastic surgical delivery systems for targeted gene therapy. AB - The expansion of gene therapy applications from inherited disorders to acquired conditions has been mirrored by an exponential rise in both experimental work and clinical trials. This review highlights current plastic surgical delivery systems and clinical applications for targeted gene therapy. We revisit some of the vectors used both experimentally and in clinical gene therapy trials, with an emphasis on developments in plastic surgical delivery systems resulting in improved targeting of therapeutic genes. In addition, we discuss a novel technique for the delivery of gene therapy using the ex vivo transduction of free flaps, developed in our laboratory. This delivery system achieves targeted high level transgene expression with minimal demonstrable systemic toxicity. Advances in delivery systems are essential for translating basic research into clinical therapeutics. PMID- 18443517 TI - Live longer, better. How to advice from mayo experts. PMID- 18443516 TI - A critical evaluation of the use of Biobrane as a biologic skin substitute: a versatile tool for the plastic and reconstructive surgeon. AB - BACKGROUND: Biobrane and Biobrane-L are becoming increasingly popular in the management of superficial and moderate-depth partial-thickness burns, particularly in pediatric patients. When used appropriately, they have been shown to reduce pain levels, healing time, inpatient stay, and nursing requirements when compared with traditional dressings. In this manuscript, we provide a critical evaluation of the evidence base for the varied uses of Biobrane within the field of plastic and reconstructive surgery. METHODS: We present a comprehensive review of MEDLINE-cited articles, the proceedings of national meetings, relevant books, and information from the suppliers to provide the reconstructive surgeon with an evidence base for the use of Biobrane. We also take this opportunity to discuss religious and ethical issues and the complications of Biobrane application. RESULTS AND CONCLUSION: Biobrane is a versatile biosynthetic wound dressing. There is good evidence (Grade A) to support the use of Biobrane in the management of burns, particularly in partial thickness burns in children. Biobrane also has many potential uses as a dressing outside the burns unit of which we feel reconstructive surgeons should be aware. Conditions resulting in disruption of the epidermis such as toxic epidermal necrolysis (TEN) and paraneoplastic pemphigus have been managed successfully using Biobrane (Grade B). Biobrane has also been successfully used following dermabrasion, skin-graft harvesting, and laser resurfacing (Grades B to C). Temporary coverage with Biobrane has been successfully used in individuals with chronic wounds such as open sternotomy sites and venous ulcers (Grades B to C). Biobrane has a wealth of potential uses outside its traditional remit; however, further prospective clinical trials are warranted if these new applications are to become more widely accepted. PMID- 18443518 TI - Is your pillow a pain in the neck? PMID- 18443519 TI - Preventive mastectomy effective for high-risk women. PMID- 18443521 TI - Migraines: taking control of your pain. PMID- 18443520 TI - Angioplasty just as effective for women as men. PMID- 18443523 TI - Food cravings: what to do when you "gotta have it.". PMID- 18443522 TI - Checkups: a time for action. PMID- 18443525 TI - One on one. I want to take a backpacking trip, but I'm allergic to poison ivy. Is there anything that I can do to protect myself from an outbreak? PMID- 18443524 TI - One on one. With all the people working out at the gym, I worry that I'm going to pick up some kind of infection there. Is this likely? PMID- 18443526 TI - One on one. I've recently noticed what appear to be pieces that float across my field of vision. Are these dangerous, and can anything be done about them? PMID- 18443527 TI - [Multiple primary carcinomas of the colon and associated extracolonic primary malignant tumors]. AB - Adenocarcinoma of the colon is the most common visceral cancer. The incidence of multiple primary colorectal carcinoma varies from 0.6% to 7.6%. A review of 837 cases of colorectal carcinoma showed 32 cases (3.8%) of colorectal multiple primary malignant tumors and 11 cases (1.3%) of colorectal primary malignant tumor associated with extracolonic primary malignant tumor. A total of 78 tumors were involved: 24 in the sigmoid, 12 transverse colon; four in the cecum; 30 in the rectum; 3 in the ascending and 5 in descending colon; 2 each in the bladder, prostate; two each in the breast, cervix, and one each in the skin, nasopharynx, lungs. If synchronous carcinomas are located in the same anatomic region, a conventional resection should be performed. When the carcinomas are widely separated, a subtotal colectomy is the operation of choice. Survival of patients with synchronous carcinomas is not significantly different from survival of patients with same-stage solitary carcinomas. PMID- 18443528 TI - [Non-Hodgkin's primary intestinal lymphoma - a cause of acute abdominal manifestation in children]. AB - AIM: Lymphomas of the gastrointestinal tract are the most common type of primary extranodal lymphomas, accounting for 5 to 10% of all non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: From January 1996 to November 2005, 10 patients with primary intestinal lymphomas were submitted with clinical signs of acute abdomen to the Pediatric surgical department in Sofia. The children presented with radiologically proven intussusception, ileal obstruction or peritonitis due to bowel perforation. RESULTS: At exploration the tumor was located in the ileum in 4 cases, in the terminal ileum and coecum in 3 cases, appendix in one and multiple sites were found in 2 cases. Children with localized disease underwent radical resection of the tumor mass with ileo - transverso anastomosis (3), partial bowel resection (4), and appendectomy (1) whereas in 2 children with advanced disease diagnostic biopsy alone with temporary ileostomy in one were accomplished. According to histology, 5 patients had Burkitt lymphoma and 5 lymphoblast NHL. The children were treated according CHOP. Over five - years relapse - free survival for localized disease accounts 6 children. CONCLUSION: Primary NHL in children often presents with acute abdominal condition requiring surgical exploration. Prognosis depends of adequacy of surgical resection and the adjuvant chemotherapy. PMID- 18443529 TI - [Operative method of pyeloplasty: X-pyeloplasty]. AB - The classic operative methods are still topical. Applying some new operative techniques makes the medical science more complete and thus help better treatment of the variety of diseases encountered in medical practice. In this article the authors present brand - new operative method of pieloplasty, named by them X pieloplasty. PMID- 18443530 TI - [Benign nodular formations of the thyroid gland and changes in cell and humoral immunity before and after surgical treatment]. AB - INTRODUCTION: The main trends concerning the volume of surgery in benign thyroid disease - thyroidectomy or organ - preserved surgery, performed in detected immunological disorders, are not well motivated. The AIM of this study was to analyze changes in humoral and cellular immunity in diseases before and after surgical treatment as well as to assess the effects of surgical procedure and to precise its volume. PATIENTS AND METHODS: Changes in immune reactivity were investigated in 100 patients. They were selected with nodular (adenomatous) hyperplastic parenchymal processes in the thyroid gland, with or without hyperfunction - euthyroid or Basedowificated nodular goitre, solitary toxic adenoma and nodular form of lymphocytic thyroiditis. Serum anti - thyroglobulin and anti - microsomal antibodies were examined in these patients, and in 56 of them immunophenotypic flowcytometric analyses of peripheral lymphocytes was performed. RESULTS: Serum antithyroid antibodies gradually decrease in one year after surgery. Pre-surgical changes in lymphocyte subsets number in peripheral blood recovered to great extent. This tendency is best demonstrated in lymphocytic thyreoiditis. DISCUSSION: Study on immune parameters can help to evaluate the positive effect of organ - preserved and at the same time - radical surgical treatment. CONCLUSION: In immune thyroid disorders the organ - preserved radical resection of thyroid gland leaving normal parenchyma is method of choice compared to thyroidectomy since it allows definite treatment with hormonal compensation. PMID- 18443531 TI - [Video-assisted thoracoscopic surgery in diagnostic and treatment of non-operable malignant pleural mesothelioma]. AB - INTRODUCTION: Mesothelioma is characterized by aggressive follow-up, difficult diagnosis and treatment fatal issue. In one side the restricted possibility for operative treatment and the other side the resistance of tumors for chemotherapy are the mean reasons for bad results in patients with malignant pleural mesothelioma. We have aim to make a retrospective study of patients with malignant pleural mesothelioma in 3-th and 4-th stage, undergoing operation in our clinic and see VATS effectiveness. PATIENTS AND METHODS: In the clinic of thoracic surgery in University Hospital "St.George" - Plovdiv we made retrospective study in 21 patients undergoing operation in the occasion of advanced pleural mesothelioma. It was thoroughly men (14) in age between 45-72 years (58.6). In 18 (85%) patients the disease was proven intraoperative or on the final histological result after operation. Before operation in this patients in help of diagnosis, we have information by image examination (radiography, CT of thorax and if it necessary to mark pleural effusion - sonography of pleural cavity ) abdominal sonohography or CT of abdomen for exclusion of distant metastasis, fibrobronchoscopy (FBS) for confirmation or exclusion of endobronchial cancer and transthoracic aspiration biopsy (TTAB). RESULTS: We describe improvement in the most of patients. In 2 patients we have not improvement. In this situation we made Bulao drainage. Death issue in early postoperative period we have in 1 patient with increased breath insufficiency despite evacuation of pleural effusion and unfolded lung. DISCUSSION: Early diagnosis of malignant pleural mesothelioma is difficult, in some times impossible. After histological verification the diagnosis is proven. Image examination is still insufficient. The difficulty comes by insufficient cytologic and histologic verification before operation and also insufficiency of image examination. Because of the chemotherapy is insufficient, surgical treatment (radical or not) in huge number of cases help improvement of patient's condition. CONCLUSION: 1. Surgical treatment is decisive for diagnosis and treatment of malignant pleural mesothelioma even in advanced cases and have evident positive effects. 2. Surgical methods improve patient's condition, even in inoperable cases. 3. VATS surgery is modern method for diagnosis and treatment and if it necessary we can continue by conventional operation for definitive treatment of mesothelioma. PMID- 18443532 TI - [Gastrointestinal stromal tumors (GIST) - clinical experience and current therapeutical aspects]. AB - Gastrointestinal stromal tumors (GIST) are specific, generally Kit (CD117) - positive, mesenchymal tumors of the gastrointestinal tract encompassing a majority of tumors previously considered gastrointestinal smooth muscle tumors. They are believed to originate from interstitial cells of Cajal or related stem cells. Diagnosis is based on histological and immunohistochemical examination, and these rare tumors are characterized by c-kit (CD117) staining. We present an analysis of clinical presentation and course, surgical management and pathological features of 11 patients with gastrointestinal stromal tumors treated in our institution from 2002 to 2007. 2 patients with malignant retroperitoneal GIST had disease progression/recurrence and died. They received adjuvant imatinib therapy. 9 patients are disease free on the 3-d year of the follow-up. Our results confirm that in stromal tumors complete surgical resection remains the mainstay of treatment in localized gastrointestinal stromal tumors. Complete removal of the tumor is often curative in localized gastrointestinal stromal tumors and is always recommended. Clinically, their behavior is difficult to predict, and mitotic count and tumor size seem to be the most effective prognostic factors. It is conceivable that treatment and prognosis of metastatic and non - resectable gastrointestinal stromal tumors, as well as the adjuvant treatment of high-risk, radically excised gastrointestinal stromal tumors will be strongly impacted by the c-kit target therapy. PMID- 18443533 TI - [Peritonitis in cases of complicated diverticulosis of the gastrointestinal tract]. AB - Within the period 2002 - 2007, a total of 29 patients with diverticulosis of the gastrointestinal tract have been treated at the surgery clinic: 26 (89,66%) male and 3 (10,34%) female patients. Their average age amounted to 65,7 years (22 y. - 81 y.). A total of 25 (86,21%) patients have had a complicated form of disease and 6 (24%) of them have had peritonitis. The operative interventions included: resection of small-intestine diverticulitis and primary anastomosis with 2 patients, Hartmann's type resection of the sigmoid colon with 2 patients, suture of sigmoid colon perforation with protective colostomy with 1 patient and resection of the sigmoid colon with primary anastomosis with 1 patient. No mortality in the postoperative period. 2 complications have been observed - suppuration and dehiscence of the operative wound. PMID- 18443534 TI - [Large primary liver cancer (> 10 cm)- diagnosis and surgical treatment]. AB - BACKGROUND: Primary liver cancer (PLC) over 10 cm. in diameter at the time of diagnosis continues to account for a number of patients undergoing hepatic resection. This study evaluated the clinicopathological features and outcome following surgery for large PLC. METHODS: Between January 1991 and December 2002 , 105 patients were operated, 68 of them (64.7%) the size of tumor was > 10 cm. Forty-five patients (66.2%) with a large PLC(greater than 10 cm) were resected and studied retrospectively. They were compared with 27 patients who had tumor less than 10 cm. They were 31 men and 14 women of mean age 53,8 (from 1 to 78 years). Cirrhosis had 13 patients (28,9%) - Child A- 10, Child B - 3. RESULTS: Surgical procedures were: major resections in 33 patients and minor resections in 12. Eight patients (17,7%) died by the 30-th day. 16 patients had postoperative complications - 6 patients developed liver failure. The 1-, 2-, 3- and 5-year overall survival rates were 68%, 43%, 22% , 2,2% respectively. CONCLUSION: Large primary liver cancer can be safely resected when cirrhosis is absent. Liver cirrhosis is contraindication for major hepatic resection. The lack of cirrhosis increases resectability and decreases morbidity and mortality. PMID- 18443535 TI - [Biliurolithiasis - a classification of a disease with complex characteristics]. AB - The development of the medicine itself, meets the current question of the common, interdisciplinary method of approach in the treatment of a series of diseases, such as biliurolithiasis. The attempt to make a classification is basic for making an optimal method of treatment of the biliurolithiasis. The biliurolithiasis is a disease influencing some new strategies of treatment in the combined efforts of the urologist and the surgeons both. PMID- 18443536 TI - [On terminology of ano-rectal abscesses and fistulae]. AB - There are different names: perianal abscesses and fistulae, periproctitis, paraproctitis, pararectal inflammatory and fistulous processes, etc. It is our opinion that the name perianal and anal fistulae does not correspond to the origin of the fistulae from an abscess of the rectal wall, although it is fairly common. OBJECTIVE: To offer a name, based on the patophysiological mechanism and anatomic localization of the inflammatory process in the pararectal area through study of the origin and the way of development of ano - rectal abscesses and fistulae. MATERIAL AND METHODS: A group of 430 (4%) patients with recto - perineal abscesses and fistulae has been analyzed out of a total of 10 726 hospitalized patients for the 1986 - 2005 period. Of them 241 patients (56,1 %) have been with recto - perineal fistulae, and 189 (43,9%) with recto - perineal abscesses. CONCLUSION: The process starts in the rectal wall, in the Morgan's crypts - cryptitis, after which the process transits to the perineal connective tissue. This succession in the development of the inflammatory process allows us to put the term " rectum" before "perineum" in the name adopted by us "recto - perineal abscesses and fistulae". It is our opinion that it is more appropriate to consider fistulae as a consequence from the abscesses, united in a single name recto - perineal abscesses and fistulae. PMID- 18443537 TI - [Gastric cancer - current state of the problem. Part I. Epidemiology. Pathology. Classification. Staging]. AB - Gastric cancer is still rampant in several countries around the world. His incidence exhibits significant geographic variability. The disease is most common in East Asia, and high rates of occurrence have also been reported in Central and South America, Eastern Europe, and parts of the Middle East. In Japan, gastric cancer remains the most common type of cancer among men. The overall incidence of this condition has decreased in the past few decades, nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. The reported reductions in gastric cancer mortality may be linked to better refrigeration and a concomitant decrease in the intake of salted, pickled, smoked, and chemically preserved foods; however, this link remains controversial. Another relevant change in the epidemiology of gastric cancer is a shift in the distribution of primary lesion sites within the stomach. In the first quarter of the 20th century, two thirds of gastric cancers were located in the antrum and the prepyloric area, and only 10% arose in the cardia or the esophagogastric junction. Since the 1970's, however, adenocarcinoma of the proximal stomach has become increasingly common. PMID- 18443538 TI - [Modern aspects of anesthesia for laparoscopic surgery: questions and answers]. AB - Recently the endoscopic surgery enters widely in clinical practice. Laparoscopic surgery has gained rapid acceptance in the anaethesiological community, mainly due to its advantages to patients in postoperative period. Recognition of pathophysiological changes in hemodynamic, respiration associated with pneumoperitoneum helps to prevention of possibly fatal complication during surgery, general anaesthesia, and also during early postoperative period. The aim of present review is using our experience and available bibliographic data to introduce anaethesiologists and surgeons to recent trends of anaesthesia in laparoscopic surgery. PMID- 18443539 TI - [Vascular complications of Baker's cyst]. AB - The presence of Baker's cyst is clinically demonstrated as compression syndrome of the vessels and nervous stem in the popliteal area. This result frequent in deep venous thrombosis, nervous injuries and blood flow insufficiency distal to the compression site. We present two cases of compression stenosis of the popliteal vessels, clinically manifested. The patients underwent surgical decompression and cystic removal, thus leading to arterial perfusion and/or venous derivation improvement of the lower extremity. PMID- 18443540 TI - [A case or operative treatment of a rare lung tumor (sclerosing haemangioma)]. AB - Sclerosing hemangioma of the lung is a rare tumor, defined as benign, but it has the propensity for recurrence and metastases. We present a case of operative treatment of a 37-years-old female patient with such tumor, with preoperatively assessed clinical and X-ray evidence for tumor formation in the right lung. At the operation we found a tumor in the third segment of the right lung, resembling visually and histologically (frozen section) a metastase. A wedge resection of the superior lobe was performed. Histological examination (including immunohistochemistry) showed sclerosing hemangioma (papillary pneumocytoma). There were no complications in the postoperative period, two years after the operation the patient is in very good condition, there is no evidence of recurrence or metastases. PMID- 18443541 TI - Antiplatelet and anticoagulants drugs. PMID- 18443542 TI - Role of tumor necrosis factor-alpha and interleukin-1beta on lung dysfunction following hemorrhagic shock in rats. AB - BACKGROUND: Hemorrhagic shock occasionally causes a fatal outcome following an outbreak of lung dysfunction, but the precise mechanism has not been clearly elucidated. Several studies have indicated that hemorrhagic shock causes a delayed vascular inflammatory decompensation and leads to inflammation-related organ dysfunction. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta are known as major proinflammatory cytokines that play an important role in excessive autolytic inflammation, finally inducing organ dysfunctions. In this study, the role of TNF-alpha and IL-1beta on lung dysfunction following hemorrhagic shock was examined by using FR167653, a potent inhibitor of TNF-alpha and IL-1beta production that acts by suppressing p38 mitogen-activated protein kinase (MAPK). MATERIAL/METHODS: Hemorrhagic shock was induced in anesthetized male rats by bleeding via a common carotid catheter for 20 minutes to 25% of total body blood volume without fluid resuscitation. Mean blood pressure, heart rate and arterial blood gas components were recorded up to 5 hours after the bleeding. The levels of TNF-alpha, IL-1beta and lactic dehydrogenase (LDH)-3 isozyme were measured in the serum of pulmonary venous blood. The lung tissue was excised for the assay of mRNA and for histopathological study. RESULTS: The expressions of mRNA for TNF-alpha and IL-1beta in the lung tissue and the concentrations of both cytokines in pulmonary serum increased after a hemorrhage. Inflammation-related injuries and function deterioration were observed in the lung following hemorrhagic shock. These hemorrhagic changes were inhibited by pretreatment with FR167653. CONCLUSIONS: TNF-alpha and IL-1beta play a key role in the development of inflammation-related lung dysfunction following hemorrhagic shock. Our model should be useful to explain the pathogenesis of lung dysfunction following hemorrhagic shock. PMID- 18443543 TI - Impact of cell culture media on the expansion efficiency and T-cell receptor Vbeta (TRBV) repertoire of in vitro expanded T cells using feeder cells. AB - BACKGROUND: The effects of different cell culture media on expansion efficiency and alterations in T-cell receptor V beta (TRBV) expression of in vitro expanded lymphocytes are not well established. MATERIAL/METHODS: Low numbers of CD3+ T cells from peripheral blood lymphocytes of healthy donors were subjected to polyclonal in vitro expansion in the presence of autologous CD3-depleted mononuclear cells as feeder cells (FCs) and their numbers and TRBV expressions were compared in media containing human (HS-RPMI) or fetal bovine serum (FBS RPMI), Panserin413, or X-Vivo 15TM designed for lymphocyte culture. RESULTS: During three courses of restimulation within 28 days with CD3-antibody (OKT-3), IL-2, and initial CD3+, T-cell: FC ratios of 1:50 lowered to 1:5 and T cells expanded more than 1,000-fold in the media containing complete sera. Loss of cluster formation, associated with expansion failure, was only observed in cultures using synthetic media and resulted in only about 70-fold expansion. Whereas TRVB expression as determined by real-time PCR was substantially altered after 14 days of culture in X-Vivo 15, at day 28 only T cells from long-term culture in HS-RPMI presented the initial TRBV composition. CONCLUSIONS: Culture media have substantial impact on in vitro T-cell expansion. In the presence of FCs, medium containing human serum is superior to synthetic media and FBS-RPMI for long-term culture regarding T-cell number and TRBV repertoire. In contrast, the synthetic media Panserin413 and XVivo15 show lower expansion efficiency and reproducibility and, as RPMI1640+10%FBS, can contribute to overstimulation of certain TRBVs at advanced culture time points. PMID- 18443544 TI - Perindopril, atenolol, and amlodipine prevent aortic ultrastructural changes in rats exposed to ethanol. AB - BACKGROUND: The effects of perindopril, an angiotensin-converting enzyme inhibitor, atenolol, a beta adrenergic receptor blocker, and amlodipine, a calcium channel blocker, were investigated in chronic alcohol administered rats. MATERIAL/METHODS: Adult male Wistar rats (240-320 g) were used in the present study. Alcohol was given to rats on a modified liquid diet for 21 days. Perindopril (2.5 and 5 mg/kg), atenolol (5 and 10 mg/kg), and amlodipine (5 and 10 mg/kg) were injected into rats in different groups intraperitoneally for 21 days. Control rats were pair fed an isocaloric liquid diet containing sucrose as a caloric substitute for alcohol. Saline was injected into the control rats for 21 days. The hearts were removed after the rats were anesthetized by ether, and 1 mm3 samples from the ascending aortas were fixed. Five fields per aorta were examined and photographed with a transmission electron microscope. Blood alcohol levels were also measured spectrophotometrically. RESULTS: Daily alcohol consumption of the rats was in the range of 12.09-15.50 g/kg. Blood alcohol concentrations were 145.63 mg/dl on the 21st day of alcohol consumption. Chronic alcohol consumption caused some marked aortic wall injuries. Perindopril, atenolol, and amlodipine at high doses, but not low doses, produced some significant beneficial effects on alcohol-induced aortic wall damage. CONCLUSIONS: These results imply that perindopril, atenolol, and amlodipine may have protective effects on heavy chronic alcohol consumption-induced aortic wall injury in rats only in high doses. PMID- 18443545 TI - The apolipoprotein E2 isoform is associated with accelerated onset of coronary artery disease in systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a highly prevalent autoimmune disease and coronary artery disease (CAD) is a complication of SLE which is often crucial for the patient's prognosis. It is hypothesized that apolipoprotein E (Apo E), which is involved in cholesterol metabolism, might play a role in this process. MATERIAL/METHODS: Patients with SLE registered at the University of Toronto Lupus Clinic who had DNA available for study had their Apo E genotype determined. Each case was assessed for the presence of CAD, and Apo E allele frequencies in patients with SLE were compared with data from the general population. Age at onset and disease duration of CAD were also recorded and compared between groups. RESULTS: DNA was stored from 152 patients, of whom 38 (25%) had CAD. There was no difference in the frequencies of the Apo E isoforms between SLE patients and the general population. Patients with the E2 allele developed CAD after a mean +/-SD of 6.0+/-1.9 yrs compared with 14.5+/-5.4 yrs in those with E3/3 (p<0.01). CONCLUSIONS: The distribution of Apo E genotypes in SLE is not significantly different from that of the North American population. In SLE, Apo E2 was associated with a more rapid development of CAD. Therefore, Apo E2 might interact with other disease-related factors to accelerate the onset of CAD in some patients with SLE and as such might be an additional marker of risk in this population. PMID- 18443546 TI - Screening for vestibular disorders: a study of clinicians' compliance with recommended practices. AB - BACKGROUND: Dizziness and vertigo are very common patient complaints encountered by clinicians in both primary as well as specialty care in otolaryngology and neurology. Vestibular impairment is an underlying cause in as many as 45% of people complaining of dizziness. Most causes of vestibular impairment can be effectively treated; however, the diagnosis is frequently missed. The aim of this study was to examine clinical assessments used by providers in evaluating dizzy patients in outpatient clinics and the emergency department. MATERIAL/METHODS: Computerized medical records of all patients receiving an ICD-9 diagnosis code for dizziness, including benign paroxysmal positional vertigo, Meniere's disease, and vestibular hypofunction over a six-month period at the Atlanta VA Medical Center were reviewed. RESULTS: 476 patients were identified and of these, 157 patients were included. Over two-thirds of providers (69%) used the patient's description of the dizziness for identifying the cause; however, significant variability was evident across disciplines, ranging from 84% of audiologists asking for a description of the dizziness to only 33% of geriatricians asking. 89% of providers did not evaluate a patient for BPPV by examining for positional nystagmus. Primary care clinicians referred 22% of dizzy patients to a specialist (neurotologist), geriatricians referred 17%, and emergency physicians referred only 16%. CONCLUSIONS: Dizzy patients were not routinely screened for vestibular impairment based on available recommended practices, likely contributing to underdiagnosis and treatment. Results indicate a need for effective dissemination of guidelines to improve health care quality, increase awareness of medical risks, and enhance patient access to appropriate treatment. PMID- 18443547 TI - Constraint-induced aphasia therapy stimulates language recovery in patients with chronic aphasia after ischemic stroke. AB - BACKGROUND: Constraint-induced aphasia therapy (CIAT) offers potential benefits to individuals with history of aphasia-producing ischemic stroke. The goals of this pilot study were to implement the original German CIAT protocol, refine the treatment program, and confirm its efficacy in patients with chronic aphasia. MATERIAL/METHODS: We translated and modified the original CIAT protocol to include a hierarchy of individual skill levels for semantic, syntactic, and phonological language production, while constraining non-use behaviors. Three male participants with moderate to severe post-stroke aphasia received CIAT 3-4 hours/day for 5 consecutive days. Pre and post-testing included formal language evaluation, linguistic analysis of story retell, and mini-Communication Activity Log (mini-CAL). RESULTS: Substantial improvements in comprehension and verbal skills were noted in 2 patients with an increase in the total number of words (31% and 95%) and in number of utterances for story-retell task (57% and 75%). All participants demonstrated an improvement on at least one linguistic measure. No subjective improvements on mini-CAL were noted by any of the participants. CONCLUSIONS: Given that the duration of treatment was only 1 week, these linguistic improvements in post stroke aphasia participants were remarkable. The results indicate that the CIAT protocol used in this study may be a useful tool in language restoration after stroke. These initial findings should be confirmed in a larger, randomized study. PMID- 18443548 TI - The effect of CYP3A5 polymorphisms on the pharmacokinetics of tacrolimus in adolescent kidney transplant recipients. AB - BACKGROUND: CYP3A5 gene polymorphism has been shown to influence tacrolimus (TAC) blood concentration and dose requirement in adult kidney transplant patients. The aim was to analyze retrospectively the modification induced by CYP3A5 gene polymorphism on TAC's pharmacokinetic parameters obtained from 26 adolescents receiving TAC as their main immunosuppressive drug. MATERIAL/METHODS: The adolescent kidney transplant patients were genotyped for CYP3A5*3 and grouped accordingly. TAC dose, blood levels, and dose-normalized TAC blood concentration and volume of distribution obtained at different post-transplant periods during the first post-transplant year were correlated with the corresponding genotype. RESULTS: During the first three months post-transplant, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration than homozygotes (CYP3A5*3/*3) (at 1 month: 7.8+/-2.1 vs. 13.4+/-6 ng/ml, p=0.007) despite a therapeutic monitoring strategy. Between 3-12 months post-transplant, TAC blood concentration was comparable between the two groups, but a two-fold increase in the daily drug dose was necessary for the heterozygotes (at 6 months: 0.23+/-0.1 vs. 0.13+/-0.06 mg/kg, p=0.04). The dose-normalized TAC concentration [(ng/ml)/(mg/kg)] was significantly lower in patients displaying the CYP3A5*1/*3 polymorphism (at 2 weeks: 33+/-2.16 vs. 71.1+/-37.8, p=0.01; 6 months: 35.4+/ 12.9 vs. 85.2+/-58.9, p=0.01). At the same time, the volume of distribution of the drug in the latter group was distinctly increased for the entire post transplant year (at 6 months: 1.79+/-0.42 vs. 0.73+/-0.5 l/kg, p=0.001). CONCLUSIONS: The great influence of CYP3A5 on the pharmacokinetics and pharmacodynamics of TAC in young transplant recipients suggests the need for pre transplant screening of this polymorphism to improve TAC therapy. PMID- 18443549 TI - C reactive protein (CRP) as a predictor for true bacteremia in children. AB - BACKGROUND: Despite the recent advances in methods for culturing bacteria, at least 24 hours are needed for most pathogens to be recognized. This period may be critical for the differentiation of a true bacteremia from a contaminated culture. We studied the value of CRP compared to total leukocytes (WBC) and absolute neutrophil count (ANC) in differentiating positive, contaminated and negative blood cultures in various pediatric infectious diseases (pneumonia, acute gastroenteritis (AGE), urinary tract infection (UTI) and acute otitis media (AOM)). MATERIAL/METHODS: Data was collected retrospectively from patients who were admitted or discharged from to the pediatric ward with one of the above diagnoses. Children with chronic diseases or with immunodeficiency were excluded from the study. RESULTS: CRP levels were significantly higher in the positive culture group versus contaminated and negative groups (101 mg/L, 30.9 mg/L, 34.3 mg/L, respectively). The total leukocytes and ANC were not of value. When divided into diagnostic subgroups, CRP levels were significantly higher in the positive blood culture groups in patients with pneumonia and AGE. The sensitivity of a CRP value above 85 mg/L for pneumonia and UTI and above 30 mg/L for AGE and AOM in discriminating true positive versus contaminated culture was 70% with a specificity of 67.6% and a positive predictive value of 60.3%. CONCLUSIONS: CRP may be used for differentiation between positive and contaminated blood cultures in children and have been shown to be a better predictor than WBC or ANC for this purpose. PMID- 18443550 TI - Physicians' knowledge and attitudes regarding periconceptional folic acid supplementation: a survey in Southern Israel. AB - BACKGROUND: Pre-conceptional folic acid supplementation is an effective way to reduce the incidence of neural tube defects (NTDs). Primary care providers are an important source of information to promote folic acid intake. This study aimed at evaluating primary care physicians' knowledge and attitudes regarding folic acid supplementation for childbearing women. MATERIAL/METHODS: A questionnaire on physicians' knowledge and attitudes, mostly including multiple-choice questions, was delivered by mail to all physicians (n=370) in a large health provider organization in southern Israel in 2006. Data regarding demographics as well as type of specialty, experience, and place of work were collected. RESULTS: Eighty seven physicians were included in the study (response rate: 24%). Seventy physicians out of 81 (94%) reported routine recommendation of folic acid for their patients. Most physicians admitted that they needed more information regarding folic acid supplementation. Knowledge about folic acid's role in preventing congenital anomalies was suboptimal, with 2% of the physicians correctly estimating the efficacy of folic acid in decreasing the risk of NTDs and 8% recognizing the association between folic acid supplementation and decreased prevalence of malformations other than NTDs. Knowledge about the correct timing (12%) and dosage (47%) of folic acid preparations for average-risk women was also lacking. CONCLUSIONS: Primary care physicians report that they routinely prescribe folic acid to women in childbearing age in order to prevent congenital anomalies, but their knowledge about folic acid supplementation is insufficient. PMID- 18443551 TI - Effects of the systemic beta-adrenoceptor antagonist nebivolol on ocular hemodynamics in glaucoma patients. AB - BACKGROUND: Systemic antihypertensive treatment in glaucoma patients with hypertension carries the potential risk of an additional deterioration in ocular hemodynamics due to the reduction in ocular perfusion pressure. Nebivolol is a beta1-selective adrenoceptor antagonist with known peripheral vasodilatory effects due to NO-releasing properties. The effect of a switch in systemic beta blocker treatment to nebivolol on retrobulbar hemodynamics in glaucoma patients with arterial hypertension was therefore investigated. MATERIAL/METHODS: Peak systolic (PSV) and end-diastolic (EDV) velocity in the short and long posterior ciliary arteries (SPCA, LPCA), central retinal artery (CRA), and ophthalmic artery (OA) were recorded by color Doppler imaging (CDI) in 23 glaucoma patients with arterial hypertension using their primary systemic beta-blocker medication and four weeks after a switch to nebivolol. RESULTS: Compared with the first recording under the primary antihypertensive medication, the CDI measurements after four weeks of nebivolol treatment revealed a significant acceleration of the PSV in the SPCA and LPCA and the EDV in the SPCA and CRA. No significant differences in flow velocities were found for the OA. Intraocular pressure and systemic blood pressure remained unchanged. CONCLUSIONS: Switching blood pressure treatment to nebivolol in glaucoma patients with hypertension leads to accelerated blood flow in the small retrobulbar vessels. A stabilization of ocular perfusion might be of particular importance in this group of co-morbid patients. PMID- 18443552 TI - Reduction of CD55 and/or CD59 in red blood cells of patients with HIV infection. AB - BACKGROUND: Anemia is a common feature in HIV infection. An increased sensitivity of lymphocytes from HIV patients to lysis by complement has been correlated with a decreased expression of CD55 and CD59 in their surface. The aim of this study was to evaluate CD55/CD59 presence in red cells of HIV patients and explore possible correlations with clinical parameters. MATERIAL/METHODS: CD55/CD59 expression was evaluated in erythrocytes of 37 patients (30M/7F, median age: 39 years) with HIV infection (25 also having hemophilia), 121 controls, and 8 PNH patients using the sephacryl-gel microtyping system. Ham and sucrose tests were also performed. RESULTS: Anemia was present in 14/37 (37%) HIV patients. Interestingly, all HIV patients had deficient CD55 and/or CD59 erythrocytes: 8 (21%) for both CD55 andCD59 and 29 (78%) isolated CD55 and/or CD59 negativity. Deficient erythrocytes did not account for more than 10% of the total in the vast majority of patients. In controls, only 2 (1%) had red cells with double CD55/CD59 negativity and 3 (2%) had isolated deficiency. All PNH patients had a simultaneous CD55/CD59 deficiency. Positive Ham and sucrose tests were found only in PNH. There was no correlation between the presence of deficient CD55/CD59 erythrocytes and anemia, hemolysis, antiretroviral therapy, CD4+ counts, viral load, or concomitant hepatitis C infection in HIV patients. CONCLUSIONS: This study provides evidence supporting the presence of erythrocytes with CD55 and/or CD59 deficiency in HIV. Further studies using molecular techniques will be required to clarify the exact role of this deficiency in HIV patients. PMID- 18443553 TI - Determination of lamivudine-resistant variants of hepatitis B virus by denaturing gradient gel electrophoresis: a novel approach to monitoring drug resistance. AB - BACKGROUND: A DGGE-based assay for hepatitis B virus (HBV) drug-resistance monitoring was designed and checked for feasibility. It detects mutations within the YMDD motif related to lamivudine resistance. MATERIAL/METHODS: The YMDD motif of HBV polymerase was amplified by the set of primers designed in this study. DGGE analysis of the amplicons was performed on 9% polyacrylamide gels containing a 20-40% gradient of urea plus formamide and electrophoresis was performed. DNA sequencing was performed using a standard protocol. RESULTS: Based on the DGGE pattern of previously sequenced HBV variants, a reference ladder consisting of bands was constructed within and near the YMDD motif of HBV with excellent resolution. The genotypes of all the fragments included in the ladder were confirmed by sequencing after DGGE analysis. The flexibility of DGGE was demonstrated by the ability to add more bands to the migration ladder when new variants were discovered during the analysis of patient specimens. Clinical samples from HBV-infected patients were also used to demonstrate the performance of this approach. CONCLUSIONS: This preliminary feasibility study of HBV drug resistance monitoring by means of DGGE shows the potential advantage of this approach for low-cost screening for viral drug resistance in clinical settings. The presented example can be extended to detect other mutations related to drug resistance in the HBV genome as well as other viruses. PMID- 18443554 TI - Atrial fibrillation as a nonpsychiatric predictor of delirium after cardiac surgery: a pilot study. AB - BACKGROUND: Preoperative atrial fibrillation (AF) increases the risk of cardiac surgery and the occurrence of postoperative complications, including arrhythmias, low-output syndrome, delirium, and death. The aim was to evaluate its direct influence on prognosis of patients subjected to cardiac surgery. MATERIAL/METHODS: This is a pilot study of the CODACS trial (COnsciousness Disorders After Cardiac Surgery). Two hundred sixty patients admitted for open heart surgery were prospectively included in the study. Preoperative AF was diagnosed on the basis of multiple electrocardiographic examinations and confirmed by 24-h Holter monitoring. Diagnosis of delirium following surgical intervention was based on DSM-IV criteria. RESULTS: Preoperative AF was diagnosed in 23 patients (8.8%): in 15 patients in the nondelirious group (7%) and 8 (27.0%) in the delirious group. Preoperative AF was an independent predictor of postoperative delirium (p<0.001), increasing its risk of occurrence over sevenfold (OR=7.2). AF also increased the risk of such postoperative complications as supraventricular arrhythmia (AF: 78.3% vs. non-AF: 22.8%, p<0.001), stroke (8.7% vs. 1.3%, p<0.001), and low-output syndrome (21.7% vs. 17.3%, p=0.033) and worsened prognosis, significantly increasing the risk of death (8.7% vs. 0.8%, p<0.001). CONCLUSIONS: Preoperative AF was an independent risk factor of postoperative delirium (OR=7.2). It was also associated with significantly worse postoperative outcome (supraventricular arrhythmia, stroke, low-output syndrome, and risk of death). These results and data from available studies suggest that preoperative AF should be considered as an important predictor of postoperative outcome. This problem should be the subject of future research to establish beneficial treatment options. PMID- 18443555 TI - Novel PRNP mutation in a patient with a slow progressive dementia syndrome. AB - BACKGROUND: Creutzfeldt-Jakob disease is a rare neurodegenerative disorder with a worldwide incidence of 1.5 per million inhabitants. About 10-15% of all cases of Creutzfeldt-Jakob disease are of genetic origin and display a large variety in clinical presentation (regarding disease duration, age at onset, and others). The goal of this report was to describe the clinical features and diagnostic tests in a patient with a novel prion protein gene (PRNP) D202G mutation. CASE REPORT: A 71-year-old patient had all the clinical signs of Creutzfeldt-Jakob disease (CJD) but an extremely prolonged disease duration of 16 years. The 14-3-3 protein test was positive, while MRI and EEG did not show CJD typical changes. Family history was positive for cerebellar and dementia disorders without definite diagnoses. Full-length sequencing of the prion protein gene (PRNP) showed a new D202G mutation associated with valine on codon 129 of unknown significance. Methionine/valine heterozygosity at codon 129 was found. CONCLUSIONS: These findings highlight the value of 14-3-3 and gene analysis in unclear neurological disorders to detect possibly atypical presentations of prion disorders. The significance of this new mutation will remain unclear until further such patients are reported. PMID- 18443556 TI - Nitric oxide synthases as shared targets for reproductive hormones. Comment to: Estrogen's actions transcend a sole reproductory function in cell signalling Kirk Mantione Med Sci Monit 2008; 14(2): SC1-3. PMID- 18443557 TI - Alzheimer's disease, aneuploidy and neurogenesis. PMID- 18443558 TI - Prognostic value of computer-assisted morphological and morphometrical analysis for detecting the recurrence tendency of basal cell carcinoma. AB - BACKGROUND: Nuclear morphometry may provide useful diagnostic and prognostic information about basal cell carcinomas (BCCs) of the skin. MATERIAL/METHODS: A morphometric analysis was performed on histological sections of 52 primary BCCs which recurred and of 52 cases of BCC which did not recur. Eighteen different morphometric parameters were considered, e.g. nuclear area, perimeter, elongation, convexivity, and gray level of the nucleus. The demographics of these patients and the histological-morphological characteristics of their tumors were also considered. Statistical analysis was performed to evaluate the prognostic and predictive value of the morphometric variables for the recurrence of BCCs. RESULTS: Increased patient age, multiple localization of BCCs at the time of diagnosis, and a low degree of peripheral palisading at the histological sections of BCCs were associated with BCC recurrence and consequently worse disease-free survival (DFS). 'Darker' values of the maximum nuclear gray level as well as greater variance of nuclear gray level values also strongly related to BCC recurrence and worse DFS. The analysis of the morphometry according to the histological types of BCC revealed that nodular BCCs consist of larger cells with statistically significant increased perimeter, minimum exterior axis, nuclear area, surface and perimeter of convexivity, and equivalent circle diameter. Infiltrating, sclerosing, and superficial BCCs, which tend to relapse, showed to consist of smaller cells with greater intercellular distance. CONCLUSIONS: Nuclear morphometry evaluated with computer-assisted image analysis may contribute to a better knowledge and outcome prediction of BCC. PMID- 18443559 TI - The high risk of IPV against Canadian women with disabilities. AB - BACKGROUND: Mounting evidence suggests that women with disabilities have a particularly high risk of experiencing violence by an intimate partner. This study examined the elevated risk for male-female intimate partner violence (IPV) against women with disabilities compared to women without disabilities across three large-scale Canadian surveys. An explanatory framework was tested that organized risk markers based on whether they referred to the context of the relationship between the couple (relationship factors), the victim (victim related characteristics), or the perpetrator (perpetrator-related characteristics). MATERIAL/METHODS: The data employed in this study were from three surveys collected by Statistics Canada: the 1993 Violence Against Women Survey, and the 1999 and 2004 iterations of the General Social Survey. Descriptive analyses consisted of cross-tabulations with Chi-square tests of significance. Logistic regression was used to calculate zero-order odds ratios and to perform multivariate analyses. RESULTS: A pattern was found in which women with disabilities reported a significantly higher prevalence of violence than those without disabilities. The perpetrator-related characteristics were the only variables that reduced the elevated odds of violence against women with disabilities. Partners of women with disabilities were more likely to engage in patriarchal domination as well as possessive and jealous behaviors. CONCLUSIONS: The apparent importance of perpetrator-related characteristics (e.g., jealousy) suggests that future research should include a focus on what it is about the context of disability that makes these men more likely to engage in behaviors that are associated with IPV perpetration. Population-based efforts, professionals working with women who are victims, and professionals working with male perpetrators need to pay attention to the role of disability in IPV. PMID- 18443560 TI - Changes in drug prescription utilization for diabetic and hypertensive outpatients after initiation of the National Health Insurance's Global Budget Program in Taiwan. AB - BACKGROUND: To examine changes in medicine utilization and prescription trends for diabetic (DM) and hypertensive (HT) patients upon initiation of the National Health Insurance (NHI) global budget (GB) program in Taiwan. MATERIAL/METHODS: Data on hospital-based outpatient prescriptions for DM and HT from the Taipei branch before and after the GB were analyzed from January 2002 to December 2004. A secondary analysis of reimbursed data, with descriptive and trend analyses of the four indicators, daily oral medication cost, daily tablets used, medicine items per prescription, and tablet cost, was conducted. RESULTS: The comparisons of before and after the GB were as follows: Daily oral medication cost increased from US $0.585 to $0.956 (64%) for the DM group and from $1.01 to $1.07 (6.12%) for the HT group. The increments for daily used tablets, medicine items per prescription, and tablet cost were 33.3%, 17.9%, and 26.5% for the DM group and 6.65%, 3.31%, and 0.27% for the HT group. Indicators for the DM group not only increased significantly compared with those of the HT group, but also had higher adjusted beta coefficients. The comparisons of before and after the GB showed that the increments for the DM group decreased slightly, but not those for the HT group. CONCLUSIONS: The indicators for DM were significantly higher than those of HT group during the implementation phase of the GB. The GB program implemented by the NHI in Taiwan slightly slowed the trend of hospital-based ambulatory prescription costs of DM, but not HT. PMID- 18443561 TI - New trends in head and neck surgery: a prospective evaluation of the Harmonic Scalpel. AB - BACKGROUND: The use of ultrasonic technology to cut and coagulate tissues with minimal tissue damage has been investigated in general surgery and gynecology. The purpose of this study was to verify the efficacy and applicability of the Harmonic Scalpel in head and neck surgery. MATERIAL/METHODS: A non-randomized study was undertaken on 40 pharyngolaryngectomies, 40 total laryngectomies, 40 radical neck dissections, and 40 superficial parotidectomies performed using the Harmonic Scalpel (80 patients) or "cold knife" dissection (80 patients). The evaluation included operation time, intraoperative blood loss, quantity of neck drainage on the first and second postoperative days, postoperative seroma formation, pattern of wound healing, days of hospitalization, and subjective assessment of postoperative pain. RESULTS: In patients treated with the Harmonic Scalpel, the mean operation time was significantly (p<0.05) shorter (119.1+/-1.35 vs. 156.9+/-1.51), intraoperative blood loss (121.5+/-1.28 vs. 257.5+/-2.32) and the quantity of neck drainage on the first (47+/-0.87 vs. 89+/-1.28) and second (38.7+/-0.86 vs. 75.5+/-1.34) postoperative days were significantly less, and the days of hospitalization (6.67+/-0.48 vs. 8.8+/-0.58) and the pain scores (3.24+/ 0.63 vs. 5.91+/-0.83) were significantly lower than in the "cold knife" group. No postoperative complications were noted in the Harmonic Scalpel group. CONCLUSIONS: The use of the Harmonic Scalpel in head and neck surgery is safe and confers some advantages over conventional methods of head and neck dissection. PMID- 18443562 TI - Hepatitis C associated cardiomyopathy: potential pathogenic mechanisms and clinical implications. AB - Hepatitis C virus (HCV) has tropism for other tissues besides the liver (e.g. lymphocytic tissues). It has been isolated from the myocardium of patients with myocarditis and cardiomyopathy hence, its inclusion among the cardiotropic viruses; however, the mechanisms by which this virus damages the myocardium have not been elucidated. It seems that the development of HCV-associated cardiomyopathy may take place in genetically susceptible individuals in whom viral, immunologic, and apotoptic mechanisms may act in concert to produce myocardial damage. In this regard, the HLA and non-HLA systems have been implicated in the susceptibility for the development of HCV-associated cardiomyopathy. In this article, possible mechanisms by which the HCV may cause cardiomyopathy are proposed based on recent knowledge on the behavior of this virus, and on current ideas on the pathogenesis of cardiomyopathy. The understanding of cardiomyopathy as an extrahepatic manifestation of HCV infection is of great importance because the treatments available for chronic hepatitis C at present are considered relative contraindications in patients with myocardial dysfunction. However, if causative and pathophysiologic mechanisms underlying HCV associated cardiomyopathy are further elucidated patients with chronic hepatitis C and non ischemic cardiomyopathy may benefit from therapeutic interventions that may result in eradication of the virus and reversal of myocardial dysfunction. PMID- 18443563 TI - Melatonin: adjuvant therapy of malignant tumors. AB - This review summarizes the most relevant data relating to the potential role of melatonin (pineal secretory product) as an adjuvant therapy of tumors. Results of clinical studies were preceded by a description of experiments conducted on tumor cell lines and on laboratory animals. Most of the reports unequivocally confirmed the antioxidative and immunostimulatory action of the pineal secretory product in both in vitro and in vivo experiments. Results of studies on cell lines of various tumors showed that the anti-proliferative effect of melatonin might involve a receptor-mediated mechanism. In experiments on animals, the cardio-, nephro-, and myelo-protective action of melatonin was confirmed in the course of application of various cytostatic drugs. A meta-analysis of clinical studies in which melatonin was applied as an adjuvant drug in the therapy of various tumors pointed to some effects of its administration. Therefore, the use of melatonin could offer hope in future antitumor therapy. PMID- 18443565 TI - A synoptic approach to weather conditions discloses a relationship with ambulatory blood pressure in hypertensives. AB - BACKGROUND: Higher blood pressure (BP) values in cold than in hot months has been documented in hypertensives. These changes may potentially contribute to the observed excess winter cardiovascular mortality. However, the association with weather has always been investigated by considering the relationship with a single variable rather than considering the combination of ground weather variables characterizing a specific weather pattern (air mass (AM)). METHODS: We retrospectively investigate in Florence (Italy) the relationship between BP and specific AMs in hypertensive subjects (n = 540) referred to our Hypertension Unit for 24-h ambulatory BP monitoring during the period of the year characterized by the highest weather variability (winter). Five different winter daily AMs were classified according to the combination of ground weather data (air temperature, cloud cover, relative humidity, atmospheric pressure, wind speed, and direction). RESULTS: Multiple variable analysis selected the AM as a significant predictor of mean 24-h BP (P < 0.01 for diastolic BP (DBP) and P < 0.05 for systolic BP (SBP)), daytime DBP (P < 0.001) and nighttime BP (P < 0.01 for both SBP and DBP), with higher BP values observed in cyclonic (unstable, cloudy, and mild weather) than in anticyclonic (settled, cloudless, and cold weather) days. When the association with 2-day sequences of AMs was considered, an increase in ambulatory BP followed a sudden day-to-day change of weather pattern going from anticyclonic to cyclonic days. CONCLUSIONS: The weather considered as a combination of different weather variables may affect BP. The forecast of a sudden change of AM could provide important information helpful for hypertensives during winter. PMID- 18443564 TI - Change of genetic determinants of left ventricular structure in adolescence: longitudinal evidence from the Georgia cardiovascular twin study. AB - BACKGROUND: Genetic contribution to left ventricular (LV) structure is generally recognized, but whether and how this influence varies by ethnicity or with age is unknown. METHODS: Participants were 517 European-American (EA) and African American (AA) twin pairs (mean age: 14.6 +/- 3.0) at visit 1 and 422 EA and AA twin pairs at follow-up 4.1 years later. Echocardiograms were obtained on both visits. Data were analyzed using the structural equation modeling software Mx. RESULTS: Body mass index (BMI) was a strong predictor for all LV measures at both visits 1 and 2, accounting for 3.5-24.2% of the total variance. Hemodynamics explained up to 4.5% additional LV measures variance. After adjusting for BMI, LV measures showed substantial heritability (range: 21-71%). Best-fitting longitudinal models revealed considerable novel genetic effects on the interventricular septum, posterior wall-, and relative wall thickness (RWT) (but not LV internal diameter), accounting for 32-41% of the phenotypic variance at visit 2, with no significant gender and ethnic effects. There was a gender difference for LV mass index in AAs (P < 0.01), with a significant influence of novel genetic effects in males (47%), but not in females. No gender difference was seen in EAs, with 34% of the phenotypic variance at visit 2 attributable to novel genetic effects. CONCLUSIONS: The heritability of cardiac structure and geometry was equally substantial in both AAs and EAs. Significant novel genetic influences were detected for all measures but LV inner diameter and LV mass index in AA females. Further developmental genetic studies are warranted to elucidate the nature of the emerging gene effects during the transition from adolescence to adulthood. PMID- 18443566 TI - Can validated wrist devices with position sensors replace arm devices for self home blood pressure monitoring? A randomized crossover trial using ambulatory monitoring as reference. AB - BACKGROUND: Electronic devices that measure blood pressure (BP) at the arm level are regarded as more accurate than wrist devices and are preferred for home BP (HBP) monitoring. Recently, wrist devices with position sensors have been successfully validated using established protocols. This study assessed whether HBP values measured with validated wrist devices are sufficiently reliable to be used for making patient-related decisions in clinical practice. METHODS: This randomized crossover study compared HBP measurements taken using validated wrist devices (wrist-HBP, Omron R7 with position sensor) with those taken using arm devices (arm-HBP, Omron 705IT), and also with measurements of awake ambulatory BP (ABP, SpaceLabs), in 79 subjects (36 men and 43 women) with hypertension. The mean age of the study population was 56.7 +/- 11.8 years, and 33 of the subjects were not under treatment for hypertension. RESULTS: The average arm-HBP was higher than the average wrist-HBP (mean difference, systolic 5.2 +/- 9.1 mm Hg, P < 0.001, and diastolic 2.2 +/- 6.7, P < 0.01). Twenty-seven subjects (34%) had a > or =10 mm Hg difference between systolic wrist-HBP and arm-HBP and twelve subjects (15%) showed similar levels of disparity in diastolic HBP readings. Strong correlations were found between arm-HBP and wrist-HBP (r 0.74/0.74, systolic/diastolic, P < 0.0001). However, ABP was more strongly correlated with arm-HBP (r 0.73/0.76) than with wrist-HBP (0.55/0.69). The wrist-arm HBP difference was associated with systolic ABP (r 0.34) and pulse pressure (r 0.29), but not with diastolic ABP, sex, age, arm circumference, and wrist circumference. CONCLUSIONS: There might be important differences in HBP measured using validated wrist devices with position sensor vs. arm devices, and these could impact decisions relating to the patient in clinical practice. Measurements taken using arm devices are more closely related to ABP values than those recorded by wrist devices. More research is needed before recommending the widespread use of wrist monitors in clinical practice. American Journal of Hypertension doi:10.1038/ajh.2008.176American Journal of Hypertension (2008); 21, 7, 753-758. doi:10.1038/ajh.2008.176. PMID- 18443567 TI - Urinary aldosterone-to-active-renin ratio: a useful tool for predicting resolution of hypertension after adrenalectomy in patients with aldosterone producing adenomas. AB - BACKGROUND: The purpose of this study was to determine the preoperative clinical and biological factors that predict the clinical outcomes after surgery, in subjects with aldosterone-producing adenomas (APAs). METHODS: Fifty-eight patients (mean age 52 +/- 11 years) with APA were followed up for 43 +/- 13 months after they had undergone unilateral adrenalectomy. The subjects were classified as "cured" (n = 23) if the blood pressure (BP) was <140/90 mm Hg without postoperative medication, "normalized" (n = 20) if BP was <140/90 mm Hg with antihypertensive therapy, and "uncontrolled" (n = 15) if a BP of < or =140/90 mm Hg was not achieved despite intensive therapy. RESULTS: The cured patients had a significantly lower mean preoperative age, cardiac mass, and serum creatinine (P < 0.001) than the other subjects. The main independent predictors of surgical curability were: age (P < 0.01), low serum potassium (P < 0.0001), and the urinary aldosterone-to-active-renin (UAAR) ratio (P < 0.008). Among the hormonal parameters, the UAAR ratio provided the best area under the receiver operating-characteristics curve (0.802 (confidence interval (CI) 95%: 0.676 0.944)). For a cutoff value of 15, the positive and negative predictive values of the UAAR ratio were 85 and 92%, respectively. In the study population as a whole, surgical treatment restored the age-systolic BP (SBP) relationship (P < 0.006), which was insignificant before surgery. CONCLUSIONS: Although all the subjects showed lowering of BP after surgery, and the age-BP relationship was restored, the long-term cure rate of APA subjects was 40%. The UAAR ratio, by comparison with other classical hormonal features of primary aldosteronism, was the best independent predictor of the cure of hypertension after adrenalectomy. PMID- 18443568 TI - Obese and nonobese patients with essential hypertension show similar N-terminal proBNP plasma levels. AB - BACKGROUND: Multiple studies have focused on the influence of obesity on natriuretic peptide levels. However, the effect of obesity on amino-terminal propeptide of B-type natriuretic peptide (NT-proBNP) levels in hypertensive (HT) patients remains uncertain. METHODS: We studied 252 asymptomatic patients (60 +/- 13 years, 136 men) with essential HT. A routine physical examination, anthropometry, laboratory analyses, echo-Doppler study, and NT-proBNP level determination were performed. RESULTS: NT-proBNP levels were similar in both obese and nonobese HT (median 56 (25-130) pg/ml vs. median 51 (26-129) pg/ml, P = 0.488). No significant differences were found in obese or nonobese patients with left ventricular hypertrophy (LVH) (median 135 (73-425) pg/ml vs. median 151 (64 274) pg/ml, P = 0.597). The area under the curve was 0.89 +/- 0.03 for NT-proBNP to diagnose LVH in the obese HT patients and 0.88 +/- 0.03 in the nonobese. A logistic regression analysis showed that age, gender, and left ventricular mass index (LVMI) were independent predictors of NT-proBNP levels. Body mass index (BMI) was not significantly associated with NT-proBNP in LVH HT patients. CONCLUSIONS: Obesity is not statistically associated with NT-proBNP levels in HT asymptomatic patients. The same results were observed in our group of patients with LVH. These data are in contrast with those previously found in heart failure, and raise questions about the role of obesity per se as primary cause of decreased NT-proBNP levels in other pathophysiological conditions. PMID- 18443569 TI - The accelerating epidemic of hypertension among rural Chinese women: results from Liaoning Province. AB - BACKGROUND: The objective of the study was to assess prevalence, awareness, treatment, and control of hypertension and its risk factors in rural women in Liaoning Province in northeast China. METHODS: We conducted a cross-sectional analysis of 23,178 women of minimum age 35 years, living in rural Liaoning province in northeast China. We measured their blood pressure (BP) and investigated associated factors. Hypertension was defined as an average systolic BP > or =140 mm Hg, and/or an average diastolic BP > or =90 mm Hg, and/or self report of current treatment for hypertension with antihypertensive medication. RESULTS: The overall prevalence of hypertension in this study was 38.6%. Among those with hypertension, 32.8% were aware that they had high BP, 27.4% were being treated with antihypertensive medications, and in 1.4% of the women the hypertension was controlled. Multivariate analysis revealed that higher age, Mongolian ethnicity, higher body mass index (BMI), higher waist circumference (WC), excessive salt intake, smoking, alcohol consumption, lipid disorder, diabetes, and family history of hypertension were associated with the prevalence of hypertension; a higher level of education (high school or beyond) and a higher income level were inversely related to hypertension prevalence. CONCLUSIONS: Our results indicate that hypertension is highly prevalent in rural women in Liaoning province and it is associated with known risk factors. There are unacceptably low percentages of those with hypertension who are aware of their condition, are receiving treatment, and in whom hypertension is controlled. Our study suggests the urgent need for a public health program to improve the prevention, detection, and treatment of hypertension in rural Chinese women. PMID- 18443570 TI - Association of body mass index with cognitive function in elderly hypertensive Japanese. AB - BACKGROUND: As hypertension, obesity, and leanness are reported to be associated with poor cognitive function, it is possible that obesity or leanness in hypertensive patients may also be associated strongly with poor cognitive function. METHODS: We recruited 184 elderly hypertensive patients comprising 93 very elderly (aged >or=80 years) and 91 younger elderly (aged 61-79 years) subjects. A mini-mental state examination (MMSE) and 24-h ambulatory blood pressure monitoring (ABPM) were performed in all participants. Patients were classified as either lean, normal physique, or obese according to the body mass index (BMI) quartile. The prevalence of poor cognitive function, total MMSE score, and MMSE subscores were compared between the groups. RESULTS: The prevalence of poor cognitive function, total MMSE score, and MMSE subscore attention/calculation were significantly different between the groups both in the total study population and in the very elderly patients. The multiple logistic regression model showed that leanness was a significant determinant of poor cognitive function in both the total study population (odds ratio (OR) 2.54, 95% confidence interval (CI) 1.13-5.73, P = 0.02) and the very elderly patients (OR 3.94, 95% CI 1.31-11.82, P = 0.01). Obesity was not a significant determinant in either the total study population, very elderly, or younger elderly groups. CONCLUSION: While obesity in hypertensive elderly patients was not associated with poor cognitive function, leanness in hypertensive elderly patients was, especially in the very elderly. PMID- 18443571 TI - Renal and metabolic disorders depend on the renin-angiotensin system in Lyon hypertensive rats associated with diabetes. AB - BACKGROUND: In Lyon genetically hypertensive (LH) rats with diabetes, the effects of angiotensin converting enzyme (ACE) inhibition with perindopril on the prevention of dyslipidemia and proteinuria were evaluated by comparison with a nonspecific antihypertensive treatment. METHODS: Diabetes was induced in 2-day old male LH rats by intraperitoneal injection of streptozotocin (75 mg/kg). Glucose tolerance (glucose 2 g/kg by gavage), blood pressure (BP), plasma lipids, and urinary protein excretion were studied in: (i) untreated diabetic LH rats, (ii) diabetic LH rats treated from 8 to 16 weeks of age with oral perindopril at a low dose (0.01 mg/kg/day), (iii) similar rats treated with oral perindopril for the same duration at a high dose (1 mg/kg/day), and (iv) similar rats treated for the same duration with a triple therapy regimen consisting of hydralazine, hydrochlorothiazide, and reserpine (75, 15, and 0.75 mg/kg/day, respectively). RESULTS: The neonatal administration of streptozotocin in LH rats increased nonfasting glycemia and induced a marked glucose intolerance which was accompanied by further increases in BP, plasma cholesterol, and urinary protein excretion. None of the treatments was able to modify glucose tolerance in diabetic LH rats. The low dose of perindopril was ineffective in the prevention of hypertension, dyslipidemia, and proteinuria in diabetic LH rats, while the high dose of perindopril normalized the BP, reduced the plasma lipids, and lowered the proteinuria. However, in spite of significant reduction in BP, the triple therapy failed to improve dyslipidemia and proteinuria; on the contrary, the therapy worsened these two conditions. CONCLUSIONS: In diabetic LH rats, only ACE inhibition is of benefit to the kidney and lipidemia, thereby demonstrating that antihypertensive regimens may differ in their capacity to protect the target organs and lipid metabolism in a diabetic setting. PMID- 18443572 TI - Age-dependent decrease in 11beta-hydroxysteroid dehydrogenase type 2 (11beta HSD2) activity in hypertensive patients. AB - BACKGROUND: The prevalence of arterial hypertension lacking a defined underlying cause increases with age. Age-related arterial hypertension is insufficiently understood, yet known characteristics suggest an aldosterone-independent activation of the mineralocorticoid receptor. Therefore, we hypothesized that 11beta-HSD2 activity is age-dependently impaired, resulting in a compromised intracellular inactivation of cortisol (F) with F-mediated mineralocorticoid hypertension. METHODS: Steroid hormone metabolites in 24-h urine samples of 165 consecutive hypertensive patients were analyzed for F and cortisone (E), and their TH-metabolites tetrahydro-F (THF), 5alphaTHF, TH-deoxycortisol (THS), and THE by gas chromatography-mass spectroscopy. Apparent 11beta-HSD2 and 11beta hydroxylase activity and excretion of F metabolites were assessed. RESULTS: In 72 female and 93 male patients aged 18-84 years, age correlated positively with the ratios of (THF + 5alphaTHF)/THE (P = 0.065) and F/E (P < 0.002) suggesting an age dependent reduction in the apparent 11beta-HSD2 activity, which persisted (F/E; P = 0.020) after excluding impaired renal function. Excretion of F metabolites remained age-independent most likely as a consequence of an age-dependent diminished apparent 11beta-hydroxylase activity (P = 0.038). CONCLUSION: Reduced 11beta-HSD2 activity emerges as a previously unrecognized risk factor contributing to the rising prevalence of arterial hypertension in elderly. This opens new perspectives for targeted treatment of age-related hypertension. PMID- 18443573 TI - Fixed combination of perindopril and indapamide at low dose improves endothelial function in essential hypertensive patients after acute administration. AB - BACKGROUND: Fixed combination of angiotensin-converting enzyme inhibitors (ACEIs) with thiazide-type diuretics at low dose has been used as first-line therapy for the treatment of essential hypertension but their effect on conduit artery endothelial dysfunction remains unknown. METHODS: Thirteen hypertensive patients were assessed after acute administration of a placebo, fixed combination of perindopril-indapamide at low dose: D1 (2 mg/0.625 mg) and twice this dose: D2 (4 mg/1.25 mg), during a double-blind, randomized, crossover study, and were compared with 13 matched controls. Mean arterial pressure (MAP), radial artery diameter (echotracking) and flow (Doppler) were measured during flow-mediated dilatation (FMD) induced by post-ischemic hyperemia (PIH). PIH was characterized by peak flow and duration of hyperemia (t(1/2)). Endothelium-independent dilatation was assessed by trinitrine. RESULTS: In hypertensive patients compared with controls, basal radial artery diameter and flow, peak flow, and trinitrine responses were similar while MAP was increased (115 +/- 3 vs. 87 +/- 2 mm Hg), t(1/2) was decreased (11.1 +/- 1.9 vs. 17.2 +/- 2.2 s), and FMD was altered (radial diameter increase: 203 +/- 14 vs. 304 +/- 15 microm). Compared with placebo, only D2 decreased MAP (placebo: 115 +/- 3; D1: 112 +/- 4; D2: 103 +/- 4 mm Hg) and increased t(1/2) (placebo: 11.1 +/- 1.9; D1: 8.7 +/- 1.5; D2:13.0 +/- 1.9 s). Conversely, D1 and D2 increased FMD (placebo: 203 +/- 14; D1: 218 +/- 22; D2: 227 +/- 23 microm) with no change in basal diameter and flow, peak flow, and trinitrine responses. CONCLUSION: These results demonstrate that a fixed combination of ACEI/diuretic at low dose significantly improves radial artery FMD in hypertensive patients and suggest a direct effect on conduit artery endothelium that may contribute to vascular protection. PMID- 18443574 TI - Home blood pressure monitoring in children: how many measurements are needed? AB - OBJECTIVE: To investigate the minimum schedule of blood pressure (BP) measurements necessary to provide a reliable assessment of home BP (HBP) in children and adolescents. METHODS: Subjects aged 6-18 years referred for elevated BP were assessed with HBP monitoring (6 workdays, duplicate morning and evening measurements) and 24-h ambulatory BP monitoring (ABP). Criteria for HBP reliability were its reproducibility (test-retest correlations and SD of differences (SDDs) between repeated measurements), its stability (average home BP of an increasing number of readings and its SD), and its relationship with ABP. RESULTS: Data from 100 subjects were analyzed (mean age 13 +/- 2.8 (SD) years, 61 boys). The reproducibility of 3-day HBP (r 0.88/0.79, SDDs 5.1/4.9, systolic/diastolic) was superior to that of a single (r 0.79/0.65, SDDs 7.6/7.1) or 2-day HBP (r 0.85/0.72, SDDs 6.1/5.4). By averaging up to 12 readings (3 days), there was a progressive decline in average HBP, with no further decline thereafter. The SD of average HBP was also progressively reduced, with little change after day 3. The association of HBP with ABP was improved by averaging more readings up to 12, with no further improvement when more readings were averaged. The exclusion of first-day measurements slightly increased the SD of average HBP and weakened the correlation with ABP, probably due to reduced number of readings. CONCLUSIONS: In children and adolescents, 3-day monitoring with duplicate morning and evening measurements appears to be the minimum schedule for the reliable assessment of HBP. PMID- 18443575 TI - Putative role of asymmetric dimethylarginine in microvascular disease of kidney and heart in hypertensive patients. AB - BACKGROUND: Despite the frequent simultaneous presentation of cardiac and renal dysfunction, the relationship between these pathophysiological processes remains unclear. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase, which has been linked to endothelial dysfunction and atherosclerosis. This study elucidates the relationship between ADMA and intrarenal and coronary microvascular diseases. METHODS: In this study, we included 66 consecutive hypertensive patients with normal renal function or mild renal insufficiency (creatinine or=90 ml/min; renal insufficiency group, eGFR <90 ml/min). Coronary flow velocity reserve (CFVR) was measured using adenosine-triphosphate stress transthoracic Doppler echocardiography. In addition, a plasma ADMA assay, echocardiography, carotid ultrasound, and brachial-ankle pulse wave velocity measurement were performed. RESULTS: The plasma ADMA level was the highest in patients with both renal insufficiency and reduced CFVR. ADMA was significantly associated with eGFR (r = -0.342, P = 0.006) and CFVR (r = -0.459, P < 0.001), and eGFR and CFVR were significantly associated with each other (r = 0.337, P = 0.006). Multiple regression analysis revealed that ADMA was an independent clinical parameter associated with both eGFR and CFVR. CONCLUSIONS: Plasma ADMA is suggested to be an incipient biochemical marker of microvascular disease in both kidney and heart in hypertensive patients. ADMA might play an important role in the pathogenesis of organ damage in the kidney and heart in essential hypertension. PMID- 18443576 TI - Starting well in Europe. PMID- 18443579 TI - Sizing up human height variation. PMID- 18443580 TI - Principal component analysis of genetic data. PMID- 18443581 TI - From gene expression to disease risk. PMID- 18443582 TI - Coevolution in the tumor microenvironment. PMID- 18443583 TI - Salt wasting and blood pressure. PMID- 18443586 TI - Year of the rat. PMID- 18443585 TI - An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. AB - Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell-like phenotypes shown by many tumors. PMID- 18443587 TI - An ENU-induced mutant archive for gene targeting in rats. PMID- 18443588 TI - Progress and prospects in rat genetics: a community view. AB - The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research. PMID- 18443589 TI - What everybody should know about the rat genome and its online resources. AB - It has been four years since the original publication of the draft sequence of the rat genome. Five groups are now working together to assemble, annotate and release an updated version of the rat genome. As the prevailing model for physiology, complex disease and pharmacological studies, there is an acute need for the rat's genomic resources to keep pace with the rat's prominence in the laboratory. In this commentary, we describe the current status of the rat genome sequence and the plans for its impending 'upgrade'. We then cover the key online resources providing access to the rat genome, including the new SNP views at Ensembl, the RefSeq and Genes databases at the US National Center for Biotechnology Information, Genome Browser at the University of California Santa Cruz and the disease portals for cardiovascular disease and obesity at the Rat Genome Database. PMID- 18443591 TI - Distribution and functional impact of DNA copy number variation in the rat. AB - The abundance and dynamics of copy number variants (CNVs) in mammalian genomes poses new challenges in the identification of their impact on natural and disease phenotypes. We used computational and experimental methods to catalog CNVs in rat and found that they share important functional characteristics with those in human. In addition, 113 one-to-one orthologous genes overlap CNVs in both human and rat, 80 of which are implicated in human disease. CNVs are nonrandomly distributed throughout the genome. Chromosome 18 is a cold spot for CNVs as well as evolutionary rearrangements and segmental duplications, suggesting stringent selective mechanisms underlying CNV genesis or maintenance. By exploiting gene expression data available for rat recombinant inbred lines, we established the functional relationship of CNVs underlying 22 expression quantitative trait loci. These characteristics make the rat an excellent model for studying phenotypic effects of structural variation in relation to human complex traits and disease. PMID- 18443590 TI - Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. AB - We aimed to identify genetic variants associated with heart failure by using a rat model of the human disease. We performed invasive cardiac hemodynamic measurements in F2 crosses between spontaneously hypertensive heart failure (SHHF) rats and reference strains. We combined linkage analyses with genome-wide expression profiling and identified Ephx2 as a heart failure susceptibility gene in SHHF rats. Specifically, we found that cis variation at Ephx2 segregated with heart failure and with increased transcript expression, protein expression and enzyme activity, leading to a more rapid hydrolysis of cardioprotective epoxyeicosatrienoic acids. To confirm our results, we tested the role of Ephx2 in heart failure using knockout mice. Ephx2 gene ablation protected from pressure overload-induced heart failure and cardiac arrhythmias. We further demonstrated differential regulation of EPHX2 in human heart failure, suggesting a cross species role for Ephx2 in this complex disease. PMID- 18443592 TI - Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass. AB - Left ventricular mass (LVM) and cardiac gene expression are complex traits regulated by factors both intrinsic and extrinsic to the heart. To dissect the major determinants of LVM, we combined expression quantitative trait locus1 and quantitative trait transcript (QTT) analyses of the cardiac transcriptome in the rat. Using these methods and in vitro functional assays, we identified osteoglycin (Ogn) as a major candidate regulator of rat LVM, with increased Ogn protein expression associated with elevated LVM. We also applied genome-wide QTT analysis to the human heart and observed that, out of 22,000 transcripts, OGN transcript abundance had the highest correlation with LVM. We further confirmed a role for Ogn in the in vivo regulation of LVM in Ogn knockout mice. Taken together, these data implicate Ogn as a key regulator of LVM in rats, mice and humans, and suggest that Ogn modifies the hypertrophic response to extrinsic factors such as hypertension and aortic stenosis. PMID- 18443593 TI - Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility. AB - Crescentic glomerulonephritis is an important cause of human kidney failure for which the underlying molecular basis is largely unknown. In previous studies, we mapped several susceptibility loci, Crgn1-Crgn7, for crescentic glomerulonephritis in the Wistar Kyoto (WKY) rat. Here we show by combined congenic, linkage and microarray studies that the activator protein-1 (AP-1) transcription factor JunD is a major determinant of macrophage activity and is associated with glomerulonephritis susceptibility. Introgression of Crgn2 from the nonsusceptible Lewis strain onto the WKY background leads to significant reductions in crescent formation, macrophage infiltration, Fc receptor-mediated macrophage activation and cytokine production. Haplotype analysis restricted the Crgn2 linkage interval to a 430-kb interval containing Jund, which is markedly overexpressed in WKY macrophages and glomeruli. Jund knockdown in rat and human primary macrophages led to significantly reduced macrophage activity and cytokine secretion, indicating conservation of JunD function in macrophage activation in rats and humans and suggesting in vivo inhibition of Jund as a possible new therapeutic strategy for diseases characterized by inflammation and macrophage activation. PMID- 18443594 TI - SNP and haplotype mapping for genetic analysis in the rat. AB - The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies. PMID- 18443596 TI - Expression of SDF-1 alpha and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. AB - Although stromal cell-derived factor (SDF)-1 alpha and its receptor CXCR4 are experimentally suggested to be involved in tumorigenicity, the clinicopathological significance of their expression in human disease is not fully understood. We examined SDF-1 alpha and CXCR4 expression in colorectal cancers (CRCs) and their related lymph nodes (LNs), and investigated its relationship to clinicopathological features. Specimens of 60 primary CRCs and 27 related LNs were examined immunohistochemically for not only positivity but also immunostaining patterns for SDF-1 alpha and CXCR4. The relationships between clinicopathological features and SDF-1 alpha or CXCR4 expression were then analysed. Stromal cell-derived factor-1 alpha and CXCR4 expression were significantly associated with LN metastasis, tumour stage, and survival of CRC patients. Twenty-nine of 47 CXCR4-positive CRCs (61.7%) showed clear CXCR4 immunoreactivity in the nucleus and a weak signal in the cytoplasm (nuclear type), whereas others showed no nuclear immunoreactivity but a diffuse signal in the cytoplasm and at the plasma membrane (cytomembrane type). Colorectal cancer patients with nuclear CXCR4 expression showed significantly more frequent LN metastasis than did those with cytomembrane expression. Colorectal cancer patients with nuclear CXCR4 expression in the primary lesion frequently had cytomembrane CXCR4-positive tumours in their LNs. In conclusion, expression of SDF-1 alpha and nuclear CXCR4 predicts LN metastasis in CRCs. PMID- 18443597 TI - Vascular tube formation on matrix metalloproteinase-1-damaged collagen. AB - Connective tissue damage and angiogenesis are both important features of tumour growth and invasion. Here, we show that endothelial cells maintained on a three dimensional lattice of intact polymerised collagen formed a monolayer of cells with a cobblestone morphology. When the collagen was exposed to organ culture fluid from human basal cell tumours of the skin (containing a high level of active matrix metalloproteinase-1 (MMP-1)), degradation of the collagen matrix occurred. The major degradation products were the $3 over 4$- and $1 over 4$ sized fragments known to result from the action of MMP-1 on type I collagen. When endothelial cells were maintained on the partially degraded collagen, the cells organised into a network of vascular tubes. Pretreatment of the organ culture fluid with either tissue inhibitor of metalloproteinase-1 (TIMP-1) or neutralising antibody to MMP-1 prevented degradation of the collagen lattice and concomitantly inhibited endothelial cell organisation into the vascular network. Purified (activated) MMP-1 duplicated the effects of skin organ culture fluid, but other enzymes including MMP-9 (gelatinase B), elastase or trypsin failed to produce measurable fragments from intact collagen and also failed to promote vascular tube formation. Together, these studies suggest that damage to the collagenous matrix is itself an important inducer of new vessel formation. PMID- 18443599 TI - Effect of weight-bearing activities on bone mineral density in spinal cord injured patients during the period of the first two years. AB - STUDY DESIGN: Prospective study on patients with spinal cord injuries. OBJECTIVES: To evaluate the loss of bone mineral density (BMD) in various body regions of patients with spinal cord injury (SCI) and its dependence on weight bearing activities during 2 years post injury. METHODS: BMD of the whole body was measured in patients with SCI. Baseline measurement was performed in 6-16 weeks after SCI, the second and the third-respectively 12 and 24 months after injury. Fifty-four subjects were selected and divided into two groups: standing and non standing. From these groups 27 pairs were made according to gender, age and height. RESULTS: There was found to be a well-marked decrease in BMD values for lower extremities, but there was no significant difference between paraplegic and tetraplegic patients 1 and 2 year after injury. Leg BMD reduced by 19.62% (95% CI, 17-22%) in the standing group and by 24% (95% CI, 21-27%) in non-standing group during the first year. Two years after SCI patients in standing group had significantly higher leg BMD-1.018 g/cm(2) (95% CI, 0.971-1.055 g/cm(2)) than in the non-standing group-0.91 g/cm(2) (95% CI, 0.872-0.958 g/cm(2)) (Por=1 h and not less than 5 days per week, had significantly higher BMD in the lower extremities after 2 years in comparison to those patients who did not perform standing. PMID- 18443598 TI - Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. AB - Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT 29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP 1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice. PMID- 18443600 TI - A critical role for type I IFN-dependent NK cell activation in innate immune elimination of adenoviral vectors in vivo. AB - Recombinant adenoviruses have been used widely for gene therapy due to their high transduction efficiency in vivo. However, the attendant innate immune response to adenoviral vectors has limited their applications for in vivo gene therapy. Recent studies have shown that adenoviruses activate the innate immunity through both Toll-like receptor-dependent (TLR-dependent) and TLR-independent pathways, leading to the production of type I interferons (IFNs) and other inflammatory cytokines. Furthermore, type I IFNs play a pivotal role in innate immune elimination of adenoviral vectors in vivo. It remains to be defined how type I IFNs regulate innate immune clearance of adenoviral vectors. In this study, we showed in vivo that natural killer (NK) cells were activated and accumulated in the liver upon intravenous administration of adenoviral vectors, leading to the loss of adenoviral genome and the reduction of transgene expression. We further demonstrated that type I IFNs were critical for the activation of NK cells. This was achieved by direct action of type I IFNs on NK cells. Overall, our observations reveal a critical role for type I IFN-dependent NK cell activation in innate immune elimination of adenoviral vectors in vivo and may help design effective strategies to improve the outcome of adenovirus-mediated gene therapy. PMID- 18443601 TI - Mannose 6-phosphate receptor-mediated transport of sulfamidase across the blood brain barrier in the newborn mouse. AB - Mucopolysaccharidosis type IIIA (MPS IIIA), which is a lysosomal storage disorder (LSD) caused by inherited deficiency of sulfamidase, is characterized by severe, progressive central nervous system (CNS) dysfunction. Enzyme replacement therapy (ERT) to treat CNS storage is challenging, because the access of enzymes to the brain is restricted by the blood-brain barrier (BBB). In a prior study, we found that phosphorylated beta-glucuronidase (P-GUS) could be transcytosed across the BBB in newborn mice by the mannose 6-phosphate (M6P) receptor. In order to determine whether sulfamidase can utilize this pathway, we examined brain influx and the specificity of uptake of sulfamidase after intravenous (i.v.) injection in 2-day-old and 8-week-old mice. [(131)I]Sulfamidase was transported across the BBB in neonates at rates higher than that of simultaneously injected [(125)I]albumin. In contrast, the transport of [(131)I]sulfamidase was negligible in 8-week-old mice, thereby showing that the BBB transport mechanism is developmentally downregulated. Capillary depletion revealed that 83.7% of the [(131)I]sulfamidase taken up by the brain was in the parenchyma, demonstrating transfer across the capillary wall. The uptake of [(131)I]sulfamidase into the brain was significantly reduced by co-injections of M6P and P-GUS. That is, the transport of sulfamidase into the brain parenchyma in early postnatal life is mediated by the M6P receptor, which is shared with P-GUS and is likely accessible to other M6P-containing lysosomal enzymes. PMID- 18443605 TI - Elevated levels of transforming growth factor beta and prostaglandin E2 in aqueous humor from patients undergoing filtration surgery for glaucoma. PMID- 18443606 TI - Tubular aggregate myopathy associated with retinal degeneration. AB - CASE REPORT: We report a case of congenital tubular aggregate myopathy associated with retinal degeneration. COMMENTS: Bilateral, asymmetric retinal degeneration developed in a 37-year-old woman with a history of congenital tubular aggregate myopathy. The major pathological feature was the presence of tubular aggregates, believed to arise from the sarcoplasmic reticulum, which are present in skeletal muscles only. The abnormal functioning of the smooth muscles of the pupillary dilator, together with retinal degeneration in our patient, suggests that tubular aggregates may represent a more generalized disequilibrium of intracellular calcium homeostasis that may not be confined to skeletal muscles. PMID- 18443602 TI - Inhibition of respiratory syncytial virus infections with morpholino oligomers in cell cultures and in mice. AB - Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants, young children, and high-risk adults. Currently, there is no vaccine to prevent RSV infection, and the available therapeutic agents are of limited utility. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are a class of antisense agents that can enter cells readily and interfere with viral protein expression through steric blocking of complementary RNA. Two antisense PPMOs, designed to target sequence that includes the 5' terminal region and translation start-site region of RSV L mRNA, were tested for anti-RSV activity in cultures of two human-airway cell lines. Both PPMOs showed minimal cytotoxicity and one of them, (AUG-2), reduced viral titers by >2.0 log(10). Intranasal (i.n.) treatment of BALB/c mice with AUG-2 PPMO before the RSV inoculation produced a reduction in viral titer of 1.2 log(10) in lung tissue at day 5 postinfection (p.i.), and attenuated pulmonary inflammation at day 7 postinfection. These data show that the AUG-2 PPMO possesses potent anti-RSV activity and is worthy of further investigation as a candidate for potential therapeutic application. PMID- 18443607 TI - Femtosecond laser astigmatic keratotomy for postkeratoplasty astigmatism. AB - CASE REPORT: Two eyes of 2 patients with high astigmatism following penetrating keratoplasty were treated with femtosecond laser-assisted paired arcuate keratotomies in the donor cornea. Outcome measures included best-corrected visual acuity, refraction, keratometry, and topographic findings. The preoperative cylinder was 8.5 diopters (D) in the first case and 7.0 D in the second case. Respectively, the postoperative cylinder improved to 4.9 D after a follow-up of 8 months and to 4.3 D after a follow-up of 7 months. Best-corrected visual acuity improved from 20/100 to 20/30 in the first case and from 20/200 to 20/60 in the second case. No complications were encountered; no microperforations were observed, and neither graft rejection nor failure occurred. COMMENTS: The results of astigmatic keratotomy performed with femtosecond laser were reliable and predictable. Femtosecond astigmatic keratotomy may prove to be a safe procedure with satisfactory results. PMID- 18443608 TI - Influencing ocular blood flow in glaucoma patients: the cardiovascular system and healthy lifestyle choices. AB - The cardiovascular system and lifestyle choices play important roles in influencing ocular blood flow regulation in patients with glaucoma. This includes the presence of vascular risk factors, abnormal autoregulatory responses, tissue oxygenation, and mitochondrial oxidative stress. Based on this comprehensive review, novel therapeutic approaches may be considered in selected patients for preventing and (or) delaying the progression of glaucoma. PMID- 18443609 TI - Measuring and interpreting ocular blood flow and metabolism in glaucoma. AB - There is a growing body of evidence suggesting that vascular dysfunction is related to several prominent ophthalmic diseases, including glaucoma. The vast majority of studies providing data on ocular circulation and disease pathophysiology use a relatively small number of complicated ocular blood flow imaging techniques. Although these imaging technologies are not commonly used in clinical settings, understanding the medical literature characterizing ocular blood flow requires familiarity with their methodology and function. This review highlights the imaging technologies most commonly used to investigate ocular blood flow, including color Doppler imaging, confocal scanning laser ophthalmoscopic angiography with fluorescein and indocyanine green dye, Canon laser blood flowmetry, scanning laser Doppler flowmetry, and retinal photographic oximetry. Each imaging technique's ability to define vascular function and reveal pathology is discussed as are limitations inherent to each technology. The ultimate goal of this review is to provide the physician with a clinically relevant foundation for differentiating the various ocular blood flow outcome measures often presented in the literature and determine how they are related to ocular health and disease. PMID- 18443610 TI - What can we learn from the disc appearance about the risk factors in glaucoma? AB - The author has been involved in 3 studies, the multicentre collaborative normal tension glaucoma study, a study of 4 phenotypes of glaucomatous disc appearances and their associations, and a study reporting on biostatistical evidence for 2 distinct chronic open-angle glaucoma populations. These studies have some common threads whose clinical implications are discussed. PMID- 18443611 TI - Vascular anatomy of the optic nerve head. AB - Although intraocular pressure remains the main modifiable risk factor for open angle glaucoma, other factors such as vascular perfusion likely play a significant role. It is not clear how mechanical deformation, axonal damage, glial responses, and ischemia interact to lead to the tissue remodeling seen clinically as glaucomatous cupping. To understand the potential role of vascular risk factors in glaucoma, it is important to understand the vascular anatomy of the optic nerve head (ONH). The focus of this review is to provide a description of the vascular anatomy of the ONH and to describe recent work in the central nervous system that suggests that astrocytes play a key role in vascular regulation. Finally, the evidence for vascular regulation in the ONH and retina is reviewed. PMID- 18443612 TI - Ocular blood flow in diabetes and age-related macular degeneration. AB - The 2 leading causes of blindness in adults in the industrialized nations, diabetic retinopathy and age-related macular degeneration, have been investigated thoroughly with respect to their pathogenesis. In recent years, it has been discovered that dysfunctional ocular microcirculation appears to play a part in the development of both diseases. In diabetic retinopathy, it has been shown that the disease is associated with early retinal vascular dysregulation. In the later states of the disease, retinal tissue hypoxia is a major trigger of sight threatening neovascularization. In age-related macular degeneration, there is increasing evidence that reduced blood flow in the choroid is associated with the development and progression of the disease. Knowledge of the pathophysiological vascular states underlying these diseases is essential for the assessment and development of future therapies. PMID- 18443613 TI - Nitric oxide and cyclic guanosine monophosphate signaling in the eye. AB - This brief review describes the components and pathways utilized in nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) signaling. Since the discovery of the effects of NO and cGMP on smooth muscle relaxation about 30 years ago, the field has expanded in many directions such that many, but not all, biochemical and biological effects seem to be regulated by these unique signaling molecules. While many of the effects of NO are due to activation of soluble guanylyl cyclase (sGC) that can be considered the receptor for NO, cGMP, in turn, can activate a cGMP-dependent protein kinase (PKG) to phosphorylate an array of proteins. Some of the effects of cGMP can be independent of PKG and are due to effects on ion channels or cyclic nucleotide phosphodiesterases. Also, some of the effects of NO can be independent of sGC activation. The isoenzymes and macromolecules that participate in these signaling pathways can serve as molecular targets to identify compounds that increase or decrease their activation and thus serve as chemical leads for discovering novel drugs for a variety of diseases. Some examples are given. However, with about 90,000 publications in the field since our first reports in 1977, this brief review can only give the readers a sample of the excitement and opportunities we have found in this cell signaling system. PMID- 18443614 TI - Closed-angle glaucoma after topiramate therapy for migraine in a patient with undiagnosed pseudotumor cerebri. PMID- 18443615 TI - Central retinal vein occlusion in an AIDS patient with presumed Pneumocystis carinii pneumonia. PMID- 18443616 TI - Retained perfluoron postvitreoretinal surgery causing secondary open-angle glaucoma. PMID- 18443617 TI - Pars plana vitrectomy and internal limiting membrane peeling in an eye with foveal lipid deposition after focal laser surgery for diabetic macular edema. PMID- 18443618 TI - Idiopathic central retinal artery occlusion in a 6-year-old. PMID- 18443619 TI - Ultrasound biomicroscopy for membranous congenital cataract. PMID- 18443620 TI - Unexpected control of a patient's refractory epilepsy when treating glaucoma with acetazolamide. PMID- 18443621 TI - From cytogenetics to next-generation sequencing technologies: advances in the detection of genome rearrangements in tumors. AB - Genome rearrangements have long been recognized as hallmarks of human tumors and have been used to diagnose cancer. Techniques used to detect genome rearrangements have evolved from microscopic examinations of chromosomes to the more recent microarray-based approaches. The availability of next-generation sequencing technologies may provide a means for scrutinizing entire cancer genomes and transcriptomes at unparalleled resolution. Here we review the methods that have been used to detect genome rearrangements and discuss the scope and limitations of each approach. We end with a discussion of the potential that next generation sequencing technologies may offer to the field. PMID- 18443622 TI - Ribosomal synthesis of nonstandard peptides. AB - It is well known that standard peptides, which comprise proteinogenic amino acids, can act as specific chemical probes to target proteins with high affinity. Despite this fact, a number of peptide drug leads have been abandoned because of their poor cell permeability and protease instability. On the other hand, nonstandard peptides isolated as natural products often exhibit remarkable pharmaco-behavior and stability in vivo. Although it is likely that numerous nonstandard therapeutic peptides capable of recognizing various targets could have been synthesized, enzymes for nonribosomal peptide syntheses are complex; therefore, it is difficult to engineer such modular enzymes to build nonstandard peptide libraries. Here we describe an emerging technology for the synthesis of nonstandard peptides that employs an integrated system of reconstituted cell-free translation and flexizymes. We summarize the historical background of this technology and discuss its current and future applications to the synthesis of nonstandard peptides and drug discovery. PMID- 18443623 TI - Solid-phase assays for small molecule screening using sol-gel entrapped proteins. AB - With compound libraries exceeding one million compounds, the ability to quickly and effectively screen these compounds against relevant pharmaceutical targets has become crucial. Solid-phase assays present several advantages over solution based methods. For example, a higher degree of miniaturization can be achieved, functional- and affinity-based studies are possible, and a variety of detection methods can be used. Unfortunately, most protein immobilization methods are either too harsh or require recombinant proteins and thus are not amenable to delicate proteins such as kinases and membrane-bound receptors. Sol-gel encapsulation of proteins in an inorganic silica matrix has emerged as a novel solid-phase assay platform. In this minireview, we discuss the development of sol gel derived protein microarrays and sol-gel based monolithic bioaffinity columns for the high-throughput screening of small molecule libraries and mixtures. PMID- 18443624 TI - Small and lethal: searching for new antibacterial compounds with novel modes of action. AB - The discovery of drugs used to combat infectious diseases is in the process of constant change to address the ever-worsening problem of antibiotic resistance in pathogens and a lack of recent success in discovering new antibacterial drugs. In the past 2 decades, research in both academia and industry has made use of molecular biology, genetics, and comparative genomics, which has led to the development of key technologies for the discovery of novel antibacterial agents. Genome-scale efforts have led to the identification of numerous molecular targets. Chemical diversity from synthetic combinatorial libraries and natural products is being used to screen for new molecules. A wide variety of approaches are being used in the search for novel antibiotics, and these can be categorized as being either biochemically focused or cell based. The over-riding goal of all methods in use today is to discover new chemical matter with novel mechanisms of action against drug-resistant pathogens. PMID- 18443625 TI - Approaches to the discovery of new antibacterial agents based on bacteriocins. AB - The development of antibiotic resistance in pathogenic bacteria has led to a search for novel classes of antimicrobial drugs. Bacteriocins are peptides that are naturally produced by bacteria and have considerable potential to fulfill the need for more effective bacteriocidal agents. In this mini-review, we describe research aimed at generating analogues of bacteriocins from lactic acid bacteria, with the goal of gaining a better understanding of structure-activity relationships in these peptides. In particular, we report recent findings on synthetic analogues of leucocin A, pediocin PA1, and lacticin 3147 A2, as well as on the significance of these results for the design and production of new antibiotics. PMID- 18443626 TI - Chemical biology of tetracycline antibiotics. AB - For more than half a century, tetracycline antibiotics have been used to treat infectious disease. However, what once used to be a commonly prescribed family of antibiotics has now decreased in effectiveness due to wide-spread bacterial resistance. The chemical scaffold of the tetracyclines is a versatile and modifiable structure that is able to interact with many cellular targets. The recent availability of detailed molecular interactions between tetracycline and its cellular targets, along with an understanding of the tetracycline biosynthetic pathway, has provided us with a unique opportunity to usher in a new era of rational drug design. Herein we discuss recent findings that have clarified the mode of action and the biosynthetic pathway of tetracyclines and that have shed light on the chemical biology of tetracycline antibiotics. PMID- 18443627 TI - Recent developments in mass spectrometry-based quantitative phosphoproteomics. AB - Protein phosphorylation is a reversible post-translational modification that is involved in virtually all eukaryotic cellular processes and has been studied in great detail in recent years. Many developments in mass spectrometry (MS)-based proteomics have been successfully applied to study protein phosphorylation in highly complicated samples. Furthermore, the emergence of a variety of enrichment strategies has allowed some of the challenges associated with low phosphorylation stoichiometry and phosphopeptide copy number to be overcome. The dynamic nature of protein phosphorylation complicates its analysis; however, a number of methods have been developed to successfully quantitate phosphorylation changes in a variety of cellular systems. The following review details some of the most recent breakthroughs in the study of protein phosphorylation, or phosphoproteomics, using MS-based approaches. The majority of the focus is placed on detailing strategies that are currently used to conduct MS-based quantitative phosphoproteomics. PMID- 18443628 TI - Steps towards a repertoire of comprehensive maps of human protein interaction networks: the Human Proteotheque Initiative (HuPI). AB - Defining human protein interaction networks has become essential to develop an overall, systems-based understanding of the molecular events that sustain cell growth in normal and disease conditions. To characterize protein interaction networks from human cells, we have undertaken the development of a systematic, unbiased technology pipeline that couples experimental and computational approaches. This discovery engine is central to the Human Proteotheque Initiative (HuPI), a multidisciplinary project aimed at building a repertoire of comprehensive maps of human protein interaction networks, the Human Proteotheque. The information contained in the Proteotheque is made publicly available through an interactive web site that can be consulted to visualize some of the fundamental molecular connections formed in human cells and to determine putative functions of previously uncharacterized proteins based on guilt by association. The process governing the evolution of HuPI towards becoming a repository of accurate and complete protein interaction maps is described. PMID- 18443629 TI - Riboswitches that sense S-adenosylmethionine and S-adenosylhomocysteine. AB - Numerous riboswitches have been discovered that specifically recognize metabolites and modulate gene expression. Each riboswitch class is defined either by the consensus sequence and structural features of its metabolite-binding aptamer domain, or by the distinct metabolite that the aptamer recognizes. Several distinct classes of riboswitches that respond to S-adenosylmethionine (SAM or AdoMet) have been discovered. Representatives of these classes have been shown to strongly discriminate against S-adenosylhomocystenine (SAH or AdoHcy), which is the metabolic byproduct produced when SAM is used as a cofactor for methylation reactions. However, a distinct class of riboswitches that selectively binds SAH, and strongly discriminates against SAM, also has been discovered. Herein we compare the features of SAM and SAH riboswitches, which help showcase the enormous structural diversity that RNA can harness to form precision genetic switches for compounds that are critical for fundamental metabolic processes. PMID- 18443630 TI - Teaching old enzymes new tricks: engineering and evolution of glycosidases and glycosyl transferases for improved glycoside synthesis. AB - The therapeutic potential of glycosides has made them an attractive target for drug development. The biological extraction and chemical synthesis of these molecules is often challenging and low yielding, thus alternative methods for the synthesis of polysaccharides are being pursued. A new class of enzymes, glycosynthases, which are nucleophile mutants of glycosidases, can perform the transglycosylation reaction without hydrolyzing the product, and thus provide a valuable resource for polysaccharide and glycan synthesis. Directed evolution of glycosynthases has expanded the repertoire of glycosidic linkages formed and the donors and acceptors (both sugar and nonsugar) that can be used by the glycosynthase. The application of new screening methods, such as FACS, to the directed evolution of glycosynthases will aid in the development of enzymes that are able to efficiently synthesize new, and therapeutically relevant glycosidic linkages. PMID- 18443631 TI - eIF4E, the mRNA cap-binding protein: from basic discovery to translational research. AB - Translational control is an important strategy by which eukaryotic cells regulate gene expression. Translation is the last step in the flow of genetic information, and regulation at this level allows an immediate and rapid response to changes under physiological conditions. Because the processes of mRNA biogenesis, including transcription, splicing, and export to the cytoplasm, are time consuming, the use of pre-existing mRNAs via the control of translation is advantageous in many circumstances. A prime target of translational control is the initiation factor eIF4E, which recognizes the m7GpppN cap structure present at the 5' end of all nuclear transcribed eukaryotic mRNAs. In this article I describe the discovery of eIF4E, its mechanism of action in translation initiation, and its role in the control of cancer and innate immunity. PMID- 18443634 TI - Opioid-related issues "popping" up again. PMID- 18443635 TI - Opioid complications and side effects. AB - Medications which bind to opioid receptors are increasingly being prescribed for the treatment of multiple and diverse chronic painful conditions. Their use for acute pain or terminal pain is well accepted. Their role in the long-term treatment of chronic noncancer pain is, however, controversial for many reasons. One of the primary reasons is the well-known phenomenon of psychological addiction that can occur with the use of these medications. Abuse and diversion of these medications is a growing problem as the availability of these medications increases and this public health issue confounds their clinical utility. Also, the extent of their efficacy in the treatment of pain when utilized on a chronic basis has not been definitively proven. Lastly, the role of opioids in the treatment of chronic pain is also influenced by the fact that these potent analgesics are associated with a significant number of side effects and complications. It is these phenomena that are the focus of this review. Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate pain management. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. The most common side effects of opioid usage are constipation (which has a very high incidence) and nausea. These 2 side effects can be difficult to manage and frequently tolerance to them does not develop; this is especially true for constipation. They may be severe enough to require opioid discontinuation, and contribute to under-dosing and inadequate analgesia. Several clinical trials are underway to identify adjunct therapies that may mitigate these side effects. Switching opioids and/or routes of administration may also provide benefits for patients. Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Opioids can be considered broad spectrum analgesic agents, affecting a wide number of organ systems and influencing a large number of body functions. PMID- 18443636 TI - Peripherally-acting opioids. AB - Opioids are broad-spectrum analgesics with potent pain-relieving qualities but also with potential adverse effects related to both short-term and long-term therapy. Researchers have attempted to alter existing opioid analgesics, utilize different routes/formulations, or combine opioid analgesics with other compounds in efforts to improve analgesia while minimizing adverse effects. Exogenous opioids, administered in efforts to achieve analgesia, work by mimicking the actions of endogenous opioids. Endogenous opioids and their receptors are located in the brain (supraspinal areas), spinal cord, and periphery. Although opioids and opioid receptors in the brain and spinal cord have received much attention over many years, peripheral endogenous opioid analgesic systems have only been extensively studied during the past decade. It has been known since 1990 that following injection into the rodent hindpaw, D-Ala(2),N-Me-Phe(4), Gly(5)-ol enkephalin (DAMGO) [a muopioid receptor agonist] probably exerts its antinociceptive effects locally, since the doses administered are too low to have an effect in the central nervous system (CNS). This notion has been supported by the observation that the quaternary compound morphine methyliodide, which does not as readily cross the bloodbrain barrier and enter the CNS, produced antinociception following intradermal administration into the hindpaw, but not when the same dose was administered systemically (subcutaneously at a distant site). With a growing appreciation of peripheral endogenous opioids, peripheral endogenous opioid receptors, and peripheral endogenous opioid analgesic systems, investigators began growing hopeful that it may be possible to achieve adequate analgesics while avoiding unwanted central untoward adverse effects (e.g. respiratory depression, somnolence, addiction). Peripherally-acting opioids, which capitalize on peripheral endogenous opioid analgesic systems, may be one potential future strategy which may be utilized in efforts to achieve potent analgesia with minimal side effects. PMID- 18443637 TI - Opioid pharmacology. AB - BACKGROUND: Mu agonists have been an important component of pain treatment for thousands of years. The usual pharmacokinetic parameters (half-life, clearance, volume of distribution) of opioids have been known for some time. However, the metabolism has, until recently, been poorly understood, and there has been recent interest in the role of metabolites in modifying the pharmacodynamic response in patients, in both analgesia and adverse effects. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxycodone, and fentanyl. Advantages and disadvantages of various opioids in the management of chronic pain are discussed. OBJECTIVE: This review looks at the structure, chemistry, and metabolism of opioids in an effort to better understand the side effects, drug interactions, and the individual responses of patients receiving opioids for the treatment of intractable pain. CONCLUSION: Mu receptor agonists and agonist-antagonists have been used throughout recent medical history for the control of pain and for the treatment of opiate induced side effects and even opiate withdrawal syndromes. PMID- 18443638 TI - Monitoring opioid adherence in chronic pain patients: tools, techniques, and utility. AB - Opioids are important, if not essential, agents in treating certain types of chronic pain. However, the prevalence of drug misuse, abuse, and addiction has fostered considerable consternation among physicians, who may hesitate to prescribe these medications both due to concern for patients (misuse, abuse, and addiction), and fears of prosecution and/or professional sanction. Such practice may reflect 1) inadequate knowledge about patients' susceptibility to, or current drug misuse or abuse; 2) lack of familiarity with extant assessments and/or regulations, and/or 3) an unanticipated reaction to existing guidelines, policies or laws. We posit that assessing patients' predisposition to, and patterns of, drug misuse/abuse is a vital first step toward establishing and maintaining the safe and effective use of opioid analgesics in the treatment of chronic pain. Adherence monitoring is critical to identify patients' prior and current drug use, establish treatment basis, and evaluate compliance, so as to avoid misuse and abuse, and ensure sound and proper pain management. This paper provides a review of the numerous monitoring approaches that have been described in the literature and addresses the benefits and limitations of these techniques and tools. The complex nature of the problem of drug misuse and abuse is discussed, and while no single monitoring technique can fully address this complex issue, we describe how multiple approaches to adherence monitoring may be employed to sustain the prudent use of opioids for the treatment of chronic pain. PMID- 18443639 TI - Effectiveness of opioids in the treatment of chronic non-cancer pain. AB - For thousands of years, opioids have been used to treat pain, and they continue to be one of the most commonly prescribed medications for pain. It is estimated that 90% of patients presenting to pain centers and receiving treatment in such facilities are on opioids. Opioids can be considered broad-spectrum analgesics that act at multiple points along the pain pathway. Unfortunately, opioids also have the potential for great harm, with multiple side effects and potential complications, some of which are lethal. They are also uniquely addictive, which can lead to misuse and diversion. We reviewed the relevant English literature and did thorough manual searches of the bibliographies of known primary and review articles. We utilized pain relief as the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, improvement in work status, and evidence of addiction. Short-term use and improvement was defined as less than 6 months and long-term relief was defined as 6 months or longer. The 3 systematic reviews evaluating long-term effectiveness of opioids for chronic non-cancer pain provided unclear and weak evidence. The results of this review showed that many patients in the included studies were dissatisfied with adverse events or insufficient pain relief from opioids and withdrew from the studies. For patients able to continue on opioids, evidence was weak suggesting that their pain scores were lower than before therapy and that this relief could be maintained long-term (> 6 months). There was also weak evidence that long-term opioid therapy with morphine and transdermal fentanyl not only decreases pain but also improves functioning. Limited evidence was available for the most commonly used opioids, oxycodone and hydrocodone. Evidence for the ability to drive on chronic opioid therapy was moderate without major side effects or complications. It is concluded that, for long-term opioid therapy of 6 months or longer in managing chronic non-cancer pain, with improvement in function and reduction in pain, there is weak evidence for morphine and transdermal fentanyl. However, there is limited or lack of evidence for all other controlled substances, including the most commonly used drugs, oxycodone and hydrocodone. PMID- 18443640 TI - Opioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians' (ASIPP) Guidelines. AB - BACKGROUND: Opioid abuse has continued to increase at an alarming rate since our last opioid guidelines were published in 2005. Available evidence suggests a continued wide variance in the use of opioids, as documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration. OBJECTIVES: The objectives of opioid guidelines by the American Society of Interventional Pain Physicians (ASIPP) are to provide guidance for the use of opioids for the treatment of chronic non-cancer pain, to bring consistency in opioid philosophy among the many diverse groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the incidence of abuse and drug diversion. DESIGN: A broadly based policy committee of recognized experts in the field evaluated the available literature regarding opioid use in managing chronic non-cancer pain. This resulted in the formulation of the review and update of the guidelines published in 2006, a series of potential evidence linkages representing conclusions, followed by statements regarding the relationships between clinical interventions and outcomes. METHODS: The elements of the guideline preparation process included literature searches, literature synthesis, consensus evaluation, open forum presentations, formal endorsement by the Board of Directors of the American Society of Interventional Pain Physicians, and peer review. Based on the criteria of the U.S. Preventive Services Task Force, the quality of evidence was designated as Level I, II, and III, with 3 subcategories in Level II, with Level I described as strong and Level III as indeterminate. The recommendations were provided from 1A to 2C, varying from strong recommendation with high quality evidence to weak recommendation with low quality or very low-quality evidence. RESULTS: After an extensive review and analysis of the literature, which included systematic reviews and all of the available literature, the evidence for the effectiveness of long-term opioids in reducing pain and improving functional status for 6 months or longer is variable. The evidence for transdermal fentanyl and sustained-release morphine is Level II 2, whereas for oxycodone the level of evidence is II-3, and the evidence for hydrocodone and methadone is Level III. There is also significant evidence of misuse and abuse of opioids. The recommendation is 2A - weak recommendation, high quality evidence: with benefits closely balanced with risks and burdens; with evidence derived from RCTs without important limitations or overwhelming evidence from observational studies, with the implication that with a weak recommendation, best action may differ depending on circumstances or patients' or societal values. CONCLUSION: Opioids are commonly prescribed for chronic non-cancer pain and may be effective for short-term pain relief. However, long-term effectiveness of 6 months or longer is variable with evidence ranging from moderate for transdermal fentanyl and sustained-release morphine with a Level II-2, to limited for oxycodone with a Level II-3, and indeterminate for hydrocodone and methadone with a Level III. These guidelines included the evaluation of the evidence for the use of opioids in the management of chronic non-cancer pain and the recommendations for that management. These guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Because of the changing body of evidence, this document is not intended to be a "standard of care." PMID- 18443641 TI - Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. AB - Therapeutic opioid use and abuse coupled with the nonmedical use of other psychotherapeutic drugs has shown an explosive growth in recent years and has been a topic of great concern and controversy. Americans, constituting only 4.6% of the world's population, have been consuming 80% of the global opioid supply, and 99% of the global hydrocodone supply, as well as two-thirds of the world's illegal drugs. With the increasing therapeutic use of opioids, the supply and retail sales of opioids are mirrored by increasing abuse in patients receiving opioids, nonmedical use of other psychotherapeutic drugs (in this article the category of psychotherapeutics includes pain relievers, tranquilizers, stimulants, and sedatives, but does not include over-the-counter drugs), emergency department visits for prescription controlled drugs, exploding costs, increasing incidence of side effects, and unintentional deaths. However, all these ills of illicit drug use and opioid use, abuse, and non-medical use do not stop with adults. It has been shown that 80% of America's high school students, or 11 million teens, and 44% of middle school students, or 5 million teens, have personally witnessed, on the grounds of their schools, illegal drug use, illegal drug dealing, illegal drug possession, and other activities related to drug abuse. The results of the 2006 National Survey on Drug Use and Health showed that 7.0 million or 2.8% of all persons aged 12 or older had used prescription type psychotherapeutic drugs nonmedically in the past month, 16.387 million, or 6.6% of the population, had used in the past year, and 20.3%, or almost 49.8 million, had used prescription psychotherapeutic drugs nonmedically during their lifetime. Sadly, the initiates of psychotherapeutic drugs used for nonmedical purposes were highest for opioids. Therapeutic opioid use has increased substantially, specifically of Schedule II drugs. Apart from lack of effectiveness (except for short-term, acute pain) there are multiple adverse consequences including hormonal and immune system effects, abuse and addiction, tolerance, and hyperalgesia. Patients on long-term opioid use have been shown to increase the overall cost of healthcare, disability, rates of surgery, and late opioid use. PMID- 18443642 TI - Intrathecal drug delivery. AB - Intrathecal analgesia has emerged as a key therapeutic option for pain relief for patients who have failed other treatment avenues as well as patients with adequate analgesia on high dose enteral or parenteral therapy but with unacceptable side effects. Intrethecal infusions of analgesics have been increasingly utilized since the later 1980s for the treatment of persistent pain. The purpose of this review is to provide research based clinical insight regarding the safe and appropriate use of the intrathecal infusion modality. Long term intrathecal infusion analgesia or long-term intrathecal or long-term intrathecal analgesic therapy has significantly progressed over the past 25 years. The evidence for implantable intrathecal infusion systems is strong for short-term improvement in pain of malignancy or neuropathic pain. The evidence is moderate for long-term management of persistent pain. Reasonably strong evidence exists for the use of ong-term intrathecal analgesic therapy in alleviation of cancer pain; however, the evidence supporting long-term efficacy in persistent noncancer pain is less convincing. Future studies are needed to better define the role of long-term intrathecal analgesic therapy in persistent pain, especially with respect to which pain conditions or subpopulations of patients are most responsive to long-term intrathecal analgesic therapy, and which agents or combination of agents are most appropriate for which pain conditions or subpopulations of patients. Novel combinations of intrathecal analgesics such as clonidine and gabapentin deserve future study. The current body of literature supports the use of intrathecal agents for the treatment of moderate or severe pain related to cancer and noncancer origins. Further clinical studies are needed to evaluate the efficacy and safety of new intrathecal drugs, the complications related to these devices, and the proper selection of patients to receive these treatments. PMID- 18443643 TI - Use of an Income-Equivalence Scale to Understand Age-Related Changes in Financial Strain. AB - Income-equivalence scales (IES) provide distinct advantages over poverty indices to adjust family income for differences in family size, including improved specification of hypothesized causal relationships involving objective measures of economic well-being. In a novel IES application, cancer patients' out-of pocket health costs are adjusted for differences in family income and size and, along with five other subindices, contribute to an overall index of "objective family financial stress." Age-related changes are modeled simultaneously within relationships between overall objective family financial stress and subjective patient perceptions about financial strain. Among the findings, the impact of age on one area of subjective financial strain, "difficulty paying bills," is negative and curvilinear. Regardless of adjusted out-of-pocket costs, as age advances, patients appear increasingly likely to accommodate to financial stress by reporting less difficulty paying bills. This phenomenon could serve to mask and isolate older adults who are foregoing needed yet unaffordable medical care and prescriptions. PMID- 18443644 TI - Innovative recycling options for biomedical research facilities. PMID- 18443645 TI - Computational Techniques for Spatial Logistic Regression with Large Datasets. AB - In epidemiological research, outcomes are frequently non-normal, sample sizes may be large, and effect sizes are often small. To relate health outcomes to geographic risk factors, fast and powerful methods for fitting spatial models, particularly for non-normal data, are required. I focus on binary outcomes, with the risk surface a smooth function of space, but the development herein is relevant for non-normal data in general. I compare penalized likelihood models, including the penalized quasi-likelihood (PQL) approach, and Bayesian models based on fit, speed, and ease of implementation.A Bayesian model using a spectral basis representation of the spatial surface via the Fourier basis provides the best tradeoff of sensitivity and specificity in simulations, detecting real spatial features while limiting overfitting and being reasonably computationally efficient. One of the contributions of this work is further development of this underused representation. The spectral basis model outperforms the penalized likelihood methods, which are prone to overfitting, but is slower to fit and not as easily implemented. A Bayesian Markov random field model performs less well statistically than the spectral basis model, but is very computationally efficient. We illustrate the methods on a real dataset of cancer cases in Taiwan.The success of the spectral basis with binary data and similar results with count data suggest that it may be generally useful in spatial models and more complicated hierarchical models. PMID- 18443646 TI - Older Motherhood and the Changing Life Course in the Era of Assisted Reproductive Technologies. AB - Midlife, once a focus of particular interest to gerontologists because of its implications for later life, has recently received little attention. But as new reproductive technologies have expanded in the United States, motherhood is occurring at older ages. While older motherhood is not a new social practice, what is unique is that an increasing number of women are becoming pregnant through technological means, often for the first time, at the end of their reproductive cycle. These women can be understood as part of a new middle age, engaging in new life course possibilities that respond to changing social, cultural, physical, and economic realities, and potentially extending much later in the life course. Drawing on interviews with 79 couples, we utilize symbolic interactionist conceptualizations of identity and stigma to consider how women negotiate the shifting social identities associated with older motherhood. We conclude that older motherhood will be one phenomenon contributing to an enduring change in views of what constitutes old age, and that it will be seen as occurring much later in the life course. PMID- 18443647 TI - Who Gains from the Demographic Dividend? Forecasting Income by Age. AB - Changes in the population age structure are known to influence the total income per person, but little is known about whether the changes are equally shared across the population or are concentrated on particular age groups and/or birth cohorts. The answer to this question has potentially important implications for income inequality, for human capital investment, and for fertility decision making. We propose a new model of intergenerational transfers which distinguishes between the effects of changes in population structure and the effects of changes in family age structure. Using age-specific data from annual income and expenditure surveys of Taiwan between 1978 and 1998, we show that changes in age structure have had a very favorable effect on Taiwan's income growth. The gains are not equally shared by all age groups, however. Children and young adults have benefited the most, while the elderly have benefited the least. The population and family age structures have independent effects on per capita income; the effect of the population age structure is most important. Generational differences in per capita income are closely related to intergenerational differences in earnings, suggesting only a weak form of altruism. Finally, we predict that, on average, population aging will adversely influence per capita income growth in Taiwan in the coming decades. PMID- 18443648 TI - Distinguishing automatic and controlled components of attitudes from direct and indirect measurement methods. AB - Distinct automatic and controlled processes are presumed to influence social evaluation. Most empirical approaches examine automatic processes using indirect methods, and controlled processes using direct methods. We distinguished processes from measurement methods to test whether a process distinction is more useful than a measurement distinction for taxonomies of attitudes. Results from two studies suggest that automatic components of attitudes can be measured directly. Direct measures of automatic attitudes were reports of gut reactions (Study 1) and behavioral performance in a speeded self-report task (Study 2). Confirmatory factor analyses comparing two-factor models revealed better fits when self-reports of gut reactions and speeded self-reports shared a factor with automatic measures versus sharing a factor with controlled self-report measures. Thus, distinguishing attitudes by the processes they are presumed to measure (automatic vs. controlled) is more meaningful than distinguishing based on the directness of measurement. PMID- 18443649 TI - Reducing Neuronal Networks to Discrete Dynamics. AB - We consider a general class of purely inhibitory and excitatory-inhibitory neuronal networks, with a general class of network architectures, and characterize the complex firing patterns that emerge. Our strategy for studying these networks is to first reduce them to a discrete model. In the discrete model, each neuron is represented as a finite number of states and there are rules for how a neuron transitions from one state to another. In this paper, we rigorously demonstrate that the continuous neuronal model can be reduced to the discrete model if the intrinsic and synaptic properties of the cells are chosen appropriately. In a companion paper [1], we analyze the discrete model. PMID- 18443650 TI - Specialized Prisons and Services: Results From a National Survey. AB - Findings from the National Criminal Justice Drug Abuse Treatment Studies (CJ DATS) National Criminal Justice Treatment Practices survey are examined to describe types of services provided by three types of prisons: those that serve a cross-section of offenders, those that specialize in serving offenders with special psychosocial and medical needs, and those that specialize in serving legal status or gender specific populations. Information is presented on the prevalence and type of specialized prisons and services provided to offenders as reported by wardens and other facility directors drawn from a nationally representative sample of prisons. Additional analyses explore organizational factors that differentiate prisons that serve specialized populations including staffing, training, other resources, leadership, and climate for change and innovation. Implications for expanding and improving services for special populations in correctional settings and the values of specialized prisons are discussed. PMID- 18443651 TI - Substrate entasis and electronic coupling elements in electron transfer from Fe in a multicopper ferroxidase. AB - Outersphere electron transfer in multicopper oxidases occurs at the type 1, blue Cu(II). One class of MCO proteins exhibits a specificity in this reaction towards Fe(II). In work carried out in collaboration with the Solomon lab over the past 7 years, we have delineated the structural motifs that support this ferroxidase specificity and have quantified the contributions that each makes to this outersphere electron transfer reaction from Fe(II) to the type 1 Cu(II). Two features of this electron transfer catalysis stand out. First, the protein provides a binding site for Fe(II) that actually favors Fe(III); this coordination sphere places the bound Fe(II) in a state of "entasis" that can be relieved by loss of an electron. In short, the E(O) of the bound Fe(II) is lowered relative to that of aqueous ferrous iron making electron transfer thermodynamically favorable. Second, carboxylates within this coordination sphere provide an electronic coupling pathway for the electron transfer via their H-bond network with type 1 Cu histidine ligands thus making electron transfer kinetically efficient. This brief report breaks down these contributions to ferroxidase specificity in terms of the semi-classical Marcus equation describing outersphere electron transfer. PMID- 18443652 TI - Convenient Synthesis of a Library of Discrete Hydroxamic Acids Using the Hydroxythiophenol (Marshall) Resin. AB - Several resins have reportedly been used to synthesize hydroxamic acids except for the hydroxythiophenol (Marshall) resin. Herein we report the use of the Marshall resin to synthesize hydroxamic acids from carboxylic acids and its application to convert a library of fourteen discrete aliphatic and aromatic carboxylic acids including N-protected amino acids to their corresponding hydroxamic acids in good yields. PMID- 18443653 TI - Do You Like Me as Much as I Like You? Friendship Reciprocity and Its Effects on School Outcomes among Adolescents. AB - Social scientists have long suspected that friendship dyads are not always reciprocated and those that are reciprocated are likely to be more intimate. Close friendships may provide youth with an environment conducive to healthy development and educational outcomes. Using the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative data set of youth, we examine how attributes of respondents and their friends affect the odds of reciprocity between adolescents. Asian Americans and females are the most likely to have reciprocated friendships. Interracial friendships are less likely to be reciprocated than intraracial friendships. Further, adolescents with reciprocated friendships report higher levels of school belonging. Finally, reciprocity and school belonging both exert independent effects on academic performance. Friendship reciprocity is an important indicator of social support above and beyond the numbers of friends reported by youth. PMID- 18443654 TI - Iron-oxidation-state-dependent O-O bond cleavage of meta-chloroperbenzoic acid to form an iron(IV)-oxo complex. AB - The mechanism of formation of [Fe(IV)(O)(N4Py)](2+) (2, N4Py = N,N-bis(2 pyridylmethyl)-N-bis(2-pyridyl)methylamine) from the reaction of [Fe(II)(N4Py)(CH(3)CN)](2+) (1) with m-chloroperbenzoic acid (mCPBA) in CH(2)Cl(2) at -30 degrees C has been studied on the basis of the visible spectral changes observed and the reaction stoichiometry. It is shown that the conversion of 1 to 2 in 90% yield requires 1.5 equiv peracid and takes place in two successive one-electron steps via an [Fe(III)(N4Py)OH](2+)(3) intermediate. The first oxidation step uses 0.5 equiv peracid and produces 0.5 equiv 3 chlorobenzoic acid, while the second step uses 1 equiv peracid and affords byproducts derived from chlorophenyl radical. We conclude that the Fe(II)(N4Py) center promotes O-O bond heterolysis, while the Fe(III)(N4Py) center favors O-O bond homolysis, so the nature of O-O bond cleavage is dependent on the iron oxidation state. PMID- 18443655 TI - Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids. AB - An intramolecular non-stabilized azomethine ylide dipolar cycloaddition was applied toward the first non-racemic synthesis of the fully-oxygenated bridged pyrrolizidine core (45) of (+)-stemofoline (1) in eleven steps from a commercially available starting material. PMID- 18443656 TI - Physical Activity and Physical Self-Concept among Sedentary Adolescent Females; An Intervention Study. AB - PROBLEM: Physical activity has been promoted as a means of enhancing self concept, yet the evidence for this connection is far from compelling. In particular, experimental research investigating this association during adolescence, a period during which many youth struggle to maintain a positive self-image, is noticeably lacking. This study investigates the impact on self concept of a 9-month physical activity intervention among sedentary adolescent females. METHOD: Female adolescents who were sedentary at baseline were assigned either to an exercise intervention or a comparison group as part of the controlled trial. The intervention was school-based, and assignment to groups was based on school attended. Intervention participants engaged in supervised activity 4 times per week and received didactic instruction promoting activity outside of school 1 day per week. Self-concept, physical activity participation, and cardiovascular fitness were assessed before, mid-way through, and after the 9 month intervention. RESULTS: The intervention had a significant positive impact on participation in vigorous activity and cardiovascular fitness. The intervention did not significantly influence any of the self-concept dimensions overall. There was, however, a three-way interaction such that there was an increase in global physical self-concept among those intervention participants who increased cardiovascular fitness. CONCLUSIONS: These findings indicate that a physical activity intervention among sedentary adolescent females enhanced global physical self-concept for a subset of intervention participants who manifested positive changes in fitness. PMID- 18443657 TI - Challenges to superfund community nutrition programs in kentucky. AB - Since 2000, the University of Kentucky's (UK's) Superfund Basic Research Program (SBRP) Community Outreach Core has provided support and guidance through Superfund Community Action through Nutrition (SCAN) programs, which meet the needs of individuals and communities affected by environmental contaminants. It has been shown that nutrition may modulate the toxicity of Superfund chemicals. SCAN programs integrate nutrition education, nutrition science research, and health communication to increase understanding of health risks associated with residing near Superfund sites. Two critical tasks must be accomplished. SCAN personnel must identify and recruit affected community members, and then, offer meaningful programs. Certain quantitative outcome measures and legal issues presented both challenges and opportunities. Community members preferred qualitative evaluation discussions, which showed increased knowledge and improved attitudes following SCAN programs. SCAN, in full partnership with affected communities, translates safe, effective nutrition information to reduce health risks associated with exposure to Superfund pollutants. PMID- 18443659 TI - Micro-computed tomography of fatigue microdamage in cortical bone using a barium sulfate contrast agent. AB - Accumulation of microdamage during fatigue can lead to increased fracture susceptibility in bone. Current techniques for imaging microdamage in bone are inherently destructive and two-dimensional. Therefore, the objective of this study was to image the accumulation of fatigue microdamage in cortical bone using micro-computed tomography (micro-CT) with a barium sulfate (BaSO(4)) contrast agent. Two symmetric notches were machined on the tensile surface of bovine cortical bone beams in order to generate damage ahead of the stress concentrations during four-point bending fatigue. Specimens were loaded to a specified number of cycles or until one notch fractured, such that the other notch exhibited the accumulation of microdamage prior to fracture. Microdamage ahead of the notch was stained in vitro by precipitation of BaSO(4) and imaged using micro-CT. Reconstructed images showed a distinct region of bright voxels around the notch tip or along propagating cracks due to the presence of BaSO(4), which was verified by backscattered electron imaging and energy dispersive spectroscopy. The shape of the stained region ahead of the notch tip was consistent with principal strain contours calculated by finite element analysis. The relative volume of the stained region was correlated with the number of loading cycles by non-linear regression using a power-law. This study demonstrates new methods for the non-destructive and three-dimensional detection of fatigue microdamage accumulation in cortical bone in vitro, which may be useful to gain further understanding into the role of microdamage in bone fragility. PMID- 18443660 TI - Efficient methods for estimating constrained parameters with applications to lasso logistic regression. AB - Fitting logistic regression models is challenging when their parameters are restricted. In this article, we first develop a quadratic lower-bound (QLB) algorithm for optimization with box or linear inequality constraints and derive the fastest QLB algorithm corresponding to the smallest global majorization matrix. The proposed QLB algorithm is particularly suited to problems to which EM type algorithms are not applicable (e.g., logistic, multinomial logistic, and Cox's proportional hazards models) while it retains the same EM ascent property and thus assures the monotonic convergence. Secondly, we generalize the QLB algorithm to penalized problems in which the penalty functions may not be totally differentiable. The proposed method thus provides an alternative algorithm for estimation in lasso logistic regression, where the convergence of the existing lasso algorithm is not generally ensured. Finally, by relaxing the ascent requirement, convergence speed can be further accelerated. We introduce a pseudo Newton method that retains the simplicity of the QLB algorithm and the fast convergence of the Newton method. Theoretical justification and numerical examples show that the pseudo-Newton method is up to 71 (in terms of CPU time) or 107 (in terms of number of iterations) times faster than the fastest QLB algorithm and thus makes bootstrap variance estimation feasible. Simulations and comparisons are performed and three real examples (Down syndrome data, kyphosis data, and colon microarray data) are analyzed to illustrate the proposed methods. PMID- 18443661 TI - [Oversight and monitoring of fundamental rights of people suffering mental disorder: the Canadian experience]. AB - This paper has as its objective the generation of a debate over different alternatives of models of oversight and monitoring of fundamental rights of people suffering mental disorder. The Consent and Capacity Board of the province of Ontario, Canada will be considered. The Board is one of the oldest and leading administrative tribunals in the area of mental health. The paper will analyse the place of the Board in the Canadian legal system and the fundamental distinctions with similar Canadian mental health tribunals. The Board's administrative structure and jurisdiction will be examined, as well as its procedures and mechanisms of review of its decisions. PMID- 18443658 TI - Cancer proteomics by quantitative shotgun proteomics. AB - A major scientific challenge at the present time for cancer research is the determination of the underlying biological basis for cancer development. It is further complicated by the heterogeneity of cancer's origin. Understanding the molecular basis of cancer requires studying the dynamic and spatial interactions among proteins in cells, signaling events among cancer cells, and interactions between the cancer cells and the tumor microenvironment. Recently, it has been proposed that large-scale protein expression analysis of cancer cell proteomes promises to be valuable for investigating mechanisms of cancer transformation. Advances in mass spectrometry technologies and bioinformatics tools provide a tremendous opportunity to qualitatively and quantitatively interrogate dynamic protein-protein interactions and differential regulation of cellular signaling pathways associated with tumor development. In this review, progress in shotgun proteomics technologies for examining the molecular basis of cancer development will be presented and discussed. PMID- 18443662 TI - [Clinical guidelines in mental health: situation in Argentina]. AB - The permanent update of mental health professionals has become an actual requirement. Nowadays, there is an important concern to offer to the patient's problems the best therapeutics that respond to their specific needs. The well known Clinical Guides are tools to address that objective. In the United Kingdom, USA, Canada, Germany, the Netherlands, France and some Latin American countries different organisms have been created with the objective to develop clinical guidelines. In Argentina, the situation is precarious. In Buenos Aires City, there are few efforts in such direction. An heterogeneous group of factors (social, economic, corporative, theoretical-academic or curricular and ideological) seem to difficult the development of a project of these characteristics, adapted to this population. PMID- 18443663 TI - [Prevalence of coca paste use and social risk]. AB - The results of a probabilistic study performed in an extremely poor area where an ethnographic methodology was applied for the identification of cocaine paste consumption are analyzed. The studied community's general population's life prevalence was of 13,2 %. Prevalence was 51,1 % within the male population between 14 and 30 years old. Within the same poverty situation, greater consumption was associated with greater deficiencies. Data shows how cocaine paste consumption compulsion accentuates the displacement of the most vulnerable groups towards the limits of social survival. PMID- 18443664 TI - [Permanent psychiatric effects in former addicts to marijuana or stimulants]. AB - It's an evidence based data that the abuse of drugs produces toxic psychiatric effects, in the acute and sub acute phases of the intoxication and also in the recent abstinence. It is more conflicting the data about if they can produce or unmask vulnerabilities to long term psychiatric disorders; or to affect its course and phenomenology; or to influence the response to the therapeutic resources used to treat them, beyond the period of abstinence. The objective is to update the knowledge available on the ability of the marijuana and the stimulants to produce long term psychiatric disorders, or to unmask vulnerabilities to them. We have done an electronic bibliographical research in MEDLINE using the following key words: psychiatric disorders, amphetamine, stimulants, marijuana, cannabis, long term effects, psychosis, cognitive and cognitive deficits. The marijuana might induce permanent psychosis in subjects with vulnerability to schizophrenia or to psychosis. The cognitive effects are acute and subacute, related with the presence of delta-9-tetrahydrocannabinol in the central nervous system. The stimulants can produce a schizophrenia-like psychosis, and they can produce long term cognitive deficits. The stimulants also might produce subsyndromic mood disorders. PMID- 18443666 TI - [Drug therapy of opioid withdrawal]. AB - Although the opiate dependence is of low frequency in our midst, it is important to know its management because it requires medical treatment in most cases. At present, in our country, we may classify the different patient populations able to submit an opioid withdrawal syndrome in patients undergoing chronic treatment with opioids, patients in intensive care units, neonatal mother addicted patients and addicts from the general population or linked to the health system. Detoxification programs are typically characterized by a low rate of completion of treatment and a high rate of relapse. The opioid withdrawal syndrome is objectively and subjectively severe and moderate and the goals of the therapy for the Opiates Withdrawal Syndrome are: to prevent or reduce the objective and subjective symptoms of abstinence; to prevent or treat its most serious complications; to treat preexisting or concurrent psychiatric disorders; to reduce the frequency or severity of relapses and to rehabilitate in the long term. PMID- 18443665 TI - [Pharmacological review of alcoholic dependence treatment]. AB - The aim of the present pharmacological update is to revise the problem of alcohol dependence. Starting from the biological bases and the impact of alcohol on the neurobiological and neurotransmission systems, a revision of the main pharmacological tools for alcohol dependence treatment will be done. Disulfiram, naltrexone, acamprosate, all of them approved by the FDA (Food and Drug Administration), have shown mechanisms of action, efficacy, tolerance and adherence dissimilar. We will also refer to topiramate, which is being studied for this indication. PMID- 18443667 TI - [Rethinking addictions: the cognitive paradigm and substance dependence disorder]. AB - The aim of this task is to review some psychotherapeutic strategies used for the treatment of Substance Dependence Disorder. Different distorted beliefs, from the cognitive paradigm, which are usually assumed in our society, are studied here. These beliefs reveal difficulty in facing the drug problem, from the scientific knowledge based on evidence. Different problems are set up, such us the illness pattern, therapeutic alliance, treatment aims, unlawful acts, medication, ideologies and implications for the social interventions. Different strategies that have proved effectiveness are reviewed. Motivational Interview, Contingencies Management, Standard Cognitive Therapy and Harm Reduction have been pointed out. We come to an end with the recommendation to use the scientific knowledge for the treatment programs and preventive policies. PMID- 18443668 TI - [Substance use disorder. Forensic issues in Argentina]. AB - This article is a review of the main legal issues in illegal drug traffic in Argentina. The penal law includes corrective punishment, educational activities and forced treatment. Forensic issues and legal controversies are discussed. PMID- 18443669 TI - [Psychotherapy in the general hospital]. PMID- 18443670 TI - [On professional formation in the field of substance abuse and other related problems. Tales from practice]. AB - It is my intention to give proof of my experience as a professional teacher, program supervisor and services and as a responsible for projects related to investigation in the drug-dependence field for more than 30 years. This is no more than a narration of my experience; it's up to you, readers, to draw your own conclusions. And for those who are connected to the subject, to reach the possibility to debate in the frame of institutional and political decisions oriented to professional formation and investigation facing a problem so complex as to be difficult to understand in this time. PMID- 18443671 TI - A randomized, double-blind, crossover comparison of the efficacy and safety of oral controlled-release tramadol and placebo in patients with painful osteoarthritis. AB - OBJECTIVE: To compare the efficacy and safety of controlled-release (CR) tramadol (Zytram XL, Purdue Pharma, Canada) and placebo in patients with painful osteoarthritis. METHODS: Patients underwent analgesic washout for two to seven days before random assignment to 150 mg daily of CR tramadol or placebo, and were titrated weekly to 200 mg, 300 mg or a maximum of 400 mg once daily. After four weeks, patients crossed over to the alternate treatment for another four weeks. Plain acetaminophen was provided as a rescue analgesic. All patients who completed the crossover study were eligible to receive open label CR tramadol for six months. RESULTS: Seventy-seven of 100 randomly assigned patients were evaluable for efficacy. CR tramadol resulted in significantly lower visual analogue scale pain intensity scores (37.4+/-23.9 versus 45.1+/-24.3, P=0.0009). Western Ontario and McMaster Universities osteoarthritis index subscale scores for pain (189.0+/-105.0 versus 230.0+/-115.4; P=0.0001) and physical function (632.4+/-361.3 versus 727.4+/-383.4; P=0.0205) were significantly better with CR tramadol. Total pain and disability (22.8+/-14.5 versus 27.2+/-14.8; P=0.0004), and overall pain and sleep (104.7+/-98.0 versus 141.0+/-108.2; P=0.0005) scores in the Pain and Sleep Questionnaire were significantly lower for CR tramadol. Short-form 36 Health Survey scores were significantly better during CR tramadol treatment for the pain index (38.8+/-10.8 versus 35.6+/-9.0; P=0.0100), general health perception (46.5+/-11.2 versus 44.4+/-11.6; P=0.0262), vitality (43.1+/ 13.2 versus 40.2+/-13.7; P=0.0255) and overall physical components (40.8+/-8.9 versus 37.8+/-7.7; P=0.0002). CR tramadol treatment was preferred by 55.8% of patients (P=0.0005) versus 20.8% and 23.4% of patients who chose placebo or had no preference, respectively. These improvements were sustained for up to six months, and 86.5% of patients reported at least moderate benefit from CR tramadol during long-term treatment. CONCLUSION: CR tramadol is effective for the management of painful osteoarthritis. PMID- 18443672 TI - Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: The present study was a randomized, parallel, double-blind comparison between controlled-release (CR) tramadol and sustained-release (SR) diclofenac in patients with chronic pain due to osteoarthritis of the hips and/or knees. METHODS: Patients with at least moderate pain intensity, and having received analgesics over the past three months, underwent a two- to seven-day washout of current analgesics before initiation of 200 mg CR tramadol or 75 mg SR diclofenac. During the eight-week study, patients returned to the clinic biweekly. CR tramadol doses were titrated to a maximum of 200 mg, 300 mg or 400 mg per day. SR diclofenac doses were titrated to 75 mg or 100 mg once daily, or 75 mg twice a day based on pain relief and the presence of side effects. For rescue analgesic, patients took acetaminophen as needed, up to 650 mg three times a day. RESULTS: Forty-five patients on CR tramadol and 52 patients on SR diclofenac were evaluable. Significant improvements from prestudy treatment were shown for visual analogue scale pain (P=0.0001), stiffness (P<0.0005) and physical function (P=0.0001) scores for both treatments. There were no significant differences between the two treatments in the Western Ontario and McMaster Universities subscales, overall pain, pain and sleep, or the clinical effectiveness evaluation. Overall incidence of adverse events was similar in both groups, with more opioid-related adverse events with CR tramadol, and two serious adverse events occurring with the use of SR diclofenac. CONCLUSIONS: CR tramadol is as effective as SR diclofenac in the treatment of pain due to knee or hip osteoarthritis, with the potential for fewer of the serious side effects that characterize nonsteroidal anti-inflammatory drug administration. PMID- 18443673 TI - Chemical and bioanalytical applications of surface enhanced Raman scattering spectroscopy. PMID- 18443674 TI - Rationally designed nanostructures for surface-enhanced Raman spectroscopy. AB - Research on surface-enhanced Raman spectroscopy (SERS) is an area of intense interest because the technique allows one to probe small collections of, and in certain cases, individual molecules using relatively straightforward spectroscopic techniques and nanostructured substrates. Researchers in this area have attempted to develop many new technological innovations including high sensitivity chemical and biological detection systems, labeling schemes for authentication and tracking purposes, and dual scanning-probe/spectroscopic techniques that simultaneously provide topographical and spectroscopic information about an underlying surface or nanostructure. However, progress has been hampered by the inability of researchers to fabricate substrates with the high sensitivity, tunability, robustness, and reproducibility necessary for truly practical and successful SERS-based systems. These limitations have been due in part to a relative lack of control over the nanoscale features of Raman substrates that are responsible for the enhancement. With the advent of nanotechnology, new approaches are being developed to overcome these issues and produce substrates with higher sensitivity, stability, and reproducibility. This tutorial review focuses on recent progress in the design and fabrication of substrates for surface-enhanced Raman spectroscopy, with an emphasis on the influence of nanotechnology. PMID- 18443675 TI - Tailoring plasmonic substrates for surface enhanced spectroscopies. AB - Our understanding of how the geometry of metallic nanostructures controls the properties of their surface plasmons, based on plasmon hybridization, is useful for developing high-performance substrates for surface enhanced spectroscopies. In this tutorial review, we outline the design of metallic nanostructures tailored specifically for providing electromagnetic enhancements for surface enhanced Raman scattering (SERS). The concepts developed for nanoshell-based substrates can be generalized to other nanoparticle geometries and scaled to other spectroscopies, such as surface enhanced infrared absorption spectroscopy (SEIRA). PMID- 18443676 TI - Single-molecule and single-nanoparticle SERS: from fundamental mechanisms to biomedical applications. AB - This tutorial review discusses a new class of colloidal metal nanoparticles that is able to enhance the efficiencies of surface-enhanced Raman scattering (SERS) by as much as 10(14)-10(15) fold. This enormous enhancement allows spectroscopic detection and identification of single molecules located on the nanoparticle surface or at the junction of two particles under ambient conditions. Considerable progress has been made in understanding the enhancement mechanisms, including definitive evidence for the single-molecule origin of fluctuating SERS signals. For applications, SERS nanoparticle tags have been developed based on the use of embedded reporter molecules and a silica or polymer encapsulation layer. The SERS nanoparticle tags are capable of providing detailed spectroscopic information and are much brighter than semiconductor quantum dots in the near infrared spectral window. These properties have raised new opportunities for multiplexed molecular diagnosis and in vivo Raman spectroscopy and imaging. PMID- 18443677 TI - Tip-enhanced Raman scattering. AB - Tip-enhanced Raman scattering (TERS) is a technique that provides molecular information on the nanometre scale. Using a nanometre-sized metal particle results in a strong signal enhancement and a lateral resolution similar to the dimensions of the particle. As TERS is in a way the ultimate SERS experiment, the theoretical background will be briefly discussed with respect to the unique features and the specific effects that occur when only a single nanoparticle is used as a probe. All the major parts of the instrument will be revealed and the specific advantages of the different instrumental set ups will be investigated with respect to the particular requirements of the sample. Selected examples ranging from material science to cell biological applications demonstrate the capabilities and the potential of TERS in this tutorial review. PMID- 18443678 TI - Characterisation and identification of bacteria using SERS. AB - Within microbiology Raman spectroscopy is considered as a very important whole organism fingerprinting technique, which is used to characterise, discriminate and identify microorganisms and assess how they respond to abiotic or biotic stress. Enhancing the sensitivity of Raman spectroscopy is very beneficial for the rapid analysis of bacteria (and indeed biological systems in general), where the ultimate goal is to achieve this without the need for lengthy cell culture. Bypassing this step would provide significant benefits in many areas such as medical, environmental and industrial microbiology, microbial systems biology, biological warfare countermeasures and bioprocess monitoring. In this tutorial review we will report on the advances made in bacterial studies, a relatively new and exciting application area for SERS. PMID- 18443679 TI - Disentangling interfacial redox processes of proteins by SERR spectroscopy. AB - Surface-enhanced resonance-Raman spectroelectrochemistry represents a powerful approach for studying the structure and reaction dynamics of redox proteins immobilized on biocompatible electrodes in fundamental and applied sciences. Using this approach it has been recently shown that electric fields of biologically relevant magnitude are able to influence crucial parameters for the functioning of a variety of soluble and membrane bound heme proteins. Electric field effects discussed in this tutorial review include modulation of redox potentials, reorganization energies, protein dynamics and redox-linked structural changes. PMID- 18443680 TI - Single molecule analysis by surfaced-enhanced Raman scattering. AB - Our main objective in this tutorial review is to provide insight into some of the questions surrounding single molecule detection (SMD) using surface-enhanced Raman scattering (SERS) and surface-enhanced resonance Raman scattering (SERRS). Discovered thirty years ago, SERS is now a powerful analytical tool, strongly tied to plasmonics, a field that encompasses and profits from the optical enhancement found in nanostructures that support localized plasmon excitations. The spectrum of the single molecule carries the quantum fingerprints of the system modulated by the molecule-nanostructure interactions and the electronic resonances that may result under laser excitation. This information is embedded in vibrational band parameters. The dynamics and the molecular environment will affect the bandwidth of the observed Raman bands. In addition, the localized surface plasmon resonances (LSPR) empower the nanostructure with a number of optical properties that will also leave their mark on the observed inelastic scattering process. Therefore, controlling size, shape and the formation of the aggregation state (or fractality) of certain metallic nanostructures becomes a main task for experimental SERS/SERRS. This molecule-nanostructure coupling may, inevitably, lead to spectral fluctuations, increase photobleaching or photochemistry. An attempt is made here to guide the interpretation of this wealth of information when approaching the single molecule regime. PMID- 18443681 TI - Practical understanding and use of surface enhanced Raman scattering/surface enhanced resonance Raman scattering in chemical and biological analysis. AB - The unique ability to obtain molecular recognition of an analyte at very low concentrations in situ in aqueous environments using surface enhanced Raman scattering (SERS) and surface enhanced resonance Raman scattering (SERRS) detection makes these spectroscopies of considerable interest. Improved understanding of the effect coupled to improvements in practical techniques make the use of SERS/SERRS much simpler than has been the case in the past. This article is designed as a tutorial review targeted at aiding in the development of practical applications. PMID- 18443682 TI - Vibrational pumping in surface enhanced Raman scattering (SERS). AB - In this tutorial review, the underlying principles of vibrational pumping in surface enhanced Raman scattering (SERS) are summarized and explained within the framework of their historical development. Some state-of-the-art results in the field are also presented, with the aim of giving an overview on what has been established at this stage, as well as hinting at areas where future developments might take place. PMID- 18443683 TI - Surface enhanced Raman optical activity (SEROA). AB - Raman optical activity (ROA) directly monitors the stereochemistry of chiral molecules and is now an incisive probe of biomolecular structure. ROA spectra contain a wealth of information on tertiary folding, secondary structure and even the orientation of individual residues in proteins and nucleic acids. Extension of ROA to an even wider range of samples could be facilitated by coupling its structural sensitivity to the low-concentration sensitivity provided by plasmon resonance enhancement. This leads to the new technique of surface enhanced ROA, or SEROA, which is complementary to both SERS and ROA. In this tutorial review, we present a survey of theoretical and experimental work undertaken to develop SEROA and discuss these efforts in the context of the ROA technique, and, based on the authors' work, outline possible future directions of research for this novel chiroptical spectroscopy. PMID- 18443684 TI - Intracellular applications of analytical SERS spectroscopy and multispectral imaging. AB - The aim of this tutorial review is to give an overview of the state of the art of intracellular applications of analytical SERS spectroscopy. We pay particular attention to nanoparticle-based SERS spectroscopy since this currently dominates the published literature on non-disturbing analysis of live cells. We describe recent advances in this domain due to the development of multispectral imaging and to the combined use of SERRS (surface-enhanced resonance Raman scattering) and fluorescence spectroscopy. Finally, a perspective view is given on the tip based approaches like tip-enhanced Raman spectroscopy (TERS) which allow micrometric and nanometric resolution. PMID- 18443685 TI - SERS as a bioassay platform: fundamentals, design, and applications. AB - Bioanalytical science is experiencing a period of unprecedented growth. Drivers behind this growth include the need to detect markers central to human and veterinary diagnostics at ever-lower levels and greater speeds. A set of parallel arguments applies to pathogens with respect to bioterrorism prevention and food and water safety. This tutorial review outlines our recent explorations on the use of surface enhanced Raman scattering (SERS) for detection of proteins, viruses, and microorganisms in heterogeneous immunoassays. It will detail the design and fabrication of the assay platform, including the capture substrate and nanoparticle-based labels. The latter, which is the cornerstone of our strategy, relies on the construction of gold nanoparticles modified with both an intrinsically strong Raman scatterer and an antibody. This labelling motif, referred to as extrinsic Raman labels (ERLs), takes advantage of the well established signal enhancement of scatterers when coated on nanometre-sized gold particles, whereas the antibody imparts antigenic specificity. We will also examine the role of plasmon coupling between the ERLs and capture substrate, and challenges related to particle stability, nonspecific adsorption, and assay speed. PMID- 18443686 TI - Quantitative surface-enhanced Raman spectroscopy. AB - The purpose of this tutorial review is to show how surface-enhanced Raman (SERS) and resonance Raman (SERRS) spectroscopy have evolved to the stage where they can be used as a quantitative analytical technique. SER(R)S has enormous potential for a range of applications where high sensitivity needs to be combined with good discrimination between molecular targets, particularly since low cost, compact spectrometers can read the high signal levels that SER(R)S typically provides. These advantages over conventional Raman measurements come at the cost of increased complexity and this review discusses the factors that need to be controlled to generate stable and reproducible SER(R)S calibrations. PMID- 18443687 TI - Electrochemical surface-enhanced Raman spectroscopy of nanostructures. AB - This tutorial review first describes the early history of SERS as the first SERS spectra were obtained from an electrochemical cell, which led to the discovery of the SERS effect in mid-1970s. Up to date, over 500 papers have been published on various aspects of SERS from electrochemical systems. We then highlight important features of electrochemical SERS (EC-SERS). There are two distinctively different properties of electric fields, the electromagnetic field and static electrochemical field, co-existing in electrochemical systems with various nanostructures. Both chemical and physical enhancements can be influenced to some extent by applying an electrode potential, which makes EC-SERS one of the most complicated systems in SERS. Great efforts have been made to comprehensively understand SERS and analyze EC-SERS spectra on the basis of the chemical and physical enhancement mechanisms in order to provide meaningful information for revealing the mechanisms of electrochemical adsorption and reaction. The EC-SERS experiments and applications are then discussed from preparation of nanostructured electrodes to investigation of SERS mechanisms and from characterization of adsorption configuration to elucidation of electrochemical reaction mechanisms. Finally, prospective developments of EC-SERS in substrates, methods and theory are discussed. PMID- 18443688 TI - Quantitative SERRS for DNA sequence analysis. AB - SERRS is an extremely sensitive and selective technique which when applied to the detection of labelled DNA sequences allows detection limits to be obtained which rival, and in most cases are better than, fluorescence. In this tutorial review the conditions are explored which enable the successful detection of DNA using SERRS. The enhancing surface which is used is crucial and in this case suspensions of nanoparticles were the focus as they allow quantitative behaviour to be achieved in systems analogous to current fluorescence based approaches. The aggregation conditions required to obtain SERRS of DNA affect the sensitivity and the reproducibility and we describe the use of spermine as an effective aggregating agent to achieve excellent reproducibility and sensitivity. The nature of the label which is used, be it fluorescent or non-fluorescent, positively or negatively charged, also affects the SERRS response and these conditions are again discussed. Finally, we show how to detect a specific target DNA sequence in a meaningful diagnostic assay using SERRS and how the approaches described previously in the review are vital to the success of such approaches. PMID- 18443689 TI - SERS--a single-molecule and nanoscale tool for bioanalytics. AB - Surface enhanced Raman scattering (SERS) at extremely high enhancement level turns the weak inelastic scattering effect of photons on vibrational quantum states into a structurally sensitive single-molecule and nanoscale probe. The effect opens up exciting opportunities for applications of vibrational spectroscopy in biology. The concept of SERS can be extended to two-photon excitation by exploiting surface enhanced hyper-Raman scattering (SEHRS). This critical review introduces the physics behind single-molecule SERS and discusses the capabilities of the effect in bioanalytics (100 references). PMID- 18443690 TI - Electronic structure methods for studying surface-enhanced Raman scattering. AB - This critical review highlights recent advances in using electronic structure methods to study surface-enhanced Raman scattering. Examples showing how electronic structure methods, in particular time-dependent density functional theory, can be used to gain microscopic insights into the enhancement mechanism are presented (150 references). PMID- 18443691 TI - Subporphyrins: emerging contracted porphyrins with aromatic 14pi-electronic systems and bowl-shaped structures: rational and unexpected synthetic routes. AB - Subporphyrin is a ring-contracted porphyrin congener consisting of three pyrrolic subunits domed in a C3 symmetric bowl arrangement. Subporphyrin had long been elusive until the first synthesis of tribenzosubporphine in 2006. Shortly after, synthetic protocols of subpyriporphyrin, meso-aryl-substituted subporphyrins, and meso-aryl substituted subchlorins were developed. Subporphyrins display interesting properties including distinct aromaticity arising from 14pi electronic conjugation, green fluorescence, and strong influences of meso-aryl substituents on the electronic network of the macrocycle. Besides the rational synthetic routes, an unexpected route to a specific subporphyrin from a [32]heptaphyrin(1.1.1.1.1.1.1) was discovered via a thermal extrusion reaction upon Cu(II)-B(III) cooperative metallation. In this Perspective, we review recent progress on subporphyrin chemistry and unprecedented ring-splitting reactions of medium size expanded porphyrins that are triggered upon metallation. PMID- 18443692 TI - Dielectric anisotropy of a homochiral rare-earth metal complex. AB - A homochiral rare-earth metal Tb complex that exhibited a very large dielectric anisotropic property with a temperature-independent feature is obtained. Our findings on high-dielectric anisotropy will provide a new impetus in this field of materials science. PMID- 18443693 TI - Generation of cationic indenyl silylamide gadolinium and scandium complexes [(Ind)Ln{N(SiMe3)2}]+[B(C6F5)4]- and their reactivity for 1,3-butadiene polymerization. AB - Highly efficient cis-polymerization of butadiene was achieved by using new bis(indenyl) silylamide rare earth complexes with the cooperation of both a borate salt and i-Bu3Al; treatment of these complexes with organoboron compounds unexpectedly yielded new cationic mono(indenyl) amido species relevant to polymerization. PMID- 18443694 TI - 4,5-di(2-pyridyl)-1,2,3-triazolate: the elusive member of a family of bridging ligands that facilitate strong metal-metal interactions. AB - The new click-adduct 4,5-di(2-pyridyl)-1,2,3-triazole acts as a doubly-chelating anionic bridging ligand that forms dinuclear ruthenium(II) complexes which exhibit strong metal-metal interactions. PMID- 18443695 TI - Dinickel complexes of disubstituted benzoate polydentate ligands: mimics for the active site of urease. AB - Two dinickel mimics, [LNi2(DMF)4](ClO4)3 () and [L'Ni2(CH3CN)4](ClO4)3 (), for the active site of urease supported by a disubstituted benzoate polydentate ligand were synthesized and fully characterized, subsequently addition of urea afforded two urea adducts, [LNi2(urea)4](ClO4)3 () and [L'Ni2(urea)4](ClO4)3 (). PMID- 18443696 TI - Ferric hydroxide supported gold subnano clusters or quantum dots: enhanced catalytic performance in chemoselective hydrogenation. AB - An attempt to prepare ferric hydroxide supported Au subnano clusters via modified co-precipitation without any calcination was made. High resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) have been employed to study the structure and chemical states of these catalysts. No Au species could be observed in the HRTEM image nor from the XRD pattern, suggesting that the sizes of the Au species in and on the ferric hydroxide support were less than or around 1 nm. Chemoselective hydrogenation of aromatic nitro compounds and alpha,beta-unsaturated aldehydes was selected as a probe reaction to examine the catalytic properties of this catalyst. Under the same reaction conditions, such as 100 degrees C and 1 MPa H2 in the hydrogenation of aromatic nitro compounds, a 96-99% conversion (except for 4-nitrobenzonitrile) with 99% selectivity was obtained over the ferric hydroxide supported Au catalyst, and the TOF values were 2-6 times higher than that of the corresponding ferric oxide supported catalyst with 3-5 nm size Au particles. For further evaluation of this Au catalyst in the hydrogenation of citral and cinnamaldehyde, selectivity towards unsaturated alcohols was 2-20 times higher than that of the corresponding ferric oxide Au catalyst. PMID- 18443697 TI - Structural diversity in bishydroxylamine complexes of gallium. AB - Reactions of bishydroxylamines of the type HON(R)CH2CH2N(R)OH (R=Me, tBu) with trimethyl- and triisopropylgallium gave bicyclic metalla cages of the formula R'2GaO(R)NCH2CH2N(R)OGaR'2 [R'=Me, R=Me (), tBu (); R'=iPr, R=Me (), tBu ()] with six-membered Ga2O2N2-rings. While the complexes show the same core constitution in the solid state, NMR spectra reveal the steric influence of the isopropyl substituent of the compounds / on its behaviour in solution. The reaction of the sterically more demanding substituted tri-tert-butylgallium with HON(Me)CH2CH2N(Me)OH yielded a heterodimeric complex O' [HON(Me)CH2CH2NH(Me)O(tBu2Ga)]-cyclo-(tBu2Ga)-O,N'-[ON(Me)CH2CH2N(Me)O] () with two gallium atoms of different surrounding and two different bishydroxylamine ligands, one doubly deprotonated and one protonated, but at one end in its tautomeric aminoxide form. Further condensation of was observed to give a tricyclic compound cyclo-[(tBuGa)ON(Me)CH2CH2N(Me)O]2 () with a central Ga2O2N2 ring resulting from two Ga-N donor-acceptor bonds. PMID- 18443698 TI - Fluorinated bismuth alkoxides: from monomers to polymers and oxo-clusters. AB - A series of new bismuth fluoroalkoxide compounds have been prepared through the treatment of 1,1,1,3,3,3-hexafluoro-2-propanol with BiAr3 (where Ar=Ph, p-Tol). Reactions were conducted without the use of any additional solvent and the reaction products distilled or extracted with non-polar or polar Lewis base solvents. Structural analyses reveal that under variable reaction conditions the interaction of BiAr3 with (CF3)2CHOH can give a mixture of bismuth complexes with varying degrees of substitution, cluster formation and aggregation. Compounds [Bi(OCH(CF3)2)3(pyr)2] () (pyr=pyridine), [Bi(OCH(CF3)2)3(thf)3] () (thf=tetrahydrofuran), [Bi2(OCH(CF3)2)3(dabco)3] () (dabco=1,4 diazabicyclo[2.2.2]octane), [PhBi(OCH(CF3)2)2]n (), [Bi2O(OCH(CF3)2)4(C7H8)]2 () (C7H8=toluene), [Bi9O7(OCH(CF3)2)13] (), [Bi2O(OCH(CF3)2)4(Et2O)]2 (), [Bi2O(OCH(CF3)2)4(thf)]2 () and [Bi2O(OCH(CF3)2)4(tmeda)2] () (tmeda=N,N,N',N' tetramethylethylenediamine) have been fully characterised including by single crystal X-ray diffraction. PMID- 18443699 TI - Design, syntheses, and characterization of dioxo-molybdenum(VI) complexes with thiolate ligands: effects of intraligand NH...S hydrogen bonding. AB - Presence of the hydrogen bonding near a metal center can influence the properties of the complex. Here, we describe changes in redox and spectral properties in discrete dioxo-molybdenum centers coordinated by a single thiolato ligand that can support an intra-ligand hydrogen bond. We have utilized thiophenolato ligands that can harbor hydrogen bonding between the thiophenolato sulfur with an amide functionality creating either a five- or a six-membered ring. Methylation of the amide functionality removes the NH...S hydrogen bonding thus providing a basis for understanding the effect of hydrogen bonding. These thiophenolato ligands have been used in synthesizing dioxo-MoVI complexes of type Tp*MoO2(S-o-RC6H4), where R=CONHMe (), CONMe2 (), NHCOMe (), and N(Me)COMe (). The complexes have been characterized by NMR, infrared, and UV-visible spectroscopy. Spectroscopic data clearly indicate the presence of hydrogen bonding in both and , and stronger in , where hydrogen bonding stabilizes a five-membered ring. All complexes exhibit a Mo(VI)/Mo(V) redox couple and redox potentials are modulated by the nature of H-bonding. Compound with the electron-releasing N(Me)COMe group has the highest reduction potential and is more difficult to reduce. PMID- 18443700 TI - A new optical/electrochemical Na+ sensor based on platinum(II) complexes containing crown ether annelated dithiolate ligands. AB - Two new platinum(II) complexes containing both 4,4'-di-tert-butyl-2,2'-bipyridine (dbbpy) and crown ether annelated dithiolate ligands, [Pt(dbbpy)(3O-C2S4)] (, 3O C2S4(2-)=1,4,7-trioxa-10,13-dithiacyclopentadec-11-ene-11,12-dithiolate) and [Pt(dbbpy)(4O-C2S4)] (, 4O-C2S(4)2-=1,4,7,10-tetraoxa-13,16-dithiacyclooctadec-14 ene-14,15-dithiolate), have been prepared and characterized. These two complexes show intense electronic absorption bands in the UV-vis region due to the intramolecular mixed metal/ligand-to-ligand charge transfer transition, and they display solvatochromic behavior. The redox properties of these compounds have been investigated by cyclic voltammetry and complex shows a significant response for Na+ ions with a large positive shift of ca. 125 mV. Moreover, complex is very sensitive in detecting Na+ cations with an obvious change in color which can be conveniently observed with the naked eye. PMID- 18443701 TI - Polyhedral structures with an odd number of vertices: nine-atom clusters and supramolecular architectures. AB - The geometries of metal clusters and supramolecular architectures that contain nine metal atoms are analyzed within the framework of continuous shape measures (CShM). The most common polyhedra in nine coordinate complexes, the capped square antiprism and the tricapped trigonal prism, are also found among these families of compounds, even if much more scarcely. In addition, a variety of new shapes, not found among coordination polyhedra, can be identified and their proximity to the ideal geometries quantified. These include a linear chain, two types of trigonal columns, the planar regular enneagon, two-dimensional hexagonal and square grids, fragments of a close-packed structure, the triangular cupola, the tridiminished icosahedron or different fragments of the icosahedron. Among the nine-atom boranes and related clusters of the groups 13 and 14 elements, those having between 18 and 20 framework electrons present the structure of the tricapped trigonal prism, the expected closo structure. However, clusters with 21 and 22 framework electrons present a variety of structures with geometries covering nearly all the path that takes one from the capped square antiprism (nido form) to the tricapped trigonal prism (closo form). PMID- 18443702 TI - Synthesis and characterization of volatile liquid cobalt amidinates. AB - Three new volatile cobalt amidinate compounds were prepared: Co(tBuNC(R)NEt)2, R=Me, Et and n-Bu. They were characterized by elemental analysis, 1H NMR, X-ray structure analysis, melting point, vapor pressure, vaporization rate, thermal stability and chemical reactivity. They were found to evaporate cleanly without decomposition. Two of them are liquids at room temperature, allowing for more convenient preparation, handling and purification by distillation. They are highly reactive compounds that have been found to be suitable precursors for vapor deposition of cobalt metal, cobalt nitride and cobalt oxide. A new synthetic method allows for the facile and inexpensive preparation of large quantities of these compounds. PMID- 18443703 TI - Structure, formation and catalytic studies of a meso-palladioporphyrin intermediate in a Heck reaction. AB - A meso-palladioporphyrin intermediate was isolated from a Heck reaction between an iodoporphyrin and a non-activated olefin using a Pd(PPh3)2Cl2/Et3N system; its structure was characterized by NMR, MS and X-ray crystallography. Studies on its formation indicate that the Pd(II) catalyst was reduced in situ by Et3N with the assistance of water. The catalytic activity of the intermediate was confirmed by stoichiometric and catalytic reactions using a more reactive olefin, ethyl acrylate. PMID- 18443704 TI - Stoichiometric and catalytic reactivity of the N-heterocyclic carbene ruthenium hydride complexes [Ru(NHC)(L)(CO)HCl] and [Ru(NHC)(L)(CO)H(eta2-BH4)] (L=NHC, PPh3). AB - Thermolysis of [Ru(AsPh3)3(CO)H2] with the N-aryl heterocyclic carbenes (NHCs) IMes (1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), IPr (1,3-bis(2,6 diisopropylphenyl)imidazol-2-ylidene) or the adduct SIPr.(C6F5)H (SIPr=1,3 bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene), followed by addition of CH2Cl2, affords the coordinatively unsaturated ruthenium hydride chloride complexes [Ru(NHC)2(CO)HCl] (NHC=IMes , IPr , SIPr ). These react with CO at room temperature to yield the corresponding 18-electron dicarbonyl complexes . Reduction of and [Ru(IMes)(PPh3)(CO)HCl] () with NaBH4 yields the isolable borohydride complexes [Ru(NHC)(L)(CO)H(eta2-BH4)] (, L=NHC, PPh3). Both the bis IMes complex and the IMes-PPh3 species react with CO at low temperature to give the eta1-borohydride species [Ru(IMes)(L)(CO)2H(eta1-BH4)] (L=IMes , PPh3), which can be spectroscopically characterised. Upon warming to room temperature, further reaction with CO takes place to afford initially [Ru(IMes)(L)(CO)2H2] (L=IMes, L=PPh3) and, ultimately, [Ru(IMes)(L)(CO)3] (L=IMes , L=PPh3). Both and lose BH3 on addition of PMe2Ph to give [Ru(IMes)(L)(L')(CO)H2](L=L'=PMe2Ph; L=PPh3, L'=PMe2Ph). Compounds and have been tested as catalysts for the hydrogenation of aromatic ketones in the presence of (i)PrOH and H2. For the reduction of acetophenone, catalytic activity varies with the NHC present, decreasing in the order IPr>IMes>>SIMes. PMID- 18443705 TI - Approaches to trinuclear half-sandwich carbene complexes containing 1,2-dicarba closo-dodecaboranes. AB - The synthesis of trinuclear half-sandwich iridium and rhodium complexes containing both N-heterocyclic carbene (NHC) and 1,2-dicarba-closo-dodecaborane ligands is described. Complexes {Cp*M[E2C2(B10H10)]}3(L) (Cp*=pentamethylcyclopentadienyl; L=tris(2-(3-methylimidazol-2 ylidene)ethyl)amine; M=Ir (), Rh (); E=S (), Se ()) were obtained from the reactions of Cp*M[E2C2(B10H10)] (M=Ir (), Rh ()) with a silver-NHC precursor or from the reactions of [Cp*MCl2]3(L) (M=Ir (), Rh ()) with Li2E2C2(B10H10) (E=S, Se). The complexes were characterized by IR, NMR spectroscopy, elemental analysis. In addition, X-ray structure analyses were performed on complexes and . PMID- 18443706 TI - Titanium and zirconium benzofuranoxides. Crystal structures and catalytic properties. AB - Reactions of Ti(OiPr)4 or Zr(OEt)4 with 4 equivalents of 2,3-dihydro-2,2-dimethyl 7-benzofuranol (ddbfoH) in toluene gave neutral complexes that in the solid state are dimers of [Ti(micro-ddbfo)2(ddbfo)6] and [Zr(ddbfo)3(EtOH)(micro-EtO)]2 composition. The former could also be conveniently synthesized in a direct reaction of TiCl4 with ddbfoH. This air-stable aryloxo compound was found to initiate living ring-opening polymerization of lactides affording polyesters with narrow molecular weight distribution. It also catalyzed addition of terminal acetylenes to aryl aldehydes. PMID- 18443707 TI - Synthesis, structure and theoretical study of mixed fluoro-trifluoromethyl derivatives of C60. Molecular structures of C60F18(CF3)6 and C60F16(CF3)6. AB - A series of novel mixed C60Fn(CF3)m compounds has been produced by trifluoromethylation of C60F18 with CF3I in ampoules at 380-420 degrees C. Two of these compounds, C60F18(CF3)6 and C60F16(CF3)6, have been characterized by X-ray crystallography, which has revealed addition of six CF3 groups to the C3v-C60F18 for the former and replacement/elimination of two outermost F atoms in the latter. Quantum chemical calculations have been employed to predict the most stable possible isomers of C60F16/18(CF3)6 in order to rationalize the experimental results. PMID- 18443708 TI - Gold(I) and silver(I) complexes containing a tripodal tetraphosphine ligand: influence of the halogen and stoichiometry on the properties. The X-ray crystal structure of two gold(I) dimeric aggregates. AB - Complexes of the type [Au2(micro-PP3)2]X2 [X=Cl (), Br (), I ()], [Ag2(micro PP3)2](NO3)2 (), Ag(PP3)Cl (), M3(micro-PP3)X3 [M=Au, X=Cl (), Br (), I (); M=Ag, X=NO3 ()] and Au4(micro-PP3)X4 [X=Cl (), Br (), I ()] have been prepared by interaction between gold(I) or silver(I) salts and the ligand tris[2 (diphenylphosphino)ethyl]phosphine (PP3) in the appropriate molar ratio. Microanalysis, mass spectrometry, IR and NMR spectroscopies and conductivity measurements were used for characterization. and are ionic dinuclear species containing four-coordinate gold(i) and four/three coordinate silver(i), respectively. Solutions of behave as mixtures of complexes in a 2:1 [Au2(micro PP3)X2; X=Cl(), Br(), I()] and 4:1 () metal to ligand ratio. and react with free PP(3) in solution to generate the ionic compounds and , respectively. Complexes and , with four linear PAuX fragments per molecule, were shown by X-ray diffraction to consist of dimeric aggregates via close intermolecular gold(I)gold(I) contacts of 3.270 A () and 3.184 A (). The resultant octanuclear systems have an inversion center with two symmetry-related gold(I) atoms being totally out of the aurophilic area and represent a new form of aggregation compared to that found in other halo complexes of gold(I) containing polyphosphines. The luminescence properties of the ligand and complexes, in the solid state, have been studied. Most of the gold systems display intense luminescent emission at room and low temperature. The influence of the halogen on the aurophilic contacts of compounds with a 4:1 metal to ligand ratio results in different photophysical properties, while and are luminescent complex is nonemissive. The luminescence increases with increasing the phosphine/metal ratio affording for complexes , without aurophilic contacts, the stronger emissions. Silver complexes and are nonemissive at room temperature and show weaker emissions than gold(I) species at 77 K. PMID- 18443709 TI - Importance of vitamin D in hospital-based fracture care pathways. AB - OBJECTIVES: This project was developed to identify ways to support hospital-based improvements for the identification and management of osteoporosis following treatment of a fragility fracture. DESIGN: This is a retrospective review of medical records of sets of consecutive patients who were admitted for surgical treatment of fragility fracture following introduction of several versions of admission and discharge care pathways. Effectiveness of the admission pathway was defined as % subjects with measurement of serum 25- hydroxyvitamin D (25(OH)D) during hospitalization; effectiveness of the discharge pathway was defined as % subjects with documentation of instructions for calcium and/or vitamin D supplementation. SETTING: This study reviewed medical records of patients admitted to hospital for surgical treatment of a fragility fracture. PARTICIPANTS: Medical records were evaluated for 98 patients older than 50-years who were admitted with a fragility fracture of the hip or femur. MEASUREMENTS: Medical records were reviewed for the % subjects with documentation of an in hospital order for serum 25(OH)D and with documentation of instructions to patients upon discharge concerning calcium and vitamin D intake. Median value of serum 25(OH)D was calculated. RESULTS: In accordance with the admission pathway, serum 25(OH)D was measured in 37% (36/98). The median 25(OH)D level was 19.5 ng/mL; 78% were vitamin D insufficient [serum 25(OH)D < or = 32 ng/mL] and 58% were vitamin D deficient [serum 25(OH)D < or = 20 ng/mL]. In accordance with the discharge pathway, 74% (71/96) were discharged on calcium and/or vitamin D. CONCLUSION: The high prevalence of vitamin D insufficiency (78%) observed in this study affirms the importance of incorporating vitamin D supplementation in hospital-based fracture care pathways. The discharge pathway was more effective than the newer admission pathway, a finding attributable to effects of familiarity, retraining, and introduction of computer-prompts. These evolving pathways represent a much-needed paradigm shift in the care of fragility fracture patients. PMID- 18443710 TI - Minimal effect on energy intake by additional evening meal for frail elderly service flat residents--a pilot study. AB - BACKGROUND: Nutritional problems are common in frail elderly individuals receiving municipal care. OBJECTIVE: To evaluate if an additional evening meal could improve total daily food intake, nutritional status, and health-related quality of life (HRQOL) in frail elderly service flat (SF) residents. DESIGN: Out of 122 residents in two SF complexes, 60 subjects agreed to participate, of which 49 subjects (median 84 (79-90) years, (25th-75th percentile)) completed the study. For six months 23 residents in one SF complex were served 530 kcal in addition to their regular meals, i.e. intervention group (I-group). Twenty-six residents in the other SF building were controls (C-group). Nutritional status, energy and nutrient intake, length of night time fast, cognitive function and HRQOL was assessed before and after the intervention. RESULTS: At the start, the Mini Nutritional Assessment classified 27% as malnourished and 63% as at risk for malnutrition, with no difference between the groups. After six months the median body weight was unchanged in the I-group, +0.6 (-1.7-+1.6) kg (p=0.72) and the C group -0.6 (-2.0-+0.5) kg (p=0.15). Weight change ranged from -13% to +15%. The evening meal improved the protein and carbohydrate intake (p<0.01) but the energy intake increased by only 180 kcal/day (p=0.15). The night time fast decreased in the I-group from 15.0 (13.0-16.0) to 13.0 (12.0-14.0) hours (p<0.05). There was no significant difference in cognitive function or HRQOL between the groups. CONCLUSION: Nine out of ten frail elderly SF residents had nutritional problems. Serving an additional evening meal increased the protein and carbohydrate intake, but the meal had no significant effect on energy intake, body weight or HRQOL. The variation in outcome within each study group was large. PMID- 18443712 TI - Evaluation of strategies to improve nutrition in people with dementia in an assessment unit. AB - OBJECTIVES: To evaluate strategies designed to improve nutrition in elderly hospitalised patients with dementia. DESIGN: Observation phase followed by sequential interventions. SETTING: A Short stay assessment unit. PARTICIPANTS: Hospital Inpatients with a variety of conditions causing dementia. INTERVENTIONS: Phase 1: Observation. Phase 2: Encouraging dietary, 'Grazing'. Phase 3: Using volunteers to feed patients. Phase 4: Improving dining room ambience by playing soothing music. MEASUREMENTS: Body Mass Index (BMI), mid arm circumference, mini nutrition index and caloric intake by plate waste measurement. RESULTS: BMI fell in the Observation phase 0.6 +/- 0.68 kg/m2 (p < 0.001), but increased in each of the Intervention phases. Phase2 0.3 +/- 0.86 kg/m2 (p < 0.04), Phase 3 0.37 +/- 0.4 kg/m2 (p < 0.04), Phase 4 0.39 +/- 0.7 kg/m2 (p < 0.007). Caloric intake increased in the intervention phases. CONCLUSIONS: Simple, inexpensive and easy to implement strategies can improve nutrition in hospital inpatients with dementia. PMID- 18443711 TI - Markers of B-vitamin deficiency and frailty in older women. AB - OBJECTIVE: To evaluate the association between markers of vitamins B12, B6 and folate deficiency and the geriatric syndrome of frailty. DESIGN: Cross-sectional study of baseline measures from the combined Women's Health and Aging Studies. SETTING: Baltimore, Maryland. PARTICIPANTS: Seven hundred three community dwelling women, aged 70-79. MEASUREMENTS: Frailty was defined by five-component screening criteria that include weight, grip strength, endurance, physical activity and walking speed measurements and modeled as binary and 3-level polytomous outcomes. Independent variables serum vitamin B6, vitamin B12, methylmalonic acid, total homocysteine, cystathionine and folate were modeled continuously and as abnormal versus normal. RESULTS: Serum biomarker levels varied significantly by race. All analyses were race-stratified and results are reported only for Caucasian women due to small African American sample size. In polytomous logistic regression models of 3-level frailty, Caucasian women with increasing MMA, defined either continuously or using a predefined threshold, had 40-60% greater odds of being prefrail (p-values < 0.07) and 1.66-2.33 times greater odds of being frail (p-values < 0.02) compared to nonfrails after adjustment for age, education, low serum carotenoids, alcohol intake, cardiovascular disease and renal impairment. Both binary and polytomous frailty models evaluating vitamin B12 as the main exposure estimated odds ratios that were similar in trend yet slightly less significant than the MMA results. CONCLUSIONS: These results suggest that vitamin B12 deficiency may contribute to the frailty syndrome in community-dwelling older women. Future studies are needed to explore these relationships longitudinally. PMID- 18443713 TI - Depressive symptoms and risk for malnutrition among hospitalized elderly people. AB - OBJECTIVES: To explore the association between depressive symptoms and risk for malnutrition in hospitalized elderly people. METHODS: 195 hospitalized medical patients older than 65 years of age were studied in a cross-sectional design. Depression was assessed by 30-item Geriatric Depression Scale (GDS), nutritional status was evaluated by the Mini-Nutritional Assessment (MNA). Eating and digestive problems were assessed using selected items of Nutrition Risk Index (NRI), cognitive and functional status by Folstein and Barthel indices respectively; demographic data, diagnoses and medications were obtained from medical records. RESULTS: The prevalence of depression in the studied population was 28%. MNA scores were significantly lower among depressed patients as compared with non-depressed (22.86 vs. 24.96, p < 0.001), indicating a higher risk for undernutrition among depressed persons. After controlling for age, cognitive status, functional ability, and number of illnesses, undernutrition was significantly associated with depression (OR = 2.23; 95% CI: 1.04-4.8). CONCLUSIONS: Nutritional risk is associated with depression in aged inpatients. Close case management of the elderly hospitalized patients that include assessment and treatment for both disorders may be beneficial. PMID- 18443714 TI - Single versus multicomponent intervention in frail elderly: simplicity or complexity as precondition for success? AB - Research on geriatric syndromes has helped to clarify risk factors and established effective intervention strategies, yet the results based on this evidence have mostly failed to translate into clinical practice. The translation of geriatric syndrome research into practice faces unique challenges, which may heighten the barriers to evidence-based implementation. The British Medical Research Council framework (MRC) for development and evaluation of complex interventions, turns out to be very valuable in developing and evaluating interventions in the complex clinical reality of geriatrics. This paper illustrates the different phases of this framework on the basis of examples from geriatric research projects in The Netherlands. The discussed barriers in complex interventions can be mapped using the different phases in the MRC-framework and thus become feasible challenges for good quality research. PMID- 18443715 TI - Nutritional status after acute stroke: is a stroke unit better than a general geriatric ward? PMID- 18443716 TI - Association between diabetes mellitus and hypertension with anthropometric indicators in older adults: results of the Mexican Health Survey, 2000. AB - OBJECTIVE: To determine the association between anthropometric indicators of adiposity with type 2 diabetes mellitus (T2DM) and hypertension (HTN) in older adults. DESIGN: Cross-sectional study of participants of the Mexican Health Survey 2000 (MHS). SETTING: Mexico, subjects recruited from the general community. PARTICIPANTS: The analytic sample included 7,322 adults who were > or = 60 years of age at the time of the survey. T2DM data were available on 6,994 individuals, who represent 95.5% of the original sample; data on HTN was available on 6,268 subjects, which accounted for 86.5% of the original sample. MEASUREMENTS: Type 2 diabetes mellitus and hypertension, as well as anthropometric indicators including body mass index (BMI), waist circumference (WC), and conicity index (CI). RESULTS: The prevalence of T2DM and HTN in this age group was 34.3% and 73.9%, respectively. After adjusting for other variables, the association between high WC and T2DM (OR = 1.59 95%CI = 1.26-2.01, P < 0.001) was stronger than the association with overweight (OR = 1.26, 95%CI = 1.01-1.58, P = 0.04) and obesity (OR = 1.38, 95%CI = 1.08-1.79, P < 0.01) using BMI, and slightly higher than tertile 2 of the CI (OR = 1.49, 95%CI = 1.20-1.88, P < 0.01), while tertile 3 showed a stronger association with T2DM (OR = 1.60, 95%CI = 1.22-2.08, P < 0.001). However, the association between obesity and HTN measured by BMI (OR = 1.98, 95%CI = 1.48-2.65, P < 0.001) was stronger than what was observed with overweight (OR = 1.42, 95%CI 1.13-1.77, P < 0.01), with high WC (OR = 1.62, 95%CI = 1.25-2.10, P < 0.001) and tertiles 2 and 3 of the CI (OR = 1.23, 95%CI = 0.99-1.55, P = 0.09); (OR = 1.53, 95%CI = 1.16-2.03, P < 0.01) respectively. CONCLUSIONS: BMI and abdominal obesity are significantly and independently associated with an increase in the prevalence of T2DM and HTN among older Mexican adults. PMID- 18443717 TI - Frailty, osteoporosis and hip fracture: causes, consequences and therapeutic perspectives. AB - OBJECTIVE: The aim of this review of the literature is to report the factors which both contribute to the frailty syndrome and increase hip fracture risk in the elderly. This work is the fruit of common reflection by geriatricians, endocrinologists, gynecologists and rheumatologists, and seeks to stress the importance of detection and management of the various components of frailty in elderly subjects who are followed and treated for osteoporosis. It also sets out to heighten awareness of the need for management of osteoporosis in the frail elderly. DESIGN: The current literature on frailty and its links with hip fracture was reviewed and discussed by the group. RESULTS: The factors and mechanisms which are common to both osteoporosis and frailty (falls, weight loss, sarcopenia, low physical activity, cognitive decline, depression, hormones such as testosterone, estrogens, insulin-like growth factor-I (IGF-I), growth hormone (GH), vitamin D and pro-inflammatory cytokines) were identified. The obstacles to access to diagnosis and treatment of osteoporosis in the frail elderly population and common therapeutic pathways for osteoporosis and frailty were discussed. CONCLUSION: Future research including frail subjects would improve our understanding of how management of frailty can can contribute to lower the incidence of fractures. In parallel, more systematic management of osteoporosis should reduce the risk of becoming frail in the elderly population. PMID- 18443719 TI - [Not Available]. PMID- 18443718 TI - Minimum geriatric screening tools to detect common geriatric problems. AB - BACKGROUND: Health services for the elderly are becoming increasingly important in industrialized nations, and comprehensive geriatric assessment (CGA) is one of the procedures designed to improve the health of this sector of the population. In 2003 a survey among Belgian geriatricians showed that despite the interest of the geriatric teams for comprehensive geriatric assessment, it was not used enough. Considering these results, as a first step, screening tools were proposed for the main geriatric domains (Minimum Geriatric Screening Tools, MGST). OBJECTIVES: To assess the feasibility of a MGST within the teams of geriatric units and to evaluate the efficacy of a MGST on the detection rate of the geriatric problems of admitted subjects. DESIGN: Prospective observational survey. METHODS: The teams were first asked to encode active geriatric problems suspected according to their conventional assessment. Then, in a second phase, a complete MGST was completed by the same team within the first week after admission. RESULTS: Three hundred and twenty six registrations from 33 centres were available. Mean (+/- SD) number of screened geriatric problems was 1.5 +/- 1.2 without MGST and 4.7 +/- 1.7 (p < 0.0001) using the MGST. Except for the assessment for the risk of falls, the MGST leads to a better screening for the seven other main geriatric domains (functional, continence, cognition, depression, nutrition, pain, social). CONCLUSIONS: An improvement associated with the use of simple minimal geriatric tools to screen geriatric problems was evident. This approach has additional value for education and quality assurance. PMID- 18443720 TI - [Not Available]. PMID- 18443721 TI - [Not Available]. PMID- 18443722 TI - [Not Available]. PMID- 18443723 TI - [Not Available]. PMID- 18443724 TI - Iodine-129 and natural iodine in tree rings in the vicinity of a small nuclear fuels reprocessing plant. PMID- 18443725 TI - [Not Available]. PMID- 18443726 TI - Respiration-linked proton extrusion from the unicellular cyanobacterium Anacystis nidulans. PMID- 18443727 TI - Immature males of Aleochara curtula avoid intrasexual aggressions by producing the female sex pheromone. PMID- 18443728 TI - Leukotrienes in teleost fish gills. PMID- 18443729 TI - Plasma-membrane "rosettes" are present in the lily pollen tube. PMID- 18443730 TI - [Not Available]. PMID- 18443731 TI - [Not Available]. PMID- 18443732 TI - [Not Available]. PMID- 18443733 TI - The relationship between early personality and midlife psychological well-being: evidence from a UK birth cohort study. AB - BACKGROUND: Individual differences in personality influence the occurrence, reporting and outcome of mental health problems across the life course, but little is known about the effects on adult psychological well-being. The aim of this study was to examine long range associations between Eysenck's personality dimensions and psychological well-being in midlife. METHODS: The study sample comprised 1,134 women from the 1946 British birth cohort. Extraversion and neuroticism were assessed using the Maudsley Personality Inventory in adolescence (age 16 years) and early adulthood (age 26). Psychological well-being was assessed at age 52 with a 42-item version of Ryff's Psychological Well-being Scale. Analyses were undertaken within a structural equation modelling framework that allowed for an ordinal treatment of well-being and personality items, and latent variable modelling of longitudinal data on emotional adjustment. The contribution of mental health problems in linking personality variations to later well-being was assessed using a summary measure of mental health (emotional adjustment) created from multiple time-point assessments. RESULTS: Women who were more socially outgoing (extravert) reported higher well-being on all dimensions. Neuroticism was associated with lower well-being on all dimensions. The effect of early neuroticism on midlife well-being was almost entirely mediated through emotional adjustment defined in terms of continuities in psychological/ psychiatric distress. The effect of extraversion was not mediated by emotional adjustment, nor attenuated after adjustment for neuroticism. CONCLUSIONS: Individual differences in extraversion and neuroticism in early adult life influence levels of well-being reported in midlife. PMID- 18443735 TI - Early evolution of histone genes: prevalence of an 'orphon' H1 lineage in protostomes and birth-and-death process in the H2A family. AB - The study of histone evolution has experienced a rebirth, for two main reasons: the identification of new essential histone variants responsible for regulating chromatin dynamics and the subsequent contradictions posed by this variability as it pertains to their long-term evolution process. Although different evolutionary models (e.g., birth-and-death evolution, concerted evolution) may account for the observed divergence of histone genes, conclusive evidence is lacking (e.g., histone H1) or totally nonexistent (e.g., histone H2A). While most of the published work has focused on deuterostomes, very little is known about the diversification and functional differentiation mechanisms followed by histone protein subtypes in protostomes, for which histone variants have only been recently described. In this study, we identify linker and core histone genes in three clam species. Our results demonstrate the prevalence of an 'orphon' H1 lineage in molluscs, a group in which the protostome H1 and sperm nuclear basic proteins are on the verge of diversification. They share an early monophyletic origin with vertebrate-specific variants prior to the differentiation between protostomes and deuterostomes. Given the intringuing evolutionary features of the histone H1 family, we have evaluated the relative importance of gene conversion, point mutation, and selection in maintaining the diversity found among H2A subtypes in eukaryotes. We show evidence for the first time that the long-term evolution of this family is not subject to concerted evolution but, rather, to a gradual evolution following a birth-and-death model under a strong purifying selection at the protein level. PMID- 18443736 TI - On the physical basis of the amino acid polar requirement. AB - Understanding how codons became associated with their specific amino acids is fundamental to deriving a theory for the origin of the genetic code. Carl Woese and coworkers designed a series of experiments to test associations between amino acids and nucleobases that may have played a role in establishing the genetic code. Through these experiments it was found that a property of amino acids called the polar requirement (PR) is correlated with the organization of the codon table. No other property of amino acids has been found that correlates with the codon table as well as PR, indicating that PR is uniquely related to the modern genetic code. Using molecular dynamics simulations of amino acids in solutions of water and dimethylpyridine used to experimentally measure PR, we show that variations in the partitioning between the two phases as described by radial distribution functions correlate well with the measured PRs. Partition coefficients based on probability densities of the amino acids in each phase have the linear behavior with base concentration as suggested by PR experiments. PMID- 18443737 TI - Recombinant Listeria monocytogenes expressing an immunodominant peptide fails to protect after intravaginal challenge with herpes simplex virus-2. AB - Recombinant Listeria monocytogenes expressing a type-common herpes simplex virus (HSV) gB-peptide was shown previously to protect against footpad inoculation with HSV-1. We tested this construct for protection against vaginal challenge with HSV 2. Primed mice demonstrated strong recall responses, had modest reductions in HSV 2 DNA in vaginal mucosa, but were not protected from disease. PMID- 18443738 TI - Effects of physical training on bone mineral density in fertile women with idiopathic osteoporosis. AB - The aim of this study was to investigate whether moderate physical training can improve the bone mineral density (BMD) in women with idiopathic osteoporosis. Ten pre-menopausal women aged 24-44 years diagnosed with idiopathic osteoporosis were included in the study. The physical training program consisted of three fast 30 min walks plus one or two sessions of 1-h training per week during 1 year at a training centre separate from the hospital. All patients were given supplements of vitamin D and calcium. Bone mineral density was measured in the femoral neck area and the lumbar spine by dual energy X-ray absorptiometry. The measurements were performed at baseline and after 12 months of training and compared with the measurements at the time of diagnosis, 1-3 years before the study. Eight women fulfilled the 12-month training period, and their mean (SD) BMD at start was 0.88 (0.08) g/cm(2) in the spine and 0.76 (0.13) g/cm(2) in the femoral neck. The mean spine BMD increase was 0.031 g/cm(2) (3.5%) after 1 year of training, which was significant (Wilcoxon's non-parametric test, p = 0.018). The mean increment in BMD in the femoral neck was insignificant, 0.007 g/cm(2) (0.9%) after the intervention (p = 0.74). However, the bone loss during the 1- to 3-year period from diagnosis to study start was, on average, 0.045 g/cm(2) or 5.0% in the femoral neck (p = 0.042), thus indicating a positive indirect effect of the intervention. There is no evidence-based therapy for women with idiopathic osteoporosis. It is therefore of importance to elucidate the impact of moderate physical activity in this group of patients. A 1-year training program was sufficient to induce a small but significant change in the spine BMD. PMID- 18443739 TI - HLA-B27-transgenic rats, amyloid deposits, and spondyloarthropathies. PMID- 18443740 TI - Successful treatment with plasma exchange in adult-onset Still's disease with hyper-IL-18-naemia and hyperallergic state. AB - Adult-onset Still's disease (AOSD) is a rheumatoid disorder characterized by high fever, polyarthritis, leukocytosis, hyperferritinaemia, and mild liver involvement. We describe the case of a patient with AOSD with severe liver dysfunction. His serum levels of interleukin-10 and 18 showed a similar trend to his disease activity. Drug lymphocyte stimulation tests were positive for three drugs in the patient. Hypercytokinaemia was controlled by plasma exchange therapy. PMID- 18443741 TI - Current status of development of anticancer agents in Japan. AB - To investigate the current status of the development of anticancer agents in Japan, we examined the number of these agents developed after 1999, their target diseases, and the association between the number of approved agents and the number of patients with the diseases. The data were obtained via the Internet. Of the 487 agents approved from 1999 to April 2007, 84 were anticancer drugs. Of these 84, 46 were approved based on clinical trials and 38 were approved through the new drug application for off-label usages without clinical trials. The target diseases of the 46 agents approved through clinical trials were nonhematologic tumors in 29, hematologic malignancies in 13, and others in 4. Of the 38 approved through the new drug application for off-label usages, 31 were for nonhematologic tumors and 7 for hematologic malignancies. The number of approved anticancer agents for hematologic malignancies per unit patient population was 6.5-times as many as that for nonhematologic tumors. This study demonstrated that the situation regarding the development of anticancer agents differs among tumor types. The majority of anticancer agents developed target hematologic malignancies, while the newly developed anticancer agents have affected treatment strategies for solid tumors. PMID- 18443742 TI - Novobiocin inhibits the self-splicing of the primary transcripts of T4 phage thymidylate synthase gene. AB - Effects of the antibiotic novobiocin on the self-splicing of primary transcripts of the phage T4 thymidylate synthase gene (td) have been investigated. Novobiocin at 10 mM concentration inhibited the splicing by about 5% but at 40 mM concentration the splicing rate was inhibited by about 50%. The novobiocin inhibition of the self-splicing reaction was not reversed even at a high concentration (200 microM) of guanosine. However, increasing the Mg(2+) ion concentrations up to 20 mM almost fully restored the splicing activity to the normal splicing level. The double reciprocal plot analysis demonstrated that novobiocin acts as a mixed noncompetitive inhibitor for the td intron RNA with a K (i) of 90 mM. The splicing inhibition by novobiocin was strongly dependent on Mg(2+) ion concentration, indicating electrostatic interactions with the td intron RNA. It is likely that the antibiotic novobiocin may interfere with the catalytic actions of Mg(2+) ion in the splicing reaction of the td intron RNA. PMID- 18443743 TI - Accuracy of continuous central venous oxygen saturation monitoring in patients undergoing cardiac surgery. AB - OBJECTIVE: Continuous assessment of central venous oxygen saturation (S(cevox)O(2)) with the CeVOX device (Pulsion Medical Systems, Munich, Germany) was evaluated against central venous oxygen saturation (S(cv)O(2)) determined by co-oximetry. METHODS: In 20 cardiac surgical patients, a CeVOX fiberoptic probe was introduced into a standard central venous catheter placed in the right internal jugular vein and advanced 2-3 cm beyond the catheter tip. After in vivo calibration of the probe, S(cevox)O(2), S(cv)O(2), mixed venous oxygen saturation (S(mv)O(2)) haemoglobin (Hb), body temperature, heart rate, central venous and mean arterial pressure, and cardiac index were assessed simultaneously at 30 min intervals during surgery and at 60 min intervals during recovery in the intensive care unit. Agreement between S(cevox)O(2), and S(cv)O(2) was determined by Bland Altman analysis. Simple regression analysis was used to assess the correlation of S(cevox)O(2), and S(cv)O(2) to Hb, body temperature and haemodynamic parameters. RESULTS: Values of S(cevox)O(2) and S(cv)O(2) (84 data pairs during surgery and 106 in the intensive care unit) ranged between 45-89% and 43-90%, respectively. Mean bias and limits of agreement of S(cevox)O(2) and S(cv)O(2) were -0.9 ( 7.9/+6.1)% during surgery and -1.2 (-10.5/+8.1)% in the intensive care unit. In 37.9% of all measured data pairs, the difference between S(cevox)O(2) and S(cv)O(2) was beyond clinically acceptable limits (> or =1 s.d.). Mean bias was significantly influenced by cardiac index. Sensitivity and specificity of S(cevox)O(2) to detect substantial (> or =1 s.d.) changes in S(cv)O(2) were 89 and 82%, respectively. CONCLUSIONS: In adult patients during and after cardiac surgery, the current version of the CeVOX device might not be the tool to replace S(cv)O(2) determined by co-oxymetry, although sensitivity and specificity of S(cevox)O(2 )to predict substantial changes in S(cv)O(2) were acceptable. PMID- 18443744 TI - Biophysical and biochemical characterization of a hyperthermostable and Ca2+ independent alpha-Amylase of an extreme thermophile Geobacillus thermoleovorans. AB - alpha-Amylases reported from various microbial sources have been shown to be moderately thermostable and Ca2+ dependent. The bacterial strain used in this investigation is an extremely thermophilic bacterium Geobacillus thermoleovorans that produces a novel alpha-amylase (26 kDa; alpha-amylase gt), which is hyperthermostable (Topt 100 degrees C) and does not require Ca2+ for its activity/stability. These special features of alpha-amylase gt make it applicable in starch saccharification process. The structural aspects of alpha-amylase gt are, therefore, of significant interest to understand its structure-function relationship. The circular dichroism spectroscopic data revealed the native alpha amylase gt to contain 25% alpha-helix, 21% beta-sheet, and 54% random coils. The addition of urea, at high concentration (8 M), appeared to expose the buried Trp residues of the native alpha-amylase gt to the aqueous environment and thus showed low fluorophore. Fluorescence-quenching experiments using KI, CsCl, N bromosuccinimide, and acrylamide revealed interesting features of the tryptophan microenvironment. Analysis of Ksv and fa values of KI, CsCl, and acrylamide suggested the overall Trp microenvironment in alpha-amylase to be slightly electropositive. Fluorescence-quenching studies with acrylamide revealed the occurrence of both collisional as well as static quenching processes. There was no change in the alpha-helix content or the enzyme activity with an increase in temperature (60-100 degrees C) that suggested a critical role of the alpha-helix content in maintaining the catalytic activity. PMID- 18443745 TI - The role of ultrasonography in the diagnosis and management of non-traumatic acute abdominal pain. AB - Our aim was to assess the effects of initial ultrasonography (US) evaluation on the diagnosis and management of non-traumatic acute abdominal pain in the emergency department. Three hundred patients with the complaint of non-traumatic acute abdominal pain who were sent for US examination with an initial clinical impression were included in the study. Pre-US and post-US surveys were designed for the clinicians who requested US. The percentage concordance of US findings with the discharge diagnosis made by clinical follow-up, imaging modalities and surgery was determined by calculating the confidence interval. The concordance of the initial clinical impression and the US diagnosis with the discharge diagnosis were compared using the McNemar test. US could not detect any pathology in 102 (34%; 95%CI, 28.6-39.3%) of the patients. The US revealed a different diagnosis than the clinical impression in 69 (23%; 95%CI, 18.2-27.7%), and confirmed the diagnosis in 121 (40%; 95%CI, 34.4-45.5%) patients. The US changed the treatment plans in 47% (95%CI, 41.3-52.6%) of the patients. The clinicians stated US helped them "very much" or "moderately" in making a diagnosis in 83% (95%CI, 78.7 87.2%). When US results were compared with the discharge diagnosis, there was concordance in 238 (79.3%; 95%CI, 74.3-83.6%) patients but not in 62 (20.6%; 95%CI, 16-25.1%). Among 121 patients the initial clinical impression agreed with the US diagnosis and there was concordance with the discharge diagnosis in 105 (86.7%; 95%CI, 80-92.7%). The concordance of US findings with the discharge diagnosis was significantly higher than that of the initial clinical impression statistically. In the initial evaluation of the patients with acute abdominal pain, US is considerably helpful in making the correct diagnosis, and that the concordance with the discharge diagnosis is high. When whole abdominal scanning is not performed, targeted US study according to the initial clinical impression decreases the clinical benefit of US. PMID- 18443746 TI - Recent improvements in the development of A(2B) adenosine receptor agonists. AB - Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A(1), A(2A), A(2B) and A(3) (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A(2B) AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A(2B) AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A(2B) AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N (6)-, C(2)-positions of the purine heterocycle and/or at the 5'-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[N'-(furan-2-carbonyl)-hydrazino] 9H-purin-9-yl}-N-ethyl-beta-D-ribofuranuronamide (19, hA(1) K (i) = 1050 nM, hA(2A) K (i) = 1550 nM, hA(2B) EC(50) = 82 nM, hA(3) K (i) > 5 muM) and its 2 chloro analogue 23 (hA(1) K (i) = 3500 nM, hA(2A) K (i) = 4950 nM, hA(2B) EC(50) = 210 nM, hA(3) K (i) > 5 muM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA(2B) AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5 dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60 6583, hA(1), hA(2A), hA(3) EC(50) > 10 muM; hA(2B) EC(50) = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis. PMID- 18443748 TI - [Rare complication after Le Fort I osteotomy]. AB - Malfunctions of the eustachian tube after Le Fort I osteotomies are rare. A 22 year-old woman was treated by Le Fort I osteotomy for maxillary retrognathism. Postoperatively she developed recurrent tubal malfunction and middle ear effusions on the left side, with no improvement after adenotomy, tonsillectomy, and grommet insertion. In consecutive computed tomography and magnetic resonance imaging scans, a forward dislocation of the left pterygoid hamulus was demonstrated. In addition, damage to the tensor veli palatini muscle was evident. Both postoperative sequelae appear to be responsible for the unilateral tubal dysfunction. PMID- 18443749 TI - A brief history of renin. PMID- 18443747 TI - Purinergic receptors in the splanchnic circulation. AB - There is considerable evidence that purines are vasoactive molecules involved in the regulation of blood flow. Adenosine is a well known vasodilator that also acts as a modulator of the response to other vasoactive substances. Adenosine exerts its effects by interacting with adenosine receptors. These are metabotropic G-protein coupled receptors and include four subtypes, A(1), A(2A), A(2B) and A(3). Adenosine triphosphate (ATP) is a co-transmitter in vascular neuroeffector junctions and is known to activate two distinct types of P2 receptors, P2X (ionotropic) and P2Y (metabotropic). ATP can exert either vasoconstrictive or vasorelaxant effects, depending on the P2 receptor subtype involved. Splanchnic vascular beds are of particular interest, as they receive a large fraction of the cardiac output. This review focus on purinergic receptors role in the splanchnic vasomotor control. Here, we give an overview on the distribution and diversity of effects of purinergic receptors in splanchnic vessels. Pre- and post-junctional receptormediated responses are summarized. Attention is also given to the interactions between purinergic receptors and other receptors in the splanchnic circulation. PMID- 18443750 TI - Genetics of the human renin angiotensin system. AB - The genes coding for the renin angiotensin system have been extensively studied. During the last 15 years, informative markers and functional polymorphisms have been identified, and numerous linkage and association studies have been performed in cardiovascular diseases, especially human hypertension. This mini-review aims to summarize the main findings observed for each component of this enzymatic cascade taken alone or in combination, with an emphasis on the most recent or innovative studies. PMID- 18443751 TI - Aliskiren--mode of action and preclinical data. AB - Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin-angiotensin system (RAS) with its major end product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data. PMID- 18443752 TI - New insights into the role of angiotensin-converting enzyme obtained from the analysis of genetically modified mice. AB - Angiotensin-converting enzyme (ACE) has been well-recognized for its role in blood pressure regulation. ACE is made by many tissues, though it is most abundantly expressed on the luminal surface of vascular endothelium. ACE knockout mice show a profound phenotype with low blood pressure, but also with hemopoietic and developmental defects, which complicates understanding the biological functions of ACE in individual tissue types. Using a promoter-swapping strategy, several mouse lines with unique ACE tissue expression patterns were studied. These include mice with ACE expression in the liver (ACE 3/3), the heart (ACE 8/8), and macrophages (ACE 10/10). We also investigated mice with a selective inactivation of either the N- or C-terminal ACE catalytic domain. Our studies indicate that ACE plays a role in many other physiologic processes beyond simple blood pressure control. PMID- 18443753 TI - Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension. AB - Angiotensin II (AngII) is a major culprit in essential hypertension. Based on a genetic rodent model of hypertension, we review here evidence that AngII may signal across the blood brain barrier to affect neuronal circuits within the nucleus tractus solitarii (NTS) of the brainstem, a pivotal region regulating both the baroreceptor reflex and set point control of arterial pressure. We have termed this form of signalling as vascular-neuronal signalling. We describe that the depressant action of AngII in NTS on the baroreceptor reflex is mediated via activation of endothelial nitric oxide synthase (eNOS) releasing NO that promotes release of the inhibitory transmitter-GABA. This could shunt the incoming excitatory baroreceptor afferent traffic impinging on NTS neurones. Chronic studies recording arterial pressure in conscious unrestrained rats using radio telemetry have revealed that eNOS in NTS plays an endogenous physiological role in the homeostatic regulation of the gain of the cardiac baroreceptor reflex. However, in the spontaneously hypertensive rat, eNOS mRNA was higher (compared to normotensive rats), and its chronic blockade in NTS restored the abnormally depressed cardiac baroreceptor reflex to levels akin to normotensive rats, improved heart rate variability and lowered arterial pressure. Hence, it seems that excessive eNOS activity in NTS of the SHR contributes to the pathological state of this animal model's cardiovascular autonomic nervous system. We speculate on why eNOS activity may be up regulated in the NTS of the SHR and propose that it is a consequence of high cerebral vascular resistance and inadequate blood perfusion of the brainstem. PMID- 18443754 TI - [Changes in geriatric traumatology. An analysis of 14,869 patients from the German Trauma Registry]. AB - The increasing average age in the industrialized nations is leading to an increasing number of elderly traumatized patients. Against this background, an analysis of the age-specific characteristics of geriatric traumatized patients is necessary. In this study, 14,869 patients > or = 18 years were analysed, who were prospectively documented in the registry of the German Trauma Society (DGU) between 1996 and 2005. Patients between 18 and 59 years were defined as the control group; their proportion declined from 81.1% in 1996-2000 to 75.4% in 2001 2005. The average age rose from 41.0 years (1996) to 45.3 years (2005). With increasing age a significant increase in severe head injuries of up to 58.9% (> or = 80 years) could be observed. Older patients stayed for a significantly shorter time in hospital and on the ICU. With a comparable injury severity, the lethality after trauma increased with age (18-59 years 13.8%, 60-69 years 24.1%, 70-79 years 35.5%, > or = 80 years 43.6%). The multiply traumatized geriatric patient is different from the normal group in regard to type of injury, therapy and outcome and should therefore be treated taking this fact into consideration. PMID- 18443755 TI - [Open arthrolysis of posttraumatic elbow stiffness]. AB - BACKGROUND: The incidence of relevant posttraumatic functional deficits in the sense of elbow stiffness with less than 30 degrees in extension or flexion less than 120 degrees , is unknown. A differentiation can be made between intraarticular, extraarticular and combined causes. An open procedure is indicated in elbow stiffness after correct analysis of the situation and failure of conservative treatment. MATERIALS AND METHODS: An open procedure was carried out on 35 patients between March 1995 and November 2001, 10 (3-24) months after the trauma. The mean age of the 24 men and 11 women was 45 (range 17-75) years. Of the patients 15 had distal humerus fractures, 10 radius head or neck fractures and 12 proximal ulnar fractures. RESULTS: Of the patients 11 (31%) had an excellent result in the Cauchoix and Deburge score, 15 (42%) a good, 4 (11%) a fair, 4 (11%) a bad and 1 (3%) a very bad result after a mean follow-up of 21.5 (range 9-60) months. Of the patients 11 (31%) had an excellent result in the Mayo elbow performance score, 14 (40%) a good, 5 (14%) a fair and 5 (14%) a poor result. CONCLUSION: Open arthrolysis for severe posttraumatic elbow stiffness carried out 10 months (range 3-24 months) after the accident led to good results in most cases with a clear improvement in functional mobility. PMID- 18443758 TI - [Clarity and legal authority in decisions to limit therapy]. AB - The decision to limit a patient's therapy can lead to conflicts in the therapeutic team if their views have not been carefully weighed. Further problems also result if they are not clearly and logically documented. The legal authority of patient will, medical indication, and interaction of the care-giving team for arriving at a common decision are examined here. Using a case history as an example, we discuss ethical and legal questions of documentation and obligations on those faced with concrete decisions whether to continue medical procedures. To widen the basis for such decisions, discussion must include the viewpoints of all participants. The final decision must then be clearly documented without any unclarity or ambivalence. Those finally required to carry out that prospective decision, however, must decide whether it actually applies to the situation at hand. PMID- 18443756 TI - [Anterolateral thigh flaps for reconstruction of traumatological and oncological defects]. AB - BACKGROUND: The anterolateral thigh flap (ALT) has become one of the most preferred options for soft tissue defect reconstruction in Asia with an increasing popularity in Europe. The article presents the authors' experience using the ALT flap for various indications in the upper and lower extremities. METHODS: Between January 2005 and March 2007, 60 free ALT flaps were operated for reconstruction of various soft tissue defects. The causes of soft tissue defects included trauma (13), infection (26), and sarcoma resection (21). We operated on 39 male and 19 female patients with an average age of 50.9 years (range: 16-84 years). RESULTS: The flap survival rate was 95.0% percent (57 of 60 flaps); 5% of the flaps died. The donor site was closed primarily in all cases. Donor site complications were minimal. The average operative time was 282 min (69-544 min). Flap-related major complications occurred in 35.0% of patients including reexploration of the anastomoses and partial flap necrosis. Minor complications, e.g., wound infection, hematoma, and swelling were seen in 23 cases. CONCLUSIONS: Our experience indicates that the free ALT flap is a reliable method for soft tissue defect reconstruction. The use of the ALT offers many advantages such as a long and large caliber vascular pedicle, a large skin island as well as minimal donor site morbidity. The surgery can simultaneously performed by two teams with the patient in a supine position. PMID- 18443757 TI - No evidence for visual context-dependency of olfactory learning in Drosophila. AB - How is behaviour organised across sensory modalities? Specifically, we ask concerning the fruit fly Drosophila melanogaster how visual context affects olfactory learning and recall and whether information about visual context is getting integrated into olfactory memory. We find that changing visual context between training and test does not deteriorate olfactory memory scores, suggesting that these olfactory memories can drive behaviour despite a mismatch of visual context between training and test. Rather, both the establishment and the recall of olfactory memory are generally facilitated by light. In a follow-up experiment, we find no evidence for learning about combinations of odours and visual context as predictors for reinforcement even after explicit training in a so-called biconditional discrimination task. Thus, a 'true' interaction between visual and olfactory modalities is not evident; instead, light seems to influence olfactory learning and recall unspecifically, for example by altering motor activity, alertness or olfactory acuity. PMID- 18443759 TI - In vitro expansion of human beta cells. PMID- 18443760 TI - Blood glucose level and mortality. PMID- 18443763 TI - Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis. AB - Oxidative stress can be defined as the imbalance between cellular oxidant species production and antioxidant capability. Reactive oxygen species (ROS) are involved in a variety of different cellular processes ranging from apoptosis and necrosis to cell proliferation and carcinogenesis. In fact, molecular events, such as induction of cell proliferation, decreased apoptosis, and oxidative DNA damage have been proposed to be critically involved in carcinogenesis. Carcinogenicity and aging are characterized by a set of complex endpoints, which appear as a series of molecular reactions. ROS can modify many intracellular signaling pathways including protein phosphatases, protein kinases, and transcription factors, suggesting that the majority of the effects of ROS are through their actions on signaling pathways rather than via non-specific damage of macromolecules; however, exact mechanisms by which redox status induces cells to proliferate or to die, and how oxidative stress can lead to processes evoking tumor formation are still under investigation. PMID- 18443762 TI - Stepwise screening for diabetes identifies people with high but modifiable coronary heart disease risk. The ADDITION study. AB - AIMS/HYPOTHESIS: The Anglo-Danish-Dutch study of intensive treatment in people with screen-detected diabetes in primary care (ADDITION) is a pragmatic randomised controlled trial of the effectiveness of intensified multi-factorial treatment on 5 year cardiovascular morbidity and mortality rates in people with screen-detected type 2 diabetes in the Netherlands, UK and Denmark. This paper describes the baseline characteristics of the study population, their estimated risk of coronary heart disease and the extent to which that risk is potentially modifiable. METHODS: Stepwise screening strategies were performed using risk questionnaires and routine general practice data plus random blood glucose, HbA(1c) and fasting blood glucose measurement. Diabetes was diagnosed using the 1999 World Health Organization criteria and estimated 10 year coronary heart disease risk was calculated using the UK Prospective Diabetes Study risk engine. RESULTS: Between April 2001 and December 2006, 3,057 people with screen-detected diabetes were recruited to the study (mean age 59.7 years, 58% men) after a stepwise screening programme involving 76,308 people screened in 334 general practices in three countries. Their median estimated 10 year risk of coronary heart disease was 11% in women (interquartile range 7-16%) and 21% (15-30%) in men. There were differences in the distribution of risk factors by country, linked to differences in approaches to screening and the extent to which risk factors had already been detected and treated. The mean HbA(1c) at recruitment was 7.0% (SD 1.6%). Of the people recruited, 73% had a blood pressure > or =140/90 and of these 58% were not on antihypertensive medication. Cholesterol levels were above 5.0 mmol/l in 70% of participants, 91% of whom were not being treated with lipid-lowering drugs. CONCLUSIONS/INTERPRETATION: People with type 2 diabetes detected by screening and included in the ADDITION study have a raised and potentially modifiable risk of CHD. ClinicalTrials.gov ID no.: NCT 00237549. PMID- 18443765 TI - Grasping future events: explicit knowledge of the availability of visual feedback fails to reliably influence prehension. AB - We examined whether or not conscious knowledge about the availability of visual feedback on an upcoming trial would influence the programming of a precision grip. Twenty healthy volunteers were asked to reach out and grasp objects under two viewing conditions: full visual feedback (closed loop) or no visual feedback (open loop). The two viewing conditions were presented in blocked, randomized, and alternating trial orders. Before each block of trials, participants were explicitly informed of the nature of the upcoming order of viewing conditions. Even though participants continued to scale their grip to the size of the goal objects which varied in size and distance, they opened their hand significantly wider when visual feedback was not available during movement execution. This difference was evident before peak grip aperture was reached, continued into the grip aperture closing phase, and presumably reflects the visuomotor system's ability to build in a margin of error to compensate for the absence of visual feedback. The difference in grip aperture between closed- and open-loop trials increased as a function of distance, which suggests that the visuomotor system can make use of visual feedback given enough time, even when that feedback is not anticipated. The difference in grip aperture between closed- and open-loop trials was larger when the two visual feedback conditions were blocked than when they were either randomized or alternated. Importantly, performance did not differ between the randomized and the alternating trial blocks. In other words, despite knowledge of the availability of visual feedback on an upcoming trial in the predictable alternating block, participants behaved no differently than they did on randomized trials. Taken together, these results suggest that motor planning tends to optimize performance largely on the basis of what has happened regularly in the past and cannot take full advantage of conscious knowledge of what will happen on a future occasion. PMID- 18443764 TI - The detection of the non-M2 muscarinic receptor subtype in the rat heart atria and ventricles. AB - Mammal heart tissue has long been assumed to be the exclusive domain of the M(2) subtype of muscarinic receptor, but data supporting the presence of other subtypes also exist. We have tested the hypothesis that muscarinic receptors other than the M(2) subtype are present in the heart as minor populations. We used several approaches: a set of competition binding experiments with pirenzepine, AFDX-116, 4-DAMP, PD 102807, p-F-HHSiD, AQ-RA 741, DAU 5884, methoctramine and tripinamide, blockage of M(1) muscarinic receptors using MT7 toxin, subtype-specific immunoprecipitation experiments and determination of phospholipase C activity. We also attempted to block M(1)-M(4) receptors using co treatment with MT7 and AQ-RA 741. Our results show that only the M(2) subtype is present in the atria. In the ventricles, however, we were able to determine that 20% (on average) of the muscarinic receptors were subtypes other than M(2), with the majority of these belonging to the M(1) subtype. We were also able to detect a marginal fraction (6 +/- 2%) of receptors that, based on other findings, belong mainly to the M(5) muscarinic receptors. Co-treatment with MT7 and AQ-RA 741 was not a suitable tool for blocking of M(1)-M(4) receptors and can not therefore be used as a method for M(5) muscarinic receptor detection in substitution to crude venom. These results provide further evidence of the expression of the M(1) muscarinic receptor subtype in the rat heart and also show that the heart contains at least one other, albeit minor, muscarinic receptor population, which most likely belongs to the M(5) muscarinic receptors but not to that of the M(3) receptors. PMID- 18443766 TI - Trans-radial upper extremity amputees are capable of adapting to a novel dynamic environment. AB - This study investigated differences in adaptation to a novel dynamic environment between eight trans-radial upper extremity (UE) prosthetic users and eight naive, neurologically intact subjects. Participants held onto the handle of a robotic manipulandum and executed reaching movements within a horizontal plane following a pseudo-random sequence of targets. Curl field perturbations were imposed by the robot motors, and we compared the rate and quality of adaptation between the prosthetic and control subjects. Adaptation was quantitatively assessed by peak error, defined as the maximum orthogonal distance between an observed trajectory and an ideal straight trajectory. Initial exposure to the curl field resulted in large errors, and as the subjects adapted to the novel environment, the errors decreased. During the early phase of adaptation, group differences in the rate of motor adaptation were not significant. However, during late learning, both error magnitude and variability were larger in the prosthetic group. The quality of adaptation, as indicated by the magnitude of the aftereffects, was similar between groups. We conclude that in persons with trans-radial arm amputation, motor adaptation to curl fields during reaching is similar to unimpaired individuals. These findings are discussed in relation to mechanisms of motor adaptation, neural plasticity following an upper extremity amputation (UEA), and potential motor recovery therapies for prosthetic users. PMID- 18443767 TI - Lifting a familiar object: visual size analysis, not memory for object weight, scales lift force. AB - The brain can accurately predict the forces needed to efficiently manipulate familiar objects in relation to mechanical properties such as weight. These predictions involve memory or some type of central representation, but visual analysis of size also yields accurate predictions of the needed fingertip forces. This raises the issue of which process (weight memory or visual size analysis) is used during everyday life when handling familiar objects. Our aim was to determine if subjects use a sensorimotor memory of weight, or a visual size analysis, to predictively set their vertical lift force when lifting a recently handled object. Two groups of subjects lifted an opaque brown bottle filled with water (470 g) during the first experimental session, and then rested for 15 min in a different room. Both groups were told that they would lift the same bottle in their next session. However, the experimental group returned to lift a slightly smaller bottle filled with water (360 g) that otherwise was identical in appearance to the first bottle. The control group returned to lift the same bottle from the first session, which was only partially filled with water so that it also weighed 360 g. At the end of the second session subjects were asked if they observed any changes between sessions, but no subject indicated awareness of a specific change. An acceleration ratio was computed by dividing the peak vertical acceleration during the first lift of the second session by the average peak acceleration of the last five lifts during the first session. This ratio was >1 for the control subjects 1.30 (SEM 0.08), indicating that they scaled their lift force for the first lift of the second session based on a memory of the (heavier) bottle from the first session. In contrast, the acceleration ratio was 0.94 (0.10) for the experimental group (P < 0.011). We conclude that the experimental group processed visual cues concerning the size of the bottle. These findings raise the possibility that even with familiar objects we predict fingertip forces using an on-line visual analysis of size (along with memory of density), rather than accessing memory related to object weight. PMID- 18443768 TI - Neuronal firing rate, inter-neuron correlation and synchrony in area MT are correlated with directional choices during stimulus and reward expectation. AB - Sensation, memories, and predictions contribute to choices in everyday life, and their relative impact should change with task constraints. To investigate how the impact from sensory cortex on decision making varies with task constraints we trained macaque monkeys in a direction discrimination task where they could maximize reward by waiting for sensory visual information early in a trial, while focusing on memory and reward prediction as a trial progressed. The task constraints caused animals to indicate decisions in complete absence of visual motion stimuli (stimulus independent decisions), as 25% of the trials were 'no stimulus' trials. On 'no stimulus' trials reward delivery depended on the current decision in relation to the decision history. Stimulus independent decisions occurred during an epoch when a stimulus could in principle have been presented, or afterwards when stimuli could not occur anymore. Stimulus independent decisions were significantly different during these two periods. Reward exploitation was more efficient late in the trial, but it was not associated with systematic activity changes in directionally selective neurons in area MT. Conversely, systematic changes of neuronal activity and firing rate correlation in directionally selective middle temporal area (MT) neurons were restricted to a short time period before early decisions. Changing task constraints in the course of a single trial thus determines how neurons in sensory areas contribute to decision making. PMID- 18443769 TI - Goal-related planning constraints in bimanual grasping and placing of objects. AB - Our primary objective was to examine the possible interplay of the end-state comfort effect and bimanual temporal and spatial coupling constraints in a grasp to-place task. Unimanual and bimanual grasping and placing tasks were employed with manipulations on initial comfort (by use of potentially interfering obstacles) and target goals (using various demands on end goal object orientations). Confirming previous temporal findings, incongruent bimanual tasks were considerably slower in initiation time and movement time than congruent ones, reflecting costs in conceptualizing, planning, and completion of the task. With respect to spatial constraints, when the same goal was present for both hands there was strong evidence of the influence of both end-state comfort and bimanual constraints. This was often not the case when the task demands differed for the two hands, although the primary task goals were still attained. We suggest that the implementation of constraints is not based on a strict hierarchy; rather, certain constraints become dominant depending on the task and situation. PMID- 18443770 TI - Visuomotor memory is independent of conscious awareness of target features. AB - A recent study by our group showed that the scaling of reach trajectories to target size is independent of conscious visual awareness of that intrinsic target property (Binsted et al. in Proc Natl Acad Sci USA 104:12669-12672, 2007). The present investigation sought to extend previous work and determine whether unconscious target information represents a temporally durable or evanescent visuomotor characteristic. To accomplish that objective, we employed Di Lollo et al's (J Exp Psychol Gen 129:481-507, 2000) object substitution masking paradigm and asked participants to complete verbal reports and reaching responses to different sized (1.5, 2.5, 3.5, 4.5, 5.5 cm) targets under masked and non-masked target conditions. To determine whether visuomotor networks retain unconscious target information, reaching trials were cued concurrent with target presentation or 1,000 or 2,000 ms after target presentation. For the perceptual trials, participants readily identified the size of non-masked trials but demonstrated only chance success identifying target size during masked trials. Interestingly, however, reaches directed to non-masked and masked targets exhibited comparable and robust scaling with target size; that is, lawful speed-accuracy relations related to movement planning and execution times were observed regardless of whether participants were aware (i.e., non-masked trials) or unaware (i.e., masked trials) of target size. What is more, the length of the visual delay period used here did not differentially influence the scaling of reach trajectories. These results indicate that a conscious visual percept is not necessary to support motor output and that unconscious visual information persists in visuomotor networks to support the kinematic parameterization of action. PMID- 18443771 TI - Evaluation of the vestibular evoked myogenic potential during parabolic flight in humans. AB - The purpose of this study was to investigate how gravity affects the vestibular evoked myogenic potential (VEMP). Eight healthy subjects (seven men, one woman; age range 19-45 years) participated in experiments in which three different gravity levels [microgravity (MG), normal gravity (NG), and hypergravity (HG)] were imposed during a parabolic flight procedure. The VEMP was evoked in response to an intense mono-aural click while the subjects kept the sternocleidomastoid (SCM) muscle contracted bilaterally. Background electromyographic activity of the SCM during the test was corrected. The p13-n23 amplitude was significantly greater under MG than under NG or HG. There was no difference in p13 latency between the three gravity levels. Possible mechanisms related to this phenomenon are discussed. PMID- 18443772 TI - Trunk antagonist co-activation is associated with impaired neuromuscular performance. AB - The goal of this paper was to determine if trunk antagonist activation is associated with impaired neuromuscular performance. To test this theory, we used two methods to impair neuromuscular control: strenuous exertions and fatigue. Force variability (standard deviation of force signal) was assessed for graded isometric trunk exertions (10, 20, 40, 60, 80% of max) in flexion and extension, and at the start and end of a trunk extensor fatiguing trial. Normalized EMG signals for five trunk muscle pairs (RA rectus abdominis, EO external oblique, IO internal oblique, TE thoracic erector spinae, and LE lumbar erector spinae) were collected for each graded exertion, and at the start and end of a trunk extensor fatiguing trial. Force variability increased for more strenuous exertions in both flexion (P < 0.001) and extension (P < 0.001), and after extensor fatigue (P < 0.012). In the flexion direction, both antagonist muscles (TE and LE) increased activation for more strenuous exertions (P < 0.001). In the extension direction, all antagonist muscles except RA increased activation for more strenuous exertions (P < 0.05) and following fatigue (P < 0.01). These data demonstrate a strong relationship between force variability and antagonistic muscle activation, irrespective of where this variability comes from. Such antagonistic co activation increases trunk stiffness with the possible objective of limiting kinematic disturbances due to greater force variability. PMID- 18443773 TI - Differential control of abdominal muscles during multi-directional support surface translations in man. AB - The current study aimed to understand how deep and superficial abdominal muscles are coordinated with respect to activation onset times and amplitudes in response to unpredictable support-surface translations delivered in multiple directions. Electromyographic (EMG) data were recorded intra-muscularly using fine-wire electrodes inserted into the right rectus abdominis (RA), obliquus externus (OE), obliquus internus (OI) and transversus abdominis (TrA) muscles. Twelve young healthy male subjects were instructed to maintain their standing balance during 40 support surface translations (peak acceleration 1.3 m s(-2); total displacement 0.6 m) that were counter-balanced between four different directions (forward, backward, leftward, rightward). Differences between abdominal muscles in EMG onset times were found for specific translation directions. The more superficial RA (backward translations) and OE (forward and leftward translations) muscles had significantly earlier EMG onsets compared to TrA. EMG onset latencies were dependent on translation direction in RA, OE and OI, but independent of direction in TrA. EMG amplitudes in RA and OE were dependent on translation direction within the first 100 ms of activity, whereas responses from the two deeper muscles (TrA and OI) were independent of translation direction during this interval. The current results provide new insights into how abdominal muscles contribute to postural reactions during human stance. Response patterns of deep and superficial abdominal muscles during support surface translations are unlike those previously described during upper-body perturbations or voluntary arm movements, indicating that the neural mechanisms controlling individual abdominal muscles are task-specific to different postural demands. PMID- 18443774 TI - Discriminating smooth from grooved surfaces: effects of random variations in skin penetration. AB - The ability to discriminate a smooth surface from a grooved one depends on several variables, including the width of the grooves and the force with which the skin is contacted. It has been hypothesized that this smooth-grooved discrimination with statically presented stimuli is based on intensity cues, namely, the overall difference in perceived intensity between the smooth and grooved surfaces. To test this hypothesis, the perceived intensities of test stimuli were varied on a trial-by-trial basis by varying the depth of penetration the contactor was allowed to travel into the skin. As compared to a control condition in which stimuli were presented with the same average penetration and contrary to the hypothesis, random variations in penetration produced no decline in smooth-grooved performance. The total amount of conformance was an accurate predictor of sensitivity across various penetrations and across two test sites (distal finger pad and finger base). It appears that subjects are making absolute rather than comparative judgments in the smooth-grooved task. A recently developed continuum mechanical model of the responses of first-order mechanoreceptive afferents to static stimuli provided both a good fit to the data and indicated what aspect of the peripheral neural image was relevant for discriminating smooth surfaces from grooved surfaces. PMID- 18443775 TI - Human subthalamic nucleus: evaluation with high-resolution MR imaging at 3.0 T. AB - INTRODUCTION: The purpose of this study was to compare the visibility of the normal subthalamic nucleus (STN) between fast spin-echo T2-weighted (FSE T2-W) images and fast short inversion time inversion-recovery (FSTIR) images, and to assess the age-related changes of the STN at 3.0 T. METHODS: We evaluated high resolution FSE T2-W and FSTIR images in 24 neurologically normal subjects. Using both sequences, we assessed the visibility of the margins of the STN, and calculated the difference in signal intensity between the STN and structures adjacent to the STN. Then, to assess the age-related changes of the STN, we calculated the contrast-to-noise ratio between the STN and the white matter, and measured the position, length, and height of the STN. All data were statistically evaluated. RESULTS: The visibility of the lower margin of the STN was significantly better on the FSTIR images than on the FSE T2-W images (P = 0.0001), while the visibility of other margins was significantly better on the FSE T2-W images than on the FSTIR mages (P = 0.002). The difference in signal intensity between the STN and substantia nigra was significantly greater on the FSTIR images than on the FSE T2-W images (P < 0.0001). The distance from the midline to the lateral border of the STN increased with age (FSE T2-W images: left r = 0.4916, P = 0.015; right r = 0.4442, P = 0.030). CONCLUSION: The combined reading of both FSE T2-W and FSTIR images at 3 T will improve the identification of the STN. The age-related positional change of the STN should be considered in target determination for deep brain stimulation procedures. PMID- 18443776 TI - Endovascular treatment in proximal and intracranial carotid occlusion 9 hours after symptom onset. AB - INTRODUCTION: A debate is emerging over whether the treatment time window in acute stroke can be extended beyond 6 h if penumbral tissue can be identified. Treatment decisions are very difficult in cases of tandem proximal carotid occlusion with arterioarterial intracranial embolism. We enter this debate with the present report on a case of atherosclerotic proximal carotid occlusion and resulting periocclusional carotid T embolism that was successfully treated 9 h after symptom onset. METHODS: The case of a 68-year-old man with fluctuating symptoms of right-hemispheric stroke is presented (NIHSS score 12-20 on admission). CT angiography demonstrated proximal carotid occlusion and periocclusional embolism of the entire internal carotid artery (ICA) including the carotid T segment. Penumbral tissue was diagnosed by nonenhanced and perfusion CT imaging 7.5 h after symptom onset. Treatment was initiated 9 h after symptom onset by passing the proximal occlusion with a microcatheter and local administration of recombinant tissue plasminogen activator (rt-PA) into the carotid T segment at the level of posterior communicating artery (PCoA) origin. RESULTS: Recanalization of the ICA and middle cerebral artery was accomplished within 1 h by flow establishment via the PCoA. The atherosclerotic proximal ICA occlusion was not stented due to the risk of embolism from remnant thrombi in the petrous and cavernous ICA segments. Follow-up MRI showed only mild haemorrhagic infarct transformation of the initial infarct core. The patient was discharged from hospital 18 days after treatment with NIHSS score 5. CONCLUSION: If penumbral tissue can be conclusively identified, endovascular treatment in proximal and intracranial tandem occlusion can be successful, even in treatments initiated 6-9 h after stroke onset. If the intracranial flow after recanalization can be established via the circle of Willis, the underlying proximal ICA occlusion may not require treatment. PMID- 18443777 TI - Wilms tumor: a new method for quantification of lung metastatic tumor burden. PMID- 18443778 TI - The influence of morphology on geldanamycin production in submerged fermentations of Streptomyces hygroscopicus var. geldanus. AB - The diverse morphology of the filamentous organism Streptomyces hygroscopicus var. geldanus was characterised by image analysis under various environmental conditions. In the presence of surfactant compounds, a significant decrease in the mean pellet diameter was observed. Cell aggregation was also influenced by spore inoculum level, with high concentrations reducing pellet size. In addition, the dispersion of pellets was found to increase with the inclusion of glass beads to submerged shake-flask cultures. In all cases, production of the secondary metabolite geldanamycin was determined to be dependent on the morphological profile of the organism, with a concomitant increase of 88% in geldanamycin yield observed as the mean pellet diameter was reduced by 70%. Thus, to maximise the yield of geldanamycin, it is necessary to limit pellet formation in Streptomyces hygroscopicus var. geldanus to an appropriate size. PMID- 18443779 TI - Toluene gas phase biofiltration by Paecilomyces lilacinus and isolation and identification of a hydrophobin protein produced thereof. AB - Paecilomyces lilacinus consumed toluene as the sole carbon source in a gas-phase biofilter packed with perlite obtaining an average elimination capacity of 50 g m(-3) h(-1), a removal efficiency of 53%, and a final biomass of 31.6 mg biomass g dry support(-1). Hydrophobin proteins from the mycelium produced in the biofilter were purified by formic acid extraction and precipitated by electrobubbling, and the molecular weight was found to be 10.6 +/- 0.3 kDa. The peptide mass fingerprinting analysis of the purified hydrophobin by matrix assisted laser desorption/ionization time-of-flight resulted in the identification of two peptides that presented high homology with sequences of class I hydrophobin proteins from other ascomycetous fungi when compared against the National Center for Biotechnology Information database. The yield of hydrophobin (PLHYD) from P. lilacinus was 1.1 mg PLHYD g biomass(-1). These proteins modified the hydrophobicity of Teflon by lowering the contact angle from 130.1 (+/-2) degrees to 57.0 (+/-5) degrees supporting hot sodium dodecyl sulfate washing. This work is the first report about biodegradation of toluene by the nematophagous fungus P. lilacinus in a gas-phase biofilter and the identification of its hydrophobin protein. PMID- 18443780 TI - Induction, purification and characterization of alpha-N-acetylgalactosaminidase from Aspergillus Niger. AB - A set of filamentous fungi (42 strains) was screened for alpha-N acetylgalactosaminidase activity, and a series of inducers and different cultivation conditions were tested. Enzyme production by the best producer Aspergillus niger CCIM K2 was optimized and scaled up. alpha-N Acetylgalactosaminidase was purified to apparent homogeneity by cation exchange chromatography, gel filtration, and chromatofocusing, and basic biochemical data of the enzyme were determined: The native molecular weight was estimated by gel filtration to be approximately 440 kDa, the molecular weight of the subunit was determined to be 76 kDa and the pI = 4.8. The K (M) was 0.73 mmol/l for o nitrophenyl 2-acetamido-2-deoxy-alpha-D-galactopyranoside (o-NP-alpha-GalNAc), and optimum enzyme activity was achieved at pH 1.8 and 55 degrees C. This alpha-N acetylgalactosaminidase is a retaining-type glycosidase, and it was N deglycosylated without any loss of activity. PMID- 18443781 TI - Molecular cloning and heterologous expression of a laccase gene from Pleurotus eryngii in free and immobilized Saccharomyces cerevisiae cells. AB - A full length cDNA encoding an extracellular laccase was isolated by reverse transcription polymerase chain reaction from the mycelia of the mushroom Pleurotus eryngii. The isolated sequence, denoted Ery3, encodes for a mature laccase isoenzyme of 531 amino acid residues with a predicted molecular weight of 56.6 kDa. All sequence motifs, being the signature sequences used to identify the laccases, were found in the Ery3 protein sequence. The Ery3 cDNA was expressed in Saccharomyces cerevisiae and the effects of copper concentration and cultivation temperature were investigated. S. cerevisiae cells were immobilized in calcium alginate gel and the optimal immobilization parameters for the enhanced production of laccase were determined. The immobilization was most effective with 3% sodium alginate, 0.1 M calcium chloride and an initial biomass of 4.5 x 10(8) cells. The enzyme yield obtained with immobilized cells (139 mU ml(-1)) showed a 1.6-fold increase compared to the highest yield obtained with free cells. The alginate beads showed good stability and retained 84% capacity of enzyme production after seven repeated cycles of batch fermentation. The immobilization system proved to increase the proteolytic stability of the recombinant Ery3 protein. To our knowledge, this is the first report on S. cerevisiae whole-cell immobilization for recombinant laccase production. PMID- 18443782 TI - Assembly of mutations for improving thermostability of Escherichia coli AppA2 phytase. AB - We previously identified a number of mutations in Escherichia coli AppA2 phytase for enhancing its thermostability. The objective of the present study was to determine if these mutations (K46E, K65E, G103S, D112N, D144N, S209G, V227A, and G344D) could be sequentially added to further improve the thermostability of AppA2. Compared with the wild-type enzyme, two variants (D144N/V227A and D144N/V227A/G344D) out of the eight resulting mutants showed 15% enhancement in thermostability (as measured by residual activity after being heated at 80 degrees C for 10 min) and 4 to 5 degrees C increases in the melting temperatures (T (m)). Based on the structural predictions with a highly homologous AppA phytase, the substitution D144N introduces a side-chain-side-chain hydrogen bond, thereby stabilizing the loop region (Gln137-Asn144), and the V227A substitution might eliminate structural hindrance between Val222 and Val227 that face each other in the beta-hairpin structure. In addition, overall catalytic efficiency (k (cat)/K (m)) of the two mutants was also improved (P < 0.05) compared to the wild type. However, no further improvement in thermostability was observed by adding other mutations to D144N/V227A/G344D, which might result from unfavorable electrostatic interactions or structural perturbation. In conclusion, our results underscore the potential as well as difficulty of predicting synergistic effects of multiple mutations on thermostability within phytase. PMID- 18443783 TI - Improvement of poly(gamma-glutamic acid) biosynthesis and redistribution of metabolic flux with the presence of different additives in Bacillus subtilis CGMCC 0833. AB - Tween-80, dimethyl sulfoxide (DMSO), and glycerol could be used as novel materials to regulate the central carbon metabolic pathway and improve gamma-PGA biosynthesis by Bacillus subtilis CGMCC 0833. With glycerol in the medium, the activity of 2-oxoglutarate dehydrogenase complex at the key node of 2 oxoglutarate was depressed, more carbon flux distribution was directed to synthesize glutamate, the substrate of gamma-PGA, which led to overproducing of gamma-PGA, reached 31.7 g/l, compared to the original value of 26.7 g/l. When Tween-80 or DMSO was in the medium, the activity of isocitrate dehydrogenase was stimulated, the branch flux from 2-oxoglutarate to glutamate was also enhanced due to the increasing of total flux from iso-citrate to 2-oxoglutarate, then a large amount of glutamate was produced, and formation of gamma-PGA was also improved, which was a different process compared with that of glycerol. Moreover, with the addition of Tween-80 or DMSO, cell membrane permeability was increased, which facilitated the uptake of extracellular substrates and the secretion of gamma-PGA by this strain; therefore, gamma-PGA production was further stimulated, and 34.4 and 32.7 g/l gamma-PGA were obtained, respectively. This work firstly employed additives to improve the biosynthesis of gamma-PGA and would be helpful in understanding the biosynthesis mechanism of gamma-PGA by Bacillus species deeply. PMID- 18443784 TI - Adsorption of monorhamnolipid and dirhamnolipid on two Pseudomonas aeruginosa strains and the effect on cell surface hydrophobicity. AB - Previously, adsorption feature of a dirhamnolipid biosurfactant on diverse microbial cells was studied and the effect of the adsorption on cell surface hydrophobicity was compared. In this paper, the adsorption behavior of a monorhamnolipid and a dirhamnolipid on cells of two Pseudomonas aeruginosa strains was investigated in order to further reveal the influence of biosurfactant structure and cell property on the adsorption and the relation between the adsorption and cell surface hydrophobicity. Experimental results showed that the adsorption capacity of all the cells to monorhamnolipid was much stronger than to dirhamnolipid, and the rhamnolipid-sourced P. aeruginosa cells, no matter grown on glucose or hexadecane, released extra dirhamnolipid when aqueous concentration of dirhamnolipid was too high. Length of surfactant alkyl chain as well as the type of carbon source used to cultivate the cell adsorbents had only minor influence on the adsorption. The adsorption was assumed to be driven by polar interaction between the rhamnolipid molecules and the cell surface chemical groups. The directional orientation of the rhamnolipid molecules with hydrophobic moiety extending to the environment may account for the rapid increase of cell surface hydrophobicity at low aqueous concentrations of the surfactant, while the stable or decreased cell hydrophobicity was probably the consequence of multiple surfactant layer formation or hemimicelle accumulation. PMID- 18443785 TI - Lactic fermentation of cellobiose by a yeast strain displaying beta-glucosidase on the cell surface. AB - The Aspergillus aculeatus beta-glucosidase 1 (bgl1) gene was expressed in a lactic-acid-producing Saccharomyces cerevisiae strain to enable lactic fermentation with cellobiose. The recombinant beta-glucosidase enzyme was expressed on the yeast cell surface by fusing the mature protein to the C terminal half region of the alpha-agglutinin. The beta-glucosidase expression plasmids were integrated into the genome. Three strong promoters of S. cerevisiae, the TDH3, PGK1, and PDC1 promoters, were used for beta-glucosidase expression. The specific beta-glucosidase activity varied with the promoter used and the copy number of the bgl1 gene. The highest activity was obtained with strain PB2 that possessed two copies of the bgl1 gene driven by the PDC1 promoter. PB2 could grow on cellobiose and glucose minimal medium at the same rate. Fermentation experiments were conducted in non-selective-rich media containing 95 g l(-1) cellobiose or 100 g l(-1) glucose as a carbon source under microaerobic conditions. The maximum rate of L-lactate production by PB2 on cellobiose (2.8 g l(-1) h(-1)) was similar to that on glucose (3.0 g l(-1) h( 1)). This indicates that efficient fermentation of cellobiose to L-lactate can be accomplished using a yeast strain expressing beta-glucosidase from a mitotically stable genomic integration plasmid. PMID- 18443786 TI - Overexpression of prefoldin from the hyperthermophilic archaeum Pyrococcus horikoshii OT3 endowed Escherichia coli with organic solvent tolerance. AB - Prefoldin is a jellyfish-shaped hexameric chaperone that captures a protein folding intermediate and transfers it to the group II chaperonin for correct folding. In this work, we characterized the organic solvent tolerance of Escherichia coli cells that overexpress prefoldin and group II chaperonin from a hyperthermophilic archeaum, Pyrococcus horikoshii OT3. The colony-forming efficiency of E. coli cells overexpressing prefoldin increased by 1,000-fold and decreased the accumulation of intracellular organic solvent. The effect was impaired by deletions of the region responsible for the chaperone function of prefoldin. Therefore, we concluded that prefoldin endows E. coli cells by preventing accumulation of intracellular organic solvent through its molecular chaperone activity. PMID- 18443787 TI - Musculoskeletal applications of flat-panel volume CT. AB - Flat-panel volume computed tomography (fpVCT) is a recent development in imaging. We discuss some of the musculoskeletal applications of a high-resolution flat panel CT scanner. FpVCT has four main advantages over conventional multidetector computed tomography (MDCT): high-resolution imaging; volumetric coverage; dynamic imaging; omni-scanning. The overall effective dose of fpVCT is comparable to that of MDCT scanning. Although current fpVCT technology has higher spatial resolution, its contrast resolution is slightly lower than that of MDCT (5-10HU vs. 1-3HU respectively). We discuss the efficacy and potential utility of fpVCT in various applications related to musculoskeletal radiology and review some novel applications for pediatric bones, soft tissues, tumor perfusion, and imaging of tissue-engineered bone growth. We further discuss high-resolution CT and omni-scanning (combines fluoroscopic and tomographic imaging). PMID- 18443788 TI - Regional wall thickening in gated myocardial perfusion SPECT in a Japanese population: effect of sex, radiotracer, rotation angles and frame rates. AB - PURPOSE: Gated single-photon emission computed tomography (SPECT) imaging of myocardium by (99m)Tc and (201)Tl is used extensively to measure quantitative cardiac functional parameters. However, factors affecting normal values for myocardial functional parameters and population-specific standards have not yet been established. The aim of the study was to determine the effect of sex, radiotracer, rotation angles and frame rates on resting myocardial wall thickening (WT) and to develop a Japanese standard of normal values for WT. METHODS: Data from a total of 202 patients with low possibility of having cardiac problems were collected from nine hospitals throughout Japan. Patients were divided into five groups according to study protocol, and WT was evaluated according to the 17-segment and four-region (basal, mid and apical regions and the apex) polar map distribution. RESULT: WT was generally higher in women than in men irrespective of the use of radiotracers, rotation angles or frame rates, and the difference was highly significant in the mid and apical regions. In any protocol used, resting myocardial thickening in the apex was higher than in the mid and apical regions, and thickening was lowest in the basal region, suggesting heterogeneous regional myocardial thickening (%) in normal subjects. Different rotation angles showed no significant change on WT, but different frame rates and tracers showed significant WT change in both sexes. Percent thickening of the myocardium was significantly higher in imaging by (99m)Tc-labelled tracers than in (201)Tl. CONCLUSION: Sex, radiotracers and frame rates had a significant effect on myocardial thickening, and the importance of population-specific standards should be emphasized. A normal database can serve as a standard for gated SPECT evaluation of myocardial thickening in a Japanese population and might be applicable to Asian populations having a similar physique. PMID- 18443789 TI - Scintigraphy or fine-needle aspiration biopsy to exclude thyroid malignancy: what should be done first in iodine deficiency? PMID- 18443790 TI - Vitamin D receptor genotypes and response to zoledronic acid therapy in thalassemia-induced osteoporosis. PMID- 18443791 TI - A first case of congenital TTP on the African continent due to a new homozygous mutation in the catalytic domain of ADAMTS13. AB - Hereditary thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by occlusive microvascular thrombosis, consumptive thrombocytopenia, and microangiopathic hemolytic anemia. Homozygous or compound heterozygous mutations in the ADAMTS13 gene result in a congenital severe ADAMTS13 deficiency and subsequent accumulation of ultra-large von Willebrand factor multimers, which tend to form platelet thrombi in the microcirculation. We report a first case of congenital TTP on the African continent with a new, homozygous mutation in the metalloprotease domain of ADAMTS13. An initially oligo symptomatic presentation was followed by acute exacerbation with ischemic stroke and acute renal failure highlighting the severity of this syndrome. PMID- 18443792 TI - Use of 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography in the early diagnosis of asymptomatic bleomycin-induced pneumonitis. PMID- 18443793 TI - A Bayesian population PK-PD model for ispinesib/docetaxel combination-induced myelosuppression. AB - PURPOSE: Ispinesib, a kinesin spindle protein inhibitor, blocks assembly of a functional mitotic spindle, leading to G2/M arrest. Docetaxel promotes tubulin assembly into microtubules while inhibiting microtubule de-polymerization leading to mitotic arrest. Prolonged (> or =5 days) Gr 4 neutropenia and/or febrile neutropenia were the observed dose-limiting toxicities with both agents. Both agents are substrates and inhibitors of CYP3A4; thus, the potential for a drug drug interaction exists. The goal was to fit a Bayesian population PK/PD model to characterize the relationship between the ispinesib/docetaxel combination and absolute neutrophil counts (ANC). METHODS: Escalating doses of docetaxel (60-75 mg/m(2)) were administered over 1 h followed by a 1-h infusion of escalating doses of ispinesib (8-12 mg/m(2)) on a 21-day schedule. At least 3 pts were treated at each dose level. Limited PK samples were obtained. ANC were measured weekly on days 1, 8, 15, and 22. More ANC samples were taken from some subjects. The PK properties of ispinesib and docetaxel, and the relationship of PK with ANC were investigated using nonlinear mixed-effects models and Bayesian methods. With a limited dataset, informative prior distributions for the model parameters were needed. These prior distributions were formed using information from a previous study for ispinesib, and from the literature for docetaxel. RESULTS: Twenty-four pts were treated in this study. The PK of ispinesib and docetaxel were well characterized by a two-compartment model and a three-compartment model, respectively. There is no obvious PK interaction between ispinesib and docetaxel. The model for ANC consisted of a proliferating compartment, three transit compartments that represented maturation, and a compartment of circulating blood cells. This ANC model has been used previously for ispinesib given as monotherapy, and for other chemotherapeutic drugs in the literature. Using Bayesian methods, the model was successfully fit for the PK of both compounds and the PD simultaneously. CONCLUSIONS: The PK/PD model developed for ispinesib/docetaxel, may be used to examine different schedules, doses, and infusion times of both agents. Bayesian methods allow for the use of prior information available for the model parameters. PMID- 18443794 TI - Carotid artery intima-media thickness, heat shock proteins and oxidized LDL autoantibodies in systemic necrotizing vasculitis. AB - In this study we evaluate early atherosclerotic changes and determine whether anti-HSP-60, anti-HSP-65 and anti-oxLDL autoantibodies are elevated in systemic necrotizing vasculitis. Thirty-two patients having systemic necrotizing vasculitis were compared with normal controls and patients with systemic lupus erythematosus (SLE). The antibodies against human HSP-60, HSP-65 and oxLDL were measured by antihuman ELISA kit. All patients underwent non-invasive measurements of carotid artery intima-media thickness (IMT). In a comparison between carotid IMT extent between vasculitis patients and SLE, no significant differences were noted. Levels of anti-HSP-60, anti-HSP-65 IgG and anti-oxLDL autoantibodies were similar among patients compared to controls. IgM anti-HSP-60 antibody levels were significantly lower in patients compared to controls and a similar trend was found regarding IgM anti-HSP-65. As a group, patients having various necrotizing vasculitis have similar extent of early atherosclerotic changes regardless of the vasculitis type, and these levels are similar to those found in SLE. PMID- 18443795 TI - Musculoskeletal affections among kidney recipients: prevalence and risk predictors. AB - The population of kidney recipients (KR) is steadily increasing in Mansoura and more than 1,800 operations were completed. The extent of musculoskeletal affections (MSA) in this population is not fully known. The purpose of this study is to determine MSA in this KR population and find possible risk predictors. Randomly selected KR (n = 117) were subjected to joint examination, joint pain and morbidity measurements and bone mineral density (BMD) estimation. Laboratory measurements included biochemical, haematological and serological variables. The majority of KR (81.2%) were complaining/suffering from MSA. These included bone loss (n = 78), joint pain (n = 63), skeletal muscle affection (n = 21), soft tissue affection (n = 25), and leg bone pain syndrome (n = 7). Serum creatinine and hepatitis PCR serology demonstrated a significant difference (P < 0.05) between KR with MSA and KR without MSA. Negative hepatitis PCR serology was the only significant (P < 0.05) risk predictor for MSA in this population of KR. This study identified MSA in this steadily increasing KR population. That hepatitis infection was a negative risk predictor for MSA in this KR population warrants further studies. PMID- 18443796 TI - A case of adult onset Still's disease showing marked accumulation in the liver and spleen, on positron emission tomography-CT images. AB - A 35-year-old woman was admitted to our hospital because of high fever and skin rash, and subsequently diagnosed as having adult onset Still's disease (AOSD). Because of resistance to the steroid hormones, high levels of the serum-soluble form of the interleukin-2 receptor and splenomegaly, we suspected a possible diagnosis of malignant lymphoma and performed positron emission tomography (PET), which disclosed an intense accumulation of 2-deoxy-2 [F18] fluoro-D-glucose (FDG) in the liver and spleen. However, bone marrow aspiration and liver biopsy did not reveal any malignant cells. After the treatment of high-dose adrenocorticosteroids and plasma exchange, her symptoms and laboratory data, including PET findings, gradually improved. This is a rare case of severe AOSD in which an intense accumulation of FDG was detected by PET, and a differential diagnosis from malignant lymphoma may be difficult by FDG-PET alone, so that careful evaluation by techniques including histopathological examination may be necessary. PMID- 18443797 TI - [Scleral buckling surgery and pneumatic retinopexy]. PMID- 18443798 TI - [The latest on amblyopia treatment]. AB - In recent years there has been a lively discussion on the benefits of early detection and treatment of amblyopia, as well as large prospective randomized controlled studies. Furthermore, we now have the opportunity to measure effective occlusion time. This leads to a better scientific base for discussion of amblyopia therapy. PMID- 18443799 TI - Effects of corticosteroids on oxidative damage and circulating carotenoids in captive adult kestrels (Falco tinnunculus). AB - Birds control body homeostasis through the secretion of corticosterone. This hormone is the end-product of the hypothalamic-pituitary-adrenal (HPA) axis response to stressors. High levels of corticosterone may be associated with low individual fitness and may affect balance between pro-oxidants and antioxidants. Given these points, chronic stress modulated by hormones could undermine individual fitness by increasing oxidative tissue damage. In this study, we administered corticosteroids by diet (20 mg/kg of diet) to captive adult kestrels (Falco tinnunculus) over a 14-day period to evaluate the effects of a simulated chronic stress modulated by corticosteroids. We found that dietary administration of corticosterone caused a 32% increase of reactive oxygen metabolites, but did not impair total serum antioxidant capacity, serum carotenoids or body mass. Oxidative stress had a 64% increase in treated birds compared to 30% in controls. The two groups did not differ in the total serum antioxidant capacity, which showed a significant decrease over the study period. In contrast, circulating carotenoids and body mass increased in both groups. These results suggest that stress hormones, such as corticosterone, may also act as modulators of oxidative stress in birds. PMID- 18443800 TI - Semseddin-i Itaki's contributions to neuroanatomy and embryology in the seventeenth century. PMID- 18443801 TI - Botulinum toxin for the treatment of chronic constipation in children with internal anal sphincter dysfunction. AB - Internal anal sphincter (IAS) dysfunction is a cause of refractory constipation in children. The goal of this study was to determine whether intrasphincteric injection of botulinum toxin is effective in the treatment of constipation in pediatric patients with IAS dysfunction. A retrospective review was performed of 24 pediatric patients with intractable constipation. All patients had abnormal anorectal manometry, with either elevated IAS resting pressure (> or =100 mm Hg) or an absent or diminished rectoanal inhibitory reflex. Patients with Hirschsprung's disease were excluded. All patients underwent botox injection into the IAS and were followed for a minimum of 6 months. Of 24 patients, 22 experienced significant improvement in their constipation lasting greater than 2 weeks. The duration of effect was variable, with 12 patients demonstrating benefit lasting at least 6 months. Transient postoperative incontinence occurred in five patients. Intrasphincteric injection of botox is a safe and effective treatment for intractable constipation in children with IAS dysfunction. PMID- 18443802 TI - Postnatal outcome of antenatally diagnosed intra-abdominal cysts. AB - The aim of this study is to establish the postnatal diagnosis and outcome of all abdominal cystic lesions diagnosed antenatally over a 13-year period. All prenatally suspected and postnatally confirmed intra-abdominal cysts seen and delivered between 1991 and 2004 were identified. Antenatal diagnosis, gestational age at delivery, sex and postnatal diagnosis and outcome were recorded. Fifty five patients were identified with an antenatal diagnosis of abdominal cystic lesion. There were 53 live births and 2 intrauterine deaths. In 13 cases (24%) the cyst had resolved on a postnatal scan. Sixteen (29%) required surgical intervention postnatally. Twenty-six (47%) were given a "non-specific" diagnosis of abdominal cyst antenatally. Three (11%) of these non-specific cysts had resolved on postnatal scan. A "specific" diagnosis of the abdominal cyst was made antenatally in 29 cases (53%) of which 12 (43%) had the diagnosis confirmed postnatally. In ten (35%) of these there was a normal postnatal scan. Antenatal ultrasound scans may not reliably predict the exact pathological diagnosis of abdominal cystic lesions. However this study provides valuable information on the proportion of correctly diagnosed lesions and those that will persist into the postnatal period allowing more informative counselling for prospective parents. PMID- 18443803 TI - Early discharge policy of patients with acute colonic diverticulitis following initial CT scan. AB - INTRODUCTION: Diverticulitis develops in 15-20% of individuals with diverticulosis. Severity ranges from mild to severe. Mild diverticulitis is uncomplicated confined per colonic inflammation commonly treated conservatively. Recent literature suggests it could be managed in an outpatient setup. AIMS: To determine if patients with mild acute colonic diverticulitis (ACD) on early CT scan can be treated and discharged at an early time. METHODOLOGY: Retrospective review of patient's charts admitted during 2005 with ACD confirmed by CT scan performed within 24 h of admission. Severity of ACD was determined according to CT classification. RESULTS: Forty-two (31 women, 11 men) patients included, mean age 66 years, CT severity classification: 61.9% mild, 7.1% moderate, and 31.0% severe diverticulitis. Patients with mild ACD were discharged safely, had no recurrence of their symptoms, and needed no readmission within 6 months of follow up. CONCLUSION: Patients with mild ACD on CT scan performed within 24 h could be safely discharged and treated according to protocols of outpatient management of diverticulitis. PMID- 18443804 TI - Diversion colitis presenting with massive rectal distension and bilateral ureteric obstruction. PMID- 18443805 TI - Glutathione-S-transferase P1, T1 and M1 genetic polymorphisms in neoadjuvant treated locally advanced gastric cancer: GSTM1-present genotype is associated with better prognosis in completely resected patients. AB - OBJECTIVE: Neoadjuvant chemotherapy in gastric cancer is now standard in the Western world; however, only 30-40% of the patients respond to induction therapy. Pretherapeutic predictors of response and prognosis would be of utmost interest to individualize treatment. Glutathione-S-transferase enzymes detoxify therapeutic drugs such as platin derivates and may influence outcome of the treated patients. Therefore, glutathione-S-transferase (GST) polymorphisms were assessed as predictive markers in cisplatinum-based neoadjuvant-treated gastric cancer. MATERIALS AND METHODS: DNA was isolated from 139 patients with locally advanced gastric cancer (cT3/4 anyN cM0) before chemotherapy. Multiplex polymerase chain reaction was used for GSTT1 and GSTM1 genes, and allelic discrimination assay with the TaqMan system for the GSTP1 gene. RESULTS: One hundred ten patients could be analyzed for GSTT1 (T-:23; T+87), 112 for GSTM1 (M :52; M+:60) and 132 for GSTP1 (Ile/Ile: 55; Ile/Val: 59; Val/Val: 18). There was no significant correlation between any of the GSTT1, GSTM1, or GSTP1 genotypes and patients' characteristics or histopathological data; only the GSTM1+ genotype was associated with the non-intestinal subtype of the Lauren classification (p=0.045). GSTT1, GSTM1, and GSTP1 genotypes were not correlated with response to chemotherapy (p=0.57, p=0.38, p=0.33). In R0 resected patients, we found an improved survival for patients with the GSTM1-present genotype compared to patients with the GSTM1-null genotype (p=0.017). Moreover, the GSTM1-present genotype showed a significantly better tumor-related (p=0.017) and disease-free survival (p=0.029). CONCLUSION: None of the common GST polymorphisms predicts response in our study, but the GSTM1+ genotype was associated with a better prognosis in completely resected patients. Further investigations on chemotherapy associated gene polymorphisms are warranted. PMID- 18443806 TI - Postoperatively parastomal infection following emergent stoma creation for colorectal obstruction: the possible risk factors. AB - BACKGROUND: The aim of the present study was to discuss the possible risk factors related to the parastomal infection after the patients received emergent stoma creation in colorectal obstruction that was caused by adenocarcinoma, diverticulitis, or a variety of other miscellaneous causes. PATIENTS AND METHODS: A total of 360 patients with colorectal obstruction underwent emergent stoma creation, including diversion and Hartmann's procedure between January 1996 and January 2005. We analyze the patients' records to document the possible risk factors associated with parastomal infection. Patients' demographics, indication for ostomy, ostomy type/location, and risk factors were recorded. Logistic regression was used to calculate adjusted odds ratios. A p value of less than 0.05 was considered significant. RESULTS: Twenty patients (5.6%) with emergent stoma creation had parastomal infection. Descending colostomy had the highest incidence (6.7%) of parastomal infection, followed by transverse colostomy (6.1%) and ileostomy (3.2%). Significant predictors of parastomal infection as presented with odds ratios and 95% confidence intervals include obstruction period, obesity, operative time, serum albumin, and serum C-reactive protein (CRP). Parastomal infection is also highly associated with abdominal surgical wound infection. CONCLUSION: We concluded that risk factors for parastomal infection include obstruction period, obesity, operative time, serum albumin, and serum CRP. Furthermore, the abdominal surgical wound infection predispose to parastomal infection. Therefore, prolonged and specific antibiotics for results of culture should be used for patients with the above risk factors to prevent parastomal infection. PMID- 18443807 TI - Clinical outcomes and patency of self-expanding metal stents in patients with malignant colorectal obstruction: a prospective single center study. AB - BACKGROUNDS AND AIMS: Self-expanding metal stents (SEMS) have been used as a palliative treatment for malignant colorectal obstruction. However, the reports about primary stent patency rate and associated factors have been limited. This study was performed to evaluate clinical outcomes and factors associated with long-term complications and patency of SEMS in patients with malignant colorectal obstruction. MATERIALS AND METHODS: Patients who underwent palliative endoscopic placement with uncovered SEMS for a malignant colorectal obstruction were prospectively enrolled at Seoul National University Hospital between April 2005 and August 2007. RESULTS: Forty-nine patients underwent 51 SEMS placements. Obstruction sites were rectum in 15 patients (30.6%), descending or sigmoid colon in 25 (51.0%), and transverse colon in nine (18.4%), respectively. The causes of obstruction were colorectal cancer in 36 patients (73.5%), direct invasion of gastric cancer in seven (14.3%) and others in six (12.2%). Technical success was achieved in 100% and clinical success in 86%, and there was one procedure-related perforation. Re-obstruction and migration occurred in 16% and 6%, respectively, during mean follow-up period of 331 days. Median stent patency duration was 204 days, and patency rates at 30, 90, and 180 days were 91.2%, 81.0%, and 53.3%, respectively, which was not associated with patient demographics, site of obstruction, or palliative chemotherapy. CONCLUSION: Endoscopic SEMS placement is a safe and effective palliative treatment for malignant colorectal obstruction, and overall long-term complication and patency were favorable irrespective of the palliative chemotherapy. PMID- 18443808 TI - [Introduction to the topic: immune reconstitution syndrome - relevance for the rheumatologist]. PMID- 18443809 TI - [Methotrexate: advantages of subcutaneous administration]. PMID- 18443810 TI - Enhanced production and secretion of glial cell line-derived neurotrophic factor and nerve growth factor from the skin in atopic dermatitis mouse model. AB - Role of neurotrophic factors including nerve growth factor (NGF) in the mechanism of overgrowth and hypersensitivity of sensory nerve in atopic dermatitis (AD) has been proposed. Glial cell line-derived neurotrophic factor (GDNF) is a member of neurotrophic factors of the nervous systems; however, the role of GDNF in dermatitis is unknown. IL-18 promotes Th2 type allergic condition in skin and various organs in the absence of IL-12. In this report, we evaluated the expression of GDNF in AD and its association with NGF and IL-18. Mice expressing skin-specific IL-18 (KIL18Tg) or caspase-1, an IL-18 converting enzyme, (KCASP1Tg) were used as AD models; GDNF expression was examined by RT-PCR, enzyme immunoassay, and immunohistochemistry. The mRNA expressions of GDNF and NGF were detected in the epidermis and they were increased in the skin of KIL18Tg and KCASP1Tg mice. GDNF protein production in the skin was also elevated in both transgenic mice and mostly expressed at the basal layer of the epidermis as assessed by immunohistochemistry. Furthermore, the number of nerve fibers was increased in KCASP1Tg, suggesting increased cutaneous innervation. The present results suggest that in addition to NGF, elevated production and secretion of GDNF in the skin associated with overproduction of IL-18 may also be a potent causative factor of itching in AD. PMID- 18443811 TI - Single-session radiofrequency tongue base reduction combined with uvulopalatopharyngoplasty for obstructive sleep apnea syndrome. AB - This study aimed to evaluate the efficacy and safety of single-session radiofrequency tongue base reduction (RTBR) combined with uvulopalatopharyngoplasty (UPPP) for the treatment of obstructive sleep apnea syndrome (OSAS). Sixty-six patients with multilevel obstruction underwent single session RTBR combined with UPPP. Snoring, Epworth sleepiness scale (ESS) and polysomnography were used to assess outcome before and 6 months after treatment. Sixty-six patients completed this study. Snoring level significantly decreased from 8.0 to 4.3. The mean ESS score significantly decreased from 11.4 to 7.5. The mean apnea-hypopnea index decreased significantly from 22.9 to 13.9. The overall success rate of the single-session RTBR combined with UPPP was 53.6%. Postoperative AHI in 50% of patients was normalized (AHI < 5). The success rates for patients with mild, moderate and severe OSAS were 62.5, 46.2 and 57.1%, respectively. There were two adverse effects, one ulceration of the tongue base and one transient taste change. Single-session RTBR combined with UPPP is an effective and safe treatment for OSAS patients with multilevel obstruction. It could be considered as first treatment for OSAS patients with multilevel obstruction, independent of the severity of OSAS. PMID- 18443812 TI - Reconstruction of (90)Sr intake for breast-fed infants in the Techa riverside settlements. AB - The Techa River (Southern Urals, Russia) was contaminated as a result of radioactive releases by the Mayak plutonium production facility during 1949-1956. The persons born after the onset of the contamination have been identified as the "Techa River Offspring Cohort" (TROC). The TROC has the potential to provide direct data on health effects in progeny that resulted from exposure of a general parent population to chronic radiation. The purpose of the present investigation is the estimation of (90)Sr intake from breast milk and river water in the period from birth to 6 months of life, necessary for an infant dose calculation. The investigation is based on all available data concerning radioactive contamination due to global fallouts and Mayak releases in the Southern Urals where extensive radiometric and radiochemical investigations of human tissues and environmental samples were conducted during the second half of the twentieth century. The strontium transfer factor from mother's daily diet to breast milk was estimated as 0.05 (0.01-0.13) d L(-1). Based on this transfer factor and data on (90)Sr water contamination, the average total (90)Sr intake for an infant born in the middle Techa River region was found to be equal to 60-80 kBq in 1950-1951. For the same period, calculations of (90)Sr intake using ICRP models gave values of 70-100 kBq. From 1952 onwards, the differences in intakes calculated using the two approaches increased, reaching a factor of 2-3 in 1953. The Techa River data provide the basis for improving and adapting the ICRP models for application to Techa River-specific population. PMID- 18443814 TI - Unilateral arm strength training improves contralateral peak force and rate of force development. AB - Neural adaptation following maximal strength training improves the ability to rapidly develop force. Unilateral strength training also leads to contralateral strength improvement, due to cross-over effects. However, adaptations in the rate of force development and peak force in the contralateral untrained arm after one arm training have not been determined. Therefore, we aimed to detect contralateral effects of unilateral maximal strength training on rate of force development and peak force. Ten adult females enrolled in a 2-month strength training program focusing of maximal mobilization of force against near-maximal load in one arm, by attempting to move the given load as fast as possible. The other arm remained untrained. The training program did not induce any observable hypertrophy of any arms, as measured by anthropometry. Nevertheless, rate of force development improved in the trained arm during contractions against both submaximal and maximal loads by 40-60%. The untrained arm also improved rate of force development by the same magnitude. Peak force only improved during a maximal isometric contraction by 37% in the trained arm and 35% in the untrained arm. One repetition maximum improved by 79% in the trained arm and 9% in the untrained arm. Therefore, one-arm maximal strength training focusing on maximal mobilization of force increased rapid force development and one repetition maximal strength in the contralateral untrained arm. This suggests an increased central drive that also crosses over to the contralateral side. PMID- 18443813 TI - Intermediate filament cytoskeleton of the liver in health and disease. AB - Intermediate filaments (IFs) represent the largest cytoskeletal gene family comprising approximately 70 genes expressed in tissue specific manner. In addition to scaffolding function, they form complex signaling platforms and interact with various kinases, adaptor, and apoptotic proteins. IFs are established cytoprotectants and IF variants are associated with >30 human diseases. Furthermore, IF-containing inclusion bodies are characteristic features of several neurodegenerative, muscular, and other disorders. Acidic (type I) and basic keratins (type II) build obligatory type I and type II heteropolymers and are expressed in epithelial cells. Adult hepatocytes contain K8 and K18 as their only cytoplasmic IF pair, whereas cholangiocytes express K7 and K19 in addition. K8/K18-deficient animals exhibit a marked susceptibility to various toxic agents and Fas-induced apoptosis. In humans, K8/K18 variants predispose to development of end-stage liver disease and acute liver failure (ALF). K8/K18 variants also associate with development of liver fibrosis in patients with chronic hepatitis C. Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated K8/K18, chaperones and sequestosome1/p62 (p62) as their major constituents. MDBs are found in various liver diseases including alcoholic and non-alcoholic steatohepatitis and can be formed in mice by feeding hepatotoxic substances griseofulvin and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). MDBs also arise in cell culture after transfection with K8/K18, ubiquitin, and p62. Major factors that determine MDB formation in vivo are the type of stress (with oxidative stress as a major player), the extent of stress-induced protein misfolding and resulting chaperone, proteasome and autophagy overload, keratin 8 excess, transglutaminase activation with transamidation of keratin 8 and p62 upregulation. PMID- 18443815 TI - Performance and metabolism in repeated sprint exercise: effect of recovery intensity. AB - This study investigated the effects of a moderate (MI) and a low intensity (LI) active recovery (both compared to a passive recovery) on repeated-sprint performance and muscle metabolism. Nine, male, subjects performed three repeated sprint cycle tests (6 x 4 s sprints, every 25 s) in a semi-randomized, counter balanced order. Recovery after each sprint for the MI and LI trials, respectively, was 60 W (approximately 35% VO(2max)) and 20 W (approximately 20% VO(2max). Biopsies were taken from the vastus lateralis pre- and immediately post test during the MI and LI trials to determine adenosine triphosphate (ATP), phosphocreatine (PCr) and lactate (MLa(-)) content. Compared to passive, significant reductions in peak power of 3.4-6.0% were recorded in the MI trial (4 of 6 sprints; P < 0.05) and reductions of 3.5-3.7% in the LI trial (2 of 6 sprints; P < 0.05), with no differences between the two active trials. No significant differences were evident in ATP, PCr and MLa(-) between the two active recovery trials. In summary, peak power indices during the repeated-sprint test were inferior in the MI and LI active recovery trials, compared to passive. The minimal differences in performance and muscle metabolites between the MI and LI trials suggest that any low-to-moderate level of muscle activation will attenuate the resynthesis of PCr and the recovery of power output during repeated short-sprint exercise. PMID- 18443816 TI - Pharmacological and biophysical properties of Ca2+ channels and subtype distributions in human adrenal chromaffin cells. AB - In this study, we explored the pharmacological and biophysical properties of voltage-activated Ca2+ channels in human chromaffin cells using the perforated patch configuration of the patch-clamp technique. According to their pharmacological sensitivity to Ca2+ channel blockers, cells could be sorted into two groups of similar size showing the predominance of either N- or P/Q-type Ca2+ channels. R-type Ca2+ channels, blocked by 77% with 20 muM Cd2+ and not affected by 50 muM Ni2+, were detected for the first time in human chromaffin cells. Immunocytochemical experiments revealed an even distribution of alpha (1E) Ca2+ channels in these cells. With regard to their biophysical properties, L- and R type channels were activated at membrane potentials that were 15-20 mV more negative than P/Q- and N-type channels. Activation time constants showed no variation with voltage for the L-type channels, decreased with increasing potentials for the R- and P/Q-type channels, and displayed a bell shape with a maximum at 0 mV for the N-type channels. R-type channels were also the most inactivated channels. We thus show here that human chromaffin cells possess all the Ca2+ channel types described in neurons, L, N, P/Q, and R channels, but the relative contributions of N and P/Q channels differ among cells. Given that N- and P/Q-type Ca2+ channel types can be differentially modulated, these findings suggest the possibility of cell-specific regulation in human chromaffin cells. PMID- 18443817 TI - Fast and reversible response of thylakoid-associated polyamines during and after UV-B stress: a comparative study of the wild type and a mutant lacking chlorophyll b of unicellular green alga Scenedesmus obliquus. AB - The functional and biochemical aspects of the photosynthetic apparatus in response to UV-B radiation were examined in unicellular oxygenic algae Scenedesmus obliquus. The wild type (Wt) and a chlorophyll b-less mutant (Wt-lhc) were used as a specific tool for the understanding of antenna role. Photosynthesis was monitored during and after UV-B stress by time resolved fluorescence spectroscopy and polarography. Carotenoids, such as neoxanthin, loroxanthin, lutein, violaxanthin, antheraxanthin, zeaxanthin, alpha- and beta carotene, cellular and thylakoid-associated putrescine, spermidine, spermine and subcomplexes of light-harvesting complex (LHCII) of photosystem II (PSII) were investigated to assess their possible involvement in response to UV-B. Oxygen evolution depression by UV-B was higher in the Wt-lhc mutant than in the Wt. Photosynthesis recovery occurred in the Wt, but not in the mutant. The dissipation of excess excitation energy during UV-B stress was accompanied by changes in the thylakoid-associated polyamines which were much higher than changes in xanthophylls. We conclude that, at least in the unicellular green alga S. obliquus, mutants lacking chlorophyll b have significant lower capacity for recovery after UV-B stress. In addition, the comparison of xanthophylls and thylakoid-associated polyamines reveals that the latter are more responsive to UV B stress and in a reversible manner. PMID- 18443818 TI - Identification and characterization of a super-stable Cu-Zn SOD from leaves of turmeric (Curcuma longa L.). AB - We report a novel super stable superoxide dismutase (SOD) extracted from the leaves of Curcuma longa L.-a post-harvest waste. The scavenging activity of this SOD remains intact both in crude and purified forms before and after heating at boiling temperatures (80-100 degrees C) up to 20 min, autoclaving (6-20 bars up to 10 min) and microwaving (frequency of 2,450 megahertz (MHz) or million cycles per second for 1-3 min). This SOD has significant shelf life at room temperature (25-35 degrees C) and is stable for at least 18 months at 4 degrees C and with the retained activity of 82% at -10 degrees C and 88% at -20 degrees C without any infection or contamination. The heat stable enzyme is present both in cytoplasm and chloroplasts. The enzyme is also stable under wide range of pH, alcohol and SDS concentrations. The heat stability of this SOD protein is not due to any associated phenolic compound as no phenolic compound was bound to the novel thermo-stable SOD. The activity staining through native PAGE and purification of the enzyme protein have shown that this form of enzyme has a native molecular weight of 30.8 kDa and has two subunits of 15 kDa as shown by SDS PAGE. The characterized novel isoform is a Cu-Zn SOD as is indicated by its sensitivity to both H2O2 and KCN. Indian, US and PCT patents have been filed and products are being developed using this hyperthermophilic enzyme. PMID- 18443819 TI - The role of crosstalk in dual-task performance: evidence from manipulating response-code overlap. AB - The present study examined the role of crosstalk in dual-task interference using a combination of a nonspeeded visual task and an auditory-manual reaction time (RT) task. The potential for dual-task crosstalk was introduced by presenting in the visual task objects (e.g., a cup with a handle), which "afford" associated responses that were either spatially compatible or incompatible with the response in the RT task. Crucially, the degree of crosstalk was varied by instructing participants either to attend to the left-right orientation of the objects, creating explicit cross-task response-code overlap ("strong crosstalk"), or to attend to object identity (no direct overlap; "weak crosstalk"). The data indicated a relative benefit for cross-task compatible trials, which was much greater with strong crosstalk than with weak crosstalk. Crucially, however, even on compatible trials dual-task performance was substantially worse with strong crosstalk than with weak crosstalk. This overall cost of crosstalk suggests interference of response codes even on compatible dual-task trials. PMID- 18443820 TI - Mixing costs and switch costs when switching stimulus dimensions in serial predictions. AB - Mixing costs and switch costs are two markers for the costs that arise in multitasking situations. To further explore mixing costs and switch costs, we used a serial prediction task in which subjects switched between stimulus dimensions (i.e., color, form, and position). Using this task, we demonstrate that both mixing costs and switch costs are influenced by task conflict and the resolution of interference. Here, we show that both mixing costs and switch costs are affected by a local factor, namely the necessity to resolve interference in the current trial in mixed blocks. However, whereas mixing costs can be sufficiently explained by interference resolution in the current trial, switch costs are also affected by carry-over effects from the preceding trial. As regards these carry-over effects, the present paradigm enabled us to demonstrate the influence of both persisting activation and persisting inhibition on the performance in switch trials. PMID- 18443821 TI - The effects of dividing attention on the encoding and performance of novel naturalistic actions. AB - Novel naturalistic actions (NNAs) are multi-step, goal-directed actions involving the manipulation of objects that are unfamiliar to a person prior to instruction. Experiment 1 investigated the cognitive processes involved with encoding and performing NNAs by selectively interfering with attention during viewing or production of a NNA using the dual-task paradigm (n = 27, healthy adults). Consistent with the central findings from the dual-task memory literature, dividing attention at viewing caused a relatively greater disruptive effect on NNA performance than selectively interfering with attention during enactment. A follow-up experiment (n = 24, healthy adults) increased difficulty of memory retrieval by having participants verbally describe previously viewed NNAs while concurrently performing a secondary task, and it revealed no significant differences between the effects of dividing attention on the verbal description and physical construction of NNAs. The implications of our findings for the processes mediating encoding and enactment of naturalistic actions were presented. As well, the utility of a dynamic technique of inducing error types normally found in neurologically impaired populations was discussed. PMID- 18443822 TI - Expression patterns of engrailed and dpp in the gastropod Lymnaea stagnalis. AB - We isolated the full-length cDNAs of engrailed and dpp-BMP2/4 orthologues from the pond snail Lymnaea stagnalis and examined their expression patterns during development by the whole mount in situ hybridization. At the gastrula and trochophore stages, engrailed is expressed in the peripheral ectoderm of the presumptive and invaginating shell gland, corroborating its role in the shell formation that is widely conserved among molluscs. At the same stages, dpp-BMP2/4 is expressed in the right-hand side ectoderm of the shell gland and in the invaginating stomodaeum. Unlike in the gastropod Patella vulgata, our results suggested that dpp-BMP2/4 has a role in the shell formation, rather than in the regional specification and that it could be involved in the specification pathway of the left-right asymmetry of the developing shell in L. stagnalis. PMID- 18443824 TI - Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3-p31.1. AB - Disseminated superficial actinic porokeratosis (DSAP) is a chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Two genetic loci for DSAP were identified, but no specific genes were reported to date. The pathogenic mechanism of this disorder remains to be elucidated. In this study, a large, five generation Chinese family with DSAP was genetically characterized. Two known DSAP loci, DSAP1 and DSAP2, two DSAP candidate genes (SART3 and SSH1), one DSP-linked locus and one PPPD-linked locus were first excluded in the family. The family was then characterized by genome-wide linkage analysis and a new DSAP locus was identified on chromosome 1p31.3-p31.1 with a maximum two-point LOD score of 5.09 with marker D1S2897 (theta = 0). Fine mapping showed that the disease gene was located within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP (DSAP3). Eight candidate genes including GNG12, IL12RB2, ITGB3BP, DNAJ6, PIN1L, GADD45A, RPE65 and NEGR1 were sequenced, but found to be negative for functional sequence variants. Further mutational analysis of the candidate genes in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP. PMID- 18443825 TI - Displacement of a native by an alien bumblebee: lower pollinator efficiency overcome by overwhelmingly higher visitation frequency. AB - Biological invasions might constitute a major threat to mutualisms. Introduced pollinators might competitively displace their native counterparts, which in turn affects the pollination of native plants, if native and alien visitors differ in pollinator effectiveness. Since its invasion in 1994 into south-west Argentina, the introduced European bumblebee Bombus ruderatus has continuously increased in abundance, along with a simultaneous decrease in the abundance of the native Bombus dahlbomii. The latter is the only native bumblebee species of the temperate forests of southern South America, and the main pollinator of the endemic herb Alstroemeria aurea. In order to evaluate the impact of the ongoing displacement of the native by the alien bumblebee, we compared the pollinator effectiveness (i.e., the combination of pollinator efficiency per visit and visitation frequency) between both bumblebee species, as well as related pollinator traits that might account for potential differences in pollinator efficiency. Native Bombus dahlbomii, which has a larger body and spent more time per flower, was the more efficient pollinator compared to Bombus ruderatus, both in terms of quantity and quality of pollen deposited per visit. However, Bombus ruderatus was a much more frequent flower visitor than Bombus dahlbomii. As a consequence, Bombus ruderatus is nowadays a more effective pollinator of A. aurea than its native congener. Despite the lack of evidence of an increase in seed set at the population level, comparisons with historical records of Bombus dahlbomii abundances prior to Bombus ruderatus' invasion suggest that the overall pollination intensity of A. aurea might in fact have risen as a consequence of this invasion. Field experiments like these, that incorporate the natural variation in abundance of native and alien species, are powerful means to demonstrate that the consequences of invasions are more complex than previous manipulated and controlled experiments have suggested. PMID- 18443823 TI - Muscle precursor cells in the developing limbs of two isopods (Crustacea, Peracarida): an immunohistochemical study using a novel monoclonal antibody against myosin heavy chain. AB - In the hot debate on arthropod relationships, Crustaceans and the morphology of their appendages play a pivotal role. To gain new insights into how arthropod appendages evolved, developmental biologists recently have begun to examine the expression and function of Drosophila appendage genes in Crustaceans. However, cellular aspects of Crustacean limb development such as myogenesis are poorly understood in Crustaceans so that the interpretative context in which to analyse gene functions is still fragmentary. The goal of the present project was to analyse muscle development in Crustacean appendages, and to that end, monoclonal antibodies against arthropod muscle proteins were generated. One of these antibodies recognises certain isoforms of myosin heavy chain and strongly binds to muscle precursor cells in malacostracan Crustacea. We used this antibody to study myogenesis in two isopods, Porcellio scaber and Idotea balthica (Crustacea, Malacostraca, Peracarida), by immunohistochemistry. In these animals, muscles in the limbs originate from single muscle precursor cells, which subsequently grow to form multinucleated muscle precursors. The pattern of primordial muscles in the thoracic limbs was mapped, and results compared to muscle development in other Crustaceans and in insects. PMID- 18443826 TI - Spatial heterogeneity and plant species richness at different spatial scales under rabbit grazing. AB - Herbivores influence spatial heterogeneity in soil resources and vegetation in ecosystems. Despite increasing recognition that spatial heterogeneity can drive species richness at different spatial scales, few studies have quantified the effect of grazing on spatial heterogeneity and species richness simultaneously. Here we document both these variables in a rabbit-grazed grassland. We measured mean values and spatial patterns of grazing intensity, rabbit droppings, plant height, plant biomass, soil water content, ammonia and nitrate in sites grazed by rabbits and in matched, ungrazed exclosures in a grassland in southern England. Plant species richness was recorded at spatial scales ranging between 0.0001 and 150 m(2). Grazing reduced plant height and plant biomass but increased levels of ammonia and nitrate in the soil. Spatial statistics revealed that rabbit-grazed sites consisted of a mixture of heavily grazed patches with low vegetation and nutrient-rich soils (lawns) surrounded by patches of high vegetation with nutrient-poor soils (tussocks). The mean patch size (range) in the grazed controls was 2.1 +/- 0.3 m for vegetation height, 3.8 +/- 1.8 m for soil water content and 2.8 +/- 0.9 m for ammonia. This is in line with the patch sizes of grazing (2.4 +/- 0.5 m) and dropping deposition (3.7 +/- 0.6 m) by rabbits. In contrast, patchiness in the ungrazed exclosures had a larger patch size and was not present for all variables. Rabbit grazing increased plant species richness at all spatial scales. Species richness was negatively correlated with plant height, but positively correlated to the coefficient of variation of plant height at all plot sizes. Species richness in large plots (<25 m(2)) was also correlated to patch size. This study indicates that the abundance of strong competitors and the nutrient availability in the soil, as well as the heterogeneity and spatial pattern of these factors may influence species richness, but the importance of these factors can differ across spatial scales. PMID- 18443827 TI - Host specialization in habitat specialists and generalists. AB - Generalists and specialists use different cues to find their habitat and essential resources. While generalists have the advantage of exploiting a wider range of resources, they are predicted to be less efficient in using one particular resource compared to specialists. The level of specialization of parasitoids can be either at the habitat or at the host level; strategies used by either type are expected to differ. We examined interactions between three aphid parasitoid species that are a habitat specialist Aphidius rhopalosiphi, a habitat generalist Aphidius ervi, and a host generalist Praon volucre on three cereal aphids, Sitobion avenae, Metopolophium dirhodum and Rhopalosiphum padi. We compared total parasitism rate across behavioral and physiological variation in a non-choice test. Next, we addressed total parasitism in two phases to examine: (1) the response of parasitoids to different hosts through the behavioral sequence from antennation through oviposition, and (2) the physiological suitability of different hosts for oviposition and larval development. Parasitization typically involved the following behavioral steps: (1) antennal contact, (2) abdominal bending, and (3) ovipositor insertion (acceptance). A. rhopalosiphi had the same number of antennal contacts with the three aphids but showed fewer instances of abdominal bending towards R. padi. Pre-contact host preference was found for A. ervi but it did not correspond to the level of acceptance. The number of antennal contacts by P. volucre corresponded to the parasitization level of the aphid species but more mummies were produced on M. dirhodum than on R. padi. These results suggest that parasitoid species that are habitat specialists react similarly to the different host species present in the same habitat, whereas generalist species exhibit clear preferences during host selection. Preferences were, however, not always related to host suitability. PMID- 18443828 TI - Never too late? Consequences of late birthdate for mass and survival of bighorn lambs. AB - In strongly seasonal environments, the timing of birth can have important fitness consequences. We investigated which factors affect parturition date and how birthdate interacts with sex, maternal characteristics and environmental variables to affect the growth and survival of bighorn sheep (Ovis canadensis) lambs in a marked population in Alberta. Over 14 years, the estimated birthdate of 216 lambs ranged from 21 May to 18 July. Parturition date was heritable and genetically correlated with maternal mass the previous fall. Weaning a lamb delayed parturition the following year by about 7 days. Birthdate did not affect summer growth rate, but late-born lambs were lighter in mid September (the approximate time of weaning) than early-born ones. Birthdate did not affect survival to weaning, but late birth decreased survival to 1 year for male lambs. Forage quality, measured by fecal crude protein, did not affect survival to 1 year. Once we accounted for lamb mass in mid September, birthdate no longer affected the probability of survival, suggesting that late birth decreased survival by shortening a lamb's growing season. Because there was no compensatory summer growth, late-born lambs were smaller than early-born ones at the onset of winter. Our data highlight the importance of birthdate on life history traits and suggest that resource scarcity had more severe consequences for juvenile males than for females. PMID- 18443829 TI - Enhancing the thermal stability of lipases through mutagenesis and immobilization on zeolites. AB - The hydrolysis reaction of p-nitrophenyl butyrate catalyzed by lipases was followed with in situ UV/vis diode array spectrophotometry. Five enzymes - Candida antarctica lipase B and Fusarium solani pisi cutinase wild-type and three single-mutation variants - were tested as catalysts in homogeneous conditions and immobilized on zeolite NaY, on a polyacrylate support and as cross-linked aggregates. Using deconvolution techniques and kinetic modeling, the thermal stability of the different biocatalysts was compared in operational conditions and the results were supported by steady-state enzyme fluorescence measurements. We concluded that both the mutagenesis and the immobilization on zeolite NaY had a positive effect on the thermal stability of F. solani pisi cutinase. PMID- 18443830 TI - [Fibromyalgia syndrome: guideline principle for a fiction?]. PMID- 18443832 TI - Relations between surgeons and industry: the time of clarification has come. PMID- 18443833 TI - Rotavirus fecal antigen retrieval in infantile intussusception. AB - This study was designed to assess the plausibility of an association between natural rotavirus infection and intussusception. It was conducted on 21 infants suffering from acute gastroenteritis (GE) complicated by intussusception who were compared to another 40 age- and sex-matched infants suffering from acute GE characterized by watery nonmucoid diarrhea without surgical complications. All enrolled patients were subjected to detailed history documentation, thorough clinical examination and laboratory investigations, complete stool analysis, and detection of rotavirus antigen in stools using the ELISA technique. Plain abdominal X-ray and ultrasound were also performed. The results of this study revealed 24 positive cases for rotavirus antigen in the stools of the acute uncomplicated GE patients (60.0%), while there were only ten positive cases in the intussusception group (47.6%). No significant difference in severity was detected between the two groups studied, especially in terms of signs of dehydration and need for IV fluids (p > 0.05). Most of the rotavirus positive cases among the intussusception group presented either in February or December (p < 0.05) with no significant seasonal pattern among the acute GE group (p > 0.05). In conclusion, rotavirus antigen retrieval from stools of GE patients complicated with intussusception was not statistically different from those detected among acute uncomplicated GE. Additionally, there was no association between seasonality or severity of rotavirus positive cases in acute GE patients and those with intussusception. It is thus prudent to say that wild rotavirus infection in GE patients does not carry an extra risk for the occurrence of intussusception. PMID- 18443834 TI - Stereotactic disconnection of hypothalamic hamartoma to control seizure and behavior disturbance: case report and literature review. AB - An 18-year-old boy with refractory epilepsy and aggressiveness associated to a hypothalamic hamartoma was submitted to a stereotactically guided lesion by thermocoagulation. The target was based on magnetic resonance (MR) images merged with computed tomography scan images taken on the day of surgery while patient was on a stereotactic frame. In order to reveal structures not discernible in MR images, the Schaltenbrand digital brain atlas was merged onto the patient's images. Target and trajectory of the depth electrode were chosen based on three dimensional imaging reconstructions. A surgical plan was devised to disconnect the hypothalamic hamartoma from the hypothalamus, medial forebrain bundle, fasciculus princeps, and dorsal longitudinal fasciculus. Our target was placed at the inferior portion of the posterolateral component of the hamartoma, bordering the normal hypothalamus. The patient evolved with marked lessening of aggressiveness. Seizure frequency was reduced from several seizures per day to less than one tonic-clonic seizure during sleep per month and only two episodes suggestive of partial complex seizures during daytime. These results have remained consistent over a 24-month postoperative follow-up. Functional neuroanatomy of hypothalamic connections involved in seizure propagation and aggressive behavior was reviewed. PMID- 18443835 TI - Spontaneous brainstem hematoma with hydrocephalus. PMID- 18443836 TI - Brucella-related cerebral aneurysms/subarachnoidal hemorrhage: a short review featuring a case report. AB - Brucellosis is a multisystem disease that may present with a large spectrum of clinical manifestations. Only five cases of intracranial aneurysm formation and/or subarachnoidal hemorrhage associated with brucellosis have been reported. In this paper, we take the opportunity to review these reports and present a new case of basilar artery aneurysm and subarachnoidal hemorrhage due to brucellosis. PMID- 18443838 TI - European Conference on Complex Systems 2007. Editorial. PMID- 18443837 TI - Neuromuscular control of a single twitch muscle in wild type and mutant Drosophila, measured with an ergometer. AB - How do deficits in neuronal growth, aging or synaptic function affect the final, mechanical output of a single muscle twitch? We address this in vivo (indeed in situ) with a novel ergometer that records the output of a large specialised muscle, the Drosophila jump muscle. Here, we describe in detail the ergometer, its construction and use. We evaluated the ergometer by showing that adult fly jump muscle output varies little between 3 h and 7 days; but newly eclosed flies produce only 65%. In a mutant with little octopamine (Tbetah), jump muscle performance is reduced by 28%. The initial responses of synaptic growth mutants (highwire and spinster) do not differ from wild type, as expected on the homeostatic hypothesis. However, responses in highwire mutations gradually decline following repeated stimuli, suggesting physiological as well as anatomical abnormalities. We conclude that the assay is robust, sensitive and reliable with a good throughput. PMID- 18443839 TI - Stability and performance of ant queue inspired task partitioning methods. AB - In this paper, we consider computing systems that have autonomous helper components which fulfill support functions and that possess reconfigurable hardware so that they can specialize to different types of service tasks. Several self-organized task partitioning methods are proposed that can be used by the helper components to decide how to reconfigure and which service tasks to execute. The proposed task partitioning methods are inspired by the so-called ant queue system that can be found in real ants for partitioning tasks between the individuals. The aim of this study is to investigate basic properties of the task partitioning methods, like stability and efficiency, in order to obtain basic insights into the design of task partitioning methods in self-organized service systems. More precisely, the investigations are threefold: (1) discrete event simulations are used to investigate systems, (2) for a simple version of the task partitioning system analytical stability results are obtained by means of delay differential equation systems and (3) by numerically solving initial value problems. PMID- 18443840 TI - Genes, information and sense: complexity and knowledge retrieval. AB - Information capacity of nucleotide sequences measures the unexpectedness of a continuation of a given string of nucleotides, thus having a sound relation to a variety of biological issues. A continuation is defined in a way maximizing the entropy of the ensemble of such continuations. The capacity is defined as a mutual entropy of real frequency dictionary of a sequence with respect to the one bearing the most expected continuations; it does not depend on the length of strings contained in a dictionary. Various genomes exhibit a multi-minima pattern of the dependence of information capacity on the string length, thus reflecting an order within a sequence. The strings with significant deviation of an expected frequency from the real one are the words of increased information value. Such words exhibit a non-random distribution alongside a sequence, thus making it possible to retrieve the correlation between a structure, and a function encoded within a sequence. PMID- 18443841 TI - The effect of maternal T1DM on the fatty acid composition of erythrocyte phosphatidylcholine and phosphatidylethanolamine in infants during early life. AB - BACKGROUND: The risk for type 1 diabetes (T1DM) in children of mothers with T1DM is different to that in children of fathers with T1DM. Fatty acid (FA) intake, in particular EPA and DHA, has been associated with T1DM risk and has been suggested to be inadequate in infants of diabetic mothers. We asked, therefore, whether EPA and DHA FA nutritional status in offspring of mothers with T1DM could contribute to their reduced T1DM risk. METHODS: BABYDIET follows children with increased genetic and familial risk for T1DM from birth to age 3 years. FA nutritional state was assessed by determining the erythrocyte membrane phosphatidylethanolamine (PE) and phosphatidylcholine (PC) composition in children of T1DM mothers and children of T1DM fathers or with T1DM siblings participating in the BABYDIET study. Samples for determination of erythrocyte membrane FA composition were collected at ages 3 and 12 months in 48 and 49 infants, respectively. FA measurements were adjusted for breastfeeding duration, FA supplementation, and gluten exposure. RESULTS: 3-months-old children of T1DM mothers and T1DM fathers/sibs had similar levels of PC DHA and EPA (DHA 1.53+/ 0.23 vs. 1.65+/-0.11 wt.%; EPA 0.15+/-0.02 vs. 0.21+/-0.03 wt.%) and PE DHA and EPA (DHA 7.54+/-0.37 vs. 7.92+/-0.38 wt.%; EPA 0.53+/-0.06 vs. 0.61+/-0.04 wt.%). No differences were also observed after stratification for breastfeeding. At age 12 months, a minor reduction of PE DHA was observed in children of T1DM mothers. Expected higher levels for DHA and EPA in fully breastfed children and in children of mothers taking fish oil supplementation were observed at 3 months in all children. Other differences included increased levels of the major saturated FA 16:0 in 3-months-old infants from T1DM mothers (PC 35.45+/-0.35 vs. 33.89+/ 0.26 wt.%, mean +/- SEM, P(corr)=0.005; PE 16.13+/-0.39 vs. 14.93+/-0.24 wt.%, P(corr)=0.05). CONCLUSION: Although FA status was not identical in children from T1DM mothers and from T1DM fathers, maternal T1DM was not associated with changes in offspring's EPA and DHA incorporation into erythrocyte membrane. PMID- 18443842 TI - Survey of organosilicone compounds, including cyclic and linear siloxanes, in personal-care and household products. AB - The determination of organosiloxanes in consumer products is important for the evaluation and characterization of sources of human and environmental exposures. In this study, we determined concentrations of cyclic siloxanes [octamethylcyclotetrasiloxane (D(4)), decamethylcyclopentasiloxane (D(5)), dodecamethylcyclohexasiloxane (D(6))], tetradecamethylcycloheptasiloxane (D(7))] and linear siloxanes (L(4) to L(14)) in a variety of consumer products (n = 76), including hair-care products, skin lotions, body washes, cosmetics, nursing nipples (i.e., pacifiers), cookware, and household sanitation products such as cleansers and furniture polishes, using gas chromatography-mass spectrometry with selected ion monitoring. Prior to the analysis of samples, a method was developed to reduce the contamination arising from organosiloxanes present in certain gas chromatograph (GC) parts, such as the inlet septum; use of a Restek BTO septum at an inlet temperature of 200 degrees C gave the lowest background level (D(4): 0.8 pg; D(5): 0.3 pg; D(6): 0.2 pg). Concentrations of cyclic siloxanes in consumer products analyzed ranged from <0.35 to 9380 microg/g, from <0.39 to 81,800 microg/g, from <0.33 to 43,100 microg/g, and from <0.42 to 846 microg/g for D(4), D(5), D(6), and D(7), respectively. Concentrations of linear siloxanes varied from <0.059 to 73,000 microg/g. More than 50% of the samples analyzed contained D(4), D(5), or D(6). Cyclic siloxanes were predominant in most of the sample categories; D(5) was predominant in hair-care products, skin lotions, and cosmetics; D(6) or D(7) was predominant in rubber products, including nipples, cookware, and sealants. Potential daily exposure to total organosiloxanes (sum of cyclic and linear siloxanes) from the use of personal-care products by adult women in the United States has been estimated to be 307 mg. Significant positive correlations (p < 0.01) existed in our study between D(4) and D(7), D(4) and linear siloxanes, D(5) and D(6), and D(5) and linear siloxanes. The correlations can be related to the composition of organosiloxanes used in consumer products. The results of our study suggest that a wide variety of consumer products that are used on a daily basis contain cyclic and linear siloxanes and these products can contribute considerably to human exposures. PMID- 18443843 TI - Effects of subchronic coexposure to arsenic and endosulfan on the erythrocytes of broiler chickens: a biochemical study. AB - Arsenic is a known global groundwater contaminant. The organochlorine insecticide endosulfan has gained significance as an environmental pollutant due to its widespread use in the control of many food- and non-food-crop-damaging insects. The adverse effects produced by arsenic or endosulfan alone in humans and animals are well documented, but very little is known about the consequences of their coexposure. We evaluated whether their simultaneous exposure can induce oxidative stress and affect antioxidative systems and certain membrane-bound enzymes in erythrocytes of broiler chickens. Day-old chicks were exposed to 3.7 ppm of arsenic via drinking water or 30 ppm of endosulfan-mixed feed or similarly coexposed to these in the same dose levels for 60 days. At term, the impact of their coexposure was assessed by evaluating lipid peroxidation (LPO), activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione-S-transferase (GST), different ATPases and acetylcholinesterase (AChE) in erythrocytes, serum glucose, and levels of glutathione (GSH) and glycosylated hemoglobin (GHb) in blood. LPO was increased with all of the treatments. Catalase was decreased with endosulfan and the coexposure, but not with arsenic, whereas GSH was decreased with arsenic and endosulfan, but not with the coexposure. All of the treatments increased SOD and GPx activities. GST activity was increased only in the coexposed birds. None of the treatments affected the activities of total ATPase and Mg2+-ATPase. Na+-K+-ATPase activity was decreased in the endosulfan-treated and the coexposed birds. All three exposures increased erythrocyte AChE activity. Endosulfan increased the serum glucose level and arsenic and endosulfan increased GHb levels, but these were not altered in the coexposed birds. Erythrocyte protein content was insignificantly decreased with these treatments. Overall, the effects of coexposure were not appreciably different from either of the agents, except on AChE, GSH, and glucose. The results do not reflect any specific type of interaction between these agents in chicken erythrocytes, but they do indicate that the coexposure induces a low level of oxidative stress, which is comparable to that induced by arsenic or endosulfan. PMID- 18443844 TI - Correlation between right ventricular Tei index by tissue Doppler imaging and pulsed Doppler imaging in fetuses. AB - The aim was to compare the right ventricular (RV) Tei index obtained by the tissue Doppler imaging (TDI) method with that obtained by the pulsed Doppler method in 29 fetuses aged 24-39 weeks (29.9 +/- 4.0 weeks). From pulsed Doppler recordings, the tricuspid closing-to-opening time (a) and RV ejection time (b) were measured. The Tei index determined by the pulsed Doppler method was calculated as (a - b)/b. From TDI recordings, the time interval during diastole (a') and the duration of the systole S-wave (b') were measured. The modified Tei index obtained by TDI was calculated as (a' - b')/b'. The time a' correlated strongly with a (r = 0.90, p < 0.0001). The mean difference between a' and a was 0.3 +/- 5.0 ms. There was also a strong correlation between b' and b (r = 0.94, p < 0.0001). The mean difference between b' and b was 0.5 +/- 3.3 ms. The TDI-Tei index correlated with the pulsed Doppler-Tei index (r = 0.83, p < 0.0001). The mean difference between the TDI-Tei index and the pulsed Doppler-Tei index was 0.003 +/- 0.04. This study demonstrated that the TDI-Tei index correlates well with the Tei index determined by pulsed Doppler in fetuses, suggesting that the TDI-Tei index is a feasible approach to assess global RV function in fetuses. PMID- 18443845 TI - Plant responses to drought stress and exogenous ABA application are modulated differently by mycorrhization in tomato and an ABA-deficient mutant (sitiens). AB - The aims of the present study are to find out whether the effects of arbuscular mycorrhizal (AM) symbiosis on plant resistance to water deficit are mediated by the endogenous abscisic acid (ABA) content of the host plant and whether the exogenous ABA application modifies such effects. The ABA-deficient tomato mutant sitiens and its near-isogenic wild-type parental line were used. Plant development, physiology, and expression of plant genes expected to be modulated by AM symbiosis, drought, and ABA were studied. Results showed that only wild type tomato plants responded positively to mycorrhizal inoculation, while AM symbiosis was not observed to have any effect on plant development in sitiens plants grown under well-watered conditions. The application of ABA to sitiens plants enhanced plant growth both under well-watered and drought stress conditions. In respect to sitiens plants subjected to drought stress, the addition of ABA had a cumulative effect in relation to that of inoculation with G. intraradices. Most of the genes analyzed in this study showed different regulation patterns in wild-type and sitiens plants, suggesting that their gene expression is modulated by the plant ABA phenotype. In the same way, the colonization of roots with the AM fungus G. intraradices differently regulated the expression of these genes in wild-type and in sitiens plants, which could explain the distinctive effect of the symbiosis on each plant ABA phenotype. This also suggests that the effects of the AM symbiosis on plant responses and resistance to water deficit are mediated by the plant ABA phenotype. PMID- 18443846 TI - High diversity of fungi may mitigate the impact of pollution on plant litter decomposition in streams. AB - We investigated how a community of microbial decomposers adapted to a reference site responds to a sudden decrease in the water quality. For that, we assessed the activity and diversity of fungi and bacteria on decomposing leaves that were transplanted from a reference (E1) to a polluted site (E2), and results were compared to those from decomposing leaves either at E1 or E2. The two sites had contrasting concentrations of organic and inorganic nutrients and heavy metals in the stream water. At E2, leaf decomposition rates, fungal biomass, and sporulation were reduced, while bacterial biomass was stimulated. Fungal diversity was four times lower at the polluted site. The structure of fungal community on leaves decomposing at E2 significantly differed from that decomposing at E1, as indicated by the principal response curves analysis. Articulospora tetracladia, Anguillospora filiformis, and Lunulospora curvula were dominant species on leaves decomposing at E1 and were the most negatively affected by the transfer to the polluted site. The transfer of leaves colonized at the reference site to the polluted site reduced fungal diversity and sporulation but not fungal biomass and leaf decomposition. Overall, results suggest that the high diversity on leaves from the upstream site might have mitigated the impact of anthropogenic stress on microbial decomposition of leaves transplanted to the polluted site. PMID- 18443847 TI - Phylogeny and ecophysiology of opportunistic "snow molds" from a subalpine forest ecosystem. AB - Mats of coenocytic "snow molds" are commonly observed covering the soil and litter of alpine and subalpine areas immediately following snow melt. Here, we describe the phylogenetic placement, growth rates, and metabolic potential of cold-adapted fungi from under-snow mats in the subalpine forests of Colorado. SSU rDNA sequencing revealed that these fungi belong to the zygomycete orders Mucorales and Mortierellales. All of the isolates could grow at temperatures observed under the snow at our sites (0 degrees C and -2 degrees C) but were unable to grow at temperatures above 25 degrees C and were unable to grow anaerobically. Growth rates for these fungi were very high at -2 degrees C, approximately an order of magnitude faster than previously studied cold-tolerant fungi from Antarctic soils. Given the rapid aerobic growth of these fungi at low temperatures, we propose that they are uniquely adapted to take advantage of the flush of nutrient that occurs at the soil-snow interface beneath late winter snow packs. In addition, extracellular enzyme production was relatively high for the Mucorales, but quite low for the Mortierellales, perhaps indicating some niche separation between these fungi beneath the late winter snow pack. PMID- 18443848 TI - Genomic analysis of freshwater cyanophage Pf-WMP3 Infecting cyanobacterium Phormidium foveolarum: the conserved elements for a phage. AB - Cyanophages are ecologically abundant, genetically diverse in aquatic environments, and affect the population and evolutionary trajectories of their hosts. After reporting the cyanophage Pf-WMP4 genome (Liu et al. in Virology 366:28-39, 2007), we hereby present a related cyanophage, Pf-WMP3, which also infects the freshwater cyanobacterium Phormidium foveolarum. The Pf-WMP3 genome contains 43,249 bp with 234 bp direct terminal repeats. The overall genome organization and core genes of the two phages are comparable to those of the T7 supergroup phages. Compared with Pf-WMP4, cyanophage Pf-WMP3 has diverged extensively at the DNA level; however, they are closely related at the protein level and genome architecture. The left arm genes for the two phages, which mainly encode the DNA replication machinery, are not conserved in the gene order. Whereas the right arm genes of the two phages coding for structural proteins show high similarity in amino acid sequences and modular architecture, indicating that they have retained similar development strategies. The differences in similarity levels between the left and right arm genes suggest that the structural genes are the most conserved elements for a phage. PMID- 18443849 TI - Evaluation of the effect of sildenafil and vascular endothelium growth factor combination treatment on skin flap survival in rats. AB - BACKGROUND: Distal ischemic necrosis of surgical flaps remains a challenging problem for the reconstructive surgeon. Recent studies have shown that either sildenafil or vascular endothelium growth factor (VEGF) treatment significantly improves ischemic skin flap viability. In this study, the effect of the combination of sildenafil and VEGF165 was evaluated on a rat skin flap model using orthogonal polarization spectral imaging and histologic analysis. METHODS: Rats were assigned to either a sham (n = 31), vehicle (n = 24), sildenafil (n = 24), VEGF (n = 23), or sildenafil and VEGF combination treatment (n = 21) groups. Distances from the distal end of the flap to avascular, stasis, and normal capillary blood flow zones were determined using orthogonal polarization spectral imaging on a skin flap model. Vessel density assessment was done at 7 days post surgery. RESULTS: Imaging analysis showed significant reduction in avascular and stasis areas in sildenafil and VEGF combination-treated groups at 7 days post surgery (p < 0.05). The combination-treated group, however, was not significantly different when compared to the group treated with sildenafil only. The sildenafil treated group showed a significant (p < 0.05) reduction in both areas at day 7 compared to the VEGF and control groups. Histologic analysis showed no significant differences in vessel density between the groups. CONCLUSION: The combination of sildenafil and VEGF decreases the extent of avascular and stasis zones in skin flaps. The skin flap improvement seen with the combination treatment was similar to the sildenafil treatment alone suggesting that enhanced flap survival was due solely to the effect of sildenafil. PMID- 18443850 TI - Thin superior medial pedicle reduction mammaplasty for severe mammary hypertrophy. AB - BACKGROUND: There are multitudes of procedures in plastic surgery used to correct hypertrophic and pendulous breasts in patients with heavy and ptotic breasts who need great resections of breast tissue, where the suprasternal notch-to-nipple distance is long and the use of nipple-areola transposition techniques is a challenge for the plastic surgeon. The purpose of this study is to present a technique of reduction mammaplasty that could solve these problems based on the following principles: mammary reduction utilizing a thin superior medial pedicle (0.8-1.5 cm thick) and the resection performed in two steps: (1) the base excess at a plane perpendicular to the breast (this determines the cone's height) and (2) central half keel (this determines the breast diameter reduction). METHODS: Ninety patients with mammary hypertrophy were operated on at the "Hospital das Clinicas," Sao Paulo University Medical School, between January 2000 and November 2005. Inclusion in this study required a minimum of 12-cm change in nipple position and a 750-g breast resection. RESULTS: The mean change in nipple position was 16 cm (range = 12-21 cm). The mean weight of each breast was 1400 (range = 750-3000 g). Considering the great amount of volume removed and the size of the operated breasts, few complications were observed and were similar to those reported following other techniques described in the literature. Patient satisfaction following this procedure was high. CONCLUSION: The results of this study clearly demonstrate that thin superior medial pedicle reduction mammaplasty is a safe and reliable technique in cases of severe mammary hypertrophy. PMID- 18443851 TI - Areola-nipple perception threshold to faradic electricity: a new measure of sensibility of the breasts. AB - BACKGROUND: We describe a new method to study the sensibility of the nipple areola complex of the breast with faradic electricity delivered through an electromyographic device used to monitor peripheral nerve conduction. METHODS: The objective results of faradic pulses (2-50 mA per pulse) delivered to the nipple-areola complex of the breast through a Nihon-Kohden II machine (Evoked potential/Electromyographs, Nihon-Kohden Co., Japan) were evaluated in normal volunteers to get a basal measure that was defined by the patient as "a soft electric discharge." The measures were recorded and their output discharges averaged (at least 5 to each complex). RESULTS: Twenty-eight volunteers with normal breasts, 28 patients with breast hypertrophy before and after breast reduction, and 28 patients before and after breast augmentation were studied. The faradic pulses were perceived from 1.5 to 3.5 mA in the areola and from 3 to 5.5 mA in the nipple in the control group and from 4.5 to 7.0 mA in the areola and from 6.5 to 9.5 mA in the nipple in the breast hypertrophy group with no significant changes before and after surgery. In the breast augmentation group the faradic pulses were very similar to the volunteers that had normal breasts, but 13 months after breast augmentation with silicone gel prosthesis, a difference was found because all the patients had a higher threshold and three cases had lost sensibility of the nipple-areola complex. CONCLUSION: In normal breasts the areola had a lower threshold for faradic pulses compared to the nipple. Hypertrophic breasts had a higher threshold to the faradic stimulation than normal subjects in the pre- and postoperative period. Hypoplastic breasts before breast augmentation had a perception threshold similar to that of the normal volunteers but after breast augmentation this perception was much higher. PMID- 18443852 TI - Anal sphincter asymmetry in anal incontinence after restorative proctectomy for rectal cancer. AB - PURPOSE: The morphology and physiology of the anorectum can be altered after restorative proctectomy, which may result in anal incontinence. Thus far, there have been few reports regarding the specific characteristics and management of anal incontinence after rectal cancer surgery. We attempted to determine the characteristics of anorectum in anal incontinence after restorative proctectomy. METHODS: We compared the clinical and physiologic factors between consecutive 138 patients with continence and 48 with iatrogenic anal incontinence at 1 year after rectal cancer resection. This study excluded patients at less than 1 year after operation or ileostomy takedown. RESULTS: The two groups were comparable with regard to age, sex ratio, radiotherapy, and complication rate. The percentages of asymmetry of the resting and squeeze sphincter were significantly higher in the anal incontinence group (37.2 +/- 9.3% vs 32.5 +/- 6.7%, P = 0.01; 32.4 +/- 7.8% vs 28.3 +/- 6.3%, P = 0.011). High-pressure zone length, mean resting vector volume, and rectal compliance were not less in the anal incontinence group than in the continence group. In multivariate analysis of manometric variables, the percentages of asymmetry of the resting and squeeze were independent factors associated with anal incontinence (P < 0.05). The mean thickness of the anal cushion and internal anal sphincter did not significantly differ between the anal incontinence and continence groups. CONCLUSION: Sphincter asymmetry is one of the hallmark characteristics of iatrogenic anal incontinence patients after proctectomy, which suggests that anal canal symmetry may be a beneficial factor with regard to anal continence. PMID- 18443853 TI - Predictive value of sonographic features in preoperative evaluation of malignant thyroid nodules in a multinodular goiter. AB - BACKGROUND: The primary goal of ultrasonography (US) in the evaluation of a thyroid nodule is to determine its malignancy, although the diagnosis of a malignant nodule on the basis of US alone is nearly impossible. The aim of this prospective study was to evaluate the predictive value of sonographic features in the preoperative diagnosis of malignant thyroid nodules, and to determine the important features of sonography. METHODS: This prospective study included 550 consecutive patients with , thyroid nodules. Nodules were divided into two groups on the basis of pathological diagnosis: group 1 consisted of 1,633 nodules with a benign pathology, and group 2 consisted of 293 nodules with a malignant pathology. RESULTS: Microcalcifications, blurred nodular margins, and solid and hypoechoic appearance were more common in malignant nodules compared to benign nodules (89.1% versus 5%; 64.5% versus 4.7%; 81.6% versus 30.6% ; and 62.5% versus 43.1%, respectively; p < 0.001). There was a positive correlation between the detection of malignant thyroid nodules and microcalcification (rs = 0.791, p = 0.0001), blurred nodular margin (rs = 0.625, p = 0.0001), solid appearance (rs = 0.376, p = 0.0001), and hypoechoic appearance (rs = 0.141, p = 0.0001). Microcalcifications, blurred nodular margins, and solid and hypoechoic appearance were independent determinants of malignancy upon US examination of thyroid nodules (OR: 159, OR: 37, OR: 9.9, and OR: 2.2, respectively). CONCLUSION: Although we did not identify a single feature indicative of malignancy in the sonographic examination of nodules, microcalcification and blurred margin were the strongest correlates for malignancy. PMID- 18443854 TI - Who was William Ray Rumel? AB - This report details the life and contributions of William Ray Rumel, an early cardiovascular surgeon known for his innovations, particularly the "Rumel tourniquet," and the ability to repair the diseased mitral valve without replacing it. PMID- 18443856 TI - Failure and success of percutaneous angioplasty in a hypertensive child with bilateral renal artery stenosis. AB - We describe the clinical course of a 5-year-old girl with severe arterial hypertension that was uncontrollable with antihypertensive medication. Renal angiography revealed bilateral renal artery stenoses. Because percutaneous transluminal renal angioplasty (PTRA) failed to dilate the stenotic lesions, a renal artery bypass grafting in both renal arteries was performed. The patient remained normotensive for 7 months, and after that the arterial pressure increased again. Digital subtraction angiography demonstrated stenosis at the peripheral and central anastomosis of the vein graft that was used for revascularization of the left kidney. PTRA was decided on and successful patency was achieved. The patient has now been normotensive for a period of 5 years. PMID- 18443855 TI - Antireflux transoral incisionless fundoplication using EsophyX: 12-month results of a prospective multicenter study. AB - BACKGROUND: A novel transoral incisionless fundoplication (TIF) procedure using the EsophyX system with SerosaFuse fasteners was designed to reconstruct a full thickness valve at the gastroesophageal junction through tailored delivery of multiple fasteners during a single-device insertion. The safety and efficacy of TIF for treating gastroesophageal reflux disease (GERD) were evaluated in a prospective multicenter trial. METHODS: Patients (n = 86) with chronic GERD treated with proton pump inhibitors (PPIs) were enrolled. Exclusion criteria included an irreducible hiatal hernia > 2 cm. RESULTS: The TIF procedure (n = 84) reduced all hiatal hernias (n = 49) and constructed valves measuring 4 cm (2-6 cm) and 230 degrees (160 degrees -300 degrees ). Serious adverse events consisted of two esophageal perforations upon device insertion and one case of postoperative intraluminal bleeding. Other adverse events were mild and transient. At 12 months, aggregate (n = 79) and stratified Hill grade I tight (n = 21) results showed 73% and 86% of patients with >or=50% improvement in GERD health-related quality of life (HRQL) scores, 85% discontinuation of daily PPI use, and 81% complete cessation of PPIs; 37% and 48% normalization of esophageal acid exposure; 60% and 89% hiatal hernia reduction; and 62% and 80% esophagitis reduction, respectively. More than 50% of patients with Hill grade I tight valves had a normalized cardia circumference. Resting pressure of the lower esophageal sphincter (LES) was improved significantly (p < 0.001), by 53%. EsophyX-TIF cured GERD in 56% of patients based on their symptom reduction and PPI discontinuation. CONCLUSION: The 12-month results showed that EsophyX-TIF was safe and effective in improving quality of life and for reducing symptoms, PPI use, hiatal hernia, and esophagitis, as well as increasing the LES resting pressure and normalizing esophageal pH and cardia circumference in chronic GERD patients. PMID- 18443857 TI - Retrieval of the protection filter with a soft coaxial catheter after carotid stenting. AB - The purpose of this study was to shorten and simplify the procedure of filter retrieval after carotid stenting with cerebral protecting devices. We propose a retrieval method with a soft-tip guiding catheter, which eliminates the step of balloon exchange and introduction of a retriever catheter for the protection filter. The technique was successfully used in our last 60 consecutive patients. One transient deficit occurred. In conclusion, retrieval of the filter with a soft coaxial catheter after carotid stenting is a feasible and safe method and may simplify cerebrovascular protection during stenting. PMID- 18443858 TI - Characterization of a highly active promoter, PBbgpd, in Beauveria bassiana. AB - The promoter of glyceraldehyde-3-phosphate dehydrogenase (gpd) gene from Aspergillus nidulans (PgpdA) is widely used to direct expression of target genes constitutively in fungi. However, in some species, a heterogeneous promoter is found to be of low efficiency. To obtain a high-efficiency promoter for transformation of Beauveria bassiana, an entomopathogenic fungus widely used as an mycoinsecticide, a glyceraldehyde-3-phosphate dehydrogenase gene (Bbgpd) promoter, was cloned and characterized. Four deletion constructs (-2118, -1153, 726, and -354) of the 5'-upstream sequence of Bbgpd linked to a bar::gus fusion gene (phosphinothricin-resistance::beta-glucuronidase fused gene), which were used as selected marker gene and report gene, respectively, were generated. GUS activities of transgenic strains harboring -726, -1153, and -2118 deletion constructs were much stronger than that of the promoter of Aspergillus nidulans gpdA (PgpdA), with a twofold to threefold increase over that in the PgpdA construct. The -726 fragment was necessary to direct GUS expression in B. bassiana. No -354 transgenic progenies were obtained, possibly because it failed to initiate the transcription of bar::gus fusion gene. A remarkable increase of GUS activity was found between the -1153 and -726 constructs, indicating that some active transcriptional elements were located in this region. With a high expression level and relatively short sequence, PBbgpd can be used to drive target genes in B. bassiana transgenic research. PMID- 18443859 TI - Realistic and affordable lo-fidelity model for learning bronchoscopic transbronchial needle aspiration. AB - BACKGROUND: Transbronchial needle aspiration (TBNA) is used to sample mediastinal abnormalities and lymph node stations for diagnostic purposes and lung cancer staging. The procedure is underused, operator dependent, and reputed to have a steep learning curve. Other difficulties arise from a bronchoscopist's failure to insert the needle satisfactorily into the target node. The purpose of this study was to evaluate the realism and helpfulness of a lo-fidelity, easily constructed hybrid model used for learning and practicing TBNA. METHODS: The model is constructed by attaching a porcine tracheobronchial tree to a Laerdal Airway Model mounted on polyvinyl chloride (PVC) piping. Twelve individuals with various levels of bronchoscopy training and experience were given a 15-min introductory PowerPoint presentation on TBNA strategy and planning, execution, and response to complications. Participants then practiced TBNA alone and with guidance, aided by an assistant, as many times as individually necessary to feel comfortable with the procedure. A five-point Likert scale 8-item questionnaire was then completed. RESULTS: Participants were unanimously positive about their experience (mean scores 4.25-4.91). The model was realistic, provided increased comfort with TBNA techniques, and allowed practice of communication skills. CONCLUSION: This realistic, affordable, and easily constructed hybrid lo-fidelity airway model allows beginner and experienced bronchoscopists opportunities to learn and practice basic TBNA techniques and team communication skills without placing patients at risk. PMID- 18443860 TI - Incidental carcinoma gall bladder during laparoscopic cholecystectomy for symptomatic gall stone disease. AB - INTRODUCTION: Carcinoma gall bladder (CaGB) is a disease with high mortality and is usually diagnosed as an incidental case among patients undergoing laparoscopic cholecystectomy (LC) for symptomatic gall stone disease. METHODS: A total of 3205 LC done between January 2004 and August 2007 for symptomatic gall stone disease were retrospectively searched for incidental CaGB (detected on histopathology). None of these cases had preoperative suspicion of malignancy and their whole data was analyzed with special attention to preoperative and intraoperative findings which could raise suspicion of CaGB. In November 2007, patients were followed up telephonically about their present status of health. RESULTS: Nineteen patients (14 female and 5 male) with incidental CaGB (incidence 0.59%) were detected. Mean age of the patients was 56 years. Only two of these patients had clinical jaundice and both had common bile duct (CBD) stones. The majority of the patients were in early pathological stages (pT) and none was in pT3 and pT4 stage. Seventeen patients could be followed up telephonically in November 2007 and of those 14 patients were alive at a mean follow-up duration of 21.2 months, with one of them having evidence of metastatic disease. CONCLUSION: Gall bladder (GB) malignancy may be curable if diagnosed in early stages as an incidental finding and LC may not worsen the prognosis in such cases. In our series, incidental CaGB was detected in 0.59% patients undergoing LC. No association could be found between preoperative and intraoperative findings that could raise a suspicion of malignancy of gall bladder and so use of retrieval bag as a routine measure in cases with bile spillage may reduce the incidence of port-site metastasis. PMID- 18443861 TI - Efficacy of laparoscopy-assisted distal gastrectomy for gastric cancer in the elderly. AB - BACKGROUND: To date, it has been unclear whether laparoscopy-assisted distal gastrectomy (LADG) is a suitable treatment for elderly patients with early gastric cancer. This study retrospectively compared surgical outcomes between elderly and nonelderly patients with gastric cancer. METHODS: The study group was comprised of 211 patients who underwent distal gastrectomy between April 2000 and March 2007. Of these, 130 patients (26 aged >or=75 years and 104 aged <75 years) underwent LADG, and the remaining 81 patients underwent conventional open distal gastrectomy (ODG). Short- and long-term patient outcomes were evaluated. RESULTS: The operation time was significantly longer in the LADG group than in the ODG group (262.6 versus 234.3 min, p = 0.005), but the other short-term outcomes did not differ between the two groups. When performed by an experienced surgeon, blood loss was significantly reduced, while operation time for LADG was similar to that for ODG. Within the LADG group, incidences of comorbid disease and lymph node metastasis were significantly greater, the histological tumor type was significantly more differentiated, and the macroscopically depressed tumor type was less common in elderly patients. However, the incidence of postoperative morbidity did not differ between the elderly and nonelderly groups (11.5% versus 3.8%, p = 0.1201), and there was no significant difference in postoperative course. Logistic regression analysis showed that body mass index, but not chronological age, was an independent predictive factor of postoperative morbidity (odds ratio = 3.674, p = 0.045). There were no significant differences in overall or disease-specific survival between elderly and nonelderly patients. CONCLUSION: LADG is an effective treatment for elderly patients with early gastric cancer if it is performed by an experienced surgeon. A high-volume study is needed to confirm this rationale. PMID- 18443862 TI - Laparoscopic surgery induced interleukin-6 levels in serum and gut mucosa: implications of peritoneum integrity and gas factors. AB - BACKGROUND: The peritoneum serves as an integral part of host immunity, and the homeostasis of intraperitoneal environment is held to be beneficial for patient recovery after abdominal surgery. How minimal invasive access to the abdomen by laparoscopy and incisions would alter the intraperitoneal immune response is not fully defined. This study examined the levels of IL-6 in serum and gut mucosa following laparoscopic surgery with reference to the peritoneum integrity and gas factors. METHODS: BALB/c mice were divided into three groups (ten animals in each group) that underwent different abdominal surgical treatments: laparotomy (open group), laparoscopy with atmospheric air (air group) or carbon dioxide pneumoperitoneum (CO(2) group). A 3-cm incision of the skin and muscle was made in all animals except the peritoneum was left intact in the latter two animal groups in order to cancel out the incisional tissue injury present in laparotomy. Four hours after surgery, serum, and jejunal mucosa were extracted for IL-6 measurement by enzyme-linked immunosorbent assay (ELISA). RESULTS: Open laparotomy resulted in significant elevation of serum IL-6 level when compared to the laparoscopic procedures in the descending order of open > air > CO(2) groups. For the mucosal IL-6 level, both the open and air groups were significantly higher than the CO(2) group. Data from multivariate analysis revealed that breaching or incision of the peritoneum was an important factor for the elevated levels of IL-6 in serum (p < 0.001) and jejunal mucosa (p = 0.032). CONCLUSION: The present study suggests that laparoscopic techniques to minimize the size of the peritoneal incision as well as exposure to atmospheric air can potentially reduce postoperative stress responses associated with abdominal surgery and prompt early recovery. PMID- 18443863 TI - Previously unreported high-grade complications of adrenalectomy. AB - BACKGROUND: Serious complications of adrenalectomy are rare but the incidence may be underestimated if they occur outside major referral centers. We report five cases of high-grade complications after adrenalectomy that have not been previously described. METHODS: The records of five cases of adrenalectomy performed at outside hospitals were reviewed. Four cases were referred for management of complications and one for medical-legal review. The nature of the adrenal lesion, operative approach, complication(s), and subsequent clinical course and complication management were assessed. Both open adrenalectomy (OA) and laparoscopic adrenalectomy (LA) cases were included. RESULTS: Operative indications were pheochromocytoma (N = 3), aldosteronoma (N = 1), and a nonfunctioning 6-cm hypervascular mass (N = 1). Complications of adrenalectomy included: case 1--complete transection of the porta hepatitis during right LA resulting in hepatic failure requiring emergent liver transplantation; case 2- ligation of the hepatic artery during right OA resulting in recurrent cholangitis and bile duct sclerosis requiring liver transplantation; case 3--ligation of the left ureter during LA resulting in postoperative hydronephrosis and loss of renal function; case 4--loss of left kidney function after OA, likely secondary to renal artery ligation ultimately requiring laparoscopic nephrectomy; case 5--LA of a normal adrenal gland for a 6-cm hypervascular mass thought to be arising from the adrenal gland. Three-month postoperative imaging demonstrated a persistent mass and the patient underwent hand-assisted laparoscopic nephrectomy for a left upper pole renal cell carcinoma that was missed at the time of LA. CONCLUSION: Despite the generally low morbidity of adrenalectomy, serious and potentially life-threatening complications can occur. Surgeon inexperience may be a factor in the occurrence of some of these complications which have not been previously described. PMID- 18443864 TI - Reply to: 'Re: "The invisible cholecystectomy"'. PMID- 18443865 TI - Is inflammation a significant predictor of bile duct injury during laparoscopic cholecystectomy? AB - BACKGROUND: Bile duct injuries (BDI) have been reported to occur more frequently during laparoscopic cholecystectomy (LC) compared to open cholecystectomy (OC). Several studies have demonstrated various potential predisposing factors for BDI. However, there is a controversy as to whether gallbladder inflammation is a significant predictor for BDI. Therefore, out primary aim was to investigate the relationship between inflammation and BDI at LC, and secondarily to present the management and clinical outcome of BDI. METHODS: We recorded all consecutive LC performed between 1993 and 2005 in our institution by nine staff surgeons. BDI were classified according to Strasberg's classification. Simple and multivariate logistic regression analysis was performed to evaluate the association between inflammation and BDI occurrence during LC. RESULTS: There were 2,184 patients. Among those, 344 had inflammation (16%). The conversion rate was 5% and was higher among male, elder patients, and those with inflammation. The BDI incidence was 0.69% (0.14% for major and 0.55% for minor injuries) and it was significantly higher in those with inflammation compared to those without inflammation (p = 0.01). In particular, the risk for BDI was almost 3.5 times higher in those with inflammation (OR = 3.61, 95% CI 1.27-10.21). Inflammation remained an independent risk factor for BDI even after adjustment for potential confounders. Among patients sustaining injury, one died and two have recurrent cholangitis. No association was observed between clinical outcome and management of BDI, time of diagnosis, sex, and inflammation. CONCLUSION: We revealed that inflammation is an independent predictor of BDI occurrence during LC. Therefore, it would be advisable for surgeons to not hesitate to convert a LC to an OC in the presence of inflammation. PMID- 18443866 TI - The anatomical limits of the posterior vaginal vault toward its use as route for intra-abdominal procedures. AB - BACKGROUND: The use of natural openings for abdominal surgery started at the beginning of the 21st century. A trans-Douglas endoscopic device has been designed to perform most of the intra-abdominal operations in women through the pouch of Douglas. The posterior vaginal vault is limited in size and could be damaged by an oversized instrument. This study investigates the optimal dimensions of the instrument by measuring the limiting factor in the passage. METHODS: In ten female embalmed bodies the transversal and sagittal diameter of the fornix posterior vaginalis was measured by two observers. The pouch of Douglas was filled to its maximal capacity with mouldable latex through an open abdomen. By internal vaginal examination the connective tissue borders of the fornix posterior were palpated and the impression in the cast was measured. The mean value of these two diameters was evaluated in this study. The level of agreement between the observers was calculated. RESULTS: The mean fornix posterior diameter was 2.6 cm (standard deviation, SD 0.5 cm) with a range of 2.0 3.4 cm. The mean difference between the two observers of all measurements was 0.08 cm (not significant). Both observers had an acceptable intraobserver variation. The interobserver agreement was excellent. CONCLUSION: Instruments with dimensions within the measured limits can be used safely for intra-abdominal operations via the natural orifice of the vagina. PMID- 18443867 TI - Surgical usefulness of indocyanine green as an alternative to India ink for endoscopic marking. AB - BACKGROUND: India ink has been commonly used for preoperative colonic tattooing, but various complications have been reported. This study aimed to evaluate the usefulness of indocyanine green (ICG) marking as a replacement for India ink. METHODS: This study enrolled 40 patients who between January 2005 and February 2006 underwent laparoscopic or open surgery for colorectal lesions considered difficult to locate intraoperatively. Because one patient had a history of allergy to iodinated contrast material, metal clipping was used instead of ICG to mark the lesion. Endoscopists injected 5 ml of ICG suspension and saline solution adjacent to the lesion at duplicate locations to evaluate the visibility, duration, and adverse effects of the dye. For 39 patients, the date of the preoperative colonoscopy was not set for examination of the appropriate interval between endoscopic marking and the surgical operation. RESULTS: The median interval between ICG marking and surgery was 4 days (range, 1-73 days). All 29 patients who underwent surgery within 8 days after marking had positive green ICG staining at the time of surgery. After 9 days or more, however, positive staining was seen clearly in only two of the remaining 10 patients. The staining tended to grow weaker and fainter over the time course, eventually dissipating. No perioperative adverse reactions to the dye were observed. CONCLUSION: This study supports the use of ICG as a safe technique that can be identified reliably during operations performed within 8 days after endoscopic injection. PMID- 18443868 TI - Force feedback and basic laparoscopic skills. AB - BACKGROUND: Not much is known about the exact role of force feedback in laparoscopy. This study aimed to determine whether force feedback influences movements of instruments during training in laparoscopic tasks and whether force feedback is required for training in basic laparoscopic force application tasks. METHODS: A group of 19 gynecologic residents, randomly divided into two groups, performed three laparoscopic tasks in both the box trainer and the virtual reality (VR) trainer. The box-VR group began with the box trainer, whereas the VR box group began with the VR trainer. The three selected tasks included different levels of force application. The box trainer provides natural force feedback, whereas the VR trainer does not provide force feedback. The performance of the two groups was compared with regard to time, path length, and depth perception. RESULTS: For the tasks in which force plays hardly a role, no differences between box-VR group and the VR-box group were found. During a task in which force application (pulling and pushing forces) plays a role, the box-VR group outperformed VR-box group in the box trainer. Moreover, training with the box trainer had a positive effect on subsequent performance of the task with the VR trainer. This was not found the other way around. No differences were found between box-VR and the VR-box group in tasks not requiring force application. CONCLUSION: Force feedback influences basic laparoscopic skills during tasks in which pulling and pushing forces are applied. For these tasks, the switch from the trainer without force feedback to the one with natural force feedback has a detrimental effect on performance. Therefore, training for tasks in which forces play an important role (e.g., stretching, grasping) should be done using systems with natural force feedback, whereas eye-hand coordination can be trained without force feedback. PMID- 18443869 TI - Biomechanical properties of lightweight versus heavyweight meshes for laparoscopic inguinal hernia repair and their impact on recurrence rates. AB - BACKGROUND: Laparoscopic inguinal hernia repair can be performed using light- or heavyweight meshes. Apart from the size of the mesh, its friction coefficient (mu(0)) and flexural stiffness are of crucial importance to avoidance of hernia recurrence. METHODS: In the current biomechanical study, tensile tests were performed to determine the ultimate tensile strength and modulus of elasticity of six lightweight meshes and six heavyweight meshes for laparoscopic inguinal hernia repair. To determine their friction coefficient (mu(0)), the meshes were placed between a resected peritoneum and groin muscles during an autopsy. Meshes measuring 15 x 10 cm in size then were used in a hernia model with an opening size of 1.5, 3, or 5 cm. RESULTS: The ultimate tensile strength and modulus of elasticity were significantly lower in the lightweight mesh group than in the heavyweight mesh group. The mean friction coefficient (mu(0)) of the meshes was 0.4. Given an opening of 1.5 cm, all meshes remained adequately stable. At opening sizes of 3 and 5 cm, the lightweight meshes flexed on the average by 3.16 +/- 0.4 mm and 10.40 +/- 2.5 mm, respectively. Heavyweight meshes, on the other hand, were significantly less flexible. Their mean flexure was, respectively, 0.34 +/- 0.2 mm and 3.97 +/- 0.7 mm (p < 0.001). CONCLUSION: Stable meshes are characterized by a small degree of flexure and do not slide into the gap even when subjected to repetitive loads. Therefore, in terms of hernia recurrence, meshes with greater flexural stiffness or well-fixed lightweight meshes that adequately overlap the hernia defect can be used for laparoscopic treatment of large inguinal hernias. PMID- 18443870 TI - Objective evaluation of expert and novice performance during robotic surgical training tasks. AB - BACKGROUND: Robotic laparoscopic surgery has revolutionized minimally invasive surgery for the treatment of abdominal pathologies. However, current training techniques rely on subjective evaluation. The authors sought to identify objective measures of robotic surgical performance by comparing novices and experts during three training tasks. METHODS: Five novices (medical students) were trained in three tasks with the da Vinci Surgical System. Five experts trained in advanced laparoscopy also performed the three tasks. Time to task completion (TTC), total distance traveled (D), speed (S), curvature (kappa), and relative phase (Phi) were measured. RESULTS: Before training, TTC, D, and kappa were significantly smaller for experts than for novices (p < 0.05), whereas S was significantly larger for experts than for novices before training (p < 0.05). Novices performed significantly better after training, as shown by smaller TTC, D, and kappa, and larger S. Novice performance after training approached expert performance. CONCLUSION: This study clearly demonstrated the ability of objective kinematic measures to distinguish between novice and expert performance and training effects in the performance of robotic surgical training tasks. PMID- 18443871 TI - 3D virtual reality and selective vascular control for laparoscopic left hepatic lobectomy. AB - BACKGROUND: Careful control of haemostasis is particularly important in laparoscopic hepatic surgery, since a bloodless operative field results in safer and smoother procedures. A selective vascular control for a left lateral segmentectomy may be facilitated by the use of three-dimensional (3D) virtual reality. MATERIALS AND METHODS: A 67-year-old male patient presenting with a 3.5 cm hepatocellular carcinoma (HCC) located between segment II and III of the liver was referred for hepatic resection. Transplant was contraindicated due to previous head and neck cancer surgery. Preoperative 3D reconstruction was used for preoperative planning and allowed a virtual resection to be done as well as peroperative simulation. RESULTS: Five ports were used. The first step was primary control of the hepatic pedicle. 3D virtual-reality reconstruction demonstrated the position of the tumor in the segment and regarding the vessels. The left hepatic artery and the portal vein were successively dissected and controlled. The real anatomy was compared to the virtual-reality reconstruction. Both demonstrated the same anatomy. Vascular section was completed and this resulted in a typical color change of the left lateral segment as well as a small decrease in size. The bisegmentectomy was performed using harmonic dissectors (Autosonix(R), Tyco Healthcare), bipolar cautery, clips, and application of Endo GIA vascular staples (Tyco Healthcare) on the portal pedicles. The procedure was completed following isolation and control of the left hepatic vein. After section, the specimen was placed in a bag and extracted following enlargement of the camera port. Follow-up was uneventful and there was no elevation of hepatic enzymes or postoperative ascites. The patient left the hospital on the fifth postoperative day. CONCLUSION: 3D reconstruction allowed the procedure to be simulated preoperatively. This facilitated the intraoperative identification of the vascular anatomy and the control of the left lateral segment arteries and veins, thus preventing intraoperative bleeding. The use of this approach in preoperative planning is recommended. PMID- 18443872 TI - Reoperations after gastric banding: replacement or alternative procedures? AB - BACKGROUND: Laparoscopic gastric banding (LAGB) is the most popular surgical procedure for morbid obesity in Europe. Long-term complications like slippage of the band or pouch dilatation are well known and lead to reoperations in a substantial number of patients. In this study, results and follow-ups of patients with reoperations after gastric banding were analyzed. METHODS: Between May 1997 and June 2006, 172 patients were treated with LAGB for morbid obesity. 41 of these patients underwent one or more band-related reoperations (female symbol = 32, male symbol = 9). Causes for and type of reoperation were analyzed. Weight loss and comorbidities were compared for different types of reoperations. RESULTS: There were no deaths following the reoperations. Band replacement (n = 18), band repositioning (n = 7), conversion to sleeve gastrectomy (SG, n = 2) and Roux-en-Y gastric bypass (RYGBP, n = 2) or band removal without any further substitution (n = 12) were performed as first reoperation. Seven patients had a second reoperation: RYGBP (n = 3), SG (n = 1), or band removal (n = 3). Median follow-up since reoperation was 56 months (range 7-113). Excess weight loss (EBWL%) of patients was 59.4% after RYGBP (n = 5), 45.1% after re-banding (n = 18), and 33.4% after SG (n = 2). Comorbidities were further reduced or even resolved after reoperation. Patients whose band was removed without subsequent bariatric procedures lost significantly less weight (n = 13, EBWL% 23.4) than patients with band replacement (n = 18, EBWL% 46.4, p = 0.04). CONCLUSION: Laparoscopic reoperation after LAGB is safe and feasible. Reoperation leads to further decrease of BMI and obesity-related comorbidities. Band replacement is a good option for patients with good weight loss after initial LAGB. Alternative procedures, preferably RYGBP, are required for cases of band failure. Overall, RYGBP appears to be the most effective option to induce further weight loss. PMID- 18443873 TI - Lifting of the umbilicus for the installation of pneumoperitoneum with the Veress needle increases the distance to the retroperitoneal and intraperitoneal structures. AB - BACKGROUND: In laparoscopy, 50% of all complications occur during establishment of the pneumoperitoneum. Elevation of the fascia is recommended for the Veress needle approach, although the benefit has not been proved to date. This study aimed to evaluate the intraabdominal changes during lifting of the fascia with regard to the distance from the fascia to the retroperitoneal vessels and the intestine for access in laparoscopy. METHODS: For 10 patients scheduled to undergo laparoscopic cholecystectomy, the operation started with the computed tomography (CT) scan. After orotracheal intubation, a CT scan of the umbilical region was performed. After a supraumbilical incision, the fascia was freed and elevated with stay sutures. During maximal elevation, a second CT scan was performed. Distances to the intestinal (small bowel) and retroperitoneal structures (iliac artery, vena cava) were measured. Intraabdominal pressure was measured with a transcystic balloon manometer before (a) and after (b) elevation of the fascia, after insertion of the Veress needle (c), and after completion of the insufflations (d). RESULTS: Lifting of the fascia increased the distance between the fascia and the intestinal structures in the patients with no prior abdominal surgery (mean distance, 1.92 cm; range, 0.87-2.67 cm) and the distance between the fascia and the retroperitoneal vessels (mean distance, 7.83 cm; range, 3-11 cm). The median intraabdominal pressures in terms of cm H(2)O were 5.4 for a, 1.1 for b, 1.1 for c, and 12. 5 for d. CONCLUSION: Elevation of the fascia before the first entrance to the abdominal cavity for laparoscopy may increase safety due to a significant enlargement of distance between the fascia and the retroperitoneal structures. PMID- 18443874 TI - Transanal endoscopic operation for rectal lesions using two-dimensional visualization and standard endoscopic instruments: a prospective cohort study and comparison with the literature. AB - BACKGROUND: The transanal endoscopic operation (TEO) has proved to be an effective alternative to conventional surgery for the treatment of rectal lesions. The TEO procedure offers reduced morbidity, faster recovery and equivalent oncologic outcome. Currently, two instrument sets are available: one with three-dimensional (Wolf) and one with two-dimensional (Storz) optic capacities. The three-dimensional (3D) instrument set is considered the golden standard. Although the advantages of TEO are imposing, the procedure with the 3D armamentarium has certain technical and financial drawbacks. This study therefore aimed to compare results for the TEO 2D alternative with recently published results for 3D TEO. METHODS: All consecutive patients with benign or malignant pT1 or pT2 rectal lesions undergoing TEO were prospectively followed. All procedures were performed with the 2D armamentarium using standard endoscopic instruments, a rectoscope (diameter, 4 cm; working length, 7.5-15 cm), and 5-mm Ligasure and Ultracision. Operating times, complications, hospital stay, and oncologic outcome were gathered and compared with published data. RESULTS: Between 2004 and 2006, 31 patients with a median age of 75 years (range, 33-87 years) underwent 31 TEOs for a total of 36 rectal lesions (29 tubulovillous adenomas and 7 adenocarcinomas). The median distance of the lesion from the anal verge was 7.5 cm (range, 5-15 cm). The median lesion diameter was 2.3 cm (range, 0.5-5.0 cm). The locations of the lesions were as follows: 18 on the dorsal, 5 on the ventral, and 5 on the lateral rectal wall. The median operating time was 55 min (range, 25-165 min), compared with 105 min reported in the literature. All the lesions except one could be radically excised. No intraoperative complications occurred. Postoperative complications occurred for three patients, all due to hemorrhage. The median hospital stay was 3 days (range, 1-21 days). During a median follow-up period of 15 months (range, 1-35 months), two recurrences took place. CONCLUSION: The study findings showed that for rectal tumors located up to 15 cm from the anal verge with a maximal diameter of 5 cm, TEO using standard laparoscopic instruments with a 2D view is feasible and provides results comparable with those associated with a 3D view and dedicated instruments. Furthermore, the 2D procedure can be performed with improved ergonomics due to movable monitors and is considerably less expensive. PMID- 18443875 TI - A 10-year follow-up study on endoscopic total extraperitoneal repair of primary and recurrent inguinal hernia. AB - BACKGROUND: To determine whether endoscopic repair is favorable in the long term, follow-up recurrence rates after 10 years need to be assessed. METHODS: Between January 1995 and January 1996, 306 consecutive patients underwent total extraperitoneal (TEP) inguinal hernia repair. Long-term follow-up assessment occurred from January 2006 to May 2006. RESULTS: After a 10-year follow-up period, six (4%) recurrences were found in the primary inguinal hernia group and three recurrences (11%) in the recurrent inguinal hernia group. Age, experience, hospital stay, and operating time were not significantly correlated with recurrences. CONCLUSION: The long-term results of TEP primary inguinal hernia repair demonstrate it to be an effective and safe procedure with an acceptable recurrence rate. Recurrence rates may be underestimated because the findings show that recurrences continue to occur for as long as 10 years. PMID- 18443876 TI - Prospective evaluation of the value of magnetic resonance imaging in suspected acute sigmoid diverticulitis. AB - PURPOSE: The purpose of this study was to prospectively investigate patients with suspected acute colonic diverticulitis and to provide sensitivity, specificity, and interobserver agreement in a blinded trial. METHODS: Fifty-five patients (29 men; 59 +/- 13 (range, 29-76) years) who reported to the emergency room with clinically suspected acute colonic diverticulitis were prospectively included in the study. All patients underwent magnetic resonance imaging scans of their abdomen before and after contrast agent administration. Two assessors blinded to all clinical, laboratory, and radiologic results evaluated the images separately. RESULTS: The assessors reported colonic wall thickening, segmental narrowing of the colon, presence of diverticula, pericolic fatty infiltration, ascites, and abscesses. The assessors had to diagnose or rule out acute colonic diverticulitis. Sensitivities, specificities, positive, and negative likelihood ratios were derived. To determine interobserver agreement, a Cohen's kappa coefficient was calculated. The two assessors exhibited sensitivities of more than 94 percent, specificities of 88 percent, positive likelihood ratios of more than 7.5, and negative likelihood ratios of less than 0.07. The kappa coefficient showed a significant, strong correlation between both assessors (kappa = 0.68). CONCLUSIONS: Magnetic resonance imaging is investigator independent and provides high sensitivity and specificity for the diagnosis of acute colonic diverticulitis. PMID- 18443878 TI - Hysterectomy does not cause constipation. AB - PURPOSE: This study was designed to evaluate the risk on development and persistence of constipation after hysterectomy. METHODS: We conducted a prospective, observational, multicenter study with three-year follow-up in 13 teaching and nonteaching hospitals in The Netherlands. A total of 413 females who underwent hysterectomy for benign disease other than symptomatic uterine prolapse were included. All patients underwent vaginal hysterectomy, subtotal abdominal hysterectomy, or total abdominal hysterectomy. A validated disease-specific quality-of-life questionnaire was completed before and three years after surgery to assess the presence of constipation. RESULTS: Of the 413 included patients, 344 (83 percent) responded at three-year follow-up. Constipation had developed in 7 of 309 patients (2 percent) without constipation before surgery and persisted in 16 of 35 patients (46 percent) with constipation before surgery. Preservation of the cervix seemed to be associated with an increased risk of the development of constipation (relative risk, 6.6; 95 percent confidence interval, 1.3-33.3; P = 0.02). Statistically significant risk factors for the persistence of constipation could not be identified. CONCLUSIONS: Hysterectomy does not seem to cause constipation. In nearly half of the patients reporting constipation before hysterectomy, this symptom will disappear. PMID- 18443879 TI - Sex pheromone of the American warble fly, Dermatobia hominis: the role of cuticular hydrocarbons. AB - Chemical communication between adults of the American warble fly, Dermatobia hominis (Diptera: Oestridae), was investigated by electroantennography and behavioral bioassays. Significant electroantennographic responses were recorded from both sexes to hexane-soluble cuticular lipids from either sex. Olfactometer tests indicated an attraction between males and females, and between females. Copulatory behavior of males with a white knotted string treated with female extract confirmed production of a sexual stimulant by females. Such behavior was not observed in tests with male extract, demonstrating that the pheromone acts also as a sex recognition factor. Cuticular hydrocarbons of sexually mature female and male D. hominis were identified by Gas chromatography-mass spectrometry and consist of a mixture of saturated n-, monomethyl-, and dimethylalkanes in both sexes. Sexual dimorphism was characterized by a higher relative concentration of dimethylalkanes in males and the presence of alkenes only in females. PMID- 18443880 TI - Belowground chemical signaling in maize: when simplicity rhymes with efficiency. AB - Maize roots respond to feeding by larvae of the beetle Diabrotica virgifera virgifera by releasing (E)-beta-caryophyllene. This sesquiterpene, which is not found in healthy maize roots, attracts the entomopathogenic nematode Heterorhabditis megidis. In sharp contrast to the emission of virtually only this single compound by damaged roots, maize leaves emit a blend of numerous volatile organic compounds in response to herbivory. To try to explain this difference between roots and leaves, we studied the diffusion properties of various maize volatiles in sand and soil. The best diffusing compounds were found to be terpenes. Only one other sesquiterpene known for maize, alpha-copaene, diffused better than (E)-beta-caryophyllene, but biosynthesis of the former is far more costly for the plant than the latter. The diffusion of (E)-beta-caryophyllene occurs through the gaseous rather than the aqueous phase, as it was found to diffuse faster and further at low moisture level. However, a water layer is needed to prevent complete loss through vertical diffusion, as was found for totally dry sand. Hence, it appears that maize has adapted to emit a readily diffusing and cost-effective belowground signal from its insect-damaged roots. PMID- 18443881 TI - Intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma: a Western experience. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an unusual tumour. METHODS: The clinicopathological data of 67 patients with ICC and combined hepatocellular cholangiocarcinoma (HCC-ICC) are presented. RESULTS: HCV-HBV infection was present in 37.3% and chronic liver disease in 38.7% of cases, a rate higher than in the normal population; in these patients the cancer was small, often asymptomatic and of combined type. Liver resection was performed in 51 patients; at 1, 3 and 5 years, overall survival was 87.9%, 59.0%, and disease-free survival was 47.7% and 78.8%, 51.4%, and 46.7%, respectively. The better results were in the group of cirrhotic patients in whom ICC was diagnosed by a screening program for HCC (5-year survival 76.6%). Nodal metastasis showed negative prognostic value for both overall and disease-free survival; in N+ patients mean survival was 14.7 months after liver resection and lymph node dissection. CONCLUSION: Viral infection and cirrhosis may be considered risk conditions for ICC and combined HCC-ICC; in resected patients survival was good. Nodal metastases must not be considered a contraindication for liver resection. PMID- 18443882 TI - Effects of increased patient cost sharing on socioeconomic disparities in health care. AB - BACKGROUND: Increasing patient cost sharing is a commonly employed mechanism to contain health care expenditures. OBJECTIVE: To explore whether the impact of increases in prescription drug copayments differs between high- and low-income areas. DESIGN: Using a database of 6 million enrollees with employer-sponsored health insurance, econometric models were used to examine the relationship between changes in drug copayments and adherence with medications for the treatment of diabetes mellitus (DM) and congestive heart failure (CHF). SUBJECTS: Individuals 18 years of age and older meeting prespecified diagnostic criteria for DM or CHF were included. MEASUREMENTS: Median household income in the patient's ZIP code of residence from the 2000 Census was used as the measure of income. Adherence was measured by medication possession ratio: the proportion of days on which a patient had a medication available. RESULTS: Patients in low income areas were more sensitive to copayment changes than patients in high- or middle-income areas. The relationship between income and price sensitivity was particularly strong for CHF patients. Above the lowest income category, price responsiveness to copayment rates was not consistently related to income. CONCLUSIONS: The relationship between medication adherence and income may account for a portion of the observed disparities in health across socioeconomic groups. Rising copayments may worsen disparities and adversely affect health, particularly among patients living in low-income areas. PMID- 18443883 TI - Recognition and management of chronic kidney disease in an elderly ambulatory population. AB - BACKGROUND: Chronic kidney disease (CKD) is a growing problem among the elderly. Early detection is considered essential to ensure proper treatment and to avoid drug toxicity, but detection is challenging because elderly patients with CKD often have normal serum creatinine levels. We hypothesized that most cases of CKD in the elderly would go undetected, resulting in inappropriate prescribing. OBJECTIVE: To determine whether recognition of CKD is associated with more appropriate treatment DESIGN: Retrospective chart review PARTICIPANTS: All patients aged >/=65 years with a measured serum creatinine in the past 3 years at 2 inner city academic health centers. MEASUREMENTS: Estimated glomerular filtration rate (eGFR) calculated using the Modified Diet in Renal Disease equation, and for patients with eGFR < 60, documentation of CKD by the provider, diagnostic testing, nephrology referral and prescription of appropriate or contraindicated medications. RESULTS: Of 814 patients with sufficient information to estimate eGFR, 192 (33%) had moderate (eGFR < 60 mL/min) and 5% had severe (eGFR < 30 mL/min) CKD. Providers identified 38% of moderate and 87% of severe CKD. Compared to patients without recognized CKD, recognized patients were more likely to receive an ACE/ARB (80% vs 61%, p = .001), a nephrology referral (58% vs 2%, p < .0001), or urine testing (75% vs 47%, p < .0001), and less likely to receive contraindicated medications (26% vs 40%, p = .013). CONCLUSIONS: Physicians frequently fail to diagnose CKD in the elderly, leading to inappropriate treatment. Efforts should focus on helping physicians better identify patients with low GFR. PMID- 18443884 TI - "You always end up feeling like you're some hypochondriac": intimate partner violence survivors' experiences addressing depression and pain. AB - OBJECTIVE: Little is known regarding how providers should use information about intimate partner violence (IPV) to care for depressed patients. Our objective was to explore what depressed IPV survivors believe about the relationship between abuse, mental health, and physical symptoms and to elicit their recommendations for addressing depression. DESIGN: Focus group study. PATIENTS/PARTICIPANTS: Adult, English-speaking, female, Internal Medicine clinic patients with depressive symptoms and a history of IPV. INTERVENTIONS: Thematic analysis using an inductive approach (consistent with grounded theory), at a semantic level, with an essentialist paradigm. MEASUREMENTS AND MAIN RESULTS: Twenty three women participated in 5 focus groups. Although selected because of their depression, participants often felt their greatest concerns were physical. They acknowledged that their abuse history, depression, and physical complaints compound each other. They appreciated the need for health care workers to know about their depression and IPV history to get a "full picture" of their health, but they were often hesitant to discuss such issues with providers because of their fear that such information would make providers think their symptoms were "all in their head" or would encourage providers to discount their pain. Participants discussed difficulties related to trust and control in relationships with providers and gave recommendations as to how providers can earn their trust. CONCLUSIONS: Understanding a patient's IPV history may allow providers to develop a better therapeutic relationship. To treat depression adequately, it is important for providers to reassure patients that they believe their physical symptoms; to communicate respect for patients' intelligence, experience, and complexity; and to share control. PMID- 18443885 TI - Acute diverticulitis of the left colon: value of the initial CT and timing of elective colectomy. AB - Computed Tomography is undeniably the most useful tool to confirm the suspected diagnosis of acute left-colonic diverticulitis and to objectively grade its severity into moderate diverticulitis (no signs of colonic perforation) and severe diverticulitis (signs of colonic perforation). Indeed, the severity of acute diverticulitis is statistically predictive of the risk both to need surgical treatment of the first episode of acute diverticulitis, and to follow a complicated evolution after successful conservative treatment of the acute phase. Consequently, CT brings a major contribution to define the place of surgery during the acute phase of diverticulitis, and, later on, inside the long-term evolution of the disease after initial successful conservative treatment. PMID- 18443886 TI - Perforated duodenal ulcer after laparoscopic gastric bypass. AB - A patient with a history of a laparoscopic gastric bypass presented with a perforated duodenal ulcer. The ulcer was laparoscopically oversewn, and an omentoplasty was performed. Postoperatively, a broad spectrum antibiotic and a proton pump inhibitor were administrated. Several questions arise regarding the diagnosis and treatment of duodenal ulcers after gastric bypass. What are the diagnostic tools to detect a duodenal ulcer, and how should Helicobacter pylori be diagnosed after gastric bypass? The key question is whether the bypassed stomach should be resected as a definitive treatment for complicated duodenal ulcers. PMID- 18443887 TI - Regulation of bone mineral density in morbidly obese women: a cross-sectional study in two cohorts before and after bypass surgery. AB - BACKGROUND: The mechanisms by which increased body weight influence bone mass density (BMD) are still unknown. The aim of our study was to analyze the relationship between anthropometric and body composition variables, insulin growth factor-I (IGF-I), adiponectin and soluble tumor necrosis factor-alpha receptors (sTNFR) 1 and 2 with BMD in two cohorts of morbid obese patients, before and after bypass surgery. METHODS: The first cohort included 25 women aged 48+/-7.6 years studied before bypass surgery. The second included 41 women aged 46+/-9.2 years, 12 months after surgery. We studied anthropometric variables obtained from whole body DEXA composition analysis. Serum IGF-I, intact serum parathyroid hormone, 25-hydroxivitamin D3, plasma adiponectin concentrations, sTNFR1, sTNFR2 concentrations were measured. RESULTS: In the first cohort, the BMI was 44.5+/-3.6 kg/m2, parathyroid hormone, IGF-I, and adiponectin concentrations were lower, and sTNFR1 concentrations were higher than in the second cohort. In the multiple regression analysis, BMD remained significantly associated with body fat percentage (beta -0.154, p=0.01), lean mass (beta 0.057, p=0.016) and phosphate concentration (beta 0.225, p=0.05). In the second cohort, BMI was 31+/-5.1 kg/m2. In the multiple regression analysis, BMD remained significantly associated with lean mass (beta 0.006, p=0.03). CONCLUSION: The inverse correlation found between body fat and BMD in the first cohort indicates morbid obesity increases the risk of osteoporosis and we found a positive correlation with lean and fat mass before bariatric surgery and with lean mass after bypass surgery. PMID- 18443888 TI - Initial evaluation of laparoscopic Roux-en-Y gastric bypass and adjustable gastric banding in Korea: a single institution study. AB - BACKGROUND: Obesity becomes a global epidemic disease, and bariatric surgery is increasing in Korea as well as in western countries. The first laparoscopic Roux en-Y gastric bypass (LRYGBP) was performed in 2003, and the Lap Band was approved for use in Korea in 2004. There are no data regarding gastric bypass and adjustable gastric banding regarding weight loss as well as changing of pre existing comorbidities up to date. METHODS: St. Mary's Hospital Center, main leader of bariatric surgery in Korea, performed 76 weight loss operations [LRYGBP = 25, laparoscopic adjustable gastric banding (LAGB) = 51] for morbid obesity. We retrospectively reviewed a series of bariatric cases and examined changes of weight loss, postoperative complications, and pre-existing comorbidities between two procedures. RESULTS: There were no significant differences in age, BMI, sex distribution, pre-existing comorbidities in two procedures. Patients undergoing LRYGBP had longer operative times, more blood loss, and longer hospital stays. There is significant difference regarding postoperative complication (p < 0.05) but neither for mortality nor pulmonary embolism with both procedures. Percentage of excess weight loss (%EWL) of LRYGBP at 12, 24, and 36 months were 76.9%, 79.7%, and 85.8%, and %EWL of LAGB were 46.8%, 55.1%, 63.3%, respectively. The patients in the LRYGBP who has dyslipidemia, sleep apnea, degenerative joint disease, and diabetes mellitus were more likely to improve than the patients after LAGB at early postoperative period. CONCLUSIONS: The results of our initial study indicate that LRYGBP and LAGB are technically feasible and safe. It is a low rate of major postoperative complications without mortality. LRYGBP and LAGB are quite satisfactory and promising bariatric procedures with significant weight loss and improvement of obesity-related metabolic comorbidities in Korean. PMID- 18443889 TI - A novel weight-reducing operation: lateral subtotal gastrectomy with silastic ring plus small bowel reduction with omentectomy. AB - BACKGROUND: "The ideal bariatric operation should preserve normal gastroduodenal continuity, reduce food intake, and allow the addition of intestinal short circuiting that would stimulate GLP-1 secretion" (Mason, Surg Obes Rel Dis, 1:123 125, 2005). METHODS: 246 obese patients underwent a subtotal lateral gastric resection with silastic gastric ring placement, plus a moderate mid-small-bowel resection with omentectomy. This configuration preserves the pylorus, duodenum, 50-200 cm of jejunum, and 200-300 cm of ileum. The residual gastric pouch is 5-10 times larger than that in a standard Roux-en-Y gastric bypass (RYGB), and the length of small bowel in digestive continuity is 4-8 times greater than that in current diversionary malabsorptive procedures. RESULTS: Weight loss and amelioration of comorbidities were similar to results following conventional RYGB. An average of 36% total body weight loss, with BMI decrease of 17 kg/m(2), was observed at 1.5 years and was largely maintained at 3 years, without eating problems or evidence of malabsorption. The rate of mortality was 0.8%, major morbidity 7.7%, and minor morbidity 4.1%-all of which are comparable to RYGB. CONCLUSION: This procedure, which is technically less demanding than RYGB, preserves all or part of every segment of the gastrointestinal tract, including absorptive sites for iron and trace minerals. Despite substantially less gastric restriction than in RYGB, and less compromise of absorptive bowel than in biliopancreatic diversion, weight loss profiles are similar to those observed after these conventional bariatric operations. Favorable changes in gut hormones, including augmentation of ileal-brake peptides and reduction of ghrelin, may play a dominant role in affecting major, long-lasting weight loss. PMID- 18443890 TI - The eradication of Helicobacter pylori is affected by body mass index (BMI). AB - BACKGROUND: Bariatric surgeons often advocate preoperative Helicobacter pylori (H. pylori) testing and eradication because of the increased risk of postoperative ulcers and foregut symptoms in H. pylori-positive patients. The aim of this pilot study was to evaluate whether body mass index (BMI) might influence the success rate of eradication. METHODS: Eighty one nondiabetic naive H. pylori positive patients were divided into two groups according to their BMI, with 41 in the control group (normal BMI) and 40 in the overweight/obese group (BMI > or = 25). Gastroscopy was performed and multiple biopsies were obtained from the antrum and corpus. Both groups were given a triple therapy consisting of pantoprazole 40 mg for 2 weeks plus amoxicillin 1 g tris in die (t.i.d), and clarithromycin 250 mg t.i.d, for the first week of treatment. Eradication was confirmed by the (13)C-urea breath test at 3 months. RESULTS: Successful eradication was observed in 55.0% of the overweight/obese group compared with 85.4% [p < 0.005; odds ratio (OR): 4.77; 95% confidence interval (CI): 1.64 13.87]. The distribution of age, gender, and smoking, as well as the proportion with corpus predominant gastritis (41.4% and 35.0% in control and overweight/obese groups, respectively), did not differ significantly between the two groups. Regression analysis showed that risk factors for treatment failure were BMI (p < 0.02) with an OR of 1.06 (95% CI: 1.01-1.11) and corpus-predominant gastritis (p < 0.001) with an OR of 8.74 (95% CI: 2.48-30.8). CONCLUSION: Overweight/obese nondiabetic patients showed a significantly lower rate of eradication rate of H. pylori infection than controls. BMI and corpus-predominant gastritis appear to be independent risk factors for eradication failure. PMID- 18443891 TI - The new concept of bariatric surgery in China--reevaluation of surgical indications and criteria of therapeutic effect of laparoscopy for treatment of obesity. AB - The etiology of morbid obesity is multifactorial and is related to inheritance, physiology, metabolism, sociocultural, behavioral, and psychological factors. In China, the incidence of obesity is increasing with the improvement of the standard of living each year. The USA is known as the nation that has a high prevalence of overweight and obese individuals, as indicated from the Nutrition and Health Status report. Obesity in China is a growing phenomenon that cannot be ignored. In this paper, we review the relatively new concept of bariatric surgery in China. PMID- 18443892 TI - Pressure pulse contour-derived stroke volume and cardiac output in the morbidly obese patient. AB - BACKGROUND: The pressure pulse contour method for measuring stroke volume (SV) and cardiac output (CO) has come of age. Various methods have been proposed, but at this time no single technique has shown clear superiority over the others. This commentary and review discusses the various methods, and particularly the pressure recording analytical method (PRAM). Dissection of the method shows that vascular wall abnormalities, which are not unique to the morbidly obese state, represent one more biophysical perturbation causing inaccuracy in stroke volume and cardiac output determination. As PRAM is an uncalibrated method, its accuracy depends on certain assumptions that may not fully explain the multitude of combinations and permutations that define pulsatile blood flow; specifically, the area under the pressure curve during systole and the morphologic characteristics of the waveform throughout the cardiac cycle. As a result of incomplete theory, referenced specifically to the morbidly obese individual, PRAM does not faithfully mimic established reference standards of flow; it systematically underestimates stroke volume and cardiac output. Field equations, that is, equations that are applicable over the full gamut of hemodynamic conditions and vascular pathology, are analytically derived truisms. They require input variables that satisfy the natural state of affairs. To realize this state of absolute biophysical bliss, these variables should ideally be measured. Unfortunately, because of the constraints of practicality, shortcuts to the absolute truth are obligatorily required. As a result, pressure pulse contour methods have evolved that employ curve analysis and neural networking techniques, providing uncalibrated facsimiles of SV and CO. PMID- 18443893 TI - Chitosan-coated stainless steel screws for fixation in contaminated fractures. AB - Stainless steel screws and other internal fixation devices are used routinely to stabilize bacteria-contaminated bone fractures from multiple injury mechanisms. In this preliminary study, we hypothesize that a chitosan coating either unloaded or loaded with an antibiotic, gentamicin, could lessen or prevent these devices from becoming an initial nidus for infection. The questions investigated for this hypothesis were: (1) how much of the sterilized coating remains on the screw with simulated functional use; (2) is the unloaded or loaded chitosan coating bacteriostatic and biocompatible; and (3) what amount and rate does an antibiotic elute from the coating? In this study, the gentamicin eluted from the coating at a detectable level during 72 to 96 hours. The coating was retained at the 90% level in simulated bone screw fixation and the unloaded and loaded chitosan coatings had encouraging in vitro biocompatibility with fibroblasts and stem cells and were bacteriostatic against at least one strain of Staphylococcus aureus. The use of an antibiotic-loaded chitosan coating on stainless steel bone screws and internal fixation devices in contaminated bone fracture fixation may be considered after optimization of antibiotic loading and elution and more expanded in vitro and in vivo investigations with other organisms and antibiotics. PMID- 18443894 TI - Galeazzi lesions in children and adolescents: treatment and outcome. AB - A Galeazzi fracture is defined as a fracture of the radius associated with dislocation of the distal radioulnar joint. Treatment in children and adolescents is usually possible with closed reduction and casting. The objective of this retrospectively designed study was to describe all Galeazzi lesions treated at our department during a 3-year period. One hundred ninety-eight patients with displaced fractures of the radius alone or both bones of the forearm were reviewed. In 26 (13%) cases, a Galeazzi lesion was found and these patients formed the study group. Outcome was assessed using the Gartland-Werley score. Eight of 26 (31%) fractures were recognized initially and classified as a Galeazzi lesion. Casting after fracture reduction was possible in 22 patients. Thirteen patients were treated with immobilization in a below-elbow cast and nine with an above-elbow cast. Four patients were treated operatively. The results were excellent in 23 cases and good in three cases. In cases of distal forearm fractures, a possible Galeazzi lesion should be considered. However, proper reduction of the radius with concomitant reduction of the distal radioulnar joint and cast immobilization provides good to excellent outcome even if the Galeazzi lesion is primarily not recognized. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 18443895 TI - The classic: inflammation of the post-calcaneal bursa associated with exostosis. 1898. PMID- 18443896 TI - Human S100A12: a novel key player in inflammation? AB - S100A12 is a member of the S100 family of EF-hand calcium-binding proteins. Human S100A12 is predominantly expressed and secreted by neutrophil granulocytes and, therefore, has been assigned to the S100 protein subfamily of calgranulins or myeloid-related proteins. Intracellular S100A12 exists as an anti-parallel homodimer and upon calcium-dependent activation interacts with target proteins to regulate cellular functions. Extracellular S100A12 exists majorily as homodimer and hexamer, respectively, and shows cytokine-like characteristics. It is part of the innate immune response and linked to certain autoimmune reactions. Human S100A12 is markedly overexpressed in inflammatory compartments, and elevated serum levels of S100A12 are found in patients suffering from various inflammatory, neurodegenerative, metabolic, and neoplastic disorders. In this regard, interaction of calcium-activated S100A12 with the multiligand receptor for advanced glycation endproducts (RAGE) and its soluble form (sRAGE) plays a central pathogenetic role. Recent clinical evidence suggests a high potential of S100A12 as a sensitive and specific diagnostic marker of localized inflammatory processes. PMID- 18443897 TI - Induction of apoptosis by L-carnitine through regulation of two main pathways in Hepa1c1c 7 cells. AB - This study shows the effects of L-carnitine treatment on cell proliferation with hepa1c1c7 mouse cancer cells and NCTC 1469 normal cells. In an MTT assay, L carnitine increased the number of dead hepa1c1c7 cells, while there was no difference in the number of NCTC 1469 cells. mRNA and protein levels of TNF alpha, Fas, and caspase-8, which are closely related to cell apoptosis by a death ligand/receptor-dependent apoptosis pathway, were increased by L-carnitine treatment. In addition, L-carnitine treatment regulated mitochondria-dependent apoptosis pathways by inducing the up-regulation of caspase-9 and caspase-3 and the down-regulation of Bcl-2 in hepa1c1c 7 cells. Taken together, the findings of this study have demonstrated that L-carnitine could induce apoptosis in hepa1c1c7 cells by regulating Fas ligands and inhibiting the expression of Bcl-2. These results suggest that L: -carnitine treatment could be related to both a mitochondrion-dependent and a death ligand/receptor-dependent apoptosis pathway in hepa1c1c7 cells. Our results could give information for understanding the L carnitine-induced apoptosis mechanism in some cancer cells. PMID- 18443898 TI - Diagnosis of breast cancer: MDCT versus MRI. AB - In Japan, helical CT has been applied to breast cancers for the accurate determination of cancer extent before surgery. In recent years, multidetector CT (MDCT) has become commercially available. Compared with mammography and ultrasonography, MDCT of the breast is thought to be useful for preoperative assessment of breast-conserving surgery. In contrast, magnetic resonance imaging (MRI) is extremely accurate in the diagnosis of intraductal carcinoma and multicentricity of breast cancer. A real problem related to the use of CT is X ray exposure. Therefore, it is controversial whether the use of CT for the patients with breast cancer is appropriate or not. Recent studies that compared the use of MDCT and MRI in the same patients concluded that MRI was more accurate for the detection and evaluation of the extent of intraductal carcinoma. We should consider the pitfalls and limitations of CT for assessing the breast cancer extent. PMID- 18443899 TI - Proton MR spectroscopy of the breast. AB - Magnetic resonance imaging (MRI) of the breast has emerged as a highly sensitive modality. In addition to morphologic and kinetic analysis obtained from contrast enhanced breast MRI, functional information has been needed for diagnosis of breast disease. In vivo proton (hydrogen 1 [(1)H]) MR spectroscopy of the breast has demonstrated that choline (Cho) can be detected in breast cancers, whereas Cho is generally undetectable in normal breast tissue. Thus, breast MR spectroscopy has shown great promise as a way to differentiate between benign and malignant lesions and to gauge the effect of chemotherapeutic agents in patients with locally advanced breast cancer. Prior studies performed on 1.5-T MR imagers have reported sensitivities of 70-100% (average 89%; 149/168) and specificity of 67-100% (average 87%; 97/112) for breast MR spectroscopy. Moreover, the presence of a Cho peak in breast cancer may reflect the increased cell proliferation, with a decrease in this peak after treatment reflecting decreased viability of the tumor. With further development and the assessment of Cho quantity in the tumor, breast MR spectroscopy may be helpful in the elucidation of the biology of breast cancer. PMID- 18443900 TI - Selective contrast enhancement of individual Alzheimer's disease amyloid plaques using a polyamine and Gd-DOTA conjugated antibody fragment against fibrillar Abeta42 for magnetic resonance molecular imaging. AB - PURPOSE: The lack of an in vivo diagnostic test for AD has prompted the targeting of amyloid plaques with diagnostic imaging probes. We describe the development of a contrast agent (CA) for magnetic resonance microimaging that utilizes the F(ab')2 fragment of a monoclonal antibody raised against fibrillar human Abeta42 METHODS: This fragment is polyamine modified to enhance its BBB permeability and its ability to bind to amyloid plaques. It is also conjugated with a chelator and gadolinium for subsequent imaging of individual amyloid plaques RESULTS: Pharmacokinetic studies demonstrated this 125I-CA has higher BBB permeability and lower accumulation in the liver and kidney than F(ab')2 in WT mice. The CA retains its ability to bind Abeta40/42 monomers/fibrils and also binds to amyloid plaques in sections of AD mouse brain. Intravenous injection of 125I-CA into the AD mouse demonstrates targeting of amyloid plaques throughout the cortex/hippocampus as detected by emulsion autoradiography. Incubation of AD mouse brain slices in vitro with this CA resulted in selective enhancement on T1 weighted spin-echo images, which co-register with individual plaques observed on spatially matched T2-weighted spin-echo image CONCLUSIONS: Development of such a molecular probe is expected to open new avenues for the diagnosis of AD. PMID- 18443902 TI - Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer. AB - Despite advances in treatment of patients with metastatic breast cancer (MBC), prognosis remains poor and median survival is 2-3 years. Resistance to antineoplastics mediated by many factors, potentially including overexpression of drug efflux proteins or altered beta-tubulin isotype expression limits the effectiveness of MBC chemotherapy. Capecitabine, approved for anthracycline- and taxane-resistant MBC, has produced modest responses, highlighting the need for more effective treatments for MBC resistant to multiple chemotherapeutic agents. Agents with potential to reverse drug resistance have not proven effective. Albumin-bound paclitaxel is a formulation that may enhance delivery to tumor tissues. Conversely, ixabepilone, an epothilone analog, has been reported to have lower susceptibility to at least some mechanisms of tumor resistance and clinical activity in resistant/refractory MBC. The topoisomerase-I inhibitor irinotecan also has low cross-resistance with other antineoplastics, and has shown some activity against refractory MBC. Development of new agents and identification of genetic biomarkers in translational studies promise to improve management of patients with resistant/refractory breast cancer. PMID- 18443901 TI - Autoimmunity in common variable immunodeficiency. AB - BACKGROUND: Autoimmunity has been increasingly recognized as a major issue in patients with common variable immunodeficiency (CVID), the most common symptomatic primary immunodeficiency in adulthood. Different authors report high prevalences of autoimmune diseases in CVID, and several mechanisms have been proposed to explain this apparent paradox. Genetic predisposition, under current surveillance, innate and adaptive immunity deficiencies leading to persistent/recurrent infections, variable degrees of immune dysregulation, and possible failure in central and peripheral mechanisms of tolerance induction or maintenance may all contribute to increased autoimmunity. CONCLUSIONS: Data on the clinical/immunological profile of affected patients and treatment are available mostly concerning autoimmune cytopenias, the most common autoimmune diseases in CVID. Treatment is based on conventional alternatives, in association with short experience with new agents, including rituximab and infliximab. Benefits of early immunoglobulin substitutive treatment and hypothetical premature predictors of autoimmunity are discussed as potential improvements to CVID patients' follow-up. PMID- 18443903 TI - Cost-effectiveness analysis of adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-positive breast cancer: modeling the downstream effects. AB - PURPOSE: BCIRG 001 demonstrated prolonged disease-free (DFS) and overall survival (OS) but increased toxicity for adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) versus 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) in women with node positive breast cancer (BC). This study evaluates quality adjusted survival and cost-effectiveness of adjuvant TAC versus FAC, taking downstream decisions and events into account, including palliative chemotherapy with taxanes. METHODS: We developed a Markov model for a cohort of women with node positive BC eligible for adjuvant anthracyclines. Data input included clinical and resource utilization data collected prospectively from BCIRG 001. Treatment decisions and outcomes with disease recurrence were based on a systematic literature review with validity reviewed by a national panel of Canadian BC oncologists. Direct costs for resource utilization following Canadian practice patterns were included. Unit costs were obtained from provincial cost list and published drug list prices. Utility scores were derived from the literature. An incremental cost-effectiveness ratio (ICER) in cost per quality adjusted life-years (QALY) gained for TAC versus FAC was calculated. RESULTS: For 1,000 women with node positive BC, the model showed that TAC would lead to a gain of 313 QALY (370 life years) at an additional cost of $5.8 Million Canadian dollars (Cdn) compared to FAC, over a 10-year time horizon. The ICER of TAC versus FAC was $18,505.54 Cdn per QALY gained. Sensitivity analyses supported the robustness of the model. By one-way sensitivity analyses of over 50 model variables, 95% of the cumulative ICER variation was from $6,000 to $28,000 Cdn/QALY. By multivariate Monte Carlo simulation, there was a 70% probability that the ICER would be under $50,000 CdN/QALY. CONCLUSION: For women with node positive BC, TAC improves DFS and OS compared to FAC and is a cost-effective adjuvant chemotherapy strategy. PMID- 18443904 TI - Increased epidermal growth factor receptor (EGFR) expression in malignant mammary phyllodes tumors. AB - Mammary phyllodes tumors are uncommon stromal-epithelial neoplasms, and are divided into benign, borderline malignant and frankly malignant groups on the basis of their histological features. Accumulating evidence shows that epidermal growth factor receptor (EGFR) is involved in the pathogenesis and progression of many malignancies. This study investigated 453 phyllodes tumors (296 benign, 98 borderline, 59 malignant) for EGFR expression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for gene amplification. The staining was correlated to tumor margin status, degree of malignancy, stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. Cases with strong positive IHC staining were selected for FISH. The overall positive rate for EGFR was 16.2% (48/296), 30.6% (30/98) and 56% (33/59) for benign, borderline malignant and frankly malignant phyllodes tumors, respectively. FISH demonstrated egfr gene amplification in 8% of immunohistochemically positive cases. The results of this study provide strong evidence that EGFR overexpression is involved in the pathogenesis of phyllodes tumors, although gene amplification may not be the major underlying mechanism for overexpression. PMID- 18443905 TI - Effect of linear alkylbenzene sulfonates on the growth of aerobic heterotrophic cultivable bacteria isolated from an agricultural soil. AB - An enrichment culture technique was used to isolate soil bacteria capable of growing in the presence of two different concentrations of linear alkylbenzene sulfonates (LAS) (10 and 500 microg ml(-1)). Nine bacterial strains, representatives of the major colony types of aerobic heterotrophic cultivable bacteria in the enriched samples, were isolated and subsequently identified by PCR-amplification and partial sequencing of the 16S rRNA gene. Amongst the isolates, strains LAS05 (Pseudomonas syringae), LAS06 (Staphylococcus epidermidis), LAS07 (Delftia tsuruhatensis), LAS08 (Staphylococcus epidermidis) and LAS09 (Enterobacter aerogenes), were able to grow in pure culture in dialysed soil media amended with LAS (50 microg ml(-1)). The three Gram-negative strains grew to higher cell numbers in the presence of 50 microg ml(-1) of LAS, compared to LAS-unamended dialysed soil medium, and were selected for further testing of their ability to use LAS as carbon source. However, HPLC analysis of culture supernatants showed that the three strains can tolerate but not degrade LAS when grown in pure cultures. A higher concentration of soluble phosphates was recorded in dialysed soil media amended with LAS (50 microg ml(-1)) compared to unamended control media, suggesting an effect of the surfactant that enhanced the bioavailability of P from soil. The presence of LAS at a concentration of 50 microg ml(-1) had an important impact on growth of selected aerobic heterotrophic soil bacteria, a deleterious effect which may be relevant for the normal function and evolution of agricultural soil. PMID- 18443906 TI - Deep vein thrombosis and pulmonary embolism in cirrhosis patients. AB - BACKGROUND AND AIMS: It is a commonly held notion that patients with cirrhosis do not suffer from deep vein thrombosis (DVT) or pulmonary embolism (PE) because they are naturally anticoagulated. However, to date, no studies have been carried out that objectively address this issue. We conducted a study to examine the relationship between cirrhosis and DVT/PE events. METHODS: A case-control study of patients seen at a tertiary care hospital was performed. Cases were hospitalized patients with biopsy and/or imaging plus clinical evidence of cirrhosis. Well-matched patients with no known evidence of cirrhosis served as controls. The DVT/PE events were identified by the international classification of disease-9 (ICD-9) codes and confirmed with radiographic/nuclear imaging. The Charlson Index was calculated to determine the comorbidity. The incidence of DVT/PE in cirrhotic patients was also compared to patients with chronic kidney disease (CKD), congestive heart failure (CHF), and solid organ cancers. RESULTS: This study consisted of 963 cirrhotics and 12,405 controls. Both the incidence of DVT/PE (1.8 vs. 0.9%, P = 0.007) and Charlson Index scores (3.2 +/- 1.8 vs. 0.9 +/- 1.5, P < 0.001) were higher in cirrhotics than in the controls. However, in the multivariate analysis, the presence of cirrhosis was not associated with DVT/PE [odds ratio (OR) 0.87, P = 0.06]. Partial thromboplastin time (PTT; OR 0.88, P = 0.04) and serum albumin (OR 0.47, P = 0.03) were the independent predictors of DVT/PE. The incidence of DVT/PE in cirrhotics (1.8%) was lower than that in patients with other medical illnesses: 7.1% in CKD, 7.8% in CHF, and 6.1% in cancers. Conclusion Patients with cirrhosis do not have a lower risk of DVT/PE than non-cirrhotic controls without other significant co-morbidities, such as CHF, CKD, and solid organ cancers. Partial thromboplastin time and serum albumin were found to be independently predictive of DVT/PE in cirrhotic patients. PMID- 18443907 TI - Sensitivity to syntactic changes in garden path sentences. AB - The results of two text-change experiments are reported. The experiments were designed to investigate the syntactic representation of garden path sentences such as While the man hunted the deer that was brown and graceful ran into the woods, specifically the claim that a significant number of misinterpretations of such sentences are due to incomplete syntactic reanalysis (Christianson et al. Cogn Psychol 42:368-407, 2001). In the experiments reported here, the pronoun it was added (Expt. 1) or deleted (Expt. 2) from short texts containing such sentences. Participants were more or less likely to notice both deletions and additions of it in certain syntactic contexts, as predicted by the incomplete reanalysis account. Correlations with reading times support this interpretation of the results. Overall, the data are consistent with a "good enough" view of language processing (Ferreira et al. J Psycholinguist Res 30:3-20, 2001). PMID- 18443908 TI - A carotenoid algal preparation containing phytoene and phytofluene inhibited LDL oxidation in vitro. AB - The antioxidative effect of the carotenoids phytoene and phytofluene in biological systems has not yet been studied. We therefore sought to investigate the effect of these carotenoids, isolated from the alga Dunaliella bardawil, in a biological system and used the in vitro low density lipoprotein (LDL) oxidation method to assay their antioxidative effects. We found that similar to beta carotene and alpha-tocopherol, a carotenoid algal preparation containing phytoene and phytofluene inhibited LDL oxidation. These findings and the presence of phytoene and phytofluene in human tissues suggest that they can be part of the defense system against oxidative stress. PMID- 18443909 TI - Design of MEMS devices with optical apertures for the detection of transparent biological cells. AB - This paper provides a novel technique to detect transparent biological living cells trapped in a microfluidic MEMS device by optical diffraction. The device essentially consists of an optical aperture or an aperture array patterned in metal layer and a microfluidic chamber positioned above the center of the aperture. When the cells in the chamber are illuminated through the aperture, the far-field diffraction pattern can be recorded by a CCD camera or a photodetector array. This diffraction pattern uniquely corresponds to the sizes, positions, and intrinsic optical properties of the aperture, cells, and the microfluidic chamber materials, so any unknown but relevant parameter is able to be extrapolated when all other parameters are fixed or identified. This paper describes in detail the designs of various microfluidic chambers and apertures for this application, and the development of a complete set of software for the analysis of the cells' optical properties. Compared with other currently available methods for the detection of transparent living cells, this method has the advantages of simple device structure, easy to manipulate, able to simultaneously detect several cells of different species, as well as providing accurate and sensitive results. Besides the detection of living cells, this technique can also be used to detect or characterize other transparent or low optical absorption particles, such as polymer spheres or insoluble droplets, inside an aqueous solution. PMID- 18443910 TI - Brain cell technology: a valuable new resource for novel techniques. PMID- 18443912 TI - Our war against bacteria in peritoneal dialysis, the last 40 years! PMID- 18443913 TI - Ovulatory dysuria: a bizarre presentation of crossed non-fused ectopic kidney with extra renal pelvis. AB - Ectopic kidneys are a unique form of congenital anomaly that in most cases remain asymptomatic. However, depending on the location and the associated anatomical variations, they can mimic certain more common conditions, posing a challenge in differential diagnosis. They could cause secondary symptoms by virtue of their location or could falsely mimic a primary urologic problem when the etiology might be from a closely opposed adjacent structure. We present a unique case of ovulatory dysuria in a young female with a crossed non-fused ectopic kidney. The patient's symptoms were recurrent and correlated with the ovulatory phase of the menstrual cycle. Work-up revealed the right ovary to be in close proximity to the pelvis of the ectopic kidney. Salpingo-oophrectomy was followed by complete resolution of the patient's symptoms. The clinical manifestations, work-up, and management of symptomatic ectopic kidneys are briefly discussed in our article. Symptoms are usually attributed only by systematically excluding other causes. Surgical intervention is a last resort option only after thorough work-up with appropriate imaging studies. PMID- 18443914 TI - Asymptomatic retained surgical gauze towel diagnosed 32 years after nephrectomy. AB - Retained surgical gauze is a rare but known problem in patients who have medical history of surgery. Suspicion and evaluation of this rare condition is sometimes very difficult for the clinician because retained surgical sponges can be totally asymptomatic or can hide themselves perfectly in the plain abdominal films. For this reason clinican should excersize high rate of suspicion, should not solely depend upon plain films and should consider more sophisticated examinations like ultrasonography (US) or computerized tomography for the appropriate management of these retained sponges. We present here a very unusual and late presentation of surgically retained gauze which gave a false appearance of a kidney with decreased functional activitity in the excretory urography (EU) 32 years after nephrectomy. PMID- 18443915 TI - Differential impairment of psychomotor efficiency and processing speed in patients with chronic kidney disease. AB - BACKGROUND: Cognitive impairment has been documented in patients with chronic kidney disease. In a recent paper, improvements in cognitive function were seen in hemodialysis (HD) patients switched from conventional HD to nocturnal HD, in two of three domains of cognitive function. Based on these findings, we hypothesized that functional decline may occur differentially in some domains more than others. METHODS: Using a cross-sectional study design, patients optimized on medical treatment at a predialysis clinic were tested using a battery of neuropsychological (NP) tests measuring three domains of cognitive functioning-attention & working memory skills; psychomotor efficiency & processing speed; and learning efficiency. Clinical subjective symptoms for cognitive functioning and depression were measured using the Patient's Assessment of Own Functioning (PAOF) inventory and the Beck Depression Inventory (BDI). RESULTS: One hundred and three patients aged 64.6+/-12.4 years were recruited. Of these, 40% were diabetic, with a mean Charlson comorbidity score of 4.4+/-2.1. Depression (defined as >16 on the BDI score) was seen in 11 patients. After adjustment for comorbid diseases, hemoglobin, the use of neurodepressor medication, and parathyroid hormone (PTH) values, renal function was negatively correlated with psychomotor efficiency & processing speed, but not with attention & working memory or learning efficiency scores. CONCLUSION: Chronic kidney disease is associated with a decline in psychomotor efficiency & processing speed, but not with attention & working memory or learning efficiency. PMID- 18443916 TI - Study on a possible effect of four longevity candidate genes (ACE, PON1, PPAR gamma, and APOE) on human fertility. AB - The present study investigated for a possible effect on fertility of four longevity candidate genes (ACE, PON1, PPAR-gamma, APOE) in order to determine whether they have a pleiotropic action at different life ages. The study population was 151 healthy unrelated subjects. Only PPAR-gamma and APOE showed an effect on fertility. The PPAR-gamma Pro/Ala genotype, which had showed an association with longevity only in men, was found associated only in men with having produced more children (6.1+/-3.3) than the Pro/Pro genotype (3.3+/-1.9; P=0.001). APOE*2 allele, which has been consistently associated with longevity, was confirmed to be associated with the lowest fertility (P=0.03). The logistic regression analysis indicated that APOE and PPAR-gamma polymorphisms may be considered independent determinants of reproductive efficiency. These data suggest that the APOE*2 allele follows the model of antagonist pleiotropy, while the PPAR-gamma Pro/Ala genotype seems to exert beneficial effects both early in life and in advanced age in a gender-specific way. PMID- 18443917 TI - Investigation on chlorosomal antenna geometries: tube, lamella and spiral-type self-aggregates. AB - Molecular mechanics calculations and exciton theory have been used to study pigment organization in chlorosomes of green bacteria. Single and double rod, multiple concentric rod, lamella, and Archimedean spiral macrostructures of bacteriochlorophyll c molecules were created and their spectral properties evaluated. The effects of length, width, diameter, and curvature of the macrostructures as well as orientations of monomeric transition dipole moment vectors on the spectral properties of the aggregates were studied. Calculated absorption, linear dichroism, and polarization dependent fluorescence-excitation spectra of the studied long macrostructures were practically identical, but circular dichroism spectra turned out to be very sensitive to geometry and monomeric transition dipole moment orientations of the aggregates. The simulations for long multiple rod and spiral-type macrostructures, observed in recent high-resolution electron microscopy images (Oostergetel et al., FEBS Lett 581:5435-5439, 2007) gave shapes of circular dichroism spectra observed experimentally for chlorosomes. It was shown that the ratio of total circular dichroism intensity to integrated absorption of the Q(y) transition is a good measure of degree of tubular structures in the chlorosomes. Calculations suggest that the broad Q(y) line width of chlorosomes of sulfur bacteria could be due to (1) different orientations of the transition moment vectors in multi-walled rod structures or (2) a variety of Bchl-aggregate structures in the chlorosomes. PMID- 18443918 TI - Toward understanding molecular mechanisms of light harvesting and charge separation in photosystem II. AB - Conversion of light energy in photosynthesis is extremely fast and efficient, and understanding the nature of this complex photophysical process is challenging. This review describes current progress in understanding molecular mechanisms of light harvesting and charge separation in photosystem II (PSII). Breakthroughs in X-ray crystallography have allowed the development and testing of more detailed kinetic models than have previously been possible. However, due to the complexity of the light conversion processes, satisfactory descriptions remain elusive. Recent advances point out the importance of variations in the photochemical properties of PSII in situ in different thylakoid membrane regions as well as the advantages of combining sophisticated time-resolved spectroscopic experiments with atomic level computational modeling which includes the effects of molecular dynamics. PMID- 18443919 TI - Dielectric relaxation in proteins: the computational perspective. AB - In photoexcitation and electron transfer, a new dipole or charge is introduced, and the structure is adjusted. This adjustment represents dielectric relaxation, which is the focus of this review. We concentrate on a few selected topics. We discuss linear response theory, as a unifying framework and a tool to describe non-equilibrium states. We review recent, molecular dynamics simulation studies that illustrate the calculation of dynamic and thermodynamic properties, such as Stokes shifts or reorganization free energies. We then turn to the macroscopic, continuum electrostatic view. We recall the physical definition of a dielectric constant and revisit the decomposition of the free energy into a reorganization and a static term. We review some illustrative continuum studies and discuss some difficulties that can arise with the continuum approach. In conclusion, we consider recent developments that will increase the accuracy and broaden the scope of all these methods. PMID- 18443920 TI - Detection of satratoxin g and h in indoor air from a water-damaged building. AB - The occurrence of Stachybotrys chartarum in indoor environments has been linked to adverse health effects as well as few cases of pulmonary haemorrhages in humans. Although the highly toxic secondary metabolites of this fungus, like satratoxin G and H, were frequently claimed with outbreaks of such diseases, these toxins have hardly been identified in the air of naturally contaminated indoor environments. Herein, a case of a LC-MS/MS-confirmed occurrence of airborne S. chartarum-toxins in a water-damaged dwelling is reported. Satratoxin G (0.25 ng/m(3)) and satratoxin H (0.43 ng/m(3)) were detected. This provides further evidence that Stachybotrys-toxins can be transferred from mouldy indoor materials into air, which could be a factor in the aetiology of health symptoms related to the sick building syndrome. PMID- 18443921 TI - Biological control of phytopathogenic fungi by fatty acids. AB - The aim of the present study was to evaluate the antifungal activity of fatty acids against phytopathogenic fungi. Two pot experiments were conducted by mixing palmitic and oleic acids in the soil in which poor plant growth was observed. In addition, the antifungal activities of nine fatty acids (butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, and linoleic acid) against four phytopathogenic fungi: Alternaria solani, Colletotrichum lagenarium, Fusarium oxysporum f. sp. Cucumerinum, and Fusarium oxysporum f. sp. lycopersici, were assessed by measuring mycelial growth and spore germination via Petri dish assay. The results of the pot experiments showed that the mixture of palmitic and oleic acids enhanced the growth of the seedlings of continuous-tomato and continuous-cucumber. Except for oleic acid, in the Petri dish assay, the fatty acids tested were observed to inhibit the mycelial growth of one or more tested fungi. In addition to the suppression of mycelial growth, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, and palmitic acid showed an inhibitory effect against spore germination and the extent of inhibition varied with both the type of fatty acids, and the fungi. In particular, capric acid displayed strong inhibitory effect against C. lagenarium on the mycelial growth and spore germination. The saturated fatty acids, i.e. palmitic acids, showed stronger antifungal activity than the unsaturated fatty acids, i.e. oleic acid. It suggests that fatty acids might be applicable to exploring for alternative approaches to integrated control of phytopathogens. PMID- 18443922 TI - Epidemiological profile of cryptococcal meningitis patients in Rio Grande do Sul, Brazil. AB - Cryptococcosis is a major opportunistic mycosis which has meningitis as its most frequent clinical presentation and can be fatal in the absence of antifungal therapy. The aetiological agents are Cryptococcus neoformans, which affects mainly immunocompromised subjects, and C. gattii, the aetiologic agent for cryptococcosis in healthy individuals. A recent outbreak of cryptococcosis on Vancouver Island, Canada, raised the level of concern about the epidemiology of this disease. In Brazil, between 1980 and 2002, six per cent of AIDS patients had cryptococcosis in course at the time of diagnosis. To identify the profile of cryptococcal meningitis patients in Rio Grande do Sul (RS), Brazil, a retroactive study was realized using data from patients registered at Laboratorio Central de Saude Publica IPB-LACEN/RS from 2000 to 2005. Most of the patients were men (77.12%), Caucasian (83.5%), median age between thirty and thirty-nine years old (46.24%) and HIV positive (95%). PMID- 18443925 TI - [Presentation]. PMID- 18443926 TI - [New director of the Revista Espanola de Quimioterapia]. PMID- 18443923 TI - Two cases of vaginitis caused by itraconazole-resistant Saccharomyces cerevisiae and a review of recently published studies. AB - Genitourinary infections caused by non-Candida yeasts are uncommon, and especially due to Saccharomyces cerevisiae. We describe the cases of two adult females with vulvovaginal infections caused by itraconazole-resistant S. cerevisiae who made a full recovery after oral fluconazole therapy. We also provide a concise review of recently published studies on this topic. PMID- 18443924 TI - Prostate cancer old problems and new approaches : Part I. epidemiology, incidence and genetic alterations. AB - Rates of prostate cancer (PCa) have increased so dramatically over the last decade that the age adjusted incidence rate for PCa is now greater than that any other cancer among men in the United States. This review, published as a three part series, provides a state-of-art assessment of the PCa problem in its divergent aspects.Part 1 covers epidemiology, incidence and progression. Several epidemiological studies have demostrated that first degree male relatives of men with PCa are at increased risk of developing the disease. Familial and genetic factors as well as medical, anthropometric, dietary, hormonal and occupational factors involved in PCa are discussed. Postmortem examination of the prostate in men without evidence of PCa documented a high frequency of adenocarcinoma. Latent disease occurred as early as the second decade of life. Although there is no significant difference in incidence between Caucasian and African-American males, high grade prostatic intraepithelial neoplasia (HGPIN) is higher in the latter group. While dietary fat, androgens and certain environmental factors may be determinants for PCa, the exact mechanism of tumorigenesis is still relatively unknown. The current thinking of the role of genomic instability, chromosomal alterations, tumor suppressor genes and the androgen receptor are explored. PMID- 18443927 TI - [Behavior of the primary care physicians in the treatment of community infections]. AB - This study aimed to evaluate the behavior of the physicians who attend to patients with community infections who are responsible for most of the antibiotic prescriptions made in the community setting. Furthermore, the evolution over the last 10 years in regards to the treatment habits of the most frequent infections in Primary Health Care (PHC) was studied and prescription behaviors were analyzed in relationship to the acquaintance and attitude of the participating physicians. A data collection sheet from 1,411 prescriptions made by 855 physicians from different specialties was used to conduct the study. This represents a statistically significant sample nationwide both from the point of view of the physicians involved in the treatment of infectious diseases in PHC as well as regarding to the prescriptions they have written. The study reveals the amplitude of respiratory and pararespiratory disease with oral antimicrobial agents, particularly beta-lactamics, and the significant advance in the last 10 years in the use of amoxicillin and clavulanic acid as treatment of choice. Treatment duration was somewhat longer while the number of containers prescribed was less than in the previous study. This would be related to the use of more spaced doses of the antimicrobial agents. Furthermore, the study reveals some discrepancies between attitudes and events of the physicians in the approach to certain diagnoses. Key words: Behavior. Primary care physicians. Prescription. Antimicrobials agents. PMID- 18443928 TI - Efficacy of cefditoren in the treatment of upper respiratory tract infections: a pooled analysis of six clinical trials. AB - OBJECTIVE: A pooled analysis of all upper respiratory tract infection studies performed with cefditoren (CDN) was performed. METHODS: Studies were prospective, comparative, multicentre and randomised. Comparators were penicillin V (pharyngitis) and cefuroxime or amoxicillin/clavulanate (sinusitis). A total of 1,322 patients were randomized, 1,241 included in intention-to-treat (ITT) and 1,010 in per-protocol populations (PP) in pharyngotonsillitis studies, and 1,819 randomized, 1,726 included in ITT and 1,589 in PP in acute sinusitis studies. RESULTS: No significant differences in pharyngitis clinical response were found (success rates: 89.4 % to 95.3 %). S. pyogenes eradication was higher with cefditoren at end of therapy (EOT) (90.4% vs. 82.7%; p=0.002) and follow-up (84.7% vs. 76.7%; p=0.008), although no statistically significant (p<0.001). In both groups, clinical failures were significantly higher (p<0.001) in patients showing S. pyogenes persistence than in those showing eradication (> or =98.5% vs. 51.4 %). No differences in sinusitis clinical response were found between CDN and comparators both at EOT (80.2% vs. 84.8%) and at end of follow-up (71.2% vs. 77.4%). CONCLUSION: Cefditoren had similar point estimates of clinical efficacy to comparators in pharyngotonsillitis and sinusitis, and a tendency to higher S. pyogenes eradication in pharyngotonsillitis. PMID- 18443929 TI - [Situation of Mycobacterium tuberculosis drug resistances in Spain]. AB - INTRODUCTION: The Mycobacteriology Spanish Working Group (MSWG) has conducted an epidemiological, descriptive and retrospective study to try to know the level of first line drug resistances in Mycobacterium tuberculosis strains in Spain. MATERIAL AND METHODS: Data were obtained from a total of 1083 strains isolated between October and November 2006 in 120 microbiology laboratories from 16 autonomous communities and Melilla. RESULTS: A primary resistance rate of 8.3% and 4.9% was obtained for isoniazid (INH). The probability of suffering resistant tuberculosis was major in the immigrant population with a resistance rate of 12%. Repeating these surveillance studies in later years is recommended. PMID- 18443930 TI - [Antimicrobial selection criteria evaluation by family doctors and general practitioners]. AB - OBJECTIVE: This study has aimed to know the criteria used by the Spanish medical practitioners/family doctors (MP/FD) when choosing an antimicrobial agent in their daily practice and to compare it with that existing one decade ago. MATERIAL AND METHODS: This is an observational, cross-sectional study performed with a structured personal interview to 450 MP/FDs randomly chosen with representativeness on the national level. The field work was made by specialized personnel in the last quarter of the year 2006. A 95.5% confidence interval margin was proposed, with a sample error = 4.7%, for maximum dispersion response (p=q=50). RESULTS: The parameter considered most when choosing an antibiotic treatment (spontaneous response) is clinical efficacy (two out of every three doctors). Clinical efficacy is following by the dosage regime and tolerability/safety, which was the principal parameter expressed ten years ago. Following these are antibacterial spectrum, administration route, price and bacterial resistances. However, they considered that the latter significantly influence clinical efficacy and when they are not relativized with other parameters, the doctors state that they take them into account <>. It seems that the opinion of the patient is usually considered and that the protocol, scientific information and expert's opinions are the principal sources of information considered when prescribing an antimicrobial agent. Amoxicillin/clavulanate is the antibiotic drug of choice in all upper and lower respiratory tract infections. There is overestimation of the bacterial etiology in throat infections and acute bronchitis and S. pyogenes to betalactamic antibiotics. It is concluded that knowledge of the Spanish MP/DF regarding antimicrobial therapy has improved in recent years and that clinical efficacy, related with bacterial eradication and not only with clinical remission, is the factor that should be considered when choosing an antibiotic. PMID- 18443931 TI - [Analysis of decrease in sensitivity in influenza A (H5N1) avian and human strains to neuraminidase inhibitors]. AB - The options for efficient control of avian influenza A (H5N1) viruses include specific vaccination and antiviral prophylaxis and treatment. However, because H5N1 viruses undergo continuous antigen mutations, the production of a matched vaccine strain is currently not possible. Thus, during the early pandemic period, specific control measures would rely solely on antiviral drugs. Now only neuraminidase inhibitors (NIs) (zanamivir and oseltamivir) are considered for prophylaxis and therapy in patients with H5N1 infection. The sensitivies of H5N1 strains to the NIs fell into 3 groups. The clade I viruses isolated before 2004 were as sensitive to NIs than reference strains (first group). But the clade I viruses isolated from 2004 were 6 to 7-fold less sensitivity to NIs (second group). The clade II strains isolated from 2005 to 2007 demonstrated a 15 to 30 fold decrease in sensitivity to oseltamivir compared with clade I viruses (third group). The specific decrease in sensitivity to oseltamivir of both Cambodian and Indonesian clade 2 influenza H5N1 isolates is disturbing, especially because they maintain their pathogenicity and transmissibility in birds and are clearly pathogenic in humans. No altered sensitivity to zanamivir has been detected. Zanamivir may also play an important role in pandemic stockpiles. Because the clade 2 virus is now spread through parts of Europe and Africa, continued global collaboration and phenotypic testing of NIs sensitivity are critical for a future pandemic. PMID- 18443932 TI - [Improvement of bactericide activity in hospital treatment of gram positive infections]. AB - Vancomycin is currently the standard treatment of gram-positive bacteria inducted nosocomial infections. However its bactericidal activity may be affected by different factors related to its antibacterial activity, pharmacokinetic properties or the infecting bacteria. Based on these facts, this article reviews the clinical importance that bactericidal activity has against susceptible bacteria and the compromise of this activity due to inadequate pharmacodynamic parameter values. From the bacterial target perspective, the clinical importance of the compromised bactericidal activity due to the decreased susceptibility, tolerance, heteroresistance and resistance is reviewed. In addition the characteristics of an antimicrobial targeted for gram positive nosocomial infections as well as the degree of adhesion to them of the bactericidal antibiotic daptomycin are described. PMID- 18443933 TI - [Diagnosis and treatment of acute rhinosinusitis: second consensus]. AB - The publication of different studies, articles and documents over recent years greatly justifies the revision of the year 2003 Consensus on the diagnosis and treatment of rhinosinusitis made jointly by the Spanish Society of Chemotherapy and the Spanish Society of Otolaryngology and Cervical Facial Pathology. The most significant features to be analyzed consider a new classification, the accumulated evidence on the role of first line of nasal corticosteroids, the demonstration of the utility of different antimicrobial agents with wide clinical experiences and the appearance of clinical studies with new antimicrobial agents that support their utility. Due to its evolution, rhinosinusitis is considered to be acute (viral or non-viral origin) if it lasts less than 12 weeks, chronic when it exceeds this time period and recurrent acute when three or more acute episodes are suffered in one year. Based on its severity, rhinosinusitis can be classified as mild, moderate or severe. Rhinosinusitis may present without or with complications. Rhinosinusitis symptoms resolve spontaneously in 40% of the patients. However, medical treatment is indicated to provide symptomatic relief, accelerate the resolution of the clinical picture, prevent possible complications and avoid evolution to chronicity. Antimicrobial agents and topical nasal corticosteroids (used alone or in combination with antimicrobial agents) are the treatments that have demonstrated therapeutical utility in rigorous and controlled clinical trials. In mild acute maxillary rhinosinusitis without previous antibiotic treatment, the treatment of choice is amoxicillin/clavulanate or cefditoren, while when it is moderate or mild in patients previously treated with antibiotics, levofloxacin or moxifloxacin are preferable, the amoxicillin/clavulanate or cefditoren drugs remaining as good alternatives. In the severe forms, third generation cephalosporins, such as cefotaxime or ceftriaxone, are indicated and amoxicillin/clavulanate or ertapenem are good options in the non-polypoidal chronic forms. PMID- 18443934 TI - [Recommendations of antimicrobial treatment in patients allergic to beta-lactam antibiotics]. AB - Beta-lactam antibiotics are the cornerstone of most of the severe bacterial infections. However, their use can be limited by resistances and allergic reactions. Allergic reactions to beta-lactam antibiotics account for only a small proportion of reported adverse drug reactions, but they are related with an important morbidity, mortality and increase of the health care costs. Drug specific IgE antibodies cause early reactions, whereas T cells play a predominant role in delayed hypersensitivity reactions. For penicillin a major antigenic determinant and several minor determinants have been identified. Clinical assessment is mandatory by medical history, skin and other testing, including provocation. If the beta-lactam should be avoided or a desensitization procedure should be performed depends on the nature and severity of the reaction. Several new antibiotics are currently available (tigecycline, linezolid, daptomycin, etc.) that are as effective and safe as beta-lactams. In this article we have developed a few recommendations for the management of patients with allergy to beta-lactams on the basis of evidence and expert opinion. PMID- 18443935 TI - The use of serial testing to identify young children in need of comprehensive neuropsychological evaluation. AB - This study was designed to use a short, two-phase testing procedure to predict the outcome of a comprehensive neuropsychological examination among young children (aged 5-8 years). Phase 1, requiring less than 10 minutes to administer, predicted Phase 2 results and results of comprehensive testing with acceptable accuracy. Phase 2 testing evaluated both lower-level (sensory-motor) and higher level functions, required about 45 minutes to administer, and also closely predicted the outcome of comprehensive testing. Cutoff scores for individual tests, areas of function, and the total score for preliminary testing were determined, and accuracy rates were identified. The results suggest that preliminary testing, as described in this article, may serve to identify young children who need a comprehensive neuropsychological examination. PMID- 18443936 TI - Serial testing of older children as a basis for recommending comprehensive neuropsychological evaluation. AB - The aim of this study was to develop a short screening battery that would predict whether older children would show significant impairment on comprehensive neuropsychological testing. The screening battery was subdivided into two phases. Phase 1 was intended as a broad catchment effort; Phase 2 was designed to be a more detailed and selective procedure. Administration of the full set of screening tests requires about 45 minutes. Their predictive validity was assessed using the Neuropsychological Deficit Scale (NDS), which summarizes results in the entire Halstead-Reitan Neuropsychological Test Battery for Older Children. Cutoff scores and guidelines for interpretation of the screening tests were developed, and the results were substantially correct in identifying children who performed normally versus children who were impaired on the testing and therefore required comprehensive testing to evaluate their neuropsychological status and deficits. PMID- 18443937 TI - The use of serial testing in evaluating the need for comprehensive neuropsychological testing of adults. AB - The aim of this study was to develop brief neuropsychological testing procedures that would identify adults (aged 15 and older) who need comprehensive neuropsychological evaluation. The tests used for screening were selected to (1) initially provide a broad catchment procedure followed by (2) a more diversified basis for prediction. The total time required to administer the screening measures is about 45 minutes. The criterion for the need for comprehensive testing was based on the General Neuropsychological Deficit Scale (GNDS), which summarizes 42 variables derived from the complete Halstead-Reitan Battery. The results indicated that the brief testing battery permitted accurate identification of persons who showed neuropsychological impairment based on comprehensive testing. Cutoff points were determined and guidelines were provided for use of the brief testing results. PMID- 18443938 TI - Can neuropsychological testing produce unequivocal evidence of brain damage? I. Testing for specific deficits. AB - Neuropsychological tests that produce continuous distributions routinely show some degree of overlap between groups with and without brain damage, and there is an inevitable degree of uncertainty in group differentiation when using statistical inferential methods. Recognizing these circumstances, Pliskin, Ramati, and Sweeney (2007) recently stated that neuropsychological testing alone does not address the underlying basis (or brain damage) for cognitive changes that may be inferred from test results. The present study proposed that brain based specific deficits, evaluated on a "present" or "absent" basis, might prove to be a valuable resource in supplementing interpretation of tests based on continuous distributions by providing, in many instances, unequivocal evidence of brain damage. Comparisons of controls with a group of brain-damaged persons, as reported in this study, strongly supported this proposal. PMID- 18443939 TI - Can neuropsychological testing produce unequivocal evidence of brain damage? II. Testing for right vs. left differences. AB - Sensation and perception, as well as motor functions, have played an important role in the history of psychology. Although tests of these abilities are sometimes included in neuropsychological assessments, comparisons of intraindividual performances on the two sides of the body (as a basis for drawing conclusions and comparisons about the functional status of the two cerebral hemispheres) are in many instances neglected or considered only casually. This study, utilizing several motor and sensory-perceptual tests, compared intraindividual differences on the two sides of the body in a group of controls and a group of persons with brain damage. The results indicated that the sensory perceptual tests were particularly effective in differentiating the groups. More than 60% of the group with brain damage had greater differences on the two sides of the body than did any of the controls. These findings suggest that a substantial proportion of persons with cerebral disease or damage may be subject to unequivocal identification using sensory-perceptual tests that take only about 20 minutes to administer. These tests may serve a valuable role as an adjunct to comprehensive neuropsychological evaluation and should be further evaluated in this respect. PMID- 18443940 TI - Playing statistical ouija board with commonality analysis: good questions, wrong assumptions. AB - Commonality analysis, as used by Hale, Fiorello, and colleagues (e.g., Hale, J. B., Fiorello, C. A., Kavanagh, J. A., Holdnack, J. A., & Aloe, A. M. [2007]. Is the demise of IQ interpretation justified? A response to special issue authors. Applied Neuropsychology, 21, 37-51), often leads to unjustified conclusions. Analyses of simulated datasets show that the highest-order commonality is a poor operationalization of the general factor of intelligence (g). Under commonly observed conditions, it is plausible that lower-order commonalities and unique components in a commonality analysis can consist entirely of g. Other problems with Hale and colleagues' (2007) analyses and interpretations are also discussed. PMID- 18443941 TI - The utility of the transverse patterning task as a measure of configural learning in a college sample. AB - This study examined the transverse patterning task, a three-phase problem developed to explore deficits in configural learning. Phases 1 and 2 of transverse patterning require elemental associations to solve the task, whereas Phase 3 requires a configural association. One hundred and sixteen college participants completed four tasks: transverse patterning, free recall memory, recognition memory, and mental rotation. Results indicated that approximately 75% of participants successfully completed all three phases of the transverse patterning task. Further, the number of trials required to meet criterion on Phases 1 and 2 significantly differed from the number of trials needed to meet criterion for Phase 3. Transverse patterning was correlated with the mental rotation, but not to either of the memory tasks; the memory tasks were significantly correlated with one another. Findings suggest that this version of transverse patterning shows promise for use in future studies. PMID- 18443942 TI - The use of a self-generation memory encoding strategy to improve verbal memory and learning in patients with traumatic brain injury. AB - The generation effect refers to the theory that optimal acquisition and retention of information is achieved by active participation rather than by passive observation. The efficacy of a self-generation memory encoding strategy was tested using a verbal paired-associate task for free recall, cued recall, and recognition memory in 40 traumatically brain-injured outpatients in two studies. In study #1, self-generation encoding procedures improved recognition memory, but not free recall, compared with the didactic presentation of information. In study #2, self-generation procedures improved cued recall test performance, but the results demonstrated that the type of cue that is provided moderates the efficacy of self-generation procedures. Results provide preliminary empirical support for the use of self-generation encoding procedures in improving upon verbal memory and learning abilities in individuals with TBI. PMID- 18443943 TI - Processing speed deficits associated with traumatic brain injury: processing inefficiency or cautiousness? AB - This study used speed-accuracy trade-off (SAT) methodology to test competing explanations for processing speed deficits due to traumatic brain injury (TBI): fixed limited capacity and volition. Twenty TBI participants and 20 comparison participants performed a visual scanning task with processing times controlled by the experimenter using a response deadline procedure. Results of the study demonstrated marked differences in SAT functions between the two groups. Participants who had TBIs were significantly slower on information accrual across processing deadlines (supporting a fixed limit explanation), but when early responding was allowed they chose to hold off responding despite being no more accurate in their responses with the additional time (a finding supporting a volitional explanation). Results of the study are discussed in terms of a resource allocation model that incorporates the influences of both processing capacity and volitional processes for individuals who suffer from brain injuries. PMID- 18443944 TI - Cognitive dysfunction associated with elemental mercury ingestion and inhalation: a case study. AB - A 63-year-old man with a history of alcohol dependence ingested elemental mercury as a suicide gesture. Serial abdominal X-rays showed gradual but incomplete clearance of mercury from the colon. Routine chest X-ray showed evidence of punctate radiopaque materials in the lower lobe of the right lung. Blood and urine mercury levels both exceeded thresholds considered to be associated with cognitive dysfunction. Elicited cognitive deficits were most prominent in processing speed, flexibility, and response inhibition. Semantic fluency, visuospatial processing, and recall memory for visual and low-context verbal material were also affected. The deficits may have been attributable primarily to alcohol abuse. Elemental mercury is not readily absorbed from the gastrointestinal tract; however, mercury vapor, which was inhaled inadvertently, readily crosses the blood-brain barrier and is neurotoxic. We argue, therefore, that mercury toxicity is more likely than not to have been a factor contributing to the patient's cognitive dysfunction. PMID- 18443947 TI - Effects of call on sleep and mood in internal medicine residents. AB - Residents on call experience decreased total sleep time (TST) and increased dysphoria. This study monitored changes in mood and sleepiness for 3 post-call days. Fifty-two internal medicine residents participated in the study. The residents wore actigraphs for the 4 to 9 days of the study. Each morning resident completed mood scales, a sleepiness scale, and estimated their prior night TST. The residents were on a 1-in-4 schedule. Call decreased subjective- and actigraphy-derived TST to less than 4 hr. During the 3 days post call, mood measures improved. Tension, depression, and anxiety stabilized on the first post call day following the first night of off-call sleep during which the residents obtained about 7 hr of sleep. Vigor, fatigue, and confusion stabilized on the second post-call day. The Epworth Sleepiness Scale dropped to less than 11 after 1 post-call night and continued to decrease up to 3 post-call days. The effects of call linger past the first recovery night. For these residents, recovery sleep appeared inadequate, and the negative effects of call persisted across succeeding off-call days. Thus, for these residents on a 1-in-4 schedule, call affects their mood for much of the time when off call and potentially their personal and professional interactions during this period as well. PMID- 18443948 TI - Cosleeping versus solitary sleeping in children with bedtime problems: child emotional problems and parental distress. AB - This study investigated sleep, behavioral and emotional problems, and parental relationships and psychological distress in a group of school-aged children with bedtime problems and persistent cosleeping, compared to solitary sleepers and controls. Participants were 148 school-aged children with bedtime problems (44 cosleepers, 104 solitary sleepers) and 228 healthy peers. Results suggested that cosleepers have a significantly later bedtime, shorter nighttime sleep duration, higher Children's Sleep Habits Questionnaire (CSHQ) bedtime resistance and sleep anxiety scores, and more behavioral and emotional problems compared to other groups. Parents of cosleepers have a significantly higher level of psychological and couple distress. A past history of sleep problems, couple and maternal distress, CSHQ bedtime resistance, sleep anxiety, and night wakings subscale scores, and nighttime fears were significantly predictive of cosleeping. Thus, when cosleeping is present, the child's emotional adjustment, family relationships, and parental psychological problems should be investigated. PMID- 18443949 TI - Self-reported sleep, demographics, health, and daytime functioning in young old and old old community-dwelling seniors. AB - Sleep, demographics, health, and daytime functioning were examined in young old (60-74 years; n = 175) and old old (75-98 years; n = 147) community-dwelling seniors. Sleep diaries (2 weeks), 6 daytime functioning measures, and a demographics-health questionnaire were collected. The old old reported worse sleep than the young old. Women reported worse sleep than men. Hierarchical regressions revealed demographic information alone was not sufficient for understanding sleep. Specifically, demographic information predicted sleep onset latency and sleep efficiency for both groups, but not number of awakenings or total nap time. Health and daytime functioning accounted for significant increases in the variance in sleep "over and above" that accounted for by demographics alone or demographics and health combined, respectively. All variables combined accounted for 15% to 30% of the variance in sleep. Because the importance of specific measures varied by group and sleep variable, research exploring the differential utility of specific measures for young old versus old old appears warranted. PMID- 18443950 TI - Actigraphy in older adults: comparison of means and variability of three different aggregates of measurement. AB - Actigraphy has emerged as a valuable method for measuring natural sleep patterns; however, it is unclear how many consecutive nights should be measured and what sleep parameter values are typical of older adults. This study examined sleep in relatively healthy community-based older adults for 14 consecutive days. The findings present comparison values for Actiwatch-L actigraphy in older adults, and can be used to determine an appropriate length of measurement. When using means of the aggregate period, a 3-day aggregate is comparable to the values obtained over 7- or 14-day aggregates. However, if variability of the sleep parameter is of interest, a minimum of a 7-day aggregate is needed, and 14-day aggregates are better when measuring sleep onset latency. PMID- 18443951 TI - Challenges of microarray data and the evaluation of gene expression profile signatures. PMID- 18443952 TI - Mechanism of growth inhibitory effects of cyclooxygenase-2 inhibitor-NS398 on cancer cells. AB - Cyclooxygenase (COX)-2 appears to play an important role in gastrointestinal carcinogenesis, and COX-2 overexpression has been demonstrated both in esophageal adenocarcinomas and lymph nodes metastasis. The aim of our study was to investigate the mechanism of growth inhibitory effect of selective inhibition of COX-2 by NS-398 on human cancer cells. The esophageal cancer cell lines (EC9706) that express COX-2 permanently and hepatocellular carcinoma cell lines (SMMC7721) while no expression of COX-2 were studied. Two kinds of cell lines were treated with various concentrations of NS-398 (selective for COX-2 inhibition) at 0.01 0.1 mM for 24 h, 48 h and 72 h. Antiproliferation effect was measured by 3H-TdR incorporation. The cell apoptosis were determined by flow cytometry (FCM) and DNA fragmentation analysis. Survivin was detected by immunocytochemical technique. The growth inhibition could be induced by NS398 in a dose- and time-dependent manner in two kinds of cell lines. FCM analysis revealed a high sub-G1 cell peak in EC9706 group. Agarose electrophroesis showed marked apoptosis ladder pattern, but no apoptosis by NS-398 in SMMC7721. The difference of apoptosis percentage in EC9706 and SMMC7721 was (45.23 +/- 1.08)% and (3.05 +/- 0.15)% (p < 0.001). After 24 h incubation with NS-398 at concentration of 0.1 dmM, the expression of survivin was markedly reduced in EC9706, but not in SMMC7721. We conclude that the administration of a selective inhibitor of COX-2 significantly decreases cell growth in cancer cell lines by different mechanism. NS-398 could inhibit cell proliferation in cancer cells whether or no COX-2 expression. Nevertheless, apoptosis in the cancer cells expressing COX-2 protein increase more than those lacking COX-2. PMID- 18443953 TI - Paradoxical expression of anti-apoptotic and MRP genes on cancer stem-like cell isolated from TJ905 glioblastoma multiforme cell line. AB - Existence of cancer stem cell is regarded as a main reason for metastasis and/or recurrences. In this study, the cancer stem-like cell derived from TJ905 glioblastoma multiforme cell line was isolated successfully. However, it was observed that generating rate of the cancer stem-like cells was lower than that of TJ905 cells, that expression of the anti-apoptotic and multidrug resistance associated protein (MRP) genes were paradoxical to the literatures, which showed the uncertainty of cancer stem cells, and that some stem cell was not the solo factor to maintain tumor growth and resist apoptosis and anti-tumor drugs. PMID- 18443954 TI - Expression of multidrug-resistance-related proteins P-glycoprotein, glutathione-S transferases, topoisomerase-II and lung resistance protein in primary gastric cardiac adenocarcinoma. AB - AIM: Multidrug resistance (MDR) is closely correlated to an unfavorable prognosis in various human cancers. However, the clinical significance of the expression of MDR-related proteins p-glycoprotein (PGP), glutathione-s-transferases (GST-pi), topoisomerase-II (Topo-II) and lung resistance protein (LRP) in primary gastric cardiac adenocarcinoma (PGCA) remains unclear. In this present study, the total of the four kinds of MDR-related proteins mentioned above were detected by using immunohistochemistry, and their clinical significance in chemoresistance were also investigated. METHODS: This retrospective study included 69 resected specimens from patients with PGCA. The expression of PGP, GST-pi, Topo-II and LRP in formalin-fixed paraffin-embedded tissue sections was determined by a labelled streptavidin-biotin immunohistochemical technique, and the results were analyzed in correlation with clinicopathological data. None of these patients received chemotherapy prior to surgery. RESULTS: The positive rates of expression of PGP, GST-pi, Topo-II and LRP in malignant tissues (49.2%, 75.4%, 68.1% and 58%, respectively) were all higher than that of the normal tissues(0, 30%, 20% and 0, respectively, P < 0.01). PGP expression in tumors that had metastasized was significantly more frequent than in tumors that had not metastasized (67.5% vs 24.1%, P < 0.01). The expression of PGP was closely related with clinicopathologic staging (staging 1/2 vs 3/4, 28.6% vs 58.3%, P < 0.05). No significant correlation was shown between PGP and increasing differentiated degree (40%, 42.4% and 61.5%, P > 0.05). GST-pi expression status progressively increased with increasing differentiated degree (40%, 75.8% and 88.5%, P < 0.05) and clinicopathologic stage (staging 1/2 vs 3/4, 57.1% vs 83.3%, P < 0.05). In addition, a significant positive correlation was also observed between GST-pi and lymphatic metastasis (with vs. without metastasis, 87.5% vs 58.6%, P < 0.05). The expression of Topo-II was associated with increasing differentiated degree (33.3%, 69.7 and 80.7%, P < 0.01). No significant differences with Topo-II expression were found in relation to the clinicopathologic stage (staging 1/2 vs 3/4, 57.1% vs 72.9%, P > 0.05) and lymphatic metastasis (with vs. without metastasis, 65.0% vs 72.4%, P > 0.05). Moreover, a significant difference with the expression of LRP was found in relation to the clinicopathologic stage (staging 1/2 vs 3/4, 38% vs 66.6%, P < 0.05), and lymphatic metastasis (with vs without metastasis, 70.0% vs 41.4%, P < 0.05). Comparing the well, moderately and poorly differentiated cohort, a non-statistical increasing trend towards LRP expression status was noted (50.0%, 54.5% and 65.3%, respectively, P > 0.05). Besides, the co-expression of all four tested MDR-related proteins also existed. The positive rates of co-expression of PGP and GST-pi, PGP and Topo-II, PGP and LRP, GST-pi and Topo-II, LRP and GST-pi, LRP and Topo-II, PGP, GST-pi, Topo-II and LRP in malignant cells were 23.2%, 15.9%, 11.6%, 13.0, 26.1, 7.24, 5.8, respectively. CONCLUSIONS: MDR-related proteins PGP, GST-pi, Topo-II alpha and LRP are involved in multiple mechanisms of drug resistance in PGCA. Combined determination of PGP, GST-pi, Topo-II and LRP may be prospectively valuable for optimizing the chemotherapy regimes, developing high quality anti-cancer drugs, and further predicting the outcomes of those patients with PGCA. PMID- 18443955 TI - Modulatory effects of acetazolomide and dexamethasone on temozolomide-mediated apoptosis in human glioblastoma T98G and U87MG cells. AB - Acetazolomide (ACZ) and dexamethasone (DXM) alleviate vasogenic edema and inflammation in glioblastoma patients. Temozolomide (TMZ) is used for treating glioblastoma. We compared modulatory effects of ACZ and DXM on TMZ mediated apoptosis in human glioblastoma T98G and U87MG cells. Cells were treated with drug(s) for 6 h and then left in drug-free medium for 48 h. Although ACZ or DXM alone did not induce apoptosis, TMZ alone induced significant amount of apoptosis. Interestingly, ACZ pretreatment enhanced apoptosis while DXM pretreatment decreased apoptosis. These results suggest that combination chemotherapy with ACZ and TMZ may control inflammation and enhance apoptosis in glioblastoma. PMID- 18443956 TI - Urocortin's inhibition of tumor growth and angiogenesis in hepatocellular carcinoma via corticotrophin-releasing factor receptor 2. AB - Urocortin (UCN) functions via corticotrophin-releasing factor receptors (CRFRs), CRFR1 & 2. CRFR2 is reported to be a tonic suppressor of vascularization, implying its role in tumor angiogenesis. Here, it was found that UCN inhibited the growth of hepatocellular carcinoma (HCC) and reduced tumor microvessel density in nude mice. Hepatoma cells didn't express CRFRs whereas vessels expressed CRFRs, mainly CRFR2. In vitro three-dimensional culture assay showed UCN inhibited angiogenesis, this effect was abolished by CRFR2 antagonist, anti sauvagine-30, demonstrating involvement of CRFR2. Furthermore, UCN inhibited the proliferation and promoted the apoptosis of endothelial cells and down-regulated VEGF expression in vivo via CRFR2. PMID- 18443957 TI - Suppression of C-myc expression associates with anti-proliferation of aloe-emodin on gastric cancer cells. AB - Aloe-emodin is a hydroxyanthraquinone found in Aloe vera, as well as in leaves and roots of other plants. The mechanisms of its anticancer effect are largely unknown. The present study investigated its molecular mechanisms. Crystal violet assay showed that aloe-emodin had a long-term anti-proliferation effect on human gastric cancer MGC-803 and SGC-7901 cells. Scratch wound-healing motility assays indicated its anti-migration effect. Aloe-emodin arrested SGC-7901 cells at G2/M phase. More importantly, aloe-emodin inhibited the expressions of protein kinase C and c-myc. In conclusion, the anticancer effect of aloe-emodin on gastric cancer cells involves suppression of c-myc expression. PMID- 18443958 TI - The extracellular matrix protein 1: its molecular interaction and implication in tumor progression. AB - The extracellular matrix protein 1 (ECM1) is expressed around blood vessels, which suggest a role for ECM1 in angiogenesis. Recombinant ECM1 stimulates proliferation of cultured endothelial cells and promotes blood vessel formation in the chorioallantoic membrane of chicken embryos. These observations make ECM1 a possible trigger for angiogenesis, tumor progression and malignancies. Interaction of ECM1 with perlecan, MMP-9 and fibulin-1C/D contributes to this hypothesis. However, the importance of ECM1 in cancer biology has been neglected so far. Nevertheless, a survey of ECM1 expression in different tumors indicated that ECM1, although not tumor specific, is significantly elevated in many malignant epithelial tumors that give rise to metastases, emphasizing its relevance in the cancer process. PMID- 18443959 TI - FKBP51 expressed by both normal epithelial cells and adenocarcinoma of colon suppresses proliferation of colorectal adenocarcinoma. AB - It has been reported, as a result of Western blot analyses, that FKBP51 is expressed in various tissues, but that it is not expressed in the pancreas, lung, colon, stomach, or spleen. In this paper, we show, using Western blot analyses, reverse transcriptase polymerase chain reaction, and immunohistochemical analyses of samples from colon cancer patients, that both normal epithelial cells and adenocarcinoma in the human colon express FKBP51, and that there are no significant differences in the expressions of FKBP51 between them. We also show that FKBP51 suppresses the proliferation of colorectal adenocarcinoma, possibly due to the suppression of functions of the glucocorticoid receptors. PMID- 18443960 TI - Hematopoiesis capacity, immunomodulatory effect and ex vivo expansion potential of mesenchymal stem cells are not impaired by cryopreservation. AB - The purpose of this study is to investigate whether hematopoiesis capacity, immunomodulatory effect and ex vivo expansion potential of mesenchymal stem cells (MSCs) are affected by cryopreservation. Chronic myeloid leukemia (CML) patients' bone marrow MSCs cryopreserved for 3 months, 6 months, and 1 year were thawed and analyzed. Cryopreserved CML-MSCs have more than 90% viability. Cell-doubling time of cryopreserved CML-MSCs is 42 to 54 hours. Cells have been expanded in culture for more than 30 passages. Under suitable conditions, cryopreserved CML-MSCs have the ability of multiple lineages differentiation, including bone, endothelial, fat and nerve. Furthermore, cryopreserved CML-MSCs express hematopoietic cytokines, and possess hematopoietic supportive ability. The growth of normal long-term culture-initiating cell (LTC-IC) on CML-MSCs (including noncryopreserved and cryopreserved CML-MSCs) was similar to that of normal derived MSCs. Cryopreserved CML-MSCs did not express costimulatory molecules CD40, CD80, and CD86. They can inhibit T lymphocyte proliferation induced by mitogens. The immunosuppressive effect of cryopreserved CML-MSCs on T-cell proliferation was dose dependent. These findings indicate that cryopreserved CML derived MSCs may be a useful tool for clinical application. PMID- 18443961 TI - Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in patients with relapsed or refractory lymphoma. AB - BACKGROUND: High dose chemotherapy with autologous stem cell transplantation is currently the treatment of choice for relapsed or refractory lymphoma patients. However, its applicability is mostly restricted to patients responding to salvage chemotherapy. Optimal salvage regimen for these patients is unclear. In this study, our aim was to compare the efficacy and toxicity profiles of DHAP (cytosine arabinoside, cisplatin and dexamethasone) and ICE (ifosfamide, carboplatin and etoposide) regimens in the salvage treatment of relapsed and refractory lymphoma. PATIENTS AND METHODS: In this retrospective analysis, 53 patients with primary refractory or relapsed Hodgkin's disease (HD) (n = 13) or non-Hodgkin lymphoma (NHL) (n = 40) who received ICE or DHAP salvage regimen were included. RESULTS: Of 53 patients, 21 (39,6%) were female and the median age was 43 years. A total of 73 courses of ICE and 59 courses of DHAP were administered. Response could be evaluated in 49 patients (36 NHL and 13 HD). Of 49 patients, 11 (22.5%) achieved complete remission (CR) and 17 (35%) achieved partial remission (PR), leading to an overall response rate (ORR: CR + PR) of 57.5%. In the evaluable ICE group (n = 22) rates of CR, PR, and ORR were 27%, 41% and 68% and in the DHAP group (n = 27) rates of CR, PR, and ORR were 18%, 30% and 48% (p = 0.24, for ORR). Toxicity with both regimens was within acceptable limits. The major grade III-IV toxicities for both groups were hematological (neutopenia and thrombocytopenia). The main non-hematological toxicity was renal and observed in 8 patients. CONCLUSION: Although the toxicity profiles of both ICE and DHAP regimens were similar in the treatment of patients with relapsed or refractory HD or NHL, ICE seems to have higher rates of response than DHAP regimen does. PMID- 18443962 TI - Erythrocyte and platelet phospholipid fatty acids as markers of advanced non small cell lung cancer: comparison with serum levels of sialic acid, TPS and Cyfra 21-1. AB - The phospholipid fatty acid profiles of erythrocytes and platelets from fifty patients with advanced non-small cell lung cancer were investigated using gas chromatography/mass spectrometry, followed by "ROC" curves analysis to gain novel biomarker information. Sialic acid and cytokeratins were also examined. Potentially useful fatty acid markers: Erythrocytes: phosphatidylcholine, 18:2n6 and 20:4n6; phosphatidylethanolamine, 22:4n6 and 22:6n3 + 24:1n9. Platelets: phosphatidylcholine, 22.0; phosphatidylethanolamine, 22:5n3 + 24:0. At the cut off value to obtain maximum accuracy, the best biomarkers were found in platelets: phosphatidylserine + phosphatidylinositol (PS + PI), 21:0; sphyngomyelin: 20:1n9 and 22:1n9. All these fatty acids showed similar/higher diagnostic yields than the commonly used markers sialic acid or cytokeratins. PMID- 18443963 TI - Role of desmoplasia in recurrence of stage II colorectal cancer within five years after surgery and therapeutic implication. AB - BACKGROUND: Colorectal cancer (CRC) metastasis is enhanced in patients with venous embolization increasing the risk of recurrence and therefore mortality rate. Several evidences indicate that stage II patients have an abrupt recurrence within five years from surgery. This fact, led us to investigate the role played by different histological variables on CRC invasiveness. AIM: To demonstrate if quantitative and qualitative desmoplastic response and lymphocytic infiltration are prognostic factor involved in the recurrence of CRC within five years from surgery, considering possible clinical and therapeutical implications. METHODS: Thirty-four patients with CRC underwent colectomy and the UICC-TNM classification was applied for disease staging. Histological variables were semi-quantitatively evaluated. Qualitative evaluation of desmoplasia was obtained with the hematoxillin-eosin method. RESULTS: Survival rate arose 88% at stage II, at five years of follow-up, and the 12% not treated with adjuvant chemotherapy developed metastasis. Desmoplasia is strongly associated with venous neoplastic invasiveness (OR: 21.93; 95%CI: 1.012-475.26, p = 0.02), and therefore, with mortality rate (OR: 14.33; 95%CI: 0.67-304, p = 0.04). Moreover, mortality rate was significantly higher in patients with immature desmoplasia compare to mature stromal tissue (OR: 15.61, 95%CI: 0.69-343.38, p = 0.04). CONCLUSIONS: These observations should prompt a future evaluation of desmoplasia to extent more suitably the use of adjuvant chemotherapy in II stage patients. Further clinical trials are needed to determine if these findings will be able to reduce mortality rate, in stage II CRC patients. PMID- 18443964 TI - Predictive value of individualized tumor response testing by ATP-based chemotherapy response assay in ovarian cancer. AB - The aim of this study is to investigate the correlation between ATP-based chemotherapy response assay (ATP-CRA) results and clinical outcomes in ovarian cancer. Twenty-nine fresh tumor specimens were collected. Tumor cells were isolated and cultured for 48 hrs in medium containing anticancer drugs. The median age of patients was 56 years. The sensitivity, positive predictive value, and accuracy of ATP-CRA were respectively 94.1%, 94.1%, and 90.0%. There was a significant relationship between ATP-CRA results and clinical responses (p = 0.046). This study suggests that ATP-CRA has high sensitivity, positive predictive value, and accuracy for predicting response to chemotherapy in ovarian cancer. PMID- 18443965 TI - Profound hypogammaglobulinemia 7 years after treatment for indolent lymphoma. AB - We report a case of a previously healthy 31 year old woman diagnosed with Stage IIIA follicular lymphoma treated with fludarabine in combination with cyclophosphamide and rituximab who presented seven years after the completion of therapy with CD4 count depression, panhypogammaglobulinema and a history of recurrent sinus infections. We performed comprehensive immunophenotypic analysis and found her to have only 1.2% switched (normal 21 +/- 8%) and 4.7% non-switched (11 +/- 4%) memory B cells with 92% of B cells belonging to the naive compartment. We have previously evaluated reconstitution of the B cell compartment during the 6 to 12 month recovery period after treatment with rituximab and found a similar immunophenotypic pattern. In our patient, this defect was observed seven years after the administration of rituximab in combination with an alkylating agent and purine analog. The patient was started on monthly intravenous immunoglobulin treatments with complete resolution of her symptoms. PMID- 18443966 TI - Association between the length of a CA dinucleotide repeat in the EGFR and risk of breast cancer. AB - We studied the association of breast cancer with the polymorphic CA repeat in 108 cases of breast cancer and 108 matched controls from Isfahan city of Iran. The most common genotype in controls and patients was homozygous with allele length of 16. Our findings demonstrate that Women with two short CA repeat (< 19) are at a significantly higher risk of breast cancer, at an estimated odds ratio of 1.86. We have also found that women with short alleles (< 19) had much greater risk of developing cancer before the age of 55 (OR, 3.36). PMID- 18443968 TI - Reduced verbal learning associated with posterior temporal lobe slow wave activity. AB - Functional imaging has revealed that during verbal-word learning there is activation of the left posterior temporo-parietal region (PTPL). The purpose of this study was to learn if differences in the ability of normal people to learn might be accounted for by differences in electrophysiological (EEG) measures of activation of their left, but not right, PTPL. The Rey Auditory Verbal Learning Test (RAVLT) was administered to 42 men without neurological diseases. Delta magnitude, as measured by quantitative electroencephalography (QEEG), was recorded from the left and right PTPL while the participants sat quietly with their eyes closed. The magnitude of delta EEG activity is inversely proportional to cerebral activation. Based on delta magnitude, comparison groups were created by separating those with low and high delta at the left and right PTPL. Cumulative word learning (CWL) on the RAVLT was computed by subtracting the number of words recalled on the first learning trial from the highest number of words recalled on the fourth or fifth trial and multiplying this difference by the total words recalled during all 5 learning trials. The group with a greater magnitude of left PTPL delta activity had a significantly poorer CWL scores than those with less delta, but the CWL scores of the group with a greater magnitude of delta of the right PTPL was no different that the group with less right-sided delta. No significant differences emerged at any frontal or parietal electrode site. Decreased activation of the left, but not right, PTPL appears to be associated with a decreased verbal leaning ability. PMID- 18443969 TI - Stability of executive function deficits in girls with ADHD: a prospective longitudinal followup study into adolescence. AB - Neuropsychological deficits in the executive system are major sources of morbidity in individuals with attention-deficit/hyperactivity disorder (ADHD). We conducted a 5-year longitudinal study of girls with (N = 140) and without (N = 122) ADHD, aged 6-18 years at baseline. Neuropsychological functioning was assessed using standard neuropsychological testing assessing executive functions (EFs). Girls with ADHD were significantly more impaired than controls in all neuropsychological domains except set shifting. Despite variability in the stability of individual domains of EFs, the majority (79%) of girls with ADHD that met the categorical definition of executive function deficits (EFDs, defined as two or more EF tasks impaired) at baseline continued to have EFDs at the five year followup. These findings document the stability of EFDs in girls with ADHD from childhood into adolescence. PMID- 18443967 TI - Becoming a face expert: a computerized face-training program for high-functioning individuals with autism spectrum disorders. AB - Typically developing individuals process faces using strategies that differ from those used for processing objects, and which tend to be holistic and based on configural information. Behavioral and neuroimaging studies suggest that individuals with autism may not utilize the same specialized strategies for face processing. The present study was designed to investigate whether computerized face-specific training, based on a modified version of Gauthier and Tarr's (1997) expertise protocol, can influence the face processing strategies and abilities of adolescents and young adults with Autism Spectrum Disorder (ASD). Ten individuals with ASD were assigned to either a training protocol designed to improve face processing (N = 5) or a control condition (N = 5). Outcomes assessed holistic processing and configural sensitivity. All trained individuals achieved a behavioral criterion of developing expertise in face recognition established in the literature. Outcome assessments indicated that the trained group showed significantly greater sensitivity to second-order configural relations compared with untrained controls, but did not differ on the measure of holistic processing. These findings suggest that face processing ability and strategies in autism can be significantly improved through training. PMID- 18443970 TI - Retrieval processes in adults with ADHD: a RAVLT study. AB - Attention-deficit hyperactivity disorder (ADHD) is associated with memory deficiencies. In the current study we compared different aspects of verbal memory using standard and constructed measures of the Rey auditory verbal learning test (RAVLT). Performance on learning and recognition measures of RAVLT was similar in both ADHD and control groups. In contrast, adults with ADHD committed more double recalls and intrusion errors, indicating inaccurate recall processes. These findings suggest that memory problems in adults with ADHD may be caused by deficient executive processes that support retrieval from memory. PMID- 18443971 TI - Regional callosal morphology in autism and macrocephaly. AB - Previous investigations have reported decreased size of the corpus callosum (CC) in autism. However, little is known of the regional distribution of these callosal abnormalities. Additional uncertainty exists regarding the role of head size with respect to variations in callosal size in individuals with autism. This study investigated the size of the CC in 5 groups of high functioning individuals: (1) normocephalic autistic individuals; (2) autism with macrocephaly; (3) non-autistic normocephalic controls; (4) non-autistic participants with benign macrocephaly; and (5) a reading disordered (RD) group, comprised of non-autistic individuals with a deficit in reading. The CC was traced from midsaggital MRIs and the outlines partitioned into 99 equidistant width measures. Factor analysis of the 99 widths revealed 10 contiguous callosal regions. Individuals with macrocephaly (autistic and non-autistic) had larger total CC size. Regional analysis revealed a significantly larger CC midbody in macrocephaly, regardless of presence or absence of autism. Within normocephalic individuals, those with autism had a smaller CC genu and midbody than either non autistic controls or RD individuals. These results underscore the importance of considering head size in studies of CC morphology in autism. These findings add to the literature implicating problems of interhemispheric connectivity being present in individuals with autism. PMID- 18443972 TI - Differential effects of aging on executive and automatic inhibition. AB - One of the major accounts of cognitive aging states that age effects are related to a deficiency of inhibitory mechanisms (Hasher & Zacks, 1988). Given that inhibition has traditionally been associated with the frontal cortex, and that the frontal cortex deteriorates early with age (Raz, 2000), this is consistent with the frontal hypothesis of aging (West, 1996). However, not all inhibitory processes require executive control, and so they are not all equally supported by the frontal cortex. As a consequence, one would expect dissociations between inhibitory tasks in the sense of a greater susceptibility of executive/frontal inhibition to aging. Based on Nigg's (2000) working inhibition taxonomy, we tested this hypothesis by combining inhibitory paradigms with different levels of executive control within the same participants. The results showed that age affects Stroop interference but not negative priming (Experiment 1) and stop signal responsiveness but not negative priming (Experiment 2). These findings suggest that tasks with a high executive (or effortful) inhibitory control are more sensitive to aging than tasks with a lower executive (more automatic) inhibitory control. The results are discussed in relation to the inhibitory and frontal accounts of aging. PMID- 18443973 TI - Comparison of caretaker report and hands-on neurodevelopmental screening in high risk infants. AB - Caretaker report in developmental screening of high-risk infants has not been investigated adequately. We compare a caretaker-completed neurodevelopmental prescreening questionnaire (NPQ) to a hands-on screener (Bayley Infant Neurodevelopmental Screener; BINS) and attempt to identify factors that influence agreement in a high-risk sample. From 1,436 infants drawn from 5 centers, 471 were prospectively evaluated at 6-months corrected age, 376 at 12-months, and 244 at 24-months. Fifty-five percent were male; 28% African American, 70% Caucasian, 3% other; M gestational age = 31.2 weeks, M birth weight = 1568 g. Caretakers completed the NPQ (based on the BINS) while watching a video depicting infants engaged in items. The BINS was subsequently administered. Sensitivity ranged from 80%-91%, specificity 57%-82%, and overall agreement 70%-83%, depending on age. Mean NPQ summary scores were lower than the BINS. Agreement varied depending on BINS risk status, being best in the high-risk group, and worst in the moderate risk group. Background variables had minimal impact at 6 and 12 months with BINS risk status being the primary influence; at 24-months, race, intraventricular hemorrhage, and respiratory distress syndrome were influential. Caretaker report is useful in a high-risk population, although the infant's neurodevelopmental status influences such early on; ethnic background and biomedical variables become more important at 2 years. PMID- 18443974 TI - Do motivational incentives reduce the inhibition deficit in ADHD? AB - The primary goal of this study was to test three competing theories of ADHD: the inhibition theory, the motivational theory, and a dual deficit theory. Previous studies have produced conflicting findings about the effects of incentives on executive processes in ADHD. In the present study of 25 children with ADHD and 30 typically developing controls, motivation was manipulated within the Stop Task. Stop signal reaction time was examined, as well as reaction time, its variability, and the number of errors in the primary choice reaction time task. Overall, the pattern of results supported the inhibition theory over the motivational or dual deficit hypotheses, as main effects of group were found for most key variables (ADHD group was worse), whereas the group by reward interaction predicted by the motivational and dual deficit accounts was not found. Hence, as predicted by the inhibition theory, children with ADHD performed worse than controls irrespective of incentives. PMID- 18443975 TI - ADHD symptoms and executive function impairment: early predictors of later behavioral problems. AB - This longitudinal study investigated ADHD symptoms and EF impairments in terms of continuity and cross-domain associations, as well as their predictive relations to a range of socioemotional problem behaviors. We applied a factorial ANOVA design to study additive and interactive effects in a sample of non-clinical preschool children (N = 87) and complemented these analyses with group contrasts. The results showed that early ADHD symptoms and EF impairments acted as predictors of continuing problems within each domain. However, it was only ADHD symptoms that predicted other aspects of socioemotional functioning such as dysfunctional emotional regulation and lower levels of social competence. There was no indication of interactive effects on any measure. In conclusion, our results showed that both ADHD symptoms and impaired EF act as early predictors of problem behaviors, although it is clear that predictions based on ADHD symptoms encompass a wider range of problems in early school age children. PMID- 18443976 TI - A developmental study of risky decisions on the cake gambling task: age and gender analyses of probability estimation and reward evaluation. AB - Decision making, or the process of choosing between competing courses of actions, is highly sensitive to age-related change, showing development throughout adolescence. In this study, we tested whether the development of decision making under risk is related to changes in risk-estimation abilities. Participants (N = 93) between ages 8-30 performed a child friendly gambling task, the Cake Gambling task, which was inspired by the Cambridge Gambling Task (Rogers et al., 1999), which has previously been shown to be sensitive to orbitofrontal cortex (OFC) damage. The task allowed comparisons of the contributions to risk perception of (1) the ability to estimate probabilities and (2) evaluate rewards. Adult performance patterns were highly similar to those found in previous reports, showing increased risk taking with increases in the probability of winning and the magnitude of potential reward. Behavioral patterns in children and adolescents did not differ from adult patterns, showing a similar ability for probability estimation and reward evaluation. These data suggest that participants 8 years and older perform like adults in a gambling task, previously shown to depend on the OFC in which all the information needed to make an advantageous decision is given on each trial and no information needs to be inferred from previous behavior. Interestingly, at all ages, females were more risk-averse than males. These results suggest that the increase in real-life risky behavior that is seen in adolescence is not a consequence of changes in risk perception abilities. The findings are discussed in relation to theories about the protracted development of the prefrontal cortex. PMID- 18443977 TI - Profile of 50 women with midlife-onset eating disorders. AB - The aim of this study was to present a detailed profile of 50 women eating disorder (ED) inpatients who reported first ED onset at age 40 or above. We assessed patients' sociodemographics, severity-of-illness, comorbid diagnoses, personality profiles, and short-term treatment outcomes. Compared to patients of more traditional young adult ages, results revealed unique features of midlife onset ED inpatients, including less severe and less common self-reported ED symptomology measured by the EDI-2; a predominance of pure restricting behaviors and rarity of bulimia; similar rates of co-occurring depression and anxiety but of less severity; fewer substance use disorders with a predominance of sedating/calming substance usage; many fewer Cluster C diagnoses on Axis II; substantially greater histories of sexual abuse; and different MMPI-2 profiles emphasizing much greater denial. The corresponding needs among midlife-onset ED inpatients for specialized assessment and treatment interventions are considered. PMID- 18443978 TI - The "double life" of bulimia: patients' experiences in daily life interactions. AB - This qualitative study, using interviews with 38 subjects, explored how and why they conceal bulimic symptoms and the understanding of concealing in terms of social interaction. A "double life" was described as a dichotomy between being active and outgoing versus performing shameful bulimic behaviors and constantly living with fear of stigmatization, and striving against exposure. Concealing was well planned to avoid such fear, and to preserve dignity. Bulimia may be understood as volitional exertion of interaction control, not just as a result of poor impulse regulation. Understanding the meaning of secrecy and "double life" may facilitate help seeking behavior and guide treatment. PMID- 18443979 TI - Reading level of Overeaters Anonymous primary educational material. AB - Educational materials are often a key component of recovery in a mutual-help group. However, in order to be helpful to a maximum number of members, these materials must be presented at a reading level that is comprehensible. Two measures of readability, The Flesch Reading Ease score and the Flesch-Kincaid Grade-Level score were applied to 20 random paragraphs chosen from The Twelve Steps and Twelve Traditions of Overeaters Anonymous. Results indicate that the average paragraph is written just below the tenth grade level and close to an optimum level of reading ease. However, due to variability, almost half (45%) of the paragraphs fell in the category of Difficult Reading Ease and half were found to be at a tenth grade reading level or beyond. In order to maximize the utility of this educational text, it is recommended that future editions take into consideration principles of readability. PMID- 18443981 TI - Bulimia nervosa and substance use disorder: similarities and differences. AB - The purpose of this study was to compare bulimia nervosa (BN) and substance use disorders (SUD) in cognitive-motivational terms. The cognitive orientation theory was used as a framework for testing the hypothesis that the commonality between BN and SUD consists of a similar motivational disposition for eating disorders, rather than for addiction, as was previously claimed. It was expected that BN and SUD patients would differ from controls but not from each other. The participants were 31 BN, 20 SUD, and 20 healthy controls. They were administered questionnaires for assessing anxiety, depression, addiction and the cognitive orientation for eating disorders. On most parameters BN and SUD scored higher than controls but did not differ from each other except in norm beliefs. Treatment of BN should consider the similarity of BN to SUD in the pathological tendency for eating disorders. PMID- 18443980 TI - What is the scientific evidence for the use of antipsychotic medication in anorexia nervosa? AB - This systematic review assesses the effectiveness of antipsychotic medication for improving core psychopathology and behavioral symptoms of anorexia nervosa. The Cochrane Depression, Anxiety and Neurosis Group Trials Register, reference lists of retrieved studies and conference abstracts were searched. Four randomized controlled trials comparing typical or atypical antipsychotic medication to other interventions were included. Clinical heterogeneity precluded meta-analysis. Overall, there is insufficient evidence to either support or refute the use of antipsychotic medication in anorexia nervosa. Further trials may be justified but should be designed with a clear theoretical framework to guide use of antipsychotic medication. PMID- 18443982 TI - Theater as a behavior change strategy: qualitative findings from a school-based intervention. AB - This study aimed to assess children's opinions about participating in a school based theater program (Very Important Kids) and to determine their perceptions as to how their participation influenced their weight-related attitudes and behaviors. Focus groups were conducted with 4th through 6th grade students who participated in a theater program where they developed and performed a play about weight-related issues. Participants identified the personal relevance of the play's material, the opportunity to be a role model, and being part of a team as the key aspects that enhanced their enjoyment of the program. Increased resilience to comments from others, positive changes in communication with peers, and improved body satisfaction emerged as the prominent changes students identified as occurring as a result of their participation in the program. Findings suggest that theater is a feasible and possibly effective strategy for use in school-based interventions aimed at the prevention of weight-related disorders. PMID- 18443983 TI - A controlled assessment of school-based preventive programs for reducing eating disorder risk factors in adolescent Spanish girls. AB - This study assesses the impact of an eating disorders universal preventive program on a representative sample of Spanish adolescents in the area of Barcelona, Spain. 323 adolescent girls were assigned to three experimental conditions: complete intervention, partial intervention, and non-treatment. The program obtained a significant change in reducing the influences of the aesthetic body ideal and in improving the knowledge of nutrition. Nevertheless, attained post-treatment changes dissipate at the 6 month follow-up. In our opinion, the lack of lasting effects should be attributed to a series of considerations such as format, tests not validated for this age, or insufficient research. PMID- 18443987 TI - Stories I tell my patients. PMID- 18443988 TI - Online participation: a content analysis of differences in utilization of two online cancer communities by men and women, patients and family members. AB - The Internet provides a new modality for health communication by facilitating the creation of virtual communities. These communities have the potential to influence health behavior beyond traditional FTF support groups. This study utilized content analysis of 1,424 e-mail messages posted to 2 online cancer communities to examine uses of these groups. Findings revealed (a) similarities in the content of communication in the 2 virtual communities, (b) gender differences in participation, and (c) differences in utilization of these online groups between patients and family members. These results are discussed in light of the diverse uses of online cancer communities that they reveal, the role of family members in support seeking and provision, and gender communication styles in health computer-mediated communication. PMID- 18443989 TI - A spiritually based approach to breast cancer awareness: cognitive response analysis of communication effectiveness. AB - The purpose of this study was to compare the communication effectiveness of a spiritually based approach to breast cancer early detection education with a secular approach, among African American women, by conducting a cognitive response analysis. A total of 108 women from 6 Alabama churches were randomly assigned by church to receive a spiritually based or secular educational booklet discussing breast cancer early detection. Based on the elaboration likelihood model (Petty & Cacioppo, 1981), after reading the booklets participants were asked to complete a thought-listing task, writing down any thoughts they experienced and rating them as positive, negative, or neutral. Two independent coders then used 5 dimensions to code participants' thoughts. Compared with the secular booklet, the spiritually based booklet resulted in significantly more thoughts involving personal connection, self-assessment, and spiritually based responses. These results suggest that a spiritually based approach to breast cancer awareness may be more effective than the secular approach because it caused women to more actively process the message, stimulating central route processing. The incorporation of spiritually based content into church-based breast cancer education could be a promising health communication approach for African American women. PMID- 18443990 TI - In their own words: the reasons why people will (not) sign an organ donor card. AB - This multisite, qualitative study of 78 family-pair dyads provides rich data on the reasons people cite for (not) wanting to sign an organ donor card in the context of family conversations. In this study, dyads were videotaped as they discussed 8 questions pertaining to their views on organ donation, beginning with the most general opinions and progressing to more detailed questions. Analysis of the transcribed data revealed that the most common reasons for wanting to donate organs were based on religion or a desire to help other people in need. The most common reasons cited for not wanting to donate organs were mistrust (of doctors, hospitals, and the organ allocation system), a belief in a black market for organs in the United States, and deservingness issues (that one's organs would go to someone who brought on his or her own illness, or who could be a "bad person"). One of the most surprising findings is that religion is offered far more often as a rationale for wanting to help sick people through organ donation than it was for not wanting to donate organs. These findings both support and contradict past studies based on quantitative survey data. Implications for the construction of more effective future organ donor campaigns are discussed. PMID- 18443991 TI - The return of the house call: the role of internet-based interactivity in bringing health information home to older adults. AB - This study provides qualitative insight into how older adults are using the Internet for health communication. The research is framed with theory from several disciplines, including health and interactive communication, as well as related theoretical models. Data from focus groups was used to develop a model of seniors' online health interactions. Three primary themes that emerged in focus groups form the key elements of the model: the health situation, health information, and the medical field. Implications are suggested for advertising and marketing on the Internet, health information providers, and academic researchers in these areas. PMID- 18443992 TI - Attitudes and self-reported behavior of patients, doctors, and pharmacists in New Zealand and Belgium toward direct-to-consumer advertising of medication. AB - Patients', doctors', and pharmacists' attitudes toward direct-to-consumer advertising (DTCA) for medication and their perceptions of its impact on patient self-reported behavior in terms of request for, and consumption of, advertised medication were investigated. Data were obtained in New Zealand, 1 of only 2 countries that allow mass-media DTCA for prescription medication, and in Belgium, which does not. Attitudes were relatively negative in both countries, but significantly more positive in New Zealand than in Belgium. The impact of DTCA (both in a positive and a negative sense) on self-reported patient behavior and patient interaction with doctors and pharmacists was limited in both countries. Although -- as already established in previous work -- the informativeness and reliability of DTCA can be much improved, and the attitude of medical professionals toward DTCA is negative in both countries, from the point of view of medical professionals and patients, DTCA does not harm the self-reported relationship between doctors, pharmacists, and patients. PMID- 18443993 TI - Information seeking and satisfaction with physician-patient communication among prostate cancer survivors. AB - Relatively little is known about prostate cancer patients' information seeking after diagnosis, how they use such information in making a treatment decision, or what role information plays in adjusting to quality-of-life issues posttreatment. This research sought to explore some of these issues by examining prostate cancer patients' information seeking and its relationship to assessments of feeling informed and satisfied with physician-patient communication about prostate cancer. Respondents felt reasonably informed about prostate cancer, although over one third of them reported being less then informed. Similarly, many respondents were generally satisfied with their communication with physicians, but nearly 40% of them reported being less than satisfied. However, there was no relationship between respondents' information seeking about prostate cancer and their assessments of being informed or satisfied with physician-patient communication. These and other results are discussed with respect to future research on prostate cancer patients' information needs and uses of such information. PMID- 18443994 TI - The relationship between health information seeking and community participation: the roles of health information orientation and efficacy. AB - Health communication scholarship has built on the health-promoting role of the community in exploring participatory communication techniques in community-based health promotion efforts. Community participation inculcates responsibility, strengthens community bonds, and provides a platform for diffusing health interventions. This power of a community to embody responsible action and promote participation in preventive behavior is examined in recent research on social capital. Exploring the link between community participation and health, this article demonstrates, through 2 survey studies, that health information orientation and health information efficacy are positively correlated with community participation. Furthermore, community participation is linked with prevention orientation, health beliefs, and health behaviors. Based on the findings, theoretical and pragmatic suggestions are presented. PMID- 18443995 TI - Can e-mail messages between patients and physicians be patient-centered? AB - This study explores the extent to which e-mail messages between patients and physicians mimic the communication dynamics of traditional medical dialogue and its fulfillment of communication functions. Eight volunteers drawn from a larger study of e-mail users agreed to supply copies of their last 5 e-mail messages with their physicians and the physician replies. Seventy-four e-mail messages (40 patient and 34 physician) were provided and coded using the Roter Interactive Analysis System. The study found that physicians' e-mails are shorter and more direct than those of patients, averaging half the number of statements (7 vs. 14; p < .02) and words (62 vs. 121; p < .02). Whereas 72% of physician and 59% of patient statements were devoted to information exchange, the remaining communication is characterized as expressing and responding to emotions and acting to build a therapeutic partnership. Comparisons between e-mail and with face-to-face communication show many similarities in the address of these tasks. The authors concluded that e-mail accomplishes informational tasks but is also a vehicle for emotional support and partnership. The patterns of e-mail exchange appear similar to those of in-person visits and can be used by physicians in a patient-centered manner. E-mail has the potential to support the doctor-patient relationship by providing a medium through which patients can express worries and concerns and physicians can be patient-centered in response. PMID- 18443996 TI - The influence of viewing an entertainment-education program on cornea donation intention: a test of the theory of planned behavior. AB - This study was designed to examine the role of issue involvement and the 3 components of the theory of planned behavior in predicting intentions to sign a cornea donor card. This study also compares viewers and nonviewers of an entertainment-education program in terms of issue involvement and the theory of planned behavior. The breakdown of effects for the latent constructs confirms that issue involvement is an important intermediary in the persuasion process. Issue involvement is a common causal antecedent of attitude, subjective norm, and perceived behavioral control, the last 2 of which, in turn, predict intentions, whereas attitude does not. The revised path model confirms that involvement directly influences intentions. In the comparison of viewers with nonviewers, viewers exhibit a significantly higher degree of involvement, attitude toward cornea donation, subjective norm, perceived behavioral control, and intention to sign a cornea donor card. The overall findings of this study suggest that adding issue involvement in the theory of planned behavior enhances the explanatory power of the theory in predicting intentions. PMID- 18443997 TI - Bibliography. Health communication. PMID- 18443998 TI - Modeling the relationship between descriptive norms and behaviors: a test and extension of the theory of normative social behavior (TNSB). AB - Informed by the theory of normative social behavior, this article sought to determine the underlying mediating and moderating factors in the relationship between descriptive norms and behavioral intentions. Furthermore, the theory was extended by asking whether and what role behavioral identity played in normative influences. Simulating the central message of norms-based interventions to reduce college students' alcohol consumption, in this field experiment, descriptive norms were manipulated by informing half of the students (n = 665) that their peers consumed less alcohol than they might believe. Others (n = 672) were not provided any norms information. students' injunctive norms, outcome expectations, group identity, behavioral identity, and behavioral intention surrounding alcohol consumption were then measured. Exposure to the low-norms information resulted in a significant drop in estimates of the prevalence of consumption. Injunctive norms and outcome expectations partially mediated and also moderated the relationship between descriptive norms and behavioral intentions. Group identity and behavioral identity also moderated the relationship between descriptive norms and behavioral intentions, but the effect size was relatively small for group identity. Implications for health campaigns are also discussed. PMID- 18443999 TI - Adolescents' perceptions of Canadian cigarette package warning labels: investigating the effects of message framing. AB - This study investigates gain-framed and loss-framed messages on graphic cigarette warning labels and their effects on adolescents' smoking-related attitudes and behaviors. Canadian cigarette warning labels emphasizing health consequences of smoking (loss-framed) were digitally manipulated into gain-framed versions. High school students (N = 210) completed a questionnaire measuring attitudes, perceptions of the warnings, and behavioral intentions. The study used a posttest only comparison group design with random assignment. The independent variable was message framing (loss-framed, gain-framed avoidance, gain-framed benefits), and the dependent variables were (a) attitudes toward the warning, (b) attitudes toward smoking, (c) effectiveness in reducing smoking levels, (d) intentions to smoke, (e) effectiveness in improving one's ability to quit, and (f) effectiveness in increasing the likelihood of a smoker quitting. Results indicate that adolescents had more favorable attitudes toward the loss-framed warnings and perceived them as more effective than the gain-framed warnings. Further, smokers exposed to the loss-framed version featuring decaying teeth had significantly lower intentions to smoke in the future. Loss-framed warning labels appear to have a positive influence on adolescents' smoking-related attitudes and behavioral intentions. PMID- 18444000 TI - The paradox of realism and "authenticity" in entertainment-education: a study of adolescents' views about anti-drug abuse dramas. AB - The successful use of drama as a vehicle to influence health-related attitudes and behaviors is credited to its ability to elicit an emotional experience and identification among audience members. This study investigated the views of adolescents regarding an entertainment-education (EE) component of their school's anti-drug program - a live performance of a professionally produced anti-drug abuse drama. The analysis draws mainly on data collected from 64 focus groups, conducted in 24 schools across Israel, and open-ended responses to questionnaires administered to more than 1,700 adolescents. The adolescents were generally entertained by the anti-drug abuse drama and moved by its "authenticity," which emerged as a central construct in this study. Yet only a fraction identified with the characters and many remained unwilling to "tell" on a friend who uses drugs. Drawing on these findings, implications to EE theory and practice are discussed, particularly as they relate to the drama's perceived realism or "authenticity," and its unintended effects. PMID- 18444001 TI - Predictors of engaging in family discussion about organ donation and getting organ donor cards witnessed. AB - Family knowledge of organ donation intentions has been found to double rates of family consent regarding organ donation; therefore, it is an important communication process to study in the effort to persuade more people to become organ donors. This article reports the results of a study based on the heuristic systematic model of persuasion designed to assess predictors of family discussion of organ donation and getting organ donor cards witnessed. Possible predictors of family discussion and getting organ donor cards witnessed included individual differences and cognitive, emotional, and behavioral factors. A path model of the process leading to family discussion and getting organ donor cards witnessed is presented and results are discussed for their practical importance. PMID- 18444002 TI - The physical examination in cosmetic surgery: communication strategies to promote the desirability of surgery. AB - Cosmetic surgery is a controversial medical practice that is rapidly expanding in the United States. In 2004 alone, 9.2 million procedures were performed. From breast augmentation to tummy tuck, Americans are taking surgical/medical/health risks to alter their bodily appearance. Although many scholars have criticized the practice, few have looked closely at how plastic surgeons interact with prospective surgical candidates. This essay explores videotaped data of naturally occurring interactions between plastic surgeons and patients seeking to transform their physical appearance. Drawing on action-implicative discourse analysis (Tracy, 2005), the article describes plastic surgeons' embodied and discursive activities during a typical physical examination. The core analysis shows how the patient's body and its aesthetic features can be used by plastic surgeons as interpretive resources to promote the desirability of surgery. By touching excess tissue, pinching it, moving it, or applying tools and artifacts (e.g., tape measurer) on and around the body, plastic surgeons literally bring to life patients' bodily "flaws." Through their multimodal performance, I argue, plastic surgeons mark the desirability of surgical transformation. As medicine meets consumerism, medical activities turn persuasive, incrementally constructing the patient's body as a territory of surgical need. PMID- 18444003 TI - Comparing college students' value-, outcome-, and impression-relevant involvement in health-related issues. AB - The purpose of this study was to examine the role of receiver involvement in the context of health communication. Students (N = 277) completed Cho and Boster's (2005) measures of value-, outcome-, and impression-relevant involvement across 6 health behaviors, including cigarette smoking, organ and tissue donation, sunscreen use, alcohol use, sexually transmitted disease testing, and nutrition. Confirmatory factor analyses across all 6 health topics provided evidence of the 3-factor structure conceptualized by Johnson and Eagly (1989) and measured by Cho and Boster (2005). When health behaviors were regressed onto value-, outcome-, and impression-relevant involvement, outcome- and value-involvement, generally speaking, emerged as significant predictors. Results and implications of considering health campaign audience members' levels of involvement are discussed in the domain of preventive medicine. PMID- 18444004 TI - Media use and health information seeking: an empirical test of complementarity theory. AB - This study compares cancer victims and cancer-free adults' use of communication channels for health information. It tests the complementarity theory (Dutta Bergman, 2004a, 2004b) with a subsample of the Health Information National Trends Survey data. The complementarity of communication channels for health information use is confirmed on 3 different levels: complementarity among mass media channels, including traditional media and the Internet; complementarity between the interpersonal channel and mass media channels; and complementarity between the interpersonal channel and mass media channels after controlling for illness severity. This study provides strong support for complementarity theory, and extends the complementarity hypothesis into the realm of interpersonal channels of communication. Finally, this investigation suggests cancer victims use the media for health information differently than adults who have not been diagnosed with cancer. PMID- 18444005 TI - Subjective knowledge and fear appeal effectiveness: implications for message design. AB - This research investigates the role of perceived health knowledge on the effectiveness of fear-based persuasive appeals. Undergraduates (N = 263) read a strong fear, weak fear, or efficacy-only message encouraging breast or testicular self-examination. As expected, results indicated that men high in subjective knowledge were less reactant and more persuaded by the efficacy-only message whereas those low in subjective knowledge did not evidence this pattern. Contrary to expectation, women high in subjective knowledge had comparable reactions to each of the 3 messages. Implications for fear appeal theory and message design are discussed. PMID- 18444007 TI - Exposures of healthy and asthmatic volunteers to concentrated ambient ultrafine particles in Los Angeles. AB - Adult volunteers (17 healthy, 14 asthmatic) were exposed in a controlled environmental chamber to concentrated ultrafine particles (UFP) collected in a Los Angeles suburb with substantial motor vehicle pollution. Exposures lasted 2 h with intermittent exercise. Inhaled particle counts (mean 145,000/cm(3), range 39,000-312,000) were typically 7-8 times higher than ambient levels. Mass concentrations (mean 100 microg/m(3), range 13-277) were not highly correlated with counts. Volunteers were evaluated for lung function, symptoms, exhaled nitric oxide (eNO), Holter electrocardiography, and inflammatory markers in peripheral blood and induced sputum. Relative to control (filtered air) studies, UFP exposures were associated with a 0.5% mean fall in arterial O(2) saturation estimated by pulse oximetry (p < .01), a 2% mean fall in forced expired volume in 1 sec (FEV(1)) the morning after exposure (p < .05), and a transient slight decrease in low-frequency (sympathetic) power in Holter recordings during quiet rest (p < .05). Healthy and asthmatic subjects were not significantly different across most endpoints. Thus, this initial experimental study of human volunteers exposed to concentrated Los Angeles area ambient UFP showed some acute deleterious cardiopulmonary responses, which, although generally small and equivocal as in previous studies of larger sized concentrated ambient particles, might help to explain reported adverse health effects associated with urban particulate pollution. PMID- 18444008 TI - Hazard and risk assessment of a nanoparticulate cerium oxide-based diesel fuel additive - a case study. AB - Envirox is a scientifically and commercially proven diesel fuel combustion catalyst based on nanoparticulate cerium oxide and has been demonstrated to reduce fuel consumption, greenhouse gas emissions (CO(2)), and particulate emissions when added to diesel at levels of 5 mg/L. Studies have confirmed the adverse effects of particulates on respiratory and cardiac health, and while the use of Envirox contributes to a reduction in the particulate content in the air, it is necessary to demonstrate that the addition of Envirox does not alter the intrinsic toxicity of particles emitted in the exhaust. The purpose of this study was to evaluate the safety in use of Envirox by addressing the classical risk paradigm. Hazard assessment has been addressed by examining a range of in vitro cell and cell-free endpoints to assess the toxicity of cerium oxide nanoparticles as well as particulates emitted from engines using Envirox. Exposure assessment has taken data from modeling studies and from airborne monitoring sites in London and Newcastle adjacent to routes where vehicles using Envirox passed. Data have demonstrated that for the exposure levels measured, the estimated internal dose for a referential human in a chronic exposure situation is much lower than the no observed-effect level (NOEL) in the in vitro toxicity studies. Exposure to nano size cerium oxide as a result of the addition of Envirox to diesel fuel at the current levels of exposure in ambient air is therefore unlikely to lead to pulmonary oxidative stress and inflammation, which are the precursors for respiratory and cardiac health problems. PMID- 18444009 TI - Lung function changes in Sprague-Dawley rats after prolonged inhalation exposure to silver nanoparticles. AB - The antimicrobial activity of silver nanoparticles has resulted in their widespread use in many consumer products. However, despite the continuing increase in the population exposed to silver nanoparticles, the effects of prolonged exposure to silver nanoparticles have not been thoroughly determined. Accordingly, this study attempted to investigate the inflammatory responses and pulmonary function changes in rats during 90 days of inhalation exposure to silver nanoparticles. The rats were exposed to silver nanoparticles (18 nm diameter) at concentrations of 0.7 x 10(6) particles/cm(3) (low dose), 1.4 x 10(6) particles /cm(3) (middle dose), and 2.9 x 10(6) particles /cm(3) (high dose) for 6 h/day in an inhalation chamber for 90 days. The lung function was measured every week after the daily exposure, and the animals sacrificed after the 90-day exposure period. Cellular differential counts and inflammatory measurements, such as albumin, lactate dehydrogenase (LDH), and total protein, were also monitored in the acellular bronchoalveolar lavage (BAL) fluid of the rats exposed to the silver nanoparticles for 90 days. Among the lung function test measurements, the tidal volume and minute volume showed a statistically significant decrease during the 90 days of silver nanoparticle exposure. Although no statistically significant differences were found in the cellular differential counts, the inflammation measurements increased in the high-dose female rats. Meanwhile, histopathological examinations indicated dose-dependent increases in lesions related to silver nanoparticle exposure, such as infiltrate mixed cell and chronic alveolar inflammation, including thickened alveolar walls and small granulomatous lesions. Therefore, when taken together, the decreases in the tidal volume and minute volume and other inflammatory responses after prolonged exposure to silver nanoparticles would seem to indicate that nanosized particle inhalation exposure can induce lung function changes, along with inflammation, at much lower mass dose concentrations when compared to submicrometer particles. PMID- 18444010 TI - Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in Sprague-Dawley rats. AB - The antibacterial effect of silver nanoparticles has resulted in their extensive application in health, electronic, and home products. However, while the population exposed to silver nanoparticles continues to increase with ever new applications, silver nanoparticles remain a controversial research area as regards their toxicity to biological systems. In particular, the oral toxicity of silver nanoparticles is of particular concern to ensure public and consumer health. Accordingly, this study tested the oral toxicity of silver nanoparticles (60 nm) over a period of 28 days in Sprague-Dawley rats following Organization for Economic Cooperation and Development (OECD) test guideline 407 with Good Laboratory Practice (GLP) application. Eight-week-old rats, weighing about 283 g for the males and 192 g for the females, were divided into four 4 groups (10 rats in each group): vehicle control, low-dose group (30 mg/kg), middle-dose group (300 mg/kg), and high-dose group (1000 mg/kg). After 28 days of exposure, the blood biochemistry and hematology were investigated, along with a histopathological examination and silver distribution study. The male and female rats did not show any significant changes in body weight relative to the doses of silver nanoparticles during the 28-day experiment. However, some significant dose dependent changes were found in the alkaline phsophatase and cholesterol values in either the male or female rats, seeming to indicate that exposure to over more than 300 mg of silver nanoparticles may result in slight liver damage. There were no statistically significant differences in the micronucleated polychromatic erythrocytes (MN PCEs) or ratio of polychromatic erythrocytes among the total erythrocytes after silver nanoparticle exposure when compared with the control. Therefore, the present results suggest that silver nanoparticles do not induce genetic toxicity in male and female rat bone marrow in vivo. Nonetheless, the tissue distribution of silver nanopaticles did show a dose-dependent accumulation of silver content in all the tissues examined. In particular, a gender-related difference in the accumulation of silver was noted in the kidneys, with a twofold increase in the female kidneys when compared with the male kidneys. PMID- 18444011 TI - Total and regional deposition of ultrafine particles in a mouse model of allergic inflammation of the lung. AB - Epidemiological studies have shown an association between ambient particle inhalation and adverse respiratory heath effects. Inhalation of ultrafine particles (UFP, diameter <100 nm) has been suggested to contribute to exacerbation of allergic airway inflammation. Here we analyze the potential effects of allergen sensitization and challenge on total and regional deposition of UFP in the lung. Ovalbumin (OVA)-sensitized and nonsensitized mice were exposed for 1 h to ultrafine iridium particles radiolabeled with (192)Ir (UF-Ir) (0.2 mg m(-3)) at 2 different time points either before or after allergen (OVA) challenge. Additional sensitized and nonsensitized mice were exposed to UF-Ir without allergen challenge. Lung total and regional UF-Ir deposition were calculated according to the distribution of radioactivity in the body and in the excreta during 3 days following UF-Ir inhalation. OVA-sensitized mice showed a 21% relative increase of total UF-Ir deposited fraction compared to nonsensitized mice. When UF-Ir inhalation was performed after allergen challenge, no difference in total UF-Ir deposited fraction between sensitized and nonsensitized mice was detectable. Furthermore, no differences in extrathoracic deposition or in regional particle deposition were detected between all experimental groups. This study indicates that allergen sensitization alone can affect UFP deposition in the lungs. Whether higher UFP deposition in sensitized individuals compared to nonsensitized individuals or whether other factors, like alterations in long-term clearance kinetics, contribute substantially to the susceptibility of allergic individuals to particle exposure has yet to be elucidated. PMID- 18444012 TI - Unsteady-state airflow and particle deposition in a three-generation human lung geometry. AB - The study of particle transport and deposition in the human lung is critical in health risk assessment of air pollutants and in pharmaceutical drug delivery. Several computational fluid dynamics (CFD) studies have investigated particle deposition in the lung for simplified airflow scenarios. A shortcoming with most CFD studies is uncertainty regarding flow boundary conditions, which directly impacts airflow and particle deposition. The influence of inlet and outlet conditions on airflow and particle deposition in lung common airways was assessed here. Common airways consisted of nine airways of the human lung ahead of lobes: the trachea, main, and lobar bronchi connected as a network of cylindrical tubes with dimensions based on morphometric measurements. Three different boundary conditions were used: (1) prescribed constant flow rate at the trachea entrance and atmospheric pressure at terminal branch exits, (2) atmospheric pressure at the trachea inlet and prescribed outlet flow rates corresponding to uniform lobar expansion, and (3) the same as case (2) with exit flow rates according to nonuniform lobar expansion. Unsteady airflow fields were numerically solved for a 2-s inhalation. Spherical particles of 1 nm to 10 microm diameter were injected at the trachea inlet, and particle deposition patterns during inhalation were evaluated. A Lagrangian particle tracking method was used that included particle inertia, gravity, and Brownian motion. Predicted flows showed similar trends but with a notable difference in magnitude. Lower particle deposition was found in case (1) for all particle sizes. The differences among these cases indicated the significance of realistic boundary conditions for accurate assessment of the flow field and particle deposition. PMID- 18444013 TI - Three-dimensional model for aerosol transport and deposition in expanding and contracting alveoli. AB - Particle transport and deposition within a model alveolus, represented by a rhythmically expanding and contracting hemisphere, was modeled by a three dimensional analytical model for the time-dependent air velocity field as a superposition of uniform and radial flow components, satisfying both the mass and momentum conservation equations. Trajectories of particles entrained in the airflow were calculated by a numerical particle trajectory code to compute simultaneously deposition by inertial impaction, gravitational sedimentation, Brownian diffusion, and interception. Five different orientations of the orifice of the alveolus relative to the direction of gravity were selected. Deposition was calculated for particles from 1 nm to 10 microm, for 3 breathing conditions, and for 5 different entrance times relative to the onset of inspiration. For the analyzed cases, the spatial orientation of the orifice of an alveolus has practically no effect on deposition for particles below about 0.1 microm, where deposition is dominated by Brownian motion. Above about 1 microm, where deposition is governed primarily by gravitational settling, deposition can vary from 0 to 100%, depending on the spatial orientation, while deposition of particles 0.1-1 microm falls between these two extreme cases. Due to the isotropic nature of Brownian motion, deposition of the 10-nm particles is practically uniform for all spatial orientations. However, for larger particles, deposition can be quite inhomogeneous, consistent with the direction of gravity. While nearly all particles are exhaled during the successive expiration phase, there are a few cases where particles still leave the alveolus even after many breathing cycles. PMID- 18444014 TI - Theories in behavioral medicine. PMID- 18444015 TI - Social-cognitive predictors of dietary behaviors in South Korean men and women. AB - BACKGROUND: Eating a diet that is high in vitamins and low in fat is considered to be governed by social-cognitive factors, such as intentions, planning, self efficacy, and outcome expectancies. PURPOSE: A longitudinal field study was designed to examine the interrelationships of these factors with dietary behaviors. METHOD: In 697 South Korean men and women, objective health-risk status was assessed at Time 1 (cholesterol, blood pressure, and body mass index) in conjunction with self-efficacy, outcome expectancies, and intentions. At Time 2, six months later, coping self-efficacy, planning, and dietary behaviors were measured. A two-group structural equation model for men and women was specified to determine the relations of distal and proximal predictors of a healthy diet. RESULTS: Self-efficacy was of equal predictive power in men and women, whereas intentions and planning were relevant only in women. Objective risk status was associated with intentions in women but not in men. CONCLUSIONS: Results confirm the predictive power of the Health Action Process Approach and point to the role of gender in the self-regulation of dietary behaviors. PMID- 18444016 TI - Gender and age disparity in health-related behaviors and behavioral patterns based on a National Survey of Taiwan. AB - BACKGROUND: This is a population-based study based on the 2002 National Survey of Taiwan on Knowledge, Attitude, and Practice of Health Promotion. PURPOSE: The objective of this study is to examine health-related behaviors and behavioral patterns among different gender and age groups. METHOD: A total of 26,755 participants were interviewed, resulting in a response rate of 81.9%. Factor analysis with orthogonal rotation was applied to identify the underlying factor structure for the health-related behaviors, including cigarette smoking, betel nut chewing, alcohol drinking, intake of fruits or vegetables, prevention service utilization, physical activity, and tooth brushing. RESULTS: Protective and risk behavioral patterns were selected consistently among various gender and age subgroups. These two behavior patterns were negatively associated with each other. In younger age groups (age < 55), a risk behavioral pattern was more dominant than a protective behavioral pattern. In the older age group (age >or= 55), the pattern order was reversed. CONCLUSION: An effective health intervention program should be based on behavioral patterns instead of an individual behavior. Gender and age play an important role in the behavioral patterns and need to be taken into consideration when designing intervention programs. PMID- 18444017 TI - Anticipatory psychological distress in women scheduled for diagnostic and curative breast cancer surgery. AB - BACKGROUND: Psychological distress is a central experience for women facing diagnostic and curative breast cancer surgery. PURPOSE: The present study was designed to predict anticipatory distress in 187 women scheduled to undergo excisional breast biopsy or lumpectomy. METHOD: Participants completed questionnaires assessing emotional distress and predictors of this distress (surgery type, worry about the surgical procedure, and worry about what the surgeon will find). RESULTS: The study found that lumpectomy patients experienced greater anticipatory distress than excisional breast biopsy patients on three of the four distress measures (all ps < 0.05) and that worry about what the surgeon might find partially mediated these effects. CONCLUSION: The results suggest that although women awaiting lumpectomy are more distressed than women awaiting biopsy, both groups report substantial distress, and, consequently, psychosocial interventions are recommended for both groups. PMID- 18444018 TI - Memory for fatigue in chronic fatigue syndrome: the relation between weekly recall and momentary ratings. AB - BACKGROUND: Understanding how patients with chronic fatigue syndrome (CFS) recall their fatigue is important because fatigue is a core clinical dimension of this poorly understood illness. PURPOSE: This study assessed the associations between momentary fatigue ratings and weekly recall of fatigue in 71 participants with CFS. METHOD: During the three-week data collection period, fatigue intensity was recorded six times a day in electronic diaries. At the end of each week, participants were asked to recall their fatigue intensity for that week. Statistical analyses were done with t-tests and Pearson's and intraclass correlations. RESULTS: Average weekly recall of fatigue intensity was significantly higher than average momentary ratings. Furthermore, moderate to high Pearson's correlations and intraclass correlations (consistency and absolute agreement) between recall and momentary fatigue ratings were found. CONCLUSION: Individuals with CFS recalled consistently higher levels of fatigue in comparison to real-time momentary ratings, yet the level of agreement between the two measures was moderate to high. These findings may have implications for the conduct of office examinations for CFS. PMID- 18444019 TI - Associations between psychological demands, decision latitude, and job strain with smoking in female hotel room cleaners in Las Vegas. AB - BACKGROUND: Little is known of the impact of the work environment on smoking among women holding low-paid jobs in the service sector. PURPOSE: To study the associations between the components of the demand-control model with smoking in hotel room cleaners. METHODS: We conducted a survey on work and health among 776 female hotel room cleaners in Las Vegas. Associations between psychosocial work characteristics and smoking were analyzed with multivariate regression analyses. RESULTS: Psychosocial work characteristics were associated with smoking after adjustment for covariates. Effect estimates were substantially reduced by additional adjustment for ethnicity, but remained significant for high psychological demands and smoking prevalence (OR = 1.97, p = 0.02), high job strain and smoking prevalence (OR = 1.87, p = 0.04), and high job strain and smoking intensity (coefficient = 3.52, p = 0.03). When analyses were restricted to Hispanic workers and further adjusted for place of birth, low decision latitude (coefficient = 3.94, p = 0.04) and high job strain (coefficient = 4.57, p = 003) were associated with smoking intensity but not with smoking status. CONCLUSION: Workplace smoking cessation programs may benefit from a primary prevention component reducing job strain among service workers. More research is needed on perceived and objective differences in psychosocial work characteristics across ethnic, immigrant, and other social groups within the same occupation. PMID- 18444020 TI - Lagged effects of active coping within the demand-control model: a three-wave panel study among Japanese employees. AB - BACKGROUND: There have been few empirical studies to explain the individual differences in and the underlying mechanism behind the Job Demand-Control (DC) Model. PURPOSE: This study examined the lagged effects of active coping on stress responses (i.e., psychological distress and physical complaints) in the context of the DC Model using three-wave panel survey data with intervals of one month. METHOD: Participants were 193 employees working in a construction machinery company in Japan. Hierarchical multiple regression analyses were conducted to examine whether or not the effectiveness of active coping would be facilitated by job control as a coping resource. RESULTS: The advantage of job control in combination with active coping became obvious after one month, which implies that job control has a delayed effect on coping effectiveness. However, the advantage disappeared after two months. These results suggest that the advantage of job control for active coping is limited in time. CONCLUSION: Conceptualization of job control as a coping resource seems to be useful in explaining how the DC Model influences employees' health, where time plays an important role. PMID- 18444021 TI - Work family balance, stress, and salivary cortisol in men and women academic physicians. AB - BACKGROUND: The stress of medical practice has been recurrently studied, but work and family-related determinants of health by gender remain under researched. PURPOSE: To test the hypothesis that cortisol excretion would be affected by the perceived severity of total workload imbalance. METHOD: By hierarchical regression analysis, the associations between work-family balance and diurnal salivary cortisol levels by sex in academic physicians (n = 40) were investigated. RESULTS: Men physicians reported more paid work hours per week than women physicians and women more time in childcare, but their total working hours were similar. Controlling for sex and age, the mean of the diurnal cortisol release was associated with a combined effect of sex and responsibility at home. When morning cortisol, sex, and children at home were held constant, cortisol levels in the evening were associated with responsibility at home without significant gender interaction. CONCLUSION: With increasing responsibility at home, women and men reacted differently with regard to cortisol responses over the day. However, in the evening, controlling for the morning cortisol, these gender differences were not as obvious. These findings highlight traditional gender patterns among both women and men physicians in the challenge of finding a balance between work and family. PMID- 18444022 TI - Factorial invariance and stability of the Effort-Reward Imbalance Scales: a longitudinal analysis of two samples with different time lags. AB - BACKGROUND: Key measures of Siegrist's (1996) Effort-Reward Imbalance (ERI) Model (i.e., efforts, rewards, and overcommitment) were psychometrically tested. PURPOSE: To study change in organizational interventions, knowledge about the type of change underlying the instruments used is needed. Next to assessing baseline factorial validity and reliability, the factorial stability over time - known as alpha-beta-gamma change - of the ERI scales was examined. METHODS: Psychometrics were tested among 383 and 267 healthcare workers from two Dutch panel surveys with different time lags. RESULTS: Baseline results favored a five factor model (i.e., efforts, esteem rewards, financial/career-related aspects, job security, and overcommitment) over and above a three-factor solution (i.e., efforts, composite rewards, and overcommitment). Considering changes as a whole, particularly the factor loadings of the three ERI scales were not equal over time. Findings suggest in general that moderate changes in the ERI factor structure did not affect the interpretation of mean changes over time. CONCLUSION: Occupational health researchers utilizing the ERI scales can feel confident that self-reported changes are more likely to be due to factors other than structural change of the ERI scales over time, which has important implications for evaluating job stress and health interventions. PMID- 18444023 TI - A combination of behavioral and physiological indicators for assessing pig welfare on the farm. AB - The purpose of this research was to identify pig welfare indicators that could help in recognizing stressful practices on farm. The study evaluated behavioral and physiological indicators (cortisol and negative acute phase proteins) in 2 groups of 20 female pigs 4 months old after a 48-hr transport. The first group (A) was transported at the end of May, the second (B) in June. Behavioral observations and blood collection occurred at arrival (D1) and 28 days later (D28). Compared with within-animal control samples obtained 28 days later, pigs of Group A had increased cortisol levels and decreased albumin concentrations after arrival. As demonstrated by lesion and behavior observations, the effect on cortisol and albumin was higher in Group B pigs after a tail-biting episode occurred. The study has reported no evidence of Retinol Binding Protein (RBP) in pigs. A method developed for swine RBP quantification found RBP strongly reduced in D28 samples of Group B, confirming it to be a negative protein in pigs. The suggested combination of physiological and behavioral indicators could provide useful information on the welfare state of an animal. PMID- 18444024 TI - Investigating fear in rainbow trout (Oncorhynchus mykiss) using the conditioned suppression paradigm. AB - Trout learned the operant task of pendulum-pressing for a food-reward in a mean of 4.3 sessions lasting 1 hr. In a separate phase, fish also learned--through classical conditioning--to associate a neutral light cue with an aversive stimulus. When again allowed to pendulum-press for food, after aversive classical conditioning, there was a drop in the rate of responding. The mean rate dropped from 3.6-2.9 responses per min. Most important, when the light-stimulus was superimposed on a steady bout of pendulum-pressing, trout ceased to press the pendulum and did not resume activity until termination of the light-stimulus (mean number of responses during a 3-min interval immediately prior to light stimulus = 14.3 vs. during 3-min light-stimulus = 0.1). Psychologists have used this decrease in operant responding, or "conditioned emotional response," as a tool to examine the psychological nature of this type of aversive conditioning. In this study, the fish demonstrated various results under this paradigm similar to those shown by "higher" nonhuman animals, therefore challenging the view of fish as unconscious, nonsentient animals. PMID- 18444025 TI - Comparison of remote versus in-person behavioral consultation for treatment of canine separation anxiety. AB - To investigate the validity of remote consultation for treatment of canine separation anxiety, this study compared the efficacy of 2 types of behavioral services offered by Tufts Cummings School of Veterinary Medicine (TCSVM): (a) "PetFax," a remote consultation service in which dog caregivers (owners) and a certified applied animal behaviorist correspond via fax or email and (b) in person clinic consultation, which requires that owners bring their dogs to the Animal Behavior Clinic at TCSVM to consult with a board-certified veterinary behaviorist, a veterinary behavior resident, or a certified applied animal behaviorist. The study tested 4 variables for significant differences between PetFax users and clinic visitors: (a) pre- and posttreatment anxiety scores; (b) owner-reported improvement; (c) percentage of rehomed dogs, dogs relinquished or euthanized because of separation anxiety; and (d) clarity of communication with owners. The study found no significant differences between the groups. Difference scores and owner reports demonstrated substantial reduction in separation anxiety in both groups. Results indicate remote consultation is a valid way for behavioral professionals to share behavior modification advice with owners regarding canine separation anxiety. PMID- 18444026 TI - Factors affecting behavior and welfare of service dogs for children with autism spectrum disorder. AB - The use of service dogs for children with autism spectrum disorder is a relatively new and growing assistance-dog application. The objectives of this article were to identify and describe the factors influencing an autism service dog's performance and the impact of this type of placement on the dog's welfare. A qualitative approach uses interview and observational data to characterize the dogs' behaviors and welfare with relevancy to the dogs' home environments. Identification of potential physical stressors included lack of rest or recovery time after working, unintentional maltreatment and prodding by children with autism, lack of predictability in daily routines, and insufficient opportunities for recreational activities. Results revealed that these dogs formed social relationships primarily with the parents and second with the children with autism. Failure to recognize and respond to the identified physical, emotional, and social needs can have serious impacts on the behavior, welfare, and performance of these autism service dogs, as well as parental satisfaction. As applications of service dogs expand to new domains, there is a need to assess and understand factors and variables affecting the relationship between family and service dog to ensure continued success of these programs. PMID- 18444027 TI - Pet owners' views of pet behavior problems and willingness to consult experts for assistance. AB - Prior research has found that dog obedience training and the receipt of advice regarding companion animal (pet) behavior reduce the risk of nonhuman animal relinquishment to an animal shelter and increase human-companion animal interactions, but research also finds that only a minority of pet guardians participates in such activities. The researchers for this study asked 170 dog and cat guardians to assess the seriousness of common problem behaviors and how likely they were to seek help. The researchers also asked them to rate different methods of obtaining expert advice. The dog and cat guardians saw behaviors directly affecting humans as most severe; those involving the destruction of property were next in severity; and those affecting the animal more than the human were least severe. There were no significant differences in ratings by participants' gender or income. Participants indicated they were more likely to use free help options than fee-based services. The lack of a clear correlation between the seriousness of a behavior problem and likelihood of seeking help suggests that other factors may play a role in pet guardians' interest in obtaining expert advice. PMID- 18444028 TI - Frustrated appetitive foraging behavior, stereotypic pacing, and fecal glucocorticoid levels in snow leopards (Uncia uncia) in the Zurich Zoo. AB - This study hypothesized that permanently frustrated, appetitive-foraging behavior caused the stereotypic pacing regularly observed in captive carnivores. Using 2 adult female snow leopards (Uncia uncia), solitarily housed in the Zurich Zoo, the study tested this hypothesis experimentally with a novel feeding method: electronically controlled, time-regulated feeding boxes. The expected result of employing this active foraging device as a successful coping strategy was reduced behavioral and physiological measures of stress, compared with a control-feeding regime without feeding boxes. The study assessed this through behavioral observations and by evaluating glucocorticoid levels noninvasively from feces. Results indicated that the 2 snow leopards did not perform successful coping behavior through exercising active foraging behavior or through displaying the stereotypic pacing. The data support a possible explanation: The box-feeding method did not provide the 2 snow leopards with the external stimuli to satisfy their appetitive behavioral needs. Moreover, numerous other factors not necessarily or exclusively related to appetitive behavior could have caused and influenced the stereotypic pacing. PMID- 18444029 TI - Caring during crisis: animal welfare during pandemics and natural disasters. AB - From April 29 to May 1, 2007, the University of Guelph hosted a symposium, Caring During Crisis: Animal Welfare During Pandemics and Natural Disasters, with the objectives (a) of raising awareness about how nonhuman animals and the people who care for them are affected during emergencies and (b) of sharing knowledge about how animal welfare may be addressed during these situations. The symposium attracted 150 participants, representing 71 organizations from across Canada, the United States, the United Kingdom, Australia, Chile, and the Cayman Islands. The audience also brought a range of perspectives to the issues - from individuals representing animal protection and commodity organizations to municipal government officials responsible for community safety and correctional services; many of these individuals had little or no animal experience. To take advantage of this diverse audience and range of interests, the symposium was structured with formal presentations by internationally recognized experts, followed by panel discussions at the end of each session to facilitate contributions by the audience. At the conclusion of the 3 days, it was clear that our emotional, economic, and ecological relationships with animals require thoughtful integration of animal care within formal policy and planning for emergency response. PMID- 18444030 TI - Why should we care about nonhuman animals during times of crisis? AB - Incentives to care for nonhuman animals derive in part from the extent to which people depend on animals for food, for livelihood, and for cultural and psychological reasons as well as from the duty to protect animals in their care. When attention is turned to solving and preventing animal welfare problems at times of crisis, it becomes clear that those problems are also associated with problems for human welfare and environmental impact. The incidence and spread of animal diseases is affected by how animals are treated, and this can have very important effects. Similarly, during disasters caused by either natural or human made events, outcomes for animals are important both in themselves and for their effects on humans and the environment. The need to plan and prepare to care for animals in advance of disease pandemics and disasters - and then to provide coordinated, measured management in response when such crises occur - requires collaboration between all agencies involved as well as increasing attention and resources. PMID- 18444031 TI - The impact of epizootics on livelihoods. AB - Epizootics (nonhuman animal disease epidemics) can have detrimental impacts on livelihoods through a complex interaction of demographic trends, food production, and animal disease. Differences in the rate of demographic shifts, including rates of population growth, economic growth, urbanization, environmental sustainability, and role of women in society, are strong driving forces that will determine to what extent food demand will be matched by food production capacity. Epizootics can negatively affect commerce and trade in all countries, and in low income countries limited infrastructure and resources as well as competing priorities provide additional disincentive to controlling or eradicating animal diseases. Economic growth is critical to overcoming disparities among countries and is best supported by integrated animal health, public health, labor, and foreign policies. The adverse impacts of epizootics can be largely overcome through programs that support job growth along the value-added chain of food production and will require significant investments in science- (risk-) based education. PMID- 18444032 TI - Humane killing of nonhuman animals for disease control purposes. AB - Reports and guidelines produced by international institutions such as the World Organization for Animal Health (OIE, 2005) describe various methods of killing nonhuman animals. Selection and implementation of a killing method may involve several factors. Preventing or minimizing risk to human health and safety may override animal welfare concerns if the disease has the potential to cause high mortality, for example, highly pathogenic avian influenza. Owing to the public health significance of this disease, the scope of this article presents only an overview of the welfare and practical aspects of large-scale killing of poultry on farms. Killing poultry in houses using a gas mixture eliminates the need for human contact with infective materials and birds. Several protocols for administering gas mixtures into poultry houses have been evaluated, mainly in Europe and North America. Overdose of anesthetics in feed and water has sedated birds kept under free-range or semi-intensive rearing systems. Containerized gas killing systems have proved successful on small-to-medium-size poultry farms. However, using nitrogen, a nonaversive gas, could greatly improve bird welfare. PMID- 18444033 TI - How is animal welfare addressed in Canada's emergency response plans? AB - In 2005, Hurricanes Katrina and Rita clearly revealed that even in the United States the welfare of companion animals and nonhuman animals in the wild, zoo, or aquarium was not considered within the evacuation plans for their human caretakers (owners). The lack of proper planning and trained individuals resulted in a huge loss of animal life as well as suffering and trauma to both animals and their owners. The present Canadian Federal Emergency Response Plan does not have adequate procedures for the evacuation of animals together with their owners, nor do Canada or the provinces and territories have a plan in place that consists of properly trained and equipped individuals to respond to this aspect of disaster management. The Canadian Veterinary Reserve (CVR) was thus organized at a national level to respond properly to disasters or emergencies of all types and thereby reduce animal suffering and loss of life. This article describes the formation of the CVR and its anticipated national role in addressing animal welfare during times of catastrophic need. PMID- 18444034 TI - Animal disease and human trauma: the psychosocial implications of the 2001 UK foot and mouth disease disaster. AB - The 2001 UK foot and mouth disease (FMD) crisis is commonly understood to have been a nonhuman animal problem, an economic industrial crisis that was resolved after eradication. By using a different lens, a longitudinal ethnographic study of the health and social consequences of the epidemic, the research reported here indicates that 2001 was a human tragedy as well as an animal one. In a diary based study, it can be seen that life after the FMD crisis was accompanied by distress, feelings of bereavement, fear of a new disaster, loss of trust in authority and systems of control, and the undermining of the value of local knowledge. Diverse groups experienced distress well beyond the farming community. Such distress remained largely invisible to the range of "official" inquiries into the disaster. That an FMD epidemic of the scale of 2001 could happen again in a developed country is a deeply worrying prospect, but it is to be hoped that contingency plans are evolving along with enhanced understanding of the human, animal, and financial cost. PMID- 18444035 TI - Special welfare concerns in countries dependent on live animal trade: the real foreign animal disease emergency for Canada. AB - Any outbreak of an Office International des Epizooties trade-disrupting (previously List-A) disease, such as classical swine fever or foot and mouth disease in a previously disease-free region can have severe consequences for nonhuman animal welfare. In addition to animals destroyed for the purposes of disease eradication, certain preexisting trade patterns may result in welfare slaughter programs affecting many more animals than the disease eradication effort. Welfare slaughter is the destruction of healthy animals to prevent overcrowding on farms under movement restriction and as a consequence of loss of access to live animal export markets. Governments of European countries have anticipated welfare slaughter as part of their disease eradication preparedness. The concept of welfare slaughter and the resource implications thereof have not been included in current, published, livestock disease emergency-planning documents in Canada or the United States. Animal welfare, specifically the killing of healthy animals (not foreign animal disease eradication) has been the focus of public concern in recent disease-eradication efforts in Europe. North American organizations responsible for livestock exotic disease emergency preparedness need to expand their plans to include welfare slaughter. PMID- 18444036 TI - Panel discussion one: front-line experiences with animal welfare, natural disasters, and disease outbreaks. PMID- 18444037 TI - Panel discussion three: addressing animal welfare in emergency response planning. PMID- 18444040 TI - Development of a cancer camp for adult Spanish-speaking survivors: lessons learned from Camp Alegria. AB - BACKGROUND: The serious psychosocial and emotional side effects of cancer and its treatment negatively affect the lives of breast cancer survivors. METHODS: Camp Alegria, in 2005, was the first oncology camp offered to Latina breast cancer survivors. This 3-day camp (N = 58 women) provided a culturally and linguistically relevant program that empowered Spanish-speaking women diagnosed with breast cancer and gave them an opportunity to gain support from other cancer survivors facing similar challenges. RESULTS: Process evaluation results illustrate high satisfaction with the overall program, format, educational and recreational activities. CONCLUSION: This paper describes the camp development, experiences, and lessons learned. PMID- 18444041 TI - Promoting breast cancer screening among Chamorro women in Southern California. AB - BACKGROUND: Asian American and Pacific Islander women represent a significant at risk population for breast cancer, with their mortality rates rising while rates fall for all other racial groups. METHODS: This 3-year study employed a quasi experimental design to test the influence of an intervention on screening rates among women age 50 years and older in Southern California compared to Northern California. RESULTS: Despite significant exposure of women to the educational elements in Southern California, the intervention did not increase women's knowledge, attitudes, or screening behaviors. CONCLUSIONS: We discuss several study design and implementation limitations that could have influenced the study's results. PMID- 18444042 TI - Disparities in colorectal screening between US-born and foreign-born populations: evidence from the 2000 National Health Interview Survey. AB - BACKGROUND: Over 11% of the US population in 2002 was foreign born. Studies that have examined disparities of cancer screening often focus on racial/ethnicity differences without considering their origins. This study examines the disparities in colorectal cancer (CRC) screening between US- and foreign-born groups and explores factors associated with such disparities. METHODS: Data were obtained from the 2000 National Health Interview Survey Cancer Control Module. Multivariate logistic models were used to compare the use of CRC screening among the foreign born and 4 US-born race/ethnicity subgroups while controlling for other factors that may affect such screening. Appropriate weighting procedures were employed to account for the complex design of the survey. RESULTS: Compared with the US-born non-Hispanic Whites, the odds ratio of ever having had a colorectal screening for the US-born Hispanic, non-Hispanic Black, non-Hispanic other races groups, and the foreign-born group with 15 or more years of residency was 0.65, 0.77, 0.98, and 0.58, respectively. An even lower odds ratio (0.46) was found among the foreign-born group with a shorter duration of residency. We found that the rate of screening for foreign-born individuals with good socioeconomic status and/or with health insurance was significantly lower than that of the US born with similar status, and the rate was not much different from that of US born individuals in lower socioeconomic levels. Having a usual source of care was found to be the most important protective factor for the foreign-born group. CONCLUSIONS: Foreign birth was associated with a lower rate of CRC screening. Future studies of health disparities should also consider immigration status. PMID- 18444043 TI - Facilitating factors for colorectal cancer screening. AB - BACKGROUND: In this retrospective study, we examined factors that facilitated receipt of colorectal cancer (CRC) screening in a sample of low-income, predominantly African Americans participating in a tailored telephone education intervention. METHODS: A total of 61 individuals who received CRC screening were matched on age and sex with 61 individuals who had not received screening. Using records collected as part of the intervention, we identified facilitating factors and compared them between groups. RESULTS: We identified 8 facilitating factors, of which there were significant bivariate relationships with 6 factors. These 6 factors were stated familiarity with CRC test, seemed to only need reminder calls, seemed ready to screen, primary care physician (PCP) encouraged CRC screening, had an upcoming PCP appointment, and being prevention oriented. CONCLUSIONS: Identifying facilitating factors in those who receive screening may lead to insights about what factors need to be cultivated in those who do not receive screening. PMID- 18444044 TI - Reasons for declining colorectal cancer screening by older Canadians: a pilot study. AB - BACKGROUND: Although colorectal cancer (CRC) is the second leading cause of cancer death in Canada, only 4% to 14% of eligible adults follow screening recommendations. In this pilot study, we explored older Canadians' perception of the barriers and enabling factors associated with CRC screening participation. METHODS: Interviews from 100 participants, age 50 through 90 years, were analyzed using a mixed qualitative and quantitative methods approach. We used constant comparative analysis, Pearson chi2, and Fisher's exact probability tests. RESULTS: Themes impacting screening participation included physician screening recommendations, reasons for declining screening, surprise at CRC information, and barriers to understanding cancer information. CONCLUSION: Education emphasizing the importance of early detection through screening is needed. PMID- 18444047 TI - Evaluation of the tumor board as a Continuing Medical Education (CME) activity: is it useful? AB - BACKGROUND: Although it has been previously reported that offering continuing medical education (CME) credit is not a major factor in tumor board attendance, the results/utility of the Accreditation Council for Continuing Medical Education mandated evaluations of those tumor boards offering CME credit has not been studied. METHODS: We reviewed the CME evaluations of our University Gastrointestinal Tumor Board; this meeting was chosen because it is multidisciplinary, well attended, and offers CME credit contingent on completing a standard CME evaluation form each session. RESULTS: Of the 2736 attendees, 660 (24%) at the 79 consecutive conferences studied completed the evaluation for CME credit. Reported satisfaction was high; the average response on the 4-question satisfaction survey was 5 (Excellent) on a 5-point Likert scale, only 6% of attendees perceived any commercial bias, and only 3 attendees stated that the conference did not achieve the stated objectives. Of the respondents, 42% indicated that the tumor board information would change their practice, although few specific examples were given. A minority of responders provided specific feedback. CONCLUSIONS: A minority of attendees at this tumor board utilized CME credit. Although satisfaction and impact ratings were high, potential response set bias, lack of specific feedback, and nonresponse bias were limitations to the evaluations. PMID- 18444045 TI - Colorectal cancer screening in Vietnamese Americans. AB - BACKGROUND: Rates of colorectal cancer screening in Vietnamese Americans are lower than those in non-Hispanic Whites. In this article, we describe rates of colorectal screening, identify determinants, and recommend educational strategies to improve screening. METHODS: A cross-sectional sample of 867 Vietnamese aged 50 to 74 years drawn from a sampling frame of individuals in the Alameda and Santa Clara Counties, California, and Harris County, Texas, area telephone directories with Vietnamese surnames were interviewed in 2004. RESULTS: Colorectal screening recognition, receipt, currency, and intention rates were low. CONCLUSIONS: Although the screening rates are low, Vietnamese are receptive to screening if providers recommend it. PMID- 18444046 TI - Teaching complementary medicine at an academic oncology department. AB - BACKGROUND: The increased use of complementary and alternative medicine (CAM) by patients with cancer is a significant phenomenon in cancer care and suggests the need for increased knowledge by clinicians of these therapies. METHODS: Aiming at bridging the gap in knowledge of the philosophy and practice of major CAM modalities in cancer care, an elective course was offered to physicians and nurses in a large academic center. RESULTS: The course also aimed at providing the tools necessary to establish open and trusting clinician-patient dialogue regarding CAM. CONCLUSIONS: Exposure to the course was successful in improving knowledge and attitudes. PMID- 18444048 TI - Attitudes and practices of Florida nurse practitioners on oral cancer prevention and early detection. AB - BACKGROUND: Oral cancer continues to have a relatively low survival rate because most tumors are diagnosed at late stages. Nurse practitioners may be optimally positioned for oral cancer prevention and early detection. METHODS: A statewide mail-based survey was conducted among 448 Florida nurse practitioners. Logistic regression was conducted to assess the independent relationships between nurse practitioners' attitudes and their practices in oral cancer prevention and early detection. RESULTS: Nurse practitioners' oral cancer practice behaviors were significantly affected by their attitudes. CONCLUSIONS: Effective strategies should be implemented to enhance positive attitudes about oral cancer early detection among Florida nurse practitioners. PMID- 18444049 TI - A medical student-staffed outpatient oncology clinic: a 10-year Brazilian experience. AB - BACKGROUND: This is an update of a 10-years student-staffed oncology clinic. METHODS: Students are divided into 4 teams; each sees 1 to 2 outpatients weekly. RESULTS: By April 2006, 95 medical students participated, 89% for 2 or more years; 70% reported activity contributed to ability to read medical papers, and 59% improved their scientific writing. Of 39 students currently involved, 33 (84%) improved clinical skills in taking history, 27 (69%) in physical examination, and 34 (87%) in physician-patient relation. A total of 21 (56%) reported increased knowledge in general internal medicine. Although only 11% of former students pursued a specialty in Medical Oncology, 77% rated this clinic as the best extracurricular activity. CONCLUSIONS: Attendance of outpatient clinic in medical oncology can contribute significantly to the general medical education. PMID- 18444050 TI - The Healer's art: education in meaning and service. PMID- 18444052 TI - Evidence-based comprehensive treatments for early autism. AB - Early intervention for children with autism is currently a politically and scientifically complex topic. Randomized controlled trials have demonstrated positive effects in both short-term and longer term studies. The evidence suggests that early intervention programs are indeed beneficial for children with autism, often improving developmental functioning and decreasing maladaptive behaviors and symptom severity at the level of group analysis. Whether such changes lead to significant improvements in terms of greater independence and vocational and social functioning in adulthood is also unknown. Given the few randomized controlled treatment trials that have been carried out, the few models that have been tested, and the large differences in interventions that are being published, it is clear that the field is still very early in the process of determining (a) what kinds of interventions are most efficacious in early autism, (b) what variables moderate and mediate treatment gains and improved outcomes following intervention, and (c) the degree of both short-term and long-term improvements that can reasonably be expected. To examine these current research needs, the empirical studies of comprehensive treatments for young children with autism published since 1998 were reviewed. Lovaas's treatment meet Chambless and colleague's (Chambless et al., 1998; Chambless et al., 1996) criteria for "well established" and no treatment meets the "probably efficacious" criteria, though three treatments meet criteria for "possibly efficacious" (Chambless & Hollon, 1998). Most studies were either Type 2 or 3 in terms of their methodological rigor based on Nathan and Gorman's (2002) criteria. Implications of these findings are also discussed in relation to practice guidelines as well as critical areas of research that have yet to be answered. PMID- 18444053 TI - Evidence-based psychosocial treatments for eating problems and eating disorders. AB - Eating disorders represent a significant source of psychological impairment among adolescents. However, most controlled treatment studies have focused on adult populations. This review provides a synthesis of existing data concerning the efficacy of various psychosocial interventions for eating disorders in adolescent samples. Modes of therapy examined in adolescent samples include family therapy, cognitive therapy, behavioral therapy, and cognitive behavioral therapy mostly in patients with anorexia nervosa. At this time, the evidence base is strongest for the Maudsley model of family therapy for anorexia nervosa. Evidence of efficacy for other treatments and other conditions is limited by several methodological factors including the small number of studies, failure to use appropriate control conditions or randomization procedures, and small sample sizes (i.e., fewer than 10 participants per treatment arm). Potential moderators and mediators of treatment effect are reviewed. Finally, results from adolescent studies are contrasted with those from adult studies of eating disorders treatment. Many studies of adult populations comprise late adolescent/young adult participants, suggesting that findings regarding the efficacy of cognitive behavioral therapy for bulimia nervosa in adults likely extend to older adolescent populations. PMID- 18444054 TI - Evidence-based psychosocial treatments for child and adolescent depression. AB - The evidence-base of psychosocial treatment outcome studies for depressed youth conducted since 1998 is examined. All studies for depressed children meet Nathan and Gorman's (2002) criteria for Type 2 studies whereas the adolescent protocols meet criteria for both Type 1 and Type 2 studies. Based on the Task Force on the Promotion and Dissemination of Psychological Procedures guidelines, the cognitive behavioral therapy (CBT) based specific programs of Penn Prevention Program, Self Control Therapy, and Coping with Depression-Adolescent are probably efficacious. Interpersonal Therapy-Adolescent, which falls under the theoretical category of interpersonal therapy (IPT), also is a probably efficacious treatment. CBT provided through the modalities of child group only and child group plus parent components are well-established intervention approaches for depressed children. For adolescents, two modalities are well-established (CBT adolescent only group, IPT individual), and three are probably efficacious (CBT adolescent group plus parent component, CBT individual, CBT individual plus parent/family component). From the broad theoretical level, CBT has well-established efficacy and behavior therapy meets criteria for a probably efficacious intervention for childhood depression. For adolescent depression, both CBT and IPT have well-established efficacy. Future research directions and best practices are offered. PMID- 18444055 TI - Evidence-based psychosocial treatments for phobic and anxiety disorders in children and adolescents. AB - The article reviews psychosocial treatments for phobic and anxiety disorders in youth. Using criteria from Nathan and Gorman (2002), 32 studies are evaluated along a continuum of methodological rigor. In addition, the treatments evaluated in each of the 32 studies are classified according to Chambless et al.'s (1996) and Chambless and Hollon's (1998) criteria. Findings from a series of meta analyses of the studies that used waitlists also are reported. In accordance with Nathan and Gorman, the majority of the studies were either methodologically robust or fairly rigorous. In accordance with Chambless and colleagues, although no treatment was well-established, Individual Cognitive Behavior Therapy, Group Cognitive Behavior Therapy (GCBT), GCBT with Parents, GCBT for social phobia (SOP), and Social Effectiveness Training for children with SOP each met criteria for probably efficacious. The other treatments were either possibly efficacious or experimental. Meta-analytic results revealed no significant differences between individual and group treatments on diagnostic recovery rates and anxiety symptom reductions, as well as other youth symptoms (i.e., fear, depression, internalizing and externalizing problems). Parental involvement was similarly efficacious as parental noninvolvement in individual and group treatment formats. The article also provides a summary of the studies that have investigated mediators, moderators, and predictors of treatment outcome. The article concludes with a discussion of the clinical representativeness and generalizability of treatments, practice guidelines, and future research directions. PMID- 18444056 TI - Evidence-based psychosocial treatments for child and adolescent obsessive compulsive disorder. AB - Child and adolescent obsessive-compulsive disorder (OCD) is a chronic and debilitating condition associated with a wide range of impairments. This article briefly discusses the phenomenology of OCD, the theory underlying current treatment approaches, and the extant psychosocial treatment literature for child and adolescent OCD relative to the criteria for classification as an evidence based intervention. Studies were evaluated for methodological rigor according to the classification system of Nathan and Gorman (2002) and then were assessed relative to the criteria for evidence-based treatments specified by Chambless et al. (1998), Chambless et al. (1996), and Chambless and Hollon (1998). Results from exposure-based cognitive behavioral therapy (CBT) trials with children and adolescents have been consistent, with remission rates of the disorder ranging from 40% to 85% across studies. Findings from this review indicate that individual exposure-based CBT for child and adolescent OCD can be considered as a probably efficacious treatment. CBT delivered in a family-focused individual or group format can be considered as a possibly efficacious treatment. Moderators, mediators, and predictors of treatment outcome are discussed, as are implications and generalizability of extant findings to real-world settings. We conclude with recommendations for best practice and future research directions. PMID- 18444057 TI - Evidence-based psychosocial treatments for children and adolescents exposed to traumatic events. AB - The article reviews the current status (1993-2007) of psychosocial treatments for children and adolescents who have been exposed to traumatic events. Twenty-one treatment studies are evaluated using criteria from Nathan and Gorman (2002) along a continuum of methodological rigor ranging from Type 1 to Type 6. All studies were, at a minimum, robust or fairly rigorous. The treatments in each of these 21 studies also are classified using criteria from Chambless et al. (1996), and Chambless and Hollon (1998). Trauma-Focused Cognitive-Behavioral Therapy met the well-established criteria; School-Based Group Cognitive-Behavioral Treatment met the criteria for probably efficacious. All the other treatments were classified as either possibly efficacious or experimental. Meta-analytic results for four outcomes (i.e., posttraumatic stress, depressive symptoms, anxiety symptoms, and externalizing behavior problems) across all treatments compared to waitlist control and active control conditions combined reveal that, on average, treatments had positive, though modest, effects for all four outcomes. We also cover investigative work on predictors, moderators, and mediators of treatment outcome, as well as the clinical representativeness and generalizability of the studies. The article concludes with a discussion of practice guidelines and future research directions. PMID- 18444058 TI - Evidence-based psychosocial treatments for attention-deficit/hyperactivity disorder. AB - Pelham, Wheeler, and Chronis (1998) reviewed the treatment literature on attention-deficit/hyperactivity disorder (ADHD) and concluded behavioral parent training (BPT) and behavioral classroom management (BCM) were well-established treatments for children with ADHD. This review updates and extends the finding of the prior review. Studies conducted since the 1998 review were identified and coded based on standard criteria, and effect sizes were calculated where appropriate. The review reinforces the conclusions of Pelham, Wheeler, and Chronis regarding BPT and BCM. Further, the review shows that intensive peer focused behavioral interventions implemented in recreational settings (e.g., summer programs) are also well-established. The results of this update are discussed in the context of the existing treatment literature on ADHD. Implications for practice guidelines are suggested, as are directions for future research. PMID- 18444059 TI - Evidence-based psychosocial treatments for children and adolescents with disruptive behavior. AB - This article reviews the literature from 1996 to 2007 to update the 1998 Brestan and Eyberg report on evidence-based psychosocial treatments (EBTs) for child and adolescent disruptive behavior, including oppositional defiant disorder and conduct disorder. Studies were evaluated using criteria for EBTs developed by the task force on promotion and dissemination of psychological procedures (Chambless et al., 1998; Chambless et al., 1996). Sixteen EBTs were identified in this review, up from 12 in the earlier report, and 9 "possibly efficacious" treatments (Chambless & Hollon, 1998) were identified as well. This article describes the EBTs and their evidence base and covers research on moderators and mediators of treatment outcome, as well as the clinical representativeness and generalizability of the studies. Best practice recommendations from the current evidence base also are offered, as well as calls for future research that increases understanding of the moderators and mechanisms of change for children and adolescents with disruptive behavior disorders. PMID- 18444060 TI - Evidence-based psychosocial treatments for adolescent substance abuse. AB - This review synthesized findings from 17 studies since 1998 regarding evaluation of outpatient treatments for adolescent substance abuse. These studies represented systematic design advances in adolescent clinical trial science. The research examined 46 different intervention conditions with a total sample of 2,307 adolescents. The sample included 7 individual cognitive behavior therapy (CBT) replications (n = 367), 13 group CBT replications (n = 771), 17 family therapy replications (n = 850) and 9 minimal treatment control conditions (n = 319). The total sample was composed of approximately 75% males, and the ethnic/racial distribution was approximately 45% White, 25% Hispanic, 25% African American, and 5% other groups. Meta-analysis was used to evaluate within-group effect sizes as well as differences between active treatment conditions and the minimal treatment control conditions. Methodological rigor of studies was classified using Nathan and Gorman (2002) criteria, and treatments were classified using criteria for well-established and probably efficacious interventions based on Chambless et al. (1996). Three treatment approaches, multidimensional family therapy, functional family therapy, and group CBT emerged as well-established models for substance abuse treatment. However, a number of other models are probably efficacious, and none of the treatment approaches appeared to be clearly superior to any others in terms of treatment effectiveness for adolescent substance abuse. PMID- 18444062 TI - The mediating effect of pet attachment support between loneliness and general health in older females living in the community. AB - The relationship between loneliness and general health was investigated in 159 older females living in the community. Pet attachment support, a variable tested as a mediator of this relationship, was examined also. Participants completed the Revised UCLA Loneliness Scale, a Pet Attachment scale, and the Psychological General Well-Being Schedule: general health subscale. A negative relationship between loneliness and general health decreased when controlling for pet attachment support as a coping mechanism. The findings from this study support that pet attachment support has a mediating effect on the relationship between loneliness and general health in this sample of older females. Implications for community health nurses and public policy are discussed. PMID- 18444063 TI - Developing a preceptorship/mentorship model for home health care nurses. AB - Preceptorship and mentorship programs are used in the health care sector to educate nurses, enhance their leadership skills, and improve their quality of work life. Recognizing the importance of these initiatives, Saint Elizabeth Health Care sought funding to create an innovative model of preceptorship/mentorship that meets the unique needs of home health care nurses. The methods utilized included focus groups, key informant interviews, and a workflow analysis. Factors that influence preceptorship such as nursing workload, preceptor training and remuneration were examined to develop a new model that offers career enhancement and leadership opportunities for preceptors and mentors, and promotes a welcoming environment for preceptees. Reward and recognition programs were created for preceptors to acknowledge their leadership contribution at the front line. This study demonstrates how evidence and innovation were used to create a preceptorship/mentorship model to develop community nursing leaders of the future. PMID- 18444061 TI - Evidence-based psychosocial treatments for ethnic minority youth. AB - This article reviews research on evidence-based treatments (EBTs) for ethnic minority youth using criteria from Chambless et al. (1998), Chambless et al. (1996), and Chambless and Hollon (1998). Although no well-established treatments were identified, probably efficacious or possibly efficacious treatments were found for ethnic minority youth with anxiety-related problems, attention deficit/hyperactivity disorder, depression, conduct problems, substance use problems, trauma-related syndromes, and other clinical problems. In addition, all studies met either Nathan and Gorman's (2002) Type 1 or Type 2 methodological criteria. A brief meta-analysis showed overall treatment effects of medium magnitude (d = .44). Effects were larger when EBTs were compared to no treatment (d = .58) or psychological placebos (d = .51) versus treatment as usual (d = .22). Youth ethnicity (African American, Latino, mixed/other minority), problem type, clinical severity, diagnostic status, and culture-responsive treatment status did not moderate treatment outcome. Most studies had low statistical power and poor representation of less acculturated youth. Few tests of cultural adaptation effects have been conducted in the literature and culturally validated outcome measures are mostly lacking. Recommendations for clinical practice and future research directions are provided. PMID- 18444064 TI - Personality as a predictor of hooking up among college students. AB - Hookups--casual sexual encounters that may or may not include intercourse - are common on college campuses. Previous research has suggested that these casual sexual encounters may have serious health-related consequences. Understanding the relationships among multiple predictors of hooking up is important if high-risk prevention programming among college students is to be effective. This study considers each of the Big Five personality traits as predictors of hooking-up behaviors in a sample of Midwestern undergraduates (N = 247). Fifty-six percent of women and 63% of men reported engaging in a hookup. In general, Extraversion was positively associated with hooking up behaviors; Conscientiousness was negatively associated with hooking up. Relationships between personality and hooking up were significant while controlling for alcohol use. Implications for prevention programming on college campuses are discussed. PMID- 18444065 TI - The management of depressed elderly care recipients: family perspectives on the skills of professional carers. AB - Recent studies have identified high levels of depression among older people, both those in their own homes and those in residential care. With the world's population ageing, it is timely for health service providers to consider how the escalating population of depressed elderly people will be managed. Although treating general practitioners may be the health professionals most expected to detect, treat, and monitor depression among the elderly, professional carers are well placed to assist in the detection and monitoring of the disorder. This study conducted individual interviews with 15 family members of depressed aged-care recipients to determine their perceptions of the skills and knowledge of depression of professional carers. Family members reported that carers are more likely to avoid than engage with their clients about depressive symptomatology and do not communicate their concerns with managers or general practitioners (GPs). Family members believed that, in general, professional carers were undertrained in these areas. The implications of these findings for health service planning and staff training are discussed. PMID- 18444068 TI - Alteration of sperm quality and hormone levels by polycyclic aromatic hydrocarbons on airborne particulate particles. AB - The objective of this study was to assess whether polycyclic aromatic hydrocarbons (PAHs) affect male reproductive functions in vivo. Male reproductive parameters included testis weight, sperm counts and motility, circulating follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. The average body weight, testis weight, and epididymis weight in the exposed group were not significantly lower than that in the control group (p < 0.01). The daily numbers of sperm in the PAH-exposed groups were significantly lower than those in the control group. The motility of sperm in the PAH-exposed groups was significantly less than those in the control group. Plasma LH concentrations increased at the end of the exposure period and continued to increase after post cessation of exposure to PAHs. Testosterone decreased at the end of the exposure period and increased after post-cessation of exposure. However, the follicle stimulation hormone level remained relatively stable during the study period. The present study showed that PAHs can compromise sperm functions and alter endocrine hormone levels. PMID- 18444069 TI - Mobility and degradation of trinitrotoluene/metabolites in soil columns: effect of soil organic carbon content. AB - There has been increasing interest in enhancing natural attenuation of munitions contaminated soils. Present study reports the effect of increasing soil organic matter content on fate and mobility of trinitrotoluene (TNT) and metabolites in soil columns. This study was performed using 30-cm-long columns containing a top 5 cm of contaminated soil as a source layer and an uncontaminated soil (25 cm) adjusted to 0.5, 1.0, 1.5 and 3.0% organic carbon (OC) content using compost. Contaminated soil layer was fortified with uniformly ring-labeled (14)C trinitrotoluene (TNT) or 2,4-dinitrotoluene (DNT); in total there were 8 treatments. Columns were leached with synthetic rain water under unsaturated flow conditions in downside up direction. There was significant increase in the retention of both (14)C-TNT and (14)C-DNT in soils with increasing soil OC content and in 3.0% soil OC content column < 1% TNT/DNT was recovered in the leachate. Further, degradation of TNT and metabolites from contaminated soil was significantly increased and resulted in greater soil-bound residues. Formation of monoamino-dinitrotoluene (ADNTs), diamino-mononitrotoluene (DANTs) and monoamino mononitrotoluene (ANTs) metabolites was greatly enhanced with increase in OC content of soils. Study suggests that increasing OC content of contaminated soil to 3.0% significantly enhanced the reduction of nitroaromatics to more polar amine metabolites and the formation of soil-bound residues. PMID- 18444070 TI - The effect of negative air ion exposure on Escherichia coli and Pseudomonas fluorescens. AB - Antibacterial activity of negative air ions (NAI) on Escherichia coli and Pseudomonas fluorescens has been investigated. Appropriately diluted cell suspensions of E. coli and P. fluorescens were inoculated onto agar and exposed to NAI (> 2 x 10(6) ions/cm(3)) in an airtight chamber. Although no bacterial killing was observed after short exposure (15-30 min), longer exposure upto 4 hours caused 33% and 42% reduction in viability of E. coli and P. fluorescens, respectively. Maximum killing was observed when the plates were positioned in front of the NAI generator. Young exponential phase cells of P. fluorescens were more resistant (8% reduction in viability) as compared to stationary phase cells (42% reduction in viability). Also, the starved cells displayed less reduction in viability (33%) as compared to normal cells (42%). The susceptibility of bacterial strains to NAI varies depending upon the strain type, their physiological state as well as the distance/orientation with respect to the source. Although application of NAI for decreasing the ambient microbial load is a valid option; extended exposures might be required for controlling physiologically different cells such as exponential phase cells and/or starved cells. PMID- 18444071 TI - Removal of nuisance aqueous anions with Ferrilig. AB - The present study describes an improved synthesis of Ferrilig, an iron(III) salt of a commercially available immobilized ligand, IMLIG, called Octolig. The resulting composite, called "Ferrilig" was used to remove arsenate, chromate, molybdate, and selenite ions from aqueous solutions by means of column chromatography. The synthesis of Ferrilig was accomplished by treating an aqueous suspension of Octolig-21 with an equal weight of ferrous sulfate heptahydrate under nitrogen. The ferrous salt was then collected by sieving and allowed to oxidize to the iron (III) salt by exposure to air; treatment with dilute sodium hydroxide converted the composite to the hydroxide. Using 300 ppb As (as Na(2)HAsO(4).7H(2)O) and column chromatography, the arsenic concentration in the effluent was less than the detection limit (< 2 ppb). Chromium as sodium chromate, molybdenum as (NH(4))(6) Mo(7)O(24).4H(2)O, and selenium as Na(2)Se0(3), were removed with fair success. The elements, their initial concentrations and their percentage removal (parenthetically) were: As (280 ppb, 99%), Cr (50.6 ppm, 95.5%), Mo (50.7 ppm, 94.6%), Se (258 ppm, 99.9%). PMID- 18444072 TI - Statistical evaluation of aerosol data from Ben Macdhui mountain, South Africa. AB - The aim of this study is re-evaluation of the data collected during Ben Macdhui High Altitude Trace Gas and Aerosols Transport Experiment (BHATTEX) to identify the dominant species of aerosols and their interactions in the atmosphere. Particularly, investigations of seasonal variations, the origin of sulphates and the formation of the ammonia sulphate were essential topics of this study. Such analyses were done by application of unique combination of supervised and unsupervised learning classification methods. Namely discriminant function analysis (DFA) for simple identification of parameters and principal component analysis (PCA) for the further investigations on hidden structure of data has been applied. The analysis shows that sulphate concentration and C,N isotopic ratios can classify winter and summer patterns of data. Differences between sulphate concentrations in summer and winter samples indicated by second PCA component were probably related to meteorological conditions over that region. The relations between anthropogenic compounds and ammonia or sulphate were much more stronger in summer samples than in winter ones, that is related with seasonal transport of that particles from industry to the investigated regions. The hypothesis of competitive reaction between sulphates, nitrates and ammonia ions has been also proven by application of simple regression analysis. Moreover the analysis of correlations coefficients shows that those relations are independent on seasons. PMID- 18444073 TI - Slow pyrolysis of poultry litter and pine woody biomass: impact of chars and bio oils on microbial growth. AB - Accidental or prescribed fires in forests and in cultivated fields, as well as primitive charcoal production practices, are responsible for the release of large amounts of gases, char and condensable organic molecules into the environment. This paper describes the impact of condensable organic molecules and chars resulting from the slow pyrolysis of poultry litter, pine chips and pine pellets on the growth of microbial populations in soil and water. The proximate and elemental analyses as well as the content of proteins, cellulose, hemicellulose, lignin, and ash for each of these bio-materials are reported. The yields and some properties of char and condensable liquids are also documented. The behavior of microbial populations in soil and water is followed through respiration studies. It was found that biological activity was highest when aqueous fractions from poultry litter were applied in water. Cumulative oxygen consumption over a 120-h period was highest in the aqueous phases from poultry litter coarse fraction (1.82 mg/g). On average the oxygen consumption when oily fractions from poultry litter were applied represented 44 to 62% of that when aqueous fractions were applied. Pine chip and pine pellet derived liquids and chars produced respiration activity that were an order of magnitude lower than that of poultry litter liquid fractions. These results suggest that the growth observed is due to the effect of protein-derived molecules. PMID- 18444074 TI - The influence of organic loading and anoxic/oxic times on the removal of carbon, nitrogen and phosphorus from a wastewater treated in a sequencing batch reactor. AB - In this study, 10 L sequencing batch reactors (SBRs) were operated at a 12-h cycle length (four alternating anoxic/oxic conditions) to assess the biological nutrient removal potential of a domestic wastewater treated at the Huay Kwang plant, Bangkok, Thailand. The wastewater was found to be carbon-limited (chemical oxygen demand (COD) to total Kjeldahl nitrogen (TKN) (i.e., COD:TKN) ratio of 6.4:1). This ratio was insufficient to support good phosphorus removal. Glucose was therefore added to increase the COD:TKN ratio ultimately to 10:1 and the COD, TKN and total phosphorus (TP) removals at this ratio were all in excess of 95%. An alternative carbon source from a local fruit canning industry was then added at the same COD:TKN ratio; and, in order to increase the throughput of the waste treated, the cycle length was simultaneously shortened to 8 h keeping approximately the same anoxic/oxic fractions. The COD removal remained high (> 95%), however the TKN and TP removals were substantially reduced (79% and 66%, respectively), indicating that the shortened cycle length was sub-optimum. The last phase of the research involved changing the anoxic/oxic fractions of the cycle time to maximize performance. It was found that for the conditions studied in this research, the performance improved in proportion to the increase in the first anoxic fraction, being most stable at the highest anoxic fraction of the cycle length (0.33). PMID- 18444075 TI - Evaluation of reactive well networks for remediating heterogeneous aquifers. AB - Alternative configurations of non-pumped wells filled with reactive media were evaluated for removing hypothetical contaminant plumes. All wells were screened across the saturated zone of a simulated unconfined aquifer. Three heterogeneous hydraulic conductivity distributions (cases) were considered. A mass transport model accounting for advection and hydrodynamic dispersion produced an initial contaminant plume for each case. Two reactive well configurations were evaluated for each case. In one configuration, evenly spaced wells occupied a linear transect perpendicular to regional groundwater flow, located downgradient of the contaminant plume. A second configuration involved the same number of wells, but along evenly spaced, nonlinear flow lines originating from the downgradient boundary of the contaminant plume. Mass transport modeling simulated contaminant plumes moving through the aquifer and wells. Results suggest that nonlinear configurations, which take into account local flow variations near the downgradient boundary of a contaminant plume, more efficiently reduce contaminant concentrations and better control offsite migration. PMID- 18444077 TI - Potential of simple filters to improve microbial quality of irrigation water used in urban vegetable farming in Ghana. AB - Irrigation water used for growing vegetables in urban areas in many low-income countries is contaminated with untreated wastewater. Many wastewater treatment methods are economically prohibitive and continued use of such irrigation water pose health risks for vegetable consumers and farmers. As part of a larger study on possible interventions for health risk reduction, the potential of simple interventions was explored. Column slow sand filters with three levels of sand depths (0.5 m, 0.75 m and 1 m) and fabric filters made of nylon, cotton and netting were assessed. More than 600 water samples were analyzed for helminth eggs and thermotolerant coliforms. Flow rates were also measured. From slow sand filters, 71-96% of helminths and 2 log units (from 7 to 5 log units) of thermotolerant coliforms were removed. Sand depths had no significant influence in the removal. Lower removal rates were achieved by fabric filters, with an average removal of 12-62% for helminth eggs and 1 log unit for thermotolerant coliforms. Nylon filters had higher removal rates especially for helminth eggs (58%). Average flow rates for sand filters were 3 m per day and fabric filters had steady flows of about 1.5 liters per second, but flow reduced with time in cotton filters. The simple filters tested improved the microbial quality of irrigation water and could easily be used in combination with other interventions to further reduce health risks. The unit cost of the filters tested also appear acceptable to farmers and some incentives like better prices will motivate many farmers to invest in such simple interventions. PMID- 18444076 TI - Application and evaluation of two nutrient algorithms of Hydrological Simulation Program Fortran in Wolf River watershed. AB - This study performs a comparison of two nutrient algorithms of Hydrological Simulation Program Fortran, PQUAL/IQUAL and AGCHEM. Watershed nutrient models with, PQUAL/IQUAL and AGCHEM, were developed and calibrated separately with observed data in the Wolf River watershed. Compared to AGCHEM modules, the PQUAL/IQUAL algorithm was found to have several disadvantages. Examples are: (i) it is a simple loading estimation algorithm, and cannot represent the soil nutrient processes; and (ii) the interactions of modeled nutrient species in the soil cannot be simulated. The AGCHEM modules are capable of explicitly representing the comprehensive nutrient processes in the soil such as fertilization, atmospheric deposition, manure application, plant uptake process, and the transformation processes. Therefore, AGCHEM modules afford the ability to evaluate the alternative management practice and model the interactions between nutrient species. However, our modeling results indicated that the inclusion of AGCHEM modules do not significantly improve the nutrient modeling performance but rather take much more time in model development. The nutrient algorithms selection for total maximum daily loads development depends on the data availability, required modeling accuracy, and available time for model development. PMID- 18444078 TI - Determining the feasibility of phosphorus recovery as struvite from filter press centrate in a secondary wastewater treatment plant. AB - In this study, the workability of a pilot-scale, fluidized reactor was examined to determine effectiveness in removing, and recovering, phosphorus as struvite, from centrate at Lulu Island Wastewater Treatment Plant (LIWWTP), Richmond, British Columbia. The crystallization process was run continuously over a period of 5 months in two runs (Run 1 for 4 months and Run 2 for a month). In addition to efficient recovery of phosphorus as struvite, the study also investigated factors that affect the growth of struvite. Chemical analyses were conducted on the harvested struvite to determine its purity. Results showed that the reactor was capable of removing over 90% of phosphate and 4% of ammonia-nitrogen, with greater than 85% of the phosphate removed being recovered as harvestable struvite crystals. It was possible to achieve over 90% P-removal at a pH of 7.5; this is contrary to the information found in literature, which recommends that a higher pH (8.2-9.0) is required. Factors that affected phosphate removal were the operating pH, the reactor supersaturation ratio (SSR), the N:P and Mg:P molar ratios. Analysis of the harvested product showed that the crystals were composed of nearly pure struvite (96% by weight), with small amounts of calcium and traces of other metals. High resolution SEM pictures were taken of the inside of the crystals to determine the influence of Mg:P molar ratio on the compactness of the crystals. PMID- 18444079 TI - Long-term performance of subsurface-flow constructed wetlands treating Cd wastewater. AB - This study was conducted to investigate the long-term performance of subsurface flow constructed wetland (SFCW) units treating a wastewater containing cadmium (Cd). The hydraulic retention time (HRT) was found to have significant effects on the SFCW performance, especially on Cd removal. During the 320 days of Cd feeding, the HRTs of 1, 3, 5 and 8 days resulted in the Cd removal efficiencies of 50, 90, 99 and 99%, respectively. The actual Cd breakthrough times in the SFCW effluent were found to be longer than the theoretical values calculated from the maximum adsorption capacities only, especially at the HRTs longer than 1 day, and were dependent on the operating HRT and Cd loading. Other mechanisms such as filtration, sedimentation and plant uptake were also responsible for Cd removal in the SFCW beds. The extents of Cd plant uptake were 21 and 6% of the Cd inputs for the SFCW units operating at the HRTs of 3 and 1 days, respectively. Based on Cd mass balance and fractionation analysis, the SFCW media were found to be most effective in Cd removal through adsorption of the residual and Fe/Mn oxide bound fractions. The results of this long-term study re-affirmed the necessity to determine actual breakthrough times of Cd or other heavy metals in the SFCW effluent which are dependent on HRT and Cd loading and are usually longer than the theoretical values calculated from the maximum adsorption capacity only. PMID- 18444080 TI - Biological decolourisation of wastewater from molasses fermentation by Trametes versicolor in an airlift reactor. AB - Continuous decolourisation of wastewater from molasses fermentation using mycelium of Trametes versicolor in pellets shape was performed in an airlift bioreactor (semi-pilot scale) with the aim of operating steadily for a long period, maintaining the colour removal activity. The influences of influent flow and glucose feed rate were tested. Induction of peroxidases secretion by Mn(2+) addition was also studied. The efficiency of the decolourisation process was followed by monitoring colour and enzymatic activities. The experimental results showed that continuous decolourisation in an airlift bioreactor can be considered a suitable alternative for treating molasses fermentation wastewater. A colour removal yield around 60% remained practically constant during 23 days under continuous operation. Laccase was found to be the main enzyme secreted by the strain, being responsible for the decolourisation process. Mn(2+) addition was not likely to induct manganese-dependent peroxidase secretion. PMID- 18444081 TI - Removal of Cu(II) from aqueous solution by adsorption on Chinese Quaternary loess: kinetics and equilibrium studies. AB - This paper dealt with the characteristics of Cu(II) adsorption on Chinese Quaternary loess. The Cu(II) adsorption isotherm and kinetics fit the Langmuir model and pseudo-second order kinetics well, respectively, with a predicted adsorption capacity of 109 mg g(-1). The adsorption is ion exchange adsorption due to D-R model. Factors that are positively correlated with the adsorption capacity of loess include equilibrating time, pH, temperature, and solid-solution ratio. The adsorption of Cu(II) on loess involves 2-3 sequential diffusing steps into the micropores, and an endothermic and spontaneous process with predicted enthalpy, entropy, and Gibb's free energy changes of 7.64 kJ mol(-1), 81.21 J mol(-1)K(-1) and -14.94-17.37 kJ mol(-1), respectively. Moreover, the applicability of loess on industrial wastewater treatment was investigated and satisfactorily proved. Finally, FT-IR spectra shows the precipitation of copper carbonate and the complexation of Cu(II) with clay minerals at pH > 5.0 and pH > 2.67, respectively. PMID- 18444082 TI - Host strain-dependent difference in susceptibility in a rat model of herpes simplex type 1 encephalitis. AB - Herpes simplex encephalitis (HSE) is characterized by severe focal brain inflammation leading to substantial loss of nervous tissue. The authors established a model of Herpes simplex virus type 1 (HSV)-1-induced acute encephalitis in the rat by injecting into the whiskers' area a virus strain isolated from a fatal human HSE case. The model might resemble natural propagation of HSV-1 in humans; spreading from the mouth and lips via the trigeminal nerve to trigeminal ganglia and subsequently entering the central nervous system (CNS). HSV-1 infected Dark Agouti (DA) rats developed a well synchronized disease and died 5 days after inoculation. HSV-1 detection by quantitative polymerase chain reaction (qPCR), virus isolation and immunohistochemistry, magnetic resonance imaging, and histopathological examination verified dramatic encephalitis mainly in the brainstem, but also in the olfactory bulb and other segments of the brain of diseased rats. In contrast, Piebald Virol Glaxo (PVG) rats were completely resistant to disease, displaying a more rapid clearance of peripheral infection and no evidence of virus entering into neither the trigeminal ganglia nor the CNS. These results suggest a regulation of susceptibility to HSV-1-induced encephalitis at the level of peripheral infection and subsequent neuronal uptake/transport of the virus. This provides a basis for future positioning of genetic polymorphisms regulating HSE and for dissection of important pathogenetic mechanisms of this severe human disease. PMID- 18444083 TI - Furious and paralytic rabies of canine origin: neuroimaging with virological and cytokine studies. AB - Furious and paralytic rabies differ in clinical manifestations and survival periods. The authors studied magnetic resonance imaging (MRI) and cytokine and virus distribution in rabies-infected dogs of both clinical types. MRI examination of the brain and upper spinal cord was performed in two furious and two paralytic dogs during the early clinical stage. Rabies viral nucleoprotein RNA and 18 cytokine mRNAs at 12 different brain regions were studied. Rabies viral RNA was examined in four furious and four paralytic dogs during the early stage, and in one each during the late stage. Cytokine mRNAs were examined in two furious and two paralytic dogs during the early stage and in one each during the late stage. Larger quantities of rabies viral RNA were found in the brains of furious than in paralytic dogs. Interleukin-1beta and interferon-gamma mRNAs were found exclusively in the brains of paralytic dogs during the early stage. Abnormal hypersignal T2 changes were found at hippocampus, hypothalamus, brainstem, and spinal cord of paralytic dogs. More widespread changes of less intensity were seen in furious dog brains. During the late stage of infection, brains from furious and paralytic rabid dogs were similarly infected and there were less detectable cytokine mRNAs. These results suggest that the early stage of furious dog rabies is characterized by a moderate inflammation (as indicated by MRI lesions and brain cytokine detection) and a severe virus neuroinvasiveness. Paralytic rabies is characterized by delayed viral neuroinvasion and a more intense inflammation than furious rabies. Dogs may be a good model for study of the host inflammatory responses that may modulate rabies virus neuroinvasiveness. PMID- 18444084 TI - Significantly increased antibody response to heterogeneous nuclear ribonucleoproteins in cerebrospinal fluid of multiple sclerosis patients but not in patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis. AB - It has been reported that antibodies (Abs) against heterogeneous nuclear ribonucleoproteins (hnRNPs) are associated with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). However, these studies were done under nonmasked conditions. In order to determine whether Abs against hnRNPs associate with HAM/TSP and MS, the authors assayed Abs against two major hnRNPs, hnRNP A1 and A2/B1, in 105 cerebrospinal fluid (CSF) samples under fully masked conditions. Samples included 40 cases of HAM/TSP, 28 of MS, and 37 of other neurological diseases. Anti-hnRNP A1 Abs, and especially anti-hnRNP A2/B1 Abs, were found significantly more often in the CSF of MS patients than in other groups. However, there was no difference in the incidence of anti-hnRNP A1 Abs between HAM/TSP and other disease groups. PMID- 18444085 TI - Genetic contributions to influenza virus attenuation in the rat brain. AB - Influenza is generally regarded as an infection of the respiratory tract; however, neurological involvement is a well-recognized, although uncommon, complication of influenza A virus infection. The authors previously described the development of a rat model for studying influenza virus infection of the central nervous system (CNS). This model was used here to study the role of virus genes in virus replication and spread in brain. In the present work, an infectious cDNA clone of the neurotoxic WSN strain of influenza virus (rWSN) was altered by site directed mutagenesis at five loci that corresponded to changes previously shown to confer temperature sensitivity and attenuation of the A/Ann Arbor/6/60 strain (PB1Delta 391, PB1Delta 581, and PB1Delta 661; PB2Delta 265, and NPDelta 34). Whereas rWSN and its mutated derivative (mu-rWSN) replicated equally well in MDCK cells at 37 degrees C (the body temperature of rats), rWSN grew to higher titers and infection was more widespread compared to mu-rWSN in rat brain. These results demonstrate that the five mutations that confer attenuation of the A/Ann Arbor/6/60 influenza virus strain for the respiratory system also confer attenuation for the central nervous system. Further in vivo and in vitro examination of these five mutations, both individually and in combination, will likely provide important information on the role of specific virus genes in virulence and pathogenesis. PMID- 18444086 TI - Lack of immune responses against multiple sclerosis-associated retrovirus/human endogenous retrovirus W in patients with multiple sclerosis. AB - The multiple sclerosis-associated retrovirus (MSRV), originally identified in cell cultures from patients with multiple sclerosis (MS), is closely related to the human endogenous retrovirus family type W (HERV-W). Different lines of evidence appear compatible with a potential role of MSRV/HERV-W in the pathogenesis of MS. The authors therefore analyzed humoral and cellular immune responses against MSRV/HERV-W antigens in patients with MS, patients with other inflammatory and noninflammatory neurological diseases, and healthy controls, using indirect immunofluorescence and enzyme-linked immunospot assays. Antibodies against the HERV-W envelope (Env) protein, Syncytin-1, were found in one of 50 patients with MS and none of 59 controls, whereas antibodies against MSRV matrix and capsid (Gag) or Env proteins were not detectable in any of the patients or controls. Similarly, in a screening of human leukocyte antigen (HLA)-B7+ patients with MS (n = 23) and controls (n = 29) for cytotoxic T-lymphocyte responses against 36 predicted HLA-B7-restricted MSRV/HERV-W Gag-, protease-, and reverse transcriptase-derived peptides, no such responses could be detected in any of the subjects studied. These data suggest that there are no appreciable humoral or cellular immune responses against MSRV/HERV-W in patients with MS. While this may be due to immunological tolerance of physiologically expressed HERV-W proteins, strategies other than measurement of immune responses will be required to further elucidate the relationship between MSRV/HERV-W and MS. PMID- 18444088 TI - Nectin-1 (HveC) is expressed at high levels in neural subtypes that regulate radial migration of cortical and cerebellar neurons of the developing human and murine brain. AB - Herpes simplex viruses (HSV) produce age-dependent encephalitis characterized by more severe involvement of the cerebral cortex in younger hosts. To elucidate the potential role of the major neural entry receptor of HSV, nectin-1, in age dependent susceptibility of cortical neurons to viral encephalitis, the authors examined the anatomical distribution of the receptor protein in the developing human and mouse cerebral cortex, hippocampus, and cerebellum by immunohistochemistry. Nectin-1 is expressed at high levels in guiding cells (radial glial cells and Cajal-Retzius cells) that regulate radial migration of neurons in cortical lamination, at lower levels in migrating neurons, and at variable levels in the transient ventricular and marginal zones of the cerebral cortical wall. These results may have implications regarding the selective spatiotemporal tropism of HSV to specific neuronal populations, and for the better understanding of neurodevelopmental defects caused by fetal HSV infections. PMID- 18444089 TI - Cortical maldevelopment in congenital cytomegalovirus infection transmitted by a woman with preexisting immunity. AB - Although cytomegalovirus (CMV) congenital infection is more severe in children born to women with primary infection, neurological symptoms have also been observed in infants born to mothers with preconceptional immunity. The authors describe for the first time a case of severe cortical development disorder associated with multiple abnormalities of the white matter, occurring in the second-born child of a woman found to be positive for anti-CMV immunoglobulin G (IgG) before pregnancy. CMV DNA was detected in the urine and blood of the infant. These findings indicate that the neurological outcome of CMV infection may be severe also in infants born to women with preexisting immunity. PMID- 18444087 TI - West Nile virus-induced acute flaccid paralysis is prevented by monoclonal antibody treatment when administered after infection of spinal cord neurons. AB - Acute flaccid polio-like paralysis occurs during natural West Nile virus (WNV) infection in a subset of cases in animals and humans. To evaluate the pathology and the possibility for therapeutic intervention, the authors developed a model of acute flaccid paralysis by injecting WNV directly into the sciatic nerve or spinal cord of hamsters. By directly injecting selected sites of the nervous system with WNV, the authors mapped the lesions responsible for hind limb paralysis to the lumbar spinal cord. Immunohistochemical analysis of spinal cord sections from paralyzed hamsters revealed that WNV-infected neurons localized primarily to the ventral motor horn of the gray matter, consistent with the polio like clinical presentation. Neuronal apoptosis and diminished cell function were identified by TUNEL (terminal deoxynucleotidyl transferase-mediated BrdUTP nick end labeling) and choline acetyltransferase staining, respectively. Administration of hE16, a potently neutralizing humanized anti-WNV monoclonal antibody, 2 to 3 days after direct WNV infection of the spinal cord, significantly reduced paralysis and mortality. Additionally, a single injection of hE16 as late as 5 days after WNV inoculation of the sciatic nerve also prevented paralysis. Overall, these experiments establish that WNV-induced acute flaccid paralysis in hamsters is due to neuronal infection and injury in the lumbar spinal cord and that treatment with a therapeutic antibody prevents paralysis when administered after WNV infection of spinal cord neurons. PMID- 18444090 TI - Diversity and personality assessment: a country boy goes city. AB - Born and raised in a country community in Northern Indiana, I mainly learn about the greater world through school, especially graduate school. Diversity and its companion, bigotry, have played major roles in my life along with many individuals--mostly women. I have been lucky to have learned from some of the major individuals in the field of personality assessment, particularly Sid Blatt and John Exner. On the verge of retirement, I look back on a career with affection and some trepidation. PMID- 18444091 TI - Inferential errors in taxometric analyses of ordered three-class constructs. AB - Taxometric analysis (Waller & Meehl, 1998) has become a popular tool for investigating whether personality and psychopathology constructs are better modeled as dimensional or categorical. Monte Carlo evidence for the validity of taxometric methods, however, has been restricted to data that are derived either from latent dimensional or dichotomous models. There are various circumstances in which the correct model for a psychosocial construct could involve three or more ordered classes. It was demonstrated both mathematically and empirically that under these circumstances, the results of taxometric analyses can lead to incorrect conclusions about the population structure. Recommendations are provided for future studies intended to distinguish between categorical and dimensional structures. PMID- 18444092 TI - Explicit rejection of an implicit dichotomy: integrating two approaches to assessing dependency. AB - The field of personality theory and assessment is characterized by a long standing divide between proponents of self-report and indirect approaches to assessment. This article reviews the increasing convergence between the two sides, using recent writings on interpersonal dependency as an example domain. The assumptions of the self-report approach to personality assessment are contrasted with those of the indirect, and research using both types of assessments is reviewed. Also considered is the importance of recognizing dissociations between a particular individual's scores on self-report and indirect measures of a given component of self-concept, and the possible implications of such dissociations. It is argued that the convergence between two traditionally disparate approaches is likely to develop, in light of hypotheses, data and conclusions that bear notable similarity. PMID- 18444093 TI - Convergence of self-report scales and Rorschach indexes of psychological distress: the moderating role of self-disclosure. AB - In this study, we addressed the weak associations found in research between self report measures and the Rorschach test (Exner, 1978, 1991), from the perspective of Bornstein's (2002) "process dissociation framework." Specifically, in the study, we focused on the associations between self-report measures of psychological distress and their corresponding Rorschach indexes while inspecting the moderating role of self-disclosure. A total of 59, nonpatient Israeli adults participated in a 2-session study. In the first session, they completed self report scales measuring self-disclosure and psychological distress (suicidality, depression, and loneliness). In the second session, the Rorschach test was administered and coded. The participants were divided into high and low self disclosure groups. A convergence between self-report and Rorschach measures of psychological distress was found only among high self-disclosers. In the discussion, we address the theoretical and clinical implications of these findings. PMID- 18444094 TI - Object relations and interpersonal problems in sexually abused female patients: an empirical study with the SCORS and the IIP. AB - In this study, we examined how retrospective reports of experiencing traumatic sexual abuse in childhood relates to both the development of self-representations and object representations and the occurrence of interpersonal problems. A total of 30 psychosomatic female patients who reported sexual abuse in childhood were compared with a corresponding number of eating-disordered patients and a nonclinical control group. The object relations technique (ORT; Phillipson, 1955), evaluated using the Social Cognition and Object Relations Scale (SCORS; Westen, 1985, 1991b), and the Inventory of Interpersonal Problems (Horowitz, Rosenberg, Baer, & Ureno, 1988) were used to measure the groups. The patients reporting sexual abuse achieved significantly lower scores in the cognitive scales of the SCORS; in the affective scales, they differed from the control group but not from the patients with an eating disorder. Concerning interpersonal problems, the patients reporting childhood sexual abuse reported interpersonal conflicts more frequently. The results of the study support the influence of traumatic sexual abuse on the formation of self-representations and object representations and on the occurrence of interpersonal conflicts. PMID- 18444095 TI - Development and validation of the Affect in Play Scale-brief rating version (APS BR). AB - The Affect in Play Scale (APS; Russ, 1987, 2004) is one of few reliable, standardized measures of pretend play, yet the fact that it requires videotaping and extensive training to score compromises its clinical utility. In this study, we developed and validated a brief rating version (APS-BR) that does not require videotaping. Construct validity was established by comparing scores from the original APS and the APS-BR using an existing data set of videotaped play (n = 46). We examined associations between scores on the APS-BR and theoretically relevant measures of divergent thinking and emotional memories. Scores on the APS BR related strongly to those on the APS, and the pattern of correlations for each scale and relevant criterion measures was similar in strength and direction, supporting the APS-BR as an alternate form of the APS. In addition, we completed a pilot study to examine the efficacy of using the APS-BR in its intended in vivo format (n = 28). Results from both studies suggest that the APS-BR is a promising brief measure of children's pretend play that can be substituted for the APS in clinical and research settings. PMID- 18444096 TI - What measure of interpersonal dependency predicts changes in social support? AB - One of the most intriguing characteristics of interpersonal dependency is its ability to predict elevated levels of social support. Yet studies of interpersonal dependency use various measures to assess this effect. In this study, I compared 3 commonly used measures of interpersonal dependency in terms of their prediction of social support: Hirschfield's Interpersonal Dependency Inventory (IDI; Hirschfeld et al., 1977), the dependency factor of the Depressive Experiences Questionnaire (DEQ; Blatt, D'Afflitti, & Quinlan, 1976), and the Dependency subscale of the Personal Style Inventory (PSI; Robins et al., 1994). A total of 152 undergraduates were administered these measures as well as measures of depressive symptoms and social support a week prior to their first exam period and a week after this period (interval time = 8 weeks). DEQ-dependency predicted an increase in social support, whereas PSI-Dependency and IDI predicted a decrease in social support over time. DEQ-dependency appears to capture better than the other 2 measures the dialectic tension between risk and resilience in interpersonal dependency. PMID- 18444097 TI - Evaluating the invariance of the factor structure of the EPQ-R-N among adolescents. AB - We examined the factor structure of the Neuroticism scale of the Eysenck Personality Questionnaire (EPQ-R-N; S. B. G. Eysenck, Eysenck & Barrett, 1985) and its factor invariance across sex and racial/ethnic groups in a sample of 1,979 adolescents. Using confirmatory factor analyses, we compared a hierarchical model to previous models of the EPQ-R-N and to single-factor and 3-factor structures. The hierarchical factor structure in which a general factor coexists with 3 group factors (depression, social concerns, and worry) was superior to alternative models. The general factor accounted for more than 60% of the variance in EPQ-R-N total scores and was invariant across sex and ethnicity. The 3 group factors varied across ethnicity and sex. We discuss the implications of these findings for conceptualization and assessment of neuroticism using the EPQ R-N. PMID- 18444098 TI - Predicting the completion of an integrative and intensive outpatient chronic pain treatment with the personality assessment inventory. AB - The effects of intensive, integrative treatments for chronic pain are affected by patient compliance, and in many cases, selecting noncompliant individuals adversely impacts the cost-effectiveness of such programs. The pretreatment identification of individuals who are at risk for dropout could assist clinicians in augmenting treatments with motivational enhancement strategies for high-risk patients or using such information to select individuals who are most likely to complete a given intervention program. In this study, we tested the ability of indicators from the Personality Assessment Inventory (PAI; Morey, 1991), administered prior to treatment, to identify individuals who dropped out of a 20 day chronic pain program. Results replicate findings from outpatient psychotherapy research in finding that PAI Mean Clinical Elevation and Treatment Process Index significantly differentiated dropouts from graduates, particularly when the Treatment Rejection scale suggested patients were motivated for treatment. We discuss these results and offer recommendations for the prediction of treatment dropout in pain settings. PMID- 18444099 TI - The MMPI-2 Clinical Scales and Restructured Clinical (RC) Scales: comparative psychometric properties and relative diagnostic efficiency in young adults. AB - We examined the psychometric properties of the Restructured Clinical (RC) scales (Tellegen et al., 2003) of the MMPI-2 (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) in a large sample (N = 744) of 18-year-old college freshman. We found that the RC scales demonstrated good convergence with their Clinical scale counterparts and were more distinctive than the Clinical scales. The patterns of discriminant correlations for the RC scales were slightly clearer than those of the Clinical scales and a set of other existing MMPI-2 scales. Diagnostic efficiency statistics based on Clinical and RC scale elevation status did not differ appreciably. However, the diagnostic efficiency statistics of cutoff scores derived from mean RC and Clinical scale T scores improved on the traditional scale elevation measures. We consider the clinical implications of these findings. PMID- 18444100 TI - Differentiating psychotic patients from nonpsychotic patients with the MMPI-2 and Rorschach. AB - The goal of this study was to examine the incremental validity and the clinical utility of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2; (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) and Rorschach (Rorschach, 1942) with regard to differential diagnosis in a sample of adult inpatients with a primary psychotic disorder or a primary mood disorder without psychotic features. Diagnostic efficiency statistics have suggested that the Rorschach Perceptual Thinking Index (PTI; Exner, 2000a, 2000b) was better than MMPI-2 scales in discriminating psychotic patients from nonpsychotic patients. We compared the 84% overall correct classification rate (OCC) for the PTI to an OCC of 70% for the MMPI-2 scales. Adding the MMPI-2 scales to the PTI resulted in a decrease in OCC of 1%, whereas adding the PTI to the MMPI-2 resulted in an increase in OCC of 14%. Sensitivity, specificity, positive predictive power, negative predictive power, and kappa were equal or higher with only the PTI in the model. PMID- 18444102 TI - A note on some measures of profile agreement. AB - Profile similarity or agreement is increasingly used in personality research and clinical practice and has potential applications in many other fields of psychology. I compared 4 measures of profile agreement--the Pearson r, Cattell's (1949) r(p), McCrae's (1993) r(pa), and an intraclass correlation coefficient (double entry), ICC(DE)--using both broad factor and specific facet profiles. Matched versus mismatched self-ratings/other ratings on the NEO Personality Inventory-3 (McCrae, Costa, & Martin, 2005) were used as criteria. At the factor level, r(pa) and ICC(DE) were comparable, and both were superior to r(p) in distinguishing matched versus mismatched profiles. At the facet level, ICC(DE) was superior to the other coefficients. The Pearson r performed better than expected. PMID- 18444103 TI - Clinical utility of the MMPI-2 Restructured Clinical (RC) Scales in therapeutic assessment: a case study. AB - In the following article, we provide a case study on a 25-year-old man who was released from a crisis stabilization unit following a suicide attempt. After completing a diagnostic intake, the client participated in a Therapeutic Assessment (Finn, 1996, 2003), which included the MMPI-2 (Butcher et al., 2001) and the Incomplete Sentences Blank (Rotter & Rafferty, 1950). In particular, in the article, we focus on how the Restructured Clinical (RC; Tellegen et al., 2003) scales can be used to form a personological conceptualization of the client. The RC scales measure important personality and affective trait dimensions including demoralization and both positive and negative affect, which allows for a clear explanation of the underlying etiological factors that influence a client's negative emotional experience. In this article, we highlight how explaining these underlying personality characteristics to the client within the framework of therapeutic assessment allowed for an increase in his insight. PMID- 18444104 TI - Empirical correlates of the MMPI-2 Restructured Clinical (RC) Scales in mental health, forensic, and nonclinical settings: an introduction. AB - We introduce 3 studies of the empirical correlates of the MMPI-2 Restructured Clinical (RC) Scales: a study by Arbisi, Sellbom, and Ben-Porath (2008/this issue) that expands the range of correlates of the RC scale in mental health settings; an investigation by Sellbom, Ben-Porath, Baum, Erez, and Gregory (2008/this issue) of the empirical correlates of the scales in a forensic setting; and a study by Forbey and Ben-Porath (2008/this issue) examining convergent and discriminant validities of the RC scale in a nonclinical setting. To serve as a general introduction to the 3 new empirical studies presented in this special section, we begin with a review of the existing literature on the RC scales and briefly describe these studies. PMID- 18444105 TI - Empirical correlates of the MMPI-2 Restructured Clinical (RC) Scales in psychiatric inpatients. AB - We identified empirical correlates of the MMPI-2 Restructured Clinical (RC) scales in 1,872 male and 498 female psychiatric inpatients drawn from 2 large tertiary care medical centers. We generated clinical criteria from a systematic review of the patients' intake and discharge medical records. We report zero order correlations between RC scales and clinical criteria and relative risk ratios for dichotomous variables. We found the RC scales to be correlated with conceptually relevant criteria such that for each scale, we identified significant increases in the risk for a variety of emotional, cognitive, and behavioral problems among individuals whose T score exceed 64. PMID- 18444106 TI - Predictive validity of the MMPI-2 Restructured Clinical (RC) Scales in a batterers' intervention program. AB - We examined the convergent and discriminant validity of the MMPI-2 Restructured Clinical (RC) scales in predicting relevant historical variables, treatment success, and recidivism in offenders enrolled in a batterers' intervention program. We used a sample studied previously by Petroskey, Ben-Porath, and Erez (2002), which included an ethnically diverse group of 483 men enrolled in a psychoeducational batterer's intervention program. We coded various historical variables (e.g., criminal history, substance abuse problems, mental health treatment, anger problems, and amount of partner violence), treatment dismissal, and recidivism up to 1 year posttreatment. Correlational analyses with the historical variables provided evidence of convergent and discriminant validity of the RC scales in this forensic sample. Regression analyses showed that these scales added to the historical variables in predicting treatment failure and recidivism. Relative risk analyses indicated the extent to which individuals entering treatment with elevated scores on RC4 and RC9 were at increased risk for these negative outcomes. PMID- 18444107 TI - Empirical correlates of the MMPI-2 Restructured Clinical (RC) Scales in a nonclinical setting. AB - We examined the empirical correlates of the MMPI-2 Restructured Clinical (RC; Tellegen et al., 2003) scales in a nonclinical setting. We administered 12 criterion measures assessing variables expected to be associated differentially with the RC Scales along with the MMPI-2 to a sample of 1,038 college students (Men, N = 407; Women, N = 631). Criteria included measures of somatization, depression, Machiavellian negativism, drug and alcohol abuse, anger, anxiety, social phobias, obsessive-compulsive tendencies, magical ideation, perceptual aberration, lability, and impulsivity. Results demonstrate good convergent and discriminant validity for the RC scales and add to a growing body of empirical correlates of these scales. PMID- 18444108 TI - The Dutch HEXACO Personality Inventory: psychometric properties, self-other agreement, and relations with psychopathy among low and high acquaintanceship dyads. AB - The HEXACO model (Lee & Ashton, 2004, 2006) of personality structure is based on 6 dimensions that have been recovered in lexical studies of personality in various languages. In this study, we examined a Dutch version of the HEXACO Personality Inventory (HEXACO-PI; Lee & Ashton, 2004) and found it to have satisfactory psychometric properties. Additionally, we examined the level of self other agreement for the HEXACO-PI variables and the relation of HEXACO-PI Honesty Humility with the Self-Report Psychopathy Scale (Williams, Paulhus, & Hare, 2007) at varying levels of self-other acquaintanceship. Self-other agreement was found to be high, especially among dyads with high levels of acquaintanceship. Self reported and other-reported Honesty-Humility and Emotionality were the strongest predictors of psychopathy. The relation between other-reported Honesty-Humility and self-reported psychopathy was near zero for dyads with low levels of acquaintanceship but was moderately strong for dyads with high levels of acquaintanceship. PMID- 18444109 TI - Development and validation of a Dutch translation of the Big Five Inventory (BFI). AB - In this article, we describe the translation and validation of the Dutch Big Five Inventory (BFI; John & Srivastava, 1999), a short instrument designed to measure the Big Five factors of personality. We obtained evidence of the instrument's good psychometric properties in terms of factorial equivalence to the English original and other BFI translations and the relative independence and internal consistency of the five scales. The findings suggest that the instrument can be used in diverse age groups without substantial changes in factor structure. The Dutch BFI scales showed similar demographic correlates as the English original, with higher Agreeableness and Conscientiousness and lower Neuroticism values in older participants, higher Neuroticism values in women, and higher Openness and Conscientiousness values in better educated participants. Use of the Dutch BFI will allow researchers to integrate their findings with the extant Big Five research literature. The brevity of the instrument will be appealing to researchers who are concerned about taxing the time and motivation of their participants. PMID- 18444110 TI - Externalizing behavior through the lens of the five-factor model: a focus on agreeableness and conscientiousness. AB - We examined relations between the Five-factor model (FFM) domains and facets of Agreeableness and Conscientiousness, hypothesized behavioral manifestations of these traits (e.g., social information processing and delay discounting), and externalizing behaviors in an undergraduate sample. Agreeableness and Conscientiousness were differentially related to the externalizing behaviors and the laboratory tasks, which in turn evinced significant relations with externalizing behaviors. The personality facets displayed evidence of modest incremental validity over the broader domains and were related to the externalizing behaviors even when controlling for the social information processing and behavioral discounting variables. In general, the results support the validity of the FFM domains and facets, particularly Agreeableness, in the prediction of a variety of externalizing behaviors. PMID- 18444111 TI - Cross-cultural diagnostic applicability of the Pictogram Test. AB - The aim of this study was to determine whether the Pictogram Test (PT; Vygostsky, 1960) a test of logical memory that was developed in Russia, is applicable for diagnosing and understanding thought disturbances in schizophrenia within an English-speaking population. Participants included 62 patients with schizophrenia or schizoaffective disorders and 80 community nonpatients from Russia and the United States. We used correlational analysis to organize PT variables into Concrete (CI), Attribute (AI), and Geometric (GI) indexes. Discriminant function analysis revealed that only AI and GI had significant discriminatory power. These indexes correctly classified 91% of English-speaking and 86% of Russian-speaking participants as either patients or nonpatients. Controlling for age and education, multivariate analysis revealed that patients had significantly lower AI and significantly higher GI scores relative to nonpatients, and those differences were similar across languages. These results indicate that the PT can discriminate between patients with schizophrenia or schizoaffective disorders and nonpatients, which suggests that characteristics of the PT could be used to understand the mechanism of logical thinking in patients and nonpatients. PMID- 18444112 TI - Factor structure of the Center for Epidemiological Studies Depression Scale in Hong Kong adolescents. AB - We present data from the Center for Epidemiological Studies-Depression Scale (CES D; Radloff, 1977) for 2 samples of Hong Kong community adolescents (combined N = 1,385). The 4 positive affect items related poorly to the remainder of the scale. Using 16 items, the data were consistent with 2 models with highly correlated factors: (a) a 2-factor model, 1 of which merged somatic and affective items, and (b) a 3-factor model separating somatic, depressed, and interpersonal items. Correlations with related constructs provide preliminary support of validity. Hong Kong adolescents are influenced both by traditional concepts of mind-body holism and Western psychological models separating psychological and somatic symptoms. PMID- 18444114 TI - Four-facet PCL-R structure and cognitive functioning among high violent criminal offenders. AB - High violent inmates (N = 126) were administered the Psychopathy Checklist Revised (PCL-R; Hare, Clark, Grann, & Thornton, 2000; Hare et al., 1990) and neuropsychological measures. No significant correlations were present between the overall PCL-R score and 14 cognitive measures. A violence score, computed as the total number of violent acts across all situations and types, was significantly correlated with the PCL-R total score and Facet 2 but not with the other three facets. Our data suggest that Facet 2 elevations may prove relevant to violence risk assessment; this link, however, needs further exploration with larger samples. PMID- 18444113 TI - Assessing interpersonal aspects of schizoid personality disorder: preliminary validation studies. AB - In 2 studies, we examined the reliability and validity of an interpersonal measure of schizoid personality disorder (SZPD) based on nonverbal behaviors and interpersonal interactions occurring during interviews. A total of 556 male jail inmates in the United States participated in Study 1; 175 mentally disordered offenders in maximum security hospitals in the United Kingdom participated in Study 2. Across both samples, scores on the Interpersonal Measure of Schizoid Personality Disorder (IM-SZ) exhibited adequate reliability and patterns of correlations with other measures consistent with expectations. The scale displayed patterns of relatively specific correlations with interview and self report measures of SZPD. In addition, the IM-SZ correlated in an expected manner with features of psychopathy and antisocial personality and with independent ratings of interpersonal behavior. We address implications for assessment of personality disorder. PMID- 18444115 TI - Is there really a dissociative taxon on the dissociative experiences scale? AB - The Dissociative Experiences Scale (DES; Bernstein & Putnam, 1986) and MMPI (Hathaway & McKinley, 1940) were administered to 1,237 college students to evaluate MMPI differences for nonpathological (n = 90) or pathological dissociators (n = 111) and nondissociative controls (n = 476). MMPIs of both dissociation groups had multiple clinical elevations with a mean 8-9 code. People classified in the pathological dissociation group had MMPI scores remarkably similar to those in the normal dissociation group. The DES and DES-Taxon (DES-T; Waller, Putnam, & Carlson, 1996) were also highly correlated. Our findings strongly suggest the DES-T does not uniquely identify categorical dissociation. PMID- 18444117 TI - One surprise after another. AB - The author of this article describes her childhood, career, and some of her main findings as a personality psychologist who studied women's creativity and adult development as she herself constructed her personal and professional identity in a changing environment and developed in a number of ways. PMID- 18444118 TI - MMPI-A forensic case studies: uses in documented court decisions. AB - In this article, we describe 8 legal cases reporting the use of the MMPI-A (Butcher et al., 1992) that were identified by an exhaustive search of the Westlaw database. These case studies provide a unique perspective on the uses of the MMPI-A as reflected in documented court decisions. For each case, we first provide a brief discussion of the legal issue or standard of law addressed by the MMPI-A findings. We then provide an abstract of the facts of the case and the nature of the involvement of the MMPI-A. We conclude each case with a more general discussion of the psychological uses and limitations of the MMPI-A as applied to this specific legal issue or standard. Not only do these cases display a wide range of legal issues, but they also provide an excellent opportunity to discuss some important uses and limitations of MMPI-A assessment when used as a component in a forensic evaluation. PMID- 18444119 TI - Detection and validation of unscalable item score patterns using item response theory: an illustration with Harter's Self-Perception Profile for Children. AB - We illustrate the usefulness of person-fit methodology for personality assessment. For this purpose, we use person-fit methods from item response theory. First, we give a nontechnical introduction to existing person-fit statistics. Second, we analyze data from Harter's (1985) Self-Perception Profile for Children (Harter, 1985) in a sample of children ranging from 8 to 12 years of age (N = 611) and argue that for some children, the scale scores should be interpreted with care and caution. Combined information from person-fit indexes and from observation, interviews, and self-concept theory showed that similar score profiles may have a different interpretation. For some children in the sample, item scores did not adequately reflect their trait level. Based on teacher interviews, this was found to be due most likely to a less developed self concept and/or problems understanding the meaning of the questions. We recommend investigating the scalability of score patterns when using self-report inventories to help the researcher interpret respondents' behavior correctly. PMID- 18444120 TI - An investigation of the psychometric properties of the MMPI-2 Restructured Clinical (RC) scales with mental health inpatients. AB - In this study, we compared the internal psychometric properties and external correlates of the MMPI-2 (Butcher et al., 2001; Tellegen et al., 2003) Restructured Clinical (RC) scales and corresponding MMPI-2 non-K-corrected Clinical scales in a sample of 280 men and 264 women admitted to inpatient psychiatric units. We evaluated the internal psychometric properties of the RC and Clinical scales by intercorrelation analyses and alpha coefficients. We investigated external correlates of scores from the RC and Clinical scales using selected chart variables, selected Symptom Checklist 90-Revised (Derogatis, 1983, 1994) items, and clinician ratings on the Brief Psychiatric Rating Scale (Overall & Gorham, 1988). Results showed psychometric support for the RC scales in terms of improved intercorrelation patterns and comparable or greater alpha coefficients. Further, external correlational analyses revealed varying degrees of evidence of improvement in convergent and discriminant validity. PMID- 18444121 TI - Personality judgment at zero acquaintance: agreement, assumed similarity, and implicit simplicity. AB - Previously unacquainted participants (N = 218) were assessed in small-group sessions in which they rated themselves and each other on (a) the Big Five (e.g., Costa & McCrae, 1992) and (b) an instrument assessing various traits not traditionally measured in the Big Five taxonomy as well as sociopolitical attitudes. Replicating earlier research, we obtained a significant self-stranger correlation on Extraversion; in addition, we found significant agreement on ratings of thriftiness, athleticism, traditionalism, conservatism, and attractiveness. Assumed similarity correlations were substantial for Neuroticism, Agreeableness, and Conscientiousness; furthermore, consistent with previous findings, there was a strong inverse relation between agreement and assumed similarity across the assessed characteristics. Finally, the correlations between Neuroticism, Openness, Agreeableness, and Conscientiousness were significantly greater in the strangers' ratings than in the self-ratings, indicating that these peer judgments are less complex. We also compared our Big Five findings with those from previous samples of varying acquaintanceship; these analyses indicated that the strangers' ratings were characterized by lower levels of self-other agreement (for all traits except Extraversion) and somewhat higher levels of assumed similarity (for ratings of Neuroticism and Agreeableness). PMID- 18444122 TI - Development and validation of the counterfactual thinking for negative events scale. AB - We examined the psychometric properties of the newly created Counterfactual Thinking for Negative Events Scale (CTNES) in two studies involving university undergraduates. In Study 1 (N = 634), factor analysis revealed four subscales that correspond with various types of counterfactual thinking: Nonreferent Downward, Other-Referent Upward, Self-Referent Upward, and Nonreferent Upward. The subscales were largely orthogonal and had adequate internal consistency and test-retest reliability. The CTNES subscales were positively correlated with a traditional method of assessing counterfactual thinking and were related as expected to contextual aspects of the negative event, negative affect, and cognitive style. In Study 2 (N = 208), we further examined the validity of the scale and demonstrated that the subscales were sensitive to an experimental manipulation concerning the type of negative event participants recalled. Moreover, the CTNES subscales correlated in the expected direction with measures of coping and cognitive style. PMID- 18444123 TI - Reliability and validity of the Fear of Intimacy Scale in China. AB - Participants in China (n = 343) and the United States (n = 283) completed measures to assess the reliability and validity of the Fear of Intimacy Scale (Descutner & Thelen, 1991) with a Chinese population. Internal consistency was strong in both cultures, and the factor structure was also similar between cultures, with confirmatory factor analysis (CFA) identifying three-factor models in both samples. As evidence of convergent validity, the scale was positively correlated with depression and negatively correlated with social support and self esteem. There were gender differences between cultures, but low levels of femininity were predictive of fear of intimacy in both cultures. The influence of individualism and collectivism varied, with high levels of individualism more predictive of a fear of intimacy in China than in the United States. PMID- 18444124 TI - The factor structure of the State-Trait Anxiety Inventory: an alternative view. AB - Past studies of the factor structure of the State-Trait Anxiety Inventory (STAI; Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, 1983) have arrived at various solutions. However, a relatively strong consensus supports a four-factor (State Anxiety Present, State Anxiety Absent, Trait Anxiety Present, and Trait Anxiety Absent) structure of the scale resulting from the combination of item polarity dimensions and the original two factors (State and Trait Anxiety). In this article, we assessed the adequacy of an alternative factor model of STAI data, the two-construct, two-method model, in three large samples using confirmatory factor analysis. The results revealed a statistical advantage of the two construct, two-method model over the one-factor model, the two-construct factor model, and the four-factor model. We discuss possible interpretational advantages of the two-construct, two-method model of the STAI. PMID- 18444125 TI - Repressive adaptation in a nonclinical sample: consistent and inconsistent reports of child psychosocial functioning across informants. AB - Using multiple indicators (self-report, parent report, school grades, and disciplinary referrals), we compared the psychosocial functioning of children across Weinberger's (1990) and Weinberger, Schwartz, and Davidson's (1979) repressive adaptive style (RAS) groups. Participants included 134 children ages 10 to 13 years that were recruited from public schools and 117 of their caregivers. Relative to nonrepressors, we hypothesized repressors to evidence lower levels of self-reported distress but higher parent-reported distress on the Behavior Assessment System for Children (BASC; Reynolds & Kamphaus, 1992). Summary scores from the BASC self-report differed significantly between repressors and nonrepressors in the expected directions. No significant group differences in parent-reported distress or school functioning emerged. Consistent with Phipps (2005), results question the predominant assumption that the RAS is associated with risk of psychosocial difficulties in children. PMID- 18444126 TI - Interpersonal subtypes within generalized anxiety disorder. AB - In this study, we addressed the heterogeneity in interpersonal problems across patients with generalized anxiety disorder (GAD). We assessed interpersonal problems by the Inventory of Interpersonal Problems (IIP-C; Horowitz, Alden, Wiggins, & Pincus, 2000) in a sample of 78 GAD patients. We used IIP-C profiles describing interpersonal characteristics of the total GAD sample as well as clustered GAD interpersonal subtypes. Although the overall sample was located in the friendly submissive quadrant of the circumplex model, this was true only for the Exploitable cluster, which includes more than 50% of the patients. Importantly, clusters of GAD patients with other locations reporting predominantly Cold, Nonassertive, or Intrusive interpersonal problems were also identified. The 4 clusters did not differ in terms of gender, comorbid disorders, or the severity of depression or anxiety. Thus, the assessment of interpersonal problems provides additional diagnostic information covering the heterogeneity of GAD patients. This information could be used for differential indication and individual case formulation in GAD. PMID- 18444127 TI - A case law survey of the Personality Assessment Inventory: examining its role in civil and criminal trials. AB - Although professional surveys suggest that the Personality Assessment Inventory (PAI; Morey, 1991) is a popular instrument among forensic and correctional psychologists, relatively little is known about the specific types of legal cases in which it is applied, the particular types of questions it is used to address, or the extent to which its admissibility has been at issue in court cases. Using a comprehensive legal database, we surveyed all published U.S., Canadian, European, and Australian criminal and civil cases in which the PAI was administered. The PAI appears to be introduced by examiners in a wide variety of civil (e.g., child custody, personal injury) and criminal (e.g., insanity, competence) cases to aid in the assessment of a broad range of psychopathology. Additionally, the PAI seems to be used frequently to assess questions concerning potential dissimulation and response styles. Surprisingly, the admissibility of the PAI into evidence was never at issue in any of the cases reviewed. PMID- 18444129 TI - The art of casting nets: fishing for the prize of personalized cancer prevention. AB - Now, more than ever, there is great need for personalized cancer prevention. We define personalized cancer prevention as a strategy that will enable each person to reduce his or her risk for lethal cancer by matching the dose, duration, and timing of an intervention with their own cancer risk profile. Most research studies provide us with data on the average person. But who is the average person anyway? The central tenet of personalized cancer prevention is that average is overrated. In this article, we frame what are the major obstacles to developing personalized cancer-reducing interventions: the lack of validated, non-invasive stratifiers of risk; the U-shaped dose response between cancer-fighting nutrients (e.g., selenium) and DNA damage, meaning that more of a good thing is not necessarily a good thing; the relatively brief duration of interventions evaluated in human prevention trials; the challenge of finding populations in which the impact of early life interventions on the incidence of cancers affecting older adults can be studied; and the interindividual differences in gene expression that may influence a person's response to a particular nutrient. Moreover, we contend that those who study personalized cancer prevention will need a unique constellation of expertise, including an understanding of cancer and aging, a passion for prevention, and proven health communication skills. We propose that becoming cross-trained in cancer and aging and taking more responsibility for communicating health-related research to the public in the proper context are two of the most important ways scientists can move us all closer to the goal of personalized cancer prevention. Every fisherman knows that where he casts his net determines his catch. Now, we ask: When it comes to solving the cancer problem, where should we be casting our nets? PMID- 18444130 TI - Effects of soy protein isolate consumption on prostate cancer biomarkers in men with HGPIN, ASAP, and low-grade prostate cancer. AB - Fifty-eight men at high risk of prostate cancer or with low-grade prostate cancer were randomly assigned to consume 1 of 3 protein isolates containing 40 g protein: 1) soy protein (SPI+, 107 mg isoflavones/d); 2) alcohol-washed soy protein (SPI-, <6 mg isoflavones/d); or 3) milk protein (MPI). Proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor, B-cell non-Hodgkin lymphoma-2 (Bcl-2), and Bcl-2-associated X protein (Bax) were assessed in baseline and ending prostate biopsy cores. Serum collected at 0, 3, and 6 mo was analyzed for total and free prostate specific antigen (PSA). Consumption of SPI+ did not alter any of the prostate cancer tumor markers. Bax expression decreased from baseline in the SPI- group, resulting in lower Bax expression than the MPI group. PCNA expression also decreased from baseline in the SPI- group, but this was not different from the other 2 groups. PSA did not differ among the groups at 3 or 6 mo. Interestingly, a lower rate of prostate cancer developed in the soy groups compared to the milk group (P = 0.01). These data suggest that 6-mo SPI+ consumption does not alter prostate tissue biomarkers, SPI- consumption exerts mixed effects, and less prostate cancer is detected after 6 mo of soy consumption regardless of isoflavone content. PMID- 18444131 TI - Oral antibiotics decrease urinary isoflavonoid excretion in children after soy consumption. AB - How oral antibiotics (OABX) alter isoflavones (IFLs) in soy-consuming children is unknown. We evaluated OABX effects on urinary IFL excretion rates (UIERs) in 17 children, ages 4 to 17 yr, who provided 2 urine collections in pairs of a baseline urine and an overnight urine collection after consuming a body-weight adjusted dose of soy nuts. The first collection was during OABX treatment for a bacterial infection and the second when healthy and off antibiotics. IFL food levels and UIERs were measured for nonmetabolites (NM), namely, daidzein, genistein (GE), and glycitein, and the metabolites (M) dihydrodaidzein, dihydrogenistein, equol, and O-desmethylangolensin (DMA), by liquid chromatography mass spectrometry. Urinary IFLs were hypothesized to change after OABX due to intestinal microflora alterations. A total of 11 children completed the study correctly. During OABX use, UIER (nmol/h/kg) for GE (6.4 +/- 1.0 vs. 10.1 +/- 1.6), all NM (27.5 +/- 4.8 vs. 36.2 +/- 4.7), and total IFLs (all NM + all M; 29.4 +/- 5.0 vs. 38.8 +/- 4.8) was reduced (P < 0.05) vs. when healthy. In contrast, a trend toward more DMA production during OABX was observed (1.2 +/- 0.6 vs. 0.4 +/- 0.3, P = 0.13). The reduction in urinary IFL appearance could be due to the changes of intestinal bacteria by OABX and/or due to processes related to the infection. PMID- 18444132 TI - Optimal methionine-free diet duration for nitrourea treatment: a Phase I clinical trial. AB - In animal models, methionine (MET) restriction in association with chloroethylnitrosoureas led to a substantial improvement. On this basis, we initiated a Phase I clinical trial of dietary MET restriction in association with chloroethylnitrosourea (cystemustine) treatment for patients with recurrent glioma or metastatic melanoma. Our purpose was 1) to determine the optimal MET free diet duration for a maximum depletion of plasma MET and 2) to evaluate the feasibility of this association. A total of 10 patients received 4 cycles of 2 wk of an association of a MET-free diet of 1, 2, 3, or 4 consecutive days and cystemustine (60 mg/m(2)). For each cycle, plasma MET concentrations, nutritional status (weight, albumin, prealbumin) and toxicity were measured. Conversely, fed state concentrations of plasma MET (12 AM) were reduced by dietary MET restriction, with an optimal depletion of 41% at the 1st day of MET-free diet without effect of the extending MET-free diet period. Indeed, we demonstrated the feasibility, that is, good diet acceptability and good tolerance (nutritional status and toxicity), of the association of a MET-free diet and cystemustine treatment. Based on these results, a Phase II clinical trial has been initiated to test the activity of the association of a 1-day MET-free diet with cystemustine treatment. PMID- 18444133 TI - The impact of a long-term reduction in dietary energy density on body weight within a randomized diet trial. AB - We examined the effect of dietary energy density change on body weight in participants of a randomized trial. Intervention participants markedly increased fruit and vegetable intake while reducing energy intake from fat. Participants were 2,718 breast cancer survivors, aged 26-74 yr, with baseline mean body mass index of 27.3 kg/m(2) (SD = 6.3). We assessed dietary intake by sets of four 24-h dietary recalls and validated with plasma carotenoid concentrations. Weight and height were measured at baseline, 1 yr, and 4 yr. Dietary energy density was calculated using food but excluding beverages. Intervention participants significantly reduced dietary energy density compared to controls and maintained it over 4 yr -- both in cross-sectional (P < 0.0001) and longitudinal (Group x Time interaction, P < 0.0001) analyses. Total energy intake or physical activity did not vary between groups. The intervention group had a small but significant weight loss at 1 yr (Group x Time interaction, P < 0.0001), but no between-group weight difference was observed at 4 yr. Our study showed that reducing dietary energy density did not result in a reduction in total energy intake and suggests that this strategy alone is not sufficient to promote long-term weight loss in a free-living population. PMID- 18444135 TI - Dietary and lifestyle correlates of urinary excretion status of equol in Japanese women. AB - The isoflavone metabolite equol has been identified in urine or blood samples in some but not all humans. In this cross-sectional study, we examined the association between lifestyle, including diet, and the urinary excretion of equol. Study subjects were 419 Japanese women who were recruited from a breast cancer screening center. Each woman responded to a self-administered questionnaire seeking information about health and lifestyle factors. Diet was assessed by a validated semiquantitative food frequency questionnaire. Urinary isoflavones were measured using spot urine samples. Equol was detected in the urine of 84 (20.0%) women. After controlling for covariates, it was found that dairy product intake was significantly lower in those who excreted detectable equol levels in urine than in those who did not. Because equol is derived from daidzein, individuals with low intake of daidzein may produce undetectable levels of equol. To account for this, the study subjects were restricted to 163 women with urinary daidzein levels of 10 nmol/mg creatinine or higher. The association of equol excretion with dairy product intake remained significant. Demographic factors, smoking status, and menstrual and reproductive factors were unrelated to equol excretion. These data suggest that dairy product intake may be associated with the production of equol. PMID- 18444134 TI - Dietary supplement use and risk of neoplastic progression in esophageal adenocarcinoma: a prospective study. AB - The incidence of esophageal adenocarcinoma (EA) and its precursor condition, Barrett's esophagus, has risen rapidly in the United States for reasons that are not fully understood. Therefore, we evaluated the association between use of supplemental vitamins and minerals and risk of neoplastic progression of Barrett's esophagus and EA. The Seattle Barrett's Esophagus Program is a prospective study based on 339 men and women with histologically confirmed Barrett's esophagus. Participants underwent baseline and periodic follow-up exams, which included endoscopy and self-administered questionnaires on diet, supplement use, and lifestyle characteristics. Use of multivitamins and 4 individual supplements was calculated using time-weighted averages of reported use over the observational period. Cox proportional-hazards models were used to calculate hazard ratios (HR) for each endpoint: EA, tetraploidy, and aneuploidy. During a mean follow-up of 5 yr, there were 37 cases of EA, 42 cases of tetraploidy, and 34 cases of aneuploidy. After controlling for multiple covariates including diet, nonsteroidal anti-inflammatory drug use, obesity, and smoking, participants who took 1 or more multivitamin pills/day had a significantly decreased risk of tetraploidy [HR = 0.19; 95% confidence interval (CI) = 0.08-0.47) and EA (HR = 0.38; 95% CI = 0.15-0.99] compared to those not taking multivitamins. Significant inverse associations were also observed between risk of EA and supplemental vitamin C (> or = 250 mg vs. none: HR = 0.25; 95% CI = 0.11-0.58) and vitamin E (> or = 180 mg vs. none: HR = 0.25; 95% CI = 0.10 0.60). In this cohort study, use of multivitamins and single antioxidant supplements was associated with a significantly reduced risk of EA and markers of neoplastic progression among individuals with Barrett's esophagus. PMID- 18444136 TI - Effect of selenium and vitamin e supplementation on plasma protein carbonyl levels in patients with arsenic-related skin lesions. AB - An estimated 35 million people in Bangladesh have been chronically exposed to arsenic in drinking water and are at risk of an array of adverse health conditions. The mechanisms of arsenic toxicity have not been well established; however, oxidative stress has been one commonly proposed pathway. In this study, we evaluated the effect of antioxidant supplementation on plasma protein oxidation among patients with arsenical skin lesions participating in a randomized double-blinded placebo-controlled trial of vitamin E and selenium. Subjects were randomized to 1 of 4 treatments arms (vitamin E, selenium, combination, or placebo) and were treated for a 6-mo period. We observed a dose dependent increase in adjusted protein carbonyl levels by arsenic exposure status in the pretreatment samples, although trends were not statistically significant. Following the 6-mo intervention, there was a decrease in protein carbonyl levels in each treatment group, although no resultant decrease was significantly different from that seen in the placebo group. Although we did not see a notable effect of selenium or vitamin E supplementation on changes in protein carbonyl levels, these preliminary data demonstrate a feasible methodological approach for the assessment of plasma protein carbonyls in relation to environmental toxicants in a human population and their potential use as endpoints in intervention trials. PMID- 18444137 TI - Low-carbohydrate diet versus caloric restriction: effects on weight loss, hormones, and colon tumor growth in obese mice. AB - Our objective was to compare the effects of a low-carbohydrate diet to a high carbohydrate/calorie-restricted diet on weight loss, hormones, and transplanted colon tumor growth. Eighty male C57BL/6 mice consumed a diet-induced obesity regimen (DIO) ad libitum for 7 weeks. From Weeks 8 to 14, the mice consumed a 1) DIO diet ad libitum (HF); 2) low-carbohydrate diet ad libitum (LC); 3) high carbohydrate diet ad libitum (HC); or 4) HC calorie restricted diet (HC-CR). MC38 cells were injected at Week 15. At the time of injection, the HC-CR group displayed the lowest body weight (25.5 +/- 0.57 g), serum insulin-like growth factor I (IGF-I; 135 +/- 56.0 ng/ml), and leptin (1.0 +/- 0.3 ng/ml) levels. This group also exhibited the longest time to palpable tumor (20.1 +/- 0.9 days). Compared to the HF group, the HC group exhibited lower body weight (39.4 +/- 1.4 vs. 32.9 +/- 0.7 g, respectively), IGF-I (604 +/- 44.2 vs. 243.4 +/- 88.9 ng/ml, respectively), and leptin (15.6 +/- 2.2 vs. 7.0 +/- 0.7 ng/ml, respectively) levels but similar tumor growth. IGF-I levels were lower in the LC group (320.0 +/- 39.9 ng/ml) than the HF group, but tumor growth did not differ. These data suggest LC diets do not slow colon tumor growth in obese mice. PMID- 18444138 TI - Inhibition of oral carcinogenesis by citrus flavonoids. AB - Six citrus flavonoids were tested for antineoplastic activity. The hamster cheek pouch model was utilized, and the solutions of the flavonoids (2.0-2.5%) and the solution of the carcinogen, 7,12-dimethylbenz[a]anthracene (0.5%), were applied topically to the pouches. The pouches of the positive controls were treated with the solvent used to dissolve the flavonoids and the solution of the carcinogen. The data show that 4 flavonoids (hesperetin, neohesperidin, tangeretin, and nobiletin) were inactive. The results with naringin and naringenin show that both of these flavonoids significantly lowered tumor number [5.00 (control group), 2.53 (naringin group), and 3.25 (naringenin group)]. Naringin also significantly reduced tumor burden [269 mm(3)(control group) and 77.1 mm(3)(naringin group)]. The data suggest that naringin and naringenin, 2 flavonoids found in high concentrations in grapefruit, may be able to inhibit the development of cancer. PMID- 18444139 TI - Continuous intravenous infusion of ghrelin does not stimulate feeding in tumor bearing rats. AB - The development of anorexia continues to be a serious treatment issue for cancer patients. Because the orexigenic peptide, ghrelin, is active through systemic routes and activates hypothalamic neuropeptide systems known to be refractory in anorectic tumor-bearing (TB) rats, we investigated whether it would prevent the development of cancer anorexia when infused continuously intravenously. The 24-h food intake was increased in nontumor-bearing (NTB) rats at a dose of 288 microg/day ghrelin. However, no tested dose of ghrelin, up to 576 microg/day, elicited increased feeding in TB rats prior to or subsequent to the development of anorexia. In hypothalamus, ghrelin-infused TB rats exhibited significantly increased concentration of neuropeptide Y (NPY) as compared to saline-infused TB rats. Hypothalamic expression of NPY and agouti-related protein (AgRP) messenger RNA were elevated in ghrelin-infused TB rats as compared to NTB rats, but saline infused TB rats also exhibited increased expression of AgRP. Proopiomelanocortin message was reduced in ghrelin-infused and saline-infused TB rats as compared to noninfused TB control rats. Although ghrelin infusion did not preserve muscle protein, a significant saving in body fat was observed in TB rats. Thus, the adiposity effects of ghrelin did not require an orexigenic response to the peptide. These results suggest that continuous ghrelin infusion may not be an effective treatment for cancer anorexia. PMID- 18444140 TI - Deoxycholic acid can induce apoptosis in the human colon cancer cell line HCT116 in the absence of Bax. AB - In the human colon cancer cells HCT116, deoxycholic acid (DCA) induces apoptosis via the mitochondrial pathway by triggering the release of mitochondrial factors such as cytochrome c. To elucidate if Bax, a proapoptotic member of the Bcl-2 family known to trigger cytochrome c release in response to various types of apoptotic stimuli, is involved in DCA-induced apoptosis in HCT116 cells, we analyzed DCA-induced apoptosis in Bax-knockout (Bax(-/-)) HCT116 cells. Cytochrome c release and caspase-9 activation were detectable after 5 min in both Bax(-/-) and Bax(+/-) HCT116 cells. Caspase-3 and caspase-8 activation was observed after 15 and 30 min, respectively. Bax(-/-) cells were protected from apoptosis by treating them with ursodeoxycholic acid for 12 h prior to DCA treatment. These results are consistent with our previous observations that were obtained by using wild-type HCT116 cells and suggest that Bax is not indispensable for DCA-induced apoptosis in HCT116 cells. PMID- 18444141 TI - Retinol Increases beta-catenin-RXRalpha binding leading to the increased proteasomal degradation of beta-catenin and RXRalpha. AB - Retinol utilizes a retinoid X receptor (RXR)-mediated degradation pathway to decrease beta-catenin protein in all-trans retinoic acid (ATRA)-resistant human colon cancer cells. In this study, we examined interactions between RXRalpha and beta-catenin in ATRA-resistant human colon cancer cells treated with retinol. Retinol treatment triggers relocation of beta-catenin and RXRalpha proteins. Cells treated with retinol for 8 and 24 h displayed increased cytosolic but decreased nuclear beta-catenin and RXRalpha. Retinol treatment increased beta catenin and RXRalpha protein interaction. Previously, we showed that 24 h of retinol treatment increased RXRalpha protein. Here we show this increase in RXRalpha levels is due to increased RXRalpha messenger RNA. Treatment with 48 h with retinol decreased RXRalpha protein levels. Last, by transfecting HCT-116 cells with a RXRalpha construct lacking the activation function-1 and DNA binding domains, we show RXRalpha and beta-catenin binding is required for proteosomal degradation of beta-catenin. These results suggest retinol induces RXRalpha and beta-catenin binding and transport to the cytosol where they are proteasomally degraded. PMID- 18444142 TI - Telomerase-associated apoptotic events by mushroom ganoderma lucidum on premalignant human urothelial cells. AB - The chemopreventive effects of Ganoderma lucidum was tested, using a tumorigenic transformable human urothelial cell (HUC-PC) model. These in vitro data show that G. lucidum can inhibit the viability and growth of HUC-PC. This could be explained by a concomitant induction of apoptosis and inhibition of telomerase activity. Significant exteriorization of phosphatidylserine was detected by Annexin-V on cell surface, and the cells subsequently lost membrane integrity for uptake of 7-amino-actinomycin D dye. Additionally, the levels of hydrogen peroxide and 8-hydroxy-2'-deoxyguanosine (8-OHdG) production of the apoptotic cells were significantly increased. The induction of apoptosis and suppression of telomerase activity help to explain the anti-HUC-PC growth properties; however, the induction of oxidative stress requires further study. This study strongly suggests that G. lucidum is a potential source of chemopreventive agents for bladder cancer based on its effectiveness in controlling the premalignant urothelial cell growth and carcinogen-induced transformation. PMID- 18444143 TI - Induction of apoptosis by lupeol and mango extract in mouse prostate and LNCaP cells. AB - Prostate cancer (PCA) is one of the most invasive malignancy and second leading cause of cancer related deaths in United States and some other countries. Long latency period makes PCA an ideal disease for pharmacologic or nutritional chemoprevention. Lupeol, a triterpene present in mango and other fruits, has shown to possess anticancer properties in in vivo and in vitro assays. Here, we recorded the apoptogenic activity in mouse prostate by lupeol and mango pulp extract (MPE). Testosterone was injected subcutaneously (5 mg/kg body weight) for 14 consecutive days to male Swiss albino mice. Lupeol/MPE supplementation resulted in arrest of prostate enlargement in testosterone-treated animals. In mouse prostate tissue, lupeol and MPE supplementation resulted in a significantly high percentage of apoptotic cells in the hypodiploid region. The induction of apoptosis in mouse prostate cells was preceded by the loss of mitochondrial transmembrane potential and DNA laddering. In testosterone-induced mouse prostate, upregulation of antiapoptotic B-cell non-Hodgkin lymphoma-2 and downregulation of proapoptotic Bcl-2-associated X protein and caspase-3 were also recorded. We further observed apoptogenic activities of lupeol in an in vitro model using human prostate cancer cells [lymph node carcinoma of the prostate (LNCaP)]. The apoptogenic response of lupeol-induced changes in LNCaP cells can be summarized as early increase of reactive oxygen species followed by induction of mitochondrial pathway leading to cell death. Thus, the results of this study demonstrate that lupeol/MPE is effective in combating testosterone-induced changes in mouse prostate as well as causing apoptosis by modulating cell-growth regulators. PMID- 18444145 TI - A combination of tomato and soy products for men with recurring prostate cancer and rising prostate specific antigen. AB - Tomato and soy products are hypothesized to reduce the risk of prostate cancer or enhance efficacy of therapy. A study was completed to determine if men with active prostate cancer will adhere to a dietary intervention rich in tomato products and a soy protein supplement men (n = 41) with recurrent, asymptomatic prostate cancer were randomized among 2 groups: Group A (n = 20) consumed tomato products (no soy) for Weeks 0 through 4, targeting a minimum of 25 mg of lycopene/day. Group B (n = 21) consumed soy (no tomatoes) for Weeks 0 through 4, providing 40 g of soy protein/day. For Weeks 4 through 8, all men consumed a combined tomato-rich diet and soy supplements. No grade II through IV toxicities were observed. During Weeks 0 through 4, mean daily lycopene intake for Group A was 43 mg (+/- 15 mg) and mean soy intake for Group B was 39 g (+/- 1 g), remaining similar during Weeks 4 through 8. Serum lycopene increased from 0.72 +/ 0.09 micromol/l to 1.21 +/- 0.10 micromol/l (P < 0.0001) and urinary isoflavone excretion increased from not detectable to 54.1 +/- 5.7 micromol/l (P < 0.05) with 8 wk of diet intervention. Serum prostate-specific antigen decreased between Weeks 0 and 8 for 14 / 41 men (34%). Mean serum vascular endothelial growth factor for the entire group was reduced from 87 to 51 ng/ml (P < 0.05) over 8 wk. In conclusion, prostate cancer patients will consume diets rich in tomato products and soy with excellent compliance and bioavailability of phytochemicals. Further studies combining tomato and soy foods to determine efficacy for prostate cancer prevention or management are encouraged. PMID- 18444144 TI - Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence. AB - Processed meat intake may be involved in the etiology of colorectal cancer, a major cause of death in affluent countries. The epidemiologic studies published to date conclude that the excess risk in the highest category of processed meat eaters is comprised between 20% and 50% compared with non-eaters. In addition, the excess risk per gram of intake is clearly higher than that of fresh red meat. Several hypotheses, which are mainly based on studies carried out on red meat, may explain why processed meat intake is linked to cancer risk. Those that have been tested experimentally are (i) that high-fat diets could promote carcinogenesis via insulin resistance or fecal bile acids; (ii) that cooking meat at a high temperature forms carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons; (iii) that carcinogenic N-nitroso compounds are formed in meat and endogenously; (iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the mucosa, through lipoperoxidation and/or cytotoxicity of fecal water. Nitrosation might increase the toxicity of heme in cured products. Solving this puzzle is a challenge that would permit to reduce cancer load by changing the processes rather than by banning processed meat. PMID- 18444146 TI - The nutritional prevention of cancer: 400 mcg per day selenium treatment. AB - Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence. PMID- 18444147 TI - No differences in DNA damage and antioxidant capacity between intervention groups of healthy, nonsmoking men receiving 2, 5, or 8 servings/day of vegetables and fruit. AB - The effects of different intake levels of vegetables and fruit (VF) on some cancer-relevant biomarkers such as DNA damage and oxidative stress were investigated. In a randomized controlled trial, 64 nonsmoking male subjects were asked to consume a diet with 2 servings of VF/day for 4 wk. Then subjects were randomly assigned to 1 of 3 groups with either a low (2 servings/day), medium (5 servings/day), or high (8 servings/day) intake level of VF for another 4 wk. At the end of study, the plasma lutein, zeaxanthin, alpha-carotene, and beta carotene but not cryptoxanthin and lycopene concentrations were significantly higher in subjects consuming 8 servings/day than in those receiving 2 servings/day. Different levels of VF consumption and plasma carotenoid concentrations did not result in differences in the levels of endogenous DNA strand breaks, oxidative DNA damage, antigenotoxic capacity of lymphocytes, plasma markers for lipid peroxidation (malondialdehyde, 8-iso-prostaglandin F2alpha) and antioxidant capacity [trolox-equivalent antioxidant capacity assay]. Thus, although consumption of 8 servings vs 2 servings/day of VF for 4 wk significantly increased the carotenoid level in plasma, there were no differences in DNA damage, lipid peroxidation, and antioxidant capacity markers among healthy, well-nourished, nonsmoking men. PMID- 18444148 TI - Serum selenium level and prostate cancer: a case-control study. AB - Selenium is a potential chemopreventive agent against prostate cancer. This study sought to evaluate and compare the serum selenium level in men with newly diagnosed prostate cancer and noncancerous patients. Between 2005 and 2006, this prospective case-control study was performed on patients referred to Sina and Imam University hospitals, Tehran, Iran; it included 62 men with clinicopathologically confirmed diagnosis of prostate cancer (case group) and 68 men with no detectable prostate cancer [normal digital rectal examination and prostate-specific antigen (PSA) level] or any other malignant disease (control group). The serum selenium level was assessed using Zeeman graphite furnace atomic absorption spectrometer (Varian Company, Australia). The mean serum selenium level in the case and control group was 66.3 +/- 17.7 microg/l and 77.5 +/- 22.5 microg/l, respectively (P = 0.002). Serum selenium was inversely associated with prostate cancer risk. After adjustment for age, body mass index (BMI), and smoking, the odds ratio was 0.16 and 95% confidence intervals were 0.06 to 0.47 (P trendq = 0.001) comparing the highest with the lowest tertile (> or = 89.3 microg/l). No correlation was observed between serum selenium level and age, BMI, or PSA level. In conclusion, serum selenium levels in prostate cancer cases were lower than in controls, which supports the hypothesis that selenium may protect against prostate cancer. PMID- 18444149 TI - Dietary factors and breast cancer risk: a case control study among a population in Southern France. AB - This case-control study examined different food groups in relation to breast cancer. Between 2002 and 2004, 437 cases and 922 controls matched according to age and area of residence were interviewed. Diet was measured by a validated food frequency questionnaire. Adjusted odds ratios (Ors) were computed across levels of various dietary intakes identified by two methods: the "classical" and the "spline" methods. Neither of the 2 methods found an association between total fruit and vegetable consumption and breast cancer. Results of the 2 methods showed a nonsignificant decreased association with cooked vegetables intake as well as legumes and fish consumption. Whereas the spline method showed no association, the classical method showed significant associations related to the lowest consumption of raw vegetables or dairy products and breast cancer risk: Adjusted OR for raw vegetable consumption between (67.4 and 101.3 g/day) vs. (< 67.4 g/day) was 0.63 [95% confidence interval (CI) = 0.43-0.93]. Adjusted OR for dairy consumption between (134.3 and 271.2 g/day) vs. (< 134.3 g/day) was 1.57 (95% CI = 1.06-2.32). However, the overall results were not consistent. Compared to the classical method, the use of the spline method showed a significant association for cereal, meat, and olive oil. Cereal and olive oil were inversely associated with breast cancer risk. Breast cancer risk increased by 56% for each additional 100 g/day of meat consumption. Studies using novel methodological techniques are needed to confirm the dietary threshold responsible for changes in breast cancer risk. New approaches that consist in analyzing dietary patterns rather than dietary food are necessary. PMID- 18444150 TI - Exploratory factor analysis of squamous cell carcinoma of the esophagus in Uruguay. AB - In the period 1996--2004, a hospital-based, case-control study on diet and risk of squamous cell carcinoma of the esophagus was conducted in Montevideo, Uruguay. The study included 234 cases and 468 controls, frequency matched on age, sex, and residence. Factor analysis (principal components) was used to identify the major food patterns associated with esophageal cancer. The analysis of food groups led to the identification of four patterns, arbitrarily labeled as traditional, healthy, high-fat, and drinker. The traditional pattern was not associated with risk of esophageal carcinoma, whereas the healthy pattern displayed a strong inverse association with this malignancy [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.17-0.48, P value for trend < 0.0001]. Unexpectedly, the high-fat foods diet was also marginally protective (OR 0.60, 95% CI 0.36-1.01, P value for trend = 0.07). On the other hand, the drinker pattern displayed a twofold increase in risk of esophageal carcinoma (OR 2.03, 95% CI 1.17-3.51, P value for trend = 0.01). The present study suggests that factor analysis might contribute to the elucidation of the contribution of diet on human cancer. Because diet represents a complex set of highly correlated exposures, dietary patterns could be more explicative of the etiology of squamous cell carcinoma of the esophagus than the traditional reductionist approach. PMID- 18444151 TI - Geographic distribution of liver and stomach cancers in Thailand in relation to estimated dietary intake of nitrate, nitrite, and nitrosodimethylamine. AB - It is our working hypothesis that the high rate of the liver and gastric cancers in North and Northeast Thailand is associated with increased daily dietary intake of nitrate, nitrite, and nitrosodimethylamine (NDMA). Samples of fresh and preserved Thai foods were systematically collected and analyzed from 1988 to 1996 and from 1998 to 2005. Consumption frequencies of various food items were determined on the basis of a dietary questionnaire given to 467 adults (212 males and 255 females) from 1998 to 2005. Food consumption data for the preceding and current year were collected and intakes (day, week, and month) of nitrate, nitrite, and NDMA were calculated. The trends in liver and stomach cancer age standardized incidence rates (ASR) in four regions of Thailand were compared with the dietary intake of nitrate, nitrite, and NDMA in those same geographic regions. Mean daily intakes of nitrate of 155.7 mg/kg, of nitrite of 7.1 mg/kg, and of NDMA of 1.08 microg/kg per day were found. Significant differences in dietary nitrate, nitrite, and NDMA intakes were seen between various Thai regions (P < 0.0001), and these corresponded to the variations in liver and stomach cancer ASR values between the regions. Dietary factors are likely to play key roles in different stages of liver and stomach carcinogenesis in Thailand. PMID- 18444152 TI - The influence of fruit and vegetable consumption and genetic variation on NAD(P)H:quinone oxidoreductase (NQO1) phenotype in an endoscopy-based population. AB - NAD(P)H:quinone oxidoreductase (NQO1) is an inducible detoxification enzyme relevant for colorectal cancer biochemoprevention. We evaluated the influence of recent fruit and vegetable (F&V) consumption and polymorphisms in NQO1 and transcription factor NFE2L2 on rectal NQO1 phenotype and also whether white blood cell (WBC) NQO1 activity reflects rectal activity. Among 94 sigmoidoscopy patients, we assessed F&V consumption by dietary record and determined the NQO1 c.609C > T and g.-718A > G and NFE2L2 g.-650C > A, g.-684G > A, and g.-686A > G polymorphisms. NQO1 mRNA level was measured in rectal biopsies and NQO1 activity in rectal biopsies and WBC. Consumption of F&V did not yield higher mRNA level or activity but rather appeared to have a repressive effect. Rectal activity was higher among NQO1 609CC-genotypes as compared to 609CT-genotypes (P < 0.0001; 609TT-genotypes were absent), whereas mRNA was higher among 609CT-genotypes (P < 0.001). mRNA and activity correlated among NQO1 609CC-genotypes (r = .50, P = 0.0001) but not among 609CT-genotypes (r = .14, P = 0.45). The NFE2L2-684A-allele was associated with higher mRNA levels (P = < 0.05). The other polymorphisms did not affect phenotype significantly. WBC and rectal activity did not correlate. In conclusion, genetic variation, especially the NQO1 609C > T polymorphism, is a more important predictor of rectal NQO1 phenotype than F&V consumption. WBC NQO1 activity is not a good surrogate for rectal activity. PMID- 18444153 TI - Dietary intake of benzo(a)pyrene and risk of esophageal cancer in north of Iran. AB - One etiologic factor for high incidence of esophageal squamous cell carcinoma (ESCC) in Golestan (Northeastern Iran) might be exposure to polycyclic aromatic hydrocarbons. We examined whether food and water are major sources of benzo(a)pyrene (BaP) exposure in this population. We used a dietary questionnaire to assess the daily intake of staple food (rice and bread) and water in 3 groups: 40 ESCC Golestan cases, 40 healthy subjects from the same area, and 40 healthy subjects from a low-risk area in Southern Iran. We measured, by high-performance liquid chromatography combined with fluorescence detection, the BaP concentration of bread, rice, and water in samples obtained from these 3 groups and calculated the daily intake of BaP. Mean BaP concentration of staple foods and water was similar and within standard levels in both areas, but the daily intake of BaP was higher in controls from the high-risk area than in controls from the low-risk area (91.4 vs. 70.6 ng/day, P < 0.01). In the multivariate regression analysis, having ESCC had no independent effect on BaP, whereas residence in the low-risk area was associated with a significant decrease in total BaP intake. Polycyclic aromatic hydrocarbons might, along with other risk factors, contribute to the high risk of ESCC in Golestan. PMID- 18444154 TI - An inverse association between preserved fish and prostate cancer: results from a population-based case-control study in Canada. AB - Epidemiological studies suggest that fish consumption may be a protective factor against the development of prostate cancer. We investigated the association between prostate cancer risk and fresh and preserved fish consumption among participants of a population-based case-control study (1,534 cases, 1,607 controls). Fish intake was measured using a dietary questionnaire that collected both frequency of consumption of a given portion size. Logistic regression analysis demonstrated an inverse association between preserved fish and prostate cancer risk for all levels of consumption, but reductions only reached statistical significance for the category of 1 to 3 servings of preserved fish per month (odds ratio = 0.78, confidence interval = 0.64-0.95). Consumption of any fat or energy from preserved fish was also associated with reduced risk. There was no suggestion of reduced prostate cancer risk with consumption of fresh and canned fish. Our results suggest that consumption of preserved fish may reduce the risk of developing prostate cancer. PMID- 18444155 TI - Dietary berries and ellagic acid diminish estrogen-mediated mammary tumorigenesis in ACI rats. AB - Estrogen acts as a complete mammary carcinogen in ACI rats. Prevention studies in this model allowed us to identify agents that are effective against estrogen induced mammary carcinogenesis. In this study, we investigated efficacy of dietary berries and ellagic acid to reduce estrogen-mediated mammary tumorigenesis. Female ACI rats (8-9 wk) were fed either AIN-93M diet (n = 25) or diet supplemented with either powdered blueberry (n = 19) and black raspberry (n = 19) at 2.5% wt/wt each or ellagic acid (n = 22) at 400 ppm. Animals received implants of 17beta-estradiol 2 wk later, were palpated periodically for mammary tumors, and were euthanized after 24 wk. No differences were found in tumor incidence at 24 wk; however, tumor volume and multiplicity were reduced significantly after intervention. Compared with the control group (average tumor volume = 685 +/- 240 mm3 and tumor multiplicity = 8.0 +/- 1.3), ellagic acid reduced the tumor volume by 75% (P < 0.005) and tumor multiplicity by 44% (P < 0.05). Black raspberry followed closely, with tumor volume diminished by > 69% (P < 0.005) and tumor multiplicity by 37% (P = 0.07). Blueberry showed a reduction (40%) only in tumor volume. This is the first report showing the significant efficacy of both ellagic acid and berries in the prevention of solely estrogen induced mammary tumors. PMID- 18444156 TI - In vivo tumor inhibitory effects of nutritional rice bran supplement MGN 3/Biobran on Ehrlich carcinoma-bearing mice. AB - This study was undertaken to investigate the in vivo anti-tumor activity of MGN 3/Biobran, a modified arabinoxylan rice bran. Swiss albino mice were inoculated intramuscularly in the right thigh with Ehrlich ascites carcinoma (EAC) cells. On Day 8, mice bearing a solid Ehrlich carcinoma (SEC) tumor were treated with MGN-3 via intraperitoneal injection. Tumor growth, cytokine production, and apoptotic effect of MGN-3 were examined. MGN-3 caused a highly significant delay in both tumor volume (63.27%) and tumor weight (45.2%) as compared to controls (P < 0.01). The mechanisms by which MGN-3 exerts its antitumor effect seem to involve its ability to induce apoptosis and immune modulation. MGN-3 induced a 1.8-fold increase in the percentage of apoptotic SEC cells as determined by flow cytometry and the histopathological examination. In addition, MGN-3 influenced plasma cytokine production by increasing the levels of tumor necrosis factor-alpha and interferon-gamma, while downregulating levels of the immune suppressing cytokine interleukin-10. Data also showed that non-tumor-bearing mice intramuscularly injected with MGN-3 resulted in a twofold increase in natural killer activity. No adverse side effects due to MGN-3 treatment were observed; all animals displayed normal feeding/drinking and life activity patterns. These data may have clinical implications for the treatment of solid cancers. PMID- 18444157 TI - Lignans are accessible to human breast cancer xenografts in athymic mice. AB - Lignan-rich diet has been linked with reduced breast cancer risk, and experimental studies have supported the hypothesis of lignans as cancer growth inhibiting compounds. However, it has not been clear if these compounds are accessible in the mammary tumor tissue in vivo. In this study, the accessibility and accumulation of lignans to breast cancer tissue was determined after oral administration of tritium labeled dietary lignan secoisolariciresinol diglucoside (3H-SDG) to athymic mice bearing MCF-7 tumors. The 3H-SDG administration increased tumor tissue radioactivity to the level similar to that in brain, skin, spleen, kidney, uterus, and lungs. The tumor tissue radioactivity was up to 92% of that found in serum, with the highest concentrations found in small (< 0.5 g) tumors. Accessibility of lignans to tumor tissue suggests that part of the anticancer activity of lignans may be due to their direct local effects on the breast cancer tissues. PMID- 18444158 TI - Niacin supplementation decreases the incidence of alkylation-induced nonlymphocytic leukemia in Long-Evans rats. AB - Niacin deficiency impairs poly(ADP-ribose) formation and enhances ethylnitrosourea (ENU)-induced carcinogenesis. Previous experiments were compromised by rapid progression of cancer, and the current study was designed with half the number of ENU doses. Weanling male Long-Evans rats were fed niacin deficient (ND), pair-fed (PF) control (30 mg nicotinic acid/kg), or pharmacological niacin (NA; 4 g nicotinic acid/kg) diets. After 2 wk, rats were gavaged every other day with ENU [30 mg/kg body weight (bw)] or vehicle (6 doses). Four days after the last dose of ENU, all rats were switched to AIN-93M diet and mildly feed restricted to maintain a constant food intake per bw. Rats were monitored for termination criteria and assessed for cancer development. Total cancers developed more rapidly in rats on the ND diet compared to those receiving high dose supplements of NA (P = 0.02; Gehan's generalized Wilcoxon test). Importantly, all of these differences occurred in the leukemias, especially the nonlymphocytic leukemia fraction (P = 0.008; Gehan's generalized Wilcoxon test), with incidences of 36%, 17%, and 11% in ND, PF, and NA rats, respectively. Because nonlymphocytic leukemias represent the majority of secondary cancers, these data support the concept that niacin supplementation may help protect cancer patients from the deleterious side effects of chemotherapy. PMID- 18444159 TI - Effect of colonic bacterial metabolites on Caco-2 cell paracellular permeability in vitro. AB - One common effect of tumor promoters is increased tight junction (TJ) permeability. TJs are responsible for paracellular permeability and integrity of the barrier function. Occludin is one of the main proteins responsible for TJ structure. This study tested the effects of physiological levels of phenol, ammonia, primary bile acids (cholic acid, CA, and chenodeoxycholic acid, CDCA), and secondary bile acids (lithocholic acid, LCA, and deoxycholic acid, DCA) on paracellular permeability using a Caco-2 cell model. Paracellular permeability of Caco-2 monolayers was assessed by transepithelial electrical resistance (TER) and the apical to basolateral flux of [14C]-mannitol. Secondary, but not primary, bile acids increased permeability as reflected by significantly decreased TER and increased mannitol flux. Both phenol and ammonia also increased permeability. The primary bile acid CA significantly increased occludin expression (P < 0.05), whereas CDCA had no significant effect on occludin expression as compared to the negative control. The secondary bile acids DCA and LCA significantly increased occludin expression (P < 0.05), whereas phenol had no significant effect on the protein expression as compared to the negative control. This suggests that the increased permeability observed with LCA, DCA, phenol, and ammonia was not related to an effect on occludin expression. In conclusion, phenol, ammonia, and secondary bile acids were shown to increase paracellular permeability and reduce epithelial barrier function at doses typical of levels found in fecal samples. The results contribute to the evidence these gut microflora-generated products have tumor-promoting activity. PMID- 18444160 TI - Effects of naturally occurring and synthetic organoselenium compounds on protein profiling in androgen responsive and androgen independent human prostate cancer cells. AB - Prostate cancer represents a major clinical public health challenge. Both epidemiological and clinical intervention studies support the protective role of selenium against development of prostate cancer. However, the mechanisms responsible for the inhibitory activity by this micronutrient remain elusive. Furthermore, literature reports consistently have shown that the dose and form of selenium are important factors in cancer chemoprevention. Thus, in the present investigation using androgen responsive (AR) lymph node carcinoma of the prostate (LNCaP) and its androgen-independent clone (AI) LNCaP C4-2 human prostate cancer cells, we compared the effects of selenomethionine (SM) and 1,4 phenylenebis(methylene)selenocyanate (p-XSC) on cell growth, DNA synthesis, and on proteomic profiles. p-XSC (5-20 microM) significantly inhibited cell growth in both cell types in a dose-dependent manner; SM was also effective but at much higher doses (50-100 microM). We hypothesize that the inhibition of cell growth is due, in part, to selenium interaction with redox-sensitive proteins. Using 2D gel electrophoresis, both organoselenium compounds altered the expression, to a varied extent, of several unrecognized selenium-responsive proteins. Employing matrix-assisted laser-desorption ionization (MALDI) and time-of-flight (TOF; MALDI-TOF) followed by tandem mass spectrometric analysis, we identified the following proteins: cofilin-2, heterogeneous nuclear ribonucleoprotein, single stranded mitochondrial DNA binding protein, chaperonin 10, nucleoside diphosphate kinase 6, and chain A Horf 6 human peroxidase enzyme. This is the first report showing that SM and p-XSC are capable of altering these proteins; their roles in prostate cancer prevention warrant further investigations. PMID- 18444161 TI - Antioxidative and apoptotic properties of polyphenolic extracts from edible part of artichoke (Cynara scolymus L.) on cultured rat hepatocytes and on human hepatoma cells. AB - Cultured rat hepatocytes and human hepatoma HepG2 cells were used to evaluate the hepatoprotective properties of polyphenolic extracts from the edible part of artichoke (AE). The hepatocytes were exposed to H2O2generated in situ by glucose oxidase and were treated with either AE, or pure chlorogenic acid (ChA) or with the well known antioxidant, N, N'-diphenyl-p-phenilenediamine (DPPD). Addition of glucose oxidase to the culture medium caused depletion of intracellular glutathione (GSH) content, accumulation of malondialdehyde (MDA) in the cultures, as a lipid peroxidation indicator, and cell death. These results demonstrated that AE protected cells from the oxidative stress caused by glucose oxidase, comparable to DPPD. Furthermore, AE, as well as ChA, prevented the loss of total GSH and the accumulation of MDA. Treatment of HepG2 cells for 24 h with AE reduced cell viability in a dose-dependent manner, however, ChA had no prominent effects on the cell death rate. Similarly, AE rather than ChA induced apoptosis, measured by flow cytometric analysis of annexin and by activation of caspase-3, in HepG2 cells. Our findings indicate that AE had a marked antioxidative potential that protects hepatocytes from an oxidative stress. Furthermore, AE reduced cell viability and had an apoptotic activity on a human liver cancer cell line. PMID- 18444163 TI - Impact of lactose containing foods and the genetics of lactase on diseases: an analytical review of population data. AB - Dairy foods (DFs) contain complex ingredients that could affect different diseases. The control of lactose digestion phenotypically divides populations into those who can [lactase persistent (LP)] and those who cannot [lactase nonpersistent (LNP)] assimilate lactose. LNP subjects, however, can adapt to lactose intolerance through intestinal bacteria. The DF/LNP status interactions may function as disease risk modifiers. We evaluated the relationship between DF and LNP with colorectal, breast, prostate, ovarian, lung, and stomach cancer and inflammatory bowel diseases (IBD; Crohn's disease and ulcerative colitis). Yearly per capita DF consumption, LNP national prevalence, cancer mortality, and incidence of IBD were obtained from several sources. A negative binomial regression model was used to derive incremental risks. There were statistically significant (P 1 was significantly associated with renal cell carcinoma and the odds ratio of having renal cell cancer was significantly higher for patients with an IMR >1. CONCLUSION: Local atherosclerosis was more pronounced in tumor-positive than in tumor-negative renal specimens with significant association between IMR > 1 and renal cancer. This finding encourages the hypothesis of atherosclerosis causing oxidative stress as a potential risk factor for the development of renal cell cancer. PMID- 18444169 TI - Alcohol, tobacco, and diet in relation to esophageal cancer: the Shanghai Cohort Study. AB - Prospective data on environmental exposures, especially with respect to alcohol, tobacco, and diet, in relation to the risk of esophageal cancer in high-risk populations are sparse. We analyzed data from a population-based cohort of 18,244 middle-aged and older men in Shanghai to identify risk factors for esophageal cancer in this high-risk population. The cohort was followed through 2006, and 101 incident esophageal cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and their corresponding 95% confidence intervals (CI) for associations between exposures and esophageal cancer risk. With adjustment for tobacco use and other potential confounders, regular drinkers vs. nondrinkers of alcoholic beverages had a twofold risk of developing esophageal cancer (HR=2.02, 95% CI=1.31-3.12). With adjustment for alcohol and other potential confounders, long-term smokers (40+ yr) vs. nonsmokers of cigarettes showed a twofold risk of developing esophageal cancer (HR=2.06, 95% CI=1.11-3.82). Increased consumption of fruits (including oranges/tangerines), seafood, and milk were found to be protective against the development of esophageal cancer; HRs were decreased by 40-60% for high vs. low consumers after adjustment for cigarette smoking, alcohol drinking, and other confounders. PMID- 18444171 TI - Metabolism and absorption of auraptene (7-geranyloxylcoumarin) in male SD rats: comparison with 7-ethoxycoumarin. AB - We previously reported that auraptene (7-geranyloxycoumarin; AUR), a coumarin that occurs widely in citrus fruit, has been shown to be a promising cancer preventive agent in several rodent models. However, its bioavailability and metabolism have not been investigated. In this study, we compared the metabolism characteristics of AUR with those of 7-ethoxycoumarin (ETC) in male Sprague Dawley rats. Each (500 micromol/kg body weight) was given separately by a single gastric intubation procedure, and digestive tract, liver, and kidney were removed at 1, 4, and 24 h after administration. The localization profiles of AUR and ETC in the gastrointestinal tract were similar. However, AUR, in contrast to ETC, showed significant localization in the liver from 1 to 4 h. Treatments of serum and urinary samples with glucuronidase/sulfatase led to the detection of significant amounts of umbelliferone (7-hydroxycoumarin; UMB), and serum and urinary concentrations of UMB following ETC administration were significantly higher than with AUR administration. Our results suggest that AUR, which bears a geranyloxyl side chain, has a longer life span than ETC, and this property may be associated with its previously reported chemopreventive and xenobiotics metabolizing activities. PMID- 18444172 TI - Dietary cooked navy beans and their fractions attenuate colon carcinogenesis in azoxymethane-induced ob/ob mice. AB - Based on the protective effects of cooked dry bean consumption in a human intervention study, we evaluated which fraction of cooked dry beans is responsible for its cancer-preventive effects. Cooked navy beans (whole beans), the insoluble fraction (bean residue) or soluble fraction of the 60% (vol:vol) ethanol extract of cooked navy beans (bean extract), or a modified AIN-93G diet (16.6% fat including 12.9% lard) as control diet were fed to 160 male obese ob/ob mice after 2 azoxymethane injections. In comparison to control-fed mice, dysplasia, adenomas, or adenocarcinomas were detected in fewer mice on either bean fraction diet (percent reduction from control: whole beans 54%, P=0.10; bean residue 81%, P=0.003; bean extract 91%, P=0.007), and any type of colon lesions, including focal hyperplasia, were found in fewer mice on each of the 3 bean diets percent reduction from control: whole bean 56%, P=0.04; bean residue 67%, P=0.01; bean extract 87%, P=0.0003. These results suggest that both the soluble and the insoluble fraction of the extract contribute to the cancer-protective effect of cooked navy beans. PMID- 18444173 TI - Caffeine overcomes genistein-induced G2/M cell cycle arrest in breast cancer cells. AB - Although inhibition of tumor cell growth by genistein is mediated by different types of cell cycle arrest, its regulation of genes related to the cell cycle is not clear. In this study, genistein caused a concentration-dependent growth inhibition in the hormone-independent cell line MDA-MB-435S. Flow cytometric analysis showed that genistein induced a concentration-dependent accumulation of cells in the G2/M phase of the cell cycle. Caffeine enhanced the inhibition of cell proliferation induced by genistein. Caffeine alone did not have an appreciable effect on the phases of the cell cycle, but caffeine at 3 mM completely eliminated genistein-induced G2/M cell cycle arrest. cDNA microarrays were used to investigate the mechanism of genistein-induced, caffeine-negated G2/M arrest. We identified 12 genes, which had opposite responses to genistein and caffeine treatments. Among these, 5 genes were upregulated by genistein and downregulated by caffeine; 7 genes were downregulated by genistein and upregulated by caffeine. Reversal by caffeine of genistein-induced G2/M phase arrest in breast cancer cell lines could increase their sensitivity to genistein and enhance genistein-induced inhibition of cell growth. Genes that have opposite responses to genistein and caffeine may be involved in regulation of the G2/M phase of the cell cycle. PMID- 18444174 TI - Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein. AB - In the azoxymethane (AOM) model of experimental rodent colon cancer, cholic acid and its colonic metabolite deoxycholic acid (DCA) strongly promote tumorigenesis. In contrast, we showed that ursodeoxycholic acid (UDCA), a low abundance bile acid, inhibited AOM tumorigenesis. Dietary UDCA also blocked the development of tumors with activated Ras and suppressed cyclooxygenase-2 (Cox-2) upregulation in AOM tumors. In this study, we compared the effect of dietary supplementation with tumor-promoting cholic acid to chemopreventive UDCA on Cox-2 expression in AOM tumors. Cholic acid enhanced Cox-2 upregulation in AOM tumors, whereas UDCA inhibited this increase and concomitantly decreased CCAAT/enhancer binding protein beta (C/EBPbeta), a transcriptional regulator of Cox-2. In HCA-7 colon cancer cells, DCA activated Ras and increased C/EBPbeta and Cox-2 by a mechanism requiring the mitogen-activated protein kinase p38. UDCA inhibited DCA-induced p38 activation and decreased C/EBPbeta and Cox-2 upregulation. Using transient transfections, UDCA inhibited Cox-2 promoter and C/EBP reporter activation by DCA. Transfection with dominant-negative (17)N-Ras abolished DCA-induced p38 activation and C/EBPbeta and Cox-2 upregulation. Taken together, these studies have identified a transcriptional pathway regulating Cox-2 expression involving Ras, p38, and C/EBPbeta that is inhibited by UDCA. These signal transducers are novel targets of UDCA's chemopreventive actions. PMID- 18444175 TI - Vitamin E analog alpha-TEA, methylseleninic acid, and trans-resveratrol in combination synergistically inhibit human breast cancer cell growth. AB - Alpha-tocopherol ether-linked acetic acid analog [2,5,7,8-tetramethyl-2R-(4R, 8R 12-trimethyltridecyl) chroman-6-yloxyacetic acid (alpha-TEA)] is a novel form of vitamin E effective at killing cancer cells but not normal cells. alpha -TEA alone and together with methylseleninic acid (MSA) and trans-resveratrol (t-RES) were investigated for ability to induce apoptosis, DNA synthesis arrest, and cellular differentiation and inhibit colony formation in human MDA-MB-435-F-L breast cancer cells in culture. The 3 agents alone were effective in inhibiting cell growth by each of the 4 different assays, and 3-way combination treatments synergistically inhibited cell proliferation in each assay in comparison to individual treatments. Furthermore, combinations of alpha -TEA, t-RES, and MSA significantly enhanced levels of apoptosis in human breast (MDA-MB-231, MCF7, and T47D) and prostate (LnCaP, PC-3, and DU-145) cancer cell lines as well as in immortalized but nontumorigenic MCF10A cells but not primary cultures of human mammary epithelial cells. Western immunoblotting confirmed the induction of apoptosis in that the 3 agents induced poly(adenosine diphosphate-ribose) polymerase cleavage, with earlier detection and more complete cleavage seen in the combination treatment. Mechanistic studies showed combination treatments to inhibit cell proliferation via downregulation of cyclin D1 and induce apoptosis via activation of caspases 8 and 9 and downregulation of prosurvival proteins FLIP and survivin. In summary, the combination of alpha-TEA, MSA, and t-RES is more effective than single treatments for inhibiting cell proliferation, inducing cellular differentiation, and inducing cell death by apoptosis in human cancer cells in culture. PMID- 18444176 TI - Allicin inhibits blood vessel growth and downregulates Akt phosphorylation and actin polymerization. PMID- 18444178 TI - Medical student acquisition of clinical working knowledge. AB - BACKGROUND: Working knowledge of physicians manifests as a combination of diagnostic pattern recognition and clinical data interpretation (analytic fact checking). PURPOSE: The purpose was to study medical student acquisition of these abilities as a function of years of medical training/experience. METHODS: A cross sectional study involving students who had completed 0, 1, 2, and 3 years of medical school. All students at all levels of training took the same tests of diagnostic pattern recognition and clinical data interpretation. Percent correct scores were calculated and used to estimate learning curves. A cohort of family physicians also took the test to provide a benchmark. RESULTS: Student diagnostic pattern recognition and clinical data interpretation ability demonstrated a steady upward growth curve but leveled off in Year 3. Diagnostic pattern recognition performance was consistently higher than clinical data interpretation performance. The rate of diagnostic performance gain with training and experience was also higher. CONCLUSIONS: Medical students acquired diagnostic pattern recognition ability and all years of medical training contributed. The rate of clinical data interpretation performance improvement was slower, and the absolute performance level was lower. What was surprising was the lower rate of improvement in diagnostic pattern recognition and clinical data interpretation performance for students during their 1st year of clinical training. Students' understanding of findings and their relationships to disease processes may be affected by their limited patient experience. PMID- 18444179 TI - Professionalism in residency training: is there a generation gap? AB - BACKGROUND: Teaching and evaluating professionalism is part of the Accreditation Council for Graduate Medical Education's training requirements for postgraduate education. Defining what constitutes professional behavior is the first step in this endeavor. Difficulty in teaching and evaluating professionalism may stem from generational differences between teachers and trainees in their definition of professional behavior. PURPOSE: We sought to explore the magnitude of generational differences by asking faculty and residents to evaluate behaviors along a continuum of professionalism. METHODS: A questionnaire composed of 16 vignettes describing unprofessional behaviors was distributed to a sample of internal medicine trainees and faculty. For each specific behavior described, participants were asked to rate the severity of the infraction on a 4-point scale. RESULTS: Within each group, responses were distributed across severity categories for most vignettes. There were no significant differences in the responses of trainees versus faculty for any of the vignettes except two. CONCLUSION: There is little consensus for determining the severity of unprofessional behaviors among faculty and trainees at one urban university training program. However, this lack of consensus does not appear to have a generational basis. Attributing difficulties in teaching and assessing professionalism cannot be blamed on differences between the generations. PMID- 18444180 TI - Medical subinternship: student experience on a resident uncovered hospitalist service. AB - BACKGROUND: Studies demonstrating the value of hospitalists to medical student education have been performed in traditional resident covered ward service settings (RCWS). PURPOSE: To compare medical subinterns' experiences on an RCWS to that on a resident uncovered hospitalist service (RUHS). METHODS: We assessed students' overall experience and knowledge learned on the two services using a 5 point Likert scale. We also assessed learning environment characteristics, workload, and time spent at the hospital on each service. RESULTS: The mean rating for knowledge learned was higher on the RCWS. Subinterns rated the two services equivalent on measures of educational value of patient problems, faculty assessment, supervision, and number and value of teaching sessions. The RCWS received higher ratings on variety of patient problems and frequency of intellectual discussion. CONCLUSIONS: The RCWS provided a superior learning experience for subinterns. Academic medical centers should take these findings into consideration before placing medical students on an RUHS. PMID- 18444181 TI - Should forensic autopsies be a source for medical education? A preliminary study. AB - BACKGROUND: Practical anatomy sessions including dissection of cadavers are essential for anatomy courses. There are many difficulties in obtaining cadavers. In addition, hardened and discolored cadavers that are fixed with formaldehyde look unrealistic and generate apathy among students. PURPOSE: We considered that forensic autopsies may be used as ancillary and supportive practice in anatomy education. METHODS: We invited the participation of Year 2 medical students in suitable forensic autopsy cases during the course of one year. Specialists of forensic medicine and anatomy provided theoretical support through talks in their specialized fields during the autopsy. At the end of the semester, feedback questionnaire forms were prepared and the students were asked to evaluate these sessions. RESULTS: Forty students participated in the evaluation by completing the questionnaire. Students made positive statements about adequacy of the time of the application, consistency of the structures with theoretical and practical issues shown in anatomy lectures, and necessary explanations of the lecturers during and after the application. CONCLUSION: We think that forensic autopsies are an attractive supplementary educational model, and we have decided to continue the forensic autopsy practices. We believe that further studies on the evaluation of the sessions using a larger student population will lead to more conclusive results. PMID- 18444182 TI - Impact of student reflective e-portfolio on medical student advisors. AB - BACKGROUND: Little is published about the role of faculty advisors and use of students' e-portfolios. PURPOSE: This article reports advisors' observations and understanding about 1st-year students based on information from students' journaling as part of an e-portfolio. METHODS: Data were collected on Blackboard survey module for 8 volunteer advisors at two medical school campuses. Responses were hand coded, verified by two authors, tallied, with example comments recorded. RESULTS: The four male and four female advisors are all mid-career, mixed between clinical and nonclinical faculty. The students' responses in the portfolio gave advisors greater insight into students' thinking, maturity, and reflective ability, and they helped advisors identify early warnings about problems. The e-portfolio enhanced meaningful interactions and more focused discussions with students. Advisors reported no improvements in efficiency of communications and had technical difficulties with Blackboard (version 6.0). CONCLUSIONS: Advisors reported students' reflective responses to focused questions in an e-portfolio contribute valuable understanding about students' thinking and attitudes. Advisors are enthusiastic about the value of the e portfolio for this purpose. We anticipate benefits will generalize when fully implemented. PMID- 18444184 TI - An acculturization curriculum: orienting international medical graduates to an internal medicine residency program. AB - BACKGROUND: The number of International Medical Graduate (IMG) applicants to residency programs has increased steadily over the past decade. Despite high motivation and significant medical knowledge, differences in training and cultural expectations can create knowledge gaps and influence how IMGs relate to patients and staff. This contributes to increased opportunities for medical errors, patient dissatisfaction, and frustration among colleagues. DESCRIPTION: To improve this transition we introduced a required, 2-week precourse for IMGs entering our program. The curriculum focused around the Accreditation Council for Graduate Medical Education core competencies. EVALUATION: Participants reported knowledge gains and rated favorably didactic sessions and small-group activities. Program directors and other key stakeholders reported positive experiences with the precourse, especially the reduction in transition stress and missed work time in July. CONCLUSION: An intensive precourse for IMGs can attenuate transition stress and increase knowledge of core medical skills and competencies. PMID- 18444183 TI - Evaluation of the congruence between students' postencounter notes and standardized patients' checklists in a clinical skills examination. AB - BACKGROUND AND PURPOSE: Questions remain about the congruence between students' written notes and checklists as summaries of encounters. METHODS: Students examined standardized patients and summarized findings in postencounter notes. The patients completed checklists. A physician read the students' notes and completed parallel checklists to document the history and physical items performed. Rates of under- and overdocumentation were calculated. RESULTS: Students documented findings for 71% of items performed - an underdocumentation rate of 29%. Approximately 94% of their documented findings were consistent with what they had done. Their rate of overdocumentation was 6%, in which they documented findings inconsistent with the checklists. About half the students had no instances of overdocumentation. CONCLUSION: Students' rate of underdocumentation was comparable to experienced clinicians. Although their overdocumentation rate was low overall, it was high for a few students. Evaluation of the congruence between checklists and postencounter notes provides useful information and informs checklist development. PMID- 18444185 TI - Just in time: technology to disseminate curriculum and manage educational requirements with mobile technology. AB - BACKGROUND: Learning objectives intended to guide clinical education may be of limited usefulness if they are unavailable to students when interacting with patients. DESCRIPTION: We developed, implemented, and evaluated a Web-based process to disseminate the Clerkship Directors of Internal Medicine curricular objectives to students via handheld computers and for students to upload patient logs to a central database. EVALUATION: We delivered this program to all students in our geographically dispersed system, with minimal technological problems. The total number of "hits" on curricular objectives was 8,932 (averaging 149 per student or approximately 2.7 times daily). The average number of "hits" per problem was 470, ranging from 18 for smoking cessation to 1,784 for chest pain. The total number of patient problems logged by students was 9,579, and 91% of students met our prespecified criteria for numbers and types of patients. CONCLUSIONS: Dissemination and use of curricular learning objectives and related tools is enhanced with mobile technology. PMID- 18444186 TI - Developing a rural workforce through medical education: lessons from down under. AB - BACKGROUND: Rural Clinical Schools in Australia are a government initiative to help address the rural workforce shortage at the medical school level. This article reports on the approaches and outcomes from one Rural Clinical School. DESCRIPTION: The program is underpinned by an 8-week rural rotation for all 3rd year students and a yearlong program of core clinical rotations for 25% of the Year 3 cohort. Aspects of experiential, situated, service, and self-directed learning along with interprofessional study are integrated to provide unique rural-focused learning opportunities. EVALUATION: Compared to their urban counterparts, rural students see more patients, perform a greater number of procedures, and achieve as well in exam results. CONCLUSIONS: Early indications suggest that our program is attracting more Year 3 students to explore the rural pathway as an option to a future career. The program demonstrates that rural students achieve as well as their urban counterparts. PMID- 18444187 TI - Developing disaster preparedness competence: an experiential learning exercise for multiprofessional education. AB - BACKGROUND: The hurricane disasters of 2005 and the threat of pandemic infectious diseases compel medical educators to develop emergency preparedness training for medical students and other health care professional students. DESCRIPTION: This article describes an experiential exercise for learning a number of the general core competencies in the 2003 AAMC report titled "Training Future Physicians about Weapons of Mass Destruction." A modified tabletop exercise for medical and veterinary students, which was developed and implemented in 2005, is described. The exercise focused on Highly Pathogenic Avian Influenza (HPAI), an emerging infectious disease scenario that raised the possibility of biological attack. The students were assigned roles in small groups, such as community physicians, hospital personnel, public health officials, veterinarians, school nurses, and emergency managers. Fifteen faculty members were recruited from these various areas of expertise. Pre- and posttesting of medical students showed significant gains in knowledge. The authors describe the scenario, small-group role playing, study questions, injects, Web sites and readings, and evaluation tools. CONCLUSIONS: This experiential exercise is an effective, inexpensive, and easily adapted tool for promoting multiple competencies in mass health emergency preparedness for a variety of health care students including medical, veterinary, public health, and nursing students. PMID- 18444188 TI - What it's really like: the complex role of medical students in end-of-life care. AB - BACKGROUND: Medical student end-of-life care training provides insight into the hidden curriculum and physician professional development. DESCRIPTION: Second year medical students at a university medical center listen to a panel discussion of 4th-year students and residents describing their end-of-life care experiences during clerkships. This discussion is intended to provide "anticipatory guidance" to 2nd-year students about challenging situations they might encounter on the wards. The purpose of this study was to analyze the content of the panel discussions by 4th-year students and residents to better understand their views of the end-of-life care curriculum. EVALUATION: We performed a qualitative content analysis of transcripts from 2 years of panel discussions. Participants' comments focused primarily on the complexity of the role of medical students in end-of-life care. Three major themes emerged in the sessions: defining professional identity, conflicting expectations, and limited medical experience. CONCLUSIONS: The role of medical students in end-of-life care can be complex, confusing, and contradictory. Emotional support and elucidating the hidden curriculum may assist students with the process of physician enculturation and end-of-life care education. PMID- 18444189 TI - A review of medical school programs that train medical students as teachers (MED SATS). AB - BACKGROUND: Medical students represent medicine's future teachers. The objective of this literature review was to identify programs teaching medical students how to teach (MED-SATS). SUMMARY: Electronic searches were conducted and identified 39 programs (1966-2005). Students have assumed varied teaching roles: group facilitator, standardized patient, tutor, teaching assistant, standardized learner, course director, and peer teacher. Most participants were 4th-year students. The teaching techniques varied: group sessions, lectures, and individual teaching. To evaluate student teaching, programs used checklists, videotape review, group discussion, observation, examination scores, course grades, self-assessment exercises, and follow-up with residency training programs. CONCLUSIONS: Reports on how students are trained in medical schools to be teachers are limited. Of the programs identified, it is difficult to determine which programs are ongoing. Data on MED-SATS graduates teaching skills as resident and attending teachers are lacking. These issues present some challenges for future study. PMID- 18444190 TI - A role for this country's medical schools in improving provided minority health care. PMID- 18444194 TI - The reputation of medical education research: quasi-experimentation and unresolved threats to validity. AB - BACKGROUND: Medical education research is often criticized for its methodological flaws. This raises questions about the prospect of evidence-based medical education practice. Critics call for more rigorous research with randomization, greater control, and tight execution. But randomization and control are rarely achieved in applied field settings, the site of most medical education research. Consequently, research in medical education has relied on quasi-experimentation, which by definition is compromised methodologically. SUMMARY: So is medical education research doomed to a reputation for flawed research that undermines the promise of evidence-based practice? We think not. We argue in this article that the problem is due to incomplete and uncritical use of quasi-experimentation. This practice ignores a critical step in the quasi-experimental process, a step that follows the design and execution of the research, that is, ruling out threats to validity posed by methodological flaws. CONCLUSION: Validity threats must be evaluated critically when drawing research conclusions, to establish a credible evidence base for medical education practice. PMID- 18444195 TI - How much do differences in medical schools influence student performance? A longitudinal study employing hierarchical linear modeling. AB - BACKGROUND: Medical school curricula have undergone considerable change in the past half century. There is little evidence, however, for the impact of various curricula and educational policies on student learning once incoming performance and the nonrandom nature of students nested within schools has been accounted for. PURPOSE: To investigate effects of school variables on United States Medical Licensing Examination (USMLE) Step 1-3 scores over an 11-year period (1994-2004). METHODS: Using Association of American Medical Colleges and USMLE longitudinal data for 116 medical schools, hierarchical linear modeling was used to study the effects of school variables on Step 1-3. RESULTS: Mean unadjusted between school variance was 14.74%, 10.50%, and 11.25%, for USMLE Step 1-3. When student covariates were included, between-school variation was less than 5%. The variance accounted for in student performance by the student covariates ranged from 27.58% to 36.51% for Step 1,16.37% to 24.48% for Step 2 and 19.22% to 25.32% for Step 3.The proportion of the between-school variance that was accounted for by the student covariates ranged between 81.22% and 88.26% for Step 1, 48.44% and 79.77% for Step 2, and 68.41% and 80.78% for Step 3 [corrected]. School-level variables did not consistently predict for adjusted mean school Step performance. CONCLUSIONS: Individual student differences account for most of the variation in USMLE performance with small contributions from between-school variation and even smaller contribution from curriculum and educational policies. PMID- 18444196 TI - Randomized comparison between traditional and traditional plus interactive Web based methods for teaching seizure disorders. AB - BACKGROUND: Teaching seizure disorders requires use of multiple formats including pictures and videos. Web technology permits combination of formats and interactive features to deliver information. PURPOSE: The purpose of this study was to determine the benefits of incorporating Web-based interactive methodology into a neurology clerkship to enhance the teaching about seizure disorders to 3rd year medical students. METHODS: A Web-based interactive program was created and administered by the University of Florida blackboard. A multiple-choice questionnaire about epileptic disorders was utilized to assess the degree of learning. Participants were randomized to a Web group or control. Twenty-two students in each group were enrolled. The control group was assigned to a traditional written material. In the Web study group 4 students failed to complete the test. RESULTS: The Web group obtained better scores on Multiple Choice Questionnaire than the control group (p = .03). CONCLUSIONS: This small study suggests that an interactive format using Web technology enhances learning about seizure disorders, perhaps by stimulation of critical thinking and promoting greater student motivation. PMID- 18444197 TI - Evaluation, grading, and use of the RIME vocabulary on internal medicine clerkships: results of a national survey and comparison to other clinical clerkships. AB - BACKGROUND: Evaluation methods within and across clerkships are rapidly evolving, including greater emphasis or frameworks for descriptive evaluation and direct observation of competence. PURPOSE: The purpose of this study is to describe current evaluation methods, use of the Reporter-Interpreter-Manager/Educator (RIME) framework, and grade assignment by internal medicine clerkship directors. METHODS: In 2005, the Clerkship Directors in Internal Medicine surveyed its 109 institutional members. Topics included evaluation methods and grade contribution, use of evaluation sessions and/or RIME, and grade assignment (criterion referenced or normative). RESULTS: Response rate was 81% (88/109). The evaluation methods were as follows: teachers' evaluations, 93% (64% of grade); National Board of Medical Examiners subject examination, 81% (25% of grade); faculty written exam, 34% (14% of grade); objective structured clinical examinations, 32% (12% of grade); direct observation, 22% (7% of grade). RIME is used by 42% of respondents. Many clerkship directors (43%) meet with teachers to discuss student performance. Criterion-referenced grading is used by 59%, and normative grading is used by 27%. Unsatisfactory grades are given for examination failures (72%), unprofessional behavior (49%), poor clinical performance (42%), and failure to meet requirements (18%). CONCLUSIONS: Internal medicine clerkship directors emphasize description and observation of students. RIME and discussions with teachers are becoming commonplace. PMID- 18444198 TI - Knowledge and use of academic portfolios among primary care departments in U.S. medical schools. AB - BACKGROUND AND PURPOSE: Portfolios are used to summarize and communicate the academic accomplishments of faculty seeking career development and promotion. METHOD: We assessed knowledge and use of the portfolio in a cross sectional survey of 435 academic chairpersons of family medicine and division directors of general internal medicine and general pediatrics. RESULTS: Of the 241 respondents (55% response rate), 69% reported knowledge of portfolios and 55% used portfolios. Satisfaction with the source of information on a faculty candidate was greater when portfolios were used (85.5% of respondents) than when they were not used (67.3% of respondents; p = .01). Increased knowledge and use of portfolios was associated with respondents working at institutions with academic fellowships/advanced education programs or who had fellowship training (ps = .01). CONCLUSION: Results suggest that leaders of primary care departments use portfolios to promote the career development of their faculty and that portfolio use is influenced by attitudes and training. PMID- 18444199 TI - Residents' perspective on the impact of the 80-hour workweek policy. AB - BACKGROUND: The 80-hour workweek was initiated in 2003 to reduce the resident workweek and subsequently improve the safety and quality of patient care. PURPOSE: The purpose is to assess the impact of the 80-hr workweek from a resident's perspective. METHOD: We surveyed residents with experience before and after the 80-hr workweek policy. The survey assessed residents' perspective on the impact of the 80-hr workweek on 4 areas: patient care/safety, training experience, resident team functioning, and personal life. RESULTS: There were 111 respondents (57% female, 65% married, average age = 32 years, 66% primary care residents). We found the 80-hr workweek had the greatest impact in personal self care and sleep hygiene. Primary care residents reported a significantly more positive impact of the 80-hr workweek on quality of the training compared to specialty residents. There was no difference between the primary care residents and specialty residents for patient care/safety, resident team functioning, and personal life. Gender, marital status, and having children did not impact how residents' evaluated the 80-hr workweek. CONCLUSION: Residents, with pre- and post-80-hr workweek experience, reported the policy change as having the greatest benefit on their self-care and personal life significantly more than any other area. PMID- 18444200 TI - Resident performance on the in-training and board examinations in obstetrics and gynecology: implications for the ACGME Outcome Project. AB - BACKGROUND: The Accreditation Council on Graduate Medical Education (ACGME) Outcomes Project has endorsed the in-training examination (ITE) as an example of a multiple-choice question examination that is a valid measure of a resident's attainment of medical knowledge. An outcome measure for performance on the ITE would be the subsequent performance on the board certification examination. However, there are few reports that attempt to correlate a resident's performance on the ITE to subsequent performance on the board certification examination. PURPOSE: The Council on Resident Education in Obstetrics and Gynecology (CREOG) has administered the ITE annually since 1970. This study tested the hypothesis that the CREOG-ITE score is a valid assessment tool to predict performance on the American Board of Obstetrics and Gynecology (ABOG) written examination. METHODS: CREOG-ITE and ABOG written board examination results were collected for 69 resident graduates between the years 1998 and 2005. Logistic regression and receiver operating characteristic analyses were used to estimate the relationship between a resident's score on the CREOG-ITE and subsequent performance on the ABOG written examination. RESULTS: Fifty-seven resident graduates passed (82.6%) and 12 graduates failed (17.4%) the ABOG written examination. The correlation between the CREOG-ITE overall score and performance on the ABOG examination was weak (correlation coefficient =.38, p =.001). Receiver operating characteristic analysis for the CREOG-ITE overall scores and the probability of passing or failing the ABOG examination revealed moderate accuracy (area under the curve = 0.77, 95% CI = 0.62-0.92) with a CREOG-ITE score of 187.5 yielding the best trade off between specificity (0.79) and sensitivity (0.75). At the cutoff value of 187.5 there was a weak positive predictive value of 43% (i.e., 43% of residents with a score less than 187.5 will fail the ABOG exam) and a strong negative predictive value of 94% (i.e., 94% of the residents with a score above 187.5 will pass the ABOG exam). Logistic regression analysis also revealed a statistically significant relationship between the CREOG-ITE overall score and performance on the ABOG written examination (p = .003). CONCLUSIONS: Similar to other specialties, resident performance on the CREOG-ITE is a weak assessment tool to predict the probability of a resident failing the ABOG written examination. Our study highlights the need, in the spirit of the ACGME Outcome Project, for residency and board specialty organizations to coordinate efforts to develop more reliable and correlative measures of a resident's medical knowledge and ability to pass the boards. PMID- 18444201 TI - Disagreement between students and preceptors regarding the value of teaching behaviors for ambulatory care settings. AB - BACKGROUND: Medical students and preceptors commonly disagree on methods of clinical instruction in ambulatory care, although the extent of the problem is not documented. PURPOSE: The purpose is to identify disagreement and concordance between students and preceptors for teaching behaviors in ambulatory care. METHODS: We surveyed students and preceptors at 4 U.S. schools. Respondents rated 58 behaviors on two scales. Disagreement was recognized when the percentage of students and preceptors who recommended a behavior and rated it important differed by over 15% (p < .01). RESULTS: Disagreement was identified for 8 behaviors (14%). Six were valued less by students, including "watch the student perform critical tasks in history taking and other communication" (59% compared with 82%). Two behaviors were valued more by students, including "delegate responsibility to the student for the wrap up discussion with the patient" (82% compared with 61%). CONCLUSIONS: Students and preceptors disagree regarding the value of a minority of teaching behaviors. Because some are potentially important, however, early negotiation regarding their use may enhance teaching effectiveness and mutual satisfaction with learning. PMID- 18444202 TI - The subinternship curriculum in internal medicine: a national survey of clerkship directors. AB - BACKGROUND: The 4th-year internal medicine subinternship (subI), with its strong emphasis on experience-based learning and increased patient responsibilities, is an important component of undergraduate medical education. Discussions have begun amongst educational leaders on the importance of standardizing curriculum and evaluation tools utilized during the subinternship. PURPOSE: The objective of this survey was to describe the current state of educational practices regarding the subI curriculum, use of Clerkship Directors in Internal Medicine (CDIM) curricular guidelines, evaluation methodologies, and subintern call frequency and duty hours. METHODS: The survey was a part of the CDIM annual survey sent to 109 institutional members in 2005. The subinternship survey included 17 questions that addressed the prevalence of formal curricula in the subinternship, use of CDIM curricular guidelines and resources, and the evaluation tools utilized for assessment of the subinternship. Two questions examined the call frequency and duty hours of the subinterns. RESULTS: Eighty-eight members responded (81%). Of the respondents, 37% have a formal curriculum and 35% used CDIM curricular guidelines for the subinternship. More than half of the respondents agreed that the curricular guide helped organize their subI rotations (53%), and 48% agreed that it enhanced the quality of subI education. A global rating summative evaluation form (56%) was the most commonly used evaluation tool in the subinternship. Objective Structured Clinical Examinations (1%) and Mini-Clinical Evaluation Exercise (mini-CEX)(2%) were much less utilized during the subinternship. The respondents expressed an interest in the development of a standardized exam (47%) and clinical assessment tools such as the mini-CEX (59%). The vast majority of IM subinterns participate in 3 to 9 calls per rotation and spend less than 80 hr in the hospital per week. CONCLUSIONS: A formal curriculum is offered in slightly more than one third of subIs. Clerkship directors expressed interest in developing standardized evaluation tools to assess subintern competencies. The majority of IM subinterns spend less than 80 hr in the hospital per week. Further studies are needed to assess barriers to incorporating a formal curriculum and develop standardized tools to assess subintern competencies. PMID- 18444203 TI - Training and assessment of CXR/basic radiology interpretation skills: results from the 2005 CDIM Survey. AB - BACKGROUND: Despite published literature demonstrating deficiencies in chest radiograph (CXR)/basic radiology interpretation skills of 4th-year medical students, studies and subsequent curricula regarding the training needed to obtain these skills are lacking. Terms such as clinical exposure and radiology teaching have been used to describe the experience for these basic interpretive skills, but best practice methods of delivery, let alone common methods, have yet to be defined. PURPOSE: The objective is to describe the current methods of teaching and assessing CXR/basic radiology interpretation skills across institutions on the 3rd-year internal medicine (IM) clerkship. METHODS: In 2005, the Clerkship Directors in Internal Medicine (CDIM), an international organization representing U.S. and Canadian medical schools, surveyed its institutional members. Twelve questions on the survey dealt with X-ray interpretation. RESULTS: Eighty-eight of 109 members (81%) responded to the survey. Overall, 81% of respondents felt that CXR interpretation is an important clinical skill for medical students. Seventy-six percent indicated that instruction in these skills occurs on the IM clerkship. The most cited methods of instruction were lectures (56%) and teaching rounds (48%). Most schools spent on average of 2 to 4 hr during the IM clerkship on formal radiology instruction. Only 33% indicated that radiology interpretation skills are assessed during the clerkship. The most common assessment methods were written examination (19%) and OSCE (19%). CONCLUSION: Substantive data regarding attainment and assessment of CXR/basic radiology interpretation skills in the undergraduate curriculum are lacking. Our study provides preliminary descriptive data regarding CXR instruction and assessment on the 3rd-year IM clerkship. PMID- 18444204 TI - An internal medicine interest group research program can improve scholarly productivity of medical students and foster mentoring relationships with internists. AB - BACKGROUND: Shortages in primary care careers such as internal medicine are projected in the future. Conducting research is an explicit requirement for graduate medical education and interest in research is growing in undergraduate medical education. PURPOSE: We hypothesized that a medical student research initiative could increase student research productivity and foster mentoring relationships with internists. METHOD: We compared the number of medical student presentations, awards, and peer-reviewed publications before and after a brief research initiative at a single institution and recorded comments from student participants; data collected before the initiative were retrospective, and data after the initiative were collected prospectively. Mann-Whitney U was used for statistical analysis. RESULTS: Twenty-seven students participated in our workshop initiative during the study period (2000-2005). Eighteen (67%) subsequently had presentations, research awards, and/or publications during the study period. Mann Whitney U testing of groups (all pre-initiative Uniformed Services University students and initiative participants) showed a statistically significant increase in regional presentations (p = .003), research awards (p = .01), and publications (p = .02) after the research initiative. Student comments not only revealed research mentoring benefits but also commented on receiving career counseling advice from mentors. CONCLUSIONS: Our study findings support the feasibility of this initiative as well as produced significant outcomes in terms of quantified research productivity and student mentoring. PMID- 18444205 TI - Development of a mission-based funding model for undergraduate medical education: incorporation of quality. AB - BACKGROUND: Increasing financial pressures, along with a desire to realign resources with institutional priorities, has resulted in the adoption of mission based funding (MBF) at many medical schools. The lack of inclusion of quality and the time and expense in developing and implementing mission based funding are major deficiencies in the models reported to date. DESCRIPTION: In academic year 2002-2003 New Jersey Medical School developed a model that included both quantity and quality in the education metric and that was departmentally based. Eighty percent of the undergraduate medical education allocation was based on the quantity of undergraduate medical education taught by the department ($7.35 million), and 20% ($1.89 million) was allocated based on the quality of the education delivered. Quality determinations were made by the educational leadership based on student evaluations and departmental compliance with educational administrative requirements. EVALUATION: Evolution of the model has included the development of a faculty oversight committee and the integration of peer evaluation in the determination of educational quality. Six departments had a documented increase in quality over time, and one department had a transient decrease in quality. CONCLUSIONS: The MBF model has been well accepted by chairs, educational leaders, and faculty and has been instrumental in enhancing the stature of education at our institution. PMID- 18444206 TI - The integrative care conference: an innovative model for teaching at the heart of communication in medicine. AB - BACKGROUND: By focusing on the biomedical aspects of a disease, physicians often dismiss the emotional effect that patients have on them and the stories that provide meaning to the patients' experience with illness. This approach often leads to strained relationships, medical errors, and dehumanized health care. DESCRIPTION: We describe the Integrative Care Conference, an interdisciplinary format for teaching enhanced communication between residents and their patients. EVALUATION: Three findings emerged: (a) The gap between what the resident knows about the patient and what is relevant to the patient's health care is wide. (b) Despite this gap, patients express great appreciation for their physician. (c) After learning about their patients' life and relationships, residents developed more humanistic approaches to their patient that reshaped treatment. CONCLUSIONS: The Integrative Care Conference provides a powerful format for teaching patient physician communication. PMID- 18444207 TI - Mid-career research training for the generalist physician: case study of a balancing act. AB - BACKGROUND: Although generalist physician faculty typically lack the skills needed to conduct research, few medical schools offer on-site faculty development programs that teach research skills. DESCRIPTION: To address this dilemma, our medical school introduced a part-time Primary Care Research Fellowship offering full-day classes once a week over 10 months. EVALUATION: We asked the 22 general internists, general pediatricians, and family physicians who participated in the program to rate their experience, and we measured their research productivity during the 3 years before and 3 years after completing the program, using a group of matched controls for comparison. Participants rated the program highly and increased their aggregate research productivity from 1 publication before completing the program to 6 publications afterward, although this increase did not reach statistical significance (p = .09). Controls exhibited substantially higher baseline productivity than fellows (10 publications vs. 1 publication, p = .03), but controls' productivity changed little between the first and second measurement periods (10 and 7 publications, respectively). CONCLUSION: Our mid career research training program enabled primary care academic faculty to gain confidence in their ability to conduct a scientific study with minimal disruption to their teaching and clinical activities. PMID- 18444208 TI - Teaching internal medicine residents to care for reproductive-age and pregnant women: an effective Web-based curriculum. AB - BACKGROUND: We sought to determine whether a Web-based curriculum could improve internal medicine residents' perceived preparedness and knowledge in the areas of preconception care, infertility evaluation, and management of medical conditions during pregnancy. Training in these areas has been previously identified as inadequate. DESCRIPTION: Three Web-based modules were developed to teach these topics. Seventy residents at one institution were invited to complete the modules and to participate in the curriculum's evaluation over 6 months. EVALUATION: Paper questionnaires assessed preparedness and comfort level among all participants. Web-based surveys that assessed pre/postknowledge and satisfaction among module completers accompanied each module. Ninety-seven percent completed paper questionnaires, and 59% completed 1 or more modules. At the end of the study period, module completers felt significantly more prepared than noncompleters, and improvement in comfort level was strongly associated with the number of modules completed. Knowledge improved significantly with module completion and curricular satisfaction was high. CONCLUSIONS: A Web-based approach to teaching these topics to internal medicine residents increased knowledge and perceived preparedness and was well received. PMID- 18444209 TI - In-house medical education: redefining tele-education. AB - BACKGROUND: Hip and tech-savvy medical students and junior doctors are likely to find lecture-based professionalism and ethics modules boring. Medical-based television dramas and films, on the other hand, are exciting and topical, and often feature real-life situations, albeit presented with artistic license. Current "hot" television series, such as House, ER, and Grey's Anatomy, feature scenarios which are thought-provoking, not only for the fascinating cases featured, but also for the ethical dilemmas and professionalism issues which present themselves. SUMMARY: We discuss the educational merits of the genre of the medical drama and propose to develop an "In-House" Medical Education Initiative, in which an episode of House is shown, and participants encouraged, at the end of the screening, to discuss the following: ethics, professionalism (communications skills, confidentiality, sensitivity, and empathy), history taking and clinical examination, diagnostic steps and mis-steps, and finally learning points (or take-home messages). CONCLUSION: Television programs, purported to "rot the mind," can actually be put to good use in the teaching of "soft skills" in medicine. PMID- 18444213 TI - Maternal blood pressure in pregnancy and stillbirth: a case-control study of third-trimester stillbirth. AB - An immense body of literature on the effects of hypertension on perinatal morbidity and mortality exists, but only a handful of studies have reported adverse outcomes associated with low maternal blood pressure during pregnancy. This study aimed to investigate if there is an increased risk of fetal loss associated with hypotension during pregnancy. A matched case-control study of stillbirth and maternal blood pressure was conducted in which maternal blood pressures for a total of 124 pregnancies culminating in stillbirth were compared with maternal blood pressures in 243 (matched) pregnancies resulting in a liveborn infant. Women whose diastolic blood pressures fell in a borderline range (60 to 70 mm Hg) were consistently at greater risk of stillbirth relative to normotensive pregnancies. Women who had three or more mean arterial pressure values < or = 83 mm Hg during the course of their pregnancy were at nearly twice the risk of stillbirth (odds ratio 1.78; 95% confidence interval [CI] 1.06 to 2.99; P = 0.03). Systolic hypotension was not significantly associated with stillbirth, but proportionately more control women were noted to have systolic hypertension (SBP > or = 130 mmHg) than cases, and the adjusted odds of stillbirth in women who were hypertensive at either their first or last antenatal visit or whose antenatal average SBP was > or = 130 mm Hg were all very close to 0.4 (95% CI 0.37 to 0.43; P = 0.02 to 0.03) relative to normotensives. We concluded that maternal hypotension, particularly borderline hypotension, may be a contributory risk factor for stillbirth. Women with hypertension in pregnancy may now be at a decreased risk of stillbirth as a result of the close care and treatment they receive. PMID- 18444214 TI - Measurement of intradiscal pressure after lumbar discectomy. AB - OBJECT: Early physiotherapeutic exercises after lumbar discectomy have been shown to be helpful for pain control and in reducing the delay until the return to work. Many strategies exclude sitting body positions during the first weeks, because raised intradiscal pressure and an increased motion range in the lower lumbar disc levels have been found in unoperated individuals when seated. To evaluate whether these results can be extrapolated to the situation of an operated patient, we examined the feasibility of an intracranial pressure sensor for measuring intradiscal pressure after lumbar discectomy. PATIENT AND METHOD: An otherwise healthy patient underwent lumbar discectomy for a right-sided lumbar disc herniation at the level L4/5. Before surgery he had agreed voluntarily to the implantation of a pressure sensor and the manufacturer had provided data on the safe use of the sensor in the disc space. Intraoperatively the sensor was positioned in the disc space from the right side. Measurements were performed by means of individual readings by three different examiners at different time points. Before removal of the sensor its correct position was demonstrated by X ray and computed tomography. RESULTS: The patient tolerated surgery very well, recovery and wound healing were un-eventful, and symptoms improved. The pressure monitoring system showed reproducible results without any signs of technical problems. The intradiscal pressure values were about ten times lower than the values known from unoperated individuals (lying: up to 130 mmHg, sitting: up to 50 mmHg, standing: up to 450 mmHg. 100 mmHg=0.013332 MPa). CONCLUSION: We present an easy to perform and technically safe technique for the measurement of intradiscal pressure after lumbar discectomy using an intracranial sensor. To assess the impact of intradiscal pressure on recovery after lumbar microdiscectomy a study with a larger cohort of patients and with long-term follow-up will be needed. PMID- 18444215 TI - Predictive value of intrathecal interleukin-6 for ventriculostomy-related Infection. AB - BACKGROUND AND STUDY AIM: Early diagnosis of ventriculostomy-related infection (VRI) is crucial for the early treatment and course of this disease. In neurosurgical patients the diagnostic criteria are equivocal, mostly because of bloodstained cerebrospinal fluid (CSF). The predictive value, sensitivity and specificity of intrathecal interleukin-6 (IL-6 (CSF)) has been proven for VRI compared with classical diagnostic CSF parameters, i.e. cell countCSF (CC (CSF)) and total protein (CSF). PATIENTS AND METHODS: We prospectively analyzed the daily clinical data and CSF samples of 75 neurosurgical patients with an external ventricular drainage (EVD), which had been inserted predominantly because of poor grade subarachnoid hemorrhage (SAH). The intrathecal interleukin-6 concentrations (IL-6 (CSF)) were correlated with the clinical course and VRI incidence, as diagnosed by the classical VRI criteria (CC (CSF), total protein (CSF), clinical symptoms). RESULTS: Based on classical criteria, bacterial meningitis occurred in 26.7% of patients. Patients with VRI manifested significantly (p<0.001) higher median values of IL-6 (CSF) (up to 2,000-fold increase) the day before (day -1) infection was diagnosed by conventional parameters. Using a cut-off value of IL-6 (CSF)>or=2,700 pg/ml [4,050 pg/ml after WHO standardization] on day -1, the relative risk for VRI was 6.09 (95% CI: 2.62-14.18%). A predictive value of IL-6 (CSF)>or=2,700 pg/ml [4,050 pg/ml] for VRI was calculated of 89% (95% CI: 79.6 98.0%), a sensitivity of 73.7% and a specificity of 91.4%. The amount of intrathecal blood was an independent risk factor for VRI occurrence, whereas the mean duration of EVD in place showed no impact on the rate of infection. CONCLUSION: Our data indicate that IL-6 (CSF) is a reliable marker for predicting VRI prior to clinically manifest meningitis, one day earlier than the common diagnostic criteria of CSF infection (CC (CSF), total protein (CSF), clinical symptoms). PMID- 18444216 TI - Cognitive decline as an important sign for an operable cause of dementia: chronic subdural haematoma. AB - BACKGROUND: Cognitive decline, slow psychomotor regression and confusion, especially in the elderly, often result in medical consultation. Frequently, these rather unspecific symptoms are interpreted as signs of beginning dementia. When mental regression is joined by tremor or motor deficits, neurodegenerative disease is commonly considered and the need for neuroimaging is underestimated. Chronic subdural haematoma (CSH) is known to be the most frequent type of intracranial bleeding, appearing mostly in the elderly after minor trauma with unspecific symptoms. The aim of this retrospective study was the identification of the leading clinical symptoms in patients with the diagnosis CSH who had been treated surgically in our Neurosurgical Department. PATIENTS AND METHOD: 356 patients with symptomatic CSH (225 male, 131 female; mean age 68.3 years), who were admitted to our Neurosurgical Department between 1992 and 2003, were included in the study. We reviewed the charts documenting preoperative clinical status, radiological signs, history of trauma, operative complications, postoperative clinical status, days of hospitalisation as well as gender and age. RESULTS: The primary surgical procedure performed in 343 patients (96.4%) was burr-hole trepanation. The leading preoperative symptoms were mnestic deficits (cognitive decline, confusion) in 192 patients (55.8%), followed by headache in 150 patients (45.5%) and motor deficit in 144 patients (41.1%). Furthermore, we found a statistically significant correlation (p<0.005) between the thickness of the left-sided haematoma and the symptoms aphasia and psychosyndrome. CONCLUSION: The leading clinical symptoms identified in our cohort were mnestic deficits, headache and motor deficit, signs that mostly appear at the beginning of demential diseases. Thus, CSH should be taken into account as an important differential diagnosis for demential and neurodegenerative diseases and neuroimaging should be demanded. Once a CSH is detected this way, the patient should be transferred to a neurosurgical department where an easy standard procedure may potentially lead to early recovery. PMID- 18444217 TI - Electrode implantation for deep brain stimulation in dystonia: a fast spin-echo inversion-recovery sequence technique for direct stereotactic targeting of the GPI. AB - OBJECTIVE: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment for medically refractory primary dystonia. We present our technique for direct preoperative visualization of the target using a fast spin echo inversion-recovery (FSE-IR) sequence. METHODS: Twenty-three consecutive patients (mean age 41 years, range 9-68 years, male to female ratio 11:12) with severe dystonia were operated using a combination of FSE-IR imaging for direct visualization of the globus pallidus internus with stereotactic, gadolinium enhanced T1-MPRage images. The complete procedure, including stereotactic MRI, was performed under general anesthesia with propofol and remifentanyl. We used multichannel microdrive systems (Medtronic; Alpha-Omega) to introduce up to five parallel microelectrodes for microelectrode recordings (MER) and test stimulation with the central trajectory directed at the anatomically predefined target. The initial standard coordinates in relation to the mid-commissural point (mid-AC-PC) were as follows: lateral 21 mm, anterior 3 mm, and inferior 2 mm, which were then adapted to the individual case based on direct visualization of the target area and further refined by the intraoperative neurophysiology. RESULTS: In ten patients (43%) atlas-based standard coordinates were modified based on the direct visualization of the GPi in the FSE-IR images (bilaterally in seven patients, unilaterally in three). The modified targets ranged from 18.5 to 23.5 mm (mean 20.76 mm) laterally, 1-7 mm (mean 2.75 mm) anteriorly and 1-2 mm (mean 1.95 mm) inferiorly to the mid-AC-PC. We implanted the permanent electrode based on the results of MER and intraoperative stimulation performed to determine the threshold for pyramidal tract responses on the central trajectory in 67%, medially in 16%, anteriorly in 11%, laterally in 4%, dorsally in 2%. The procedure resulted in excellent clinical benefits (average reduction of the Burke Fahn-Marsden Dystonia Rating Score (BFMDRS) or the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) were respectively 65.9%, range 20.9-91.4%) within the first year after surgery. Safety was demonstrated by the absence of intracranial bleeding or other surgical complications causing neurological morbidity. CONCLUSION: Inversion recovery sequences are an excellent tool for direct visualization of the GPi. These images can be fused to stereotactic MRI or CCT and may help to improve anatomical targeting of the GPi for the implantation of DBS electrodes. PMID- 18444218 TI - Failure of deep brain stimulation of the posterior inferior hypothalamus in chronic cluster headache - report of two cases and review of the literature. AB - OBJECTIVE: Deep brain stimulation (DBS) has become a standard procedure for movement disorders such as Parkinson's disease, essential tremor or dystonia. Recently, deep brain stimulation of the posterior hypothalamus has been shown to be effective in the treatment of drug-resistant chronic cluster headache. METHODS: DBS of the posterior inferior hypothalamus was performed on two patients with chronic cluster headaches, one 55-year-old man with medically intractable chronic cluster headache since 1996, and one 31-year-old woman with a chronic form since 2002. Both patients showed continuous worsening headaches in the last years despite high dose medical treatment. The patients fulfilled the published criteria for DBS in chronic cluster headaches. Electrodes were implanted stereotactically in the ipsilateral posterior hypothalamus according to the published coordinates (2 mm lateral, 3 mm posterior, 5 mm inferior) referenced to the mid-AC-PC line. RESULTS: The intra- and postoperative course was uneventful and postoperative MRI control documented regular position of the DBS electrodes. The current stimulation parameters were at 12 months postoperatively 0 neg., G pos.; 5.5 V; 60 micros; 180 Hz (Case 1) and 0 neg., G pos.; 3.0 V; 60 micros; 185 Hz, at 3 months postoperatively (Case 2). Surgery- or stimulation-related side effects were not observed. Both patients showed initial pain reduction in the first days whereas 12 respectively 3 month follow-up did not show a significant reduction in attack frequency or intensity. CONCLUSION: Deep brain stimulation of the posterior inferior hypothalamus is an experimental procedure and should be restricted to selected therapy-refractory patients and should be performed in centers experienced in patient selection and performance of DBS as well as postoperative pain treatment. A prospective multi-centre study is necessary to evaluate its effectiveness. PMID- 18444219 TI - A new scoring system for malignant astrocytomas. AB - BACKGROUND: Currently there are a few scoring systems for malignant astrocytoma, but they are not widely accepted. The aim of this study was to create a scoring system for supratentorial malignant astrocytoma, which could be used in both developed and developing societies. METHODS: This study was performed in 128 patients who had supratentorial malignant astrocytoma (grade III or IV). They were operated, and after the operation patients were irradiated with 50-60 Gy. FINDINGS: The mean age was 55.1 years. The mean Karnofsky performance status (KPS) was 51. The tumour removal >90% was achieved in 57.8%. A biopsy was never exclusively performed. The mean survival was 8.2 months and 12-month survival was 25%. Thirteen out of 35 data that we tested had a prognostic value for survival time. By using the most appropriate four parameters (age, KPS, initial seizure and histopathological grade) we created a scoring system - MAS (Malignant Astrocytoma Score). The scores range from 0-16. The area under the ROC (Receiver Operating Characteristic) curve showed that the AUC for the prediction of 6-, 12- and 18-month survival was 0.729, 0.755, and 0.927. We compared MAS with two of the most commonly used scoring systems. The AUC for the same prediction, using the MRC (Medical Research Council) was 0.673, 0.637, and 0.888. For the RTOG (Radiation Therapy Oncology Group) score the AUC was 0.672, 0.700, and 0.854. CONCLUSIONS: We are of the opinion that MAS represents a useful scoring system to determine the severity of the illness and make a prognosis for both individuals and groups of patients with malignant supratentorial astrocytoma. MAS is more accurate than predictions made by other systems currently in use; it includes prognostic factors that are widely accepted; it can be done at the patient's bedside and in clinics in developing societies. PMID- 18444220 TI - Giant schwannoma of the cauda equina: case report and review of the literature. AB - Schwannomas arise from the neoplastic transformation of nerve sheath cells and are considered benign tumors. We report here on a 43-year-old patient seen for radiculopathic pain and loss of sphincter control. Magnetic resonance imaging of the spine revealed a giant intraspinal mass extending from L1 to L5. The patient underwent laminectomy for excision of the solitary mass and histological findings were consistent with schwannoma. Giant schwannoma of the cauda equina is a rare tumor, with variable manifestations. PMID- 18444221 TI - Osteoid osteoma of a cervical vertebral body. AB - We report a very rare case of 5-year-old boy with osteoid osteoma of the cervical vertebral body. The patient presented with a 6-month history of neck pain with radiation into the shoulder and arm on the left side, which was relieved by ibuprofen. Neurological examination and plain radiographs of the cervical spine were normal. CT scan and bone scintigraphy, rather than MRI suggested the pathological diagnosis, which was confirmed on histological examination. The patient underwent excision of the lesion via an anterior approach with complete resolution of the pain postoperatively. PMID- 18444222 TI - Cervical spondylolisthesis C6-C7 in a young wrestler: case report. AB - We present both the clinical and radiographic data of a 15-year-old boy, suffering from a lytic spondylolisthesis C6-C7 and treated by circumferential fusion. PMID- 18444223 TI - Primary cerebral rhabdomyosarcoma presenting as haemorrhagic stroke. AB - Intracerebral haemorrhage (ICH) occurs mostly in the context of arterial hypertension, with typical localisations. Tumour-associated bleeding is the cause of 6-10% of ICHs, mostly from metastases. We present the case of a 40-year-old female admitted originally for neck pain of sudden onset, accompanied by nausea and marked right arm paresis. A CT-scan revealed left fronto-central cortico subcortical haemorrhage. Cerebral angiography was normal. Two months after the initial event the residual paresis worsened and the patient developed neuropsychological deficits. A CT-scan showed oedema around the original bleeding site, on MRI a solid lesion with a diameter of 5 cm could be seen, with some cystic alterations and contact to the meninges. The tumour was surgically removed, and removal at the time was considered complete. Histological analysis proved it to be an embryonal rhabdomyosarcoma. The patient's neurological deficits gradually improved. Almost three months after the operation she complained of intense left-sided headache. On CT a hyperdense left fronto-central lesion with positive enhancement could be seen; MRI confirmed a relapse tumour and showed bleeding in the rostral portion of the tumour as well as oedema. The patient started radiation therapy with a total dose of 60 Gy. Whole body image studies at the time failed to reveal any other neoplastic lesions. Two months later a CT-scan showed continued tumour growth. We present this case as a rare aetiology of intracerebral haemorrhage, more frequently associated with arterial hypertension or vascular pathology, as well as being an unusual manifestation of embryonal rhabdomyosarcoma, rarely found in the brain. The case also serves to illustrate the importance of a thorough diagnosis including MRI imaging in patients with so-called atypical ICH. PMID- 18444224 TI - Retrospective detection of transaldolase deficiency in amniotic fluid: implications for prenatal diagnosis. PMID- 18444225 TI - Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations. AB - OBJECTIVE: Modern in vitro fertilization practices involve transfer of embryos as blastocysts, when anabolic metabolism is well established and pregnancy rates can be maintained while transferring embryos singly to avoid multiple pregnancies. Embryo biopsy for preimplantation genetic diagnosis (PGD), however, is generally performed on day 3, when the embryo comprises just 6 to 8 cells, one or two of which are removed for testing. Implantation rates and clinical pregnancy rates have remained relatively low and a harmful effect from losing one or more cells from such early embryos has not been excluded. METHODS: We performed a sequential study involving 399 egg retrievals and 1879 embryo biopsies for patients undergoing PGD to avoid a serious monogenic disease or an unbalanced chromosomal translocation. We compared implantation and viable pregnancy rates after biopsies taken on day 3 (cleavage-stage biopsy) with biopsies delayed until day 5 or 6, when the embryo is a blastocyst and 5 or more cells can be sampled from the trophectoderm while the inner cell mass, from which the fetus develops, remains intact. All embryos were transferred as blastocysts. RESULTS: Despite fewer blastocysts than cleavage embryos biopsied and tested (3.6 compared to 6.6), implantation rates per embryo transferred were 43.4% if biopsied at the blastocyst stage and 25.6% if biopsied at the cleavage stage (P < 0.01), with ongoing or live-birth pregnancy rates per egg retrieval of 34.2% (average transfer number 1.1) for blastocyst biopsies and 25.5% (transfer number 1.6) for cleavage stage biopsies (P < 0.05, 1-tailed). The multiple pregnancy rate for monogenic disease exclusion fell from 16.7% to 2% (P = 0.04, 1-tailed). CONCLUSIONS: For exclusion of genetic disease, day 5-6 blastocyst-stage biopsies are more likely to be followed by implantation and singleton births than is the case after PGD performed on day 3. PMID- 18444226 TI - Correlation between ultrasound and pathological examination in a prenatal diagnosis of Cri du Chat syndrome associated with partial trisomy 17q. PMID- 18444227 TI - Surgery and parental separation as potential risk factors for abnormal eating attitudes-longitudinal study. AB - Due to the susceptibility of eating disorders (ED) to stressful life events, we wanted to examine longitudinally whether two childhood adversities: (1) surgery and (2) parental separation, will affect abnormal eating attitudes in adolescents. Consecutively for 4 years, the eating attitude test (EAT-26) and the eating disorder inventory-2 (EDI-2) questionnaires were administered to students from grades 7th through 10th and 8th through 11th. Multilevel analysis revealed that parental separation and oral or cosmetic dermatologic surgeries were significantly correlated with EAT-26 and EDI-2 scores throughout the 4 years of the study. Post-hoc interpretation suggests a connection between (A) chirurgic intervention in the oral cavity and problematic eating attitudes, and (B) cosmetic dermatologic surgery and greater awareness to body appearance-a feature which might characterize adolescents who are prone to develop ED. PMID- 18444228 TI - The development of the childhood retrospective perfectionism questionnaire (CHIRP) in an eating disorder sample. AB - This investigation explored the prevalence and predictive value of childhood obsessive-compulsive personality traits (OCPTs) in the development of eating disorders (EDs) using a novel retrospective questionnaire. To reduce bias associated with retrospective self-report data, an identical informant version of the questionnaire was also utilised. Substantial test-retest and inter-rater reliabilities were found for the questionnaire, as well as concordant validity with the semi-structured interview from which it was derived. Participants with an ED (n = 246) endorsed more childhood behaviours reflecting OCPTs than the control group (n = 89). This was mirrored in the informant report data (n = 93). The prevalence rate for each OCPT in childhood was significantly higher in the total ED sample compared to the control group. Both proband and informant reports of childhood traits predict the later development of an ED according to a strong dose-response relationship. The potential utility of this measure in future retrospective and prospective research studies is highlighted. PMID- 18444229 TI - A joint back calculation model for the imputation of the date of HIV infection in a prevalent cohort. AB - In studies of the natural history of HIV-1 infection, the time scale of primary interest is the time since infection. Unfortunately, this time is very often unknown for HIV infection and using the follow-up time instead of the time since infection is likely to provide biased results because of onset confounding. Laboratory markers such as the CD4 T-cell count carry important information concerning disease progression and can be used to predict the unknown date of infection. Previous work on this topic has made use of only one CD4 measurement or based the imputation on incident patients only. However, because of considerable intrinsic variability in CD4 levels and because incident cases are different from prevalent cases, back calculation based on only one CD4 determination per person or on characteristics of the incident sub-cohort may provide unreliable results. Therefore, we propose a methodology based on the repeated individual CD4 T-cells marker measurements that use both incident and prevalent cases to impute the unknown date of infection. Our approach uses joint modelling of the time since infection, the CD4 time path and the drop-out process. This methodology has been applied to estimate the CD4 slope and impute the unknown date of infection in HIV patients from the Swiss HIV Cohort Study. A procedure based on the comparison of different slope estimates is proposed to assess the goodness of fit of the imputation. Results of simulation studies indicated that the imputation procedure worked well, despite the intrinsic high volatility of the CD4 marker. PMID- 18444230 TI - Testing whether genetic variation explains correlation of quantitative measures of gene expression, and application to genetic network analysis. AB - Genetic networks for gene expression data are often built by graphical models, which in turn are built from pair-wise correlations of gene expression levels. A key feature of building graphical models is the evaluation of conditional independence of two traits, given other traits. When conditional independence can be assumed, the traits that are conditioned on are considered to 'explain' the correlation of a pair of traits, allowing efficient building and interpretation of a network. Overlaying genetic polymorphisms, such as single nucleotide polymorphisms (SNPs), on quantitative measures of gene expression provides a much richer set of data to build a genetic network, because it is possible to evaluate whether sets of SNPs 'explain' the correlation of gene expression levels. However, there is strong evidence that gene expression levels are controlled by multiple interacting genes, suggesting that it will be difficult to reduce the partial correlation completely to zero. Ignoring the fact that some sets of SNPs can explain at least part of the correlation between gene expression levels, if not all, might result in missing important clues on the genetic control of gene expression. To enrich the assessment of the causes of correlation between gene expression levels, we develop methods to evaluate whether a set of covariates (e.g. SNPs, or even a set of quantitative expression transcripts) explains at least some of the correlation of gene expression levels. These methods can be used to assist the interpretation of regulation of gene expression and the construction of gene regulatory networks. PMID- 18444231 TI - Colchicinoids from Colchicum crocifolium Boiss.: a case study in dereplication strategies for (-)-colchicine and related analogues using LC-MS and LC-PDA techniques. AB - As a part of a project designed to investigate Colchicum species in Jordan, the chemical constituents of Colchicum crocifolium Boiss. (Colchicaceae) were investigated using LC-MS and LC-UV/Vis PDA. A decision tree for working with colchicinods has been developed by incorporating data from LC-UV/PDA and LC-MS. This dereplication strategy draws upon the UV/PDA spectra to classify compounds into one of four structural groups and combines this with retention time and mass spectra/molecular weight to identify the compounds. This strategy was applied on a small amount of extract (2 mg) of Colchicum crocifolium to dereplicate 10 known compounds from four different structural groups, namely (-)-demecolcine, 2 demethyl-(-)-colchicine or 3-demethyl-(-)-colchicine, N-deacetyl-(-)-colchicine, (-)-colchiciline, (-)-colchicine, beta-lumidemecolcine, 2-demethyl-beta lumicolchicine or 3-demethyl-beta-lumicolchicine, N,N-dimethyl-N-deacetyl-beta lumicornigerine, (-)-isoandrocymbine and (-)-autumnaline. Furthermore, a new compound was identi?ed as N,N-dimethyl-N-deacetyl-(-)-cornigerine. Three compounds, which had molecular ions at m/z 325, 340 and 374, could not be dereplicated into any obvious structural classes that have been isolated in our laboratories previously or reported in the literature. PMID- 18444239 TI - Self-assembly of [B-SbW9O33]9- subunit with transition metal ions (Mn2+, Cu2+, Co2+) in aqueous solution: syntheses, structures and magnetic properties of sandwich type polyoxometalates with Subvalent Sb(III) heteroatom. AB - Rational self-assembly of Sb(2)O(3) and Na(2)WO(4), or (NH(4))(18)[NaSb(9)W(21)O(86)] with transition-metal ions (Mn(2+), Cu(2+), Co(2+)), in aqueous solution under controlled conditions yield a series of sandwich type complexes, namely, Na(2)H(2)[Mn(2.5)W(1.5)(H(2)O)(8)(B-beta SbW(9)O(33))(2)]32 H(2)O (1), Na(4)H(7)[Na(3)(H(2)O)(6)Mn(3)(mu-OAc)(2)(B-alpha SbW(9)O(33))(2)]20 H(2)O (OAc=acetate anion) (2), NaH(8)[Na(2)Cu(4)Cl(B-alpha SbW(9)O(33))(2)]21 H(2)O (3), Na(8)K[Na(2)K(H(2)O)(2){Co(H(2)O)}(3)(B-alpha SbW(9)O(33))(2)] 10 H(2)O (4), and Na(5)H[{Co(H(2)O)(2)}(3)W(H(2)O)(2)(B-beta SbW(9)O(33))(2)]11.5 H(2)O (5). These structures are determined by using the X ray diffraction technique and further characterized by obtaining IR spectra and performing elemental analysis. Structure analysis reveals that polyoxoanions in 1 and 5 comprise of two [B-beta-SbW(9)O(33)](9-) building units, whereas 2, 3, and 4 consist of two isomerous [B-alpha-SbW(9)O(33)](9-) building blocks, which are all linked by different transition-metal ions (Mn(2+), Cu(2+), or Co(2+)) with different quantitative nuclearity. It should be noted that compound 2 represents the first one-dimensional sinusoidal chain based on sandwich like tungstoantimonate building blocks through the carboxylate-bridging ligands. Additionally, 3 is constructed from sandwiched anions [Na(2)Cu(4)Cl(B-alpha SbW(9)O(33))(2)](9-) linked to each other to form an infinitely extended 2D network, whereas 5 shows an interesting 3D framework built up from offset sandwich type polyoxoanion [{Co(H(2)O)(2)}(3)W(H(2)O)(2)(B-beta SbW(9)O(33))(2)](6-) linked by Co(2+) and Na(+) ions. EPR studies performed at 110 K and room temperature reveal that the metal cations (Mn(2+), Cu(2+), Co(2+)) reside in a square-pyramidal geometry in 2, 3, and 4. The magnetic behavior of 1 4 suggests the presence of weak antiferromagnetic coupling interactions between magnetic metal centers with the exchange integral J=-0.552 cm(-1) in 2. PMID- 18444240 TI - Synthesis of novel monodentate phosphoramidites and their application in iridium catalyzed asymmetric hydrogenations. AB - New monodentate H(8)-binaphthol based phosphoramidites 6 b-i have been prepared. Starting from (S)-3,3'-dibromo-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl-2,2' diol 3, a general protocol for the synthesis of ligands 6 is presented. A small ligand library bearing aryl substituents in the 3,3'-position of the binaphthol core was synthesized and successfully tested in the iridium-catalyzed asymmetric hydrogenation of 2-amidocinnamates to obtain different alpha-amino acid derivatives in up to 99 % ee. PMID- 18444242 TI - Wild-type APC regulates caveolin-1 expression in human colon adenocarcinoma cell lines via FOXO1a and C-myc. AB - Genetic evidence suggests that caveolin-1, an essential component of membrane caveolae, acts as a tumor promoter in some, and a tumor suppressor in other cancers. The role of caveolin-1 in colon carcinogenesis is controversial. We report here, for the first time, that caveolin-1 is transcriptionally induced in colon cancer cells in response to conditional expression of a full length adenomatous polyposis coli (APC) gene. This induction of caveolin-1 by APC is mediated by both FOXO1a, a member of the Forkhead family of transcription factor, and c-myc. The FOXO1a protein, which is increased by wild-type APC expression, induces caveolin-1 promoter-reporter activity and binds directly to a FKHR consensus binding sequence in the caveolin-1 promoter. The c-myc protein, which is reduced in the presence of wild-type APC, acts to repress caveolin-1 expression by acting at non-E-box containing elements in the caveolin-1 promoter. These data predict that caveolin-1 protein expression would be decreased early in colonic carcinogenesis, which is associated with loss of wild-type APC. Our results would be consistent with the interpretation that caveolin-1 may have tumor suppressing functions during early stages of colon carcinogenesis. PMID- 18444243 TI - Disturbance of circadian gene expression in hepatocellular carcinoma. AB - Circadian rhythm plays an important role in the regulation of digestive system. The human circadian rhythm is controlled by at least nine circadian genes. The aims of this study are to understand the expression of the circadian genes between hepatocellular carcinoma tissues and nontumor tissues, and to explore the possible mechanism(s) contributing to the difference. We analyzed differential expression of the 9 circadian genes in 46 hepatocellular carcinoma and paired noncancerous tissues by real-time quantitative RT-PCR and immunohistochemical detection. We also tested the possible regulatory mechanism(s) by direct sequencing and methylation PCR analysis. Our results showed that decreased expression levels of PER1, PER2, PER3, CRY2, and TIM in hepatocellular carcinomas were observed. Decreased-expression of these genes was not caused by genetic mutations, but by several factors, such as promoter methylation, overexpression of EZH2 or other factors. The down expression of more circadian genes may result in disturbance of cell cycle, and it is correlated with the tumor size. Downregulation of circadian genes results in disturbance of circadian rhythm in hepatocellular carcinoma which may disrupt the control of the central pacemaker and benefit selective survival of cancerous cells and promote carcinogenesis. PMID- 18444244 TI - Carbonic anhydrase III promotes transformation and invasion capability in hepatoma cells through FAK signaling pathway. AB - Carbonic anhydrase III (CAIII) is distinguished from the other members of the CA family by low carbon dioxide hydratase activity, resistance to the CA inhibitor acetazolamide, and a predominant expression in the liver of males. In this report the effects of CAIII expression on liver cancer cells invasiveness were explored. Overexpression of CAIII in the HCC cell line SK-Hep1 resulted in increased anchorage-independent growth and invasiveness. And siRNA-mediated silencing of CAIII expression decreased the invasive ability of SK-Hep1 cells. Furthermore, CAIII transfectants showed elevated focal adhesion kinase (FAK) and Src activity. Silencing of FAK expression in CAIII transfectants led to suppression of HCC cell invasion. More importantly, the CAIII transfectants acidified the culture medium at an accelerated speed than the control cells did. Taken together, these data suggest that the CAIII-promoted invasive ability of HCC cells may probably be mediated through, at least in part, the FAK signaling pathway via intracellular and/or extracellular acidification. PMID- 18444245 TI - Effects of oral administration of Stephania tetrandra S. Moore on neovascularization of retinal and choroidal capillaries of diabetes in rats. AB - In rats, an injection of streptozotocin (STZ) elevated blood levels of glucose 4 weeks later (STZ-induced diabetes) and an over-production of microvessels of retinal and choroidal capillaries of eyes developed. A previous study has shown that administration of Stephania tetrandra S. Moore (STSM) in culture prevented the over-production of microvessels of those capillaries of STZ-induced diabetes in vitro. Therefore, the study investigated whether or not orally administered STSM could inhibit over-production of microvessels of those capillaries of STZ injected rats in vivo. When STSM was given at the same time as the STZ injection and continued daily for 7 weeks, STSM prevented the elevation of blood glucose level and over-production of microvessels of those capillaries. When STSM was given after elevation of blood glucose level of glucose (4 weeks after STZ injection) and continued daily for 4 weeks, STSM lowered the elevated blood glucose level but had no effect on the over-production of microvessels of those capillaries. It was inferred that deposition of N(epsilon)(carboxymethyl) lysine in retinal and choroidal tissues, which is induced by STZ-induced diabetes may deteriorate the blood-retinal barrier and the blood-choroidal barrier. One might, therefore, speculate that advanced STZ-induced diabetes may deteriorate the blood retinal barrier and blood-choroidal barrier. Therefore, STSM may not reach the retinal and choroidal tissues in the posterior ocular region in vivo. PMID- 18444246 TI - Tissue culture of some lichens and screening of their antioxidant, antityrosinase and antibacterial properties. B. C. Behera, Neeraj Verma, Anjali Sonone and Urmila Makhija. Phytother. Res. 21, 1159-1170 (2007). PMID- 18444247 TI - Antihyperglycemic and hypolipidemic effects of Costus speciosus in alloxan induced diabetic rats. AB - Hyperglycemia, abnormal lipid and antioxidant profiles are the most usual complications in diabetes mellitus. In the present study, the antihyperglycemic, antihyperlipemic and antioxidant potency of an ethanol extract of Costus speciosus root was investigated in alloxan-induced diabetic male (Charles Foster) rats. Four groups of alloxan diabetic rats (n = 6) were administered orally with different doses of Costus speciosus root extract (150, 300 and 450 mg/kg BW) and a standard drug, glibenclamide (600 microg/kg BW), for 4 weeks. Two groups of rats (n = 6) served as normal and diabetic controls. While the diabetic controls showed significant abnormal carbohydrate, lipid and antioxidant profiles, administration of 150 mg/kg BW dose neither improved glucose nor lipid metabolism and antioxidant levels. Administration of 300 and 450 mg/kg BW doses, however, resulted in a reversal of diabetes and its complications. Both doses significantly brought down blood glucose concentration (26.76%, 34.68%), increased glycogenesis and decreased glyconeogenesis bringing the glucose metabolism toward normalcy. These doses also reversed the hyperlipidemia by reducing plasma total lipid (12.87%, 178.24%), cholesterol (21.92%, 30.77%) and triglyceride (25.32%, 33.99%) and improved hepatic antioxidant enzyme activities. The high dose (450 mg/kg BW) was found to have more potential antioxidant activities compared with glibenclamide. It is concluded that Costus speciosus root extract possesses anti-hyperglycemic, antihyperlipemic and antioxidative effects, which may prove to be of clinical importance in the management of diabetes and its complications. PMID- 18444248 TI - Antiproliferative effect of Scutellaria barbata D. Don. on cultured human uterine leiomyoma cells by down-regulation of the expression of Bcl-2 protein. AB - Scutellaria barbata D. Don (Lamiaceae; SB) inhibited the growth of leiomyomal cells (LM). A time-dependent antiproliferative effect was noted when 10(-5) m buserelin, gonadotrophin-releasing hormone (GnRH) agonist or 20-40 microg/mL SB was added. The inhibition of cell growth decreased with the addition of the PKC activator (12-O-tetradecanoylphorbor-13-acetate; TPA) much as it did with the addition of SB, and the decreases in the viable cells caused by the addition of SB were reversed completely by pretreatment with a protein kinase C (PKC) inhibitor (calphostin C). The findings suggest that SB inhibits cell proliferation in cultured human uterine leiomyoma cells accompanied by PKC activation. Next, the study investigated the effect of SB on fetal development for toxicity. Pregnant Sprague-Dawley rats, from gestation day 6-15, were administered 20 g/L or 50 g/L SB in the drinking water and then killed on day 20. No maternal toxicity was observed, however, embryonic loss in the treatment groups was double that of the controls (p < 0.05). No gross morphologic malformations were seen in the treated fetuses. Fetuses exposed to SB were found to be significantly heavier than the controls, an effect that was greater in female fetuses and was not correlated with increased placental size. The results suggest that the SB had no toxicity and that in utero exposure to SB resulted in increased early embryo loss with increased growth in surviving fetuses. On the other hand, Western blot analyses revealed that Bcl-2 protein of a 26 kDa was abundant in leiomyomal cells, but not in normal myometrial cells. The addition of progesterone (100 ng/mL) resulted in a striking increase in Bcl-2 protein expression in the cultured leiomyoma cells. However, the addition of SB (20 microg/mL) resulted in a significant reduction in Bcl-2 protein expression in the cells. The results indicated that human uterine leiomyomal cells express Bcl-2 protein and progesterone enhances its expression, however, SB reduces the expression of Bcl-2 protein in human uterine leiomyoma cells. PMID- 18444249 TI - Optimized multi-stage designs controlling the false discovery or the family-wise error rate. AB - When a large number of hypotheses are investigated, we propose multi-stage designs where in each interim analysis promising hypotheses are screened, which are investigated in further stages. Given a fixed overall number of observations, this allows one to spend more observations for promising hypotheses than with single-stage designs, where the observations are equally distributed among all considered hypotheses. We propose multi-stage procedures controlling either the family-wise error rate (FWER) or the false discovery rate (FDR) and derive asymptotically optimal stopping boundaries and sample size allocations (across stages) to maximize the power of the procedure. Optimized two-stage designs lead to a considerable increase in power compared with the classical single-stage design. Going from two to three stages additionally leads to a distinctive increase in power. Adding a fourth stage leads to a further improvement, which is, however, less pronounced. Surprisingly, we found only small differences in power between optimized integrated designs, where the data of all stages are used in the final test statistics, and optimized pilot designs where only the data from the final stage are used for testing. However, the integrated design controlling the FDR appeared to be more robust against misspecifications in the planning phase. Additionally, we found that with increasing number of stages the drop in power when controlling the FWER instead of the FDR becomes negligible. Our investigations show that the crucial point is not the choice of the error rate or the type of design, but the sequential nature of the trial where non promising hypotheses are dropped in the early phases of the experiment. PMID- 18444251 TI - Overexpression of cyclooxygenase-2 (COX-2) in the mouse urinary bladder induces the expression of immune- and cell proliferation-related genes. AB - The mechanisms whereby cyclooxygenase-2 (COX-2) overexpression may contribute to bladder carcinogenesis remain unknown. We recently developed a transgenic mouse model overexpressing COX-2 under the control of a bovine keratin 5 (BK5) promoter causing a high incidence of transitional cell hyperplasia (TCH) in the bladder with a proportion of lesions progressing to invasive carcinoma. Microarray gene analysis was employed to determine the effects of COX-2 overexpression on gene expression profiles in the urinary bladder. Statistical analysis revealed that 70 genes were upregulated and 60 were downregulated by twofold or more in bladders from transgenic compared to wild-type mice. Expression Analysis Systematic Explorer (EASE) analysis revealed that genes associated with Immune/Stress Response and Cell Cycle/Proliferation biological processes were overexpressed in the transgenic mice. Relevant downregulated genes included three transforming growth factor (TGF)-beta related genes, Tgfb2, Tgfb3, and Tgfbi. The growth factor epiregulin was the most highly induced gene among those validated by qRT PCR in TCH of BK5.COX-2 mouse bladders in parallel with increased staining for Ki67. Prostaglandin E(2) (PGE(2)) directly induced the expression of epiregulin mRNA in bladders from wild-type FVB mice ex vivo. We further determined that recombinant epiregulin increased both cell proliferation and Erk phosphorylation in UMUC-3 bladder cancer cells. These results indicate that the response of the mouse urinary bladder to elevated COX-2 expression includes enhanced inflammatory response and induction of cell proliferation. The growth factor epiregulin may play a role in bladder carcinogenesis and may serve as a novel target for the prevention and treatment of bladder cancer. PMID- 18444250 TI - Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells. AB - Development of chemoresistance in androgen-refractory prostate cancer cells is partly due to constitutive activation of Rel/NF-kappaB transcription factors that regulate several cell survival and anti-apoptotic genes. In this study we examined whether betulinic acid (BetA), a pentacyclic triterpene from the bark of white birch, is effective in inhibiting NF-kappaB expression in androgen refractory human prostate cancer cells exhibiting high constitutive NF-kappaB expression. Treatment of PC-3 cells with BetA inhibited DNA binding and reduced nuclear levels of the NF-kappaB/p65. BetA-mediated NF-kappaB inhibition involved decreased IKK activity and phosphorylation of IkappaBalpha at serine 32/36 followed by its degradation. Reporter assays revealed that NF-kappaB inhibition by BetA is transcriptionally active. These effects were found to correlate with a shift in Bax/Bcl-2 ratio and cleavage of poly(ADP)ribose polymerase more towards apoptosis. BetA also inhibited TNFalpha-induced activation of NF-kappaB via the IkappaBalpha pathway, thereby sensitizing the cells to TNFalpha-induced apoptosis. Our studies demonstrate that BetA effectively inhibits constitutive NF kappaB activation and supports the rationale for targeting NF-kappaB through combination protocols with BetA in androgen-refractory prostate cancer. PMID- 18444253 TI - Additional functional variation at the SLC6A4 gene. PMID- 18444254 TI - Do Ramadan fasting restrictions alter eating behaviours? AB - During Ramadan month, Muslims should refrain from drinking, eating and smoking from dawn to sunset. Ramadan fasting can be considered as a kind of dietary restriction. Eating restriction is a risk factor for later development of eating disorders. The purpose of this study is to evaluate whether Ramadan fasting changes the eating behaviours of young people, especially girls who are known as the most vulnerable group for eating disorders. Our sample consisted of 79 healthy volunteers from a high school (63 females; mean age = 16.29; 16 males; mean age = 16.31) who fasted during the Ramadan month. No statistically significant differences were found between the scores of EAT (Eating Attitude Test) and BITE (Bulimic Investigatory Test, Edinburgh) which were administered within the weeks before and after Ramadan. According to our results Ramadan fasting restrictions do not seem to change the eating behaviours of young girls and boys. PMID- 18444252 TI - Neurotransmission and bipolar disorder: a systematic family-based association study. AB - Neurotransmission pathways/systems have been proposed to be involved in the pathophysiology and treatment of bipolar disorder for over 40 years. In order to test the hypothesis that common variants of genes in one or more of five neurotransmission systems confer risk for bipolar disorder, we analyzed 1,005 tag single nucleotide polymorphisms in 90 genes from dopaminergic, serotonergic, noradrenergic, GABAergic, and glutamatergic neurotransmitter systems in 101 trios and 203 quads from Caucasian bipolar families. Our sample has 80% power to detect ORs >or= 1.82 and >or=1.57 for minor allele frequencies of 0.1 and 0.5, respectively. Nominally significant allelic and haplotypic associations were found for genes from each neurotransmission system, with several reaching gene wide significance (allelic: GRIA1, GRIN2D, and QDPR; haplotypic: GRIN2C, QDPR, and SLC6A3). However, none of these associations survived correction for multiple testing in an individual system, or in all systems considered together. Significant single nucleotide polymorphism associations were not found with sub phenotypes (alcoholism, psychosis, substance abuse, and suicide attempts) or significant gene-gene interactions. These results suggest that, within the detectable odds ratios of this study, common variants of the selected genes in the five neurotransmission systems do not play major roles in influencing the risk for bipolar disorder or comorbid sub-phenotypes. PMID- 18444255 TI - Bipolar disorder in the Bulgarian Gypsies: genetic heterogeneity in a young founder population. AB - We report the results of follow-up analyses of 12 genomic regions showing evidence of linkage in a genome-wide scan (GWS) of Gypsy families with bipolar affective disorder (BPAD). The Gypsies are a young founder population comprising multiple genetically differentiated sub-isolates with strong founder effect and limited genetic diversity. The BPAD families belong to a single sub-isolate and are connected by numerous inter-marriages, resulting in a super-pedigree with 181 members. We aimed to re-assess the positive GWS findings and search for evidence of a founder susceptibility allele after the addition of newly recruited subjects, some changes in diagnostic assignment, and the use of denser genetic maps. Linkage analysis was conducted with SimWalk2, accommodating the full complexity of pedigree structure and using a conservative narrow phenotype definition (BPAD only). Six regions were rejected, while 1p36, 13q31, 17p11, 17q21, 6q24, and 4q31 produced nominally significant results in both the individual families and the super-pedigree. Haplotypes were reconstructed and joint tests for linkage and association were done for the most promising regions. No common ancestral haplotype was identified by sequencing a strong positional and functional candidate gene (GRM1) and additional STR genotyping in the top GWS region, 6q24. The best supported region was a 12 cM interval on 4q31, also implicated in previous studies, where we obtained significant results in the super-pedigree using both SimWalk2 (P = 0.004) and joint Pseudomarker analysis of linkage and linkage disequilibrium (P = 0.000056). The size of the region and the characteristics of the Gypsy population make it suitable for LD mapping. PMID- 18444257 TI - Mutations in human monoamine-related neurotransmitter pathway genes. AB - Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org). PMID- 18444259 TI - Equilibrium kinetics of chemisorption processes. AB - A new approach to describe the equilibrium kinetics of chemisorption is proposed. The description of the system is based on first-principles chemical reaction kinetics and statistical thermodynamics. The rate constants are described by using a novel way of activation energy characterization. General expressions for equilibrium gas pressure isotherms and forward/backward reaction rates are obtained as a function of surface coverage. A strong influence of attraction and repulsion interaction energies between the adsorbed species on the equilibrium kinetics is found. PMID- 18444262 TI - The art of self-defence. PMID- 18444258 TI - Tuning of the H-transfer coordinate in primitive versus well-evolved enzymes. PMID- 18444263 TI - [Essential composition of honey and methods of analysis of honey]. PMID- 18444264 TI - [Pet food and animal feed contaminated with melamine]. PMID- 18444265 TI - Antimycobacterial substances from Phaeosphaeria sp BCC8292. AB - Eleven substances including naphthalenones, naphthoquinones, unsymmetrical naphthoquinone dimers and a chlorinated diphenyl ether, three of which are new, have been isolated from the fungus Phaeosphaeria sp. The absolute stereochemistry of naphthalenones has been determined by the Mosher and exciton chirality methods. The biological activity of these compounds against Mycobacterium tuberculosis and cytotoxicity against KB, BCA, NCI-H 187 and Vero cell lines were evaluated. PMID- 18444266 TI - Emergency medicine in the VA: the battleship is turning. PMID- 18444267 TI - Leak: Avandia and the integrity of the peer review process. PMID- 18444268 TI - Alternating right bundle-branch block. PMID- 18444269 TI - Pseudosupraventricular tachycardia. PMID- 18444270 TI - Pseudoatrial flutter. PMID- 18444271 TI - Pseudopremature ventricular complexes. PMID- 18444272 TI - Bradycardia. PMID- 18444273 TI - Pseudoventricular fibrillation. PMID- 18444274 TI - Pseudoventricular fibrillation. PMID- 18444275 TI - Stature, economy and migration during the 19th century: comparative analysis of Haute-Vienne and Hautes-Alpes, France. AB - Data sources are achieved records of men workers' passbooks and registry for work permits in two rural parts of Southern France. We obtained three samples: masons from Rancon, a Limousin village, local sedentary alpine workers and Italian immigrants. The results obtained provide two types of information. The first concerns adult height, which is thought to be a result of both a growth pattern and environmental factors. The second concerns growth rates at the end of adolescence. The results seem to contradict the statements made above concerning the relationships between misery, elevation and height. While the alpine inhabitants are shorter, the Limousin inhabitants are taller in sprite they live in a miserable environment. It appears that taller individuals select themselves into migration. Thus, this model would contradict the idea of a regional genetic base. PMID- 18444276 TI - Social neuroscience: applications to addiction. PMID- 18444277 TI - Psychological medicine. In this issue. PMID- 18444278 TI - 'It's not over when it's over': persistent neurobiological abnormalities in recovered depressed patients. AB - The tendency of major depression to recur is a leading problem in clinical management and is responsible for much of the illness burden. Until recently, biological studies of depression have focused on the mechanisms involved in acute illness but there are now many data to suggest that neurobiological abnormalities persist when depressed patients are clinically recovered and withdrawn from medication. These abnormalities encompass a number of neurochemical and neuropsychological mechanisms that could be relevant to recurrence, including changes in the availability of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes, decreases in cortical gamma-aminobutyric acid (GABA), increases in cortisol secretion and negative biases in the processing of emotional information. Studies of groups at high risk of depression before illness onset will help to clarify which biological abnormalities precede the development of depression and which are the product of recurrent illness. Ultimately this work should lead to a better understanding of the neurobiology of vulnerability to depression and more innovative approaches to primary and secondary prevention. PMID- 18444279 TI - Oncodiagnosis Panel: 2006. Ovarian, cervical, and endometrial cancer. PMID- 18444280 TI - An unkind cut. PMID- 18444281 TI - Re: Treatment of perinatal mood and anxiety disorders: a review. PMID- 18444282 TI - Prime target: hospitals? Spending growth could attract feds looking for cuts. PMID- 18444283 TI - Education payments in sights. MedPAC recommends cuts for teaching hospitals. PMID- 18444284 TI - Following the money to nursing. Current job trend may lessen predicted shortage: study. PMID- 18444285 TI - Methodist struggles back. Ind. system relies on consultants for turnaround. PMID- 18444286 TI - The essence of healthcare. Charity, generosity and loving care should be fundamental for hospitals. PMID- 18444287 TI - Numbers that count. Disease-management industry is taking steps to deliver more reliability, consistency in data on program outcomes. PMID- 18444288 TI - Geting rid of bad debt blues. Another option when managing receivables. PMID- 18444289 TI - What is ProCure21? PMID- 18444290 TI - A safe place. PMID- 18444291 TI - Built to last a life. PMID- 18444292 TI - Arrangement with teeth. AB - * Buildings at Bristol's school of dentistry needed modernising. * A "decant, refurbish, move in" cycle was chosen. * It was completed on time and within budget. PMID- 18444293 TI - Classroom clients. PMID- 18444294 TI - Small scale. Big savings. PMID- 18444295 TI - A crisis is developing in the treatment of infectious diseases. Preface. PMID- 18444296 TI - Preventing pediatric medication errors. PMID- 18444297 TI - Germline stem cells. Preface. PMID- 18444298 TI - Planning today for leadership tomorrow in pediatric nursing. PMID- 18444299 TI - Patient safety--a shared responsibility. PMID- 18444300 TI - Exploring the moral distress of Registered Nurses. PMID- 18444301 TI - Review of policy and practice consultations 2006-2007. PMID- 18444302 TI - Take time to think. Question your practice about appropriate use of employer resources. PMID- 18444303 TI - Errors with injectable medications: unlabelled syringes are surprisingly common! PMID- 18444304 TI - Let's get emotional, emotional. I want to get emotional. PMID- 18444305 TI - Rising above moral distress. PMID- 18444307 TI - Why teamwork will make or break your practice. PMID- 18444308 TI - Contemplating Robin Hood practice. PMID- 18444309 TI - Curing Baumol's disease. PMID- 18444310 TI - A systematic approach to identifying drug-seeking patients. PMID- 18444311 TI - A new approach group visits: helping high-need patients make behavioral change. PMID- 18444312 TI - Closing the physician-staff divide: a step toward creating the medical home. PMID- 18444313 TI - Stark III: Refinement not revolution (Part 2). PMID- 18444314 TI - How to protect your data when you're on the Web. PMID- 18444315 TI - What you need to know when called upon to be a Good Samaritan. PMID- 18444316 TI - A new epidemic: administrative fibrillation. PMID- 18444317 TI - Taking genomes personally. PMID- 18444318 TI - Finding fossils faster. PMID- 18444319 TI - Naps for better recall. PMID- 18444320 TI - Taking heed. PMID- 18444321 TI - The African green revolution. PMID- 18444322 TI - The mad scientist myth. PMID- 18444324 TI - Are you buying this? PMID- 18444323 TI - A new phrenology? PMID- 18444325 TI - The genesis of planets. AB - Barely a decade ago scientists who study how planets form had to base their theory on a single example-our solar system. Now they have dozens of mature systems and dozens more in birth throes. No two are alike. The basic idea behind the leading theory of planetary formation--tiny grains stick together and swoop up gas--conceals many levels of intricacy. A chaotic interplay among competing mechanisms leads to a huge diversity of outcomes. PMID- 18444326 TI - Regulating evolution. AB - Because genes encode instructions for building animal bodies, biologists once expected to find significant genetic differences among animals, reflecting their great diversity of forms. Instead very dissimilar animals have turned out to have very similar genes. Mutations in DNA "switches" that control body-shaping genes, rather than in the genes themselves, have been a significant source of evolving differences among animals. If humans want to understand what distinguishes animals, including ourselves, from one another, we have to look beyond genes. PMID- 18444327 TI - Science 2.0. AB - Science 2.0 generally refers to new practices of scientists who post raw experimental results, nascent theories, claims of discovery and draft papers on the Web for others to see and comment on. Proponents say these "open access" practices make scientific progress more collaborative and therefore more productive. Critics say scientists who put preliminary findings online risk having others copy or exploit the work to gain credit or even patents. Despite pros and cons, Science 2.0 sites are beginning to proliferate; one notable example is the OpenWetWare project started by biological engineers at the Massachusetts Institute of Technology. PMID- 18444328 TI - How cells clean house. AB - Inside the cytoplasm of a living cell, organelles called autophagosomes continually engulf bits of cytoplasm, along with damaged cell parts and invading bacteria and viruses. The "sweepings" are carried to digestive organelles for breakup and recycling. The process is called autophagy. Cell biologists are learning about autophagy in great detail by tracing the protein signals that drive and control the process. A fuller understanding of autophagy is opening up new options for treating cancer, infectious disease, immune disorders and dementia, and it may one day even help to slow down aging. PMID- 18444329 TI - Hooked from the first cigarette. AB - New research has overturned the dogma that cigarette addiction takes years to develop. Studies of adolescent smokers show that symptoms of addiction, such as withdrawal, craving for cigarettes and failed attempts at quitting, can appear within the first weeks of smoking. To account for these findings, scientists have developed a new theory positing that the brain quickly develops adaptations that counter the effects of nicotine. These adaptations lead to withdrawal symptoms when the effects of nicotine wear off. The results highlight the importance of boosting government funding for antismoking campaigns, particularly those aimed at youngsters. PMID- 18444330 TI - Rethinking nuclear fuel recycling. AB - Spent nuclear fuel contains plutonium which can be extracted and used in new fuel. To reduce the amount of long-lived radioactive waste, the U.S. Department of Energy has proposed reprocessing spent fuel in this way and then "burning" the plutonium in special reactors. But reprocesssing is very expensive. Also, spent fuel emits lethal radiation, whereas separated plutonium can be handled easily. So reprocessing invites the possibility that terrorists might steal plutonium and construct an atom bormb. The authors argue against reprocessing and for storing the waste in casks until an underground repository is ready. PMID- 18444331 TI - Fighting killer worms. AB - Parasitic worms known as schistosomes are a major cause of disability and death in many parts of the world, especially sub-Saharan Africa. Although a treatment exists, reinfection is the rule. A vaccine would make a world of difference, but none has yet proved effective. Genetic and other tools hold promise for generating new candidates. PMID- 18444332 TI - Dark forces at work. PMID- 18444333 TI - Green roofs. Living cover. PMID- 18444334 TI - The quality of trauma care needs urgent improvement. PMID- 18444335 TI - Hybrid cardiac surgery for hypoplastic left heart syndrome. PMID- 18444336 TI - Early breast cancer: are START radiotherapy data too good to be true? PMID- 18444337 TI - Pitfalls in the diagnosis of hydrocephalus. AB - Hydrocephalus is a life-threatening condition presenting with a wide range of symptoms to a variety of specialties. Resulting delays in diagnosis can be hazardous. Doctors in all specialties should be familiar with the protean presentations of hydrocephalus. PMID- 18444338 TI - Pituitary disorders: an overview for the general physician. AB - The pituitary gland is responsible for the production of the trophic hormones that control normal homeostasis. The hyper- or hypofunction of one or more of these may result in a distinct pathological clinical presentation, particularly in the presence of macroadenoma. Most pituitary disorders, however, present with non-specific signs and symptoms. This review gives an overview of pituitary disorders, their causes, clinical presentation, diagnosis and management. PMID- 18444339 TI - Neck lumps and head and neck tumours in children. AB - This article discusses the presentation, investigation and treatment of both benign and malignant lumps encountered in the head and neck region in children. PMID- 18444340 TI - Dealing with complaints 1: a guide for the foundation year doctor. PMID- 18444341 TI - Ultrasound imaging of the kidneys. PMID- 18444342 TI - Acute skin conditions in children. PMID- 18444343 TI - How to make the most of your imaging department. PMID- 18444344 TI - A guide to organizing FY2 training in Australia. PMID- 18444345 TI - Assessment and treatment of pain in children. AB - Treating acute pain in the paediatric population poses challenges which include the lack of high levels of evidence and a universal pain measuring tool, contributing to the undertreatment of pain. A multimodal approach of topical and systemic analgesia, comfort measures and parental involvement remains the mainstay of pain management. PMID- 18444346 TI - Current management of varicose veins. AB - There has been an increasing trend towards less invasive methods of treating varicose veins, e.g. foam sclerotherapy, radiofrequency ablation and endovenous laser ablation, which has led many to question the more conventional methods of treating varicose veins. This review focuses on current techniques of managing varicose veins. PMID- 18444347 TI - Cerebrospinal fluid: the role of biochemical analysis. AB - Biochemical analysis of cerebrospinal fluid may provide answers to important clinical questions. This review summarizes these questions and outlines the value and limitations of cerebrospinal fluid analysis. PMID- 18444348 TI - The role of heart rate reduction in angina management and beyond. AB - This article highlights the significance of heart rate as an independent risk factor and prognostic marker for cardiovascular disease and examines the pharmacological measures available that lead to effective heart rate reduction. PMID- 18444349 TI - Adult-onset diabetes insipidus caused by congenital midline brain abnormalities. PMID- 18444350 TI - Sporadic Creutzfeldt-Jakob disease presenting as stroke mimic. PMID- 18444351 TI - Digital ischaemia: vasculitis vs trauma. PMID- 18444352 TI - Diagnosing multiple sclerosis: expect the unexpected. PMID- 18444353 TI - A newly described tumour: Burkitt's sarcoma. PMID- 18444354 TI - Are logbooks of training in anaesthesia a valuable exercise? PMID- 18444355 TI - Data envelopment analysis comparison of hospital efficiency and quality. AB - Using a sample of Virginia hospitals, performance measures of quality were examined as they related to technical efficiency. Efficiency scores for the study hospitals were computed using Data Envelopment Analysis (DEA). The study found that the technically efficient hospitals were performing well as far as quality measures were concerned. Some of the technically inefficient hospitals were also performing well with respect to quality. DEA can be used to benchmark both dimensions of hospital performance: technical efficiency and quality. The results have policy implications in view of growing concern that hospitals may be improving their efficiency at the expense of quality. PMID- 18444356 TI - AR spectral analysis technique for human PPG, ECG and EEG signals. AB - In this study, Fast Fourier transform (FFT) and autoregressive (AR) methods were selected for processing the photoplethysmogram (PPG), electrocardiogram (ECG), electroencephalogram (EEG) signals recorded in order to examine the effects of pulsed electromagnetic field (PEMF) at extremely low frequency (ELF) upon the human electrophysiological signal behavior. The parameters in the autoregressive (AR) method were found by using the least squares method. The power spectra of the PPG, ECG, and EEG signals were obtained by using these spectral analysis techniques. These power spectra were then used to compare the applied methods in terms of their frequency resolution and the effects in extraction of the features representing the PPG, ECG, and EEG signals. Some conclusions were drawn concerning the efficiency of the FFT and least squares AR methods as feature extraction methods used for representing the signals under study. PMID- 18444357 TI - Wavelet-based multi-resolution deformation for medical endoscopic image segmentation. AB - Image segmentation is an essential technique in image analysis. In spite of issues in contour initialization, boundary concavities and high-level computation, active contour models (snakes) are popular and successful method for segmentation among researchers. Segmentation process in snakes consists of calculation of energy and deformation of contour. In this paper, we present a new deformation method for active contour model, multi-resolution deformation based on wavelet ensuring powerful time reduction, high accuracy supported by stable results in convergence of an initial contour to target boundary in medical image segmentation. PMID- 18444358 TI - A radial basis function neural network (RBFNN) approach for structural classification of thyroid diseases. AB - The thyroid is a gland that controls key functions of body. Diseases of the thyroid gland can adversely affect nearly every organ in human body. The correct diagnosis of a patient's thyroid disease clarifies the choice of drug treatment and also allows an accurate assessment of prognosis in many cases. This study investigates Multilayer Perceptron Neural Network (MLPNN) and Radial Basis Function Neural Network (RBFNN) for structural classification of thyroid diseases. A data set for 487 patients having thyroid disease is used to build, train and test the corresponding neural networks. The structural classification of this data set was performed by two expert physicians before the input variables and results were fed into the neural networks. Experimental results show that the predictions of both neural network models are very satisfying for learning data sets. Regarding the evaluation data, the trained RBFNN model outperforms the corresponding MLPNN model. This study demonstrates the strong utility of an artificial neural network model for structural classification of thyroid diseases. PMID- 18444359 TI - Personnel and patient scheduling in the high demanded hospital services: a case study in the physiotherapy service. AB - High demand but limited staffs within some services of a hospital require a proper scheduling of staff and patients. In this study, a hierarchical mathematical model is proposed to generate weekly staff scheduling. Due to computational difficulty of this scheduling problem, the entire model is broken down into manageable three hierarchical stages: (1) selection of patients, (2) assignment of patients to the staff, (3) scheduling of patients throughout a day. The developed models were tested on the data collected in College of Medicine Research Hospital at Cukurova University using GAMS and MPL optimization packages. From the results of the case study, the presented hierarchical model provided a schedule that ensures to maximize the number of selected patients, to balance the workload of physiotherapist, and to minimize waiting time of patients in their treatment day. PMID- 18444360 TI - MR images restoration with the use of fuzzy filter having adaptive membership parameters. AB - A new fuzzy adaptive median filter is presented for the noise reduction of magnetic resonance images corrupted with heavy impulse (salt and pepper) noise. In this paper, we have proposed a Fuzzy Adaptive Median Filter with Adaptive Membership Parameters (FAMFAMP) for removing highly corrupted salt and pepper noise, with preserving image edges and details. The FAMFAMP filter is an improved version of Adaptive Median Filter (AMF) and is presented in the aim of noise reduction of images corrupted with additive impulse noise. The proposed filter can preserve image details better than AMF while suppressing additive salt and pepper or impulse type noise. In this paper, we placed our preference on bell shaped membership function with adaptive parameters instead of triangular membership function without variable coefficients in order to observe better results. PMID- 18444361 TI - Field testing of a remote controlled robotic tele-echo system in an ambulance using broadband mobile communication technology. AB - We report the testing of a mobile Robotic Tele-echo system that was placed in an ambulance and successfully transmitted clear real time echo imaging of a patient's abdomen to the destination hospital from where this device was being remotely operated. Two-way communication between the paramedics in this vehicle and a doctor standing by at the hospital was undertaken. The robot was equipped with an ultrasound probe which was remotely controlled by the clinician at the hospital and ultrasound images of the patient were transmitted wirelessly. The quality of the ultrasound images that were transmitted over the public mobile telephone networks and those transmitted over the Multimedia Wireless Access Network (a private networks) were compared. The transmission rate over the public networks and the private networks was approximately 256 Kbps, 3 Mbps respectively. Our results indicate that ultrasound images of far higher definition could be obtained through the private networks. PMID- 18444362 TI - Comparison of different classifier algorithms on the automated detection of obstructive sleep apnea syndrome. AB - In this paper, we have compared the classifier algorithms including C4.5 decision tree, le artificial neural network (ANN), artificial immune recognition system (AIRS), and adaptive neuro-fuzzy inference system (ANFIS) in the diagnosis of obstructive sleep apnea syndrome (OSAS), which is an important disease that affects both the right and the left cardiac ventricle. The goal of this study was to find the best classifier model on the diagnosis of OSAS. The clinical features were obtained from Polysomnography device as a diagnostic tool for obstructive sleep apnea in patients clinically suspected of suffering this disease in this study. The clinical features are arousals index, apneahypopnea index (AHI), SaO2 minimum value in stage of rapid eye movement, and percent sleep time in stage of SaO2 intervals bigger than 89%. In our experiments, a total of 83 patients (58 with a positive OSAS (AHI>5) and 25 with a negative OSAS such that normal subjects) were examined. The decision support systems can help to physicians in the diagnosing of any disorder or disease using clues obtained from signal or images taken from subject having any disorder. In order to compare the used classifier algorithms, the mean square error, classification accuracy, area under the receiver operating characteristics curve (AUC), and sensitivity and specificity analysis have been used. The obtained AUC values of C4.5 decision tree, ANN, AIRS, and ANFIS classifiers are 0.971, 0.96, 0.96, and 0.922, respectively. These results have shown that the best classifier system is C4.5 decision tree classifier on the diagnosis of obstructive sleep apnea syndrome. PMID- 18444364 TI - [The time of changes]. PMID- 18444363 TI - Anesthetic level prediction using a QCM based E-nose. AB - Anesthetic level measurement is a real time process. This paper presents a new method to measure anesthesia level in surgery rooms at hospitals using a QCM based E-Nose. The E-Nose system contains an array of eight different coated QCM sensors. In this work, the best linear reacting sensor is selected from the array and used in the experiments. Then, the sensor response time was observed about 15 min using classic method, which is impractical for on-line anesthetic level detection during a surgery. Later, the sensor transition data is analyzed to reach a decision earlier than the classical method. As a result, it is found out that the slope of transition data gives valuable information to predict the anesthetic level. With this new method, we achieved to find correct anesthetic levels within 100 s. PMID- 18444365 TI - [Oral anti-diabetes medicines, an update]. AB - The use of oral anti-diabetes medicines should be considered when nutritional control methods and physical exercise programs have failed. These medicines have several types of active mechanisms: to stimulate pancreatic secretion of insulin, to delay the absorption of carbohydrates in the intestines, to sensitize tissues to the action of insulin. Sulfonylureas are the pharmaceutical group most commonly utilized in the treatment of type 2 diabetes mellitus. PMID- 18444366 TI - [How to develop professionally through investigation and research. A methodological strategy in education]. AB - The authors present, and evaluate, from the viewpoint of participating students, an investigation-development project put into action during the 2003-04 academic year on the elaboration of a career-ending thesis at the Vitoria School of Nursing, as part of the European Nursing Licentiate program. This project establishes the starting point for a long-term project begun having the objective to develop theoretical principles and practical procedures which will permit the authors to systemize educational processes which, based on investigation and research, articulate theory and practice while integrating a communicative and cooperative perspective. PMID- 18444367 TI - [Blood vessel access, skill and tricks]. AB - From a personal viewpoint, the author explains diverse "tricks" and skills which can be used when facing various emergency situation. In this case, the author deals with means of applying blood vessel access. PMID- 18444368 TI - [The influence of the concept of oriental sanitation in nursing practice]. AB - The word "sanitation", similar to the concept care for has become popularized in such a way that it is difficult to determine its meanings. This article hopes to follow the Hernandez Madrid model and guidelines since this is the clearest one available when one tries to understand the reason why, at present times, certain nursing theories communicate their new research tied to their introspection projects but, as we shall see shortly, prove to be of little practical use with real patients, at least in the Spanish sanitary world. PMID- 18444369 TI - [Psycho-social necessities for an informal caretaker]. AB - Of the many activities which nurses in primary attention care teams carry out, health promotion and prevention of diseases have a prominent place. These activities are not carried out only in Primary Attention Care Centers. For some time now, there has been a tendency to keep dependent patients in their homes as much as possible. For this reason, At Home Care has an important place in nurses' daily practices. This article reviews the concept of an informal caretaker and the main reasons which can cause an overload. At the same time, the authors show the tool which nurses use to know the emotional state of informal caretakers, as well as the environment and the circumstances where they are found. The authors propose to use nursing diagnoses as a planning tool for objectives and action strategies to overcome the shortages detected. PMID- 18444370 TI - [Clinical evaluation of a silver dressing in the treatment of infected and colonized ulcers]. AB - In the event of ulcers with critical colonization, a correct diagnosis and adequate treatment are vital for healing to occur since the presence of a possible infection would impede an adequate evolution leading to healing the ulcer The authors publish a prospective and multi-centric study which included 375 patients who were evaluated regarding the healing of their ulcers over a 12 week period in which the "Biatain Plata" dressing was used. The average initial size of their ulcers was 30 cm2 +/- 67. After 72 weeks of treatment, patients' ulcers were reduced by 80% in relative value. 33% of these ulcers showed a complete healing, while another 47.4% evidenced a noticeable improvement. The product studied proved to be highly effective in the treatment of chronic ulcers with critical colonization. Regarding the safety of this dressing, the authors did not observe any adverse reaction to it, nor did they observe any toxicity associated with the release of silver, in spite of having used this dressing over 12 weeks. In the same way, the authors did not notice any indications of possible development of bacterial resistance to the dressing's anti-bacterial action. PMID- 18444371 TI - [Clinical case: a patient with necrotising fasciitis in two legs]. PMID- 18444372 TI - [Prevention of occupational risks. Occupational safety within the scope of nursing]. PMID- 18444373 TI - Now we're cooking! PMID- 18444374 TI - Lean times ahead. Interview by Nick Lipley. PMID- 18444375 TI - Reducing infection rates. PMID- 18444376 TI - Finding time for older staff. PMID- 18444377 TI - Caring for the bereaved. PMID- 18444378 TI - Clinical audit: a guide. PMID- 18444379 TI - Exploring leadership styles. PMID- 18444380 TI - Managing performance. PMID- 18444381 TI - [In memoriam of Isidro Claret Corominas]. PMID- 18444382 TI - [EBM in pediatric surgery: critical reading of articles. Etiology]. PMID- 18444383 TI - [Intraluminal impedance technique in the diagnosis of apparent life-threatening events (ALTE)]. AB - BACKGROUND: Apparent life threatening events (ALTE) affect children younger than one year. This syndrome is characterized by several symptoms: apnoea, change in colour or muscle tone, coughing or gagging. Approximately 50 percent of these children are diagnosed of an underlying pathology that explains the ALTEs, being gastroesophageal reflux one of the most important conditions to investigate. AIM: To demonstrate the effectiveness of intraluminal impedance technique for the diagnosis of the gastroesophageal reflux associated to ALTEs in infants. MATERIALS AND METHODS: Stationary esophageal manometric is used to define the low esophageal sphincter, a pH and impedance 24 hours was recorded. We determinate association between gastroesophageal reflux-ALTEs and characterisation of the reflux that occurs. RESULTS: Intraluminal esophageal impedance has been made to 16 children with the diagnosis of ALTEs between 1 and 6 months of age (mean of age 3.04 months). 23.4 episodes of reflux (9,500-31,275, P25 and P75 respectively) have been diagnosed by pHmetry whereas with impedance the number of reflux obtained were 70.88 (60.25 - 80.00), 36.21% acid and 63.78% weakly acidic. We have found 4 episodes of apnoea in one patient that seems to be connected with gastroesophageal reflux (3 nonacid and one acid event) in a statistically positive relation (SI > or = 50%; SSI > or = 10%). CONCLUSIONS: Intraluminal gastroesophageal impedance is a useful method for the diagnosis of gastroesophageal reflux in infants who present a gastric alkaline content most of time, allowing in addition, to differentiate between acid and nonacid reflux. According to our sample, the patients with the diagnosis of ALTEs do not present greater rate of gastroesophageal reflux than the healthy population of the same age. Only in one patient we have found a statistically significant relation between reflux and apnoea. PMID- 18444384 TI - [Minimally invasive endourological management of urinay tract calculi in children]. AB - BACKGROUND: The urinary tract calculi in children is a very unfrequent problem in the pediatric age group. Endourology plays a major role in pediatric surgery. We reported our experience in endoscopic management of pediatric calculi. METHODS: Eighteen children (age range: 2 year-19 years) underwent endourology procedures for extraction of urinary tract lithiasis in the period from 1992 until 2006. We reviewed retrospectively the following features: calculi size, location, procedures, surgical complications, recurrent, results and time of follow-up. RESULTS: Twenty-one endourolgy procedures were performed: nine ureteroscopies (43%), 10 bladder extractions (47.5%) and two percutaneous nephrolithotomies (9.5%). The mean size bladder stone was 2.75 cm. and 6.3 mm. in the ureteral stones. A patient had staghorn calculi. The stone was located in distal ureter in 7 occasions (33.3%), in upper ureter in 2 (9.5%), in kidney in 2 (9.5%), in bladder in 9 (43%) and in urethra in one (4.7%). Ten cases (55.5%) had urology associated anomalies: 6 patients neurogenic bladder, two bladder exstrophy, one ureterocele and one diagnosed of primary megaureter. Four patients (22%) underwent open surgery for the extraction of the lithiasis: a patient with a bladder stone and three cases with ureteral calculi. Three patients (16, 5%) had recurrence of stones and were successfully treated with endoscopy procedure again. By the moment all the patients are stone-free. The time of follow-up has been 2 years and 6 months (range: 1-13 years). CONCLUSIONS: The endourology is a safe and effective therapeutic option for the management of urinary tract calculi in children. With improvements in instrumentation and technology, it will be possible to expand the patients' selection criterion. PMID- 18444385 TI - [Mammary reconstruction in Poland's syndrome]. AB - Poland's syndrome is considered to be a polimalformative entity with different degrees of severity. We retrospectively reviewed our patients with Poland's syndrome diagnosis, treated between 2000 and 2006. The aim of our study is to assess the different choices of surgical treatment for mammary reconstruction according to the importance of malformation and taking into account our own experience and literature references. A total o f 13 patients (5 males and 8 females) were studied and only 6 of them (1 male and 5 females) underwent surgery. Surgical indication was based on Foucras's classification, considering 3 grades of severity. We propose a surgical approach adapted to each stage, as well as surgical refinements to improve the aesthetic aspect. Most of our patients were very satisfied with final results even though they underwent complex procedures with a considerable rate of complications. PMID- 18444386 TI - [Laparoscopic Kasai portoenterostom: present and future of biliary atresia treatment]. AB - INTRODUCTION: Kasai's operation has proved its value in surgical treatment of biliary atresia (BA). Its laparoscopic approach is a new challenge for pediatric surgeons, with all the potential advantages of minimally invasive surgery. The aim of the present study has been to report our experience in laparoscopic management of five patients with biliary atresia. PATIENTS AND METHODS: The average of age of five patients with biliary atresia, three boys and two girls was 58 days (range 40-64). Pre and postoperative management included antibiotic prophylaxis and choleretic treatment. Laparoscopic procedure was accomplished using one umbilical 10-mm trocar and two additional 5-mm trocars. We carried out the same technique in all the patients except in one of them with a total situs inversus and who compelled us to modify the original procedure. RESULTS: All five patients underwent a laparoscopic procedure, conversion was not necessary. The mean surgical time was 3 hours and 40 minutes (range: 5:30 y 3:10). There were not intra operative complications and all of them had a satisfactory recovery, except for the patient with situs inversus, who suffered a small bowel volvulus 9 days after the operation, leading us to perform an extensive bowel resection. All the patients, except this one, showed signs of adequate bile flow, with disappearance of clinical cholestasis. Biochemistry test became normal. CONCLUSIONS: Besides the certain advantages compared with conventional surgical procedures (lower surgical damage, diminished post-operative recovery), laparoscopic management of BA, allows a better exposure of the porta hepatis without hepatic mobilization so it shows similar or better preliminary results than conventional techniques. The advantages of laparoscopic portoenterostomy are yet to be proved whenever liver transplantation is indicated. PMID- 18444387 TI - [Parotid gland's tumors in children]. AB - The tumors of the salivary glands are infrequent in children, and parotid gland is involved in 80% of them. When a salivary gland tumor is present, the chance of malignancy is greater in the child than in the adult. We reviewed 8 cases identified in patients aged 14 years and younger in our hospital, analyzing its antecedents, signs and symptoms, histological features, diagnosis, treatment and evolution. All the patients displayed preauricular painless, non-inflammatory and slow-growing masses to an age between 10 months and 14 years. Four or them were pleomorphic adenomas, two haemangiomas, one epidermal cysts and one myoepithelial carcinoma. We emphasize the exceptional nature of the carcinoma for its rareness and for the high degree of malignancy expressed. We made a fine needle aspiration biopsy in four cases but they were conclusive only in three. All were treated by surgical resection of the tumour except for the myoepithelial carcinoma and the recurrent pleomorphic adenoma that were treated by total parotidectomy. The malignant tumours of the parotid gland are clinically indistinguishable of the benign ones, thus when any palpable mass appears in the zone of the parotid gland, an accurate diagnosis should be made without delay. The treatment of choice is the surgical excision with wide margins, being other adjuvant treatments less useful to this age than in the adult age. PMID- 18444388 TI - [Is effective the initial management of primary nonrefluxing megaureter with double-J stent?]. AB - BACKGROUND: Initial management of patients with primary nonrefluxing megaureter (PNRM) associated with impaired renal function or with high risk rate of decreased kidney function can be a dilemma. We present our experience in the use of double -J stent in these patients to evaluate the role as a method to decompressing the system, to prevent function loss or to temporize surgical treatment. METHODS: In the period 1996-2006 27 patients were diagnosed of PNRM. The patients classified themselves in two groups according to the initial treatment received: those with conservative management and those managed with double-J stent insertion during 6 months. A complete reassessment was performed after one year from the diagnosis in the first group and three months after stent removal in the second one. Patients underwent uretereral reimplantation if, at assessment, an obstructed excretion pattern was found on diuretic testing. The following data have been studied in each case: age at diagnosis, sex, renal function previous and after the treatment, morbidity associated to the double- J stent insertion, excretion pattern on diuretic testing after initial management, surgical technique, ureteral tapering, outcome and time of follow-up. RESULTS: 15 cases were managed with conservative conduct. After a 12 month period an obstructed excretion pattern was found on diuretic testing in eight patients (53.3%), and an unobstructed one in seven (46.7%). The differential function of the affected kidney got worse in two cases (15.4%), being in one of them less than 10%. Eight patients underwent a surgical intervention (53.3%), in seven cases was performed ureteral reimplantation and in one case was performed a nefrectomy. Four cases needed ureteral tapering (57.1%). Twelve patients were selected to undergo double- J stent insertion for al 6-month period. Stent related complications developed in 5 cases (41.7%), including upper migration in two cases, distal migration in two and breakthrough infections in one patient. At reassessment three months after stent removal, 6 patients (50%) presented an obstructive pattern and the other cases an unonobstructive pattern (50%). In one of the patients with impaired function, the kidney function got worse until becoming smaller than 10%. Six patients underwent surgical treatment (50%), a nefrectomy and 5 ureteral reimplantation. None case needed ureteral tapering. Mean time of follow-up has been 7 months in the first group and 3 years and 3 months in the second one. CONCLUSIONS: Double-J stent insertion in patients with PNRM is associated with high morbidity and there weren't differents in the final outcomes between both groups, therefore it's necessary to create severe prognosis indicators to use the double-J stent as a method to temporize a surgical treatment. PMID- 18444389 TI - [Neovagina with intestine: 13 cases]. AB - INTRODUCTION: The absence or hipoplasia vaginal can turn out to be isolated, associated with ambiguous genitalia, or as anatomical variant in a syndrome of sewer. The fundamental aim in the creation of a new vagina is: to obtain a good aesthetic result, to fulfil functional criteria (elasticity, sensibility, physiological inclination) and to improve the quality of life of the patients avoiding the use of molds and minimizing the morbidity of the zones donors. In this work let's sense beforehand our experience in the accomplishment of neovaginas with intestine. AIM AND METHODS: We analyze the clinical record of 13 patients treated surgically in the last ten years. We differentiate two groups according to the age, the diagnosis and the type of surgery: a) the first group of 8 patients present syndrome of insensibility to the androgens (4), syndrome of Rokitansky (2), extrofia of sewer (1) and mixed gonadal disgenesia (1). This group of patients were controlled in the adolescence by an average of age of 19 years (11-35 years), they fulfilling a neovagina with sigma; b) the second group of 5 patients with sewer (3), extrofia of sewer (1) and congenital suprarrenal hiperplasia (1). This group was controlled prematurely by a middle ages of one year (4 months-3 years). The intestinal segment used as neovagina was sigma (2), ileon (2) and rectum (1), and was performed during the surgical correction of her congenital malformation. RESULTS: Two patients have presented intestinal obstruction in the postoperatory immediate one. Four patients have needed removal of a small vaginal prolapse, and three have needed vaginal transitory expansions for introit stenosis. The long-term evolution has been favorable with an excellent aesthetic aspect. Four patients recount sexual fully satisfactory relations. CONCLUSIONS: We believe that the neovagina with sigma is at present the best option in patients with absence or hipoplasia vaginal. The advantages are the possibility of precocious and one time correction, a neovagina of dimensions and oiling adapted without need of expansions or molds, an aesthetic excellent aspect, and sexual satisfactory sexual relations. PMID- 18444390 TI - [Medical and/or surgical treatment of appendicular mass and appendicular abscess in children]. AB - BACKGROUND: There is controversy about the immediate or delayed treatment of the cases of acute appendicitis which are diagnosed in the form of appendicular mass and/or apendicular abscess. At first, do we have to follow a medical or a surgical treatment? In those cases of conservative treatment, do we always have to carry out a delayed appendectomy? We have revised our experience to discuss the different options in order to try to define some implementation criteria. MATERIAL AND METHODS: We have revised the cases of appendicitis from January 2003 to December 2005, choosing the cases of appendicular mass on this study. We have assessed the following parameters: age, sex, days of evolution, previous diagnostic, hemogram, PCR, ultrasound, computer tomography (TAC), medical treatment, initial surgical treatment, period of treatment and types of antibiotic, surgical treatment in a second term and pathological anatomy. From the 154 appendicular processes, 10 patients were diagnosed of appendicular mass, which means 6.49%. RESULTS: From the 154 appendicular processes, 10 patients were diagnosed of appendicular plastron, which means 6.49%. The age range is between 2 and 15 (average 6,9). There are no differences regarding sex, 50% each. The initial diagnosis in 60% of the cases was sharp gastroenteritis. The average of days of evolution until the definitive diagnosis was 5 days (between 1 and 10 days). In 90% of the cases the diagnosis was confirmed through ultrasound scan and two cases needed computerized tomography (CT). In two cases we had to carry out an initial surgical operation to drain the abscess. The appendectomy in a second term was carried out in 7 cases. Three cases still await operation. CONCLUSIONS: Unless there is intestinal occlusion, in those patients with tender mass or appendicular abscess, we must start a medical treatment based on antibiotics and, later on, carry out the appendectomy through laparoscopy. In the period between the sharp symptoms and the definitive operation, there have not been any further complications or pathology related to the appendicular mass, despite the fact that the operations have taken place 5.5 months later on average. A proper antibiotic treatment always solves the sharp symptoms. On few occasions, besides the initial medical treatment, we have to act surgically to drain an abscess, especially on Douglas. PMID- 18444391 TI - [Cystic adenomatoid malformations of the lung: presentation of 5 cases and review]. AB - We describe five cases of cystic adenomatoid malformations of the lung collected from our files from 1994 to 2006. It is an unusual malformation and has features of immaturity with less than 400 cases previously published. All patients were surgically treated in our institution. We review the clinical outcome, microscopic findings, current classification schemes and prenatal surgical treatment. Our study includes 3 newborn males and two girls, 3 and 9 years old. All of them radiographically showed air or fluid filled cystic masses involving a single lobe. After lobectomy, four lung specimens were classified as Stoker type 2 lesions and the older one as type 1. PMID- 18444392 TI - [Currarino syndrome]. AB - The Currarino syndrome is a form of caudal regression syndrome characterized by the classic triad of presacral mass, sacral bone defect and anorectal malformation in which an autosomal dominant inheritance has been described. In case of clinical suspicion it is necessary to search for the classic alterations and to detect other possible associated malformations in order to avoid complications. The management is multidisciplinary and depends on the type of alterations that the patient has. We report a 17-month-old female baby that initially passed unnoticed and was detected during a rectoplasty for reconstruction of a rectal stenosis. The baby presented complications derived from ignorance of the existence of a presacral mass. Early diagnose and adequate treatment is very important. PMID- 18444393 TI - What will pay deal mean for you? PMID- 18444395 TI - 'Indifference says much more about an individual nurse's attitude than the NHS'. PMID- 18444396 TI - Why NHS Direct is more than a call centre. Interview by Louise Hunt. PMID- 18444397 TI - Vascular screening programme moves focus to early prevention. PMID- 18444398 TI - The lymphatic system. Part 3--The lymphatic system and immunity. PMID- 18444399 TI - Fluid resuscitation in burn patients. 2: Nursing care. AB - This is the second in a two-part unit on caring for patients with burns. Part 1 focused on the two formulas used to calculate fluid resuscitation. This part discusses the nurse's role in managing patients with burns. PMID- 18444400 TI - Improving patient experience for coronary angioplasty. PMID- 18444401 TI - Venipuncture syncope--one occupational health clinic's experience. PMID- 18444402 TI - Domestic violence screening and treatment in the workplace. AB - The purpose of this study was to survey occupational health nurses about their perceived ability to screen for and treat domestic violence in the workplace. Occupational health nurses providing direct care or case management anonymously responded to the mailed Occupational Health Nurses' Survey on Screening for Domestic Violence in the Workplace. Findings indicate that occupational health nurses consider domestic violence screening and treatment to be components of their nursing role, but do not believe they have adequate training to competently care for workers who have experienced domestic violence. The occupational health nurses also did not believe policies existed in their workplace to assist them in treating these workers. Findings from this study can be used as the foundation for domestic violence education, policy development, and intervention research. PMID- 18444403 TI - Occupational health nursing practice, education, and research in Taiwan. AB - This article describes occupational health nursing practice, education, research, and future perspectives in Taiwan. It also provides a brief overview of major occupational health and safety problems, laws and regulations, and organizations in Taiwan. PMID- 18444404 TI - Health effects following 9/11: implications for occupational health nurses. AB - The attacks on the World Trade Center in 2001 resulted in hazardous environmental exposures of enormous magnitude, bringing about persistent respiratory and psychological problems among survivors. Approximately 40,000 men and women worked at Ground Zero, the former site of the World Trade Center in New York City, and at the Staten Island landfill, the main wreckage depository, in the days, weeks, and months following 9/11. First responders such as firefighters and police, construction workers, and utility and public sector workers were involved. These individuals were at high risk for injury, respiratory complications, and psychological distress from the traumatic event. This article highlights the controversy surrounding 9/11 research and reports, identifies populations at high risk for exposure, and examines the health effects. Occupational health nurses should not only be empowered to provide the best care for workers affiliated with 9/11, but also contribute to research to protect worker health in future disaster responses. PMID- 18444405 TI - Workplace incivility and productivity losses among direct care staff. AB - The purpose of this study was to examine incivility experienced by direct health care staff in their workplaces. The sample (N = 184) was 91% female and 77% White, with 71% of the participants having earned an associate degree or above and 81% being registered nurses. The Work Limitations Questionnaire and the Incivility in Healthcare Survey were distributed to all direct care staff at a major metropolitan hospital (22% response rate). Correlations were found between workplace incivility from direct supervisors and productivity (r = 0.284, p = .000) and workplace incivility from patients and productivity (r = 0.204, p = .006). Incivility from physicians, incivility from other direct care staff, and general environmental incivility were not shown to be significantly related to productivity. Demographics were not related to levels of workplace incivility. Workplace incivility from patients and management appears to have a greater impact on employees' productivity than workplace incivility from other sources. PMID- 18444406 TI - Proper handling of fluorescent and metal halide lamps to prevent injury, illness, and environmental damage. PMID- 18444407 TI - The Reynolds Risk Score--improving cardiovascular risk prediction in women. PMID- 18444408 TI - Stressed out at the front. PMID- 18444409 TI - Mad cow: what's safe now? PMID- 18444410 TI - Feeling fishy about fish. PMID- 18444411 TI - Cold comfort indeed. PMID- 18444412 TI - You can do it. Really. (Click here for help). PMID- 18444413 TI - No pain, some gain: the new workouts. PMID- 18444414 TI - [Diagnosis and treatment of geographic choroiditis]. PMID- 18444415 TI - [Combined intravitreal triamcinolone and photodynamic therapy for retinal angiomatous proliferation after photodynamic therapy]. AB - PURPOSE: To investigate the 1-year results of treatment for retinal angiomatous proliferation (RAP), especially focused on the combination therapy of intravitreal injection of tiamcinolone acetonide with photodynamic therapy (IVTA PDT). METHODS: Between July 2004 and July 2005, IVTA-PDT was performed in 7 patients (9 eyes) with RAP at the Ohtsuka Eye Hospital. We reviewed the records of 4 of these patients (5 eyes) who had received IVTA-PDT during follow-up. RESULTS: PDT was effective in only 1 of the 9 eyes. During IVTA-PDT, leakage from neovascularization was observed on angiography, and retinal edema and retinal pigment epithelial detachment (RPED) were observed on optical coherence tomography (OCT), even though PDT had been performed several times in all 5 eyes receiving IVTA-PDT. Complete resolution of angiographic leakage and improvement of retinal edema and RPED were observed at the examination 3 months after IVTA PDT. At 1 year after IVTA-PDT, the fundus findings remained stable in 4 eyes, but angiographic leakage and RPED had progressed slightly in one eye. Visual acuity 1 year after IVTA had decreased compared with that at the primary PDT, but was almost the same as that at the beginning of IVTA-PDT. CONCLUSIONS: IVTA-PDT for eyes with RAP, in which PDT had been performed several times, may be effective for improvement or elimination of retinal edema, achieving rapid regression of neovascularization, and stabilizing visual acuity. PMID- 18444416 TI - [Correlation of age and intraocular pressure with visual field damage in patients with normal-tension glaucoma]. AB - OBJECTIVE: We investigated the correlation of age and intraocular pressure (IOP) with visual field damage in patients with normal-tension glaucoma (NTG) and asymmetric visual field defects. METHODS: A total of 88 NTG patients (176 eyes) were investigated. Patients in whom visual field defects were more severe in the eye with higher IOP than in the fellow eye were grouped as IOP-visual field concordant patients, and the others as IOP-visual field-discordant patients. Mean 24-hour IOP was used as an indicator of IOP, and mean deviation (MD) as an indicator of visual field defects. Patients were also compared by age tertile. RESULTS: The IOP-visual field-concordant group comprised 53 of the 88 patients (60.2%), among whom the >70-years tertile had significantly greater absolute values for MD asymmetry. In contrast, no significant differences in asymmetry by age tertile were seen in the IOP-visual field-discordant group. CONCLUSION: Elevated IOP is a cause of visual field defects in many NTG patients. Among IOP visual field-concordant patients, particular attention is required to visual field changes in the eyes of patients with higher IOP. PMID- 18444417 TI - [Influence of accommodative response and visual symptoms on visual display terminal adult operators with asthenopia through adequately corrected refractive errors]. AB - PURPOSE: Application of adequate correction of refractory errors for the treatment of asthenopia of young visual display terminal (VDT) workers was evaluated from subjective complaints and the effect on accommodation dynamics (step response) before and after 6 months. METHODS: Young VDT workers who visited the clinic because of eye strain were consecutively selected. Fifteen workers who were under-corrected for myopia and three workers who were over-corrected for myopia were treated by "adequate correction of refractory errors" with spectacles or soft contact lenses. The adequate correction was defined as minimum convex lenses which could obtain visual acuity of 1.2 or better, similar to daily life conditions, without cyclopegia or fogging. The workers were in their 20's. Accommodative responses to step stimuli were recorded by infrared optometer, and questionnaires were filled out by the VDT workers concerning the severity (a severity rating in percent in five steps) of subjective symptoms (headache, dry eye, eye strain, and eye irritation). Spectacles or disposable contact lenses were prescribed for the workers for "adequate correction". Six months later, accommodative responses and subjective symptoms were evaluated and compared with under-or over-corrected conditions and adequate correction. RESULTS: In under corrected workers, the adequate correction significantly improved complains i.e. headache, eye strain, eye tiredness (p < 0.005). Accommodative responses also improved in gain (%), maximum velocity (D/sec), and time of accommodation and relaxation (p < 0.05). Three over-corrected workers showed improvement of complains and also accommodative response in gain, maximum velocity, and time of accommodation and relaxation. CONCLUSIONS: Application of "adequate correction" to young VDT workers with asthenopia by using adequately corrected spectacles or soft contact lenses improved the asthenopia and accommodative dynamics. PMID- 18444418 TI - [Evaluation of the efficacy of intravitreal gas injection for submacular hemorrhages]. AB - PURPOSE: To evaluate the efficacy of intravitreal gas injection for submacular hemorrhages(SMH). PATIENTS AND METHODS: The records of 29 patients with SMH, who were treated by pneumatic displacement with expansile gas, were reviewed retrospectively. RESULT: In observable cases, SMH had started moving within five days after the procedure. After 6 months visual acuity had been improved 2 or more lines in 23 eyes(79%). The causes of SMH were age-related macular degeneration (17 eyes) and microaneurysm (12 eyes). The larger the size of SMH, had the greater the risk of developing vitreous hemorrhage. Twelve eyes of the 29 eyes required vitrectomy owing to vitreous hemorrhage, insufficient removal of SMH, etc. but this pneumatic procedure often eliminated the need for vitrectomy. The visual acuity of the patients with additional vitrectomy was improved with only pneumatic displacement. None of the patients had serious complications with this pneumatic procedure and the vitrectomy. CONCLUSION: The first choice for SMH is intravitreal gas injection which saves foveal function, and improves the prognosis for better vision. PMID- 18444419 TI - [Multifocal choroiditis associated with serpiginous choroiditis and choroidal neovascularization: a case report]. AB - BACKGROUND: We treated a patient with multifocal choroiditis (MFC) associated with serpiginous choroiditis and choroidal neovascularization (CNV). CASE: In a 27-year-old woman whose left eye showed serpiginous choroiditis near the optic disc and multiple irregular chorioretinal scars and exudates in peripheral and near-peripheral zones, fluorescein angiography demonstrated diffusely scattered hyperfluorescent dots and late leakage from retinal vessels. The lesion near the optic disc showed hypofluorescence in the early venous phase, and hyperfluorescence in the late phase. Sub-Tenon injection of triamcinolone acetonide did not effectively treat the CNV secondary to serpiginous choroiditis, but direct laser photocoagulation was successful, achieving improved visual acuity. CONCLUSIONS: We suggest that this patient's MFC and serpiginous choroiditis represented a single process rather than independent events. With lesions at the posterior pole, CNV developed secondarily. In this case, direct laser photocoagulation proved useful. PMID- 18444420 TI - [Structure and function of integral membrane proteins of tight junction, claudins]. PMID- 18444421 TI - Large volume autologous plasma predonation and retransfusion in orthopedic surgical patients. AB - BACKGROUND: Intraoperative washed autologous transfusion of the scavenged blood can reduce the deterioration of anemia, even during the operation with a comparatively large blood loss. On the other hand, plasma level can not be collected by this system. The preoperative donation and perioperative retransfusion of autologous plasma may reduce the plasma dilution. PURPOSE: The influence of a large volume plasma predonation and perioperative retransfusion on the plasma protein level was investigated. METHODS: Thirteen patients (63.2 +/- 13.2 yr, 70.3 +/- 12.1 kg) were examined regarding their serum protein (SP), IgG, coagulation systems, colloid osmotic pressure (COP), blood cell count before, just after, 2 h after and 7 days after the donation of 900 ml plasma by plasmapheresis with a simultaneous volume replacement. Twenty surgical patients (52.8 +/- 17.3 yr, 72.6 +/- 16.6 kg, the mean predonated autologous plasma: 2100 ml) with intra- and postoperative retransfusion of autologous plasma were examined perioperatively for SP, IgG, coagulation systems and COP. These parameters were compared with that of the predonated plasma. RESULTS: All data including SP, coagulation and COP, with the exception of IgG, completely recovered within 7 days after preoperative plasmapheresis. Perioperatively, autologous washed blood transfusion system was used. The retransfused volume of autologous predonated plasma was 1740 ml on average. Although about 41 of blood on average was lost perioperatively, only one patient out of 20 patients had to be administered homologous red blood cell transfusion. The levels of most parameters, except for COP, constantly recovered in accordance with the autologous plasma transfusion. Differences in the patterns of improvement were also observed between the parameters. CONCLUSION: A 900 ml plasma predonation can therefore be safely performed with an interval of not less than a week between the last donation and the operation. Autologous plasma retransfusion is thus considered to improve the protein levels. PMID- 18444422 TI - Successful endoscopic hemostasis for bleeding from an acquired ileal diverticulum. AB - We herein report successful endoscopic hemostasis in a patient with a bleeding from acquired ileal diverticulum. A 65-year-old woman was introduced to our hospital after the sudden onset of painless hematochezia. When emergency colonoscopy was performed, the site of bleeding could not be identified because of extensive blood pooling in the colon and ileocecal region. After admission, repeat colonoscopy with a transparent hood device after bowel preparation disclosed oozing of blood from an ileal diverticulum approximately 15 cm proximal to the ileocecal junction. We performed endoscopic therapy with injection of a hypertonic saline-epinephrine solution and placement of additional hemoclips in the diverticulum. Since the latter treatment, the patient had no recurrent hematochezia, and occult blood tests in stool had been negative. In cases of lower gastrointestinal bleeding, bleeding from an acquired ileal diverticulum should be considered and the terminal ileum carefully observed. PMID- 18444423 TI - Overcoming the shock of the new. AB - Modernising day services isn't easy, but the potential benefits are immense, for service users, staff and the wider community. PMID- 18444424 TI - The power of choice. PMID- 18444425 TI - The state of America's health: the CDC reports. PMID- 18444426 TI - Restorative success: treatment planning. PMID- 18444427 TI - The art and science of periodontal prognosis. AB - In this paper, periodontal literature related to making a periodontal prognosis is reviewed. Factors that can influence both an overall and tooth-specific prognosis are enumerated. Factors influencing the overall periodontal prognosis include age, genetics, oral hygiene, systemic conditions, and tobacco use. Tooth specific influences include the amount of attachment loss, crown:root ratio, position in the arch, and presence or absence of furcation invasions. These factors are then synthesized into a scheme for determining a periodontal prognosis. PMID- 18444428 TI - Strategic extraction: comparison of traditional and implant therapies. AB - According to the evidence-based dentistry principles, the superior treatment options should be pursued. As endosseous dental implants gain greater acceptance, the critical question is whether a tooth with a questionable prognosis should be managed conservatively in a traditional fashion or extracted in preparation for a dental implant. The evidence regarding this issue will be examined in this paper as the outcomes for various treatments are compared. PMID- 18444429 TI - Esthetic crown lengthening: appropriate diagnosis for achieving gingival balance. AB - A gummy smile poses a restorative challenge for dentists attempting to achieve ideal esthetics. Many have advocated the use of a gingivectomy or laser-assisted gingival contouring procedure. However, this simplistic approach can potentially create a mucogingival defect or a biological width violation. To avoid these periodontal-restorative complications, it is important during treatment planning to assess the anatomical relationship that resulted in the gummy smile and choose the appropriate surgical treatment to eliminate this condition. PMID- 18444430 TI - Thick vs. thin gingival biotypes: a key determinant in treatment planning for dental implants. AB - During the treatment planning process, it is important to recognize differences in gingival tissue can affect treatment outcomes. The concept that thick and thin gingival biotypes have different responses to inflammation and trauma was previously introduced. In this paper, this concept is expanded in that gingival biotypes dictate different procedures for implant site preparation. With appreciation of these differences, preparatory steps can be taken to create a more ideal implant placement site. PMID- 18444431 TI - SNAP! Liti-gators and a lawsuit with teeth. PMID- 18444432 TI - Spring 2008 in the Journal. PMID- 18444433 TI - Politics of the federal budget process. PMID- 18444434 TI - Perceptions of an ideal career versus perceptions of six health careers. AB - OBJECTIVE: This study was intended to compare and contrast young adults' perceptions of an ideal career versus their perceptions of six health professions: medical laboratory science, nursing, pharmacy, physical therapy, radiation technology, and respiratory therapy. STUDY DESIGN: The study used a survey developed by May et al., which was modified and tested for application to the allied health workforce. The instrument measures 17 parallel items on a five point Likert scale and has been assessed for reliability (coefficient a, 0.81 0.84) and content validity by a panel of experts. Analysis included descriptive statistics and paired t tests, with Bonferroni adjusted a significance set at p < 0.0028. POPULATION: The study used a convenience sample of 720 young adults aged 18 to 24 yrs who were recruited between January and September 2005 at job fairs and community events in one urban area and two adjacent rural communities in a northeastern U.S. state. FINDINGS: All six health professions were perceived as significantly less desirable (p < 0.001) than the ideal career in the areas of "being respected" and "working with high technology." "Care for people" was the third highest ranked attribute of an ideal career, and pharmacy and radiation technology were found to be statistically significantly lower in this area (p < 0.001). Only nurses were perceived as having job security that matched the ideal, with the other professions perceived as offering significantly less job security than the ideal (p < 0.001). CONCLUSIONS: Health care is increasingly dependent on highly collaborative multidisciplinary teams. Inaccurate perceptions of allied health occupations likely hamper the development of an adequate pipeline of new recruits to these professions, which has the potential to impact all health disciplines. This points to the importance of increased media/marketing portrayal of the positive aspects of careers in the allied health professions. Strategies to address this challenge and areas for further research are outlined. PMID- 18444435 TI - Dental health knowledge in a group of Black adolescents living in rural South Carolina. AB - This study investigated levels of dental health knowledge and factors associated with adequate dental health knowledge in a group of black adolescents living in rural areas. Using a self-administered questionnaire, data were collected on a convenience sample of 151 black adolescents aged 10 to 18 yrs living in rural South Carolina. The mean percent correct on the dental health knowledge questions was 55.0%. Using 75% as the cutoff for adequate dental health knowledge, only 7.9% of the respondents achieved this level. Two thirds of the younger adolescents (aged 10-12 yrs) were below the median on dental health knowledge. Respondents selected dental health professionals, family, and school as the three main sources of dental health information. Results from univariate logistic regression analyses indicated that being older, having a regular dentist for routine care, and having learned about dental health from dental health professionals, family, mass media, and friends were significantly associated with adequate dental health knowledge. After adjusting for other explanatory factors, adequate dental health knowledge was associated with being older and having learned about dental health from friends. This group of adolescents seems to have limited dental health knowledge with misconceptions concerning periodontal health and caries prevention. This was especially evident in younger adolescents. Incorporation of peer dental health education in school is worthwhile to investigate as a means to enhance the dental health knowledge of these adolescents. PMID- 18444436 TI - Differences in types and levels of altruism based on gender and program. AB - An individual's decision to enter into a career is based on several factors, such as his or her interests, personality, family, abilities, and values. This article considers altruism as a possible factor relating to the choice of a career in "helping" professions. The differences between altruism levels of students in relation to program choice and sex are examined, using both an altruism scale, which measures intention to help others in certain situations, and an interview format. Finally, qualitative results are presented to further describe possible altruistic differences between men and women. Overall, the results suggest there were no differences in self-reported altruism either between five helping programs (speech pathology, education, occupational therapy, physiotherapy and social work) or between sexes as measured by the altruism scale. However, from the interviews, men reported different altruistic reasons for entering helping professions that focused more on "society," whereas women focused more on the "individual" person. These sex differences will be discussed in light of future student recruitment. This research provides more descriptive information on altruistic motives for career choice in the helping professions than previously available. PMID- 18444437 TI - The mediating role of secondary beliefs: enhancing the understanding of emotional responses and illness perceptions in arthritis. AB - Chronic illnesses are a significant issue across many health professional domains, becoming an increasing burden on limited and costly resources. The current study investigated the relationship between secondary beliefs and emotional responses, beyond the relationship accounted for by illness perceptions, using the framework of Rational Emotive Behavior Therapy. Sixty-five adults with arthritis participated in the questionnaire-based study. Multivariate analysis found that different emotional representations of the illness were significantly predicted by the individual's secondary belief, above and beyond that predicted by the cognitive representation of their illness alone. The study found that individuals who utilized an achievement secondary belief experienced feelings of worry, whereas individuals who used an approval orientation to understand their arthritis experienced emotions such as depression, being upset, anger, anxiety, and fear. No significant pattern emerged for individuals who used a comfort secondary belief to understand their arthritis. These findings are in line with the theory of secondary beliefs, as articulated by Rational Emotive Behavior Therapy. PMID- 18444438 TI - Occupational therapy practitioners' perceptions of rehabilitation managers' leadership styles and the outcomes of leadership. AB - The purpose of this research was to serve as a pilot study to investigate the association between occupational therapy practitioners' perceptions of rehabilitation managers' leadership styles and the outcomes of leadership. Data for this study were collected using the Multifactor Leadership Questionnaire Form 5X and a self-designed demographic questionnaire. The study working sample included 73 occupational therapy practitioners. Major findings from the study indicate that overall, transformational, and transactional leadership styles are associated with leadership outcomes. Transformational leadership had a significant (p < 0.01) positive association with the leadership outcomes, whereas transactional leadership had a significant (p < 0.01) negative association with the leadership outcomes. The contingent reward leadership attribute (although belonging to the transactional leadership construct) was found to be positively associated with leadership outcomes, similar to the transformational leadership constructs. The results of this research suggest that transformational leadership styles have a positive association with leadership outcomes, whereas transactional leadership styles have a negative association, excluding the positive transactional contingent reward attribute. A larger, random sample is recommended as a follow-up study. PMID- 18444439 TI - Coming together, moving apart: a history of the term allied health in education, accreditation, and practice. AB - In recent years, several groups, including the physician assistant, health information management, ophthalmic medical technician/technologist, and athletic training review committees, have left the Commission on Accreditation of Allied Health Education Programs (CAAHEP) system to form their own, profession-specific accrediting bodies. Their motivation was typically a desire for greater professional visibility and autonomy. Combined, these professions represented one third of the CAAHEP's programs. This article reviews the history of allied health and examines current attempts to bring cohesion and identity to this increasingly fractured segment of the U.S. health care system. PMID- 18444440 TI - A clinical education and practice placements in the allied health professions: an international perspective. AB - This report describes the outcomes of extensive discussions surrounding clinical education and practice placement issues undertaken by an international group of allied health educators (in audiology, occupational therapy, physiotherapy, and speech pathology) who have met since 2001 as part of Universitas 21 Health Sciences annual meetings. The report outlines key issues associated with clinical education and practice placements from an international perspective and across these four allied health professions. The allied health practice context is described in terms of the range of allied health educational programs in Universitas 21 and recent changes in health and tertiary education sectors in represented countries. Some issues and benefits related to supervision during allied health students' practice placements are addressed. A new approach is proposed through partnership such that frameworks for the provision of practice placements can be created to facilitate student learning and educate and support clinical educators. A set of guidelines that can enhance partnerships and collaborative practice for the benefit of clinical education within complex and changing health/human service and educational environments is proposed. PMID- 18444441 TI - Is oral tramadol a reasonable PRN analgesic? PMID- 18444442 TI - Why does the pain specialist not meet the needs of the referring physicians? PMID- 18444443 TI - Do pain specialists meet the needs of the referring physician? A survey of primary care providers. AB - OBJECTIVE: To study the factors that influence the use of opioids in the management of chronic noncancer pain (CNCP) by primary care providers (PCPs) for patients returning from a pain specialist. DESIGN: A survey of PCPs. SETTING: Two physician groups in the Minneapolis-St. Paul metropolitan area. PARTICIPANTS: Two seventy-six PCPs surveyed and 80 surveys returned. MAIN OUTCOME MEASURES: Participants rated the importance of specific concerns regarding the role of pain specialists and the use of opioids in the management of CNCP. Past experience with pain specialists, comfort using opioids, and opinions regarding a trilateral opioid agreement were also examined. RESULTS: The top concerns for PCPs were as follows: the use of opioids in patients with chemical dependency or psychological issues, the escalation of opioid dosing, and the use of opioids in pain states without objective findings. They also ranked highly the importance of coordinating the return of patients from a pain specialist with explicit opioid instructions and the availability of consultation by phone or a timely follow-up visit. PCPs were supportive of the concept of a trilateral opioid agreement. CONCLUSIONS: PCPs have significant concerns regarding the prescribing of opioids in CNCP. They desire closer collaboration with pain specialists, including more explicit plans of care when patients are transferred back to them. The trilateral agreement may provide one framework for better collaboration. PMID- 18444444 TI - Patients with chronic pain on opioid therapy taking dronabinol: incidence of false negatives using radioimmunoassay. AB - BACKGROUND: Serum blood toxicology screens are believed to be important to monitor compliance and to identify levels of illicit substances in patients taking opioids for their chronic pain. METHODS: In this study, the authors examine the incidence of tetrahydrocannabinol (THC) in consecutive blood samples of patients given dronabinol. We assessed the incidence of THC in 27 patients who participated in a single-dose, double-blind crossover trial of dronabinol (Marinol capsules), a synthetic Delta9-THC, as part of a larger study, to determine the reliability of the toxicology screening. Subjects were randomly administered 10 mg or 20 mg of dronabinol or placebo over the course of three 8 hour visits for a combined 228 serum blood samples. Levels of THC were quantified using radioimmunoassay. RESULTS: The majority of the samples (57.4 percent) showed presence of study drug as expected. However, 43 samples (42.6 percent) showed no detectable evidence of THC 4 and 8 hours after administration of dronabinol. Five subjects showed lower serum levels on the higher dose (20 mg) than on the lower dose (10 mg) after 4 hours, and two subjects showed lower levels with the higher dose after 8 hours. One subject had no detectable THC on any dose of dronabinol. CONCLUSIONS: These toxicology reports point to higher than anticipatedfalse-negative results with radioimmunoassay blood serum screening. Results could be explained by the lower sensitivity of this screening technique and also in how oral cannabinoids are metabolized. Further investigations are needed on the accuracy of the detection of THC among patients known to have used dronabinol. PMID- 18444445 TI - Relationship between fentanyl dosage and immune function in the postoperative period. AB - BACKGROUND: Anesthesia and surgery are associated with impairment of the immune system expressed as an excessive proinflammatory immune response and suppression of cell mediated immunity. Opioids, an integral part of anesthetic technique, possess an inhibitory effect on both humoral and cellular immune responses. It was the aim of the present study to examine the effect of various doses of fentanyl on cytokine production during the perioperative period. INTERVENTION: The effect of large (LDFA, 70-100 microg/kg), intermediate (IDFA, 23-30 microg/kg) and small (SDFA, 2-4 microg/kg) doses of fentanyl on the immune function in the postoperative period was investigated. PARTICIPANTS: Sixty patients, randomly assigned to one of the three groups according to the dose of fentanyl were included in the study. METHODS: The ex vivo secretion of IL-1beta, IL-2, IL-6, and IL-10 and NK cell cytotoxicity (NKCC) of peripheral blood mononuclear cells (PBMC) was tested before, and at 24, 48, and 72 hours following surgery. RESULTS: The pattern of postoperative secretion of the proinflammatory cytokines IL-1beta and IL-6 and that of the anti-inflammatory cytokine IL-10 differed significantly between patients receiving SDFA and those receiving IDFA and LDFA, but was similar between the last two groups. A similar suppression of NKCC and IL-2 secretion was observed in the three groups. CONCLUSIONS: The diminished proinflammatory cytokine response observed in patients treated by LDFA and IDFA suggests that although more stable immune function can be achieved by those methods in comparison with SDFA, it is recommendable to apply IDFA to avoid the side effects that might be observed using LDFA method. PMID- 18444446 TI - The addition of haloperidol, propofol, or midazolam to sufentanil for intravenous sedation in the intensive care unit using bispectral index. AB - AIM: Inadequate sedative techniques may adversely affect morbidity and mortality in the intensive care unit (ICU), and the search for the ideal sedative agent continues. Combinations of hypnotics and opiates have are commonly used for sedation. In this study, the authors aimed to assess whether or not the addition of a haloperidol, propofol, or midazolam infusion decreased the sufentanil requirements by using bispectral index (BIS). MATERIAL AND METHODS: The study involved 60 patients in the ICU. All patients received 0.5 microg/kg sufentanil IV bolus. Immediately after, group S received 0.25 microg/kg sufentanil infusion, group SH received sufentanil infusion + haloperidol 3 mg/h infusion, group SP received sufentanil infusion + propofol 25 microg/kg/min infusion, and group SM received sufentanil infusion + midazolam 0.04 mg/kg/h infusion, for 6 hours. Average BIS values 61-80 and Ramsay Sedation Score 2-5 were kept at a range of by decreasing or increasing sufentanil levels in all groups and hourly sufentanil consumption was determined. Hemodynamic and biochemicalparameters and arterial blood gases were determined at baseline and were repeated in study hours. RESULTS: There was no significant difference in hemodynamic and biochemical parameters and arterial blood gases among the groups. Propofol, midazolam, haloperidol infusion, when added to sufentanil infusion, decreased the consumption of sufentanil in all the measured times (p < 0.001). CONCLUSIONS: The authors aimed to determine the effects of haloperidol, propofol, or midazolam infusion when added to sufentanil infusion in a short period of time. The authors found that propofol, midazolam, and haloperidol infusion decreased the sufentanil requirements in ICU patients. PMID- 18444447 TI - Effect of buprenorphine on psychomotor functions in patients on buprenorphine maintenance. AB - OBJECTIVE: Patients on buprenorphine maintenance for opioid dependence often abuse its additional doses over and above the maintenance dose. Being a psychoactive agent, it may affect psychomotor performance with all its consequences, for example, effect on quality of life. This study was conducted to assess the effects of its additional doses on psychomotor performance in patients who are maintained on it. DESIGN AND SETTING: This was an interventional study, carried out in an in-patient setting in a tertiary care national drug dependence treatment center. PARTICIPANTS: It included 19 subjects maintained on buprenorphine, 4 mg/d (s/L) for at least a month. INTERVENTION: Maintenance dose was followed by three administrations of buprenorphine, 2 mg, at two hourly intervals (cumulative dose design). MAIN OUTCOME MEASURES: Subjects were assessed on digit symbol substitution test, trail making, digit span, and delayed recall, after each administration and the next morning. RESULTS: Performance of subjects on Digit Symbol Substitution Test (chi2 = 52.98, p < 0.000) and Trail Making Test A (chi2 = 26.29, p < 0.000) and B (chi2 = 42.08, p < 0.000) improved significantly with each assessment while other tests were unaffected. CONCLUSIONS: Improvement in psychomotor performance (which could be true effect of drug itself or a result of other factors, eg, inadequate maintenance dose or practice effect) though contrasting with some of the earlier findings, does have significant clinical implications regarding the long-term use of buprenorphine. It would be worthwhile repeating this type of study in a placebo controlled design to further verify the results. PMID- 18444448 TI - Early analgesic effects of intravenous parecoxib and rectal diclofenac following laparoscopic sterilization: a double-blind, double-dummy randomized controlled trial. AB - The aim of this double-blind double-dummy randomized controlled trial was to investigate if there was any difference in analgesia between the maximum recommended doses of rectal diclofenac and iv parecoxib after laparoscopic sterilization. The authors studied 55 ASA I-II patients undergoing gynecological laparoscopy; each patient received either preoperative rectal diclofenac 100 mg and 2 mL of normal saline at induction of anesthesia, or preoperative placebo suppository and 2 mL of parecoxib 40 mg at induction. Pain intensity, sedation, and nausea were measured using a 100-mm visual analogue scale on awakening and at 1, 2, and 3 hour postoperatively. Median (interquartile range) pain intensity at rest on awakening and at 1, 2, and 3 hour postoperatively were 15 (0-40), 37 (10 56), 16 (6-29), and 13 (2-32) mm, respectively, in the parecoxib group, and 3 (0 34), 22 (5-45), 24 (6-37), and 10 (4-21) mm, respectively, in the diclofenac group. There was no significant difference in these scores. Furthermore, there was no significant difference between the two groups in sedation, nausea, rescue analgesia, or rescue antiemetic consumption. Preoperative rectal diclofenac 100 mg and parecoxib 40 mg iv at induction of anesthesia were found to have equianalgesic effects after laparoscopic sterilization. Both drugs appear to be useful after short anaesthetics. PMID- 18444449 TI - Very-low-dose ketamine for the management of pain and sedation in the ICU. AB - Management of pain in critically ill patients can be very difficult. In the attempt to provide comfort with adequate levels of opioids and sedatives, respiratory depression and cardiovascular instability may become difficult to control in patients with labile hemodynamics and poor cardiopulmonary reserve. The use of medications like ketamine, an anesthetic agent that in subanesthetic doses has been reported to be effective in preventing opioid-induced tolerance and to have analgesic properties, may be of help, especially in patients who develop tolerance, leading to rapidly escalating doses of opioids and sedatives. The case report presented here shows how a very low dose of ketamine can be helpful for the management of pain and sedation in critically ill patients, especially when they are ready to be weaned from mechanical ventilation, and very high doses of opiods and sedatives do not permit it. PMID- 18444450 TI - Fighting discrimination and stigma against people with mental disorders. PMID- 18444451 TI - Stigma and discrimination against people with mental illness: a critical appraisal. AB - This editorial gives an overview of the different roots and forms of discrimination and stigmatisation towards people with mental illness. It explains the differences between stereotype, prejudice and discrimination. It further highlights some research foci of stigma research in the last decade. The emphasis was mostly on investigating the attitudes of the general population, but barely addressed other groups that have probably more intensive and more crucial contact with people with mental illness. Furthermore, only very few intervention programs were evaluated. This editorial concludes that other groups than the general population, e.g., mental health professionals, should be investigated about their attitudes to people with mental illness. Moreover, intervention campaigns should be additionally evaluated after a given period as it is not well known whether effects of interventions are long-lasting. It might be that anti-stigma campaigns, as every public health campaign, must be repeated if sustainability is the goal. Furthermore, the message must be carefully chosen. One option is to replace the "traditional" messages by focussing, e.g., on symptoms of mental illness, for instance anxiety, affective symptoms or suicidal ideations. Finally, a plea for more stigma-related research is given as research in stigma-related issues is also stigmatised. PMID- 18444452 TI - Stigma and discrimination limit access to mental health care. AB - This editorial provides an overview of how far access to mental health care is limited by perceptions of stigma and anticipated discrimination. Globally over 70% of young people and adults with mental illness receive no treatment from healthcare staff. The rates of non-treatment are far higher in low income countries. Evidence from some descriptive studies and epidemiological surveys suggest that potent factors increasing the likelihood of treatment avoidance, or long delays before presenting for care include: (i) lack of knowledge about the features and treatability of mental illnesses; (ii) ignorance about how to access assessment and treatment; (iii) prejudice against people who have mental illness, and (iv) expectations of discrimination against people who have a diagnosis of mental illness. The associations between low rates of help seeking, and stigma and discrimination are as yet poorly understood and require more careful characterisation and analysis, providing the platform for more effective action to ensure that a greater proportion of people with mental illness are effectively treated in future. PMID- 18444453 TI - Implementing local projects to reduce the stigma of mental illness. AB - This editorial describes strategies used and the lessons learned in implementing two local anti-stigma projects. The WPA Programme to Reduce Stigma and Discrimination Because of Schizophrenia established projects to fight stigma in 20 countries, using social-marketing techniques to enhance their effectiveness. First steps at each site were to establish an action committee and conduct a survey of perceived stigma. Based on survey results, the action committees selected a few homogeneous and accessible target groups, such as employers, and criminal justice personnel. Messages and media were selected, tested, and refined. Guidelines are provided for setting up a consumer (service-user) speakers' bureau and for establishing a media-watch organization, which can lobby news and entertainment media to exclude negative portrayals of people with mental illness. Improvements in knowledge about mental illness were effected in high school students and criminal justice personnel. Positive changes in attitude towards people with mental illness were achieved with high school students, but were more difficult to achieve with police officers. Local antistigma projects can be effective in reducing stigma and relatively inexpensive. The involvement of consumers is important in working with police officers. Project organizers should be on the lookout for useful changes that can become permanent. PMID- 18444454 TI - What is an intention to treat analysis? PMID- 18444455 TI - Is there a neurobiological basis of insight in schizophrenia? PMID- 18444456 TI - Stigma and its impact on help-seeking for mental disorders: what do we know? AB - AIMS: Many people suffering from serious mental illness do not seek appropriate medical help. The stigma of mental illness has often been considered a potential cause for reluctance in seeking help. We review recent evidence on this topic. METHODS: Narrative review of the recent literature on stigma and help-seeking for psychiatric disorders. RESULTS: There is proof of a particular stigma attached to seeking help for a mental problem. Anticipated individual discrimination and discrimination qua self-stigmatisation are associated with a reduced readiness to seek professional help for mental disorders. Intervention studies show that destigmatisation may lead to increased readiness to seek professional help, but other aspects like knowledge about mental diseases seem to be at least as important. The belief that seeking help for a mental health problem is actually helpful has been shown to be at the core of help-seeking intentions and thus offers a promising target for information programmes. Population based time-trend studies show that public attitudes towards help-seeking have improved over the last decade. DISCUSSION: The relationship between help-seeking intentions and actual help-seeking needs further exploration. While many studies have been able to relate attitudes to intentions, predicting actual help-seeking has proved more difficult. PMID- 18444457 TI - Regionalised tertiary psychiatric residential facilities. AB - AIMS: Psychiatric hospitals remain the main venue for long-term mental health care and, despite widespread closures and downsizing, no country that built asylums in the last century has done away with them entirely--with the recent exception of Italy. Differentiated community-based residential alternatives have been developed over the past decades, with staffing levels that range from full time professional, to daytime only, to part-time/on-call. METHODS: This paper reviews the characteristics of community-based psychiatric residential care facilities as an alternative to long-term care in psychiatric hospitals. It describes five factors decision makers should consider: 1. number of residential places needed; 2. staffing levels; 3. physical setting; 4. programming; and 5. governance and financing. RESULTS: In Italy, facilities with full-time professional staff have been developed since the mid-1990s to accommodate the last cohorts of patients discharged from psychiatric hospitals. In the United Kingdom, experiments with hostel wards since the 1980s have shown that home-like, small-scale facilities with intensive treatment and rehabilitation programming can be effective for the most difficult-to-place patients. More recently in Australia, Community Care Units (CCUs) have been applying this concept. In the Canadian province of British Columbia (BC), Tertiary Psychiatric Residential Facilities (TPRFs) have been developed as part of an effort to regionalise health and social services and downsize and ultimately close its only psychiatric hospital. CONCLUSIONS: This type of service must be further developed in addition to the need for forensic, acute-care and intermediate-level beds, as well as for community-based care such as assertive community treatment and intensive case management. All these types of services, together with long-term community-based residential care, constitute the elements of a balanced mental health care system. As part of a region's balanced mental health care plan, these Tertiary Psychiatric Care Facilities have the potential to act as hubs of expertise not only for treatment, rehabilitation, community integration and service co ordination for the severely mentally ill, but also for research and training. PMID- 18444458 TI - Developing mental health services in response to research evidence. AB - Over the last thirty to forty years, psychiatric care in England has relocated from hospital-based settings to community mental health teams (CMHTs) and supported accommodation. Since the 1980s, two forms of intensive home based treatment have evolved in addition to CMHTS, assertive community treatment (ACT) and crisis resolution teams (CRTs). On the basis of evidence for their efficacy in the US and other countries, they have been implemented across England through the Government's National Service Framework for Mental Health. This paper describes this evidence and the first UK studies that were carried out to evaluate these newly implemented services. METHODS: Descriptions of the evaluations of ACT and CRTs in the inner London boroughs of Camden and Islington. RESULTS: The implementation of CRTs in North London were associated with reduced use of inpatient services, but the ACT teams were not. Both types of team were associated with greater patient satisfaction with services and the ACTs were better able to engage patients than CMHTs. CONCLUSIONS: The authors comment on the implications of the findings for service planners in terms of the difficulties in implementing innovative approaches based on the best available evidence when it originates outside the local context. PMID- 18444459 TI - [Residential facilities and day centres in mental health. Is there any difference?]. AB - AIMS: We wanted to investigate to what extent and in what characteristics the patients cared in the psychiatric residential facilities (RF) were similar to those in the day-centres (DC), and whether 6-month improvements in the two settings were comparable. METHODS: We described 141 patients admitted to the RF and 180 in DC of three mental health service networks in Milan and near Milan. They were evaluated again after six months. RESULTS: In both groups, we identified subgroups of more intensive treatment: 45% of those in residential treatment were in high intensity rehabilitation facilities, and those who followed a residential program of >12 hours/week were 53%. The mean duration of treatment in the residential treatment was 40 months (SD 55.7) and in DC 49.6 months (49.3). The two groups differed in the overall scores of the HoNOS, but differences emerged in the subscales relative to daily life activities and living conditions. Among those in RF, about half had a house, versus 99% among those in DC. After six months, clinically significant modifications were small in both groups. CONCLUSIONS: Residential patients had more needs than DC patients. It is possible that some of the residential patients might be treated with intensive DC program, but the absence of a home for the majority of residential facilities patients makes this unlikely. PMID- 18444460 TI - [The communication of the diagnosis of schizophrenia. Focus group findings on psychiatrists' point of view]. AB - AIMS: Evidence from the literature show that patients affected by psychosis rarely are informed about their diagnosis and/or involved in the decision making process regarding the therapeutic program. The aim of the present study is to investigate psychiatrists' clinical experiences, beliefs and attitudes towards communicating the diagnosis to patients affected by psychosis. METHOD: Three focus groups were conducted with 28 psychiatrists of different levels of expertise (10 senior psychiatrists and 18 psychiatrists in training), all working at the South-Verona Community-based Mental Health Service. The group discussions were audiotaped and transcribed. The authors derived different thematic categories which were used by two raters to classify all contributions of the psychiatrists. RESULTS: The main themes of interest which emerged were: experience with the communication of the diagnosis of psychosis and main communication strategies used; obstacles and personal difficulties in giving such information. CONCLUSIONS: In the psychiatric setting the disclosure of the diagnosis of psychosis implies different clinical and ethical issues and is felt as highly problematic. These findings suggest a need of psychiatrists to involve the psychotic patient in the information giving process in order to learn his/her informative needs which are the starting point for individually tailored information. The authors have no potential conflict of interest related to the subject of the paper. PMID- 18444461 TI - Does HIV serostatus affect outcomes of dually diagnosed opiate dependents in residential treatment? AB - BACKGROUND: Little is known about specific treatment needs of mentally ill clients abusing substances and infected by HIV. The major gap concerns residential programmes. AIMS: To explore differences in outcomes between seropositive and seronegative dually diagnosed opiate dependent clients who participated in a residential therapy programme. METHODS: Data were gathered on 154 clients treated in a therapeutic community in Milan between October 1999 and September 2004. Odds ratios with 95% confidence intervals were used to study the association between HIV serostatus and outcome. RESULTS: At 12-month followup, seropositive clients were more likely to relapse. CONCLUSIONS: The impact of HIV seropositivity on behavioural outcomes should be taken into consideration when planning residential programmes for the HIV (+) dually diagnosed population. Further research could test the need of incorporating dedicated treatments into existing programmes. PMID- 18444462 TI - [Clinical and sociodemographic features associated with the high and prolonged utilization of resources by outpatients of a community psychiatric service]. PMID- 18444463 TI - [Legal consideration of permit issuance under Article 11 par. 1 no. 3 letter(d) of the German Animal Welfare Act]. AB - The article looks at the legal situation concerning the permission for commercial activities with animals due to Article 11 par. 1 no.3 (d) of the German Animal Welfare Act, in particular in combination with activities at changing places. Regardingly the German legislator has recently (especially since 1998) started to approach the problems of animal welfare by adopting specific regulations, e. g. by enacting an obligation to inform the authority of the planned change of place of activity. Currently the legislator discusses an extension of the enabling act for an ordinance by the Federal Government on the central register for circusses. Standardized data collection and transmission shall contribute to an effective control of the companies' compliance with animal welfare law. Article 11 par. 2a of the German Animal Welfare Act is an important regulation concerning activities at changing places. It allows to combine the permission with time limits, conditions and impositions of duties. Such collateral clauses can be set down to keep an animal stock book or--in a wider sense--a documentation of the company's activities to guarantee an effective control by the authority. In the case of American rodeo shows it is to mention that collateral clauses to introduce more animal welfare are imposed by the local authorities responsible for the area where the shows will take place rather than by the authority which actually has given the permission. The authorities have to distinguish subsequent collateral clauses or directives on one hand and the revocation of the permission on the other hand, since in this case the requirements are more strict. The recent preliminary judicial decisions of the administrative courts concerning this legal problem are contradictory so that they cannot serve as a guideline for the authorities. PMID- 18444464 TI - [Implementation of cross-compliance in the area of animal welfare]. AB - From 1 January 2007, requirements concerning animal welfare were introduced with effect to cross-compliance. Farmers receiving single payment as well as agri environmental payments (payments of second pillar) shall respect the statutory management requirements of the following 3 directives in the area of animal welfare: Council Directive 91/629/EEC laying down minimum standards for the protection of calves; Council Directive 91/630/EEC laying down minimum standards for the protection of pigs; Council Directive 98/58/EC concerning the protection of animals kept for farming purposes. The competent authority shall carry out annual systematic inspections on at least 1% of all farmers submitting payments on the basis of a risk analysis and partly at random. In case of non-compliance with the conditions due to specific rules, there will be a reduction or cancellation of the payments to be granted in the calendar year in which non compliance occurs. Cross-compliance controls should take place on the basis of documented procedures so as to ensure that these controls are carried out uniformly and are of a consistently high quality. For this purpose, a working group composed of representatives from the Federal Ministry of Food, Agriculture and Consumer Protection and from the Lander developed uniform control reports in order to monitor compliance and a guidance booklet for control execution of animal welfare requirements. In the control report (Level 1), the outcomes of inspections of all systematic testable animal welfare requirements are summarized in 6 items. Furthermore, the non-systematically testable requirements are integrated in the control report as a independent item. The guidance booklet (Level 2) with a matrix of validation serves as a specification for on-the-spot checks. Where appropriate, on-the-spot checks provided for cross-compliance and any other checks in animal welfare rules as well as requirements to animal identification and registration shall be carried out at the same time in Baden Wurttemberg (integrated control system). Farmers subjected to on-the-spot checks shall be selected on the basis of a centralized common risk analysis and partly at random. This is the best way of safeguarding that the control rate will not be much higher than the established 1% with a minimum administrative burden and costs for farmers and competent control authorities. Integrated check lists for on-the-spot checks were established which take into account systematic cross compliance inspections to improve compliance with 3 existing standards in the area of animal welfare and official controls as proved in Council Directives concerning animal welfare and Regulation (EC) No 882/2004. All staff of the competent authorities performing controls received, for their area of competence, appropriate training enabling them to make their duties competently and to carry out controls in a consistent manner. Integrated systematic controls are very time consuming and a burden for farmers and the competent authorities. For the beginning of this year, we will expect a discharge by Decision (EC) 2006/778. A controlling system was installed to ensure that cross compliance rules are applied consistently, for example by making subsequent controls by controlling institutions. PMID- 18444465 TI - [Animal welfare guideline of Lower Saxony for the keeping of dairy cows]. AB - In May 2007 a working group passed a guideline, which deals with requirements for the indoor keeping of dairy cows to perform Article 2 of the animal welfare legislation. The guideline should support the local district veterinary authorities and the stockman in the animal welfare judgement both of new and rebuilding as well as already existing stables. Whereas for new buildings minimum standards for the protection of cows are put together and beyond that additional recommendations for more "cow comfort" are given, for old buildings only standard values are presented. The guideline mentioned especially those aspects, which from previous experience always gives cause for discussion. For example: size and construction of cubicles, width and floor design of passageways or the relation between the number of animals and the number of feeding places and cubicles. All together the guideline enables the local district veterinary authorities in Lower Saxony to judge the keeping of dairy cows following equal standards. This leads to confidence in planning and investment for the livestock owners. PMID- 18444466 TI - [Import of dogs by public animal shelters and private animal protection societies]. AB - Every year thousands of dogs from EU Member States and third countries are brought to Germany by private animal protectionists, animal protection societies and public animal shelters offering them for an average charge of 250,00 Euro each. In addition to violations of current legal regulations, there might also be real crime offence behind the matter. Moreover, people, especially children, are increasingly endangered by various infectious diseases imported to Germany and spreading throughout the country as well as by dogs suffering from bad deprivation damage. The fact that the new owners are often not told the truth about the dogs'foreign origin is another problem. They are often marked with a chip after being brought to Germany and only then they are provided with a national vaccination record or a German pet passport. Finally the question arises whether the "rescue" of dogs and finding a place for them in Germany is just "big business"--for animal protection societies, practitioners, dog shelters, dog psychologists and the media. PMID- 18444467 TI - [Animal welfare in prevention and therapy of laminitis]. AB - Laminitis is a systemic disease which is manifested as a non infectious condition in the foot. The management of feeding and housing conditions is necessary to treat the endocrinological and metabolic disturbances of laminitic horses. The Equine Metabolic Syndrome (EMS) is predisposing for developing laminitis, and it is characterised by obesity, insulin resistance, hypertension and dyslipidaemia. A genetical predisposition is supposed and EMS is accompanied by a lack of exercise and inadequate energy intake. Laboratory examinations are of great importance for diagnosis. Analyses of insulin, glucose and ACTH are of interest. Several approaches to treat laminitis are available, including pharmacological and orthopaedic strategies as well as the management of the feeding and housing conditions. However, the prophylaxis to prevent laminitis has to be emphasised. Predisposed horses should be detected and adequately treated; especially weight reduction in obese horses is in the focus of interest. Horses in the acute stage of laminitis have to be stabled. Furthermore redistributing weight from the most stressed wall is necessary to prevent pain and to minimise laminar damage and displacement of the distal phalanx. In cases of displacement of the distal phalanx a close communication between the veterinarian and the authorised farrier is necessary, in these cases treatment should be supported by x-ray diagnosis. Horses have to be treated with NSAISs to ensure a proper therapy to consider animal welfare. Horses have to be fed with hay and supplemented with minerals and vitamins. Feeding exclusively straw and feed restriction has to be avoided. PMID- 18444468 TI - ["Reasonable cause"--an undefined legal term for the justification of the killing of equids]. AB - Killing of a vertebrate animal in Germany is allowed or not punishable only if a "reasonable cause" can be identified (Article 17 No. 1 TierSchG). A legal definition of the term "reasonable cause" does not exist. Currently the following definitions of the "reasonable cause" for the killing of equids are accepted: 1. Slaughter (in accordance with the equid pass and waiting periods) reasonable cause: Food production, initiated by the owner's desire. The requirements for slaughter of a sick animal or an emergency slaughter are defined through EU legislations. 2. Euthanasia (in its original meaning) Reasonable cause: a) Compassion, initiated through medical indication b) scientific purposes (experimental animals) initiated through governmental authorization of a research request c) Epidemiological reasons initiated through veterinary legislative measures. According to the law for the protection of animals (TierSchG) "non curable pain or suffering" is a prerequisite for the killing of an animal because of a medical indication. Presuming an adequate knowledge base of the veterinarian this should leave enough room for an adequate medically reasoned decision. However, both a faulty veterinary explanation of a reasonable cause and an undue delay of the euthanasia (follow Article 17) can lead to an illegal punishable act (severe pain or suffering). Examples of veterinary medical indications for euthanasia will be presented. In addition, the question whether euthanasia can be considered as an alternative to treatment will be discussed. Finally, the more restrictive interpretations of the "reasonable cause" put forth by insurance companies will be explained. Future higher court decisions should lead to an adaptation of the insurance companies' interpretations of the "reasonable cause" to the outline presented above. PMID- 18444469 TI - [Fattening bull raising--alternative housing on slatted floors]. AB - Rubber topped slatted floor gives more lying comfort to intensive fed fattening bulls, reduces risks of integument lesions as well as increases their locomotion comfort. On the other side there are more fissured alterations and defects in the sole and heel horn due to lack of sufficient wear away which often made the bearing surface to be overgrown. Overgrown claws are also seen on solid slatted floors, but these horn parts were normally grated down in short time that frequently goes along with abrasions of the claw peak and the wall horn as well. The current experiences of our study show favour to the use of a floor that combines hard and soft qualities. Weak claw performance and health has a link to a bad state of cleanness of the pens and the animals as well and must be assessed with regard to permanent wetness on the grounds. Animals out of greater pens are less dirty because the solid floor becomes sooner dry than in cases with higher crowding degrees of animals. More space per animal and higher comfort gives chance for higher daily weight gain. The recordings and evaluations of this project are still in progress. PMID- 18444470 TI - [Training of dogs--legal assessment of the use of electric collars]. AB - The use of an electric collar for training dogs is fundamentally forbidden. The verdict of the Federal German Administrative Court dated February 23, 2006 (ref. 3 C 14.05) provides legal clarity and indicates the approach to be taken to enable exceptions from the fundamental ban on electric collars. It is particularly to prevent the misuse of electric collars in the interests of animal welfare that federal legislation should further develop the approach specified in 1998 by including Article 3, No. 11 of the German act on the prevention of cruelty to animals (TierSchG). In this context, it is recommended to continue intensive specialist debate on the question of whether and, where applicable, to what extent the use of electric collars may be permitted, e.g. within the context of training dogs. PMID- 18444471 TI - The use of video as a pedagogic tool for the training of perioperative nurses: a literature review. AB - This review of the literature considers the use of video as a pedagogic tool (teaching instrument) for the training of new perioperative nurses. The literature review seeks to address the question of which usage of the video medium can be integrated into the education of new OR nurses. Kolb's model of experiential learning, whereby knowledge is acquired by transforming experience into new ways of thinking and behaviours, is the theoretical framework used to analyze the pertinent literature. The selected articles were obtained from the following search engines: CINAHL, ERIC and PSYCH INFO. In addition, articles were obtained from experts in the clinical field. The reviewed literature can be classified into three main categories: the use of video to demonstrate content; the use of video for self-analysis; and the integration of video in to multimedia teaching programs. PMID- 18444472 TI - Vancomycin-resistant enterococci (VRE) and the role of the healthcare worker. AB - Antibiotic resistance has increased dramatically within the last decade. The spread of antibiotic resistant strains of bacteria has become a threat within hospitals. Vancomycin-resistant enterococci (VRE) has emerged as one of these strains. VRE is a robust microorganism and can survive for long periods of time on environmental surfaces. VRE spreads quickly from patient to patient through contact with health care workers. This strain can increase the mortality rate in immuno-compromised patients. Hospital health care workers have an important role to play in the prevention and control of VRE. Proper, and frequent, hand-washing significantly contribute to preventing and controlling the spread of VRE. Providing health care workers with education and resources is also a key factor. The health belief model helps to explain how to approach and implement changes to practice. PMID- 18444473 TI - Bossonomics destructive leadership. PMID- 18444474 TI - Reliability of the perceptual evaluation of adductor spasmodic dysphonia. AB - OBJECTIVES: Although perceptual assessment by experienced voice clinicians remains the gold standard for the diagnosis and assessment of severity of adductor spasmodic dysphonia (ADSD), the interrater reliability of voice experts for this task has not been assessed. In addition, it is unknown whether telephone recorded or -transmitted voice samples could be used for this task. The aims of this study were (1) to assess the reliability of perceptual analysis of ADSD severity by voice experts and (2) to compare the results between digitally recorded voice samples and those recorded over the telephone. METHODS: Five laryngologists randomly selected voice samples from 46 ADSD patients and rated the severity of ADSD on a 5-point rating scale. A set of digital voice recordings and a set of telephone voice recordings made from filtering the digital set via the telephone were rated, and each voice set was rated twice. Measures of intrarater and interrater reliability, as well as a measure of the probability of agreement among the raters, were calculated. RESULTS: There was a high level of agreement on ADSD severity, with excellent interrater and intrarater reliability (Cronbach's alpha, .93 to .96). The probabilities of rater agreement on the digitally recorded and telephone-filtered voice samples were similar (chi2, p = .07). The ratings of digital versus telephone voice samples were highly correlated (Pearson r, 0.99; p < .001). CONCLUSIONS: These results demonstrate that voice experts are reliably able to judge and agree on the severity of ADSD. Telephone-filtered voices appear to convey adequate ADSD perceptual cues for expert listeners to judge the severity of spasmodic dysphonia. PMID- 18444475 TI - Pilot study of universal newborn hearing screening in Japan: district-based screening program in Okayama. AB - OBJECTIVES: Newborn hearing screening was started in Okayama Prefecture in 2001 as part of a nationwide pilot study in Japan. Nearly 50,000 infants have been screened to date, and an observational study and more than 2 years of follow-up of this population are described in this report. METHODS: Between June 2001 and March 2005 (45 months), 47,346 neonates were screened with automated auditory brain stem response systems and followed up for at least 2 years. This total corresponds to 95% of the infants born in the 44 gynecologic institutions in this district. RESULTS: After undergoing the screening process twice, 248 infants (0.52%) received referrals; 108 of them had apparent bilaterally affected hearing, and 140 had apparent unilaterally affected hearing. Among the bilateral cases, hearing impairment was diagnosed in 40 infants, for a total prevalence of hearing impairment of 0.08%. In 3 additional infants who received a bilateral pass result and 1 infant who received a unilateral pass result, hearing impairment that was progressive or of late onset was subsequently diagnosed. The positive and negative predictive values were calculated as 40% and 99.993%, respectively. CONCLUSIONS: The screening program was carefully designed to work in the Japanese society and to be well managed in Okayama Prefecture. PMID- 18444476 TI - Oropharyngeal kaposi sarcoma in related persons negative for human immunodeficiency virus. AB - OBJECTIVES: Kaposi sarcoma (KS) is a vascular tumor that can affect the mucosa of the upper aerodigestive tract. Although KS is the most common malignancy in patients with acquired immunodeficiency syndrome, it is rare in immunocompetent persons. We describe an unusual presentation of KS in 2 related individuals and describe our attempts to determine whether oropharyngeal KS is associated with human herpesvirus 8 (HHV-8). METHODS: All relevant clinical and surgical information, including information on tumor histopathologic and human immunodeficiency virus (HIV) serologic tests, was abstracted from the patient charts and electronic databases. HHV-8 immunohistochemistry was performed on paraffin-fixed specimens. RESULTS: Both patient 1 and patient 2 (the nephew of patient 1) were referred for workup of a tonsillar mass that was pathologically confirmed to be KS. In each case, HIV serologic testing was negative, and a screening immunologic workup, including a quantitative natural killer cell count, a B- and T-lymphocyte count, and immunoglobulin analysis, also yielded findings that were within normal limits. Immunohistochemistry performed on 1 pathological specimen showed positive staining for the presence of HHV-8, the etiologic agent of KS. CONCLUSIONS: The presence of oropharyngeal KS in 2 related HIV-negative individuals supports a role for genetic factors in susceptibility to KS, a common exposure to an infectious agent such as HHV-8, or both. Whereas most KS cases in industrialized countries are associated with immunodeficiency, clinical and laboratory data do not suggest that either of the patients described in this report are immunodeficient. Their susceptibility to KS may be secondary to a subtle inherited defect in host resistance to HHV-8, or another unknown factor. PMID- 18444477 TI - Image-guided endoscopic orbital decompression for Graves' orbitopathy. AB - OBJECTIVES: We studied the efficacy and safety of image-guided balanced orbital decompression for Graves' orbitopathy. METHODS: The data of 24 patients (45 orbits) were reviewed for demographics, ophthalmologic outcomes, and complications in regard to image-guided (18 orbits) versus non-image-guided surgery (27 orbits). RESULTS: Overall, all patients had a reduction in proptosis (mean reduction, 6.2 mm in proptosis) as measured by Hertel exophthalmometry. There was improvement in the visual acuity of all 12 orbits with preoperative acuity of 20/40 or worse and either complete resolution (38%) or improvement (62%) in the 16 orbits with optic neuropathy. These measures reached statistical significance. Despite subjective improvement in surgeon confidence, the use of image guidance did not result in a statistically significant difference in postoperative ophthalmologic outcomes. Medical and sinonasal complications were experienced by 11.1% and 18.5% of patients who underwent image-guided and non image-guided orbital decompression, respectively. CONCLUSIONS: Image guidance may be a useful adjunct to balanced orbital decompression for Graves' orbitopathy, but it was not associated with a statistically significant improvement in outcomes in this study. PMID- 18444478 TI - Sequential bilateral hearing loss in multiple sclerosis. AB - OBJECTIVES: We describe a case of multiple sclerosis presenting with sequential bilateral hearing loss. METHODS: A 46-year-old woman underwent a series of audiological and neurologic evaluations for sequential bilateral hearing losses that occurred 6 months apart. RESULTS: Initially, the patient suffered from sudden left hearing loss, and magnetic resonance imaging documented an enhancing lesion in the left middle cerebellar peduncle. Six months later, another episode of sudden vertigo, right hearing loss, and right facial palsy developed. Magnetic resonance imaging disclosed a new lesion in the right middle cerebellar peduncle. CONCLUSIONS: Sequential bilateral hearing loss may be a manifestation of multiple sclerosis. In younger patients with sudden hearing loss, multiple sclerosis should be included in the differential diagnosis. PMID- 18444479 TI - Expression and clinical significance of epidermal growth factor receptor and type 1 insulin-like growth factor receptor in nasopharyngeal carcinoma. AB - OBJECTIVES: Epidermal growth factor (EGF) and type 1 insulin-like growth factor (IGF-1) receptors play an important role in the growth and apoptosis of nasopharyngeal carcinoma (NPC). They were separately found to be associated with prognosis in patients with NPC. To date, their expression correlation and clinicopathologic significance have never been specifically addressed in NPC. METHODS: Seventy-five patients with NPC and 21 noncancerous nasopharyngeal epithelial samples were accrued between 1998 and 2006 in a single hospital. The expressions of EGF and IGF-1 receptors were detected by immunohistochemical staining in the 75 NPC samples and the 21 noncancerous samples. Furthermore, the messenger RNA and protein expressions were assessed by real-time quantitative polymerase chain reaction and the Western blot technique, respectively, in NPC cell lines and normal nasopharyngeal epithelial cells. RESULTS: The 5-year survival rates, assessed by the Kaplan-Meier method, were 71.4% and 66.6% in the EGF and IGF-1 receptor protein-negative groups, respectively, whereas they were only 28.6% and 33.3% in the receptor protein-positive groups. The levels of these two proteins significantly correlated with each other, and the overexpression rates of EGF and IGF-1 receptors were 65.3% and 56% in nasopharyngeal samples, respectively. Furthermore, both protein expressions were significantly higher in NPC patients with cervical lymph node or distant metastasis than in NPC patients without lymph node or distant metastasis. Recurrence more often appears in cases positive for both proteins than in cases negative for both proteins. The expression levels of the receptor messenger RNA and proteins were higher in several NPC cell lines than in normal nasopharyngeal epithelial cells. CONCLUSIONS: These findings demonstrate that both receptor proteins may play an important role in the invasion, metastasis, and recurrence of NPC. Both receptors are valuable markers for assessing the prognosis of NPC. Their expression at such high frequencies provides the basis of combined targeted therapy with specific pharmacologic inhibitors to enhance the effects of radiotherapy and chemotherapy. PMID- 18444480 TI - Clinical and pathologic predictors of survival in patients with squamous cell carcinoma of the hypopharynx after surgical treatment. AB - OBJECTIVES: Hypopharyngeal squamous cell carcinoma (HPSCC) usually presents at an advanced stage. Although chemoradiotherapy has become more popular in treating HPSCC in recent years, surgery with postoperative adjuvant therapy still plays an important role. The purpose of this study was to identify the clinicopathologic factors that predict survival in patients with HPSCC who underwent surgical treatment. METHODS: Between 1986 and 1995, 94 previously untreated HPSCC patients who underwent surgery with or without postoperative radiotherapy were enrolled. The surgical specimens were reexamined by a single pathologist. The clinicopathologic parameters and prognostic data were analyzed. RESULTS: With a median follow-up of 50 months, the 5-year overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) were 47%, 60%, and 58%, respectively. Thirty-seven patients (39%) had tumor recurrence. The level of lymph node metastasis was an independent factor in OS, DSS, and RFS. Neck biopsy before surgery, tumor involvement of more than 1 subsite, and extracapsular spread were independent factors in DSS, as was lymphovascular permeation in RFS. CONCLUSIONS: The level of cervical lymph node metastasis is the only independent prognostic factor in OS, DSS, and RFS. The addition of postoperative chemoradiotherapy may benefit high-risk cases. PMID- 18444481 TI - Bilateral stapedectomy: association between first- and second-ear surgical findings and their effects on the second-ear outcome. AB - OBJECTIVES: We assessed the association between first-ear and second-ear surgical findings in patients undergoing second-ear stapedectomy for bilateral otosclerosis and the impact of such findings on the audiometric outcome of the second ear. METHODS: A retrospective chart review of all stapedectomy patients who underwent stapes surgery by one of two surgeons in a single tertiary referral institution from 1962 to 2001 was performed, and those patients who underwent bilateral stapedectomy were identified. Patient demographic data, surgical findings, procedure performed, and preoperative and postoperative audiometric data were recorded. RESULTS: A total of 459 patients (918 ears) underwent bilateral stapedectomy for bilateral otosclerosis during the study period, of whom 426 had complete data for analysis. The finding of a white or obliterated footplate in the second ear was significantly higher if the first ear had this disease manifestation (p < .001, chi2 test). The association between a second drill-out's being performed and a drill-out in the first operation was significant (p < .001, chi2 test). Statistical analysis identified that those who underwent a drill-out procedure had a 2.9-fold increase in unsuccessful outcome in comparison to those who did not have a drill-out (odds ratio, 2.89; 95% confidence interval, 1.41 to 5.89). Facial nerve anomalies were infrequently encountered, affecting only 23 patients, of whom 3 had bilateral abnormalities. The finding of an overhanging or dehiscent facial nerve in the second ear was significantly more likely if such an abnormality was identified during the first procedure (23% versus 2.5%; p = .005, Fisher's exact test). CONCLUSIONS: Second ear hearing results are poorer in those who require a drill-out of this ear, and this is more likely to be required if a drill-out was required in the first ear, regardless of a successful outcome of the first procedure. Patients should be aware of the reduced likelihood of success in these cases and be counseled regarding risks and benefits of second-ear surgery based, in part, on the findings from the first ear. This study confirms that bilateral advanced footplate obliteration and overhanging or dehiscent facial nerves may be anticipated in patients found to have these abnormalities during first-ear stapedectomy. PMID- 18444482 TI - Effects of cochlear nuclei electrical stimulation with surface brain stem implants in nonhuman primates. AB - OBJECTIVES: We undertook morphological evaluation of the cochlear nucleus complex (CNC) after implantation of a surface auditory brain stem implant (ABI). METHODS: We used 14 nonhuman primates (Macaca fascicularis). They underwent translabyrinthine bilateral auditory deafferentation and simultaneous unilateral implantation of an ABI. In 6 cases the ABI was not activated, whereas it was activated in 8 cases. The ABI array consisted of 3 platinum disc electrodes mounted on a silicone pad with the back side covered with polyethylene terephthalate mesh, connected via a cable to an external stimulator in animals undergoing electrical stimulations. RESULTS: All animals tolerated the procedures well. In both groups of animals, neuropathologic lesions or changes attributed to surgical trauma were found. The biotolerance of neural tissue to the materials used was adequate. The stimulation times ranged from 0 to 732 hours. Neuropathologic examination and stereological assessment revealed that the animals showed no signs of significant neural damage after CNC chronic stimulation if this took place within the safety limits. Time of stimulation did not seem to play a significant role in changes. CONCLUSIONS: Besides surgical trauma, the most important factors responsible for CNC changes are the electrical stimulation parameters. PMID- 18444483 TI - Inflammatory cytokine responses to synthetic extracellular matrix injection to the vocal fold lamina propria. AB - OBJECTIVES: We determined cytokine profiles for tumor necrosis factor alpha (TNF alpha), interleukin (IL)-6, IL-1alpha, and IL-1beta after injection of a synthetic extracellular matrix into the vocal fold lamina propria. METHODS: Transcript expression of inflammatory cytokines was measured with real-time polymerase chain reaction on postoperative days 1, 3, 5, 10, and 21 in 25 rabbits that underwent bilateral vocal fold biopsy with Extracel-LG (Carbylan-GSX 5%) immediately injected into the wound in the left vocal fold and saline solution injected into the wound in the right vocal fold. Two unwounded normal rabbit larynges were also harvested for controls. RESULTS: Significantly elevated levels of TNF-alpha, IL-1beta, and IL-6 were measured on day 3 in a comparison between Extracel-LG-injected vocal folds and saline solution-injected control vocal folds and between Extracel-LG-injected vocal folds and normal vocal folds. All cytokine levels returned to baseline by day 21. CONCLUSIONS: A mild short-term inflammatory response was measured early after injection of a synthetic extracellular matrix into the vocal fold lamina propria. PMID- 18444485 TI - The measurement of nasal airway and other things. PMID- 18444484 TI - Changes in cytokine signaling and extracellular matrix production induced by inflammatory factors in cultured vocal fold fibroblasts. AB - OBJECTIVES: Modulating cytokine signaling in vocal fold fibroblasts after injury may influence extracellular matrix (ECM) production and eventual fibrotic outcome. To evaluate previously established in vivo cytokine and ECM gene expression hypotheses, we examined in vitro vocal fold fibroblast responses to exogenous inflammatory factor stimulation. METHODS: Rat vocal fold fibroblast lines derived from explants were separately treated with interleukin-13 (IL-13), interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta subtype 1 (TGF-beta1), or prostaglandin E2 (PGE2). We examined the in vitro messenger RNA expression profiles of IL-1beta, IFN-gamma, TNF-alpha, TGF-beta1, and cyclooxygenase 2 (COX-2), as well as those of hyaluronic acid synthase (HAS) 1, HAS-2, procollagen subtype 1, and procollagen subtype 3, at 1,4, 8, 16, 24, and 72 hours after treatment, and compared them to those of untreated fibroblasts and in vivo data, using real-time reverse transcription-polymerase chain reaction. RESULTS: IL-1beta and TNF-alpha induced each other and synergistically increased HAS-1 and HAS-2 expression. PGE2 also up-regulated HAS-1 and HAS-2 expression. IFN-gamma, IL-1beta, TNF-alpha, and TGF-beta1 up-regulated HAS expression alongside either transient up-regulation of, or no change in, procollagen 1 and 3 expression. Most treatments appeared to suppress procollagen expression, possibly through HAS up-regulation. All inflammatory factors attenuated TGF-beta1 expression. CONCLUSIONS: These results confirm several in vivo trends, identify potential cytokine pathways and therapeutic candidates, and suggest the utility of this in vitro setup for future studies. PMID- 18444486 TI - Treatment alternatives for chronic rhinosinusitis persisting after ESS: what to do when antibiotics, steroids and surgery fail. AB - BACKGROUND: It is estimated that over 500,000 individuals in the United States currently suffer from chronic rhinosinusitis (CRS), which has persisted or recurred despite maximal medical therapy and endoscopic sinus surgery (ESS). Management of these individuals remains uncertain, as recent published guidelines on CRS do not extend to this population. OBJECTIVE: Our objective is to provide a framework for the management of patients who fail standard therapy for CRS while providing recommendations based on the strength of the evidence for alternative medical therapies that can be used for the treatment of recurrent CRS. This guideline targets ENT physicians and allergists managing this increasingly frequent clinical situation and attempts to assist them in selecting from the increasing array of potential therapies available. To this end, factors contributing to the pathophysiology of post-ESS CRS are reviewed to identify method of action of existing and potential therapies and recommendations are made for their use. RESULTS: Given the accessibility of the sinus cavities after ESS, topical therapies are privileged. Saline spray or irrigation is recommended for all patients. Corticosteroids in oral or topical forms are recommended for controlling the inflammatory component, while the use of a short term course of oral or topical antibiotics are recommended mainly for the treatment of exacerbations. Long-term therapy with oral macrolides is also recommended as an alternative therapy. Desensitization with acetylsalicylic acid (ASA) for individuals with documented ASA sensitivity is recommended where available, while revision surgery, anti-leukotriene agents and intravenous immunoglobulins are options in management in selected patients. Antifungal therapy is not recommended. No recommendations for potentially experimental strategies are made in the absence of published experience and safety data in human subjects. PMID- 18444487 TI - Nasal lavage with sodium hypochlorite solution in Staphylococcus aureus persistent rhinosinusitis. AB - OBJECTIVE: To determine a selected concentration of sodium hypochlorite (NaOCl) in saline solution for nasal lavage and evaluate its clinical efficiency in the treatment of symptomatic patients with persistent, Staphylococcus aureus (SA) associated rhinosinusitis (RS). MATERIAL AND METHODS: In vitro tests for cilia and epithelial cell viability were done on reconstituted primary epithelial cells in vitro. Cells were exposed for 5 and 15 minutes twice daily for 5 consecutive days to one of the following conditions, (1) saline, (2) 0.5% NaOCl in saline, and (3) 0.05% NaOCl in saline. In order to evaluate tolerance, immunostaining was done for ezrin and F-actin network and observed with confocal microscopy. The patients (n=20) were all persistent SA symptomatic carriers, with unique patient specific SA clonotypes, and multiple infection recurrence despite effective systemic antibiotic therapy. Each patient applied first saline alone for 3 months followed by saline + 0.05% NaOCl solution, as nasal lavage twice daily on both nostrils for 3 months. Symptom intensity and endoscopic findings were recorded with visual analogue scale (VAS). Nasal airway resistance (NAR) and nasal Nitric Oxide (NO) levels were measured before and after the saline lavage regimen, and after the saline + NaOCl treatment. RESULTS: F-actin network loss and decreased expression of ezrin were significant in cells exposed to 0.5%, but not in those exposed to 0.05% NaOCl. These changes were more obvious when exposed for 15 min. than 5 min. daily. The nasal lavage with 0.05% NaOCl in saline was well tolerated and a significant improvement in nasal obstruction (p = 0.001), posterior nasal discharge (p = 0.018), olfaction (p = 0.007) and headache (p = 0.009) was demonstrated. Significant improvement was also recorded in nasal endoscopic grading of oedema (p = 0.001), erythema (p = 0.001), purulent discharge (p = 0.002), nasal crusts (p = 0.001), and NAR (p = 0.05) as measured by rhinomanometry. There was no significant improvement in nasal NO production or subjective anterior nasal discharge. Bacteriological cultures of middle meatus secretions collected one month after the end of the treatment revealed the persistence of SA. CONCLUSION: Nasal lavage with 0.05% NaOCl solution in saline is suitable for long-term use and seems to be a good alternative to lavage with saline alone in the management of symptomatic RS associated with recurrent SA infections due to patient-specific SA clonotypes. PMID- 18444488 TI - Nasal fractional exhaled nitric oxide analysis with a novel hand-held device. AB - AIM: To assess the performance of a novel hand-held nitric oxide (NO) analyzer in the measurement of nasal fractional exhaled NO (FE(NO)). METHODS: In ten healthy subjects (controls) and ten patients with chronic rhinosinusitis (CRS), oral and nasal FENO were obtained with the NIOX MINO Airway Inflammation Monitor (Aerocrine AB, Solna, Sweden) on two consecutive days, complying with current standards. RESULTS: Intraclass correlation coefficient (ICC) of oral FENO was 0.91 and of nasal FE(NO) 0.79. In controls, mean (+/- SD) nasal FENO (40.3 +/- 23.6 ppb) was higher than oral FENO (15.6 +/- 2.7 ppb; p = 0.005). In CRS patients, mean oral FENO (23.9 +/- 12.2 ppb) was higher than in controls (15.6 +/ 2.7 ppb; p = 0.01). CRS patients with nasal polyps had lower nasal FE(NO) levels (19.7 +/- 5.9) than healthy controls (40.3 +/- 23.6 ppb; p = 0.01). CONCLUSIONS: The novel hand-held NO analyzer was found suitable for nasal FE(NO) measurements. It may be useful in differentiating hyperplasic eosinophil rhinosinusitis from chronic unspecific rhinosinusitis. Moreover, nasal FE(NO) may be used to monitor the clinical course of CRS with polyps. PMID- 18444489 TI - Foreign bodies in the nose causing complications and requiring hospitalization in children 0-14 age: results from the European survey of foreign bodies injuries study. AB - INTRODUCTION: The occurrence of foreign bodies (FB) in otorhinolaryngological practice is a common and serious problem among pediatric patients. The aim of this work is to characterize the risk of complications and prolonged hospitalization due to FBs in the nose in terms of the characteristics of the injured patients (age, gender), typology and features of the FBs, the circumstances of the accident and the hospitalization's details. MATERIALS AND METHODS: A retrospective study of FB associated injuries, assessing the characteristics of the injured child and the FB, the circumstances of the accident and finally the hospitalization details took place on children aged 0-14 in major hospitals of 19 European countries. RESULTS: In total 688 cases were assessed. Complications and hospitalization occurred in 59 and 52 cases, respectively. Over 51% of patients were females. The median age of children who experienced a complication was four years. In the majority of cases FB removal was accomplished by means of a non-invasive technique (rhinoscopy with a nasal speculum or rigid fiberoptic endoscope. The majority of children were directly referred to the ENT department. The most common FBs associated with complications and hospitalization were nuts, seeds, berries, corn and beans, batteries and other inorganic objects such as broken parts of pens, paper clips and pearls. Over 38% of the injuries occurred under adults' supervision. DISCUSSION: FB injuries in the nose are commonly encountered in clinical practice. Even if the presence of a FB is not usually life threatening, it may result in long-term complications such as perforation of the septum. Because the risks associated with FB injuries, public education about this problem is recommended. PMID- 18444490 TI - A study of olfactory testing in patients with rhinological pathology in the ENT clinic. AB - BACKGROUND: Despite the common occurrence of rhinological pathology presenting to the ENT clinic, routine testing of olfactory ability is rarely performed. OBJECTIVES: The aim of this study was to determine the role of routine olfactory testing. METHODS: This was a prospective study conducted in the outpatient clinic of a district general hospital. Patients presenting with rhinological complaints had their olfactory status assessed using the combined olfactory test (COT) before and after rhinological surgery. RESULTS: Eighty patients (56 men, 24 women) had tests completed over a 12-month period. Patients assessed mostly had nasal polyposis, chronic rhinosinusitis or septal deformity. 83% of patients had either a complaint of olfactory disturbance or a COT score of 6 or less, or had both; but correlation between symptoms and scores was poor. Post-operative COT scores showed significant improvement (p = 0.02) with post-septoplasty patients showing the most significant improvement as a group (p = 0.001). CONCLUSIONS: Olfactory disturbance is very common in rhinological pathology and the patient's history alone cannot be relied upon. Simple olfactory assessment, such as with the combined olfactory test, is easy to perform and cheap to use and should be a commonly used resource in the ENT clinic. Formal testing can help to document any pre-existing olfactory loss and any post-operative changes as well as detecting unreported hyposmia. PMID- 18444491 TI - Chronic rhinosinusitis and nasal polyposis; indicia of heterogeneity. AB - BACKGROUND: Nasal polyposis (NP) is considered to be a subgroup of chronic rhinosinusitis (CRS). However differences in cellular and mediator profiles suggest that they could be distinct entities. OBJECTIVE: To look for group differences in characteristics and symptom severity before and after surgery in patients suffering from CRS and bilateral NP that could clinically support the hypothesis that NP and CRS are different pathological processes and to compare the effect of functional endoscopic sinus surgery (FESS) in CRS patients and NP patients. MATERIALS AND METHODS: Forty-five patients with CRS and 57 patients with bilateral NP were included in this prospective trial. We used t-tests for independent groups to compare preoperative symptoms as recorded on visual analogue scale (VAS). To evaluate if there were differences in symptom improvement between the groups we used analysis of covariance. Categorical variables were compared using exact tests. RESULTS: Mean age was 38 years for the CRS group and 47 years for the NP group, the difference was significant (p = 0.0001). NP patients underwent significantly more posterior ethmoidectomies than patients suffering from CRS (p = 0.001), and asthma was significantly more prevalent in NP than in CRS (p = 0.007). Comparing preoperative symptoms as recorded on VAS we found significant differences. While patients with NP suffered significantly more from nasal blockage and change in their sense of smell than CRS patients, patients with CRS presented with more facial pain and headache. There were no differences in symptom improvement, as both conditions responded similarly to FESS. CONCLUSION: Differences in symptom severity, nasal endoscopy, age of patients and prevalence of asthma indicate that NP and CRS are different entities. Nevertheless, both conditions respond similarly to FESS. PMID- 18444492 TI - Investigation of the effects of intranasal botulinum toxin type A and ipratropium bromide nasal spray on nasal hypersecretion in idiopathic rhinitis without eosinophilia. AB - Idiopathic rhinitis without eosinophilia is a group of frequently observed diseases, the aetiopathogenesis of which is not yet well known. One of the most disturbing symptoms for patients within this disease group is nasal hypersecretion. Although many different treatments have been tried for hypersecretion, nasal topical drugs form the basis of any such therapy today. Ipratropium bromide (IB) is a drug offirst choice in nasal hypersecretion therapy. It displays a parasympatholytic effect in topical use and antagonizes acetylcholine transport in efferent parasympathetic nerves, thus decreasing submucosal gland secretion, which is the cause of hypersecretion. Botulinum toxin type A (BTX-A) is among the alternative treatment choices that is increasingly used in symptomatic treatment of nasal hypersecretion. Our study was planned with the aim of comparing the effect of these two groups of drugs on nasal hypersecretion. Thirty-eight patients who were diagnosed with idiopathic rhinitis without eosinophilia were included in the study and were divided in 3 different groups: In the first group, a total of 10 units of BTX-A were injected into both nasal cavities. In the second group, 3x2 IB was injected into both nasal cavities for 4 weeks. The third group received intranasal physiologic saline as placebo. The patients were evaluated in terms of nasal hypersecretion with visual analogue scale prior to the treatment and at weeks 1, 2, 4, 8, and 12 during the follow-up period. Throughout the 8 weeks follow-up period, the patient complaints displayed a 41.2% decrease in the group that received BTX-A and a 61.4% decrease in the group which received IB, while no change was observed in the control group. Both drug groups were well tolerated by the patients, with no serious adverse or systemic effects. As a result, while IB and BTX-A differ in terms of method of application, they display a similar degree and duration of efficiency in hypersecretion therapy. PMID- 18444493 TI - Dynamics of early phase congestion after nasal allergen provocation. AB - BACKGROUND: It is generally accepted that congestion during the nasal provocation is most pronounced at about 15 minutes after allergen application. However, it may reach its peak at a different time. This can cause inaccurate assessment of the nasal challenge. The aim of this study was to evaluate the dynamics of early phase congestion during nasal allergen provocation (NPT) and its reproducibility. METHODS: Two nasal allergen challenges were performed in 26 allergic rhinitis volunteers. Acoustic Rhinometry measurements were recorded beJbre, and then every 5 minutes/for 30 minutes after the allergen application. The sum of cross sectional areas at the level of the head of inferior nasal turbinate (CSA-2) of both nasal passages was analyzed. RESULTS: The mean time to the occurrence of maximum congestion was 20 minutes. The maximum congestion differed significantly from that recorded at 10, 15 and 20 minutes. The observed patterns of congestive response were not consistent, with inter- and intra-individual differences regarding the time to maximum congestion. Percentage change in airway dimension recorded at the maximum congestion was found the least variable. CONCLUSIONS: Evaluation of the maximum congestion pattern during the NPT gives more accurate data compared to a single measurement of nasal patency. PMID- 18444494 TI - Objective measurement of the deviated nose and a review of surgical techniques for correction. AB - Although many surgical techniques have been introduced, there are few clinical studies investigating postoperative results in crooked nose deformity. The aim of this study is to discuss the surgical choices for specific deformities and to report the long-term quantitative surgical results of our cases. One hundred and twenty cases (38 women, 82 men) with crooked noses (48 I-shaped, 72 C-shaped) operated on by the authors were included in the study. The patients have been followed for 6 to 46 months (mean 19 months) postoperatively. The Scion Image software program was utilized for numerical measurement of the nasal crookedness. In cases with I-shaped and C-shaped crooked nose deformity, preoperative and postoperative angle values were as follows: 6.84 +/- 2.58 degrees, 2.01 +/- 1.53, 152.97 +/- 9.03 degrees and 173.67 +/- 4.55 degrees, respectively. In both groups, postoperative correction rates were statistically significant (p = 0.0001). Despite these results, patients undergoing surgical treatment should be informed about imperfect outcomes, possibility of persistent deformity and the need of revision surgery. PMID- 18444495 TI - Septal cartilage reshaping with the use of an Erbium doped glass fiber laser. Preliminary results. AB - STATEMENT OF PROBLEM: To evaluate the efficacy of Erbium doped glass fiber laser in patients undergoing nasal septal cartilage reshaping. METHOD OF STUDY: A prospective study was conducted in patients undergoing laser nasal septal cartilage reshaping. Microsurgical sponges soaked in a tetracaine solution plus adrenaline were applied in each side of the nose for ten minutes before the procedure. The cartilage of nasal septum was straightened and fixed in the median position using a modified nasal speculum. An optothermomechanical contactor with transparent indenter and thermocouple sensor was placed on septal regions of maximum mechanical stress. Patients were asked to evaluate the severity of pain during the procedure on a visual analog scale. A rhinomanometric evaluation was conducted preoperatively and postoperatively. All patients were asked to evaluate the improvement of their symptoms. All patients' data and potential complications were entered in a database and were statistically assessed. MAIN RESULTS: Our series consisted of 64 patients. Statistical analysis showed significant improvement of their symptoms and of rhinomanometric results. No complications or side effects occurred. The mean operative time was 35 minutes. PRINCIPAL CONCLUSION: Septal cartilage reshaping is an easy painless and bloodless method using en Erbium doped glass fiber Laser. Laser device LSC-701 (Arcuo Medical Inc.) is effective, safe and inexpensive medical equipment. PMID- 18444496 TI - Nasal valve surgery; our experience with the valve suspension technique. AB - OBJECTIVE: To describe and evaluate our experience with the surgical technique of nasal valve suspension for treating nasal valve insufficiency. METHODS: Twenty patients with nasal valve insufficiency underwent nasal valve suspension (a total of 33 sides). The patients were prospectively studied and their nasal patency was rated per side pre- and postoperatively, by subjective self-evaluation on a scale from 1 to 10. RESULTS: Post-operatively 7 sides (21%) were rated as unchanged, on 17 sides (52%) the improvement was from 1 to 3 out of 10, and on 9 sides (27%) 4 or more out of 10. The average post-operative improvement for all sides was 2.3 out of 10. In five patients (25%) complications occurred, such as pain, inflammation and suborbital swelling and three eventually underwent a re exploration of the surgical area, resulting in a permanent scar in one patient. CONCLUSIONS: Although nasal valve suspension may be beneficial for some patients, based on our experience, we would not recommend this technique as first line treatment for nasal valve insufficiency. In this series we found relatively limited improvement in most patients and a far higher complication rate compared with other nasal valve procedures we have had experience with in the past. PMID- 18444497 TI - Frontal sinus obliteration--a successful treatment option in patients with endoscopically inaccessible frontal mucoceles. AB - OBJECTIVE: This study evaluates non-standardized subjective patient satisfaction- and clinical outcome variables following frontal sinus obliteration with abdominal fat in endoscopically inaccessible mucoceles. METHODS: In a retrospective chart review, all patients who underwent frontal sinus obliteration for endoscopically inaccessible mucoceles at the Ludwig Maximilian University in Munich between 1996 and 2006 were identified and the postoperative outcomes were evaluated by a non-standardized patient questionnaire rating the degree of symptoms before and after surgery. Additionally, the postoperative clinical status and MRI-scans were analysed in a subgroup of patients. RESULTS: Nine out of 10 patients were generally satisfied with the obliteration. Most had a significant improvement in their main symptoms and reported a decrease in annual days of missed work and a reduced use of disease-specific drugs. The sense of smell and the intensity of postnasal dripping remained subjectively unchanged. Seventy percent of patients complained about temporary pain at the abdominal donor side. CONCLUSIONS: Based on these results, osteoplastic frontal sinus obliteration using abdominal fat seems to be a successful treatment option in patients in whom mucoceles of the frontal sinus are not endoscopically accessible. PMID- 18444498 TI - Ewing's sarcoma/primitive neuroectodermal tumour occurring in the maxillary sinus. AB - A 12-year-old boy complained of swelling of the left cheek. Fiberscopic examination revealed the presence of a soft reddish mass in the middle meatus of the left nostril. CT scan showed a large mass completely filling the left maxillary sinus. The lesion originated from the maxillary sinus and extended to the middle nasal meatus; bone destruction and invasion of the subcutaneous tissue of the cheek were noted. T2-weighted MRI images revealed a heterogeneous signal in the left maxillary sinus. Under general anaesthesia, biopsies were obtained through an intraoral incision. On pathology, atypical cells containing irregular nuclei with scanty cytoplasm were noted. The tumour cells were strongly positive for CD99 and reacted weakly with NSE however the cells were negative for synaptophysin, LCA and cytokeratin on immunohistochemical examination. Based on these findings, the tumour was diagnosed as a Ewing's sarcoma/primitive neuroectodermal tumour. The patient was treated with radiotherapy and combination chemotherapy; subsequently, the tumour's size decreased markedly. After 20 months of follow-up, the patient showed no evidence of local tumour growth or metastasis. PMID- 18444499 TI - [Face the facial furuncle]. AB - The furuncle is a staphylococcal infection of a single hair follicle which can occur on the skin in the maxillofacial region. Untreated, this infection can lead to life-threatening situations. This article discusses the etiology, clinical findings, possible complications as well as a series of differential diagnoses. In addition, several therapeutic and preventive strategies are described. PMID- 18444500 TI - [Orthodontics in general practice. 4. Eruption guidance appliances in orthodontics]. AB - Eruption guidance appliances are recommended for early orthodontic treatment or prevention of malocclusions. The treatment effect of eruption guidance appliances and functional appliances is similar. In addition to dentoalveolar and skeletal effects, eruption guidance appliances would also have myofunctional effects for treating open mouth behaviour and swallowing problems. However, there is no solid evidence for the myofunctional effect claimed. The position of erution guidance appliances in the orthodontic treatment arsenal is limited: early treatment of Angle Class II malocclusion in 2 phases has no advantage over a 2 phase treatment. When eruption guidance is needed, preference is given to an individually produced appliance. PMID- 18444501 TI - [Dissertations 25 year after date 18. Skin colour and facial prosthesis]. AB - The traditional 'trial and error' methods for skin colour recording are not satisfactory. In 1982 a dissertation was published, titled 'Skin colour and facial prosthetics, a colorimetric study'. The dissertation was concerned with a clinical study of skin colour recording objectively in a random sample of 100 people, using subtraction colorimetry. Subsequently, facial prostheses were fabricated for a group of patients with a facial defect who had to undergo radiotherapy. From the results of the study the 3 following conclusions were drawn. Skin colour recording for producing a facial prosthesis need to be carried as close to the facial defect as possible. Alterations of skin colour are determined by light scattering in the skin as well as skin pigments. In patients with facial defects who have to undergo adjuvant radiotherapy, skin colour alterations are present until on average 13-14 weeks after completion of the radiotherapy and from that time point the skin colour remains rather stable. After publication of the dissertation, other research results demonstrated that light scattering in the skin, a sign of skin translucency, may be determined with a fiberoptic scattering meter (volume reflectometer). Using the fiberoptic scattering meter, a colour formula can be made, which by calculation shows the amount of pigments and scattering objects needed to produce the correct translucency and colour of a facial prosthesis. Currently, a small beam reflectometer is used for this purpose. PMID- 18444502 TI - [Carotid calcification on a panoramic radiograph: what to do?]. AB - A 71-year-old man is discussed in whom the oral and maxillofacial surgeon observed, by chance, a radiopacity on the panoramic radiograph that was highly suggestive of a calcification at the bifurcation of the internal and external carotid artery. While, on the basis of international literature, various treatments are advanced with respect to the importance of vascular investigation and possible surgical removal of significant calcification, at present the view in The Netherlands is that the family doctor has the responsibility to assess whether such patient should be referred for further evaluation by the neurologist or vascular surgeon. The same applies to the possible indication for prescription of antitrombotics. PMID- 18444503 TI - [Injury following sodium hypochlorite irrigation during endodontic treatment]. AB - A 58-year-old woman was referred by her dentist to a maxillofacial surgeon because of a rapidly increasing facial swelling. The swelling developed after sodium hypochlorite irrigation during the endodontic treatment of tooth 25. A mechanical heart valve, a heart rhythm disorder, and antithrombotic therapy were complicating medical conditions. Treatment consisted of 12 mg dexamethason administered once intravenously, augmentin administered thrice daily intravenously, and oral analgetics. Damage following sodium hypochlorite irrigation during endodontic treatment is a rare disorder which is associated with a severe reaction in the surrounding tissue. Damage can be permanent. PMID- 18444504 TI - Topical drug delivery to the posterior segment of the eye: anatomical and physiological considerations. AB - Drug delivery to the posterior segment of the eye is important for potentially treating various disorders in retina, choroid, vitreous humor and optic nerve. Due to anatomic membrane barriers and the lacrimal drainage it can be quite challenging to obtain therapeutic drug concentrations in the posterior parts of the eye after topical drug administration. Since the membrane barriers cannot be altered with non-invasive methods invasive methods such as direct drug injection into the vitreous humor and subconjunctival, subtenons capsule or suprascleral injections are gaining popularity. However, invasive methods can cause discomfort for the patient and can also lead to complications that are even more serious than the disease being treated. Alternatively, novel ophthalmic formulations can be developed that specifically target topical drug delivery to the posterior segment of the eye. Anatomical and physiological barriers in the eye are reviewed as well as the theoretical model of passive drug diffusion from the eye surface into the eye. It is shown that enhanced drug delivery through conjunctiva/sclera to retina can be obtained by formulating lipophilic drugs as hydrophilic drug/cyclodextrin complex solutions. Optimization of the delivery system by formulating the drug as a low-viscosity aqueous drug/cyclodextrin complex suspension results in sustained high concentrations of dissolved drug in the tear fluid which further increases the targeted drug delivery to the posterior segment. PMID- 18444505 TI - Spermined dextran, a cationized polymer, as absorption enhancer for pulmonary application of peptide drugs. AB - Sperminated dextrans (SD) having different average molecular weights (MWs; 10, 40 and 70 kDa) and numbers of amino groups were prepared as cationized polymers for use as absorption enhancers. The absorption enhancing effects on the pulmonary absorption of insulin in rats and the permeation of FITC-dextran (MW 4,400, FD4) through calu-3 cell (human airway epithelial cell) monolayers by SD were evaluated. SD significantly enhanced the pulmonary absorption of insulin SD and the permeation of FD4 through calu-3 cells. The enhancing effects on the absorption insulin and permeation of FD4 through calu-3 cells increased with an increase in the molecular weigh of SD over the range 10-70 kDa. SD may interact directly with the luminal surface of mucus membranes via an ion-ion interaction and then induce signals that open tight junctions resulting in intercellular permeation of water soluble drugs. SD may be useful as an absorption enhancer for pulmonary delivery of peptide and protein drugs. PMID- 18444506 TI - The importance, design and modeling of biodegradable complexants. An extension of the structure-soft character relations. AB - Complexing Chem. or chelating agents are used in plant cultivation to avail of different phytobiologically useful macro- and microelements. The great majority of the traditional chelators (e.g. EDTA) are, however, essentially non biodegradable, which can lead to environmentally incalculable consequences. In the present work we sum up our results and conclusions on the modeling of the structure-property relationships of some biodegradable complexes in light of modern plant cultivation criteria. We have systematically investigated some new biodegradable ligands with poliamino-polycarboxylic structure, EDTA analogs, using the molecular modeling method and other possibilities of modern computer techniques. These compounds may be considered as a special group of "soft" chemicals. We established mathematical relations between the steric energy of the complexes and the properties of their components. One can conclude that the new complexes with poliamino-polycarboxylic chelators are less stable, therefore easier degradable than the complexes with EDTA. We have drawn conclusions regarding the regression parameters and the stereochemical properties of the complexes and have interpreted the probable causes of the deviations from the theoretically presumable values. The suitability of some general rules known in the complex chemistry (the Dyrssen-Sillen's diparametric compensatory equation, the van Panthaleon-van Eck's, the Schwarzenbach-Ackermnn's, the Irving-Rosotti's, the Larsson's, the Yatsimirsky's relations, the natural stability rank) and the significance of the differences observed were analyzed in detail. PMID- 18444507 TI - Parallel artificial membrane permeability assay (PAMPA) combined with a 10-day multiscreen Caco-2 cell culture as a tool for assessing new drug candidates. AB - The parallel artificial membrane permeability assay (PAMPA) is extensively used for the evaluation of early drug candidates. It is high throughput, low cost and is amenable to automation. This method has been shown useful in assessing transmembrane, non-energy dependent, diffusion of drugs such that reasonable predictability with in vivo (passive) absorption is possible. Cell cultures mimicking the gastrointestinal tract such as the CACO-2 cultures have the advantage of taking into account other transport mechanism including paracellular and carrier-mediated uptake but are lower throughput and labor-intensive. In this study, the applicability of two high throughput permeability assays namely PAMPA (PSR4p, pION Inc.) and 96-well Caco-2 cell assay (MultiScreen, Millipore) were used to rank drug permeability as well as to predict passive and active drug absorption/secretion for a series of marketed drugs as well as a collection of structurally diverse drug candidates. CACO-2 cells were cultured using MultiScreen hardware over a period of 10 days with the integrity of the cells assessed using transepithelial electrical resistance (TEER) and by the ability of the monolayer to the transport a paracellular marker, sodium fluorescence. Effective permeability (Peff) data were calculated using spectrophotometric data and were binned based on a pre-defined cut-off values as either highly and poorly permeable. A comparison of a well characterized drug training set indicate at least 85% concordance between the data generated from PAMPA and Caco-2 MultiScreen. The values obtained using the MultiScreen approach were also similar to data obtained from the literature using the conventional 21-day Caco-2 cell assay. Differences between PAMPA and CACO-2 ranking were useful indicators of either drug efflux (PAMPA (Peff) > CACO-2 (Peff)) or absorptive transport (CACO-2 (Peff) > PAMPA (Peff)). These results indicate that PAMPA combined with the MultiScreen Caco-2 cell culture may be a useful high throughput screening for predicting passive diffusion and active transport of new drugs. PMID- 18444508 TI - Stereoisomers of N-substituted soft anticholinergics and their zwitterionic metabolite based on glycopyrrolate--syntheses and pharmacological evaluations. AB - PURPOSE: In this study, isomers of two N-substituted soft anticholinergics based on glycopyrrolate, SGM (PcPOAGP_NA.Me) and SGE (PcPOAGP_NA.Et) [3'-(2-cyclopentyl 2-phenyl-2-hydroxyacetoxy)-1'-methyl-1'-alkoxycarbonylpyrrolidinium bromide] and their zwitterionic metabolite, SGa (PcPOAGP_NA.H) [3'-(2-cyclopentyl-2-phenyl-2 hydroxyacetoxy)-1'-methyl-1'-carboxymethylpyrrolidinium inner salt] were synthesized and their pharmacological activities were evaluated in vitro and in vivo. METHODS: The isomers of SGM and SGE were synthesized with both optically pure methyl-cyclopentylmandelate and 3-hydroxy-N-methylpyrrolidine. Trans esterification followed by quarternization with alkyl bromoacetate gave four isomers of SGM or SGE with the nitrogen chiral center unresolved (2R3'S-SGM, 2R3'R-SGM, 2S3'S-SGM, 2S3'R-SGM or 2R3'S-SGE, 2R3'R-SGE, 2S3'S-SGE, 2S3'R-SGE). The hydrolysis of these four isomers followed by HPLC separation resulted in eight fully resolved isomers of SGa (2R3'R1'R, 2R3'S1'R, 2R3'R1'S, 2R3'S1'S, 2S3'R1'R, 2S3'S1'R, 2S3'R1'S, and 2S3'S1'S). Pharmacological activities were assessed by using in vitro receptor-binding assay and guinea pig ileum pA2-assay, and by evaluating the in vivo rabbit mydriatic effects. Results were compared to those obtained with conventional anticholinergic agents, such as glycopyrrolate, N-meythylscopolamine, and tropicamide, as well as those obtained with previously prepared racemic mixtures and 2R isomers. RESULTS: Receptor binding pKi values at cloned human muscarinic receptors (M1-M4 subtypes) were in the 6.0-9.5 range for the newly synthesized SGM and SGE isomers, and in the 5.0-8.6 range for the SGa isomers. In all cases, 2R isomers were significantly more active than 2S isomers (27 to 447 times for SGM isomers, and 6 to 4467 times for SGa isomers). Among the four SGM isomers with unresolved 1' (N) chiral center, the 3'R isomers were more active than the corresponding 3'S isomers (1.5-12.9 times), whereas, among the SGa isomers, the 3'S isomers were not always more active than the corresponding 3'R isomers indicating that activity determined based on configuration at chiral center 3' is significantly affected by the configuration of the other two chiral centers, 2 and 1'. Among the completely resolved eight SGa isomers (all three chiral centers resolved), 1'S isomers were always more active than the corresponding 1'R isomers (1.8-22.4 times). Results also indicate that some isomers showed good M3/M2 muscarinic-receptor subtype-selectivity (about 3-5 times), and 2R and 3'S were the determining configurations for this property. Guinea pig ileum assays and rabbit mydriasis tests on SGa isomers further confirmed the stereospecificity. In rabbit eyes, some 2R-SGa isomers showed mydriatic potencies similar to glycopyrrolate and exceeded tropicamide, but their mydriatic effects lasted considerably shorter, and they did not induce dilation of the pupil in the contralateral, water-treated eye. These results indicate that these compounds are locally active, but safe and have a low potential to cause systemic side effects. The pharmacological potency of the eight SGa isomers was estimated as 2R3'S1'S approximately equal to 2R3'R1'S approximately equal to 2R3'S1'R > 2R3'R1'R > 2S3'R1'S > 2S3'S1'S approximately equal to 2S3'R1'R > 2S3'S1'R (p < 0.05). CONCLUSIONS: The stereospecificity and M3/M2 muscarinic receptor subtype-selectivity of soft anticholinergics, SGM, SGE, and SGa have been demonstrated. In agreement with previous results, the potential for their effective and safe use has been confirmed. PMID- 18444509 TI - Determination of estredox, a compound with sustained estradiol function, and its impurity profile by HPLC. AB - The HPLC methods described here for the assay and purity test of Estredox (E2CDS), a molecule with a redox-based, brain-targeted chemical delivery system for estradiol, allow reliable conclusions to be made on the potency and purity of API and E2CDS/HPCD complex samples. Extensive work was done to isolate and characterize the major, potential contaminants, and ensure the required stability of solutions of E2CDS, an inherently labile compound by design. Both the sample solvent and the eluent were thoroughly tested to avoid unwanted changes in sample solutions during analyses. The 12 minute isocratic assay method at 220 or 360 nm is simple, well-founded, highly precise and accurate. Purity profiling of E2CDS raised several problems in detection, stability and accuracy, owing to the fact that the pattern of the UV spectra and the stability of the compound and those of the potential contaminants often differed greatly. As a result of meticulous analysis of the UV spectra and the factors influencing the behaviour, in solution, of the compounds concerned, the 20 minute gradient method developed for the purity test, at 220 nm, of E2CDS and E2CDS/HPCD complex samples has proved to be a reliable means of adequately resolving 15-20 peaks of known and unknown compounds, and establishing the purity of various E2CDS samples. Sample impurity can be expressed as area % at 220 nm, and/or as approximate w/w % (if needed), since the relative response factors, at 220 nm, of the 6 major, potential contaminants have also been determined. PMID- 18444510 TI - Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions. AB - Supersaturating drug delivery systems (SDDS) utilize two important design elements in their preparation including converting the drug of interest into a high energy state or other rapidly dissolving form to facilitate the formation of supersaturated drug solutions and providing a means for stabilizing the formed supersaturated solution such that significant drug absorption is possible from the gastrointestinal tract. This has been referred to as a "spring" and "parachute" approach. The current effort is designed to assess materials which may affect properties in SDDS. To this end, a series of excipients was tested in a co-solvent/solvent quench method to assess their ability to attain and maintain supersaturation for a group of 14 drug development candidates. The approach focussed on hydrophilic cyclodextrins including hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutyl-beta-cyclodextrin (SBEbetaCD). Various rheological polymers and surfactants were also included in the study. Consistent with previous investigations, the pharmaceutical polymers, as a class, had minimal effects on the extent of supersaturation but tended to be good stabilizers while the surfactants tended to provide for the greatest degree of supersaturation but the formed systems were poorly stable. This study found that hydrophilic cyclodextrins, especially SBEbetaCD, gave superior results in terms of attaining and maintaining supersaturation. A knowledge of the behavior and performance of excipients in this context can be useful in designing solid oral dosage forms for difficult-to-formulate drugs and drug candidates. PMID- 18444511 TI - Delivery of a DNAzyme targeting c-myc to HT29 colon carcinoma cells using a gold nanoparticulate approach. AB - The objective of the current study was to develop cellular delivery approaches for catalytic DNA enzymes (DNAzymes) which cleave targeted messenger RNA, using vectors based on colloidal gold. The model DNAzyme was a 32mer oligonucleotide designed to specifically interact with and cleave c-myc mRNA. Colloidal gold particles were prepared by reduction of tetrachlororauric [III] acid with sodium citrate. Particles could be produced in the 1-90 nm range. A cationic substrate linked to transferrin was electrostatically/hydrophobically bound to the gold particle. These vectors were then treated with the DNAzyme to yield the condensed DNA-cationic polymer-particulate product. The pH (4-11.5), the quantity of the DNAzymes (0.079-0.567 microg/probe), the cationic polymer (polylysine (PL) or polyethylenimine (PEI)) as well as the surfactant (PVP) concentration (0-0.5%) were varied to give stable constructs which decomplexed under the desired conditions (i.e., in lysosomes and at lower pH values). Cellular uptake of the FITC-labelled c-myc DNAzyme incorporated in this vector was measured using FACS analysis in human HT29 colon carcinoma cells. Data suggested that PEI gave better delivery efficiencies than PL. The use of PVP to stabilize the formed dispersions was detrimental to DNAzyme delivery when PL was used but had little effect in the PEI systems. In the best cases, delivery to 77% of the cells was possible using PEI with the PVP stabilizer and completing the DNA condensation at pH 5.5 with 0.118 microg of DNAzyme/probe. In contrast, the best conditions for PL gave only transfection to 43% of the cells (no PVP, condensed at pH 5.7 and with a loading of 0.079 microg DNAzyme/probe). The PL probe tended to be more toxic than the PEI based systems (65% cell death in PL transfected cells compared to 22% for PEI). These results suggest that cellular targeting using colloidal gold appears feasible for DNAzyme delivery. PMID- 18444512 TI - Soft corticosteroids for local immunosuppression: exploring the possibility for the use of loteprednol etabonate for islet transplantation. AB - Transplantation of pancreatic islets into subcutaneous, neovascularized devices is one of the possibilities explored as part of our search for a cure of diabetes. We have recently reported that syngeneic transplantation in a subcutaneous prevascularized device can restore euglycemia and sustain long-term function in rats and that explanted grafts showed preserved islets and intense vascular networks. Because all of the transplanted tissue is localized within the device, if such a bioartificial pancreas approach is used, localized immunosuppression might provide sufficient protection against rejection to achieve long-term function, while also avoiding the serious systemic side effects and the susceptibility for opportunistic infections that are commonly associated with systemic immunosuppressive therapies as only much smaller and localized doses are needed. Soft steroids are obvious candidates because soft drugs are specifically designed to produce targeted local activity, but no systemic side effects due to prompt metabolic (preferably extrahepatic, e.g., hydrolytic) inactivation. However, local concentrations that are effective for immunosuppression, but non-toxic to insulin-producing beta-cells have to be found, and nontrivial difficulties related to long-term local deliverability have to be addressed. Here, we report preliminary results obtained using in vitro studies with human islets used to establish a tentative therapeutic concentration range together with fully scaled three-dimensional finite element method (FEM) based Comsol multiphysics computational models that were used to explore various possibilities to achieve and maintain these concentration levels within the device. PMID- 18444513 TI - Different reactivities of amphetamines with N-methyl-bis(trifluoroacetamide) in heated gas chromatographic injectors. AB - A fast gas chromatographic mass spectrometric method has been developed earlier for the determination of amphetamine derivatives in human serum and urine. For derivatization, N-methyl-bis(trifluoroacetamide) (MBTFA) was used. Derivatization was performed using an on-line mode, since 1 microl of MBTFA and 1 microl sample extract, dissolved in toluene were injected simultaneously. In this study, the reactivity of the several amphetamine type analytes with MBTFA was investigated. MBTFA used for flash derivatization was applied undiluted on the one hand and diluted 4--4096-fold with acetonitrile on the other hand. Studying several amphetamines in the test sample spiked at the same concentrations we found that they could be divided into 3 groups based on relative target ion peak areas as a function of MBTFA dilution. Group 1, containing only primary amines showed an early increase of the relative peak areas if we increased MBTFA concentration, where group 2 (mainly N-methyl secondary amines) showed that relative peak areas started to increase intensively at higher MBTFA concentrations. Finally, MDEA as an N-ethyl secondary amine, representing group 3, showed significant increase if only slightly diluted MBTFA was used as a flash reagent. This phenomenon can be explained mainly with the less and less reactivity of amine groups in the case of groups 2 and 3, compared to group 1. These findings could help to optimise analytical methods involving flash derivatization processes. PMID- 18444514 TI - Spontaneously self-assembled micelles from poly(ethylene glycol)-b-poly(epsilon caprolactone-co-trimethylene carbonate) for drug solubilization. AB - Di-block copolymers composed of polyethylene glycol (PEG) and a second block of (co)polyesters of epsilon-caprolactone (CL) and/or trimethylene carbonate (TMC) were synthesized and characterized. Tin octoate was used as catalyst and polymerization were completed over a period of 24 h with high conversion (> 95%). Self-assembling properties in water were evaluated. All di-block copolymers behave similarly except when PCL served as the second block. Stable crew-cut micelles of about 20 nm were obtained by direct dissolution of the liquid di block copolymers in water at room temperature. When PCL was present as the second block, no solubilization occurred. Drug encapsulation of poorly water-soluble drugs belonging to biopharmaceutics classification system (BCS) class II (ketoprofen and furosemide) was evaluated. Experimental solubility for these two drugs shows a significant enhancement such that a maximum value of 23.4 mg/ml was obtained for ketoprofen in a 10% w/v micellar solution as compared to 0.14 mg in water. In the case of furosemide, the solubility increased from 0.04 mg/ml in water to about 3.2 mg/ml in a 10% w/v micellar solution. Enzymatic degradation of diblock copolymers was also studied in the presence of Pseudomonas lipase in a phosphate buffer solution (pH 7.4). Results indicated rapid degradation of copolymers containing relatively higher amounts of CL compared to TMC suggesting the potential in vivo degradation. PMID- 18444515 TI - Fate of quinidine, a P-glycoprotein substrate, in the gastrointestinal tract after oral administration in rats. AB - P-Glycoprotein (P-gp), an ATP-dependent efflux transporter, is expressed in brush border membranes in the intestines of humans and rodents. In this study, the fate of quinidine, a P-gp substrate, in the gastrointestinal tract after oral administration was examined in conscious rats. The animals received quinidine (3 mg/ml/kg) or FITC-dextran of molecular weight of 10,000 (FD-10S, 5 mg/ml/kg, a poorly absorbable compound) orally, and the remaining amount of the compound in the upper gastrointestinal tract was measured at designated time intervals. As a control, FD-10S was distributed almost evenly throughout the gastrointestinal tract at 30 min, and most of FD-10S was accumulated in the distal small intestine at 60 min after administration. In contrast, most of the orally administered quinidine disappeared at the proximal intestine, and only small amounts reached the distal region. Also, the gastrointestinal transit of FD-10S was markedly slowed by stopping or inhibiting the bile flow, indicating that bile flow significantly affects the transit of drugs in the gastrointestinal tract. In conclusion, this study has demonstrated that compounds with high solubility and high permeability, such as quinidine, can be absorbed rapidly at the proximal intestine,escaping the barrier function of P-gp, because P-gp is mostly expressed in the distal intestine. PMID- 18444517 TI - Roman digit naming: evidence for a semantic route. AB - Earlier research with monolinguals and bilinguals showed that numbers may be named through both a semantic and a phonological route, depending on the number's language and format (Arabic or verbal), task demands, and naming language. The present study investigated the importance of the semantic route for the processing of a third representation of magnitude, namely Roman digits. Using an interference paradigm, we showed that the processing of Roman target digits is influenced by Arabic digit distractors, both in a naming task and a parity judgment task. Roman digits were processed faster if the target and distractor were of the same magnitude. If this was not the case, processing speed slowed down as the numerical distance between target and distractor increased. This strongly suggests that semantic access is mandatory when naming Roman digits. Implications are discussed for the number processing domain and for models of translation in bilinguals. PMID- 18444516 TI - Does impairment of renal and hepatic function influence the metabolism of thrombolytics in patients with myocardial infarction? AB - Thrombolytic agents activate plasminogen and induce a systemic fibrinolytic and anticoagulant state. Two thrombolytic drugs are used frequently in practice: streptokinase (SK) and alteplase (t-PA). Streptokinase mainly undergoes renal elimination with a half-life of 11-17 min, while alteplase is eliminating by the liver with a half-life of 4-6 min. Our goal was to examine whether renal and hepatic function influence the elimination and metabolism of thrombolytics and the efficacy of percutaneous coronary intervention (PCI) after using alteplase or streptokinase. 416 patients with myocardial infarction (MI) were treated from January 2001 to December 2003 (228 male and 189 female). Alteplase was used in 9 men and 6 women (mean age: 53.88 +/- 9.61 vs. 65.33 +/- 9.87 years, p = 0.07). Patients who underwent rescue PCI after administration of alteplase had slightly higher hepatic enzyme levels/alanine transaminase (ALT): 47.85 vs. 41.4 U/l; gamma-glutamyl transpeptidase (GGT): 69.5 vs. 44.8 U/l/. All patients treated with alteplase survived, rescue PCI was done in 8 cases. Streptokinase was used in 36 men and 28 women (mean age: 63.33 +/- 10.51 vs. 63 +/- 12.03 years, p = 0.9). We did not find a difference between serum creatinine levels of patients who received streptokinase and underwent PCI as compared to those who had not. Rescue PCI was done in 16 cases. 12 patients died in this group. In conclusion we have not found a significant correlation between the use of the thrombolytics and hepatic or renal function; this could indicate that such a slight impairment of liver and renal function does not influence pharmacokinetic properties of thrombolytics. PMID- 18444518 TI - Distractor eccentricity and its effect on selective attention. AB - Previous research has shown conflicting results regarding the effect of distractor eccentricity on selective attention. The present study examines the relationship between a distractor's retinal location and participants' response latencies to a target while holding constant the distribution of attention. In three experiments, the participants searched for a target among several distractors. The retinal location of the critical distractor was manipulated so that it was at either a central or a peripheral location. The results show that all else being equal, an incompatible distractor causes more interference at a peripheral location than at a central location. This distractor eccentricity effect suggests that the visual system can overcome the default bias in the distribution of attention that favors a central stimulus. PMID- 18444519 TI - The Stroop effect in English-Japanese bilinguals: the effect of phonological similarity. AB - English-Japanese bilinguals performed a Stroop color-word interference task with both English and Japanese stimuli and responded in both English and Japanese. The Japanese stimuli were either the traditional color terms (TCTs) written in Hiragana or loanwords (LWs) from English written in Katakana. Both within language and between-language interference were found for all combinations of stimuli and responses. The between-language interference was larger for Katakana LWs (phonologically similar to English) than for Hiragana TCTs, especially with Japanese responses. The magnitude of this phonological effect increased with self rated reading fluency in Japanese. Overall responding was slower and the Stroop effect larger with English than with Japanese stimuli. These results suggest that unintentional lexical access elicits automatic phonological processing even with intermediate-level reading proficiency. PMID- 18444520 TI - Semantic access in number word translation: the role of crosslingual lexical similarity. AB - The revised hierarchical model of bilingualism (e.g., Kroll & Stewart, 1994) assumes that second language (L2) words primarily access semantics through their first language (L1) translation equivalents. Consequently, backward translation from L2 to L1 should not imply semantic access but occurs through lexical wordform associations. However, recent research with Dutch-French bilinguals showed that both backward and forward translation of number words yields a semantic number magnitude effect (Duyck & Brysbaert, 2004), providing evidence for strong form-to-meaning mappings of L2 number words. In two number-word translation experiments with Dutch-English-German trilinguals, the present study investigated whether semantic access in L1-L2 and L1-L3 number-word translation depends on lexical similarity of the languages involved. We found that backward translation from these more similar language pairs to L1 still yields a semantic magnitude effect, whereas forward translation does not, in contrast with the Dutch-French results of Duyck and Brysbaert (2004). We argue against a dual route model of word translation and suggest that the degree of semantic activation in translation depends on lexical form overlap between translation equivalents. PMID- 18444521 TI - Market entry decisions: effects of absolute and relative confidence. AB - In a market entry game, the number of entrants usually approaches game-theoretic equilibrium quickly, but in real-world markets business start-ups typically exceed market capacity, resulting in chronically high failure rates and suboptimal industry profits. Excessive entry has been attributed to overconfidence arising when expected payoffs depend partly on skill. In an experimental test of this hypothesis, 96 participants played 24 rounds of a market entry game, with expected payoffs dependent partly on skill on half the rounds, after their confidence was manipulated and measured. The results provide direct support for the hypothesis that high levels of confidence are largely responsible for excessive entry, and they suggest that absolute confidence, independent of interpersonal comparison, rather than confidence about one's abilities relative to others, drives excessive entry decisions when skill is involved. PMID- 18444522 TI - Multisensory identification of natural objects in a two-way crossmodal priming paradigm. AB - The question of how vision and audition interact in natural object identification is currently a matter of debate. We developed a large set of auditory and visual stimuli representing natural objects in order to facilitate research in the field of multisensory processing. Normative data was obtained for 270 brief environmental sounds and 320 visual object stimuli. Each stimulus was named, categorized, and rated with regard to familiarity and emotional valence by N=56 participants (Study 1). This multimodal stimulus set was employed in two subsequent crossmodal priming experiments that used semantically congruent and incongruent stimulus pairs in a S1-S2 paradigm. Task-relevant targets were either auditory (Study 2) or visual stimuli (Study 3). The behavioral data of both experiments expressed a crossmodal priming effect with shorter reaction times for congruent as compared to incongruent stimulus pairs. The observed facilitation effect suggests that object identification in one modality is influenced by input from another modality. This result implicates that congruent visual and auditory stimulus pairs were perceived as the same object and demonstrates a first validation of the multimodal stimulus set. PMID- 18444523 TI - Mask-induced priming and the negative compatibility effect. AB - Under certain conditions, masked primes have produced counter-intuitive negative compatibility effects (NCE), such that RT is increased, not decreased, when the target is similar to the prime. This NCE has been interpreted as an index of automatic motor inhibition, triggered to suppress the partial motor activation caused by the prime. An alternative explanation is that perceptual interactions between prime and mask produce positive priming in the opposite direction to the prime, explaining the NCE without postulating inhibition. Here the potential role of this "mask-induced priming" was investigated in two experiments, using masks composed of random lines. Experiment 1 compared masks that included features of the primes and targets with masks that did not. The former should create more mask-induced priming, but the NCE did not differ between masks. Experiment 2 employed masks that contained features of either one target or the other, but not both. These asymmetric masks produced significant mask-induced priming, but it was insufficient in size to account for the prime-related NCE. Thus mask composition can contribute to NCEs, but when random line masks are employed, the major source of the NCE seems to be motor-inhibition. PMID- 18444524 TI - [Thoracic involvement revealing lymphomas: report on 17 cases]. AB - BACKGROUND: Thoracic manifestations of lymphomas are frequents and various. They are frequently described in secondary than as a primary manifestation. AIM: This work aims to analyze the clinical, radiological, and prognostic characteristics of initial thoracic features of lymphomas. The authors stress the diagnosis and therapeutic difficulties which they encountered. METHODS: We report a retrospective work of initial thoracic involvement of lymphomas and their radiologic features observed in 17 patients hospitalized in pneumology service of Sfax. RESULTS: There were 10 cases of non Hodgkin's lymphoma and 7 cases of Hodgkin disease. For the patients with non Hodgkin's lymphoma, the mediastinal involvement was present in 8 cases. The parenchymal involvement was noted among 2 patients such as nodules or masses, with concomitant mediastinal lymph nodes. The pleural effusion such as pleurisy or solid mass was seen in 3 cases. Pericardial and parietal involvements were noted in one case. For the patients with Hodgkin's disease, the mediastinal lymph nodes were seen among 6 patients. The parenchymal involvement was noted in one case. One case of primary thymic lymphoma involvement and one case of tracheal involvement were noted. No case of pleural effusion was deplored. CONCLUSION: Initial thoracic involvements, rarely described, cause a variety of features which are often nonspecific. The diagnosis, often difficult, has beneficiated, from imaging and endoscopy's progress. However, treatment should be optimized in order to improve the prognosis which is also reserved particularly in non Hodgkin lymphoma. PMID- 18444525 TI - [Feasibility of laparoscopic treatment of duodenal ulcers: results of 160 cases]. AB - AIM: The objective of this study is to evaluate the feasibility, efficacy and safety of laparoscopic repair for perforated duodenal ulcer. METHODS: One hundred and sixty patients were treated by coelioscopic procedure for a perforated duodenal ulcer. The procedure consists on a suture of perforated ulcer associated with a peritoneal lavage. A medical treatment of Helicobacter pylori associated with an inhibitor of the protons pomp was conducted. RESULTS: The coelioscopic procedure permitted to confirm the diagnostic of perforated duodenal ulcer in all cases. A simple suture of the ulcer was done in 155 cases. The conversion was compulsory in 5 cases, because of difficulties of the peritoneal lavage in 2 cases, a bleeding associated with perforation of the ulcer in one case and associated stenosis in 2 cases. Mean duration was 90 min (extremes 50 - 120 min). Complications occur in 3,1%. They were post - operative peritonitis in 3 cases and duodenal fistulae in 2 cases. All patients were reviewed at 16 months. A recurrence, either clinical or endoscopic occurs in 4 cases because of no adhesion to medical treatment. CONCLUSION: Coelioscopic treatment of perforated duodenal ulcer is a safe and efficacy method. It permits to avoid potential septic and parietal complications of laparotomy. The actual efficacy of medical treatment mustn't allow place to the radical treatment of ulcerous illness. PMID- 18444526 TI - [Cytology and immunophenotype features of hairy cell leukemia: 6 cases]. AB - BACKGROUND: Hairy cell leukemia is a rare lymphoproliferative disorder. AIM: with cytological and immunophenotypic features. METHODS: We report 6 cases of hairy cell leukemia diagnosed in the Biological Department of Hematology at the Aziza Othmana Hospital of Tunis. RESULTS: Hairy cells was observed in blood smears of 5 cases. Flow cytometry analysis shown monoclonal a monoclonal population B while gatinting on the expression of the CD19 and SSC signal. The positivity of the CD103 is noted in 5 cases and the CD11c signal is intense in all the cases. CONCLUSION: Immunophenotype is of great interest in the diagnosis of hairy cell leukemia. PMID- 18444527 TI - [The interest of biochemical markers of bone turnover for monitoring treatment of postmenopausal osteoporosis]. AB - BACKGROUND: Postmenopausal osteoporosis is especially female pathology, whose incidence increases with age. AIM: The purposes of this study are to evaluate the level of bone turnover by the determination of markers of bone formation (PAL, BAP) and marker of bone resorption (CTX) in the osteoporotic women, to study the correlations between bone biochemical markers, clinical parameters and radiological measurements and to assess the interest of biochemical markers therapeutic monitoring after 6 months of antiresorptive treatment. METHODS: The authors report a prospective study of 134 osteoporotic women classified in two groups according to the presence of osteoporotic fracture. Patients of the first group G1 (n=102) with fractures, were treated by the bisphosphonates (risedronate), whereas the ones of the second group G2 (n=32) without fractures, were submited to calcic supplementation and vitamin D. RESULTS: The analyses showed that the femoral and lumbar BMD were statistically lower in the presence of osteoporotic fractures. However, the values of CTX were statistically higher in the patients of G1 group compared to those of the G2 group (0,708 +/- 0,332 ng/ml versus 0,514 +/- 0,225 ng/ml). The CTX were statistically correlated with the femoral and lumbar BMD (r = -0,21, p<0,05 and r= -0,348, p<0,001). The hypovitminosis were observed in 50,98% (52/102) of women with osteoporotic fractures, whereas it was only 25% (8/32) in women without fractures. After 6 months of treatment by the bisphosphonates, the PAL, the BAP and the CTX have decreased with an average of, respectively, 19%, 46,5% and 62,9%. These variations were significantly more important in G1 group. CONCLUSION: The biochemical markers of bone turnover, in particular those of the resorption (CTX), can predict the postmenopausal woman's bone loss evaluated by BMD, the risk of fractures and the efficiency of the bone treatments. PMID- 18444528 TI - [Cholestasis in infants: a study of the Children's Hospital of Tunisia]. AB - BACKGROUND: Cholestasis in infant constitutes an heterogeneous group of disease; diagnosis and management are often difficult. THE AIM of the study is to describe clinical, paraclinical characteristics and outcome of infants hospitalized for cholestasis in children's Hospital of Tunis. METHODS: A retrospective study of 94 infants with cholestasis was conducted. Patients were hospitalized in four departments of paediatrics of our hospital between January 1995 and December 2005. Cholestasis complicating severe sepsis and visceral leishmaniasis were excluded. RESULTS: Incidence of cholestasis was 8.5 cases/year which represented 0.72% of the hospitalizations. Sex ratio was 1.08 and mean age at diagnosis was 105 days (extremes: 1 day- 24 months). Biliary atresia was the most common cause of extra hepatic cholestasis (13.8%). Normal A GT cholestasis (11.7 %), benign neonatal cholestasis (11.7%) and bile duct hypoplasia (9.5%) represented the most common aetiologies of intra hepatic cholestasis. Aetiology remained unknown in 12.7% of cases. Only three infants with biliary atresia had Kasai operation. After a mean follow-up of 6 years, 18% of patients had portal hypertension, 14.8% had hepatic failure and mortality rate was 14.8%. CONCLUSION: Cholestasis of unknown aetiologies are frequent in our hospital. Poor prognosis, in our study, is due to delay to diagnosis and difficulties in medical and surgical management. PMID- 18444529 TI - [Early-onset neonatal bacterial infections: a retrospective series of 144 cases]. AB - BACKGROUND: Early-onset neonatal bacterial infections continue to be a major cause of morbidity and mortality in the newborn. THE AIM of this study was to determine the incidene, the risk factors and bacterial epidemiology of these infections. METHODS: All cases of early-onset neonatal bacterial infections were identified for the years 2001-2003 using data from obstetric and neonatal reports at the neonatal unit of Charles Nicolle Hospital. RESULTS: 144 cases were identified over 11,201 live births, that is an incidence of 12.85 per thousand, of which 22 cases of sepsis infections. 22.9% of all newborns were premature and 18% had a low birth weight. Membrane rupture occurred more than 12 hours before delivery in 63.2% of cases and an intra-partum fever in 57.7% of cases. Half of newborns were symptomatic with a mean age of 7.5 hours at onset of symptomatology. The principal etiologic agents were Group B Streptococcus (GBS) and Escherichia coli (E.coli), responsible respectively of 50% and 29.1% of proved infections. GBS had been recognised as the most prevalent agent in term newborn (58.9%) and the E.coli in premature newborn (38.5%). The neonatal mortality before discharge was 2.77% of all cases. CONCLUSION: Neonatal bacterial infections continue to be a major cause of morbidity in the newborn. The most common etiologic agents remain GBS and E. coli. PMID- 18444530 TI - [Surgical treatment of secondary hyperparathyroidism in chronic renal failure. Report of 57 cases]. AB - AIM: The aim of this study was to report the experience of the department of general surgery (Aile III) Ibn Rochd Hospital in surgical management of hyperparathyroidism in patients with end-stage renal disease (ESRD). METHODS: Fifty seven patients (24 M, 33F) with hyperparathyroidism underwent surgical parathyroidectomy from 1998 to 2004. Surgical indication was established according to clinical or biological assessment. Fifty nine operations were performed (57 first-hand cervicotomies and resumptions in too cases). RESULTS: Histological examination of parathyroid gland specimens disclosed adenoma in 33 patients and hyperplasia in 14 patients. The follow-up was normal in 52 patients, marqued by cervical hematoma in 2 cases and death was deplored in 4 patients. The post-operative calcium level was in the normal range in 43 cases, low comparatively to the baseline in 12 cases and high in 2 cases. The PTH levelwas normal in 55 patients and high in two patients. Long-term outcome was evaluated in 36 patients mean follow-up (18 months). A good evolution was noted in all patient referring to clinical, biological and radiological investigations. CONCLUSION: That, in our context, surgical parathyroidectomy still an appropriate approach for the treatment of hyperparathyroidism in patients with end-stage renal disease. PMID- 18444531 TI - [Patient controlled epidural analgesia: interest in thoracic surgery]. AB - AIM: To compare efficacy of pain control, the consumption of local anaesthetics and opioids as well as the side effects between continuous epidural analgesia, patient controlled analgesia and patient controlled epidural analgesia in thoracic surgery. METHODS: Prospective randomised study included 66 patients who had thoracotomy. Patients were divided into 3 groups, to receive different pain control methods. Group 1 (n=22) received patient control analgesia Group 2 (n=22) received continuous epidural analgesia (Bupivacaine 0,125% + 5 microg/ml of Fentanyl) between 6 and 10 ml/h in order to obtain a T2 level Group 3 (n=22) received patient controlled epidural analgesia (Bupivacaine 0,08% + 3 microg/ml of Fentanyl) 6 ml/h and bolus of 5 ml. RESULTS: There was no difference between the three groups in age, delay of surgical operation and per operative morphine consumption. VAS was less at rest and after cough in patient group with patient controlled epidural analgesia. The difference was less significant in local anaesthetics and opioids consumption in patient with controlled epidural analgesia. CONCLUSION: The benefit of patient controlled epidural analgesia in thoracic surgery is proven by the following analgesic efficiency which allows good respiratory rehabilitation, decreasing the risk of drug toxicity by decreases consumption, weak hemodynamic effects and absence of motor block. PMID- 18444532 TI - [A comparison of the effect of oral captopril and nicardipine in hypertensive crisis]. AB - BACKGROUND: Hypertensive crisis is defined as a severe elevation in blood pressure (BP) without target organ injury. There are few data about the efficacy and safety of comparative oral antihypertensive drugs. AIM: To compare the efficacy and safety of oral captopril (25 mg) and nicardipine (20 mg) in hypertensive crisis. METHODS: This prospective, randomized study included 50 patients attended at the emergency department with a hypertensive crisis (arterial blood pressure of at least 180/110 mmHg without target organ damage confirmed after 15 min of rest. Systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were assessed at several intervals during 4 h after the drug administration. Therapeutic success was defined by a SBP< or =160 and DBP< or =90 mmHg two hours after drug administration. The initial clinical characteristics as age, sex, initial systolic and diastolic BP and HR were no different in the two groups. RESULTS: BP levels started to significantly decrease within 15 minutes. At 2 hours, SBP and DBP dropped were similar in captopril group and nicardipine group,respectively to 162/94 vs 161/89 mmHg; p=ns. The therapeutic success at the second hour has been obtained in 68% of cases in the two groups. Age >70 years was a predictor's factor of therapeutic failure in the captopril group. Heart rate significantly dropped after 30 min in the captopril group (82.3 +/- 11.8 vs 77.6 +/- 12.7 c/min; p=0.037). This effect was maintained over four hours. There were no side effects in this study. CONCLUSION: Oral captopril or nicardipine are efficacy and safe in the treatment of hypertensive crisis. PMID- 18444533 TI - Clinicopathological characteristics of synchronous bilateral breast carcinomas. Report of 30 patients. AB - AIM: The objective of this study is to determine the clinicopathologic characteristics; incidence and prognosis value of synchronous bilateral breast carcinoma (SBBC). METHODS: This is a retrospective study done in Salah Azaiz Institute of Tunis about 30 patients with synchronous bilateral breast carcinomas diagnosed and treated over a 21-years period going from 1977 to 1997. The definition of synchronous breast lesions is the developpement of the contralateral breast cancer within 6 months. RESULTS: Median age was 49 years. The incidence of SBBC was 0.52%. History family was noted in 3% of our population. Mean tumor size was 40 mm (15-145). Breast conserving therapy was done in 16% of cases (9 patients). Five-year overall survival was 40%. Five year survival rates were 72 and 17% for stage II and III, respectively. Main prognostic factors for survival were lymph node involvement (P=0.004) and disease stage (P=0.02). CONCLUSION: Synchronous bilateral breast carcinoma is a rare entity, with a problem of definition concerning the delay of bilaterlisation. Their prognosis is similar to that of unilateral breast carcinoma patients of equal stage. Hence, breast conserving therapy can be used s fely if indicated. PMID- 18444534 TI - [How a diabetic lives during the month of Ramadan]. AB - AIM: The research is about diabetic people who can fast Ramadan. In order to do so in a good physical health must have some stipulations. METHODS: In a certain research, about 278 diabetic people of the two types were examinated, making comparaison between those who were fasting and who weren't. RESULTS: 52,3% people are fasting of diabetic type 2 where's 18,4% people of diabetic type 1. 43% people who haven't spent yet five years affected by this disease. We have also noticed that 45% of diabetic type 2 fasting, and those who are older than 40 years have lost weight and improved their health. However, the blood sugar has deteriorate of those diabetic type 1 are fasting. CONCLUSION: Fasting Ramadan is possible for those diabetic type 2, and preferable plump people. PMID- 18444535 TI - Mucormycosis: four case reports. AB - INTRODUCTION: Mucormycosis is a rare and invasive fungal infection, but frequently fatal when it occurs. It commonly affects patients with diabetes mellitus. The aim of this study is to assess the clinical presentation, radiological findings, management and prognosis of mucormycosis. METHODS: This retrospective study was conducted in the department of infectious diseases of Rabta hospital between January 1988 and December 2004 and included patients hospitalized for mucormycosis confirmed by mycological and/or histological findings. RESULTS: the study is about four diabetic patients with mucormycosis (3 men and a woman). Three of them had diabetic ketoacidosis at the time of diagnosis. The infection was sinusal in 2 cases and rhinocerebral in the the other two cases. Treatment consisted in systemic amphotericin B combined with surgical debridement in 3 cases. A fatal outcome was noted in 2 cases. CONCLUSION: Mucormycosis remains a severe infectious disease in diabetic patients. Early diagnosis and treatment is mandatory for a successful management of this infection. PMID- 18444536 TI - Squamous cell carcinoma arising in Verneuil's disease. AB - BACKGROUND: Verneuil's disease or hidradenitis suppurativa is a chronic suppurative, and cicatricial inflammatory disease, mainly affecting apocrine bearing area of the skin. Squamous cell carcinoma is an uncommon but a frightening complication of hidradenitis suppurativa. AIM: To report a new case of squamous cell carcinoma arising in Verneuil's disease. CASE REPORT: We reported a case of 60 year old man with a 30 years history of hidradenitis suppurativa in which squamous cell carcinoma arise. A wide surgical excision removing the tumour and leaving a large defect was performed. The patient had a well recovery, wounds healed well by primary intention. No recurrence observed at 18 months of follow up. CONCLUSION: Squamous cell carcinoma is an uncommon complication of hidradenitis suppurativa. Surgical excision represents also the treatment of choice. PMID- 18444537 TI - Prenatal diagnosis of ectopia cordis: case report. AB - Ectopia cordis is a rare and impressive malformation presenting as an isolated lesion or as part of the Cantrell's pentology syndrom. It is defined as an anomaly in which the fetal heart lies outside the thoracic cavity. THE AIM of the study is to report the prenatal diagnostic features and management of ectopia cordis. CASE REPORT: We report a prenatal diagnosis case of ectopia cordis using two-dimensional ultrasound at 19 weeks of gestation. Multiple congenital anomalies were found. The most important one was the presence of a ventral thoracoabdominal wall defect with exstrophy of the heart, liver, stomach and intestines. Histopathological examination confirmed the ultrasound findings. Due to severity of the malformations, termination of pregnancy was made. PMID- 18444538 TI - [Diagnosis of spinal diseases by MRI]. AB - For a long time the imaging diagnosis of spine disease was based on conventional radiology (plain radiography, myelography and arteriography). The recent employment of MRI had changed the study of spine disease thanks to an excellent contrast and a multiplanar approache. In fact, nowadays MRI is the most sensible technic for a combined study of spine container and contents and medullar tissue. PMID- 18444539 TI - [Clinical and therapeutic particularities of depression in the elderly]. AB - Depression in older people slightly differs from younger subjects adults. Generally, typical depressive symptoms are overlooked by other symptoms. The most frequent ones are excessive preoccupation with health and complaints about physical symptoms. Anxiety is a common accompaniment of depression in later life. Poor subjective memory or dementia-like and psychotic symptoms are also common in depression in the elderly. The exogenous depression, the most common forms of depression in elderly people, has a little response to antidepressants. The endogenous depression is associated with high risk of suicide. Depression in older people often coexists with physical disorders. The most frequently encountered is Parkinson's disease. Depression could also be one of the side effect of the use of drugs for physical illnesses. The Tricyclic antidepressants (TCAs) are generally too toxic for elderly people and should not be considered as drugs of first choice. Currently, the drugs of choice are the serotonin-selective reuptake inhibitors (SSRIs). They have an antidepressant effect similar to that of (TCAs), but they are less toxic. The antidepressant treatment in the elderly is usually initiated at a low starting dose, ideally no more than half the usually recommended for the adults. For psychotic depression a combination of an antidepressant used in conjunction with antipsychotic drug is more effective than an antidepressant administered alone. The treatment should be continued for six months at least in order to reduce the risk of relapse. Moreover, long-term treatment is recommended because of the high risk of recurrence. PMID- 18444540 TI - [Pancreatic lipoma. A case report]. PMID- 18444541 TI - [Prostatic cyst causing urinary retention. Diagnostic and therapeutic particularities]. PMID- 18444542 TI - [Adult gastric duplication cyst: a case report]. PMID- 18444543 TI - [Multiple myeloma associated with hepatic infiltration: one case report]. PMID- 18444544 TI - [Eosinophilic pustular folliculitis in a child]. PMID- 18444545 TI - [Pancreatic tuberculosis, a source of diagnostic error!]. PMID- 18444546 TI - [Eruptive vellus hair cysts: a rare dermatosis needing histological diagnosis]. PMID- 18444547 TI - [Strumal carcinoid tumour. Report of a case]. PMID- 18444548 TI - [Antisynthetase syndrome]. PMID- 18444549 TI - [Peripartum cardiomyopathy: echocardiography and recovery]. PMID- 18444550 TI - [Mediastinal cystic lymphangioma: report of four cases]. PMID- 18444551 TI - [Coronary atherosclerosis and familial hypercholesterolemia: a case report]. PMID- 18444552 TI - [Slow channel syndrome: clinical and neurophysiological aspects]. PMID- 18444553 TI - [Hepatomegaly and early cytolysis as presenting symptoms in CDG syndrome type Ia]. PMID- 18444554 TI - [Acute pancreatitis and pre-eclampsia: case report]. PMID- 18444555 TI - [Primary carcinoma of fallopian tube: report of 3 cases]. PMID- 18444556 TI - [Eosinophilic cystitis: a rare inflammatory pathology. Report of 3 cases]. PMID- 18444557 TI - [Extended-spectrum beta-lactamase production and antimicrobial resistance patterns of Klebsiella pneumoniae strains isolated from nosocomial bacteremic patients: evaluation of the results of 2001-2005 period]. AB - Extended spectrum beta-lactamase (ESBL) producing Klebsiella pneumoniae is a global health problem. This study was aimed to retrospectively evaluate the resistance patterns of K. pneumoniae strains, microbiologically proven as agents of nosocomial bacteremia, between 2001-2005 and also to compare the 2001-2002 and 2004-2005 data to investigate the effect of 2003 budget application on antimicrobial resistance in our country. Data of antimicrobial resistance and hospital admission dates were extracted from the hospital patient record database. 2003 data was excluded to better evaluate the probable effect of governmental antibiotic restriction policy, which was started in March 2003. Blood cultures were performed on Bact/Alert (bioMerieux, Durham, NC) automated system and bacterial identifications were done by conventional methods. Double or more isolates during each episode were counted as one episode. Antibacterial susceptibility testing was done by disc diffusion method according to the recommendations of Clinical Laboratory Standards Institute. Resistance patterns in the 2001-2002 and 2004-2005 periods were compared by chi-square test. No resistance to carbapenems were detected in the strains. The comparison of 2001 2002 and 2004-2005 periods revealed that resistance to amikacin (30% and 19%, respectively), cefuroxime (55% and 37%, respectively), amoxycillin/clavulonate (59% and 46%, respectively), piperacillin/tazobactam (51% and 39%, respectively) and cotrimoxazole (53% and 35%, respectively) were decreased significantly (p < 0.05). The rate of ESBL K. pneumoniae strains was 49% in 2001-2002 period while it decreased to 35% in 2004-2005 period (p < 0.025). The decrease in the resistance rates after the 2003 budget application suggested that this success could be attributed to the evaluation of each patient to be given an extended spectrum antibiotic, by an infectious disease specialist and also more active use of the clinical microbiology laboratory. PMID- 18444558 TI - [Extended spectrum beta-lactamase types in Klebsiella pneumoniae strains isolated from blood cultures]. AB - The aim of this study was to investigate and type the extended spectrum beta lactamases (ESBL) in Klebsiella pneumoniae strains isolated from blood cultures. Following the detection of antibiotic susceptibilities in 32 K. pneumoniae isolates, ESBL were detected in 13 (41%) of them by using double disc synergy test. Minimum inhibition concentrations for ceftazidime, cefotaxime, and aztreonam of ESBL positive strains were determined by E-test. After the extraction of the enzymes, the types of ESBLs were investigated by isoelectric focusing method. It was seen that, of all ESBL positive strains, one strain had four bands, one had three bands, six strains had two bands, and each of the others had only one beta-lactamase band. The results of polymerase chain reaction (PCR) revealed bla(SHV) in ten samples, bla(TEM) in six samples, and bla(SHV) with bla(TEM) in four samples. Ten SHV enzymes were typed as ESBL by PCR-RFLP (restriction fragment lenght polymorphism) method. The results of isoelectric focusing, PCR and RFLP performed in these ESBL positive K. pneumoniae isolates showed that the ESBL types could be SHV-2, SHV-5 and SHV-12 in the tested strains. It should always be taken into consideration that K. pneumoniae isolates could produce ESBLs and antibiotic treatment protocols should be adjusted in accordance. PMID- 18444560 TI - [Investigation of the virulence genes in methicillin-resistant Staphylococcus aureus strains isolated from biomaterial surfaces]. AB - Staphylococci are the most important agents of nosocomial infections originating from biomaterials. The aim of this study was to investigate the presence of virulence genes and their phenotypic expressions in 11 methicillin-resistant Staphylococcus aureus strains isolated from the surfaces of clinically used biomaterials of 48 thorasic intensive-care unit patients. By the use of specific primers, the presence of genes encoding the attachment and biofilm production (icaA, icaC, bap), methicillin resistance (mecA), enterotoxins A-E (sea, seb, sec, sed, see), toxic shock syndrome toxin (tst), exfoliative toxins A and B (eta and etb), alpha- and beta-hemolysins (hla and hlb), staphylococcal exotoxin-like protein-1 (set1), proteases (sspA, sspB, aur, serine proteaz gene), lipase (geh) and the regulatory genes (sarA and agrCA) were investigated by polymerase chain reaction (PCR). The phenotypic properties of the isolates such as biofilm formation, antibiotic susceptibility, extracellular protease and lipase production were also evaluated. None of the isolates were found to be biofilm and/or slime producers, however, all strains were found to have icaA gene which is responsible for biofilm formation. Nevertheless the presence of icaC and bap genes that are also responsible for biofilm formation were not detected. All the strains have had mecA gene and were resistant to oxacillin, penicilin G and gentamicin, while 10 were also resistant to erythromycin and nine were also resistant to ofloxacin. The isolates were susceptible to vancomycin, teicoplanin and co-trimoxazole. Screening of toxin and regulatory genes revealed that all the strains harboured sea, set1, hla, hlb and sarA genes. The phenotypic tests for the determination of extracellular protease production revealed that all the strains formed very weak zones on skim milk and milk agar plates, and yielded negative results on casein agar plates. Furthermore, all strains were found to harbour sspA, sspB, aur and serine protease genes. Tween 20, Tween 80 and tributyrin containing media were used to detect lipase production and all strains gave late-positive results (on the third day of incubation), although they all lacked for lipase gene (geh). As a result, S. aureus strains isolated from biomaterial surfaces yielded positivity for some of the tested virulence genes, of which some of them have not been expressed phenotypically. Although there were some limitations in the study, it could be concluded that the presence of these virulence genes in S. aureus strains might be considered as potential threats especially in intensive care unit patients. PMID- 18444559 TI - [Prospective evaluation of the risk factors, etiology and the antimicrobial susceptibilities of the isolates in nosocomial bacteremic patients]. AB - This study was aimed to assess the frequency, risk factors and etiology of bacteremia and antimicrobial susceptibilities of strains isolated from adult bacteremic patients hospitalized in Kocaeli University Hospital, Turkey during a 12-month period. Blood specimens obtained from a total of 2602 patients after at least 48 hours of hospitalization, were cultured in aerobic BACTEC 9120 and BACTEC 9050 (Becton-Dickinson, USA) automatized systems, and the identification and antibiotic susceptibilities of bacteria were performed by VITEK 1 (bioMerieux, France) system. Blood cultures of a total of 385 (14.7%) patients yielded bacterial growth; the contamination rate being 9.1% (238/2602) and nosocomial bacteria rate being 5.6% (147/2602). The distribution of the 147 (81 female, 67 male) bacteremic patients were as follows: 45% internal ward, 28% surgical ward and 27% intensive care unit. A total of 148 patients (81 female, 67 male) with no growth in their blood cultures were randomly chosen as the control group. The pathogens isolated from nosocomial bacteremias revealed 101 gram positive bacteria (68.7%), 39 gram- negative bacilli (26.5%) and seven Candida species (4.7%). The most frequent gram-positive bacteria were staphylococci 84/101; 83.1%) and gram-negative bacteria were E. coli (14/39; 35.8%). Coagulase negative staphylococci (CNS) were isolated from 79% of the cultures evaluated as contaminants. Methicillin resistance was determined in 61.6% of S. aureus and 68.1% of CNS. Extended spectrum beta-lactamases were detected in 64% of E. coli, 62% of Pseudomonas spp., 47% of Klebsiella spp. and 24% of Acinetobacter spp. and resistance rates to ceftazidime and beta-lactam/beta-lactamase inhibitor combinations in these strains were 39-67%. The most effective drug group was found to be carbapenems with 3-26% resistance rates. The evalution of risk factors between patient and control groups revealed that mechanical ventilation (p < 0.05) and interventional catheters (except for intravenous catheters) (p < 0.05) were the most frequent sources of bacteremias. The most frequent focus of infection were the lungs (29.9%), followed by abdominal and catheter originated infections (23.8% each). The high rate of antibiotic resistance determined in the nosocomial bacterial isolates in our hospital indicated that antibiotic use policies in our setting should be taken under control. The high rate of contamination in blood cultures emphasize that more attention should paid for continous education about collection of blood culture specimens. PMID- 18444561 TI - [Investigation of Listeria monocytogenes serotype O antibodies in maternal and cord sera and the evaluation of risk factors for listeriosis in pregnant women]. AB - Listeria monocytogenes may lead to intrauterine infections which can be treated if diagnosed promptly. However, there is not a rapid routine screening test with high specificity and sensitivity for the diagnosis of listeriosis during pregnancy. We investigated the presence of different L. monocytogenes O antibodies for diagnosis of listeriosis in 275 paired maternal-cord sera using the agglutination test, and aimed to evaluate the correlation between poor pregnancy outcomes, level of L. monocytogenes serotype O antibodies and risk factors for listeriosis. Maternal-cord bloods were collected from a total of 275 pregnant women (age range 16-38 years) between April-August 2002 from a State Hospital in Ankara. A total of 550 sera were tested against antigens with the O formulation of serotypes 1/2c, 3b, 4ab, 4c, 4d by tube agglutination method and titers > or = 1/320 were considered as positive. Sixtynine patients with the history of poor pregnancy outcomes were in group I, while 206 patients with no obstetric pathology in previous pregnancies were in group II. L. monocytogenes antibodies to one or more serotypes were detected in 21.5% (59/275) of the patients, the rate being 20.3% in group I and 21.8% in group II. No statistically significant difference was detected between the two study groups (p > 0.05), indicating that this test was not an appropriate marker for the diagnosis of listeriosis during pregnancy. The total rate of positive results in cord sera was 0.7% (2/275) and the positive two sera were from samples in group II. The follow up of the newborns, including the two cord blood positive ones, revealed no fetomaternal infection. The most frequently detected serotypes were 4ab (40%) and 1/2c (37%). Risk factors such as non-specific febrile illness during pregnancy (p < 0.001), consumption of ready-made food (p = 0.008), consumption of raw milk and milk products (p < 0.001) were found to be related to the presence of > or = 1/320 titers of L. monocytogenes antibodies. The major limiting factor in this study was the inability to obtain second serum samples from the mothers and newborns following delivery, to confirm the diagnosis by seroconversion. These results emphasize the need for the development of rapid, simple and reliable tests, alternative to culture methods, for the early and proper diagnosis of Listeria infections during pregnancy. PMID- 18444562 TI - [A small water-borne tularemia outbreak]. AB - The aim of this study was to investigate a small tularemia outbreak in a village of Karamursel county of Kocaeli province (located in North-west part of Turkey), between 22 January - 8 March 2005 and to present the anti-epidemic measures implemented. Following diagnosis of oropharyngeal tularemia in two patients living in the same village, a field investigation was performed at this region. All patients have undergone physical examination. Blood samples and if possible throat swabs and lymph node aspirates were taken from the patients and water samples from the natural spring water suspected to be the source of the infection, were also taken. Cultures were performed from the clinical samples and filtrated water samples. Francisella tularensis antibodies were screened by microagglutination (MA) test in the serum samples of the patients. F. tularensis DNA was investigated in the filtrated water samples by real-time PCR assay. A total of 17 patients were diagnosed as tularemia with their clinical features and MA test results (> or = 1/80). All the patients had oropharyngeal tularemia except one who had ulceroglandular form. The age range of the patients was 27-80 years (mean age: 48 +/- 17 years), and 10 (59%) were female. Weakness (100%), swelling on the neck (94%) and sore throat (88%) were the most common symptoms, whereas cervical lymphadenopathy (94%) was the most frequently seen clinical finding. F. tularensis could not be grown in the cultures, however F. tularensis DNA was detected in the samples of the natural spring water by real time PCR. The patients were treated with streptomycin, ciprofloxacin, or doxycycline, and all the patients have recovered. The outbreak was taken under control after cleaning the spring water tank and chlorination of the water. PMID- 18444563 TI - [Occupational exposures to blood and body fluids among health care workers: a questionary survey]. AB - The major concern following occupational exposures of the health care workers is the possible transmission of blood-borne pathogens, especially hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). This questionary survey was undertaken to determine the frequency and epidemiological characteristics of incidents involving biological exposures to blood and body fluids among health care workers (HCWs), at a University Hospital, in Izmir, Turkey. The survey was conducted using a questionnaire including questions related to demographics and epidemiological information. A total of 350 HCWs [162 physicians (academicians, seniors and juniors), 71 nurses, 55 interns of medical faculty, 45 cleaning staff, 12 nurse's aides, five technical/ managerial staff] were included to the survey. Of them, 203 (58%) have reported at least one exposure, 108 (%53.2) of them were physicians (p < 0.000) and 53 (26.1%) were nurses. The highest injury rate was reported by the nurse group (74.6%) followed by physicians (66.7%), cleaning staffs (57.8%) and interns (23.6%). Most of the occupational injuries (62.5%) have eventuated in the last one year. Types of exposure included percutaneous injury (97%) which was commonly caused by needle recapping (36%), suturing (25.6%) and handling of garbage bags (10.3%). Of the exposed HCWs, 138 (68%) have reported to use a protective equipment during the exposure and only 51.7% sought for medical assistance from the related department. Among 350 HCWs, 291 (83.1%) had been previously vaccinated against HBV, while two (0.6%) HCWs were chronically infected with HBV, unrelated with exposures. No transmission was reported following 16 incidents, in which the index patient was HBV, HCV or HIV carrier. In conclusion, percutanenous injuries are still common among HCWs. The results support the importance of the use of universal precautions and safety-enhanced devices, introducing effective training and efficient vaccination programs against HBV, in the clinical settings. PMID- 18444564 TI - [Development of a hepatitis B virus carrier transgenic mice model]. AB - The studies for the development of transgenic mice models which provide important profits for the studies concerning immunopathogenesis of hepatitis B virus (HBV) infections are in progress since 20 years. For this purpose different lineages bearing whole HBV genome or selected viral genes have been developed and their usage in clarifying the HBV replication and pathogenesis mechanisms have been emphasized. The aim of this study was to develop and breed a HBV carrier mice model. In the study the full HBV genome has been transferred to mouse embryos by microinjection procedure. Following transgenic manipulation, the HBV carriers among the daughter mice have been detected by molecular methods in which HBV-DNA replication and expression have been shown. The manipulations for transgene transfers have been performed in TUBITAK Marmara Research Center Transgene Laboratory, Gebze, Istanbul. The HBV-DNA carrier mice have been demonstrated by polymerase chain reaction (PCR) using the DNA samples obtained from tail tissues and also by dot-blot hybridization of the mice sera. Integrated HBV-DNA has been detected by applying in-situ hybridization to the liver tissue sections. HBV-DNA expression has been shown by reverse transcriptase PCR method with total RNA molecules that have been isolated from the liver tissues of the HBV-DNA carrier mice. HBsAg has been detected in the liver by immunohistochemical method, and HBsAg and HBeAg have additionally been demonstrated by ELISA. HBV genome, expression of the genome and the expression products have been determined in approximately 10% of the mice of which HBV-DNA have been transferred. By inbreeding heterozygote carrier mice, homozygote HBV transgenic mice line have been obtained. These HBV transgenic mice are the first lineages developed in our country. It is hopefully thought that this HBV carrier transgenic mouse model may contribute to the studies on the pathogenesis of HBV infections which are important health problems in the world as well as in Turkey. PMID- 18444565 TI - [Investigation of the effect of constructions in hospital environment on the crucial units for immunocompromised patients and the development of opportunistic mold infections]. AB - This study was planned to determine the effect of building constructions in and around our hospital, on the development of opportunistic mold infections in immunocompromised patients hospitalized in bone marrow and kidney transplantation units and haematology and oncology units. Samples were collected from high risk units by an air sampler (Air Ideal) from indoors and outdoors of a total of 43 patient rooms. The most commonly isolated species from indoor air cultures of our hospital were Penicillium spp. (50.6%), Cladosporium spp. (20%), Chrysonilia spp. (11%) and Aspergillus (10.6%) species. When outdoor samples were considered, Penicillium spp. (38.8%) was still in the first line, followed by Cladosporium spp. (24.3%), Paecillomyces spp. (10.7%) and Aspergillus (8.7%) species. There was no statistically significant difference of total colony and spore numbers between the samples obtained from indoor and outdoor air (p > 0.05), indicating the close relation with the construction studies in and around the hospital. Clinical samples including bronchoalveoler lavage (BAL) fluid, sputum, endotracheal aspirate and sinus tissue were collected from the total of 43 patients staying at these air sampled rooms, and eight of them (18.6%) yielded positivity for the growth of molds. Of them four were identified as Penicillium chrysogenum (sputum isolates), two as Aspergillus fumigatus (sputum and BAL isolates), one as Aspergillus flavus (BAL isolate), and one as Valsa sordida (sinus tissue) which is considered as a plant pathogen. A total of 53 sera, BAL, and tissue supernatant samples were screened by ELISA for the presence of galactomannan antigen, and five of the eight patients whose cultures were positive were also found positive for galactomannan antigen. One patient has died due to invasive aspergillosis whose BAL specimen and indoor air sample were positive for A. fumigatus. In evaluation of indoor air samples before and after the change of HEPA filters, statistically significant decrease was detected in total colony and spore numbers between the samples taken before and after the filter changes (p < 0.005). This study has emphasized the importance of examination of mold flora of indoor air and clinical samples of high risk group patients intermittantly, in order to prevent opportunistic mold infections in crucial units especially during hospital constructions. PMID- 18444566 TI - [Investigation of the agents and risk factors of dermatophytosis: a hospital based study]. AB - The aims of this study were the detection of distribution of dermatophyte species isolated from the clinical samples of patients with dermatophytosis and the evaluation of risk factors for the development of dermatophytosis. A total of 441 skin, nail and scalp/hair specimens obtained from 301 patients (151 were male; age range 2 months-80 years, median 42 years) and 884 foot and hand skin and nail specimens obtained from 221 control subjects (110 were male; age range 5-75 years, median 36 years) were included to the study between the period of January to December 2005. All the samples have been evaluated by direct microscopic (DM) examination and by culture. A total of 121 (40.2%) patients yielded positivity for dermatophytes, of them 63 were positive by both DM and culture methods, seven were only culture positive, and 51 were only DM positive. Nine (9.8%) of 92 culture positive samples from 70 patients were found negative in DM, while 85 (50.6%) of 168 DM positive samples from 114 patients were negative in culture. 23.5% (12/51) of DM positive but culture negative patients were given antifungal therapy previously. The most prominent species isolated from the cultures were Trichophyton rubrum with a rate of 68.4% (63/92), followed by T. mentagrophytes (18.4%); T. violaceum (3.3%); T. verrucosum, T. tonsurans and Epidermophyton floccosum (2.2% for each); T. schoenleini, Microsporum canis and Trichophyton sp. (1.1% for each). Of the patient samples whose cultures were positive, 45% were from the foot skin. The presence rate of dermatophytes in controls was found as 3.2% (7/221); T. rubrum was isolated from the foot skin of five and T. mentagrophytes was isolated in toenail of two control subjects. About 42% of the samples belonged to the patients who admitted to hospital between December to February period. The evaluation of the risk factors revealed that presence of trauma, pet contact, ritual cleansing and diabetes mellitus had no effect on the development of dermatophytoses, however the presence of fungal infection in the family, male gender, some professions (being farmer, worker and retired), and the use of immunosupressive drugs have been found to increase the risk of dermatophytosis. The number of cases with dermatophytoses started to increase beginning from the age of 20 and peaked in the ages between 40-59 years old. As a result T. rubrum was determined as the most frequently isolated dermatophyte and tinea pedis was the most frequently observed clinical form in our hospital, emphasizing the importance of early diagnosis and effective treatment in superficial fungal infections which have high morbidity. PMID- 18444567 TI - [Investigation of anti-Leishmania seroprevalence by different serologic assays in children inhabiting in the northwestern part of Turkey]. AB - Human visceral leishmaniasis (VL) caused by Leishmania infantum in Mediterranean region is still an important public health problem in those countries including Turkey. The asymptomatic presentation of the infection in most of the cases leads to difficulties in the diagnosis and prevention of the spread of infection. The aim of this study was to investigate the seroprevalence of anti-Leishmania antibodies in children inhabiting in the northwestern part of Turkey. A total of 572 healthy children (260 girls, 312 boys) aged between 1-17 years old (mean age: 8.1 years) inhabiting in Eskisehir, Bilecik, Kutahya and Afyon provinces and their counties were included to the study with the informed consent obtained from their families. All serum samples were screened by a commercial ELISA (Leishmania Ab Panel, Cypress Diagnostics, Belgium), two in-house ELISA (with whole antigens and rK39 antigen) tests and an in-house indirect fluorescent antibody test (IFAT). The sera yielding a positive result by commercial ELISA, have been re evaluated with rK39 dipstick test. Of 572 children, 5.2% (n = 30) were found positive with commercial ELISA, 3.8% (n = 22) with IFAT, 4.7% (n = 27) with in house whole ELISA, and 3.6% (n = 21) with in-house rK39 ELISA. Of 30 commercial ELISA positive sera, 19 (63.3%) gave positive result also by dipstick test. This difference was attributed to the use of multiple antigens belonging to different Leishmania species in commercial ELISA test. The number of children who were seropositive with all of the tests were 15 (2.6%) and with at least three of the tests were 24 (4.2%). Most (76.7%) of the 30 seropositive children with commercial ELISA were found to be inhabiting in Iscehisar town of Afyon province (n = 16) and Sogut town of Bilecik province (n = 7) where canine VL was also endemic. Our results also indicated that 93.3% (28/30) of seropositive children were living in the rural parts of the study region. Thirty seropositive children were followed-up for one year, but none of them have exhibited clinical findings of VL. As a result, the rate of anti-Leishmania seropositivity (5.2% with at least one test, and 4.2% with at least three tests) in healthy children in the study area should not be ignored, and prevention strategies should be undertaken since our previous study have also showed that the rate of VL in dogs was high and the vector Phlebotomus species were determined in these areas of Turkey. PMID- 18444568 TI - [Investigation of Leishmania infantum seropositivity in HIV/AIDS patients]. AB - In recent years an increase in the rate of detection of HIV and Leishmania co infections has been reported from many countries especially countries in Southern Europe. Visceral leishmaniasis (VL) is sporadically detected in some parts of Turkey. Although the natural transmission is via sandfly bites, VL may be transmitted by needle sharing of intravenous drug addicts or by blood transfusion in HIV/AIDS patients. The aim of this study was to investigate the presence of specific antibodies against Leishmania infantum, which is the causative agent of VL, in the sera of HIV/AIDS patients. A total of 79 HIV/AIDS patients (61 male, 18 female; mean age: 30 +/- 2 years) with confirmed diagnosis by HIV Reference Laboratory of Refik Saydam Hygiene Center between the years of 2004-2006, were included in the study. L. infantum antibodies were searched by fast agglutination screening test (FAST), direct agglutination test (DAT), indirect immunofluorescent antibody test (IFAT) and rK39 dipstick assay. Only one serum sample (1.2%) was found to be seropositive by all of the serological tests (> 1/100 by FAST, 1/3200 by DAT, 1/256 by IFAT, and specific bands for L. infantum by rK39 dipstick test), while the remaining samples were negative with all of the methods. The seropositive serum was from a 49 years-old heterosexual male, living on the Mediterranean cost and has had acquired the HIV infection by sexual contact. He has no history of intravenous drug use but he had experienced blood transfusion. Since the seropositive serum sample was collected 2-3 weeks after the transfusion, the transmission of L. infantum was thought to be during blood transfusion, however it could also be acquired via a previous sandfly bite. In conclusion although the rate of L. infantum seropositivity was low in HIV/AIDS patients in our study, the possibility of HIV/Leishmania co-infections should be considered. PMID- 18444569 TI - [Short communication: Determination of methicillin resistance in staphylococci with different methods and detection of multiple antibiotic resistance]. AB - The aims of this study were to determine the methicillin resistance of a total of 256 staphylococcus strains [213 Staphylococcus aureus and 43 coagulase negative staphylococci (CNS)], isolated from different clinical samples and hospital environmental specimens by different methods and to detect multiple antibiotic resistance in these isolates. Methicillin resistance of staphylococci was investigated by using oxacillin agar screening (OAS), oxacillin disk diffusion (ODD), cefoxitin disk diffusion (CDD), PBP2a latex agglutination (LA) and microdilution tests. The resistance of the strains against penicillin G, amoxycillin/clavulanate, cephalothin, tetracycline, erythromycin, fusidic asid, ofloxacin, vancomycin, co-trimoxazole and gentamicin was investigated by standard disk diffusion method. As a result, 152 (71.3%) S. aureus and 30 (69.7%) CNS isolates were found to be methicillin-resistant with the use of OAS and PBP2a LA tests, respectively. The numbers of the isolates which were detected as methicillin-resistant and methicillin-susceptible were 182 and 74 by OAS; 183 and 73 by ODD; 181 and 75 by SDD; 180 and 76 by PBP2a LA; 183 and 73 by microdilution tests, respectively. There was no statistically significant differences-between the results obtained by all of the methods (p > 0.05), however the sensitivity of PBP2a LA test was lower in the detection of methicillin resistance in S. aureus strains. CDD test which was found to be as sensitive as ODD test, may be preferred in the detection of methicillin resistance in staphylococci. In our study staphylococci which were sensitive to methicillin, were also found generally sensitive to the other antibiotics, whereas staphylococci which were resistant to methicillin were also resistant to the other antibiotics. The difference between methicillin sensitive and resistant staphylococci in terms of the rates of resistance against other antibiotics was found statistically significant with the exception of fusidic acid (p < 0.05). The resistance rates of isolates for fusidic acid were very low and all of the strains were susceptible to vancomycin. In conclusion, for better determination of methicillin resistance, agar screening test which is proposed as a confirmatory test by CLSI, should be used when necessary. PMID- 18444570 TI - [Short communication: Investigation of in vitro antibiotic susceptibility of Brucella melitensis]. AB - The aim of this study was to investigate the in vitro susceptibilities of Brucella melitensis clinical isolates against antibiotics used in conventional treatment regimens and additionally against quinolones. A total of 65 B. melitensis strains isolated from blood and bone marrow specimens of patients who were admitted to an university hospital localized in a region endemic for brucellosis. Minimum inhibitory concentration values (MIC50 and MIC90) of trimethoprim-sulphamethoxazole (TMP-SMX), rifampin, doxycycline, ciprofloxacin, ofloxacin, sparfloxacin and levofloxacin for B. melitensis isolates have been detected by using E-test (AB Biodisk, Sweden). In our study the most effective antimicrobial agent was found to be TMP-SMX (MIC90 = 0.023 mg/L) followed by doxycycline (MIC90 = 0.032 mg/L). With regard to fluoroquinolones, the most active antibiotic was sparfloxacin (MIC90 = 0.064mg/L), followed by levofloxacin and ciprofloxacin (MIC90 = 0.125 mg/L), and ofloxacin (MIC90 = 0.50 mg/L). Rifampin exhibited the highest MIC90 value (1.5 mg/L), and eight isolates yielded intermediate resistance to rifampin. There was no serious resistance problem for TMP-SMX and doxycycline in our study, however, enough care should be taken for the use of rifampin which is frequently used for the treatment of tuberculosis and brucellosis which are endemic in our country. As a result, the antimicrobial susceptibilities of Brucella species should be determined periodically to avoid the possible development of resistance problems in the future. PMID- 18444571 TI - [Short communication: Extended-spectrum beta-lactamase production in Klebsiella pneumoniae strains isolated from blood cultures and their antibiotic susceptibilities]. AB - This study was carried out to detect the extended-spectrum beta-lactamase (ESBL) producing Klebsiella pneumoniae strains isolated from blood cultures of hospitalized patients, and to determine their antimicrobial susceptibilities. A total of 102 K. pneumoniae strains isolated from blood samples were taken in the study, and ESBL production and susceptibilities to amikacin, gentamicin, imipenem, ciprofloxacin, amoxicillin/clavulonate (AMX/CA), ceftazidime, ceftriaxone, trimethoprim/ sulphametoxazole (TMP-SMX), piperacilin-tazobactam (PIP/TAZ) and chloramphenicol were investigated by using E-test (AB Biodisk, Sweden). ESBL positivity was observed in 65 (63.7%) of the isolates, and all of the strains were found susceptible to imipenem. The resistance rates of ESBL producing isolates were detected as 27.7% for amikacin, 41.5% for chloramphenicol, 49.2% for TMP-SMX, 55.4% for ciprofloxacin and 60% for PIP/TAZ; whereas these rates for ESBL non-producers were 2.7%, 5.4%, 5.4%, 2.7%, and 13.5%, respectively. Both the resistance rates and MIC values (MIC50 and MIC90) of the tested antimicrobial agents except imipenem, were found higher in ESBL positive strains than the ESBL negative strains (p < 0.05). The results of this study, in accordance with the previous national and international reports, indicated high rate of ESBL positive K. pneumoniae and also increased rate of antimicrobial resistance in such strains. Clinical microbiology laboratories should put ESBL detection tests into practice and each hospital should determine their antibiotic treatment policies according to their data. PMID- 18444572 TI - [Short communication: Evaluation of the flu vaccine administered to health care workers in Trakya University Hospital in 2006]. AB - After the detection of human cases of highly pathogenic avian influenza A (H5N1) virus in Eastern Turkey in January 2006, Turkish Ministry of Health has had declared "National Plans of Activity for Pandemic Influenza". All health-care facilities were recommended to develop contingency plans. Then the essential activities were started in August 2006 in Trakya University, Faculty of Medicine (Edirne, Trace region of Turkey), and institutional education about pandemic influenza and preventive measures was implemented to health care workers (HCWs). In November 2006, health care workers were offered inactivated flu vaccine (Vaxigrip, Sanofi Pasteur, France) supplied by the Ministry of Health. The aim of this questionary survey was to evaluate the visions and conceptions of health care workers about influenza vaccination during the vaccination campaign. All the participants were informed by using an information form including the indications, contraindications and possible adverse reactions of flu vaccine, and were requested to complete the questionnaire about influenza vaccination according to their own perception before vaccination. Vaccine recipients were also invited to the vaccination unit if they had any adverse reaction. A total of 1041 HCWs (560 female, 481 male; mean age: 32.8 +/- 8.2 years) completed the questionnaire. Of them 884 subjects (85%) have accepted to be vaccinated, while 157 subjects (15%) have not. It was determined that 72 HCWs (6.9%) had been administered flu vaccine in 2005, and 38 (3.7%) have had an underlying chronic disease requiring medical therapy. Six subjects (16%) with an underlying chronic disease were vaccinated in 2005, while 66 HCWs (6.6%) without any chronic disease received vaccination voluntarily. Seven workers (0.7%) declined vaccination as they defined hypersensitivity to egg, and 84 workers (8%) had influenza vaccine voluntarily before the campaign in 2006. Sixty six workers (6.3%) have refused to be vaccinated as they considered influenza vaccination ineffective to protect against flu. Two workers (0.2%) had allergic skin reactions such as erythema and itching after vaccination. It can be concluded that influenza vaccination of the health care workers is a part of infection control policies and it is also a matter of patient safety. The implementation of necessary education programmes and attempts to emphasize the importance of vaccination of health care workers especially dealing with high risk patients, would be of crucial importance to decrease the morbidity and mortality due to influenza infections. PMID- 18444574 TI - [Short communication: In vitro activity of amphotericin B with fluconazole or voriconazole combinations against Candida albicans isolates]. AB - The aim of this study was to investigate the in vitro interaction of amphotericin B in combination with fluconazole or voriconazole against Candida albicans clinical isolates by using a broth microdilution checkerboard assay and E-test. A total of 30 C. albicans strains isolated from blood, urine, sputum and pus samples were included to the study and the minimum inhibitory concentrations (MICs) of amphotericin B (AMB), fluconazole (FLU) and voriconazole (VOR) were determined by broth microdilution method and E-test. All strains tested for susceptibility were interpreted as susceptible by both methods (FLU MICs < 8 microg/ml, VOR and AMB MICs < 1 microg/ml). The rates of MIC agreement between two methods were as follows: AMB, 83%; FLU, 97%; VOR, 97%. AMB+ FLU and AMB+VOR combinations were tested by checkerboard broth microdilution and E-test methods. The combination test results were determined by using the fractional inhibitory concentration (FIC) index as synergistic, indifferent or antagonistic. AMB+FLU combination tested by checkerboard broth microdilution revealed synergy in one strain (3.3%) and antagonism in none, while the same combination tested by E-test revealed synergy in two (6.6%) and antagonism in four (13.3%) strains. The strains which exhibited synergy were different from eachother in two assays. This combination led to indifferent results in 23 (76.6%) of the strains. On the other hand AMB+VOR combination yielded synergistic results in two (6.6%) strains by both of the methods, however, these two strains were again different from eachother. No antagonism was detected by AMB+VOR combination while the combination was indifferent in 26 (86.6%) of the strains. Agreement between the checkerboard and E-test results was 87%. Although significant synergy was not detected in AMB+azole combinations, it was yet hopeful to obtain no antagonism. However, multi-center, large-scale, well standardized in-vitro and clinical studies about AMB and azole interaction which is a matter of debate, are necessary. PMID- 18444573 TI - [Short communication: The sensitivity of measles diagnosis by physicians and families during an intraepidemic period in Edirne: implications for measles surveillance]. AB - Measles is still a leading cause of death among young children, despite the availability of a safe and effective vaccine for the past 40 years. EURO Region of World Health Organisation including Turkey has targeted elimination of measles by the year 2010. It is concluded that there must be a sensitive surveillance system to investigate all suspicious measles cases, and diagnosis should be based on both standardized case definition and laboratory confirmation. Standardized case definition based notification has started in 2005 in Turkey. This study was carried out to determine the sensitivity and specificity of clinical measles diagnosis by physicians and families during a measles epidemic affecting 597 cases in Edirne province in 1997. Blood samples and data were collected by trained teams consisting of one physician and one nurse. Thirty clusters sampling method was used for sampling and 210 blood samples were taken from the children. The sera were then sent to Refik Saydam Hygiene Institute, Ankara, for the detection of measles specific IgG and IgM antibodies. Positive results for IgM were considered as acute measles during epidemics, and positive results for IgG were considered as acquired immunity due to vaccination or passed infection. Of 210 children, 19 were found to have recent infection (IgM+, IgG-), 101 were found immune (IgM-, IgG+), 67 were found in convalescence phase after infection (IgM+, IgG+), and 23 were found susceptible (IgM-, IgG-) to measles. The overall IgM seropositivity was detected as 40.9% in the study group. Only half of confirmed cases (43/86) were diagnosed as measles clinically by the physicians. The sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) of clinical diagnosis by physicians were estimated as 33%, 89%, 67% and 86%, respectively. Validity measures for measles diagnosis by the families were as follows; 8% sensitivity, 96% specificity, 6% PPV and 60% NPV. It is concluded that, all required measures should be taken for the availability of laboratory confirmation of all suspicious measles cases and field investigation via structured case investigation forms, is necessary for the success of measles surveillance system in our country. PMID- 18444575 TI - [A case of endobronchial aspergilloma]. AB - Infections caused by Aspergillus spp. in immunocompromised or atopic patients may present as invasive aspergillosis, allergic bronchopulmonary aspergillosis and aspergilloma. In this report a 69 years old female patient admitted to the hospital with the complaints of intermittent cough and sputum and diagnosed as endonbronchial aspergilloma, has been presented. The patient was not immunocompromised, however she has bronchial asthma for 10 years and the disease is now under control. The chest radiography and computed tomography revealed lung infiltration with undefined borders, and bronchoscopy demonstrated the presence of a mass at left lower lobe. In the pathologic examination of biopsy specimen with the use of methenamine silver and PAS methods, hyphae formations concordant with Aspergillus were detected. The direct microscopic examinations of biopsy material and sputum obtained after bronchoscopy, have also revealed the presence of hyphae. A. fumigatus was isolated from the cultures of biopsy material and sputum specimen. The patient was diagnosed as endonbronchial aspergilloma, however the follow-up was failed since she has not accepted medical or surgical treatment. In conclusion, aspergilloma should be considered in the differential diagnosis of mass lesions in the endobronchial area. PMID- 18444576 TI - [Bartonella henselae and its infections]. AB - In recent years the number of identified Bartonella species has increased rapidly and several species in Bartonella genus isolated from various mammalian reservoirs were recognized as zoonotic agents in humans. Three Bartonella species are considered to be pathogenic for humans; B. henselae, B. quintana and B. bacilliformis. B. henselae causes asymptomatic intraerythrocytic bacteraemia in the feline reservoir host and is the most important zoonotic species as the cause of human diseases including cat scratch disease, bacillary angiomatosis, bacillary peliosis, bacteraemia, endocarditis and neurological disorders. In this review article general characteristics of B. henselae, infection types and clinical features, laboratory diagnosis, treatment and preventive measures have been discussed. PMID- 18444577 TI - [Helicobacter pylori infection and phagocytosis]. AB - Helicobacter pylori is a chronic infectious agent defined as the major pathogen causing gastritis, gastric and duodenal ulcer, gastric carcinoma and mucosa associated lenfoid tissue (MALT) lymphoma. H. pylori is the only microorganism known to get colonized in human stomach and inhabit in gastric mucosal cells. To achieve this, H. pylori must escape from both innate and adaptive immune responses. The host immune response is unable to eliminate the infection and this is generally associated with pathogenesis. The persistence of the induced H. pylori infection suggests that the response is not effective to eliminate the infection. In this review article, the correlation between H. pylori infection and innate immune response with emphasis on the avoidance of killing by phagocytosis, have been discussed. PMID- 18444578 TI - [The value of culture and serological methods in the diagnosis of human brucellosis]. AB - Human brucellosis is a potentially life-threatening multisystem disease. During the first week of infection, IgM antibodies against lipopolysaccharide antigens appear in the serum, followed by IgG antibodies as early as the second week. Both antibody isotypes peak during the fourth week, and the use of antibiotics was associated with a decline of both IgM and IgG class antibodies. The diagnosis of brucellosis is based on a detailed history obtained from the patients and the isolation of Brucella spp. from blood cultures are accepted as the standard method. The definitive diagnosis of brucellosis requires isolation of the bacterium from blood, bone marrow or tissue samples. Although the sensitivity of blood culture method varies depending on the individual laboratory practices, quantity of bacteria in blood and the methods used, it changes between 15-70 percent. Bone marrow culture is considered as the gold standard for the diagnosis of brucellosis, since the relatively high concentration of Brucella in reticuloendothelial system enables the detection of the organism. The standard tube agglutination test (SAT) is the most widely used serologic test for the confirmation of human brucellosis. The detection of seroconversion or high antibody titers (> or = 1/160) are considered diagnostic together with a compatible clinical presentation. The lack of seropositivity in patients with strongly suspected clinical picture may be attributed to the performance of tests early in the course of infection, the presence of blocking antibodies (non agglutinating, incomplete) or the so-called "prezone" phenomenon. Enzyme immunoassays (ELISA) which measure specific IgM, IgG and IgA antibodies, allow for a better interpretation of the clinical situation and overcome the false negativities/positivities which may arise in SAT. In this review article, the use and the values of culture methods and serological tests (Rose-Bengal test, SAT, Coombs' test, mercaptan-based tests, dipstick assay, flow assay, ELISA and brucellacapt) in the diagnosis of brucellosis have been discussed. PMID- 18444579 TI - Child abuse. PMID- 18444580 TI - Experience with splenic trauma in Ayub Teaching Hospital, Abbottabad. AB - BACKGROUND: This study was carried out to estimate the prevalence, severity and mode of splenic trauma and management technique from amongst the abdominal trauma cases admitted in Ayub Teaching Hospital. METHODS: The study was carried out at Surgery units of Ayub Teaching Hospital, Abbottabad, the only referral hospital for major trauma cases, from July 2001 to Dec. 2002. One hundred consecutive abdominal trauma patients admitted to all surgical units which were followed up through complete documentation were included in the study. Their injuries were classified, treatment strategies outlined and complications were documented. RESULTS: Out of the 100 patients presenting in emergency, 25% presented with blunt and 75% with penetrating trauma. 97 patients underwent laparotomy and 03 treated conservatively. Mean age was 27.26 (range 19-49) years. Out of these cases 19 patients had splenic injury, 6 (31.57%) with Type-I & II while 13 (68.42%) with Type-III & IV. 11(57.89%) of the splenic injuries were due to blunt abdominal trauma and 8 (42.10%) due to penetrating abdominal injuries. 14 (83.6%) of the patients with splenic injury underwent splenectomy and 5(26.3%) splenorrhaphy. CONCLUSION: The commonest cause of splenic injury was blunt abdominal trauma; Assessment of the severity of splenic injuries at the time of laparotomy resulted in splenic salvage procedures in some cases. Splenorraphy was associated with fewer complications. PMID- 18444581 TI - Evaluation of efficacy of management protocol in allergic rhinitis. AB - BACKGROUND: Allergic rhinitis represents a global health issue affecting between 10% to 25% of the world population, with increasing prevalence, resulting in a significant impact on quality of life, multiple comorbidities and the considerable socio-economic burden. Majority of the patients are younger than 30 years and it may be inherited. Symptoms typically occur as a result of exposure to dust, dander or certain seasonal pollen. Lack of standardized management protocol is one of the major factors responsible for poor control of this condition. This study was designed to evaluate the patients suffering with allergic rhinitis and manage them with a protocol based on the pathogenesis of the condition. METHOD: This prospective study was conducted in the Department of Ear, Nose & Throat and Head & Neck Surgery, Ayub Teaching Hospital, Abbottabad, over a period of two years (2005 - 2006), to assess the efficacy of a standard protocol of treatment developed and followed in the department. 1167 patients, clinically diagnosed as suffering with allergic rhinitis, were evaluated and managed. Age ranged from 08 months to 64 years. All the patients were prescribed medical treatment, divided into initial phase of 10 days to two weeks duration followed by a maintenance phase, and a regular follow-up schedule was maintained upto two years. RESULTS: 634 (54.32%) patients were male and 533 (45.67%) were female. Age ranged from 08 months to 64 years, 85% being between 05 and 45 years. 91% of patients had symptom duration of 06 months to 03 years. 96% of the patients were getting treated on as required basis, whereas 98% had no educational sessions with the treating doctor, especially regarding preventive measures. Typical presentation in most of the patients was nasal obstruction, runny & itchy nose, post nasal drip and bouts of sneezing. 90.57% patients reported improvement in symptoms. 53.21% patients had a relapse of symptoms at some stage during the study period. 37.53% patients had surgery done for associated pathologies, mostly a DNS. Compliance regarding medication was more than 90% in the initial phase of treatment that dropped to 50% in the maintenance phase. 93% of the patients tolerated the treatment well. CONCLUSION: Allergic rhinitis is a growing problem worldwide. Optimal treatment protocol is still lacking especially in the developing countries. Patient's education on avoidance of allergens must be stressed. Associated problems that may need surgical treatment. Regular follow-up must be ensured to monitor the progress of treatment as well as to identify patients who might be candidates for immunotherapy. Newer modalities of treatment need to be further explored. A team approach is mandatory in the presence of symptoms related to lower respiratory tract. PMID- 18444582 TI - Early left ventricular remodeling after aortic valve replacement. AB - BACKGROUND: Aortic valve disease is associated with eccentric or concentric left ventricular (LV) hypertrophy and changes in the LV mass. The relationship between LV mass and function and the effect of LV remodeling after aortic valve replacement (AVR), in patients with aortic valve disease needs evaluation, that is largely unknown in our population. The aim of this study was to evaluate the effect of AVR on LV remodeling, in patients with aortic valve disease. METHODS: Fifty patients with aortic valve disease were studied using transthoracic echocardiography to assess LV mass before AVR and compared with early postoperative changes in the LV dimensions and function. LV mass was studied preoperatively and before discharge in 50 consecutive patients undergoing isolated aortic valve replacement. RESULTS: Out of fifty patients, 47 (94%) were male and 03 (6%) were female. Mean age of the patients was 40.42 years. 22 (44%) had isolated aortic stenosis (AS), 16 (32%) patients had isolated aortic regurgitation (AR) and 12 (24%) patients had mixed aortic valve disease (MAVD). 02 (4%) patients died. LV mass regression was studied in all the patients. In group A, with aortic stenosis, LV regressed to 69.88 gm (mean) with maximum of 156.88 gms and minimum of 0.00 gms (SD 43.67 gms, p value = 0.001). In group B, with aortic regurgitation, LV mass regressed to 203.96 gms (mean) with maximum 453.79 gms and minimum of 45.65 gms (SD 95.33, p value = < 0.001). In group C, with mixed aortic valve disease, postoperatively LV mass regressed to 122.94 gms (mean) with minimum 9.57 and maximum of 224.75 gms (SD 69.53, p value = 0.524). CONCLUSION: There was significant early LV mass regression after aortic valve replacement in patients with pre existing aortic valve disease. However, it was noticed that LV mass regressed in all patients except no significant changes in LV wall thickness (hypertrophy). PMID- 18444583 TI - Transperitoneal approach for radical nephrectomy: five years experience at Pakistan Institute of Medical Sciences, Islamabad, Pakistan. AB - BACKGROUND: Renal cell carcinoma (RCC) comprises 85% of all renal neoplasms. Radical nephrectomy is the only hope of cure for patients with RCC. Role of chemotherapy and radiotherapy is very limited because of the chemo-radio resistant nature of these tumours. Several surgical approaches have been employed depending upon surgeon preference, size and location of the tumour. Objective of this study is to share the five years experience (from 1999 to 2004) of radical nephrectomy at Urology Department, Pakistan Institute of Medical Sciences (PIMS), that was performed through anterior sub costal trans-peritoneal incision. METHODS: It was a descriptive type of study with convenient non probability sampling technique. 100 patients were included. Patients were assessed by their mode of presentation, laboratory investigations, intra-operative findings, control of renal pedicle, total operative time, blood loss, intra-operative and post operative complications. The observations were noted on a proforma and analysed on SPSS version 10. RESULTS: Out of 100 patients, 64% were male and 36% were female with mean age of 58 years. Most common presentation was pain, present in 60% of patients. 88% of patients had normal renal function test. Average tumour size was 7.93 cm, diagnosed on ultrasonography (USG) and CT scan. Average time taken to get control of renal pedicle was 73.2 minutes. 20% of patients needed venacavatomy and thrombectomy, which was easier through this approach. Mean operative time was 129.44 minutes. Average blood loss was 274.2 ml. No intra operative complications were seen. Mortality rate was 4%. CONCLUSION: Radical nephrectomy is still the best option for treatment of renal cell carcinoma. There are various surgical approaches, however, anterior subcostal transperitoneal approach is more effective with early control of renal pedicle, less blood loss and minimal manipulation of the kidney thus minimizing the risk of embolism. PMID- 18444584 TI - Frequency and pattern of psychiatric disorders in patients with vitiligo. AB - BACKGROUND: Vitiligo affects one to four percent of the population, regardless of age, race or sex. People with this disorder may experience emotional stress, particularly if vitiligo develops on visible areas of the body, such as face, hands, arms, feet, or on the genitals. Some feel embarrassed, ashamed, depressed, or worried about how others will react. Severel indices have been used from time to time to measure the extent of psychiatric disabilty caused by skin disorders. Regarding vitiligo, not much work has been done in Pakistan. This study was aimed to determine the frequency and pattern of psychiatric disorders amongst patients with vitiligo. METHODS: This cross sectional study was conducted in the Departments of Psychiatry and Dermatology, Ziauddin University, KDLB campus, Karachi and Institute of Surgery and Medicine, Karachi from April 2004 to March 2006. Clinically diagnosed cases of vitiligo, belonging to both sexes, aged above 15 years, fulfilling the inclusion criteria were enrolled in the study. The study was conducted in 2 stages. In the first stage, psychiatric illness was detected with the help of GHQ 12 (Urdu version), a validated tool for screening general population. In the second stage, "Psychiatric Assessment Schedule", Urdu version was administrated to every patient with high scores as per GHQ 12 to differentiate between the most frequent psychiatric disorders. All the findings were recorded, compiled and tabulated. RESULTS: A total of 100 patients comprising 62 females and 38 males ranging between 15-60 years with a mean age of 24.6 years completed the study. Exposed parts of the body were involved in 64 patients while covered sites in 36. Of the patients studied, 54 were married and 46 unmarried. In accordance with the GHQ-12 screening, 42 patients were positive for psychiatric caseness comprising 26 females and 16 males, 17 patients being married. Psychiatric caseness featured in patients below 30 years of age (28 patients) and those having exposed parts of the body being involved (27 patients). On evaluation with Psychiatric Assessment Schedule (PAS), major depressive illness (15), was the most frequent psychiatric illness followed by generalized anxiety (10), mixed anxiety and depression, social phobia, agarophobia and sexual dysfunction. CONCLUSION: Psychiatric caseness has a probable association with vitiligo, the frequency being influenced by variables of disease and life. Major depression and anxiety remain the most common psychiatric disorders in these patients. PMID- 18444585 TI - Alanine aminotransferase/aspartate aminotransferase ratio reversal and prolonged prothrombin time: a specific indicator of hepatic cirrhosis. AB - BACKGROUND: Both ALT/AST ratio reversal (AST/ALT > 1) and prolonged prothrombin time are separately related to hepatic cirrhosis. Ratio reversal means that in normal individuals ALT is more than AST and thus ALT/AST > 1 but with development of cirrhosis AST becomes > ALT and so AST/ALT > 1 or ALT/AST < 1. This study was conducted with the idea that prolonged prothrombin time and reversed (AST/ALT > 1) ratio together can prove a more specific indicator with a high positive predictive value for the detection of hepatic cirrhosis in patients of chronic liver disease than either of the two alone. METHOD: This is a comparative cross sectional study. The data of hepatitis B & C patients was collected from the general medical ward and medical out patient department. Clinical and Ultrasonographic features, detected by a single ultrasonologist, were used to diagnose cirrhosis. Patients who were alcoholic were excluded from the study as alcohol itself causes ALT/AST ratio reversal. To avoid laboratory errors and variations the facilities of only a single specific laboratory were used for this study. The sensitivity and specificity of ALT/AST ratio reversal along with positive predictive value were calculated. Then prolonged prothrombin time (PT) and reversed ratio together were used and the results of these two groups were compared. RESULTS: It was found that the reversal of ratio alone is 88% specific as an indicator of hepatic cirrhosis and almost 70% sensitive and have a positive predictive value of 94.5%. The statistical significance test based on z-test for difference of proportion yields: z = 6.96 with ap value = 0.0000. On the other hand, the prolonged PT and ratio reversal are 98% specific and 53.9% sensitive with a positive predictive value of 98.2%. z-test for difference of proportion yields here: z = 6.23 with ap value = 0.0000. CONCLUSION: ALT/AST ratio reversal alone has a high sensitivity and the combined effect of these two parameters increases the specificity as compared to either of the two alone. The high positive predictive value here shows that almost all the patients with reversed ratio and prolonged PT will have cirrhosis. PMID- 18444586 TI - Comparision between bed side testing of blood glucose by glucometer vs centralized testing in a tertiary care hospital. AB - BACKGROUND: To determine the accuracy, turnaround time and cost effectiveness of bedside monitoring of blood glucose levels by non-laboratory health care workers and centralized testing of blood glucose by automated analyzer in a tertiary care hospital. METHODS: The study was conducted in Section of Chemical Pathology, Department of Pathology and Microbiology and Section of Endocrinology Department of Medicine, Aga Khan University and Hospital Karachi, from April 2005 to March 2006. One hundred and ten patients were included in the study. The blood glucose levels were analyzed on glucometer (Precision Abbott) by finger stick, using Biosensor Technology. At the same time venous blood was obtained to analyze glucose in clinical laboratory on automated analyzer (SYNCHRON CX7) by glucose oxidase method. RESULTS: We observed good correlation between bed side glucometer and laboratory automated analyzer for glucose values between 3.3 mmol/L (60 mg/dl) and 16.7 (300 mg/dl). A significant difference was observed for glucose values less than 3.3 mmol/L (p = 0.002) and glucose values more than 16.67 mmol/l (p = 0.049). Mean Turnaround time for glucometer and automated analyzer were 0.08 hours and 2.49 hours respectively. The cost of glucose testing with glucometer was 48.8% lower than centralized lab based testing. CONCLUSION: Bedside glucometer testing, though less expensive does not have good accuracy in acutely ill patient with either very high or very low blood glucose levels. PMID- 18444587 TI - Blood volumes of Pakistani male donors: implications for blood donation. AB - BACKGROUND: Safety of blood donors rest on withdrawing only appropriate quantities of blood. Adjusting the volumes drawn according to the average blood volumes of any population can ensure this. This requires knowledge of total blood volume of donors, which should ideally be measured by standard methods or derived by alternate suitable method. This observational, cross sectional study was undertaken to calculate blood volumes of Pakistani male donor using recommended equations and obtain safe donation volume limits for our population. METHODS: Height and weight of male Pakistani donors reporting to Combined Military Hospital blood bank was recorded by standardized method. Blood volumes were calculated by two different equations using body surface area. The data was entered in SPSS 10.0 version for Windows and statistical analysis done. RESULTS: Mean total blood volumes of 625 male donors calculated was 4819.2 ml with first equation and 4566.8 ml with second equation. 95% CI was between 4796.7 and 4841.6 with first equation and 4541.6 and 4591.9 with second equation. The maximum volumes of donation recommended for western population constitutes less than 12 % of calculated total blood volume of our population, with either equation. This is with in safe limits by any standard. CONCLUSION: 450 ml +/- 45 ml including samples in pilot tubes should be the recommended donation volume in Pakistani donors. The maximum volume being collected in other countries constitute safe limits for Pakistani donors as well. Equations showing better correlation with measured volumes should preferably be used to calculate blood volumes. Impact of collecting blood volumes recommended in this study, on blood donors, should be studied. PMID- 18444588 TI - Evaluation of management of tibial non-union defect with Ilizarov fixator. AB - BACKGROUND: Tibial bone defect lead to limb shortening and functional deficit and needs proper treatment. There are various treatment modalities for bone defect in long bone to restore length and function of the limb, i.e. bone grafting, vascularised bone graft, allograft and bone transport. Bone transport can be done through fixators (uniplaner or ring) and intramedullary nail system. This study was conducted on management of tibial non-union with Ilizarov external fixator. METHOD: This descriptive study was performed on 58 patients in Agency Headquarter Hospital, Bajawar and Lady Reading Hospital, Peshawar, from January 2000 to January 2006. Patients of either gender with age between 9 to 58 years, having nonunion (clean and infected nonunion) in tibia with defect of 2 to 7cm due to trauma or firearm injury were included in the study. These patients were followed up upto one year. Outcome measures were according to the classification of Association for the Study and Application of the Method of Ilizarov (ASAMI), which is based on radiological (defect filling) and clinical (functional) findings. RESULTS: Out of 58 patients, 44 (75%) were male and 14 (25%) were female. Mean age was 30 years (9 to 58 years). 38 (65.52%) patients had infected non-union while 20 (34.48%) had clean non-union. Right tibia was involved in 32 patients (51.17%) and left was involved in 26 (44.83%) patients. The cause of initial trauma was road traffic accident in 27 patients (46.55%), firearm injury in 23 patients (39.65%) and a simple fall in 8 patients (13.79%). The length of average bone defect was 2.90 cm (200-7.00 cm). Radiological results were excellent in 33 (58.89%) patients, good in 12 (20.68%) patients, fair in 8 (13.79%) patients and poor in 5 (8.62%) patients. The clinical results were excellent in 33 patients (56.89%), good in 18 patients (31.05%), fair in 4 (6.89%) patients and poor in 3 patients (5.17%). CONCLUSION: Ilizarov ring fixator is excellent treatment modality for tibial non-union with a defect, regarding bone union, deformity correction, infection eradication, limb length achievement and limb function but this needs prolonged learning curve for fresh orthopedic surgeons. PMID- 18444589 TI - Studying the association between postgraduate trainees' work hours, stress and the use of maladaptive coping strategies. AB - BACKGROUND: The growing debate regarding long working hours of postgraduate trainees has been receiving considerable attention recently. This greater workload contributes to increasing stress. Our objective was to specifically study the association between long working hours, stress and the greater use of 'maladaptive' coping strategies. METHODS: A cross-sectional descriptive study was carried out on all interns and residents at the Aga Khan University Hospital during February to May, 2005. Level of stress was measured by use of General Health Questionnaire (GHQ-12) and the use of maladaptive coping mechanisms through Brief Cope-28. RESULTS: 55.1% scored over the threshold for mild stress i.e. GHQ > 3, while more than 46% of the trainees scored over the threshold of more than 4 for morbid stress. Trainees under stress reported more working hours on average as compared to those not under stress, 83.8 and 74.7 hours respectively. At the same time, those working for longer hours were more likely to have used these negative coping mechanisms, which would further contribute to more stress rather than relieving it. CONCLUSIONS: Significant levels of stress have been identified. Along with this, those working for longer hours were more likely to have used these negative coping mechanisms. Reduction of working hours is important. Simultaneously, interventions need to be planned at imparting knowledge, awareness and skills to cope with various kinds of stressors encountered by a trainee during his/her training. Additionally, limits need to be devised for the working hours of the trainees. PMID- 18444591 TI - Recurrent laryngeal nerve injury: an experience with 310 thyroidectomies. AB - BACKGROUND: Thyroid surgery has been associated with complications ranging from nerve injury to death. Improvements in techniques have reduced the mortality rate to minimum. Morbidity, however, remains a significant concern. This study was designed to determine the prevalence of recurrent laryngeal nerve (RLN) injury and duration of recovery following transient recurrent laryngeal nerve injury, during thyroid surgery. METHODS: This prospective, observational study was carried out in the Surgical Department of Fauji Foundation Hospital, Rawalpindi, from January 2000 to December 2005. All patients undergoing Thyroid surgery were included. RESULTS: 310 patients, predominantly female (97.09%), were operated. Majority were euthyroid (90.33%). 3.22% patients had recurrent laryngeal nerve injury. Amongst them, 87.5% had transient and 12.5% had permanent nerve lesion. Majority of the patients (87.5%) showed signs of recovery within 12 weeks after surgery. Injury was observed more in huge goiters (3.57% transient and 1.42% permanent), total thyroidectomy (7.69% transient and 3.84% permanent) and during lobectomy and total thyroidectomy (6.25% respectively for transient and permanent nerve injury. CONCLUSION: Thyroid surgery should be done by experienced surgeon and care should be taken especially in huge goiters and patients undergoing total thyroidectomy. PMID- 18444590 TI - Job satisfaction among doctors working at teaching hospital of Bahawalpur, Pakistan. AB - BACKGROUND: Doctor's profession has long been among one of the most attractive professions in Pakistani society, but doctors are increasingly getting dissatisfied with their jobs. The focus of this study is to point out the most prominent factors of job dissatisfaction among doctors working at Bahawal Victoria Hospital / Quaid-e-Azam Medical College, Bahawalpur. METHODS: A questionnaire was mailed to a random sample of 60 out of 244 doctors working at Bahawal-Victoria Hospital / Quaid-e-Azam Medical College, Bahawalpur. Questions included satisfaction with respect to designation, income, service structure, career prospects etc. RESULTS: Overall 56% doctors were not satisfied with the level of their income. It is found that 92% of all the doctors were neither satisfied with the present service structure nor with the career prospects in Pakistan. Further, 78% of the doctors would like to serve abroad. Main factors contributing towards job satisfaction were designation and working environment whereas service structure turned out to be the source of dissatisfaction. CONCLUSIONS: Most of the doctors in all ranks and with different qualifications were not found satisfied with their job due to lack of proper service structure and low salaries. PMID- 18444592 TI - Management protocol of mandibular fractures at Pakistan Institute of Medical Sciences, Islamabad, Pakistan. AB - BACKGROUND: Maxillofacial trauma is very frequent and associated with a high incidence of mandibular fractures. Although there is universal agreement as to the treatment goals and basic therapeutic principles of reduction and stabilization, a variety of currently accepted treatment modalities indicate a lack of consensus. The authors evaluate the incidence, etiology, management and complications of 344 mandibular fractures in 228 patients treated in the Department of Plastic and Reconstructive Surgery at Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan, during a three year period. Indications and techniques for closed and open treatment of mandibular fractures are reviewed along with any complications of these fractures or their management. METHODS: A total of 344 mandibular fractures in 228 patients were included in this study. The sex, age, etiology, presentation, fracture characteristics, associated injuries, various methods of management and any pre or postoperative complications were evaluated. RESULTS: Although various devices and techniques have been used to treat these fractures, modern plate and screw fixation systems have proved to provide the best rigid stabilization, early mobility and associated with least complications. There was a satisfactory bone healing in all the patients and a minimal complication rate associated with open reduction and internal fixation (ORIF). CONCLUSION: Mandibular fractures occur with high frequency in road traffic accidents and interpersonal violence. They are among the most common types of facial fractures treated by the plastic surgeons. They must be managed carefully to maintain the function of the mandible, reestablish proper occlusion, and minimize secondary complications. Open reduction and internal fixation has proven to be the most effective method for treatment of mandibular fractures. PMID- 18444593 TI - Frequency of primary solid malignant neoplasms in different age groups as seen in our practice. AB - BACKGROUND: To determine in a large series of surgical biopsies, the frequency of various histologic types of primary solid malignant neoplasms in males and females in different age groups. METHODS: A retrospective study of 20,000 consecutive surgical biopsies reposted in the section of histopathology, AKU in 2004. RESULTS: Malignant neoplasms are commonest in the fifth and sixth decades of life. The commonest malignant neoplasms in the first decade were Hodgkin's lymphoma and Wilm's tumor in males and females respectively. In the second decade, osteosarcoma in males and Ewing's sarcoma / PNET in females. In the third decade, colorectal adenocarcinoma in males and infiltrating. Ductal carcinoma of breast in females. In the fourth decade, squamous cell carcinoma of oral cavity in males and infiltrating ductal carcinoma of breast in females. In the fifth decade squamous cell carcinoma of oral cavity in males and infiltrating ductal carcinoma of breast in females. In sixth decade, squamous cell carcinoma of oral cavity in males and infiltrating ductal carcinoma of breast in females and in the seventh decade, prostatic adenocarcinoma in males and infiltrating ductal carcinoma of the breast in females. Above age of 70 years, the commonest malignant were again prostatic adenocarcinoma in males and infiltrating ductal carcinoma of breast in females. CONCLUSION: Malignant neoplasms are commonest in the fourth, fifth and sixth decades of life. PMID- 18444594 TI - Cancelled elective general surgical operations in Ayub Teaching Hospital. AB - BACKGROUND: Cancellation of operations in hospitals is a significant problem with far reaching consequences. This study was planned to evaluate reasons for cancellation of elective surgical operation on the day of surgery in Ayub Teaching Hospital, Abbottabad. METHODS: From July 2006 to June 2007 the medical records of all the patients who had their operations cancelled on the day of surgery in all the three General Surgical units of Ayub Teaching Hospital, Abbottabad were audited prospectively. The number of operation cancelled and reasons for cancellations were documented. RESULTS: 3756 patients were scheduled for surgery during the study period. 2820 (75%) patients were operated upon. 936 (25%) operations were cancelled out of which 338 (36%) were cancelled due to shortage of time, 296 (31.6%) were cancelled due to medical reasons, 152 (16.2%) were cancelled due to shortage of beds while 55 (5.8%) were cancelled due to shortage of anaesthetists. Three operation lists were lost completely. The Anaesthetist cancelled 43%, Surgeon 39% while 18% of operations were cancelled due organizational reasons. CONCLUSION: Cancellation of patients on operation lists occupy a substantial population (25%) of cases. Majority of cancellation were due to reasons other than patients medical conditions. Better management could have avoided most of these cancellations. PMID- 18444595 TI - Risk factors of birth asphyxia. AB - BACKGROUND: Birth asphyxia is a serious clinical problem worldwide. There are many reasons a baby may not be able to take in enough oxygen before, during, or just after birth. Damage to brain tissues is a serious complication of low oxygen that can cause seizures and other neurological problems. This study was designed to asses the risk factors of birth asphyxia in neonates. METHODS: This descriptive, prospective study was conducted in the Department of Paediatrics, Isra University Hospital, Hyderabad, from April 2005 to April 2006. 125 newborn (75 males and 50 females) admitted to the neonatal care unit, who were delivered with delayed cry or low apgar score (< 7) were included. Detailed maternal history was taken, regarding their age, gestational age, and complications, if any. RESULTS: Out of 125 neonatal encephalopathy cases, 28% were diagnosed as suffering with moderate or severe encephalopathy, whereas 36% had mild encephalopathy. Risk of neonatal encephalopathy increased with increasing or decreasing maternal age. Antepartum risk factors included non-attendance for antenatal care (64%). Multiple births increased risk in 4.8%. Intrapartum risk factors included non-cephalic presentation (20%), prolonged rupture of membranes (24%) and various other complications. Particulate meconium was associated with encephalopathy in 9.6%. 60% mothers were anemic. Vaginal bleeding was strongly associated with birth asphyxia in 34.44% of neonates. 56% of mothers delivered at home, while 28% delivered at a private hospital or maternity home. Only 12% delivered at a tertiary care hospital. CONCLUSION: Lack of antenatal care, poor nutritional status, antepartum hemorrhage and maternal toxaemia were associated with higher incidence of asphyxia. Improvements in the public health of women with associated gains in female growth and nutrition must remain a longer-term goal. Early identification of high-risk cases with improved antenatal and perinatal care can decrease such high mortality. Safe motherhood policy is recommended. PMID- 18444596 TI - Role of ultrasound in acute appendicitis. AB - BACKGROUND: Misdiagnosis of acute appendicitis is a common and crucial problem in general surgery. Graded compression ultrasonography is one of the new diagnostic technique that is reported to have improve the diagnostic accuracy and clinical outcome. The aim of current study is to assess the role of this diagnostic modality in the management of acute appendicitis. METHODS: This is a cohort observational study comparing the adverse outcome in two different groups of patients admitted with suspected acute appendicitis at two different hospitals in two different countries. The first group of 200 patients at Ayub Teaching Hospital Abbottabad, Pakistan, was managed without preoperative ultrasonography. In the second group of 200 patients admitted at Najran General Hospital Najran Saudi Arabia, graded compression abdominal ultrasonography was routinely performed preoperatively. Diagnostic accuracy of the protocol in each group was measured statistically and rates of negative appendicectomy and perforation were determined. RESULTS: Addition of routine ultrasonography in clinical assessment for acute appendicitis decreases the sensitivity but significantly increases the specificity of the protocol thereby reducing the false positive rate translating into decreased negative appendicectomy rate. Rate of negative appendicectomy was 22.5% in group one and 4.7% in group two. Perforation rate was 15.6% in group 1 and 15% in group two. CONCLUSION: Proper clinical assessment is the mainstay of diagnosis in acute appendicitis and addition of routine ultrasound by graded compression technique can improve the diagnostic accuracy and adverse outcome. PMID- 18444597 TI - Anaesthesia for interventional neuroradiology. AB - There have been rapid and significant advances in diagnostic and interventional radiology, including interventional neuroradiology, in recent years. Many intracranial vascular pathologies are being successfully managed by endovascular interventional neuroradiology techniques. These techniques include procedures like embolization of vascular tumours and arterio-venous malformations, coiling of cerebral aneurysms. etc. The support of anaesthesia team is requested for these therapeutic endovascular neuroradiological procedures. The main aims of the anaesthesiologist during any interventional neuroradiology procedure are provision of a physiologically stable and immobile patient, alteration of arterial blood pressure as necessary, and appropriate and timely management of complications. Provision of anaesthesia in remote locations, such as the radiology suite, has its own inherent risks. In this article the anaesthetic considerations for therapeutic interventional neuroradiology procedures performed in the radiology suite have been reviewed, including the preprocedure preparation, monitoring requirements, suitable anaesthetic techniques, postprocedure management and complications. PMID- 18444598 TI - Renal transplant in a patient with augmentation cystoplasty. AB - A 20 years old girl, had undergone surgery for meningocele six weeks after birth, suffered from neurogenic bladder dysfunction. She underwent an augmentation ileocystoplasty and was trained to perform clean intermittent self catheterization (CISC). After two years she developed renal failure secondary to recurrent urinary tract infections and she was started on chronic hemodialysis. On account of repeated line sepsis, a live related donor renal transplant was performed. About three months after renal transplantation she reported in emergency with an episode of graft rejection secondary to severe infection and later on complicated by leakage of urine from the renal pelvis of the allograft into the peritoneal cavity suggestive of a rent. A percutaneous nephrostomy of the allograft was performed which facilitated healing of the rent in the renal pelvis. The nephrostomy was withdrawn and patient started voiding through urethral catheter and gradually returned to CISC. PMID- 18444599 TI - Vacuum assisted closure of laparostomy wounds "a novel technique". AB - Management of a laparostomy wound is contentious. Specific pathologies like severe intraabdominal sepsis, trauma requiring damage control, abdominal compartment syndrome, staged abdominal repair and other complex abdominal pathologies can be managed with a novel technique of Vacuum Assisted Closure dressing. This device applies sub-atmospheric pressure that leads to reduced bowel wall edema, bacterial count and inflammatory burden found in open abdominal wounds. This leads to a reduced need for frequent dressing changes, maintaining intact skin and improvement in fluid management. Controlled clinical studies are needed to establish the safety and effectiveness of this treatment strategy. We present our experience with this technique suggesting it to be safe and effective. A brief outline of the working of Vacuum Assisted Closure dressing is also presented. PMID- 18444600 TI - Giant cell granuloma of the maxilla. AB - The case report is of a 30 year old male, who complained of a slowly expanding swelling in the maxilla in the left premolar region. The swelling was clinically and radiographically diagnosed as Central Giant Cell Granuloma. The patient also had Angles Class 2 Division 2 Malocclusion in which repeated micro trauma may have possibly contributed to the formation of the tumor. The tumor was surgically removed under general anesthesia followed by local injections of corticosteroids. PMID- 18444601 TI - Did Mendel cheat? PMID- 18444602 TI - American College of Surgeon's new Washington, DC, office building. PMID- 18444603 TI - The College's Division of Advocacy and Health Policy: an overview. PMID- 18444604 TI - "The best and worst week of my life": a surgeon at war. PMID- 18444605 TI - Emphasis on public reporting of health care data intensifies. PMID- 18444606 TI - A humanitarian effort by the department of surgery of the USUHS to a third-world country: the Philippines. PMID- 18444607 TI - How rural is it? PMID- 18444608 TI - Practices' minimum income is a guarantee of health inequity. PMID- 18444611 TI - Coibamide A, a potent antiproliferative cyclic depsipeptide from the Panamanian marine cyanobacterium Leptolyngbya sp. AB - Coibamide A (1) is a new, potent antiproliferative depsipeptide which was isolated from a marine Leptolyngbya cyanobacterium collected from the Coiba National Park, Panama. The planar structure of 1 was elucidated by a combination of NMR spectroscopy and mass spectrometry. Exhaustive 1D and 2D NMR spectroscopy included natural abundance 15N and variable temperature experiments; mass spectrometry included TOF-ESI-MSn and FT-MSn experiments. Chemical degradation followed by chiral HPLC- and GC-MS analyses was used to assign the absolute configuration of 1. This highly methylated cyclized depsipeptide exhibited an unprecedented selectivity profile in the NCI 60 cancer cell line panel and appears to act via a novel mechanism. PMID- 18444612 TI - Pathways and populations: stereoelectronic insights into the exocyclic torsion of 5-(hydroxymethyl)tetrahydropyran. AB - High level ab initio computations in vacuum and with the IEFPCM implicit solvent model are carried out on 5-(hydroxymethyl)tetrahydropyran to investigate the effects of water on the exocyclic torsional surface. Rotamer populations evaluated from the omega(C-C-C-O), theta(C-C-C-O) solvent surface agree almost quantitatively with experimental values for the closely related methyl 4-deoxy alpha-D-xylohexopyranoside. Potentials of mean force obtained from the two surfaces show substantial solvent stabilization of the TG (omega = 180 +/- 60 degrees) rotamer and the barriers at omega= 120 and 240 degrees but solvent destabilization at the cis barrier (omega = 0 degrees). Natural bond orbital analyses indicate that energetics of these effects are largely explained by overstabilization of the vacuum GT (omega= 60 +/- 60 degrees) and GG (omega = 300 +/- 60 degrees) rotamers. Solvent stabilization of theta conformations provides entropic stabilization. PMID- 18444613 TI - Asymmetric synthesis of (-)-incarvillateine employing an intramolecular alkylation via Rh-catalyzed olefinic C-H bond activation. AB - An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield. The key step is a rhodium-catalyzed intramolecular alkylation of an olefinic C-H bond to set two stereocenters. Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed. PMID- 18444614 TI - The role of tandem acyl carrier protein domains in polyunsaturated fatty acid biosynthesis. AB - Acyl carrier protein (ACP) plays an essential role in fatty acid and polyketide biosynthesis, and most of the fatty acid synthases (FASs) and polyketide synthases (PKSs) known to date are characterized with a single ACP for each cycle of chain elongation. Polyunsaturated fatty acid (PUFA) biosynthesis is catalyzed by the PUFA synthase, and all PUFA synthases known to date contain tandem ACPs (ranging from 5 to 9). Using the Pfa PUFA synthase from Shewanella japonica as a model system, we report here that these tandem ACPs are functionally equivalent regardless of their physical location within the PUFA synthase subunit, but the total number of ACPs controls the overall PUFA titer. These findings set the stage to interrogate other domains and subunits of PUFA synthase for their roles in controlling the final PUFA products and could potentially be exploited to improve PUFA production. PMID- 18444616 TI - Enantioselective iridium-catalyzed carbonyl allylation from the alcohol or aldehyde oxidation level using allyl acetate as an allyl metal surrogate. AB - Protocols for highly enantioselective carbonyl allylation from the alcohol or aldehyde oxidation level are described based upon transfer hydrogenative C-C coupling. Exposure of allyl acetate to benzylic alcohols 1a-i in the presence of an iridium catalyst derived from [IrCl(cod)]2 and (R)-BINAP delivers products of C-allylation 2a-i. Employing isopropanol as terminal reductant, exposure of allyl acetate to aryl aldehydes 3a-i in the presence of an iridium catalyst derived from [IrCl(cod)]2 and (-)-TMBTP delivers identical products of C-allylation 2a-i. In all cases examined, exception levels of enantioselectivity are observed. Thus, enantioselective carbonyl allylation is achieved from the alcohol or aldehyde oxidation level in the absence of any preformed allylmetal reagents. These studies define a departure from preformed organometallic reagents in carbonyl additions that transcend the boundaries of oxidation level. PMID- 18444617 TI - Ruthenium-catalyzed C-C bond forming transfer hydrogenation: carbonyl allylation from the alcohol or aldehyde oxidation level employing acyclic 1,3-dienes as surrogates to preformed allyl metal reagents. AB - Under the conditions of ruthenium-catalyzed transfer hydrogenation, commercially available acyclic 1,3-dienes, butadiene, isoprene, and 2,3-dimethylbutadiene, couple to benzylic alcohols 1a-6a to furnish products of carbonyl crotylation 1b 6b, carbonyl isoprenylation 1c-6c, and carbonyl reverse 2-methyl prenylation 1d 6d. Under related transfer hydrogenation conditions employing isopropanol as terminal reductant, isoprene couples to aldehydes 7a-9a to furnish identical products of carbonyl isoprenylation 1c-3c. Thus, carbonyl allylation is achieved from the alcohol or the aldehyde oxidation level in the absence of preformed allyl metal reagents. Coupling to aliphatic alcohols (isoprene to 1-nonanol, 65% isolated yield) and allylic alcohols (isoprene to geraniol, 75% isolated yield) also is demonstrated. Isotopic labeling studies corroborate a mechanism involving hydrogen donation from the reactant alcohol or sacrificial alcohol (i-PrOH). PMID- 18444618 TI - Encapsulation of protonated diamines in a water-soluble, chiral, supramolecular assembly allows for measurement of hydrogen-bond breaking followed by nitrogen inversion/rotation. AB - Amine nitrogen inversion, difficult to observe in aqueous solution, is followed in a chiral, supramolecular host molecule with purely rotational T-symmetry that reduces the local symmetry of encapsulated monoprotonated diamines and enables the observation and quantification of Delta G (++) for the combined hydrogen-bond breaking and nitrogen inversion/rotation (NIR) process. Free energies of activation for the combined hydrogen-bond breaking and NIR process inside of the chiral assembly were determined by the NMR coalescence method. Activation parameters for ejection of the protonated amines from the assembly confirm that the NIR process responsible for the coalescence behavior occurs inside of the assembly rather than by a guest ejection/NIR/re-encapsulation mechanism. For one of the diamines, N, N, N', N'-tetramethylethylenediamine, the relative energy barriers for the hydrogen-bond breaking and NIR process were calculated at the G3(MP2)//B3LYP/6-31++G(d,p) level of theory, and these agreed well with the experimental data. PMID- 18444619 TI - Mechanistic studies of the copolymerization reaction of oxetane and carbon dioxide to provide aliphatic polycarbonates catalyzed by (Salen)CrX complexes. AB - Chromium salen derivatives in the presence of anionic initiators have been shown to be very effective catalytic systems for the selective coupling of oxetane and carbon dioxide to provide the corresponding polycarbonate with a minimal amount of ether linkages. Optimization of the chromium(III) system was achieved utilizing a salen ligand with tert-butyl groups in the 3,5-positions of the phenolate rings and a cyclohexylene backbone for the diimine along with an azide ion initiator. The mechanism for the coupling reaction of oxetane and carbon dioxide has been studied. Based on binding studies done by infrared spectroscopy, X-ray crystallography, kinetic data, end group analysis done by (1)H NMR, and infrared spectroscopy, a mechanism of the copolymerization reaction is proposed. The formation of the copolymer is shown to proceed in part by way of the intermediacy of trimethylene carbonate, which was observed as a minor product of the coupling reaction, and by the direct enchainment of oxetane and CO 2. The parity of the determined free energies of activation for these two processes, namely 101.9 kJ x mol (-1) for ring-opening polymerization of trimethylene carbonate and 107.6 kJ x mol (-1) for copolymerization of oxetane and carbon dioxide supports this conclusion. PMID- 18444620 TI - Effects of alkaline earth metal ion complexation on amino acid zwitterion stability: results from infrared action spectroscopy. AB - The structures of isolated alkaline earth metal cationized amino acids are investigated using infrared multiple photon dissociation (IRMPD) spectroscopy and theory. These results indicate that arginine, glutamine, proline, serine, and valine all adopt zwitterionic structures when complexed with divalent barium. The IRMPD spectra for these ions exhibit bands assigned to carboxylate stretching modes, spectral signatures for zwitterionic amino acids, and lack bands attributable to the carbonyl stretch of a carboxylic acid functional group. Structural and spectral assignments are strengthened through comparisons with absorbance spectra calculated for low-energy structures and the IRMPD spectra of analogous ions containing monovalent alkali metals. Many bands are significantly red-shifted from the corresponding bands for amino acids complexed with monovalent metal ions, owing to increased charge transfer to divalent metal ions. The IRMPD spectra of arginine complexed with divalent strontium and barium are very similar and indicate that arginine adopts a zwitterionic form in both ions. Calculations indicate that nonzwitterionic forms of arginine are lowest in free energy in complexes with smaller alkaline earth metal cations and that zwitterionic forms are preferentially stabilized with increasing metal ion size. B3LYP and MP2 calculations indicate that zwitterionic forms of arginine are lowest in free energy for M = Ca, Sr, and Ba. PMID- 18444621 TI - Valence parity renders z(*)-type ions chemically distinct. AB - Here we report that the odd electron z (*) -type ions formed by the electron based peptide dissociation methods (electron capture or transfer, ECD or ETD) have distinctive chemical compositions from other common product ion types. Specifically, b-, c-, and y-type ions have an odd number of atoms with an odd valence (e.g., N and H), while z (*)-type ions contain an even number of atoms with an odd valence. This tenet, referred to as the valence parity rule, mandates that no c-type ion shall have the same chemical composition, and by extension mass, as a z (*) -type ion. By experiment we demonstrate that nearly half of all observed c- and z (*) -type product ions resulting from 226 ETD product ion spectra can be assigned to a single, correct, chemical composition and ion type by simple inspection of the m/ z peaks. The assignments provide (1) a platform to directly determine amino acid composition, (2) an input for database search algorithms, or (3) a basis for de novo sequence analysis. PMID- 18444622 TI - Onset of 3(10)-helical secondary structure in aib oligopeptides probed by coherent 2D IR spectroscopy. AB - We have investigated the onset of the secondary structure and the evolution of two-dimensional infrared (2D IR) spectral patterns as a function of chain length with a study of 3(10)-helical peptides. The results show that 2D IR is highly sensitive to peptide conformation, disorder, and size. An extensive set of 2D IR spectra of C (alpha)-methylated homopeptides, Z-(Aib) n -O tBu ( n = 3, 5, 8, and 10), in CDCl 3 was measured in the amide-I region. The 2D spectral patterns of the tripeptide are quite different from those of the longer peptides. The spectral signatures begin to converge at the pentapeptide and become almost the same for the octa- and decapeptide. Simulations employing a vibrational exciton model were performed, with the local mode frequency shifts estimated from the intramolecular hydrogen bond electrostatic energies. The 2D spectra are well simulated using dihedral angle distributions around the average values (phi, psi) approximately (-57 degrees , -31 degrees) with a width of approximately 21 degrees. The simulated site-dependent amide-I local mode frequencies are in agreement with those from scaled semiempirical AM1 calculations. The tripeptide exhibits a more noticeable discrepancy between the experimental and simulated cross-peak patterns. This behavior suggests the presence of a peptide population outside the single beta-turn conformation. The onset of the 3(10)-helical secondary structure appears to already occur at the pentapeptide level. PMID- 18444623 TI - Identification and characterization of a new family of catalytically highly active imidazolin-2-ylidenes. AB - A new class of easily accessible and stable imidazolin-2-ylidenes has been synthesized where the side chains are comprised of substituted naphthyl units. Introduction of the naphthyl groups generates C 2 -symmetric ( rac) and C s- symmetric ( meso) atropisomers, and interconversion between the isomers is studied in detail both experimentally and computationally. Complete characterization of the carbenes includes rare examples of crystallographically characterized saturated NHC structures. Steric properties of the ligands and an investigation of their stability are also presented. In catalysis, the new ligands show versatility comparable to the most widely used NHCs IMes/SIMes or IPr/SIPr. Excellent catalytic results are obtained when either the NHC salts (ring-opening alkylation of epoxides), NHC-modified palladium compounds (C-C and C-N cross-couplings), or NHC-ruthenium complexes (ring-closing metathesis, RCM) are employed. In several cases, this new ligand family provides catalytic systems of higher reactivity than that observed with previously reported NHC compounds. PMID- 18444624 TI - A general and rapid cell-free approach for the interrogation of protein-protein, protein-DNA, and protein-RNA interactions and their antagonists utilizing split protein reporters. AB - Split-protein reporters have emerged as a powerful methodology for imaging biomolecular interactions which are of much interest as targets for chemical intervention. Herein we describe a systematic evaluation of split-proteins, specifically the green fluorescent protein, beta-lactamase, and several luciferases, for their ability to function as reporters in completely cell-free systems to allow for the extremely rapid and sensitive determination of a wide range of biomolecular interactions without the requirement for laborious transfection, cell culture, or protein purification (12-48 h). We demonstrate that the cell-free split-luciferase system in particular is amenable for directly interrogating protein-protein, protein-DNA, and protein-RNA interactions in homogeneous assays with very high sensitivity (22-1800 fold) starting from the corresponding mRNA or DNA. Importantly, we show that the cell-free system allows for the rapid (2 h) identification of target-site specificity for protein-nucleic acid interactions and in evaluating antagonists of protein-protein and protein peptide complexes circumventing protein purification bottlenecks. Moreover, we show that the cell-free split-protein system is adaptable for analysis of both protein-protein and protein-nucleic acid interactions in artificial cell systems comprising water-in-oil emulsions. Thus, this study provides a general and enabling methodology for the rapid interrogation of a wide variety of biomolecular interactions and their antagonists without the limitations imposed by current in vitro and in vivo approaches. PMID- 18444625 TI - One-electron reductive template-directed ligation of oligodeoxynucleotides possessing a disulfide bond. AB - Hypoxic X-radiolysis of diluted aqueous solutions was performed to generate hydrated electrons that induced one-electron reduction of oligodeoxynucleotides (ODNs) possessing a disulfide bond. Upon hypoxic irradiation of dinucleotides, two forms of dinucleotides were produced via intermolecular exchange of the disulfides and ligation that proceeded with a multiple turnover. In contrast to the efficient reaction induced by hypoxic irradiation, the reaction efficiency was dramatically decreased when irradiation was performed under aerobic conditions, presumably due to capturing reactive hydrated electrons by molecular oxygen. We subsequently applied these unique reaction characteristics to template directed ligation. In the presence of a complementary template ODN, two ODNs possessing a disulfide bond produced a prescribed ODN with high regioselectivity via interstrand crossing upon hypoxic irradiation. PMID- 18444626 TI - Engineering target-responsive hydrogels based on aptamer-target interactions. AB - In this communication, we report a simple, but highly adaptable, method of constructing selective target-responsive hydrogels using DNA aptamers. The simplicity of the design is accomplished by using linear polymer chains as the hydrogel backbone and a DNA aptamer as the cross-linker. In this design, competitive binding of target to the aptamer causes the decrease of cross-linking density and, hence, dissolution of the hydrogel. The adaptability of this strategy for therapeutic applications was demonstrated using two different types of targets, small molecules and proteins. Our results indicated that this molecular engineering provides a highly selective and controllable release system whereby efficient release of therapeutic agents can occur at specific environments in which the target biomarker is found. PMID- 18444628 TI - DFT study of the 1-octene metathesis reaction mechanism with WCl6/C catalytic system. AB - A catalytic system consisting of tungsten carbene generated from WCl(6) and an atomic carbon is investigated theoretically for the metathesis of 1-octene at B3LYP/extended LANL2DZ level of DFT. The ground-state geometries and charge distributions of the structures belonging to the reaction mechanism are located. Energetics for the complete set of reactions, involving the formation of the tungsten carbene precatalyst, Cl(4)W?CCl(2), the formation of tungsten methylidene and tungsten heptylidene with this precatalyst, and finally productive and degenerative metathesis steps with these alkylidene species are calculated in terms of total electronic energy and thermal energies. The free energy (DeltaG(298)) surfaces of the structures involved in the related reactions are constructed. In addition, solvent effects on the single point energies of the structures are investigated for two different solvents, namely, cyclohexane and chloroform. The results indicate that the formation of the catalytically active heptylidene is energetically favored in comparison to the formation of methylidene, while the degenerative and productive metathesis steps are competitive. In the catalytic cycle, the formation of ethylene is exothermic, while the formation of 7-tetradecene is endothermic. As expected, solvent effects on the metathesis reactions are minor and solvation does not cause any change in the directions of the overall metathesis reactions. PMID- 18444627 TI - Receptor-based modeling and 3D-QSAR for a quantitative production of the butyrylcholinesterase inhibitors based on genetic algorithm. AB - Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of structurally related steroidal alkaloids as butyrylcholinesterase (BuChE) inhibitors. Docking studies were employed to position the inhibitors into the BuChE active site to determine the most probable binding mode. The strategy was to explore multiple inhibitor conformations in producing a more reliable 3D-QSAR model. These multiple conformations were derived using the FlexS program. The conformation selection step for CoMFA was done by genetic algorithm. The genetic algorithm based CoMFA approach was found to be the best. Both CoMFA and CoMSIA yielded significant cross-validated q(2) values of 0.701 and 0.627 and the r(2) values of 0.979 and 0.982, respectively. These statistically significant models were validated by a test set of five compounds. Comparison of CoMFA and CoMSIA contour maps helped to identify structural requirements for the inhibitors and serves as a basis for the design of the next generation of the inhibitor analogues. The results demonstrate that the combination of ligand-based and receptor-based modeling with use of a genetic algorithm is a powerful approach to build 3D-QSAR models. These data can be used for the lead optimization process with respect to inhibition enhancement which is important for the drug discovery and development for Alzheimer's disease. PMID- 18444629 TI - Theoretical evidence for temperature-induced proton mobility in isolated lysine rich polyalanines. AB - A multistate molecular mechanics method is introduced to model the possible competition between various protonation sites in gas-phase biomolecules with excess protons. The method relies on the Amber force field for each site and is calibrated against density-functional theory benchmark calculations at the 6 31+G(d,p) level. In its adiabatic version, where it has similarities with constant-pH algorithms, the model predicts that the small protonated Ala(4)-Lys peptide, unprotected at the N-terminus, changes protonation site above 400 K. In the larger [Ala(9)-Lys+H ](+) peptide, the proton remains at the lysine amine group in a favored charge/electric dipole conformation. In the three-state Ala(4) Lys-Ala(4)-Lys peptide, the excess proton is found to be partially delocalized on the amine group of the first lysine and on the N-terminus. The statistical properties of the protonated peptides are found to significantly depend on the localized character of the proton. Finally, the model is extended by considering possible couplings between the protonation sites, in an empirical valence-bond version. Strong couplings can stabilize the peptides into unexpected proton-bound conformations over broad ranges of temperature. PMID- 18444630 TI - Reactive uptake of N2O5 on aqueous H2SO4 solutions coated with 1-component and 2 component monolayers. AB - Reactive uptake of N(2)O(5) on aqueous sulfuric acid solutions was studied in the presence of 1-component (octadecanol) and 2-component (octadecanol + phytanic acid) monolayers. In the 1-component monolayer experiments, the reactive uptake coefficient depended strongly on the molecular surface area of the surfactant. Also, the 1-component monolayer showed significant resistance to mass transfer even when the fractional surface coverage of the surfactant was less than 1. For example, a monolayer of 1-octadecanol with a fractional surface coverage of 0.75 decreased the reactive uptake coefficient by a factor of 10. This is consistent with previous studies. In the 2-component monolayer experiments, the reactive uptake coefficient depended strongly on the composition of the monolayer. When the monolayer contained only straight-chain molecules (1-octadecanol), the reactive uptake coefficient decreased by a factor of 42 due to the presence of the monolayer. However, when the monolayer contained 0.20 mole fraction of a branched surfactant (phytanic acid) the reactive uptake coefficient only decreased by a factor of 2. Hence, a small amount of branched surfactant drastically changes the overall resistance to reactive uptake. Also, our results show that the overall resistance to reactive uptake of 2-component monolayers can be predicted reasonably accurately by a model that assumes the resistances to mass transfer can be combined in parallel. PMID- 18444631 TI - Ab initio molecular dynamics study of the solvated OHCl- complex: implications for the atmospheric oxidation of chloride anion to molecular chlorine. AB - We have studied the OHCl(-) complex in a six-water cluster and in bulk liquid water by means of Born-Oppenheimer molecular dynamics based on generalized gradient-corrected BLYP density functional theory. Self-interaction-corrected results, which predict a hydrogen-bonded OH...Cl(-) complex, are compared to the uncorrected results, which predict a hemibonded (HO-Cl)(-). A second-order Moller Plesset potential energy landscape of the gas-phase complex in its ground-state was computed to determine which of the two configurations represents the true nature of the complex. Because no evidence of a local minimum was found in the vicinity of the geometry corresponding to (HO-Cl)(-), we conclude that the self interaction-corrected results are more accurate and, therefore, that the complex is held together by a hydrogen-bond-like interaction in both an asymmetric solvation environment, as represented by the cluster, and a symmetric solvation environment, as represented by the bulk system. We postulate that the mechanism that governs the atmospheric oxidation of Cl(-)(aq) to Cl(2)(g) on the surface of marine aerosols is initiated by the formation of a H-bonded OH...Cl(-) complex. Furthermore, because no evidence of charge transfer from Cl(-) to OH was found, in either the liquid or the cluster environment, we propose that the second step of the oxidation of Cl(-) is the reaction of the complex with a second Cl(-), resulting in the formation of the species Cl(2)(-) and OH(-). Cl(2)(g) could then be formed via an electron-transfer reaction with an impinging OH molecule. PMID- 18444632 TI - Vibrational spectroscopy and conformational structure of protonated polyalanine peptides isolated in the gas phase. AB - The conformational structures of protonated polyalanine peptides, Ala(n)H(+), have been investigated in the gas phase for n = 3, 4, 5, and 7 using a combination of resonant-infrared multiphoton dissociation (R-IRMPD) spectroscopy in the NH and OH stretch regions and quantum chemical calculations. Agreement between theoretical IR and experimental R-IRMPD spectral features has enabled the assignment of specific hydrogen-bonded conformational motifs in the short protonated peptides and revealed their conformational evolution under elevated temperature conditions, as a function of increasing chain length. The shortest peptide, Ala(3)H(+), adopts a mixture of extended and cyclic chain conformations, protonated, respectively, at a backbone carbonyl or the N-terminus. The longer peptides adopt folded, cyclic, and globular charge-solvated conformations protonated at the N-terminus, consistent with previous ion-mobility studies. The longest peptide, Ala(7)H(+), adopts a globular conformation with the N-terminus completely charge-solvated, demonstrating the emergence of "physiologically relevant" intramolecular interactions in the peptide backbone. The computed conformational relative free energies highlight the importance of entropic contributions in these peptides. PMID- 18444633 TI - Structural, electronic, and magnetic properties of Fe3C2 cluster. AB - On the basis of density-functional theory and all-electron numerical basis set, 20 stable isomers of Fe(3)C(2) cluster are found through optimization calculations and frequency analysis from 108 initial structures. A nonplanar C(s) structure with nonet spin multiplicity and 482.978 kcal/mol of binding energy is found as the candidate of global minimum geometry of Fe(3)C(2) cluster. The binding energies, the energy gaps between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, and the magnetic moments of all the isomers are reported. The relationship between the molecular properties and geometrical structures is also investigated. PMID- 18444634 TI - New observations on the pressure dependence of luminescence from Eu2+-doped MF2 (M = Ca, Sr, Ba) fluorides. AB - The luminescence from Eu(2+) ions in MF2 (M = Ca, Sr, Ba) fluorides has been investigated under the pressure range of 0-8 GPa. The emission band originating from the 4f(6)5d(1) --> 4f(7) transition of Eu(2+) ions in CaF2 and SrF2 shows the red-shift as increasing pressure with pressure coefficients of -17 meV/GPa for CaF2 and -18 meV/GPa for SrF2. At atmospheric pressure, the emission spectrum of BaF2:Eu(2+) comprises two peaks at 2.20 and 2.75 eV from the impurity trapped exciton (ITE) and the self-trapped exciton (STE), respectively. As the pressure is increased, both emission peaks shift to higher energies, and the shifting rate is slowed by the phase transition from the cubic to orthorhombic phase at 4 GPa. Due to the phase transition at 4-5 GPa pressure, the ITE emission disappears gradually, and the STE emission is gradually replaced by the 4f(6)5d(1) --> 4f(7) transition of Eu(2+). Above 5 GPa, the pressure behavior of the 4f(6)5d(1) --> 4f(7) transition of Eu(2+) in BaF2:Eu(2+) is the same as the normal emission of Eu(2+) in CaF2 and SrF2 phosphors. PMID- 18444635 TI - Structure of isolated 1,4-butanediol: combination of MP2 calculations, NBO analysis, and matrix-isolation infrared spectroscopy. AB - Theoretical calculations at the MP2 level, NBO and AIM analysis, and matrix isolation infrared spectroscopy have been used to investigate the structure of the isolated molecule of 1,4-butanediol (1,4-BDO). Sixty-five structures were found to be minima on the potential energy surface, and the three most stable forms are characterized by a folded backbone conformation leading to the formation of an intramolecular H-bond. To better characterize the intramolecular interactions and particularly the hydrogen bonds, natural bond orbital analysis (NBO) was performed for the four most stable conformers, and was further complemented with an atoms-in-molecules (AIM) topological analysis. Infrared spectra of 1,4-BDO isolated in low-temperature argon and xenon matrixes show a good agreement with a population-weighted mean theoretical spectrum, and the spectral features of the conformers expected to be trapped in the matrixes were observed experimentally. Annealing the xenon matrix from 20 to 60 K resulted in significant spectral changes, which were interpreted based on the barriers to intramolecular rotation. An estimation of the intramolecular hydrogen bond energy was carried out following three different methodologies. PMID- 18444636 TI - A microwave and quantum chemical study of cyclopropanethiol. AB - The microwave spectra of cyclopropanethiol, C(3)H(5)SH, and one deuterated species C(3)H(5)SD, have been investigated in the 20 - 80 GHz frequency range. The spectra of the ground vibrational state and of three vibrationally excited states of the parent species of a conformer which has a synclinal ("gauche") arrangement for the H-C-S-H chain of atoms, was assigned. The H-C-S-H dihedral angle is 76(5) degrees from synperiplanar (0 degrees ). The b-type transitions of the ground and of the vibrationally excited states of the parent species were split into two components, which is assumed to arise from tunneling of the proton of the thiol group between two equivalent synclinal potential wells. No splitting was resolved in the spectrum of C(3)H(5)SD. The tunneling frequency of the ground vibrational state of C(3)H(5)SH is 1.664(22) MHz. The tunneling frequency of the first excited-state of the C-S torsion is 52.330(44) MHz, whereas this frequency is 26.43(13) and 3.286(61) MHz, respectively, for the first excited states of the two lowest bending vibrations. The dipole moment of the ground vibrational state of the parent species is MU(a) = 4.09(5), MU(b) = 2.83(11), MU(c) = 0.89(32), and MU(tot) = 5.06(16) * 10(-30) C m. The microwave study has been augmented by high level density functional and ab initio quantum chemical calculations. PMID- 18444637 TI - Heterocycle-based isomeric chromophores with substantially varying NLO properties: a new structure-property correlation study. AB - A number of heterocycle-based aromatic and quinonoid molecular systems have been considered for the theoretical study of their electric response properties. The nonlinear optical (NLO) parameters have been calculated by using the ab initio MO and DFT methods. An approximate scheme for calculating the first hyperpolarizability (beta) and second hyperpolarizability (gamma) in the framework of the sum-over-state (SOS) method have been proposed by exploiting the generalized Thomas-Kuhn sum rule (TK-SR). The NLO properties in the present scheme can be evaluated solely from the ground-state dipole moment (mu) and linear polarizability (alpha) and have been found to correlate fairly with the ab initio calculated values. The approximate scheme can be reasonably used to explain the wider range of variation of higher-order polarizabilities in terms of the above quantities. The position of the N atom in the thiazole ring at the ortho position (versus meta position) to the acceptor increases beta and decreases gamma for aromatic compounds, while the reverse trend is found with quinonoid compounds. In the case of the pyridine ring, the shifting of the N atom toward the acceptor enhances gamma, with insignificant variation of beta predicted for both the aromatic and quinonoid molecules. The negative contribution of the cubic polarizability of the quinonoid species increases linearly with alpha(2)/mean transition energy (Delta E). PMID- 18444638 TI - Ab initio molecular orbital study on the Ge-, Sn-, Zr- and Si/Ge-mixed silsesquioxanes. AB - For the purpose of designing new functional silsesquioxanes (POSS), the structure and stability of the analogous compounds of the heavier group 14 and 4 elements such as germanium (Ge-POSS), tin (Sn-POSS) and zirconium (Zr-POSS) analogues of POSS were investigated and compared with those of the parent POSS and the titanium analogue (Ti-POSS) with electronic structure theory calculations, including electron correlation effects. In order to obtain information about the metalloxane (-X-O-X-) linkage, the structures and properties of the building blocks of metallasilsesquioxanes, such as dimetalloxanes, H(OH)2XOX(OH)2H, X = Ge, Sn and Zr, and cyclometalloxanes, [H(OH)XO]n , n = 3-6, X = Ge, Sn and Zr, were examined. The stability of the Si/Ge-mixed POSS were also studied in comparison with POSS and the completely germanium-substituted POSS. PMID- 18444640 TI - Structure of ternary imide Li2Ca(NH)2 and hydrogen storage mechanisms in amide hydride system. AB - The crystal structure of the ternary imide Li 2Ca(NH) 2 has been determined using neutron powder diffraction data on a deuterated sample. The structure consists of infinite layers of edge-shared Ca[NH] 6 octahedra, which are separated by Li cations. The mobile Li (+) ions in such two-dimensional channels defined by Ca[NH] 6 octahedra layers are shown to have a great impact on the hydrogenation properties of the imide. Through detailed structural analysis on the products at various stages of desorption and absorption of the amide-hydride mixture, we proposed a dehydrogenation mechanism involving the mobile small ions in both amide and hydride and a hydrogen storage mechanism for the ternary imide. PMID- 18444639 TI - Highly reactive, general and long-lived catalysts for palladium-catalyzed amination of heteroaryl and aryl chlorides, bromides, and iodides: scope and structure-activity relationships. AB - We describe a systematic study of the scope and relationship between ligand structure and activity for a highly efficient and selective class of catalysts containing sterically hindered chelating alkylphosphines for the amination of heteroaryl and aryl chlorides, bromides, and iodides. In the presence of this catalyst, aryl and heteroaryl chlorides, bromides, and iodides react with many primary amines in high yields with part-per-million quantities of palladium precursor and ligand. Many reactions of primary amines with both heteroaryl and aryl chlorides, bromides, and iodides occur to completion with 0.0005-0.05 mol % catalyst. A comparison of the reactivity of this catalyst for the coupling of primary amines at these loadings is made with catalysts generated from hindered monophosphines and carbenes, and these data illustrate the benefits of chelation. Studies on structural variants of the most active catalyst indicate that a rigid backbone in the bidentate structure, strong electron donation, and severe hindrance all contribute to its high reactivity. Thus, these complexes constitute a fourth-generation catalyst for the amination of aryl halides, whose activity complements catalysts based on monophosphines and carbenes. PMID- 18444641 TI - A new silicon lewis acid for highly enantioselective mannich reactions of aliphatic ketone-derived hydrazones. AB - The first general method for the highly enantioselective Mannich reaction of aliphatic ketimines is reported. A new, second generation chiral silane Lewis acid has been developed that promotes the reaction between ketone-derived hydrazones and silyl ketene acetals, providing the beta,beta-disubstituted beta amino esters with good enantioselectivity even for the hydrazone derived from 2 butanone (methyl vs ethyl, 91% ee). Several examples are provided, including a reaction with a substituted (propanoate-derived) silyl ketene acetal. PMID- 18444642 TI - Organogel formation by a cholesterol-stoppered bistable [2]rotaxane and its dumbbell precursor. AB - The switching properties, gelation behavior, and self-organization of a cholesterol-stoppered bistable [2]rotaxane containing a cyclobis(paraquat-p phenylene) ring and tetrathiafulvalene/1,5-dioxynaphthalene recognition units situated in the rod portion of the dumbbell component have been investigated by electrochemical, spectroscopic, and microscopic means. The cyclobis(paraquat-p phenylene) ring in the [2]rotaxane can be switched between the tetrathiafulvalene and 1,5-dioxynaphthalene recognition units by addressing the redox properties of the tetrathiafulvalene unit. The organogels can be prepared by dissolving the [2]rotaxane and its dumbbell precursor in a CH2Cl2/MeOH (3:2) mixed solvent and liquified by adding the oxidant Fe(ClO4)3. Direct evidence for the self organization was obtained from AFM investigations which have shown that both of the [2]rotaxane and its dumbbell precursor form linear superstructures which we propose are helical in nature. PMID- 18444643 TI - Organized formation of 2D extended covalent organic frameworks at surfaces. AB - The development of nanoscale masking for particle deposition is exceedingly important to push the future of nanoelectronics beyond the current limits of lithography. We present the first example of ordered hexagonal covalent nanoporous structures deposited in extended arrays of near monolayer coverage across a Ag(111) surface. The networks were formed from the deposition of the reagents from a heated molybdenum crucible between 370 and 460 K under ultrahigh vacuum (UHV) onto a cleaned Ag(111) substrate and imaged using a scanning tunneling microscope (STM). Two surface covalent organic frameworks (SCOFs) are presented; the first is formed from the deposition of 1,4-benzenediboronic acid (BDBA) and its dehydration to form the boroxine-linked SCOF-1, the second is formed from the co-deposition of BDBA and 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) to form a dioxaborole-linked SCOF-2 network. The networks were found to produce nanoporous structures of 15 A for SCOF-1 and 29 A for SCOF-2, which agreed with theoretical pore sizes determined from DFT calculations. Both SCOFs were found to have exceptional thermal stability, maintaining their structure until approximately 750 K, which was found to be the polymer degradation temperature from thermal gravimetric analysis (TGA). PMID- 18444644 TI - Quantum sieving effect of three-dimensional Cu-based organic framework for H2 and D2. AB - The crystal structure of [Cu(4,4'-bipyridine) 2(CF 3SO 3) 2] n metal-organic framework (CuBOTf) of one-dimensional pore networks after pre-evacuation at 383 K was determined with synchrotron X-ray powder diffraction measurement. Effective nanoporosity of the pre-evacuated CuBOTf was determined with N 2 adsorption at 77 K. The experimental H 2 and D 2 adsorption isotherms of CuBOTf at 40 and 77 K were measured and then compared with GCMC-simulated isotherms using the effective nanoporosity. The quantum-simulated H 2 and D 2 isotherms at 77 K using the Feynman-Hibbs effective potential coincided with the experimental ones, giving a direct evidence on the quantum molecular sieving effect for adsorption of H 2 and D 2 on CuBOTf. However, the selectivity for the 1:1 mixed gas of H 2 and D 2 was 1.2. On the contrary, experimental H 2 and D 2 isotherms at 40 K had an explicit adsorption hysteresis, originating from the marked pore blocking effect on measuring the adsorption branch. The blocking effect for quantum H 2 is more prominent than that for quantum D 2; the selectivity for D 2 over H 2 at 40 K was in the range of 2.6 to 5.8. The possibility of the quantum molecular sieving effect for H 2 and D 2 adsorption on [Cu 3(benzene-1,3,5-tricarboxylate) 2(H 2O) 3] n of three-dimensional pore networks was also shown at 77 K. PMID- 18444646 TI - Nonadiabatic deactivation of 9H-adenine: a comprehensive picture based on mixed quantum-classical dynamics. AB - Mixed quantum-classical dynamics simulations at the multireference configuration interaction (MR-CIS) level were performed for 9 H-adenine in order to understand its ultrafast nonradiative decay process. Dynamics simulations were also performed for the model system 6-aminopyrimidine. MR-CIS and complete active space perturbation theory (CASPT2) have been employed to characterize a large variety of qualitatively different conical intersections, the branches of the crossing seam connecting them, and the reaction paths from the Franck-Condon region for 9 H-adenine. The results show a two-step process consisting of ultrashort deactivation from S 3 to S 1 and a longer exponential decay step corresponding to the conversion from S 1 to S 0. PMID- 18444645 TI - Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide. AB - Aggregation of Islet Amyloid Polypeptide (IAPP) has been implicated in the development of type II diabetes. Because IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers causes disruption of the cellular membrane and is responsible for the death of beta-cells during type II diabetes. Previous studies have shown that the N-terminal 1-19 region, rather than the amyloidogenic 20-29 region, is primarily responsible for the interaction of the IAPP peptide with membranes. Liposome leakage experiments presented in this study confirm that the pathological membrane disrupting activity of the full-length hIAPP is also shared by hIAPP 1-19. The hIAPP 1-19 fragment at a low concentration of peptide induces membrane disruption to a near identical extent as the full-length peptide. At higher peptide concentrations, the hIAPP 1-19 fragment induces a greater extent of membrane disruption than the full-length peptide. Similar to the full-length peptide, hIAPP 1-19 exhibits a random coil conformation in solution and adopts an alpha-helical conformation upon binding to lipid membranes. However, unlike the full-length peptide, the hIAPP 1-19 fragment did not form amyloid fibers when incubated with POPG vesicles. These results indicate that membrane disruption can occur independently from amyloid formation in IAPP, and the sequences responsible for amyloid formation and membrane disruption are located in different regions of the peptide. PMID- 18444647 TI - Molecular weight recognition in the multiple-stranded helix of a synthetic polymer without specific monomer-monomer interaction. AB - Stereoregular isotactic and syndiotactic poly(methyl methacrylate)s (it- and st PMMAs) are known to form a multiple-stranded complementary helix, so-called stereocomplex (SC) through van der Waals interactions, which is a rare example of helical supramolecular structures formed by a commodity polymer. In this study, we prepared SCs by using uniform it- and st-PMMAs and those with a narrow molecular weight distribution having different molecular weights and investigated their structures in detail using high-resolution atomic force microscopy as a function of the molecular weight and molecular weight distribution of the component PMMAs. We found that complementary it- and st-PMMAs with the longer molecular length determine the total length of the SC, and molecules of the shorter component associate until they fill up or cover the longer component. These observations support a supramolecular triple-stranded helical structure of the SCs composed of a double-stranded helix of two intertwined it-PMMA chains included in a single helix of st-PMMA, and this triple-stranded helix model of the SCs appears to be applicable to the it- and st-PMMAs having a wide range of molecular weights we employed in this study. In homogeneous double-stranded helices of it-PMMA, it has been found that, in mixtures of two it-PMMAs with different molecular weights, chains of the same molecular weight selectively form a double-stranded it-PMMA helix, or recognize the molecular weights of each other ("molecular sorting"). We thus demonstrate that molecular weight recognition is possible, without any specific interaction between monomer units, through the formation of a topological multiple-stranded helical structure based upon van der Waals interaction. PMID- 18444649 TI - Water-enhanced low-temperature CO oxidation and isotope effects on atomic oxygen covered Au(111). AB - Water-oxygen interactions and CO oxidation by water on the oxygen-precovered Au(111) surface were studied by using molecular beam scattering techniques, temperature-programmed desorption (TPD), and density functional theory (DFT) calculations. Water thermally desorbs from the clean Au(111) surface with a peak temperature of approximately 155 K; however, on a surface with preadsorbed atomic oxygen, a second water desorption peak appears at approximately 175 K. DFT calculations suggest that hydroxyl formation and recombination are responsible for this higher temperature desorption feature. TPD spectra support this interpretation by showing oxygen scrambling between water and adsorbed oxygen adatoms upon heating the surface. In further support of these experimental findings, DFT calculations indicate rapid diffusion of surface hydroxyl groups at temperatures as low as 75 K. Regarding the oxidation of carbon monoxide, if a C (16)O beam impinges on a Au(111) surface covered with both atomic oxygen ( (16)O) and isotopically labeled water (H 2 (18)O), both C (16)O (16)O and C (16)O (18)O are produced, even at surface temperatures as low as 77 K. Similar experiments performed by impinging a C (16)O beam on a Au(111) surface covered with isotopic oxygen ( (18)O) and deuterated water (D 2 (16)O) also produce both C (16)O (16)O and C (16)O (18)O but less than that produced by using (16)O and H 2 (18)O. These results unambiguously show the direct involvement and promoting role of water in CO oxidation on oxygen-covered Au(111) at low temperatures. On the basis of our experimental results and DFT calculations, we propose that water dissociates to form hydroxyls (OH and OD), and these hydroxyls react with CO to produce CO 2. Differences in water-oxygen interactions and oxygen scrambling were observed between (18)O/H 2 (16)O and (18)O/D 2 (16)O, the latter producing less scrambling. Similar differences were also observed in water reactivity toward CO oxidation, in which less CO 2 was produced with (16)O/D 2 (16)O than with (16)O/H 2 (16)O. These differences are likely due to primary kinetic isotope effects due to the differences in O-H and O-D bond energies. PMID- 18444648 TI - The reactivity patterns of low-coordinate iron-hydride complexes. AB - We report a survey of the reactivity of the first isolable iron-hydride complexes with a coordination number less than 5. The high-spin iron(II) complexes [(beta diketiminate)Fe(mu-H)] 2 react rapidly with representative cyanide, isocyanide, alkyne, N 2, alkene, diazene, azide, CO 2, carbodiimide, and Bronsted acid containing substrates. The reaction outcomes fall into three categories: (1) addition of Fe-H across a multiple bond of the substrate, (2) reductive elimination of H 2 to form iron(I) products, and (3) protonation of the hydride to form iron(II) products. The products include imide, isocyanide, vinyl, alkyl, azide, triazenido, benzo[ c]cinnoline, amidinate, formate, and hydroxo complexes. These results expand the range of known bond transformations at iron complexes. Additionally, they give insight into the elementary transformations that may be possible at the iron-molybdenum cofactor of nitrogenases, which may have hydride ligands on high-spin, low-coordinate metal atoms. PMID- 18444650 TI - Single-molecule detection of nitrogen mustards by covalent reaction within a protein nanopore. AB - Mustards, including sulfur mustards and nitrogen mustards, form a class of cytotoxic, vesicant chemical warfare agents. Mustards have also been used to treat cancer and played a vital role in the development of chemotherapy. Additionally, because of their destructive properties, ease of synthesis, and the lack of effective antidotes, mustards are unquestionably terrorist threats. Therefore, quick and convenient detection of mustards is a critical issue. In the present study, we achieved detection of various mustards on the basis of their chemical reactivity by using engineered alpha-hemolysin (alphaHL) protein pores as sensor elements. We describe four classes of reactions for detecting mustards. These reactions occur between mustards and thiol groups contributed by cysteine side-chains within the lumen of the alphaHL pore or on an internal molecular adapter. The approach is quick and straightforward. It can confirm the existence of mustards in as little as 10 min at 50 microM or lower. PMID- 18444651 TI - Sequence of intramolecular carbonylation and asymmetric hydrogenation reactions: highly regio- and enantioselective synthesis of medium ring tricyclic lactams. AB - The intramolecular cyclocarbonylation reaction with palladium-complexed dendrimers on silica is a very effective method for the regioselective synthesis of methylene 8-, 9-, and 10-membered rings. The heterogeneous dendritic catalysts are easily recovered by simple filtration and reused for up to 10 cycles with only a slight loss of activity. Asymmetric hydrogenation of the resulting unsaturated heterocycles affords optically active tricyclic lactams in excellent yields and in high enantiomeric excess. This process can tolerate a wide array of functional groups, including halide, ether, nitrile, ketone, and ester. Moreover, the variation of heteroatom on the rings does not have any influence on the efficiency and enantioselectivity of the reaction. PMID- 18444652 TI - Steric control in the thermal rearrangement of a bicyclo[3.1.0]hex-2-ene substituted at a radical-nonstabilizing position. AB - Introduction into the long-known bicyclo[3.1.0]hex-2-ene system of a large substituent in an electronically inactive, interconnected pair of positions brings to light the importance of sterics as a major factor in the determination of products. Far from the "flat" surface that so well describes the caldera of diradicals of the archetype, a "bumpy" surface is required as the conceptual scheme. The relief of "compressional" strain serves to explain the dramatic effect on kinetics and composition at equilibrium. PMID- 18444653 TI - Encapsulation and dynamic behavior of two H2 molecules in an open-cage C70. AB - An open-cage C70 derivative having a 13-membered ring opening (2) was synthesized by a three-step reaction; thermal reaction of C70 with a pyridazine derivative, oxidative cleavage of the CC double bond, and insertion of a sulfur atom to the opening. The structure of 2 was determined by X-ray analysis. One H2 molecule was introduced into 2 to give H2@2 in 97% yield. Furthermore, two H2 molecules were encapsulated in 2 in 3% yield. The positional exchange of two H2 molecules inside 2 was clearly observed by the dynamic low-temperature NMR measurements. PMID- 18444655 TI - Simple enantioselective approach to synthetic limonoids. AB - An enantioselective and short approach to the synthesis of limonoids has been applied successfully to the simplest limonoid, 2. The carbon atoms of the tetracyclic framework were assembled in a single operation from the acylsilane 3 and the acetylenic sulfone 4 to form the chiral epoxide 5. Successive cationic and free-radical cyclizations starting with 5 generated the tetracyclic intermediates 9a, which was transformed into limonoid 2 by a sequence consisting of (1) oxidative cleavage of the exocyclic double bond, (2) stereoselective alpha methylation, (3) furyl attachment, and (4) introduction of a 16-keto function. PMID- 18444656 TI - A novel DNA hairpin substrate for bleomycin. AB - A 16-nucleotide DNA hairpin containing 4-aminobenzo[g]quinazoline-2-one 2' deoxyribose at position 15 has been prepared and found to lack significant fluorescence. When treated with Fe(II).BLM, the hairpin was found to undergo oxidative transformation selectively at position 15. The predominant fluorescent product was characterized and quantified. The pro-fluorescent DNA hairpin was used as a substrate for 15 bleomycin congeners, and the results were compared with those obtained following cleavage of a radiolabeled DNA duplex and PAGE analysis. PMID- 18444657 TI - O-TBS-N-tosylhydroxylamine: a reagent for facile conversion of alcohols to oximes. AB - A variety of oximes were synthesized from the corresponding alcohols, alkyl halides, or alkyl sulfonates without using external oxidants. With this simple two-step procedure involving substitution with readily available TsNHOTBS and subsequent treatment with CsF, a range of oximes were prepared including the ones hardly preparable with conventional procedures. PMID- 18444658 TI - Total synthesis of (-)-brevenal: a concise synthetic entry to the pentacyclic polyether core. AB - Total synthesis of (-)-brevenal, a novel marine polycyclic ether natural product, is described. Highly efficient and scalable entries to the AB-ring exo-olefin and the DE-ring enol phosphate and a rapid construction of the C-ring by means of our Suzuki-Miyaura coupling-based strategy realized a concise synthesis of the pentacyclic skeleton of (-)-brevenal. The present synthesis is considerably more efficient than our previous synthesis (longest linear sequence: 50 steps from 2 deoxy-d-ribose). PMID- 18444659 TI - 5-caffeoylquinic acid and caffeic acid down-regulate the oxidative stress- and TNF-alpha-induced secretion of interleukin-8 from Caco-2 cells. AB - Although chlorogenic acid (CHA) easily reaches a millimolar level in the gastrointestinal tract because of its high concentration in coffee and fruits, its effects on intestinal epithelial cells have been little reported. We investigated in this study the down-regulative effects of 5-caffeoylquinic acid (CQA), the predominant isomer of CHA, on the H(2)O(2-) or TNF-alpha-induced secretion of interleukin (IL)-8, a central pro-inflammatory chemokine involved in the pathogenesis of inflammatory bowel diseases, in human intestinal epithelial Caco-2 cells. After the cells had been pre- and simultaneously treated with CQA, the oversecretion of IL-8 and overexpression of its mRNA induced by H(2)O(2) were significantly suppressed in a dose-dependent manner in the range of 0.25-2.00 mmol/L. We further found that a metabolite of CQA, caffeic acid (CA), but not quinic acid, significantly inhibited the H(2)O(2)-induced IL-8 secretion and its mRNA expression in the same dose-dependent manner. Both CQA and CA suppressed the TNF-alpha-induced IL-8 secretion as well. Caffeic acid at 2.00 mmol/l was able to absolutely block the H(2)O(2)- or TNF-alpha-induced oversecretion of IL-8 in Caco 2 cells. However, CQA and CA did not suppress the TNF-alpha-induced increase in the IL-8 mRNA expression, indicating that the suppressive mechanisms are different between TNF-alpha-induced and H(2)O(2)-induced IL-8 production models. These results suggest that the habit of drinking coffee and/or eating fruits with a high CHA content may be beneficial to humans in preventing the genesis of inflammatory bowel diseases. PMID- 18444660 TI - Mycotoxins in ethanol co-products: modeling economic impacts on the livestock industry and management strategies. AB - The rapidly expanding U.S. ethanol industry is generating a growing supply of co products, mostly in the form of dried distillers' grain and solubles (DDGS) or wet distillers' grains (WDG). In the United States, 90% of the co-products of maize-based ethanol are fed to livestock. An unintended consequence is that animals are likely to be fed higher levels of mycotoxins, which are concentrated up to three times in DDGS compared to grain. The model developed in this study estimates current losses to the swine industry from weight gain reduction due to fumonisins in added DDGS at $9 million ($2-18 million) annually. If there is complete market penetration of DDGS in swine feed with 20% DDGS inclusion in swine feed and fumonisins are not controlled, losses may increase to $147 million ($29-293 million) annually. These values represent only those losses attributable to one mycotoxin on one adverse outcome on one species. The total loss due to mycotoxins in DDGS could be significantly higher due to additive or multiplicative effects of multiple mycotoxins on animal health. If mycotoxin surveillance is implemented by ethanol producers, losses are shifted among multiple stakeholders. Solutions to this problem include methods to reduce mycotoxin contamination in both pre- and postharvest maize. PMID- 18444661 TI - Phytoecdysteroids increase protein synthesis in skeletal muscle cells. AB - Phytoecdysteroids, which are structurally similar or identical to insect molting hormones, produce a range of effects in mammals, including increasing growth and physical performance. To study the mechanism of action of phytoecdysteroids in mammalian tissue, an in vitro cellular assay of protein synthesis was developed. In C2C12 murine myotubes and human primary myotubes, phytoecdysteroids increased protein synthesis by up to 20%. In vivo, ecdysteroids increased rat grip strength. Ecdysteroid-containing plant extracts produced similar results. The effect was inhibited by a phosphoinositide kinase-3 inhibitor, which suggests a PI3K-mediated mechanism. PMID- 18444662 TI - Application of comprehensive two-dimensional liquid chromatography to elucidate the native carotenoid composition in red orange essential oil. AB - In the present work, the ability of a LC x LC-DAD/APCI-MS method developed at this laboratory to identify the native composition of carotenoid in an extremely complex matrix such as red orange essential oil was demonstrated. To carry out this task, two independent and orthogonal separation mechanisms were coupled through a 10-port switching valve that simultaneously collected the eluent from a microbore cyano column used as the first dimension in normal phase mode and injected it to a conventional reversed phase monolithic C(18) column in the second dimension separation. By using this novel analytical technique together with the use of DAD and APCI-MS detectors it was possible to identify in the sample, without the need of any pretreatment, 40 different carotenoids. Among them, 16 carotenoid monoesters were identified, mainly beta-cryptoxanthin palmitate (C(16:0)), myristate (C(14:0)), and laureate (C(12:0)) as well as several lutein, violaxanthin, antheraxanthin, and luteoxanthin monoesters. Moreover, 21 carotenoid diesters composed by several antheraxanthin, luteoxanthin, violaxanthin, and auroxanthin diesters were found in the native carotenoid composition of the orange oil. The main carotenoid diesters were the laureate palmitate (C(12:0), C(16:0)), myristate palmitate (C(14:0), C(16:0)), and dipalmitate (C(16:0), C(16:0)) diesters, although other diesters were also identified. Besides, two different free carotenes, zeta-carotene and phytofluene, and a xanthophyll, lutein, were also determined. To the authors' knowledge, this is the first time that carotenoid diesters are described and identified in orange essential oil. Likewise, it has been demonstrated that the LC x LC approach proposed in this study is capable of coping with the direct analysis and identification of a complex natural source of carotenoids such as the orange. PMID- 18444663 TI - Dehydroascorbate reductase cDNA from sweet potato (Ipomoea batatas [L.] Lam): expression, enzyme properties, and kinetic studies. AB - A cDNA encoding a putative dehydroascorbate reductase (DHAR) was cloned from sweet potato. The deduced protein showed a high level of sequence homology with DHARs from other plants (67 to approximately 81%). Functional sweet potato DHAR was overexpressed and purified. The purified enzyme showed an active monomeric form on a 12% native PAGE. The protein's half-life of deactivation at 50 degrees C was 10.1 min, and its thermal inactivation rate constant K(d) was 6.4 x 10(-2) min(-1). The enzyme was stable in a broad pH range from 6.0-11.0 and in the presence of 0.8 M imidazole. The K(m) values for DHA and GSH were 0.19 and 2.38 mM, respectively. PMID- 18444664 TI - A mechanism for SRC kinase-dependent signaling by noncatalytic receptors. AB - A fundamental issue in cell biology is how signals are transmitted across membranes. A variety of transmembrane receptors, including multichain immune recognition receptors, lack catalytic activity and require Src family kinases (SFKs) for signal transduction. However, many receptors only bind and activate SFKs after ligand-induced receptor dimerization. This presents a conundrum: How do SFKs sense the dimerization of receptors to which they are not already bound? Most proposals for resolving this enigma invoke additional players, such as lipid rafts or receptor conformational changes. Here we used simple thermodynamics to show that SFK activation is a natural outcome of clustering of receptors with SFK phosphorylation sites, provided that there is phosphorylation-dependent receptor SFK association and an SFK bound to one receptor can phosphorylate the second receptor or its associated SFK in a dimer. A simple system of receptor, SFK, and an unregulated protein tyrosine phosphatase (PTP) can account for ligand-induced changes in phosphorylation observed in cells. We suggest that a core signaling system comprising a receptor with SFK phosphorylation sites, an SFK, and an unregulated PTP provides a robust mechanism for transmembrane signal transduction. Other events that regulate signaling in specific cases may have evolved for fine-tuning of this basic mechanism. PMID- 18444665 TI - Critical role of arginine 160 of the EutB protein subunit for active site structure and radical catalysis in coenzyme B12-dependent ethanolamine ammonia lyase. AB - The protein chemical, kinetic, and electron paramagnetic resonance (EPR) and electron spin-echo envelope modulation (ESEEM) spectroscopic properties of ethanolamine ammonia-lyase (EAL) from Salmonella typhimurium with site-directed mutations in a conserved arginine residue (R160) of the active site containing EutB protein subunit have been characterized. R160 was predicted by a comparative model of EutB to play a critical role in protein structure and catalysis [Sun, L., and Warncke, K. (2006) Proteins: Struct., Funct., Bioinf. 64, 308-319]. R160I and R160E mutants fail to assemble into an EAL oligomer that can be isolated by the standard enzyme purification procedure. The R160K and R160A mutants assemble, but R160A EAL is catalytically inactive and reacts with substrates to form magnetically isolated Co(II) and unidentified radical species. R160A EAL activity is resurrected by externally added guanidinium to 2.3% of wild-type EAL. R160K EAL displays catalytic turnover of aminoethanol, with a 180-fold lower value of k(cat)/ K(M) relative to wild-type enzyme. R160K EAL also forms Co(II)-substrate radical pair intermediate states during turnover on aminoethanol and (S)-2 aminopropanol substrates. Simulations of the X-band EPR spectra show that the Co(II)-substrate radical pair separation distances are increased by 2.1 +/- 1.0 A in R160K EAL relative to wild-type EAL, which corresponds to the predicted 1.6 A change in arginine versus lysine side chain length. 14N ESEEM from a hyperfine coupled protein nitrogen in wild type is absent in R160K EAL, which indicates that a guanidinium 14N of R160 interacts directly with the substrate radical through a hydrogen bond. ESEEM of the 2H-labeled substrate radical states in wild type and R160K EAL shows that the native separation distances among the substrate C1 and C2, and coenzyme C5' reactant centers, are conserved in the mutant protein. The EPR and ESEEM measurements evince a protein-mediated force on the C5'-methyl center that is directed toward the reacting substrate species during the hydrogen atom transfer and radical rearrangement reactions. The results indicate that the positive charge at the residue 160 side chain terminus is required for proper folding of EutB, assembly of a stable EAL oligomer, and catalysis in the assembled oligomer. PMID- 18444666 TI - FTIR and XPS study of Pt nanoparticle functionalization and interaction with alumina. AB - Platinum nanoparticles with a mean size of 1.7 nm were synthesized by reduction in sodium acetate solution in 1,2-ethanediol. The particles were then functionalized with dodecylamine, dodecanethiol, and omega-mercapto-undecanoic acid (MUDA). Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS) showed important variations of the particle surface state with functionalization whereas their structure differs only slightly. Platinum-to-sulfur charge transfer inferred from XPS of thiol-coated particles enabled the identification of the formation of Pt (delta+)-S (delta-) bonds. The native carbon monoxide (CO) at the surface of the particles was a very efficient probe for following the functionalization of the particles by FTIR. The red shift of nu(CO) accounts for the nature of the ligands at the surface of the particles and also for their degree of functionalization. Immobilization on alumina substrates of particles functionalized with MUDA was realized by immersion in colloidal solutions. Free molecules, isolated particles, and aggregates of particles interconnected by hydrogen bonds at the surface of alumina were evidenced by FTIR. With successive washings, the energy variation of the CO stretch of carbon monoxide and of carboxylic acid groups and the relative intensity nu(CH2)/nu(CO) showed that the free molecules are eliminated first, followed by aggregates and less-functionalized particles. Particles presenting a high degree of functionalization by MUDA remain and interact strongly with alumina. PMID- 18444667 TI - Surface characterization of biocidal polyurethane modifiers having poly(3,3 substituted)oxetane soft blocks with alkylammonium side chains. AB - This paper focuses on surface characterization of P[ AB] copolyoxetane soft block polyurethanes having either fluorous (3FOx, -CH2OCH 2CF3) or PEG-like (ME2Ox, CH2(OCH2CH2) 2OCH3), A side chains and alkylammonium, B side chains. Physical surface characterization data were analyzed in light of the previously observed order of antimicrobial effectiveness for a set of four surface modifiers. Ample physical evidence for surface concentration of fluorous 2 wt % P[ AB] polyurethane modifiers was obtained from XPS, contact angles, ATR-IR spectroscopy, and TM-AFM. In TM-AFM phase imaging, the most effective biocidal surface modifier, 2 wt % HMDI-BD(30)/P[(3FOx)(C12)-0.89:0.11]-PU, showed a nanoscale phase-separated structure consisting of 200 nm domains with background features about 10 times smaller. Despite similar surface characterization data, the 2 wt % fluorous C6 analog ranked third in contact biocidal effectiveness. Physical evidence for surface concentration of 2 wt % P[(ME2Ox)(C12)-0.86:0.14] PU was modest, considering that antimicrobial effectiveness was second only to 2 wt % HMDI-BD(30)/P[(3FOx)(C12)-0.89:0.11]-PU. In this set of surface modifiers, nanoscale morphology is largely driven by the fluorous component, whereas antimicrobial effectiveness is more strongly influenced by alkylammonium chain length. The effect of alkylammonium side chain length on surface concentration and antimicrobial behavior is more pronounced for ME2Ox polyurethanes compared to the 3FOx analogs. PMID- 18444668 TI - Regioselective competitive adsorption of water and organic vapor mixtures on pristine single-walled carbon nanotube bundles. AB - Sequential adsorption of water and organic vapor mixtures onto single-walled carbon nanotube (SWNT) bundles is studied experimentally and by grand canonical Monte Carlo (GCMC) simulation to elucidate the distinct interactions between select adsorbates and the nanoporous structure of SWNTs. Experimental adsorption isotherms on SWNT bundles for hexane, methyl ethyl ketone, cyclohexane, and toluene individually mixed in carrier gases that were nearly saturated with water vapor are compared with the GCMC-simulated isotherms for hexane, as a representative organic, on the external surface of the heterogeneous SWNT bundles. From the nearly perfect overlap between the experimental and simulated isotherms, it is concluded that until near saturation only the internal pore volume of pristine SWNT bundles fills with water. The adsorption of water vapor on the peripheral surface of the bundles remains insignificant, if not negligible, in comparison to the adsorption of water in the internal volume of the bundles. This is in contrast with the adsorption of pure hexane, which exhibits appreciable adsorption both inside the bundles and on their external surface. It is also suggested that during competitive adsorption, water molecules take precedence over small nonpolar and polar organic molecules for adsorption inside SWNTs and leave unoccupied the hydrophobic external surface of the bundles for other more compatible adsorbates. PMID- 18444669 TI - Layer-by-layer assembly of aqueous dispersible, highly conductive poly(aniline-co o-anisidine)/poly(sodium 4-styrenesulfonate)/MWNTs core-shell nanocomposites. AB - Poly(aniline-co- o-anisidine) (P(An-co- o-As)) ionomers and poly(sodium 4 styrenesulfonate) (PSS) were layer-by-layer (LbL) assembled on carboxylic acid functionalized multiwalled carbon nanotubes (MWNTs). The multilayered polyelectrolyte greatly enhanced the dispersibility and stability of MWNTs in aqueous solutions. More importantly, the nanocomposites showed 3 orders of magnitude of conductivity increase, 4.2 S/cm, compared to that of neat ionomers, 0.004 S/cm. The deposition procedure was monitored with zeta (zeta) potential changes. Fourier transform infrared (FT-IR), ultraviolet-visible (UV-vis), and Raman spectra confirmed charge transfer from the quinoid units of the P(An-co- o As) to MWNTs, which effectively delocalize the electrons. Further, we explored the pH response of the assembled P(An-co- o-As)/PSS/MWNTs multilayer nanocomposites. The sharp transition of the conductivity in the pH range of 2 to 6 makes the nanocomposites promising candidates for chemical-biological sensing. PMID- 18444670 TI - MBC94, a conjugable ligand for cannabinoid CB 2 receptor imaging. AB - Cannabinoid CB 2 receptor is a particularly attractive target for noninvasive imaging of neuroinflammation and monitoring of therapeutic efficacy. Its expression is low to undetectable in healthy brain and induced in resident microglial cells (the macrophage of the brain) after cerebral ischemia, injury, and in neuroinflammatory disease. Additionally, immune cells migrating across the blood-brain barrier typically express CB 2 receptors, which adds to the expression pool of this target and provides a reliable indicator of inflammation in the brain. Here, we synthesized a novel conjugable CB 2 receptor ligand, mbc94, which has a terminal amino group that allows for facile conjugation to imaging moieties. A near-infrared (NIR) dye labeled mbc94, NIRmbc94, was developed for CB 2 targeted imaging. Preliminary evidence, including in vitro fluorescence imaging and a competition study, showed that NIRmbc94 specifically labeled CB 2-expressing cells. PMID- 18444671 TI - MALDI-MS monitoring of differential biomolecule secretion from human lung cells in vitro following incubation with <150 particles. AB - Knowledge of how the chemical composition of a given ambient particle affects varied biological response upon inhalation is of considerable interest regarding the pathogenesis of respiratory and cardiovascular diseases. Characterization of initiating events, using measurements of proinflammatory mediator differential expression by lung tissues, is an objective of our studies. Results demonstrating the capability to monitor changes in the secreted proteome of a human lung cell line culture dosed with <150 particles, for incubation periods ranging from 30 min to 24 h using matrix assisted laser desorption ionization (MALDI) mass spectrometry, are presented. Each population of particles was created within an electrodynamic balance to have the same size and chemical composition prior to being deposited onto a culture of A549 cells. The carbon particles, and the lipopolysaccharide (52 pg/particle) containing carbon particles, were 6.3 microm in diameter. Numerous biomolecules are observable in the mass spectra of supernatants of lung cells. The relative abundance of many of these biomolecules changes as a function of particle type and incubation time, suggesting the ion signal intensities observed are indicative of the relative differential expression of these compounds, some of which could be proinflammatory mediators. PMID- 18444672 TI - Snake venomics and antivenomics of the arboreal neotropical pitvipers Bothriechis lateralis and Bothriechis schlegelii. AB - We report the comparative proteomic characterization of the venoms of two related neotropical arboreal pitvipers from Costa Rica of the genus Bothriechis, B. lateralis (side-striped palm pit viper) and B. schlegelii (eyelash pit viper). The crude venoms were fractionated by reverse-phase HPLC, followed by analysis of each chromatographic fraction by SDS-PAGE, N-terminal sequencing, MALDI-TOF mass fingerprinting, and collision-induced dissociation tandem mass spectrometry of tryptic peptides. The venom proteomes of B. lateralis and B. schlegelii comprise similar number of distinct proteins belonging, respectively, to 8 and 7 protein families. The two Bothriechis venoms contain bradykinin-potentiating peptides (BPPs), and proteins from the phospholipase A 2 (PLA 2), serine proteinase, l amino acid oxidase (LAO), cysteine-rich secretory protein (CRISP), and Zn (2+) dependent metalloproteinase (SVMP) families, albeit each species exhibit different relative abundances. Each venom also contains unique components, for example, snake venom vascular endothelial growth factor (svVEGF) and C-type lectin-like molecules in B. lateralis, and Kazal-type serine proteinase inhibitor like proteins in B. schlegelii. Using a similarity coefficient, we estimate that the similarity of the venom proteins between the two Bothriechis taxa may be <10%, indicating a high divergence in their venom compositions, in spite of the fact that both species have evolved to adapt to arboreal habits. The major toxin families of B. lateralis and B. schlegelii are SVMP (55% of the total venom proteins) and PLA 2 (44%), respectively. Their different venom toxin compositions provide clues for rationalizing the distinct signs of envenomation caused by B. schlegelii and B. lateralis. An antivenomic study of the immunoreactivity of the Instituto Clodomiro Picado (ICP) polyvalent antivenom toward Bothriechis venoms revealed that l-amino acid oxidase and SVMPs represent the major antigenic protein species in both venoms. Our results provide a ground for rationalizing the reported protection of the ICP polyvalent antivenom against the hemorrhagic, coagulant, defibrinating, caseinolytic and fibrin(ogen)olytic activities of Bothriechis ( schlegelii, lateralis) venoms. However, these analyses also evidenced the limited recognition capability of the polyvalent antivenom toward a number of Bothriechis venom components, predominantly BPPs, svVEGF, Kazal-type inhibitors, some PLA 2 proteins, some serine proteinases, and CRISP molecules. PMID- 18444673 TI - Unperturbed volume transition of thermosensitive poly-(N-isopropylacrylamide) microgel particles embedded in a hydrogel matrix. AB - The thermoresponsive behavior of poly-(N-isopropylacrylamide) (PNiPAM) microgels embedded in a covalently cross-linked polyacrylamide hydrogel matrix was investigated using ultraviolet-visible (UV-vis) spectroscopy, small-angle neutron scattering (SANS), and confocal laser scanning microscopy. The hydrogel synthesis was performed at two different temperatures, below and above the volume phase transition temperature of PNiPAM, resulting in highly swollen or fully collapsed PNiPAM microgel particles during the incorporation step. UV-vis spectroscopy experiments verify that the incorporation of thermosensitive microgels leads to temperature-sensitive optical properties of the composite materials. SANS measurements at different temperatures show that the thermosensitive swelling behavior of the PNiPAM microgels is fully retained in the composite material. Volume and structure criteria of the embedded microgel particles are compared to those of the free microgels in acrylamide solution. To visualize the temperature responsive behavior of larger PNiPAM particles, confocal fluorescence microscopy images of PNiPAM beads, of 40-microm size, were taken at two different temperatures. The micrographs also demonstrate the retained temperature sensitivity of the embedded microgels. PMID- 18444674 TI - Molecular dynamics simulation of LiTFSI-acetamide electrolytes: structural properties. AB - The liquid structures of nonaqueous electrolytes composed of lithium bis(trifluoromethylsulfonyl)imide (LiTFSI) and acetamide, with LiTFSI/acetamide molar ratios of 1:2, 1:4, and 1:6, were studied by molecular dynamics simulations. The simulations indicate that the Li+ cations prefer to be six coordinate by the sulfonyl oxygen atoms of the TFSI- anions and the carbonyl oxygen atoms of the acetamide molecules, rather than by the most electronegative nitrogen atom of the TFSI- anion. Therefore, close Li+-TFSI- contact pairs exist in the system. The TFSI- anion prefers to provide only one of four possible oxygen atoms to coordinate to the same Li+ cation. Three conformations (cis, trans, and gauche) of the TFSI- anions were found to coexist in the liquid electrolyte. At high salt concentrations, the TFSI- anions mainly adopt the gauche conformation in order to provide more oxygen atoms to coordinate to different Li+ cations, while simultaneously reducing the repulsion among the Li+ cations. On the other hand, the fraction of TFSI- anions adopting the cis conformation is largest for the system with the molar ratio of 1:6, in which many clusters, mainly composed of the Li+ cations and the TFSI- anions, are immersed in the acetamide molecules. The size and charge distribution of clusters were also investigated. In the system with the molar ratio of 1:2, nearly all of the ions in the PBC (periodic boundary conditions) box aggregate into a bulky cluster that gradually disassembles into small clusters with decreasing salt concentration. The addition of acetamide molecules was found to effectively relax the liquid electrolyte structure, and the system with the molar ratio of 1:4 was found to exhibit a more homogeneous liquid structure than the other two electrolyte systems with molar ratios of 1:2 and 1:6. PMID- 18444675 TI - Biocompatible ZnO/Au nanocomposites for ultrasensitive DNA detection using resonance Raman scattering. AB - A novel method for identifying DNA microarrays based on ZnO/Au nanocomposites functionalized with thiol-oligonucleotide as probes is descried here. DNA labeled with ZnO/Au nanocomposites has a strong Raman signal even without silver acting as a surface-enhanced Raman scattering promoter. X-ray photoelectron spectra confirmed the formation of a three-component sandwich assay, i.e., constituted DNA and ZnO/Au nanocomposites. The resonance multiple-phonon Raman signal of the ZnO/Au nanocomposites as a spectroscopic fingerprint is used to detect a target sequence of oligonucleotide. This method exhibits extraordinary sensitivity and the detection limit is at least 1 fM. PMID- 18444676 TI - Experimental dipole moments for nonisolatable acetic acid structures in a nonpolar medium. A combined spectroscopic, dielectric, and DFT study for self association in solution. AB - Acetic acid can exist in many possible structural forms depending on its surrounding medium. A recently developed inverse problem methodology (J. Phys. Chem. B 2007, 111, 13064-13074) was utilized in order to elucidate acetic acid structures in a dilute nonpolar medium. In this regard, simultaneous and stopped flow measurements of the bulk solution densities, refractive indices, relative permittivities, and IR spectra of acetic acid in toluene were performed at several different concentrations in a semibatch closed-loop experimental setup at 298.15 K and 0.1013 MPa. This combined IR spectroscopic and dielectric, density, and refractive index analysis was employed in order to distinguish acetic acid structures and to further determine the dipole moments of the monomer, cyclic dimer, and "lumped-sum" open dimers. The infrared spectra were first analyzed to provide qualitative understanding as well as quantitative estimates for each acetic acid species. Subsequently, the dipole moments of these species were calculated using a direct approach which was primarily based on response surface models. The present method allows the determination of individual dipole moments not only for the monomer but also for the cyclic dimer and the open dimer. The results obtained from this study experimentally show that the cyclic dimer with centrosymmetric structure has a dipole moment approximately 0 D. The results also suggest that the linear dimers are present as mixtures of linear dimers structures. The existence of the linear dimers mixture was also indicated by the experimental infrared analysis of the OH-stretching region (particularly for measurements in n-hexane as solvent) and comparison of these spectra with DFT predictions. Finally, the present methodology which incorporates simultaneous physicochemical and spectroscopic analysis is undoubtedly useful for physicochemical characterization for other nonisolatable solute species and self associated structures in solution. PMID- 18444677 TI - Reductive openings of acetals: explanation of regioselectivity in borane reductions by mechanistic studies. AB - The mechanisms of regioselective reductive openings of acetals were investigated in several model systems by a combination of Hammett plots, kinetic experiments, density functional calculations, and (11)B NMR. The regioselectivity of borane reductions of cyclic acetals can be controlled by the choice of borane. Lewis acid activation of BH3 x NMe3 increases the reaction rate and renders the borane the most electrophilic species, which associates to the more electron-rich oxygen of the acetal. In contrary, without activation, the regioselectivity is instead directed by the Lewis acid, as exemplified by the reaction with BH3 x THF. PMID- 18444678 TI - New substituted tetrathiafulvalene-quinone dyads: the influences of electron accepting abilities of quinone units on the metal ion-promoted electron-transfer processes. AB - The metal ion-promoted electron transfer occurs to all new dyads 1, 2, 3, and 4, even one of them, dyad 4, which has a rather weak electron acceptor unit. The results also indicate that the metal ion-promoted electron transfer within the dyads is influenced by the electron accepting abilities of quinone units; dyad 2 with the strongest electron acceptor among the four dyads shows the strongest absorption and ESR signals attributed to TTF.+ in the presence of metal ions. PMID- 18444679 TI - Lanthanide triflate-catalyzed arene acylation. Relation to classical Friedel Crafts acylation. AB - Lanthanide trifluoromethanesulfonates, Ln(OTf) 3 (OTf (-) = trifluoromethanesulfonate), serve as effective precatalysts for the rapid, regioselective, intermolecular acylation of activated arenes. This contribution probes mechanism and metal ionic radius effects in the catalytic lanthanide triflate-mediated acylation of anisole with acetic anhydride. Kinetic studies of Ln(OTf) 3 (Ln = La, Eu, Yb, Lu)-mediated anisole acylation with acetic anhydride in nitromethane reveal the rate law nu approximately k 3 [Ln (3+)] (1)[acetic anhydride] (1)[anisole] (1). Eyring and Arrhenius analyses yield Delta H++ = 12.9 (4) kcal.mol (-1), Delta S++ = -44.8 (1.3) e.u., and E a = 13.1 (4) kcal.mol (-1) for Ln = Yb, with the negative Delta S++ implying a highly organized transition state. The observed primary kinetic isotope effect of k H/ k D = 2.6 +/- 0.15 is consistent with arene C-H bond scission in the turnover-limiting step. The proposed catalytic pathway involves precatalyst formation via interaction of Ln(OTf) 3 with acetic anhydride, followed by Ln (3+)-anisole pi-complexation, substrate-electrophile sigma-complex formation, and turnover-limiting C-H bond scission. Lanthanide size effects on turnover frequencies are consistent with a transition state lacking significant ionic radius-dependent steric constraints. Substrate-Ln (3+) interactions using paramagnetic Gd (3+) and Yb (3+) NMR probes and factors affecting reaction rates such as arene substituent and added LiClO 4 cocatalyst are also explored. PMID- 18444680 TI - Synthetic studies toward halichlorine: complex azaspirocycle formation with use of an NBS-promoted semipinacol reaction. AB - The investigations of a synthetic route incorporating a NBS-promoted semipinacol rearrangement to the 6-azaspiro[4.5]decane fragment within halichlorine ( 1) are presented. A convergent approach was pursued, utilizing two chiral, enantiomerically enriched building blocks, 2-trimethylstannyl piperidene 10 and substituted cyclobutanone 19. Noteworthy synthetic operations in this study include the following: (a) a highly diastereoselective NBS-promoted semipinacol reaction that established four stereogenic centers in ketone 25 and (b) the use of a N- p-toluenesulfonyl-2-iodo-2-piperidene as a precursor to a basic organometallic reagent, which was critical to the success of the coupling of fragments 10 and 19. PMID- 18444681 TI - Polymer-supported organocatalysts: asymmetric reduction of imines with trichlorosilane catalyzed by an amino acid-derived formamide anchored to a polymer. AB - Asymmetric reduction of ketimines 1a-e with trichlorosilane can be catalyzed by the N-methylvaline-derived Lewis basic formamide anchored to a polymeric support (5a and 5b) with good enantioselectivity (< or =82% ee) and low catalyst loading (typically 15 mol %) at room temperature. This protocol represents a considerable simplification of the isolation procedure and is particularly suitable for a parallel synthesis of chiral amines 2a-e. The polymer-supported catalysts retain full activity after a multiple use. PMID- 18444682 TI - A simple, modular method for the synthesis of 3,4,5-trisubstituted pyrazoles. AB - A modular approach for the regiocontrolled preparation of pyrazoles bearing substituents on all three carbon atoms is described. Central to this method is the use of a switchable metal-directing group (MDG) to enable sequential direct lithiation of the 3- and 5-positions of the pyrazole ring. Pyrazole boronic esters obtained from these lithiated intermediates can undergo efficient Suzuki cross-coupling under the developed nonaqueous conditions, which minimize undesirable protolytic deboronation. Halogenation of the 4-position provides the means for substitution at the remaining carbon atom. PMID- 18444683 TI - Apratoxin D, a potent cytotoxic cyclodepsipeptide from papua new guinea collections of the marine cyanobacteria Lyngbya majuscula and Lyngbya sordida. AB - Cancer cell toxicity-guided fractionation of extracts of the Papua New Guinea marine cyanobacteria Lyngbya majuscula and Lyngbya sordida led to the isolation of apratoxin D (1). Compound 1 contains the same macrocycle as apratoxins A and C but possesses the novel 3,7-dihydroxy-2,5,8,10,10-pentamethylundecanoic acid as the polyketide moiety. The planar structures and stereostructures of compound 1 were determined by extensive 1D and 2D NMR and MS data analyses and by comparison with the spectroscopic data of apratoxins A and C. Apratoxin D (1) showed potent in vitro cytotoxicity against H-460 human lung cancer cells with an IC 50 value of 2.6 nM. PMID- 18444684 TI - Click chemistry approach to assembly proline mimetic libraries containing 1,4 substituted 1,2,3-triazoles. PMID- 18444685 TI - Disorder dominated microwave conductance spectra of doped silicon nanowire arrays. AB - Conductance spectra of doped silicon nanowire (SiNW) arrays were measured from 0.5 to 50 GHz at temperatures between 4 and 293 K. For arrays consisting of 11 to >10(4) SiNWs, the conductance was found to increase with frequency as f(s), with 0.25 < s < 0.45, consistent with behavior found universally in disordered systems. A possible cause is disorder from Si/SiO x interface states dominating the conductance due to the high surface-to-volume ratio of the nanowires. PMID- 18444686 TI - Functional characterization and atomic force microscopy of a DNA repair protein conjugated to a quantum dot. AB - Quantum dots (QDs) possess highly desirable optical properties that make them ideal fluorescent labels for studying the dynamic behavior of proteins. However, a lack of characterization methods for reliably determining protein-quantum dot conjugate stoichiometry and functionality has impeded their widespread use in single-molecule studies. We used atomic force microscopic (AFM) imaging to demonstrate the 1:1 formation of UvrB-QD conjugates based on an antibody-sandwich method. We show that an agarose gel-based electrophoresis mobility shift assay and AFM can be used to evaluate the DNA binding function of UvrB-QD conjugates. Importantly, we demonstrate that quantum dots can serve as a molecular marker to unambiguously identify the presence of a labeled protein in AFM images. PMID- 18444688 TI - Reversible photo-switching of single azobenzene molecules in controlled nanoscale environments. AB - We drive reversible photoinduced switching of single azobenzene-functionalized molecules isolated in tailored alkanethiolate monolayer matrices on Au{111}. We designed molecular tethers to suppress excited-state quenching from the metal substrate and formed rigid assemblies of single tethered azobenezene molecules in the domains of monolayer to limit steric constraints and tip-induced and stochastic switching effects. Single molecules were reversibly photoisomerized between trans and cis conformations by cycling exposure to visible and UV light. Trans and cis conformations were imaged as high (2.1 +/- 0.3 A) and low (0.7 +/- 0.2 A) protrusions in STM images and were assigned to the on and off states of the molecule, respectively. PMID- 18444687 TI - Measurement of carrier mobility in silicon nanowires. AB - We report the first direct capacitance measurements of silicon nanowires (SiNWs) and the consequent determination of field carrier mobilities in undoped-channel SiNW field-effect transistors (FETs) at room temperature. We employ a two-FET method for accurate extraction of the intrinsic channel resistance and intrinsic channel capacitance of the SiNWs. The devices used in this study were fabricated using a top-down method to create SiNW FETs with up to 1000 wires in parallel for increasing the raw capacitance while maintaining excellent control on device dimensions and series resistance. We found that, compared with the universal mobility curves for bulk silicon, the electron and hole mobilities in nanowires are comparable to those of the surface orientation that offers a lower mobility. PMID- 18444689 TI - Highly efficient solar cells using TiO(2) nanotube arrays sensitized with a donor antenna dye. AB - Donor antenna dyes provide an exciting route to improving the efficiency of dye sensitized solar cells owing to their high molar extinction coefficients and the effective spatial separation of charges in the charge-separated state, which decelerates the recombination of photogenerated charges. Vertically oriented TiO(2) nanotube arrays provide an optimal material architecture for photoelectrochemical devices because of their large internal surface area, lower recombination losses, and vectorial charge transport along the nanotube axis. In this study, the results obtained by sensitizing TiO(2) nanotube arrays with the donor antenna dye Ru-TPA-NCS are presented. Solar cells fabricated using an antenna dye-sensitized array of 14.4 microm long TiO(2) nanotubes on Ti foil subjected to AM 1.5 one sun illumination in the backside geometry exhibited an overall conversion efficiency of 6.1%. An efficiency of 4.1% was obtained in the frontside illumination geometry using a 1 microm long array of transparent TiO(2) nanotubes subjected to a TiCl(4) treatment and then sensitized with the Ru-TPA NCS dye. Open circuit voltage decay measurements give insight into the recombination behavior in antenna-dye sensitized nanotube photoelectrodes, demonstrating outstanding properties likely due to a reduction in the influence of the surface traps and reduced electron transfer from TiO(2) to ions in solution. PMID- 18444690 TI - From nanorings to nanodots by patterning with block copolymers. AB - We demonstrate three different transfer patterns that can be achieved by use of a surface reconstructed block copolymer film where metal is evaporated onto the surface of the film, providing the contrast. Thin films of diblock copolymers having cylindrical microdomains oriented normal to the surface with long-range lateral order were used. Solvent reconstruction of the film, followed by a glancing angle metal evaporation and thermal annealing, led to three different decorations of the films with gold. These films were used as masks for pattern transfer of pores, columns, and rings to underlying substrate with high fidelity. PMID- 18444691 TI - Graphene-based liquid crystal device. AB - Graphene is only one atom thick, optically transparent, chemically inert, and an excellent conductor. These properties seem to make this material an excellent candidate for applications in various photonic devices that require conducting but transparent thin films. In this letter, we demonstrate liquid crystal devices with electrodes made of graphene that show excellent performance with a high contrast ratio. We also discuss the advantages of graphene compared to conventionally used metal oxides in terms of low resistivity, high transparency and chemical stability. PMID- 18444692 TI - Cell-specific integration of artificial organelles based on functionalized polymer vesicles. AB - Cell organelles are subcellular structures characterized by specific functionalities. They often consist of membrane-delineated microcompartments with a unique set of enzymes. Here we report the design of synthetic organelles based on nanometer-sized polymer vesicles, show their introduction into cells in a target-specific fashion, document their intact biochemical functionality in the cellular environment, and study their intracellular trafficking. This novel paradigm of introducing polymer-based artificial organelles to specific target cells for expansion of their biochemical capabilities appears suited for biomedical applications such as enzyme replacement in genetic diseases or, more generically, to add a desired biochemical function to a cell. PMID- 18444693 TI - Gold nanoelectrode ensembles for the simultaneous electrochemical detection of ultratrace arsenic, mercury, and copper. AB - Simultaneous electrochemical detection of As(III), Hg(II), and Cu(II) using a highly sensitive platform based on gold nanoelectrode ensembles (GNEEs) is described. GNEEs were grown by colloidal chemical approach on thiol functionalized solgel derived three-dimensional silicate network preassembled on a polycrystalline gold (Au) electrode. GNEEs on the silicate network have been characterized by field emission scanning electron microscopy, X-ray diffraction, diffuse reflectance spectroscopy, and electrochemical measurements. Square wave anodic stripping voltammetry (SWASV) has been used for the detection of As(III) and Hg(II) without any interference from Cu(II) at the potentials of 0.06 and 0.53 V, respectively. The GNEE electrode is highly sensitive, and it shows linear response for As(III) and Hg(II) up to 15 ppb. The detection limit (signal-to noise ratio = 4) of the GNEE electrode toward As(III) and Hg(II) is 0.02 ppb, which is well below the guideline value given by the World Health Organization (WHO). The potential application of the GNEE electrode for the detection of As(III) in a real sample collected from the arsenic-contaminated water in 24 North Parganas, West Bengal is demonstrated. The GNEE electrode has been successfully used for the simultaneous detection of As(III), Cu(II), and Hg(II) at sub-part-per-billion level without any interference for the first time. The nanostructured electrode shows individual voltammetric peaks for As(III), Cu(II), and Hg(II) at 0.06, 0.35, and 0.53 V, respectively. The analytical performance of the GNEE electrode is superior to the existing electrodes. PMID- 18444694 TI - More than inorganic copper is bioavailable to aquatic mosses at environmentally relevant concentrations. AB - The present study investigates how dissolved organic matter (DOM) alters copper bioavailability at environmentally relevant concentrations (1-5 microg/L of dissolved copper, 1-4 mg/L of dissolved organic copper). A methodology combining two biological endpoints (short-term and steady-state bioaccumulation of copper by the aquatic moss Fontinalis antipyretica) and a sampling of labile copper with diffusion gradient in thin films (DGT) is proposed for batch experiments conducted with mineral water and various DOM, ethylenediaminetetra-acetic acid (EDTA), humic acid, and natural Seine River (France) extracts (hydrophobic and transphilic fractions). All types of DOM reduce the bioavailability of copper to aquatic mosses, and this reduction was more pronounced for the short-term biological endpoint, which was taken as being representative for environmental exposure. Labile copper sampled with DGT made it possible to estimate short-term bioaccumulation in the case of EDTA and natural Seine River extracts. With humic acid solutions, however, labile copper was lower than bioavailable copper. This result suggests that at realistic metal concentrations and with certain types of natural DOM, bioavailable copper might comprise not only inorganic copper but also some weak organic complexes. Hence, labile copper, in situ sampled with DGT, might not systematically overestimate bioavailable copper, as suggested previously on the basis of in vitro toxicity studies. PMID- 18444695 TI - Differential metallothionein induction patterns in fed and starved carp (Cyprinus carpio) during waterborne copper exposure. AB - Starved and fed carp (Cyprinus carpio) were exposed to sublethal waterborne copper exposure (1 microM) for 28 d in softened Antwerp, Belgium, city tap water. Copper accumulation in liver and gill tissues was determined, and changes in branchial Na+/K+-adenosine 5'-triphosphatase (ATPase) activity and metallothionein (MT) induction in gill and liver tissues were investigated following 28-d copper exposure. Gill Na+/K+-ATPase activity in exposed fish, both starved and fed, was at its lowest values after 3 d of exposure, after which it slowly recovered to preexposure values. No significant differences in branchial Na+/K+-ATPase activity were found between starved and fed fish. Copper accumulation in the liver and gills of the exposed starved carp was significantly higher than that in the exposed fed carp. The highest MT induction was found in liver tissues. Different patterns of MT induction were observed in the starved and fed carp during copper exposure. Before exposure, MT concentrations in the livers of the starved fish were significantly higher than those in the fed ones. Copper exposure significantly increased MT concentration in the liver of the fed fish, but no changes occurred in the starved fish. In contrast, copper exposure increased MT concentrations in the gills of the starved fish during the first week of exposure, whereas only a slight increase in MT concentration in the gills of the fed fish was observed. When taking into account the role of feeding status in MT induction, hepatic MT was a more relevant indicator for long-term monitoring of copper pollution in carp, but gill MT provided useful information regarding short-term copper toxicity. PMID- 18444696 TI - Butyltin accumulation in two marine bivalves along a pollution gradient. AB - In the present study, we describe a field survey regarding the effect of ambient water conditions in the accumulation of tributyltin (TBT) and its metabolites in green mussels (Perna viridis) and Pacific oysters (Crassostrea gigas). The results showed that following the changes in TBT pollution levels, the accumulation of butyltins exhibited clear differences between oysters and mussels. The ratio of TBT to total butyltin (TBT:SigmaBT) decreased from 0.87 to 0.31 with increasing TBT burdens in the oysters. This status suggests that following the increases of TBT burdens, the metabolic rates of TBT were clearly enhanced in oysters; however, this phenomenon was not shown in mussels. The TBT:SigmaBT remained relatively constant at approximately 0.7 in the mussels despite the TBT burdens. Because of this phenomenon, the opposite status of different TBT burdens between oysters and mussels were present at different TBT pollution levels. These observations may provide valuable insight when evaluating or comparing TBT pollution in the environment using oysters and/or mussels as bioindicators. PMID- 18444697 TI - Mercury correlations among six tissues for four waterbird species breeding in San Francisco Bay, California, USA. AB - Despite a large body of research concerning mercury (Hg) in birds, no single tissue has been used consistently to assess Hg exposure, and this has hampered comparisons across studies. We evaluated the relationships of Hg concentrations among tissues in four species of waterbirds (American avocets [Recurvirostra americana], black-necked stilts [Himantopus mexicanus], Caspian terns [Hydroprogne caspia; formerly Sterna caspia], and Forster's terns [Sterna forsteri]) and across three life stages (prebreeding adults, breeding adults, and chicks) in San Francisco Bay, California, USA. Across species and life stages, Hg concentrations (least square mean +/- standard error) were highest in head feathers (6.45 +/- 0.31 microg/g dry wt) and breast feathers (5.76 +/- 0.28 microg/g dry wt), followed by kidney (4.54 +/- 0.22 microg/g dry wt), liver (4.43 +/- 0.21 microg/g dry wt), blood (3.10 +/- 0.15 microg/g dry wt), and muscle (1.67 +/- 0.08 microg/g dry wt). Relative Hg distribution among tissues, however, differed by species and life stage. Mercury concentrations were highly correlated among internal tissues (r2 > or = 0.89). Conversely, the relationships between Hg in feathers and internal tissues were substantially weaker (r2 < or = 0.42). Regression slopes sometimes differed among species and life stages, indicating that care must be used when predicting Hg concentrations in one tissue based on those in another. However, we found good agreement between predictions made using a general tissue-prediction equation and more specific equations developed for each species and life stage. Finally, our results suggest that blood is an excellent, nonlethal predictor of Hg concentrations in internal tissues but that feathers are relatively poor indicators of Hg concentrations in internal tissues. PMID- 18444698 TI - Paint solvent to food additive: an environmental route of dehalogenation for 4 chlorobenzotrifluoride. AB - In an effort to reduce volatile organic compounds (VOCs) in paint solvents, replacements containing non-VOC compounds have been proposed. One such compound is 4-chlorobenzotrifluoride (CBTF), for which environmental fate studies have not been conducted. The objective of the present study was to determine the products of the atmospheric oxidation of CBTF and the aqueous fate of these products. Smog chamber experiments were performed to measure the kinetics and mechanism of atmospheric oxidation. A rate constant of 2.22 (+/-0.30) x 10(-13) cm3 molecule( 1) s(-1) was determined for the reaction of hydroxyl radicals with CBTF in 700 Torr of air at 296 K. Using offline sampling and gas chromatography coupled to mass spectroscopic analysis, it was determined that 2-chloro-5 trifluoromethylphenol (o-CTFP) was the primary product of CBTF atmospheric oxidation. Aqueous photolysis of o-CTFP in deionized water proceeded at a rate of 1.3 (+/-0.1) x 10(-4) s(-1), corresponding to a half-life of 1.5 +/- 0.1 h and a quantum yield of 6.6 (+/-0.4) x 10(-4). The mechanism of photolysis was investigated using liquid chromatography coupled to tandem mass spectrometry, which suggested that degradation of o-CTFP occurred via photonucleophilic displacement of chlorine, followed by photoinduced hydrolysis of the trifluoromethyl group to yield 3,4-dihydroxybenzoic acid (an approved food additive considered to be nontoxic). PMID- 18444699 TI - Influence of lake characteristics on the biomagnification of persistent organic pollutants in lake trout food webs. AB - The biomagnification of polychlorinated biphenyls (PCBs) and major organochlorine pesticides (OCPs) was studied using lake trout (Salvelinus namaycush) and other food web organisms collected from 17 lakes in Canada and the northeastern United States between 1998 and 2001. Whole lake trout (n = 357) concentrations of the sum (Sigma) of 57 PCB congeners ranged between 1.67 and 2,890 ng/g wet weight (median 61.5 ng/g wet wt). Slimy sculpin had the highest mean concentrations of SigmaPCB of all forage fish (32-73 ng/g wet wt). Positive relationships between log (lipid wt) concentrations of PCB congener 153, PCB congener 52, p,p' dichlorodiphenyldichloroethylene, hexachlorobenzene, cis-chlordane, trans nonachlor, or dieldrin and trophic level (determined using stable nitrogen isotope ratios) were found for most of the 17 food webs, indicating biomagnification of these PCBs and OCPs. The p,p' dichlorodiphenyldichloroethylene had the highest trophic magnification factors (TMFs) of the 14 individual compounds studied, averaging 4.0 +/- 1.8 across the 17 lakes, followed by trans-nonachlor (3.6 +/- 1.5) and PCB congener 153 (3.4 +/- 1.2). Average TMFs for 14 individual PCBs or OCPs were significantly correlated with log octanol-water partition coefficient, implying that the rate of accumulation along the food web is dependent on hydrophobicity and recalcitrance. Significant correlations (p < 0.05) were found between TMFs of SigmaPCBs, hexachlorobenzene, alpha-hexachlorocyclohexane, and lindane and lake area, latitude, and longitude, but not for 11 other PCBs or OCPs. Overall, the results of the present study show that biomagnification of PCBs and most OCPs, as measured by TMFs, is only weakly influenced by such factors as latitude and longitude. Exceptions are hexachlorocyclohexane isomers and hexachlorobenzene, which had generally greater TMFs in northern lakes, possibly due to lower rates of elimination and biotransformation in the food web. PMID- 18444700 TI - Developmental reversals in false memory: a review of data and theory. AB - Can susceptibility to false memory and suggestion increase dramatically with age? The authors review the theoretical and empirical literatures on this counterintuitive possibility. Until recently, the well-documented pattern was that susceptibility to memory distortion had been found to decline between early childhood and young adulthood. That pattern is the centerpiece of much expert testimony in legal cases involving child witnesses and victims. During the past 5 years, however, several experiments have been published that test fuzzy-trace theory's prediction that some of the most powerful forms of false memory in adults will be greatly attenuated in children. Those experiments show that in some common domains of experience, in which false memories are rooted in meaning connections among events, age increases in false memory are the rule and are sometimes accompanied by net declines in the accuracy of memory. As these experiments are strongly theory-driven, they have established that developmental improvements in the formation of meaning connections are necessary and sufficient to produce age increases in false memory. PMID- 18444703 TI - Determinants of linear judgment: a meta-analysis of lens model studies. AB - The mathematical representation of E. Brunswik's (1952) lens model has been used extensively to study human judgment and provides a unique opportunity to conduct a meta-analysis of studies that covers roughly 5 decades. Specifically, the authors analyzed statistics of the "lens model equation" (L. R. Tucker, 1964) associated with 249 different task environments obtained from 86 articles. On average, fairly high levels of judgmental achievement were found, and people were seen to be capable of achieving similar levels of cognitive performance in noisy and predictable environments. Further, the effects of task characteristics that influence judgment (numbers and types of cues, inter-cue redundancy, function forms and cue weights in the ecology, laboratory versus field studies, and experience with the task) were identified and estimated. A detailed analysis of learning studies revealed that the most effective form of feedback was information about the task. The authors also analyzed empirically under what conditions the application of bootstrapping--or replacing judges by their linear models--is advantageous. Finally, the authors note shortcomings of the kinds of studies conducted to date, limitations in the lens model methodology, and possibilities for future research. PMID- 18444702 TI - Not all emotions are created equal: the negativity bias in social-emotional development. AB - There is ample empirical evidence for an asymmetry in the way that adults use positive versus negative information to make sense of their world; specifically, across an array of psychological situations and tasks, adults display a negativity bias, or the propensity to attend to, learn from, and use negative information far more than positive information. This bias is argued to serve critical evolutionarily adaptive functions, but its developmental presence and ontogenetic emergence have never been seriously considered. The authors argue for the existence of the negativity bias in early development and that it is evident especially in research on infant social referencing but also in other developmental domains. They discuss ontogenetic mechanisms underlying the emergence of this bias and explore not only its evolutionary but also its developmental functions and consequences. Throughout, the authors suggest ways to further examine the negativity bias in infants and older children, and they make testable predictions that would help clarify the nature of the negativity bias during early development. PMID- 18444705 TI - The role of the media in body image concerns among women: a meta-analysis of experimental and correlational studies. AB - Research suggests that exposure to mass media depicting the thin-ideal body may be linked to body image disturbance in women. This meta-analysis examined experimental and correlational studies testing the links between media exposure to women's body dissatisfaction, internalization of the thin ideal, and eating behaviors and beliefs with a sample of 77 studies that yielded 141 effect sizes. The mean effect sizes were small to moderate (ds = -.28, -.39, and -.30, respectively). Effects for some outcome variables were moderated by publication year and study design. The findings support the notion that exposure to media images depicting the thin-ideal body is related to body image concerns for women. PMID- 18444704 TI - Structural priming: a critical review. AB - Repetition is a central phenomenon of behavior, and researchers have made extensive use of it to illuminate psychological functioning. In the language sciences, a ubiquitous form of such repetition is structural priming, a tendency to repeat or better process a current sentence because of its structural similarity to a previously experienced ("prime") sentence (J. K. Bock, 1986). The recent explosion of research in structural priming has made it the dominant means of investigating the processes involved in the production (and increasingly, comprehension) of complex expressions such as sentences. This review considers its implications for the representation of syntax and the mechanisms of production and comprehension and their relationship. It then addresses the potential functions of structural priming, before turning to its implications for first language acquisition, bilingualism, and aphasia. The authors close with theoretical and empirical recommendations for future investigations. PMID- 18444706 TI - Prospective memory impairment in individuals with Parkinson's disease. AB - This study investigated prospective memory and its relationship to executive and memory functions in persons with Parkinson's disease (PD). Twenty-three individuals with PD and 25 healthy comparison participants participated in the study. In the prospective memory tasks, participants were asked to execute 3 actions after 20 min (time-based condition) or after a timer ring (event-based condition). A score was computed for the correct recall of the intention to perform the actions (prospective component) and for the correct execution of the actions (retrospective component). Participants with PD also received an extensive neuropsychological test battery. PD participants were less accurate than comparison participants in the prospective component of the time-based but not the event-based task. Individuals with PD were also impaired on the retrospective component of both tasks. In the PD group, a general trend toward significant correlations was found between performance level on the prospective memory component of the time-based task and scores on executive and working memory measures. These results document that prospective memory is impaired in PD possibly in relation to a dysregulation of cognitive functions associated with frontal systems. PMID- 18444707 TI - Children's event-related potentials of auditory selective attention vary with their socioeconomic status. AB - Past research suggests a link between socioeconomic status (SES) and brain processes in children, but direct evidence from neuroimaging is scarce. The authors investigated the relationships among SES, performance, and the neural correlates of auditory selective attention, by comparing event-related potentials (ERPs) in lower- and higher-SES preadolescent children during a task in which they attended to two types of pure tones but ignored two other types. Our hypothesis was that, at comparable performance levels, higher-SES children ignore distracters (the unattended, irrelevant tones) while lower-SES children attend equally to distracters and to targets (the attended, relevant tones). The authors found that ERP waveform differences between attended and unattended tones (Nd, difference negativity) were significant in the higher-SES but not in the lower SES group. However, the groups did not differ in reaction times or accuracy. Electroencephalographic power analysis revealed a differential pattern of theta activity concomitant with irrelevant tones for the two groups, indicating that although they performed similarly the children from these groups recruited different neural processes. Lower-SES children, the authors suggest, deployed supplementary resources to also attend to irrelevant information. PMID- 18444709 TI - Second-order facial information processing in schizophrenia. AB - This study investigated the processing of second-order relational face information in schizophrenia. Twenty-eight schizophrenic patients and 28 controls were asked to say whether the space between the eyes was the same in 2 side-by side faces. The 2 faces were derived from the same original face, but the spacing between the eyes was either the same or differed by various distances. The results showed that schizophrenic patients needed a space that was twice as great as controls to see a difference. The authors conclude that schizophrenic patients have a deficit in processing second-order relational face information. PMID- 18444708 TI - The structure of intelligence in children and adults with high functioning autism. AB - Confirmatory factor analyses of the commonly used 11 subtests of the Wechsler child and adult intelligence scales were accomplished for 137 children and 117 adults with high functioning autism (HFA) and for comparable age groups from the standardization samples contained in the Wechsler manuals. The objectives were to determine whether the structure of intelligence in HFA groups was similar to that found in the normative samples, and whether a separate "social context" factor would emerge that was unique to HFA. Four-factor models incorporating a Social Context factor provided the best fit in both the autism and normative samples, but the subtest intercorrelations were generally lower in the autism samples. Findings suggest similar organization of cognitive abilities in HFA, but with the possibility of underconnectivity or reduced communication among brain regions in autism. PMID- 18444710 TI - Cognitive, clinical, and functional characteristics of verbally superior schizophrenia patients. AB - The existence of small numbers of schizophrenia patients with superior ability in specific cognitive domains is implied by meta-analytic evidence as well as by occasional empirical reports. The authors identified 25 patients with superior (i.e., > or =90th percentile) ability on the Vocabulary subtest of the Wechsler Adult Intelligence Scale 3rd edition (Wechsler, 1997). These cognitively advantaged patients were compared with 22 healthy participants performing at the superior level and with 126 schizophrenia patients and 50 healthy participants scoring below the superior range. Verbally superior schizophrenia patients and verbally superior healthy participants had similar cognitive profiles and life skills performance, but diverged markedly in terms of independent "real-world" functioning. Verbally superior patients significantly outperformed more typical patients in other aspects of cognitive performance, life skills, and support requirements. However, severity of positive and negative symptoms was equivalent in the patient groups. Detailed biobehavioral study of cognitively exceptional patients may offer new insights into mechanisms mediating psychotic disorders. PMID- 18444711 TI - Executive functioning in children with attention-deficit/hyperactivity disorder: combined type with and without a stimulant medication history. AB - Behavioral and neuropsychological functioning in unmedicated children with attention-deficit/hyperactivity disorder (ADHD) who have a history of medication treatment (Rx) versus those who are treatment naive (TN) has, to our knowledge, not been previously studied. Ninety-four children in four groups (ADHD/Rx, ADHD/TN, learning disabilities [LD], and controls) were evaluated, while unmedicated, on measures of achievement, neuropsychological functioning, and behavior. The ADHD/Rx group performed significantly better than the TN group on writing, Stroop interference, and measures of attention, and performed as well as the control group on executive functioning, verbal working memory, and academics. Behaviorally, the ADHD groups showed more difficulty with mood and externalizing behaviors compared with the LD and control groups, with the ADHD/TN performing the most poorly. Findings suggest that the ADHD/Rx group shows better executive and academic functioning even when unmedicated. PMID- 18444712 TI - Corpus callosum morphology in children and adolescents with attention deficit hyperactivity disorder: a meta-analytic review. AB - Several studies have examined corpus callosum (CC) morphology in children and adolescents with attention deficit hyperactivity disorder (ADHD). A meta-analysis of atypical brain morphology in children and adolescents with ADHD by Valera, Faraone, Murray, and Seidman (2006) reported a reduction in the splenium of the CC in this group compared with healthy controls. This meta-analysis undertook a more detailed examination of callosal morphology by also considering comorbid conditions and gender differences. The data from 13 studies were analyzed. Consistent with Valera et al. (2006), the splenium was smaller in children and adolescents with ADHD than in healthy controls. However, this result appears to be the result of a smaller splenium in females with ADHD. In addition, boys exhibited a smaller rostral body. There were no significant differences in CC measurements of studies that included ADHD samples with comorbid conditions. However, comorbidities were not consistently reported, making it difficult to accurately evaluate the impact of comorbidity on CC size. Additional research is needed to investigate whether gender differences reflect different ADHD subtypes. In addition, it is not known if these CC differences persist into adulthood. PMID- 18444713 TI - Examining the relationship between degree of handedness and degree of cerebral lateralization for processing facial emotion. AB - This paper examines the relationship between degree of handedness and degree of cerebral lateralization on a task of processing positive facial emotion in right handed individuals. Three hundred and thirteen right-handed participants (157 women) were given two behavioral tests of lateralization: a handedness questionnaire and a chimeric faces test. Two further handedness measures were taken: familial left-handedness and writing posture. Regression analysis showed that both degree of handedness and sex were predictive of degree of lateralization. Individuals who were strongly right-handed were also more strongly lateralized to the right hemisphere for the task. Men were more strongly lateralized than women. Data were reanalyzed for men and women separately. The relationship between handedness and lateralization remained for men only. Neither familial left-handedness nor writing posture were associated with cerebral lateralization for men or women. The results suggest a positive relationship between degree of handedness and degree of cerebral lateralization, and further that there is a sex difference in this relationship. PMID- 18444714 TI - Correlates of social problem solving during the first year after traumatic brain injury in children. AB - Effects of pediatric traumatic brain injury (TBI) on social problem-solving were examined in a longitudinal study of 103 children with moderate-to-severe TBI (n = 52) or orthopedic injury (OI; n = 51) using the Interpersonal Negotiation Strategies task (INS). Children solved age-appropriate hypothetical social conflicts, with responses for four problem-solving steps scored by developmental level. The OI group performed better than the TBI group, but rate of change in performance over time did not differ between groups, suggesting improvement in children with TBI was not due to recovery from injury. Strong relations between INS performance and memory and language skills emerged, but emotional processing was only weakly related to INS performance. Frontal focal lesions influenced INS performance in younger (but not older) children with TBI. Diffusion tensor imaging (DTI), revealed strong relationships between the INS and increased apparent diffusion coefficient (ADC) measures indexing connectivity in the dorsolateral and cingulate regions in both TBI and OI groups, and in the temporal and parietal regions in the TBI group. These findings inform studies of social problem-solving skills during the first year post TBI. (PsycINFO Database Record (c) 2008 APA, all rights reserved). PMID- 18444715 TI - Central perceptual load does not reduce ipsilesional flanker interference in parietal extinction. AB - In healthy individuals, filtering of distractors improves when the perceptual difficulty, or load, of a central task increases. Following an earlier study by Lavie and Robertson (2001), this study examined whether increasing the perceptual load of a visual discrimination task attenuates the influence of ipsilesional and contralesional distractors in patients with spatial extinction. The authors used a flanker task in which participants identified a central target letter flanked by congruent, incongruent, or neutral distractors in the left and right hemifields. Perceptual load was manipulated by positioning the central target letter above or below a hash mark (#) in the low-load condition, or a letter ("R") in the high-load condition. Target identification was significantly more difficult under high load than low load. Despite this difference in task difficulty, the interference from incongruent flankers was equivalent across the two load conditions, for both contralesional and ipsilesional flankers. Our results suggest that perceptual load does not attenuate the distracting influence of ipsilesional stimuli. Rather, selectivity is strongly influenced by the strength of representations in brain areas that code salience across the visual field. PMID- 18444716 TI - Visual hallucinations in schizophrenia: confusion between imagination and perception. AB - OBJECTIVE: An association between hallucinations and reality-monitoring deficit has been repeatedly observed in patients with schizophrenia. Most data concern auditory/verbal hallucinations. The aim of this study was to investigate the association between visual hallucinations and a specific type of reality monitoring deficit, namely confusion between imagined and perceived pictures. METHOD: Forty-one patients with schizophrenia and 43 healthy control participants completed a reality-monitoring task. Thirty-two items were presented either as written words or as pictures. After the presentation phase, participants had to recognize the target words and pictures among distractors, and then remember their mode of presentation. RESULTS: All groups of participants recognized the pictures better than the words, except the patients with visual hallucinations, who presented the opposite pattern. The participants with visual hallucinations made more misattributions to pictures than did the others, and higher ratings of visual hallucinations were correlated with increased tendency to remember words as pictures. No association with auditory hallucinations was revealed. CONCLUSIONS: Our data suggest that visual hallucinations are associated with confusion between visual mental images and perception. PMID- 18444717 TI - On the perception of sarcasm in dichotic listening. AB - The purpose of the present study was to investigate the processing of sincere and sarcastic statements by the cerebral hemispheres. Forty right-handed students were asked to localize sincere and sarcastic statements presented dichotically. Participants either indicated the ear that perceived the sarcastic statement or the ear that perceived the sincere statement in counterbalanced blocks of trials. As expected, results revealed a left ear advantage for sarcastic statements and a right ear advantage for sincere statements. In addition, participants showed faster response time when localizing targets (both sarcastic and sincere) to the left ear compared to the right. Finally, a significant negative correlation between laterality effects in the two tasks provided support for causal hemispheric complementarity. Results are discussed with reference to the contribution of the right and left hemispheres to language processing. Their implications for models of sarcasm perception are also discussed. PMID- 18444718 TI - Exploring the structure of a neuropsychological battery across healthy elders and those with questionable dementia and Alzheimer's disease. AB - An exploratory factor analysis (EFA) and a series of confirmatory factor analyses were conducted on 17 variables designed to assess different cognitive abilities in a sample of healthy older adults. In the EFA, 4 factors emerged corresponding to language, memory, processing speed, and fluid ability constructs. The results of the confirmatory factor analyses suggested that a 5-factor model with an additional Attention factor improved the fit. The invariance of the 5-factor model was examined across 3 groups: a group of cognitively healthy older adults, a group of patients diagnosed with questionable dementia (QD), and a group of patients diagnosed with probable Alzheimer's disease (AD). Results of the invariance analysis suggest that the model may have configural invariance across the 3 groups but not metric invariance. Specifically, preliminary analyses suggest that the memory construct may represent something different in the QD and AD groups as compared to the healthy older adult group, consistent with the underlying pathology in early AD. PMID- 18444719 TI - Emotional and motivational changes after bilateral lesions of the globus pallidus. AB - This study investigated motivational changes in a 44 year-old man (PJ) who developed considerable reduction in spontaneous activity and speech, flat affect, social withdrawal, loss of interest, inability to "feel," and lack of concern regarding his medical condition after bilateral, focal, anoxic lesions of the globus pallidus. PJ and 30 male controls performed a task designed to parse hedonic evaluation, or liking, from incentive motivation, or wanting. Affective stimuli were presented on a computer screen and subjects controlled viewing time by pressing keys. PJ's liking and wanting of unpleasant stimuli was similar to that of controls. In response to pleasant stimuli, PJ showed normal ratings of wanting and hedonic appreciation, but significantly reduced viewing time or made no responses. Active withdrawal from liked stimuli could constitute the basic mechanism underlying poor motivation and social withdrawal associated with globus pallidus damage. PMID- 18444721 TI - Siblings of children with severe emotional disturbances: risks, resources, and adaptation. AB - This study examines risks, resources, and adjustment among siblings of children with severe emotional disturbances (SED) involved in an initiative to develop family centered Systems of Care in North Carolina. These siblings experience many of the same risks as the children who have been diagnosed with SED (i.e., "targets"), but have received relatively little attention from the system or researchers. This first systematic study of these siblings describes an early sample (n = 56), compares them to their system-identified brothers and sisters, and explores contextual factors related to sibling resources and adjustment. Findings suggest the siblings, much like the targets: (a) have been exposed to extremely high levels of adversity, and (b) evidence substantial variability in behavioral and emotional strengths and social-emotional adjustment. Although many siblings exhibit significant strengths and positive adjustment, a substantial proportion displays levels of competencies or problem behaviors on par with those targeted to receive services. Factors associated with positive sibling adjustment are consistent with those identified in prior risk and resilience work. Additional systematic study of these children could have implications for service delivery and preventive interventions. PMID- 18444722 TI - Behavioral outcomes for substance-exposed adopted children: fourteen years postadoption. AB - From a life course perspective, studies of cumulative disadvantage often identify early risk factors as predictors of poor outcomes. This study examined the influence of prenatal substance exposure on children's externalizing behaviors at 14 years postadoption. Using Wave 4 data from the California Long-Range Adoption Study, the authors employed growth curve modeling to examine behavioral trajectories of 275 children as influenced by foster care status, age at adoption, and gender. Outcomes are measured using a shortened Behavioral Problem Index. Prenatal exposure predicted elevated behavior problems that increased normatively compared with nonexposed children, and were not found to trigger the negative behavior sequelae once feared. Foster children tended to fare better over the life course than those adopted through other means, except for children adopted at older ages. Adopted children's problem behaviors may be directly associated with the success of their placements. The authors discuss implications for practice and future research. PMID- 18444723 TI - Ego development, psychopathology, and parenting problems in substance-abusing mothers. AB - The authors examined maternal ego development in relation to psychopathology and parenting problems in a sample of substance abusing mothers. Given predilections at higher levels of ego development for introspection and guilt, the authors expected mothers at higher levels to report more psychopathology. Given predilections at lower levels of ego development for dichotomous perceptions and limited conceptions of causation, the authors expected mothers at low levels to report more problematic parenting behaviors. Intelligence was expected to correlate but not overlap with ego development. Subjects were 182 mothers who expressed interest in a randomized clinical trial for a new parenting intervention. Measures included the Washington University Sentence Completion Task--Short Form, the Parental Acceptance-Rejection Questionnaire, the Brief Symptom Inventory and the Kaufman Brief Intelligence Test. Results of correlation and multivariate analyses of variance confirmed predictions. Implications for future development of interventions for substance abusing mothers are discussed. PMID- 18444724 TI - Beyond treatment effects: comorbid psychopathologies and long-term outcomes among substance-abusing delinquents. AB - Secondary analyses of a randomized clinical trial controlled for treatment condition effects and examined the impact of comorbid psychopathologies on the mental health, physical health, and criminal behavior of 80 substance abusing delinquents approximately 5 years later in emerging adulthood. Overall, emerging adults with a comorbid disorder during adolescence scored higher on psychopathology, criminal behavior, and health problems. Participants with both internalizing and externalizing disorders exhibited more negative outcomes than those with a comorbid externalizing disorder. For the entire sample, more internalizing diagnoses forecasted higher internalizing and aggression scores, more criminality, and poorer physical health. More externalizing disorders predicted higher internalizing, delinquency, and criminality scores, but was unrelated to physical health. More internalizing diagnoses for females but not males predicted greater criminality, and especially more aggressive crimes in emerging adulthood. PMID- 18444725 TI - Addressing economic stress in the treatment of depression. AB - This study investigates the importance of addressing issues of economic stress in standardized treatments for major depression. Using a sample from the National Institute of Mental Health Treatment of Depression Collaborative Research Program, the study found high levels of patient introduction of economic stress topics, with relatively high levels of therapist approach of this material. There was significant evidence for a positive association between therapist approach of these economic stress topics and outcome. There was very little evidence for socioeconomic status differences in any of these findings. PMID- 18444726 TI - Relationship network quality: adolescent adjustment and perceptions of relationships with parents and friends. AB - Early, mid-, and late adolescents (N = 406) from an ethnically diverse community completed questionnaires describing positive and negative features of relationships with their mothers, fathers, and same-sex best friends. School grades, self-reported adjustment problems, and self-worth differed as a function of both the number of relationships that adolescents described as high on positive features and the number of relationships that adolescents described as high on negative features. Adolescents with relationships that were uniformly good quality (i.e., high on positive features and low on negative features) were better adjusted than adolescents with relationships that were uniformly poor quality (i.e., low on positive features and high on negative features). The results failed to support the proposition that a single high quality relationship buffers against suboptimal levels of support in other relationships. PMID- 18444727 TI - The permanence of family ties: implications for youth transitioning from foster care. AB - Research on the experiences of youth leaving foster care as they enter adulthood has noted that they often reconnect, and sometimes live with, members of their family of origin. This is often thought to be a curious finding because at some earlier point, the families were deemed unsafe, requiring removal of the child to foster care. Although this finding has been consistent, it has not been the central focus of a research study and, therefore, its implications have been largely unexamined. In this article, the authors review what is known about the extent to which young adults reunite with their families after they leave foster care. To provide guidance in thinking further about former foster youth reuniting with their families, the authors also examine research and theoretical literature on family development and family transition. Implications for research, policy, and practice are identified. PMID- 18444728 TI - Child internalizing and externalizing behavior as predictors of age at first admission and risk for repeat admission to a child inpatient facility. AB - Gaining a better understanding of the types of child symptomatology that predict age at first admission and risk for readmission to a child psychiatric inpatient facility could help to inform the focus of intervention. Accordingly, the current study examined whether internalizing and externalizing behavior problems, alone or in combination, were associated with age at first admission and risk for repeat admission. Analyses were based on a sample of 372 children (M = 9.13 years, SD = 1.91) admitted to an acute psychiatric inpatient facility. Internalizing behavior was associated with a later age at admission, but unrelated to repeat admission. Externalizing behavior was associated with an earlier age at admission and increased risk for repeat admission. Co-occurring internalizing and externalizing behavior problems were associated with increased risk for repeat admission, but were unrelated to age at first admission. Implications for findings are discussed. PMID- 18444729 TI - Violence exposure across multiple contexts: individual and joint effects on adjustment. AB - This study examined the relationship between violence exposure in three different contexts (home, school, and community) and internalizing and externalizing outcomes in early adolescents. We modeled both context-specific and cumulative effects of exposure to violence. After controlling for a number of risk factors associated with violence exposure, violent incidents encountered at school and at home were consistently related to multiple outcomes. Violence exposure in the community was related only to aggressive fantasies but not to other externalizing or internalizing problems. High levels of violence exposure in the community attenuated the relationship between home violence and internalizing symptoms and school violence and externalizing problems. Cumulative exposure to violence was related to all aspects of adjustment, but the number of contexts in which violence occurred did not predict beyond the effects of cumulative exposure. Finally, high levels of cumulative violence exposure were associated with a plateau or decrease in emotional distress. PMID- 18444730 TI - Mental health in Japanese members of the United Nations peacekeeping contingent in the Golan Heights: effects of deployment and the Middle East situation. AB - This study evaluates the mental health of Japan Self-Defense Force (JSDF) members of the peacekeeping contingent in the Golan Heights before and since the Second Gulf War between 1998 and 2003. Before the war, the General Health Questionnaire 30 (GHQ30) scores during and after duty tended to be lower than those before duty; all scores were lower than those of adult Japanese men in general. After the war, GHQ30 scores did not significantly change between before, during, and after duty. Manifest Anxiety Scale (MAS) scores were not significantly different between groups. Stressors identified included problems with foreign language and familial matters at home. Post war stressors included work content and relationships with collaborating foreign army units. These findings suggest that the mental health of contingent members remained stable, with some variation in mental health conditions influenced by the situation in the Middle East. This study suggests that the stable mental condition of JSDF personnel during their deployment in the absence of combat, and that this could be enhanced by education about mental health issues and by providing counseling support to their families. PMID- 18444731 TI - Parents' experience and meaning construction of the loss of a child in a national terror attack. AB - This paper describes a qualitative study aimed at exploring the meanings that are given by parents to the loss of their children in terror attacks in Israel and examining how specific aspects of these meanings help or hinder them in coping with the loss. This paper focuses the collective context of loss, a theme that emerged from in-depth interviews with 16 bereaved parents who lost their children in different terror attacks. The collective context of loss includes three subthemes: (a) the loss in the context of Jewish and Israeli history; (b) assigning responsibility for the loss; and (c) using the collective meaning in the process of coping. Overall, the findings highlight the role of the sociocultural context in the bereavement process. The discussion raises possible explanations for the significance of this role, focusing on the reciprocal processes between the bereaved parents and society, which are functional and effective for both. PMID- 18444732 TI - Cumulative trauma and posttraumatic stress disorder among children exposed to the 9/11 World Trade Center attack. AB - Two and one-half years after the September 11, 2001 World Trade Center attack, 204 middle school students in an immigrant community located near Ground Zero were assessed for posttraumatic stress disorder (PTSD) symptoms as influenced by "dose" of exposure to the attack and accumulated lifetime traumas. Ninety percent of students reported at least one traumatic event other than 9/11 (e.g., community violence) with an average of 4 lifetime events reported. An interaction was obtained such that the dose-response effect depended on presence of other traumas. Among students with the lowest number of additional traumas, the usual dose-response pattern of increasing PTSD symptoms with increasing 9/11 exposure was observed; among those with medium to high cumulative life trauma, PTSD symptoms were substantially higher and uniformly so regardless of 9/11 exposure dose. Results suggest that traumas that precede or follow mass violence often have as much as if not greater impact on long-term symptom severity than high dose exposure to the event. Implications regarding the presence of continuing or previous trauma exposure for postdisaster and early intervention policies are discussed. PMID- 18444733 TI - Psychological distress and adjustment of Vietnamese refugees in the United States:Association with pre- and postmigration factors. AB - The purpose of this study was to examine how pre- and postmigration factors affect the psychological distress and adjustment for a community sample of Vietnamese refugees resettled in the United States. The sample included a substantial proportion of ex-political detainees who experienced a particularly large number of traumatic events prior to migration. Additionally, the study assessed postmigration experiences using multidimensional and bidirectional measures of acculturation to the Vietnamese and American cultures and measures of satisfaction with social support from like-ethnic and host culture network members. Psychological adjustment and distress were assessed with depression, anxiety, alienation, and life satisfaction. Findings show that premigration traumatic experiences predicted only measures of anxiety. The other measures of adjustment and distress were predicted by postmigration factors, including acculturation and social support. In sum, findings suggest that different psychological outcomes are predicted by different pre- and postmigration factors, suggesting that adjustment is a complex process that involves multiple indicators and dimensions. Significant differences were also found between ex-political detainees and other Vietnamese refugees suggesting the importance of considering their unique experience. PMID- 18444734 TI - International Family, Adult, and Child Enhancement Services (FACES): a community based comprehensive services model for refugee children in resettlement. AB - The development of evidence-based mental health interventions for refugees is complicated by the cultural and linguistic diversity of the participants, and the need to balance treatment of past traumatic experiences with ongoing support during the process of acculturation. In an effort to gather "practice-based evidence" from existing mental health services for refugees, a collaborative study of International Family, Adult, and Child Enhancement Services (FACES), a comprehensive, community-based mental health program working with refugee children, was conducted to describe the program participants and service delivery model and to assess whether participants improved over time as a function of services. Results showed that participants improved, but that the improvement was not related to dosage of services. Implications of these findings for refugee mental health services are discussed and suggestions are made for future evaluation research of mental health services with refugees. PMID- 18444735 TI - Lifetime and 12-month intermittent explosive disorder in Latinos. AB - This study examined the occurrence, correlates, and psychiatric co-morbidities of lifetime and 12-month intermittent explosive disorder (IED) and whether impairment due to IED differed across Latino groups. We used data on 2,554 Latino adults (75.5% response rate) from the National Latino and Asian American Study (NLAAS). Lifetime and 12-month prevalence of IED among Latinos were 5.8% and 4.1%, respectively. Unemployment was a common risk factor for both lifetime and 12-month IED. Protective factors for both lifetime and 12-month IED were having poor/fair English proficiency and being born outside the U.S. mainland. Cubans, Mexicans and other Latinos had lower odds of both lifetime and 12-month IED relative to Puerto Ricans, while Puerto Ricans with IED did not demonstrate worse impairment compared with the other groups with IED. Lifetime and 12-month IED were associated with several depressive, anxiety, and substance use disorders. Given its significant association with a wide-range of mental disorders, future research should consider the validity of IED as a unique disorder or whether it is merely a constellation of symptoms that accompanies a variety of mental diseases. PMID- 18444736 TI - Hedonic tone and activation level in the mood-creativity link: toward a dual pathway to creativity model. AB - To understand when and why mood states influence creativity, the authors developed and tested a dual pathway to creativity model; creative fluency (number of ideas or insights) and originality (novelty) are functions of cognitive flexibility, persistence, or some combination thereof. Invoking work on arousal, psychophysiological processes, and working memory capacity, the authors argue that activating moods (e.g., angry, fearful, happy, elated) lead to more creative fluency and originality than do deactivating moods (e.g., sad, depressed, relaxed, serene). Furthermore, activating moods influence creative fluency and originality because of enhanced cognitive flexibility when tone is positive and because of enhanced persistence when tone is negative. Four studies with different mood manipulations and operationalizations of creativity (e.g., brainstorming, category inclusion tasks, gestalt completion tests) support the model. PMID- 18444737 TI - Judgments of the lucky across development and culture. AB - For millennia, human beings have believed that it is morally wrong to judge others by the fortuitous or unfortunate events that befall them or by the actions of another person. Rather, an individual's own intended, deliberate actions should be the basis of his or her evaluation, reward, and punishment. In a series of studies, the authors investigated whether such rules guide the judgments of children. The first 3 studies demonstrated that children view lucky others as more likely than unlucky others to perform intentional good actions. Children similarly assess the siblings of lucky others as more likely to perform intentional good actions than the siblings of unlucky others. The next 3 studies demonstrated that children as young as 3 years believe that lucky people are nicer than unlucky people. The final 2 studies found that Japanese children also demonstrate a robust preference for the lucky and their associates. These findings are discussed in relation to M. J. Lerner's (1980) just-world theory and J. Piaget's (1932/1965) immanent-justice research and in relation to the development of intergroup attitudes. PMID- 18444738 TI - How to heat up from the cold: examining the preconditions for (unconscious) mood effects. AB - What are the necessary preconditions to make people feel good or bad? In this research, the authors aimed to uncover the bare essentials of mood induction. Several induction techniques exist, and most of these techniques demand a relatively high amount of cognitive capacity. Moreover, to be effective, most techniques require conscious awareness. The authors proposed that the common and defining element in all effective mood induction techniques is the dominating salience of evaluative tone over descriptive meaning. This evaluative-tone hypothesis was tested in two paradigms in which the evaluative meaning of the "primed" concept was more salient than its descriptive meaning (i.e., when subliminal stimulus exposure was so short that mainly the evaluative meaning was activated [see D. A. Stapel, W. Koomen, & K. I. Ruys, 2002] and when the primed concepts were sufficiently extreme such that evaluative meaning always dominated descriptive meaning). Explicit and implicit mood measures showed that the activation of a dominating evaluative tone affected people's mood states. Implications of these findings for theories on unconscious mood induction are discussed. PMID- 18444739 TI - Forming implicit and explicit attitudes toward individuals: social group association cues. AB - The authors explored how social group cues (e.g., obesity, physical attractiveness) strongly associated with valence affect the formation of attitudes toward individuals. Although explicit attitude formation has been examined in much past research (e.g., S. T. Fiske & S. L. Neuberg, 1990), in the current work, the authors considered how implicit as well as explicit attitudes toward individuals are influenced by these cues. On the basis of a systems of evaluation perspective (e.g., R. J. Rydell & A. R. McConnell, 2006; R. J. Rydell, A. R. McConnell, D. M. Mackie, & L. M. Strain, 2006), the authors anticipated and found that social group cues had a strong impact on implicit attitude formation in all cases and on explicit attitude formation when behavioral information about the target was ambiguous. These findings obtained for cues related to obesity (Experiments 1 and 4) and physical attractiveness (Experiment 2). In Experiment 3, parallel findings were observed for race, and participants holding greater implicit racial prejudice against African Americans formed more negative implicit attitudes toward a novel African American target person than did participants with less implicit racial prejudice. Implications for research on attitudes, impression formation, and stigma are discussed. PMID- 18444740 TI - Maintaining sexual desire in intimate relationships: the importance of approach goals. AB - Three studies tested whether adopting strong (relative to weak) approach goals in relationships (i.e., goals focused on the pursuit of positive experiences in one's relationship such as fun, growth, and development) predict greater sexual desire. Study 1 was a 6-month longitudinal study with biweekly assessments of sexual desire. Studies 2 and 3 were 2-week daily experience studies with daily assessments of sexual desire. Results showed that approach relationship goals buffered against declines in sexual desire over time and predicted elevated sexual desire during daily sexual interactions. Approach sexual goals mediated the association between approach relationship goals and daily sexual desire. Individuals with strong approach goals experienced even greater desire on days with positive relationship events and experienced less of a decrease in desire on days with negative relationships events than individuals who were low in approach goals. In two of the three studies, the association between approach relationship goals and sexual desire was stronger for women than for men. Implications of these findings for maintaining sexual desire in long-term relationships are discussed. PMID- 18444741 TI - Receiving support as a mixed blessing: evidence for dual effects of support on psychological outcomes. AB - Although social support is thought to boost feelings of closeness in dyadic relationships, recent findings have suggested that support receipt can increase distress in recipients. The authors investigated these apparently contrary findings in a large daily diary study of couples over 31 days leading up to a major stressor. Results confirm that daily support receipt was associated with greater feelings of closeness and greater negative mood. These average effects, however, masked substantial heterogeneity. In particular, those recipients showing greater benefits on closeness tended to show lesser cost on negative mood, and vice versa. Self-esteem was examined as a possible moderator of support effects, but its role was evident in only a subset of recipients. These results imply that models of dyadic support processes must accord a central role to between-individual heterogeneity. PMID- 18444742 TI - Nomina sunt omina: on the inductive potential of nouns and adjectives in person perception. AB - Six studies (N = 491) investigated the inductive potential of nouns versus adjectives in person perception. In the first 5 studies, targets were either described by an adjective (e.g., Mark is homosexual) or by the corresponding noun (e.g., Mark is a homosexual) or by both (Study 3). The authors predicted and found that nouns, more so than adjectives, (a) facilitate descriptor-congruent inferences but inhibit incongruent inferences (Studies 1-3), (b) inhibit alternative classifications (Study 4), and (c) imply essentialism of congruent but not of incongruent preferences (Study 5). This was supported for different group memberships and inclinations (athletics, arts, religion, sexual preference, drinking behavior, etc.), languages (Italian and German), and response formats, suggesting that despite the surface similarity of nouns and adjectives, nouns have a more powerful impact on person perception. Study 6 investigated the inverse relationship, showing that more essentialist beliefs (in terms of a genetic predisposition rather than training) lead speakers to use more nouns and fewer adjectives. Possible extensions of G. R. Semin and K. Fiedler's (1988) linguistic category model and potential applications for language use in intergroup contexts are discussed. PMID- 18444743 TI - Taking the easy way out: preference diversity, decision strategies, and decision refusal in groups. AB - It has often been argued and found that preference diversity is beneficial for the quality of group decisions. However, this literature has neglected the fact that in many situations, it is also possible not to choose. Further, preference diversity can be based on attractions, aversions, or both. The authors argue that some types of preference diversity can lead to biased discussions and choice refusal (i.e., the group refuses to choose any of the available options). In a laboratory experiment, three different patterns were observed. When group members held different aversions before discussion, discussions were aversion driven and group members quickly agreed to refuse all alternatives. When each alternative had both a proponent and an adversary, discussions were longer and unbiased but still often led to refusal, which was accompanied by relatively low levels of outcome satisfaction. Only when preference diversity was based only on attractions did it lead to unbiased discussion, low prevalence of refusal, and high outcome satisfaction. Implications for group decision making are discussed. PMID- 18444744 TI - Distinguishing between silent and vocal minorities: not all deviants feel marginal. AB - People's opinions can deviate from that of the average group member in two ways. Descriptive deviants diverge from the average group attitude in a direction consistent with the desirable group attitude; prescriptive deviants diverge from the average group attitude in a direction inconsistent with the desirable group attitude. Three studies tested the hypothesis that descriptive deviants are more willing to express their opinions than either nondeviants or prescriptive deviants. Study 1 found that college students reported more comfort in expressing descriptive deviant opinions because descriptive deviance induced feelings of superior conformity (i.e., being "different but good"). Study 2 found that descriptive deviants reported more pride after expressing their opinions, were rated as more proud by an observer, and were more willing to publicize their opinions. Study 3 showed that political bumper stickers with descriptive deviant messages were displayed disproportionately more frequently than were those with prescriptive deviant messages. PMID- 18444745 TI - Making choices impairs subsequent self-control: a limited-resource account of decision making, self-regulation, and active initiative. AB - The current research tested the hypothesis that making many choices impairs subsequent self-control. Drawing from a limited-resource model of self-regulation and executive function, the authors hypothesized that decision making depletes the same resource used for self-control and active responding. In 4 laboratory studies, some participants made choices among consumer goods or college course options, whereas others thought about the same options without making choices. Making choices led to reduced self-control (i.e., less physical stamina, reduced persistence in the face of failure, more procrastination, and less quality and quantity of arithmetic calculations). A field study then found that reduced self control was predicted by shoppers' self-reported degree of previous active decision making. Further studies suggested that choosing is more depleting than merely deliberating and forming preferences about options and more depleting than implementing choices made by someone else and that anticipating the choice task as enjoyable can reduce the depleting effect for the first choices but not for many choices. PMID- 18444747 TI - Societal threat, authoritarianism, conservatism, and U.S. state death penalty sentencing (1977-2004). AB - On the basis of K. Stenner's (2005) authoritarian dynamic theory, it was hypothesized that the number of death sentences and executions would be higher in more threatened conservative states than in less threatened conservative states, and would be lower in more threatened liberal states than in less threatened liberal states. Threat was based on state homicide rate, violent crime rate, and non-White percentage of population. Conservatism was based on state voter ideological identification, Democratic and Republican Party elite liberalism conservatism, policy liberalism-conservatism, religious fundamentalism, degree of economic freedom, and 2004 presidential election results. For 1977-2004, with controls for state population and years with a death penalty provision, the interactive hypothesis received consistent support using the state conservatism composite and voter ideological identification alone. As well, state conservatism was related to death penalties and executions, but state threat was not. The temporal stability of the findings was demonstrated with a split-half internal replication using the periods 1977-1990 and 1991-2004. The interactive hypothesis and the results also are discussed in the context of other threat authoritarianism theories and terror management theory. PMID- 18444746 TI - Adolescent personality moderates genetic and environmental influences on relationships with parents. AB - In contrast with early theories of socialization that emphasized the role of parents in shaping their children's personalities, recent empirical evidence suggests an evocative relationship between adolescent personality traits and the quality of the parent-adolescent relationship. Research using behavior genetic methods suggests that the association between personality and parenting is genetically mediated, such that the genetic effects on adolescent personality traits overlap with the genetic effects on parenting behavior. In the current study, the authors examined whether the etiology of this relationship might change depending on the adolescent's personality. Biometrical moderation models were used to test for gene- environment interaction and correlation between personality traits and measures of conflict, regard, and involvement with parents in a sample of 2,452 adolescents (M age = 17.79 years). They found significant moderation of both positive and negative qualities of the parent-adolescent relationship, such that the genetic and environmental variance in relationship quality varied as functions of the adolescent's levels of personality. These findings support the importance of adolescent personality in the development of the quality of the parent-adolescent relationship. PMID- 18444748 TI - How to say no: single- and dual-process theories of short-term recognition tested on negative probes. AB - Three experiments with short-term recognition tasks are reported. In Experiments 1 and 2, participants decided whether a probe matched a list item specified by its spatial location. Items presented at study in a different location (intrusion probes) had to be rejected. Serial position curves of positive, new, and intrusion probes over the probed location's position were mostly parallel. Serial position curves of intrusion probes over their position of origin were again parallel to those of positive probes. Experiment 3 showed largely parallel serial position effects for positive probes and for intrusion probes plotted over positions in a relevant and an irrelevant list, respectively. The results support a dual-process theory in which recognition is based on familiarity and recollection, and recollection uses 2 retrieval routes, from context to item and from item to context. PMID- 18444749 TI - Stereotypes and retrieval-provoked illusory source recollections. AB - When expectations and stereotypes are activated at retrieval, they spontaneously create distorted and illusory recollections that are consistent with these expectations. Participants studied doctor (physician)-related and lawyer-related statements that were presented by 2 different people. When informed, on a subsequent source memory test, (i.e., of who presented what) that one of the study sources was actually a doctor and the other source was a lawyer, there was a strong tendency to attribute the test items in a stereotype-consistent manner. In 3 experiments, participants frequently reported recollecting specific details, such as via "remember" judgments, to justify their stereotype-consistent but incorrect responses. These experiments rule out explanations involving either the misattribution of strong familiarity or differences in the bias to making remember responses as accounts for the illusory source attributions. Instead, the illusory recollections are consistent with the notion that recollective experience is manufactured from both the information in the memory trace and information in the retrieval environment, such as an individual's expectations, stereotypes, and general knowledge. PMID- 18444750 TI - Working memory costs of task switching. AB - Although many accounts of task switching emphasize the importance of working memory as a substantial source of the switch cost, there is a lack of evidence demonstrating that task switching actually places additional demands on working memory. The present study addressed this issue by implementing task switching in continuous complex span tasks with strictly controlled time parameters. A series of 4 experiments demonstrate that recall performance decreased as a function of the number of task switches and that the concurrent load of item maintenance had no influence on task switching. These results indicate that task switching induces a cost on working memory functioning. Implications for theories of task switching, working memory, and resource sharing are addressed. PMID- 18444751 TI - On the additive effects of stimulus quality and word frequency in lexical decision: evidence for opposing interactive influences revealed by RT distributional analyses. AB - The joint effects of stimulus quality and word frequency in lexical decision were examined in 4 experiments as a function of nonword type (legal nonwords, e.g., BRONE, vs. pseudohomophones, e.g., BRANE). When familiarity was a viable dimension for word-nonword discrimination, as when legal nonwords were used, additive effects of stimulus quality and word frequency were observed in both means and distributional characteristics of the response-time distributions. In contrast, when the utility of familiarity was undermined by using pseudohomophones, additivity was observed in the means but not in distributional characteristics. Specifically, opposing interactive effects in the underlying distribution were observed, producing apparent additivity in means. These findings are consistent with the suggestion that, when familiarity is deemphasized in lexical decision, cascaded processing between letter and word levels is in play, whereas, when familiarity is a viable dimension for word nonword discrimination, processing is discrete. PMID- 18444752 TI - The Stroop effect: why proportion congruent has nothing to do with congruency and everything to do with contingency. AB - The item-specific proportion congruent (ISPC) effect refers to the observation that the Stroop effect is larger for words that are presented mostly in congruent colors (e.g., BLUE presented 75% of the time in blue) and smaller for words that are presented mostly in a given incongruent color (e.g., YELLOW presented 75% of the time in orange). One account of the ISPC effect, the modulation hypothesis, is that participants modulate attention based on the identity of the word (i.e., participants allow the word to influence responding when it is presented mostly in its congruent color). Another account, the contingency hypothesis, is that participants use the word to predict the response that they will need to make (e.g., if the word is YELLOW, then the response is probably "orange"). Reanalyses of data from L. L. Jacoby, D. S. Lindsay, and S. Hessels (2003), along with results from new experiments, are inconsistent with the modulation hypothesis but entirely consistent with the contingency hypothesis. A response threshold mechanism that uses contingency information provides a sufficient account of the data. PMID- 18444753 TI - Learning correct responses and errors in the Hebb repetition effect: two faces of the same coin. AB - In a serial recall task, the Hebb repetition effect occurs when recall performance improves for a sequence repeated throughout the experimental session. This phenomenon has been replicated many times. Nevertheless, such cumulative learning seldom leads to perfect recall of the whole sequence, and errors persist. Here the authors report evidence that there is another side to the Hebb repetition effect that involves learning errors produced in a repeated sequence. A learning measure based on past recalls (correct or incorrect) shows that the probability of a given response increases with the number of prior occurrences of that response. The pattern of results reveals another manifestation of the Hebb repetition effect and speaks to the nature of implicit learning. PMID- 18444754 TI - The impact of stimulus and response variability on S-R correspondence effects. AB - Six experiments investigated how variability on irrelevant stimulus dimensions and variability on response dimensions contribute to spatial and nonspatial stimulus-response (S-R) correspondence effects. Experiments 1-3 showed that, when stimuli varied in location and number, S-R correspondence effects for location or numerosity occurred when responses varied on these dimensions but not when responses were invariant on these dimensions. These results are consistent with the response-discrimination account, according to which S-R correspondence effects should only arise for a dimension that is used for discriminating between responses in working memory. Experiments 4-6 showed that, when responses varied in location and number, both invariant and variable stimulus number produced correspondence effects in S-R numerosity. In summary, the present results indicate that the usefulness of a particular dimension for response discrimination can be sufficient for producing S-R correspondence effects, whereas variability of a stimulus dimension is not sufficient for producing such effects. PMID- 18444755 TI - Bidirectional associations in multiplication memory: conditions of negative and positive transfer. AB - A variety of experimental evidence indicates that the memory representation for multiplication facts (e.g., 6 x 9 = 54) incorporates bidirectional links with a forward association from factors to product and a reverse association from product to factors. Surprisingly, the authors did not find evidence in Experiment 1 of facilitative transfer-of-practice from multiplication (6 x 9 = ?) to factoring (54 = ? x ?); in fact, multiplication practice produced item-specific interference with factoring. Similarly, the authors found no evidence in Experiment 2 that repetition of specific factoring problems (54 = ? x ?) facilitated performance of corresponding multiplication problems (6 x 9 = ?). In Experiment 3, participants practiced both multiplication and factoring and presented facilitative transfer in both directions. Thus, bidirectional facilitation occurred if both operations were practiced, but interference occurred when only one operation was practiced. We propose that this seemingly paradoxical behavior occurs because it is adaptive for the bidirectional retrieval structure to retain operational flexibility in the context of practicing both operations, whereas it is adaptive to specialize the memory representation for the practiced operation (i.e., factoring or multiplication) when only one operation is practiced. PMID- 18444756 TI - Revisiting evidence for modularity and functional equivalence across verbal and spatial domains in memory. AB - The authors revisited evidence in favor of modularity and of functional equivalence between the processing of verbal and spatial information in short term memory. This was done by investigating the patterns of intrusions, omissions, transpositions, and fill-ins in verbal and spatial serial recall and order reconstruction tasks under control, articulatory suppression, and spatial tapping conditions. The authors observed that when tasks were fully equated, all patterns of errors were equivalent between the verbal and spatial domains. Moreover, articulatory suppression interfered more with the verbal memory tasks than with the spatial memory tasks. This interference was mostly due to an increase of omissions and transpositions. Similarly, tapping was more disruptive of spatial memory than of verbal memory tasks and affected primarily the number of omissions and transpositions. The patterns of errors and their interaction with interference are discussed in light of the predominant approaches to modeling memory and provide a rich set of data for modeling efforts. PMID- 18444757 TI - A simplified conjoint recognition paradigm for the measurement of gist and verbatim memory. AB - The distinction between verbatim and gist memory traces has furthered the understanding of numerous phenomena in various fields, such as false memory research, research on reasoning and decision making, and cognitive development. To measure verbatim and gist memory empirically, an experimental paradigm and multinomial measurement model has been proposed but rarely applied. In the present article, a simplified conjoint recognition paradigm and multinomial model is introduced and validated as a measurement tool for the separate assessment of verbatim and gist memory processes. A Bayesian metacognitive framework is applied to validate guessing processes. Extensions of the model toward incorporating the processes of phantom recollection and erroneous recollection rejection are discussed. PMID- 18444758 TI - Conceptual coherence affects phonological activation of context objects during object naming. AB - In 4 picture-word interference experiments, speakers named a target object that was presented with a context object. Using auditory distractors that were phonologically related or unrelated either to the target object or the context object, the authors assessed whether phonological processing was confined to the target object or not. Phonological activation of the context objects was reliably observed if the target and context objects were embedded in a conceptually coherent scene (e.g., if the picture showed a mouse eating some cheese), regardless of whether the target was cued by its thematic role (agent vs. patient) or by color. However, this activation dissipated if the two objects were presented in an arbitrary object array (e.g., if the cheese was presented along with a finger). These findings suggest that conceptual coherence among multiple objects affects the information flow in the conceptual-lexical system during speech planning. PMID- 18444760 TI - Speed and accuracy of accessing information in working memory: an individual differences investigation of focus switching. AB - Three experiments examined the nature of individual differences in switching the focus of attention in working memory. Participants performed 3 versions of a continuous counting task that required successive updating and switching between counts. Across all 3 experiments, individual differences in working memory span and fluid intelligence were related to the accuracy of the counts, but not to the time cost associated with switching between counts. The authors suggest that working memory span and fluid intelligence measures partially index the ability to accurately switch information in and out of the focus of attention, but this variation is not related to the speed of switching. PMID- 18444759 TI - Spatial memory during progressive disorientation. AB - Human spatial representations of object locations in a room-sized environment were probed for evidence that the object locations were encoded relative not just to the observer (egocentrically) but also to each other (allocentrically). Participants learned the locations of 4 objects and then were blindfolded and either (a) underwent a succession of 70 degrees and 200 degrees whole-body rotations or (b) were fully disoriented and then underwent a similar sequence of 70 degrees and 200 degrees rotations. After each rotation, participants pointed to the objects without vision. Analyses of the pointing errors suggest that as participants lost orientation, represented object directions generally "drifted" off of their true directions as an ensemble, not in random, unrelated directions. This is interpreted as evidence that object-to-object (allocentric) relationships play a large part in the human spatial updating system. However, there was also some evidence that represented object directions occasionally drifted off of their true directions independently of one another, suggesting a lack of allocentric influence. Implications regarding the interplay of egocentric and allocentric information are considered. PMID- 18444761 TI - Supramodality effects in visual and haptic spatial processes. AB - In this article, the authors investigated unimodal and cross-modal processes in spatial working memory. A number of locations had to be memorized within visual or haptic matrices according to different experimental conditions known to be critical in accounting for the effects of perception on imagery. Results reveal that some characteristics of the generated mental image remained strictly inherent to the modality in which information was acquired; in general, accuracy was higher when configurations were visually rather than haptically explored (Experiments 1 and 3). Interestingly, the same pattern emerged when the effects of simultaneous versus sequential processing of the stimuli inherent to vision and haptics were isolated from perceptual modality (Experiment 2). Supramodal elements were also identified (Experiment 3) that were specifically associated to the nature of the cognitive processes, regardless of the original characteristics of the sensory information. These data indicate that both unimodal modality specific and higher order supramodal mechanisms are simultaneously used in spatial processes. PMID- 18444762 TI - Feedback consistency effects in visual and auditory word recognition: where do we stand after more than a decade? AB - The role of phonology-to-spelling consistency (i.e., feedback consistency) was investigated in 3 lexical decision experiments in both the visual and auditory modalities in French and English. No evidence for a feedback consistency effect was found in the visual modality, either in English or in French, despite the fact that consistency was manipulated for different kinds of units (onsets and rimes). In contrast, robust feedback consistency effects were obtained in the auditory lexical decision task in both English and French when exactly the same items that produced a null effect in the visual modality were used. Neural network simulations are presented to show that previous demonstrations of feedback consistency effects in the visual modality can be simulated with a model that is not sensitive to feedback consistency, suggesting that these effects might have come from various confounds. These simulations, together with the authors' results, suggest that there are no feedback consistency effects in the visual modality. In contrast, such effects are clearly present in the auditory modality. Given that orthographic information is absent from current models of spoken word recognition, the present findings present a major challenge to these models. PMID- 18444763 TI - Attention and implicit memory in the category-verification and lexical decision tasks. AB - Prior research on implicit memory appeared to support 3 generalizations: Conceptual tests are affected by divided attention, perceptual tasks are affected by certain divided-attention manipulations, and all types of priming are affected by selective attention. These generalizations are challenged in experiments using the implicit tests of category verification and lexical decision. First, both tasks were unaffected by divided-attention tasks known to impact other priming tasks. Second, both tasks were unaffected by a manipulation of selective attention in which colored words were either named or their colors identified. Thus, category verification, unlike other conceptual tasks, appears unaffected by divided attention, and some selective-attention tasks, and lexical decision, unlike other perceptual tasks, appears unaffected by a difficult divided attention task and some selective-attention tasks. Finally, both tasks were affected by a selective-attention task in which attention was manipulated across objects (rather than within objects), indicating some susceptibility to selective attention. The results contradict an analysis on the basis of the conceptual perceptual distinction and other more specific hypotheses but are consistent with the distinction between production and identification priming. PMID- 18444764 TI - List context fosters semantic processing: parallels between semantic and morphological facilitation when primes are forward masked. AB - The authors examined patterns of facilitation under forward-masked priming conditions across 3 list contexts (Experiments 1-3) that varied with respect to properties of filler trials -- (a) mixed (morphological, orthographic, semantic), (b) identity, and (c) semantic -- but held the relatedness proportion constant (75%). Facilitation for targets that were related morphologically to their prime occurred regardless of filler context, but facilitation for semantically related pairs occurred only in the context of identity and semantic fillers. Facilitation was absent for orthographically similar prime-target pairs in all 3 filler contexts when matching numbers of orthographically similar word-word and word nonword prime-target pairs rendered orthographic similarity uninformative with respect to lexicality of the target. Enhanced semantic and morphological facilitation in the context of identity and semantic relative to mixed fillers support a semantically attuned, as contrasted with a purely form-based, account of early morphological processing. PMID- 18444765 TI - The time course of object-feature retrieval in recognition. AB - The time course of perception and retrieval of object features was investigated. Participants completed a perceptual matching task and 2 recognition tasks under time pressure. The recognition tasks imposed different retention loads. A stochastic model of feature sampling with a Bayesian decision component was used to estimate the rate of feature perception and the rate of retrieval of feature information. The results demonstrated that retrieval rates did not differ among object features if only a single object was held in memory. If 2 objects were retained in memory, differences among retrieval rates of features emerged, indicating that features that were quickly perceived were also quickly retrieved. The results from the 2-object retention condition are compatible with process reinstatement models of retrieval. PMID- 18444766 TI - Attention orienting effects of hesitations in speech: evidence from ERPs. AB - Filled-pause disfluencies such as um and er affect listeners' comprehension, possibly mediated by attentional mechanisms (J. E. Fox Tree, 2001). However, there is little direct evidence that hesitations affect attention. The current study used an acoustic manipulation of continuous speech to induce event-related potential components associated with attention (mismatch negativity [MMN] and P300) during the comprehension of fluent and disfluent utterances. In fluent cases, infrequently occurring acoustically manipulated target words gave rise to typical MMN and P300 components when compared to nonmanipulated controls. In disfluent cases, where targets were preceded by natural sounding hesitations culminating in the filled pause er, an MMN (reflecting a detection of deviance) was still apparent for manipulated words, but there was little evidence of a subsequent P300. This suggests that attention was not reoriented to deviant words in disfluent cases. A subsequent recognition test showed that nonmanipulated words were more likely to be remembered if they had been preceded by a hesitation. Taken together, these results strongly implicate attention in an account of disfluency processing: Hesitations orient listeners' attention, with consequences for the immediate processing and later representation of an utterance. PMID- 18444767 TI - Response bias in "remembering" emotional stimuli: a new perspective on age differences. AB - Older adults sometimes show a recall advantage for emotionally positive, rather than neutral or negative, stimuli (S. T. Charles, M. Mather, & L. L. Carstensen, 2003). In contrast, younger adults respond "old" and "remember" more often to negative materials in recognition tests. For younger adults, both effects are due to response bias changes rather than to enhanced memory accuracy (S. Dougal & C. M. Rotello, 2007). We presented older and younger adults with emotional and neutral stimuli in a remember-know paradigm. Signal-detection and model-based analyses showed that memory accuracy did not differ for the neutral, negative, and positive stimuli, and that "remember" responses did not reflect the use of recollection. However, both age groups showed large and significant response bias effects of emotion: Younger adults tended to say "old" and "remember" more often in response to negative words than to positive and neutral words, whereas older adults responded "old" and "remember" more often to both positive and negative words than to neutral stimuli. PMID- 18444768 TI - Context-sensitive adjustments of cognitive control: conflict-adaptation effects are modulated by processing demands of the ongoing task. AB - Dynamic adjustments of cognitive control in response to interference from irrelevant stimulus attributes have repeatedly been shown. The purpose of the current research was to investigate how these control adjustments are modulated by the processing demands of a primary task. To this end, the authors combined a primary task (a number comparison task: classifying digits as smaller or larger than 5) with a Simon task. Control adjustments were observed in the form of typical sequential modulations of the Simon effect. In addition, the authors found sequential modulations of the numerical distance effect and an interaction of both effects. Results suggest that not only response conflict due to interference from task-irrelevant features but also processing demands of task relevant features determine the level of control adjustment in the subsequent trial. PMID- 18444769 TI - Clarifying the nature of the distinctiveness by domain interaction in conceptual structure: comment on Cree, McNorgan, and McRae (2006). AB - The conceptual structure account of semantic memory (CSA; L. K. Tyler & H. E. Moss, 2001) claims that feature correlation (the degree to which features co occur) and feature distinctiveness (the number of concepts in which a feature occurs) interact with domains of knowledge (e.g., living vs. nonliving) such that the distinctive features of nonliving things are more highly correlated than the distinctive features of living things. Evidence for (B. Randall, H. E. Moss, J. M. Rodd, M. Greer, & L. K. Tyler, 2004) and against this claim (G. S. Cree, C. McNorgan, & K. McRae, 2006) has been reported. This comment outlines the CSA, discusses Cree et al.'s (2006) critiques of the Randall et al. (2004) experiments and the CSA, and reports new analyses of property norm and behavioral data, which replicate the results reported by Randall et al. (2004). PMID- 18444770 TI - 3-year results of a collaborative school-based oral health program in a remote First Nations community. AB - INTRODUCTION: Surveys of dental health among Aboriginal children in Canada, using scales such as the Decayed, Missing, and Filled Teeth (DMFT) score, indicate that Aboriginal children have 2 to 3 times poorer oral health compared with other populations. A remote First Nations community approached requested assistance in addressing the health of their children. The objective was to work with the community to improve oral health and knowledge among school children. The hypothesis formulated was that after 3 years of the program there would be a significant decrease in dmft/DMFT (primary/permanent) score. METHODS: This was a cross-sectional study of all school-aged children in a small, remote First Nations community. Pre- and post- intervention evaluation of oral health was conducted by a dentist not involved in the study. The intervention consisted of a school-based program with daily brush-ins, fluoride application, educational presentations, and a recognition/incentive scheme. RESULTS: Twenty-six children were assessed prior to the intervention, representing 45% of the 58 children then in the community. All 40 children in the community were assessed following the intervention. Prior to the intervention, 8% of children were cavity free. Following 3 years of the intervention, 32% were cavity free. Among the 13 children assessed both pre- and post-intervention, dmft/DMFT score improved significantly (p <0.005). The visiting hygienist noted increased knowledge about oral health. CONCLUSION: A community- and university-supported, school-based, collaborative oral health program improved oral health and knowledge among children in a remote First Nations community. PMID- 18444771 TI - In this issue. Mental health literacy. PMID- 18444772 TI - Have broad-based community and professional education programs influenced mental health literacy and treatment seeking of those with major depression and suicidal ideation? AB - Mental health literacy is the knowledge and beliefs about mental disorders that aid in their recognition, management, or prevention; it is also a determinant of help seeking. As such, it is presumed to be important in community suicide prevention programs. In Australia there have been a number of government, professional, and charitable organizations as well as pharmaceutical company suicide prevention initiatives which have been designed to enhance public and professional knowledge about mental disorders, particularly depression. This naturalistic study conducted between 1998 and 2004 in a random and representative population sample examined the changes in mental health literacy and treatment seeking of those with major depression, both with and without suicidal ideation, and those who were neither depressed nor suicidal. Results indicated that there was marked improvement in mental health literacy for all three groups, although there was less change for those most in need of intervention (i.e., those with major depression and suicidal ideation). Furthermore, there were fewer changes in appropriate treatment seeking in those with major depression and suicidal ideation. These findings are consistent with literature reporting limited problem solving and decision making in those who are suicidal, and indicate that there are limits to broadbased community education programs. More focused suicide prevention initiatives are required, specifically for those who are depressed and suicidal. PMID- 18444773 TI - Mortality of geriatric and younger patients with schizophrenia in the community. AB - Little is known about the differences in mortality among non-institutionalized geriatric and younger patients with schizophrenia. In this study long-term mortality and suicidal behavior of all the geriatric (age > or = 65 years), middle-age (age 41-64 years), and young (age 15-40 years) subjects with schizophrenia living in a Chinese rural community were compared. A 10 year follow up investigation among a 1994 cohort (n = 510) of patients with schizophrenia was conducted in Xinjin County, Chengdu, China. Compared with young subjects, geriatric subjects with schizophrenia were more likely to be female, have more previous physical illness, never accepted treatment, and practice religious (p < or = 0.01). There were no significant differences of suicide attempts among the three groups. Young subjects had a higher rate of suicide (1,033.8 per 100,000 person-years), and geriatric subjects had a higher rate of deaths due to other causes (accident and natural causes) (4,314.2 per 100,000 person-years). Standardized mortality ratios for both suicide and deaths due to other causes were highest in young subjects and the lowest in geriatric subjects. Patients with schizophrenia in all age groups had a marked increase in mortality and suicide. Specific intervention strategies for decreasing mortality and suicide should be developed for patients with schizophrenia in different age groups. PMID- 18444774 TI - Prevalence, course, incidence, and 1-year prediction of deliberate self-harm and suicide attempts in early Norwegian school adolescents. AB - In this survey of early Norwegian school adolescents, the prevalence, course, and incidence of self-harm behavior with or without suicide intent were examined, in addition to predictors of self-harm for a 1-year follow-up period. Lifetime prevalence rates of self-harm without suicide intent and suicide attempts were 2.9% and 3.0%, respectively, while 1-year incidence rates were 3.6% and 1.7%, respectively. In multivariate analysis, five predictors significantly differentiated self-harmers from non-self-harming adolescents. Early school adolescents having frequent or intense suicidal ideation over an extended time period and attempting self-harm repeatedly with or without suicide intent should be identified and offered treatment. PMID- 18444775 TI - Peer victimization, depression, and suicidiality in adolescents. AB - The association between specific types of peer victimization with depression, suicidal ideation, and suicide attempts among adolescents was examined. A self report survey was completed by 2,342 high-school students. Regression analyses indicated that frequent exposure to all types of peer victimization was related to high risk of depression, ideation, and attempts compared to students not victimized. Infrequent victimization was also related to increased risk, particularly among females. The more types of victimization the higher the risk for depression and suicidality among both genders. Specific types of peer victimization are a potential risk factor for adolescent depression and suicidality. It is important to assess depression and suicidality among victimized students in order to develop appropriate intervention methods. PMID- 18444776 TI - Assessing the effects of peer suicide on youth suicide. AB - Using data from all waves of the National Longitudinal Survey of Adolescent Health, we investigated the short-term and long-term impact of an adolescent friend's suicide on an adolescent's depression and suicidality. Results suggest that a friend's suicide is associated with heightened suicide thoughts and attempts and greater depression during the first year after loss. Six years later, analyses show concurrent behaviors most relevant to explain suicidality fluctuations. Findings suggest the importance of therapeutic availability, especially during the first year, for those losing a friend to suicide. PMID- 18444777 TI - Changes in suicide methods in Quebec between 1987 and 2000: the possible impact of bill C-17 requiring safe storage of firearms. AB - This study presents the changes in the overall and firearm suicide rates for Quebec (Canada) before and after Bill C-17, which was implemented to secure safe storage of firearms. It covers 20,009 suicide cases reported to the coroner's office. Interrupted time series analysis is used to compare suicide rates in the two periods. Firearm suicide rates have dropped among males and females, but the downward trends were not significant when compared to those prior to the law. Hanging suicide rates have risen considerably among men and women, but those upward trends did not increase significantly when compared with those preceding the law. The decline in suicide rates involving firearms has not resulted in a parallel decline in overall suicide rates. The analyses suggest that Bill C-17 neither improved the downward trend in firearm suicide, which had already begun before the enactment of the law, nor reduced the upward trend of the overall suicide rate. Correlation analyses between firearm suicide, hanging suicide, and the overall suicide rate suggest that firearm suicide is replaced by hanging suicide among males. PMID- 18444778 TI - Pattern analysis of suicide mortality surveillance data in urban South Africa. AB - The typical circumstances of suicide occurrence in post-apartheid urban South Africa are described. Data comprise suicide cases from all geographical locations (urban municipalities) where an injury surveillance system has full coverage. Typical patterns were identified by means of a classification technique applied to eight variables descriptive of the events, their victims, and the suicide level of the cities. Six suicide mortality patterns were identified, most being race-specific and each associated with particular suicide methods. Preventive strategies should target local communities and specific population subgroups, and be appropriate and responsive to their sociocultural needs. PMID- 18444779 TI - Completed suicide among Sinhalese in Sri Lanka: a psychological autopsy study. AB - Sri Lanka has the one of highest rates of suicide. Important factors associated with suicide were determined via the psychological autopsy approach (which had not been carried out previously in Sri Lanka). Over a 3-month period, in a catchment area, 31 suicides among Sinhalese were identified and 27 were investigated. Males were more likely to commit suicide and alcohol abuse and domestic violence were reported as contributory factors. We found it possible to use psychological autopsy methods to obtain information which can inform planned prevention measures. PMID- 18444780 TI - Religion and spirituality along the suicidal path. AB - The inner experience of spiritual and religious feelings is an integral part of the everyday lives of many individuals. For over 100 years the role of religion as a deterrent to suicidal behavior has been studied in various disciplines. We attempt to systematize the existing literature investigating the relationship between religion/spirituality and suicide in this paper. After an overview of the attitudes of the dominant religions (e.g., Catholicism, Islam, and Buddhism) toward suicide, the three main theories that have speculated regarding the link between religion and suicide are presented: "integration theory" (Durkheim, 1897/1997), "religious commitment theory" (Stack, 1983a; Stark, 1983), and "network theory" (Pescosolido & Georgianna, 1989). Subsequent to this theoretical introduction, we report on studies on religion/spirituality keeping the suicidal path as a reference: from suicidal ideation to nonlethal suicidal behavior to lethal suicidal behavior. Studies presenting indications of religious beliefs as a possible risk factor for suicidal behavior are also presented. The last section reviews possible intervention strategies for suicidal patients and suicide survivors. Indications for future research, such as more studies on nonreligious forms of spirituality and the use of qualitative methodology to achieve a better and deeper understanding of the spiritual dimension of suicidal behavior and treatment, are offered. PMID- 18444781 TI - Brief report: preliminary results of a suicide awareness mass media campaign in Cuyahoga County, Ohio. AB - Little information is currently available concerning the effects of suicide awareness and prevention campaigns. This brief report provides preliminary information about the influence of such a media campaign on the number of suicide related telephone calls to an emergency mental health service in Cuyahoga County, Ohio. Examination of the pattern of calls before, during, and between phases of the campaign suggests that the media campaign significantly increased telephone calls to the emergency service. We provide this information to catalyze similar sharing of data and experiences among those organizations and agencies working to prevent suicide. PMID- 18444782 TI - Fair, reasonable and just versus responsibility. PMID- 18444783 TI - The minimum influences for murine normal joint tissue by novel bactericidal treatment and photodynamic therapy using na-pheophorbide a for septic arthritis. AB - OBJECTIVE: In this study, we examined the effect of photodynamic therapy (PDT) using Na-pheophorbide a (Na-Phde a) on normal joint tissue. BACKGROUND DATA: The treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection is a serious issue. Recently, an experimental in vivo and in vitro model for the inactivation of MRSA by PDT using a photosensitizer, Na-Phde a, has been developed. MATERIALS AND METHODS: The knee joints of mice were injected with 560 or 280 micromol/L of Na-Phde a. Thirty minutes after injection, percutaneous laser irradiation was applied for 5 min using a semiconductor laser (power: 125 mW; wavelength: 664 nm; total energy: 12 J/cm2). The joint perimeter and body weight of the treated mice were monitored, and histological evaluation was also done. RESULTS: Joint swelling was observed up to 3 wk after PDT (p < 0.05). On histology 1 wk post-PDT, the treated knees were found to have inflammatory changes, primarily in synovial tissue. Eight weeks after PDT, the synovitis was no longer present. No significant effects were observed on cartilage, bone marrow, or menisci. CONCLUSIONS: The results of this experiment showed that PDT with Na-Phde a induced arthritis for a short time after treatment. However, this arthritis was reversible, and the PDT did not appear to induce osteoarthritic changes in normal joint tissue. These findings indicate that PDT using Na-Phde a caused minimal but reversible changes in joint tissue, suggesting that it would be a safe and useful treatment for bacterial septic arthritis. PMID- 18444785 TI - Photomedicine and LLLT Literature Watch. PMID- 18444786 TI - Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. AB - Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) after lymphodepletion mediates regression in 50% of patients with metastatic melanoma. In vivo persistence and telomere length of the transferred cells correlate with antitumor response. In an attempt to prolong the in vivo survival of the transferred cells, TILs were genetically engineered to produce interleukin (IL) 2. In vitro, these transduced TILs secreted IL-2 while retaining tumor specificity and exhibited prolonged survival after IL-2 withdrawal. In a phase I/II clinical trial, seven evaluable patients received transduced TILs and one patient experienced a partial response associated with in vivo persistence of IL 2-transduced TILs in circulating lymphocytes. An additional five patients received transduced TILs in conjunction with IL-2 administration. Persistence of IL-2-transduced TILs was observed in three patients, including one partial responder. The transgene DNA as well as vector-derived IL2 mRNA could be detected for 4 months in responding patients. The low response rate in this trial was possibly due to a reduction in telomere length in cells as a result of prolonged in vitro culture. In this study, insertion of the IL-2 gene into antitumor TILs increased their ability to survive after IL-2 withdrawal in vitro but did not increase their in vivo persistence or clinical effectiveness. PMID- 18444787 TI - Acute adrenergic stress inhibits proliferation of murine hematopoietic progenitor cells via p38/MAPK signaling. AB - Acute adrenergic stress is a cause of hematopoietic failure that accompanies severe injury. Although the communication between neuronal and immune system is well documented and catecholamines are known as important regulators of homeostasis, the molecular mechanisms of hematopoietic failure are not well understood. To study the influence of adrenergic stress on hematopoietic progenitor cells (HPCs), which recently have been found to express adrenergic receptors, Lin(-),Sca(+), cells were isolated and treated with alpha- and beta adrenergic agonists in vitro. Indeed, this stimulation resulted in significantly decreased colony formation capacity using granulocyte/macrophage colony-forming unit assays. This decline was dependent on the formation of reactive oxygen species (ROS) and activation of the p38/mitogen-activated protein kinase (MAPK) pathway, since the addition of antioxidants or a p38 inhibitor restored CFU formation. DNA damage by adrenergically induced ROS, however, does not seem to account for the reduction of colonies. Thus, catecholamine/p38/MAPK is identified as a key signal transduction pathway in HPCs besides those dependent on Wnt, Notch, and sonic hedgehog. Furthermore, a well-known target of p38 signaling, p16 is transcriptionally activated after adrenergic stimulation, suggesting that cell cycle arrest might importantly contribute to hematopoietic failure and immune dysfunctions after severe injury. Since increased levels of catecholamines are also observed in other conditions, such as during aging which is linked with decline of immune functions, adrenergic stress might as well contribute to the lowered immune defence in the elderly. PMID- 18444788 TI - Morpho-functional characterization of human mesenchymal stem cells from umbilical cord blood for potential uses in regenerative medicine. AB - Mesenchymal stem cells (MSCs) represent a promising source of progenitor cells having the potential to repair and to regenerate diseased or damaged skeletal tissues. Bone marrow (BM) has been the first source reported to contain MSCs. However, BM-derived cells are not always acceptable, due to the highly invasive drawing and the decline in MSC number and differentiative capability with increasing age. Human umbilical cord blood (UCB), obtainable by donation with a noninvasive method, has been introduced as an alternative source of MSCs. Here human UCB-derived MSCs isolation and morpho-functional characterization are reported. Human UCB-derived mononuclear cells, obtained by negative immunoselection, exhibited either an osteoclast-like or a mesenchymal-like phenotype. However, we were able to obtain homogeneous populations of MSCs that displayed a fibroblast-like morphology, expressed mesenchym-related antigens and showed differentiative capacities along osteoblastic and early chondroblastic lineages. Furthermore, this study is one among a few papers investigating human UCB-derived MSC growth and differentiation on three-dimensional scaffolds focusing on their potential applications in regenerative medicine and tissue engineering. UCB-derived MSCs were proved to grow on biodegradable microfiber meshes; additionally, they were able to differentiate toward mature osteoblasts when cultured inside human plasma clots, suggesting their potential application in orthopedic surgery. PMID- 18444789 TI - Bleach sedimentation: an opportunity to optimize smear microscopy for tuberculosis diagnosis in settings of high prevalence of HIV. AB - BACKGROUND: The purpose of the study was to evaluate the performance and feasibility of tuberculosis diagnosis by sputum microscopy after bleach sedimentation, compared with by conventional direct smear microscopy, in a setting of high prevalence of HIV. METHODS: In a community-based study in Kenya (a population in which 50% of individuals with tuberculosis are infected with HIV), individuals with suspected pulmonary tuberculosis submitted 3 sputum specimens during 2 consecutive days, which were examined by blind evaluation. Ziehl-Neelsen-stained smears were made of fresh specimens and of specimens that were processed with 3.5% household bleach followed by overnight sedimentation. Two different cutoffs for acid-fast bacilli (AFB) per 100 high-power fields (HPF) were used to define a positive smear: >10 AFB/100 HPF and 1 AFB/100 HPF. Four smear-positive case definitions, based on 1 or 2 positive smears with the 1 AFB or 10 AFB cutoff, were used. RESULTS: Of 1879 specimens from 644 patients, 363 (19.3%) and 460 (24.5%) were positive by bleach sedimentation microscopy, compared with 301 (16.0%) and 374 (19.9%) by direct smear microscopy, with use of the 10 AFB/100 HPF (P < .001) and 1 AFB/100 HPF (P < .001) cutoffs, respectively. Regardless of the case definition used, bleach sedimentation microscopy detected significantly more positive cases than did direct smear microscopy: 26.7% (172 of 644) versus 21.7% (140 of 644), respectively, with the case definition of 1 positive smear and the 1 AFB/100 HPF cutoff (P < .001), and 21.4% (138 of 644) versus 18.6% (120 of 644), respectively, with the case definition of 1 positive smear and the 10 AFB/100 HPF cutoff (P < .001). Inter- and intrareader reproducibility were favorable, with kappa coefficients of 0.83 and 0.91, respectively. Bleach sedimentation was relatively inexpensive and was not time consuming. CONCLUSIONS: Bleach sedimentation microscopy is an effective, simple method to improve the yield of smear microscopy in a setting of high prevalence of HIV. Further evaluation of this method, under operational conditions, is urgently needed to determine its potential as a tool for tuberculosis control. PMID- 18444790 TI - Population seroprevalence of human papillomavirus types 6, 11, 16, and 18 in men, women, and children in Australia. AB - BACKGROUND: Representative population-based data on human papillomavirus (HPV) epidemiology are important for public health decision making but are difficult to obtain. Seroepidemiology is a valuable tool, although the relationship between HPV infection and seropositivity is incomplete. METHODS: We obtained a large representative sample using residual diagnostic test serum samples obtained from individuals aged 0-69 years (1247 samples from male patients and 1523 samples from female patients) in Australia. Serum antibody levels to HPV types 6, 11, 16, and 18 were measured using an immunoassay. RESULTS: Overall, seroprevalence of HPV types 6 and 16 was higher than seroprevalence of HPV types 11 and 18. Among female patients, peak HPV seropositivity occurred among those who were 30-39 years of age for types 6, 16, and 18 (22%, 22%, and 10.5%, respectively) and among those who were 40-49 years of age for HPV 11 (11.8%). Among male subjects, peak HPV seropositivity occurred among those who were 40-49 years of age for types 6 and 11 (15.4% and 9.1%, respectively) and among those who were 50-59 years of age for types 16 and 18 (14.3% and 8.2%, respectively). No cases of HPV seropositivity were detected in individuals <10 years of age. CONCLUSIONS: Australian seroepidemiological data, showing differing age-specific patterns of HPV seropositivity in male and female patients, are likely to be generalizable to other developed countries and add to other data supporting completion of HPV vaccination before adolescence. PMID- 18444792 TI - Stay it with flora: maintaining vaginal health as a possible avenue for prevention of human immunodeficiency virus acquisition. PMID- 18444791 TI - Telavancin versus vancomycin for the treatment of complicated skin and skin structure infections caused by gram-positive organisms. AB - BACKGROUND: Telavancin is an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action. METHODS: We conducted 2 parallel, randomized, double-blind, active-control, phase 3 studies with a prespecified pooled analysis design. Patients aged > or = 18 years who had complicated skin and skin-structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin (10 mg/kg intravenously every 24 h) or vancomycin (1 g intravenously every 12 h). RESULTS: A total of 1867 patients were randomized and received > or = 1 dose of study medication. In the clinically evaluable population, at 7-14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, -2.1 to 4.6). Methicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, -1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, -0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity. CONCLUSIONS: Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with complicated skin and skin-structure infections, including those infected with methicillin-resistant S. aureus. PMID- 18444793 TI - Improvement of vaginal health for Kenyan women at risk for acquisition of human immunodeficiency virus type 1: results of a randomized trial. AB - BACKGROUND: Vaginal infections are common and have been associated with increased risk for acquisition of human immunodeficiency virus type 1 (HIV-1). METHODS: We conducted a randomized trial of directly observed oral treatment administered monthly to reduce vaginal infections among Kenyan women at risk for HIV-1 acquisition. A trial intervention of 2 g of metronidazole plus 150 mg of fluconazole was compared with metronidazole placebo plus fluconazole placebo. The primary end points were bacterial vaginosis (BV), vaginal candidiasis, trichomoniasis vaginalis (hereafter, "trichomoniasis"), and colonization with Lactobacillus organisms. RESULTS: Of 310 HIV-1-seronegative female sex workers enrolled (155 per arm), 303 were included in the primary end points analysis. A median of 12 follow-up visits per subject were recorded in both study arms (P = .8). Compared with control subjects, women receiving the intervention had fewer episodes of BV (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.49-0.63) and more frequent vaginal colonization with any Lactobacillus species (HR, 1.47; 95% CI, 1.19-1.80) and H(2)O(2)-producing Lactobacillus species (HR, 1.63; 95% CI, 1.16-2.27). The incidences of vaginal candidiasis (HR, 0.84; 95% CI, 0.67 1.04) and trichomoniasis (HR, 0.55; 95% CI, 0.27-1.12) among treated women were less than those among control subjects, but the differences were not statistically significant. CONCLUSIONS: Periodic presumptive treatment reduced the incidence of BV and promoted colonization with normal vaginal flora. Vaginal health interventions have the potential to provide simple, female-controlled approaches for reducing the risk of HIV-1 acquisition. PMID- 18444794 TI - Maternal-fetal DNA admixture is associated with intrapartum mother-to-child transmission of HIV-1 in Blantyre, Malawi. AB - BACKGROUND: The mechanism of mother-to-child transmission (MTCT) of HIV-1 is not well described. METHODS: Of 328 HIV-infected mother-infant pairs, we identified 91 that had discordant angiotensin I-converting enzyme and glutathione S transferase M1 alleles. Maternal alleles in cord blood were quantified with real time polymerase chain reaction, as indicators of microtransfusions. RESULTS: HIV 1 infected infants had more maternal DNA in cord blood than their uninfected counterparts. Increased maternal DNA in cord blood was associated with preterm delivery, low birth weight, and maternal immunosuppression. CONCLUSION: Intrapartum MTCT was associated with placental microtransfusions. The associations among placental microtransfusion, in-utero MTCT, maternal immunosuppression, and poor birth outcome should be further investigated. PMID- 18444795 TI - HIV-1 tropism and survival in vertically infected Ugandan infants. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) may utilize the CXCR4 coreceptor (X4 virus), the CCR5 coreceptor (R5 virus), or both (dual/mixed [DM] virus). We analyzed HIV-1 coreceptor tropism in Ugandan infants enrolled in the HIVNET (HIV Network for Prevention Trials) 012 trial. METHODS: Plasma or serum was analyzed using a commercial coreceptor tropism assay. HIV env subtype was determined by phylogenetic methods. RESULTS: Tropism results were obtained for 57 samples from infants collected 6-14 weeks after birth. Fifty-two infants had only R5 virus, and 5 had either X4 or DM virus. The mothers of those 5 infants also had X4 or DM virus. In infants, subtype D infection was associated with high level infectivity in CCR5-bearing cells and also with the detection of X4 or DM strains. High-level infectivity in CCR5-bearing cells was associated with decreased infant survival, but infection with X4 or DM virus was not. HIV clones from infants with DM viral populations showed different patterns of coreceptor use. V3 loop sequence-based algorithms predicted the tropism of some, but not all, env clones. CONCLUSIONS: Complex patterns of HIV tropism were found in HIV infected newborn infants. Subtype D infection was associated with X4 virus and with high-level replication in CCR5-bearing cells. High-level replication of R5 virus was associated with decreased infant survival. PMID- 18444796 TI - Coinfection with HIV-1 and simian foamy virus in West Central Africans. AB - Frequent infection with zoonotic simian foamy virus (SFV) has been reported among HIV-negative primate hunters in rural Cameroon. Plasma samples obtained from urban commercial sex workers (CSWs; n = 139), patients with sexually transmitted diseases (n = 41), and blood donors (n = 179) in the Democratic Republic of Congo [formerly known as Zaire] and Cameroon were tested for SFV and HIV-1 infection. One CSW and one blood donor were found to be seropositive for both SFV and HIV-1, thereby documenting what are, to our knowledge, the first reported cases of dual SFV and HIV infection. The findings of the present study suggest opportunities for bloodborne and sexual transmission of SFV and highlight the importance of defining the clinical consequences of dual infections. PMID- 18444797 TI - Coinfection with herpes simplex virus type 2 is associated with reduced HIV specific T cell responses and systemic immune activation. AB - BACKGROUND: Chronic coinfection with herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus (HIV) has been associated with an increased HIV viral load and more rapid disease progression, perhaps related to HSV-2 associated alterations in host immunity. METHODS: Studies were nested within (1) a cross-sectional study of men coinfected with HIV and HSV-2 and (2) women not infected with HIV, both before and after HSV-2 acquisition. HSV-2 infection status was determined by ELISA. HIV-specific CD8(+) T cell epitopes were mapped, and proliferation of HIV-specific cells was also assessed. Systemic inflammatory and regulatory T cell populations were assayed by flow cytometry. RESULTS: The breadth of both the HIV-specific CD8(+) T cell interferon-gamma and proliferative responses was reduced in participants coinfected with HIV and HSV-2, independent of the HIV plasma viral load and CD4(+) T cell count, and the magnitude of the responses was also reduced. HSV-2 infection in this group was associated with increased T cell CD38 expression but not with differences in the proportion of CD4(+) FoxP3(+) regulatory T cells. However, in women not infected with HIV, acquisition of HSV-2 was associated with an increase in the proportion of regulatory T cells. CONCLUSIONS: HSV-2 coinfection was associated with reduced HIV-specific T cell responses and systemic inflammation. The immune effects of HSV-2 may underlie the negative impact that this coinfection has on the clinical course of HIV infection. PMID- 18444798 TI - CD8(+) T cell activation in women coinfected with human immunodeficiency virus type 1 and hepatitis C virus. AB - Immune activation is a hallmark of human immunodeficiency virus type 1 (HIV-1) infection and impacts innate and adaptive immunity. Individuals coinfected with HIV-1 and hepatitis C virus (HCV) may have increased immune activation early in HIV disease because of a high HCV antigen load in tissues such as the liver. We evaluated T cell markers of activation and maturation in women with or without HIV-1 infection, by HCV antibody and HCV RNA status. We found increased percentages of activated CD8(+) T cells (i.e., CD8(+)HLA-DR(+)38(+) cells and CD8(+)CD28(+)HLA-DR(+) cells) but not of CD4(+) T cells among women who tested positive for HIV-1, HCV antibody, and HCV RNA, compared with HIV-1-positive women who tested negative for HCV antibody. Because CD8(+) T cell activation is related to HIV-1 disease progression, these data may have implications for the medical management of patients coinfected with HIV-1 and HCV. PMID- 18444799 TI - Humoral and cellular immune responses to a hepatitis B vaccine booster 15-18 years after neonatal immunization. AB - BACKGROUND: Whether hepatitis B (HB) vaccine-conferred immunity persists into adulthood is unknown. We aimed to investigate long-term HB immunity in adolescents. METHODS: In 2004-2005, 6156 high school students (15-21 years old) who had been vaccinated with plasma-derived HB vaccine as infants were recruited for HB seromarker screening. The immune response to an HB vaccine booster was evaluated in 872 subjects who were seronegative. HB surface antibody (anti-HBs) titers and levels of HB surface antigen (HBsAg)-specific interferon (IFN)-gamma- or interleukin (IL)-5-secreting peripheral blood mononuclear cells (PBMCs; measured by enzyme-linked immunospot assay) were determined 4 weeks later. RESULTS: Although the vaccine remained highly efficacious in reducing the HBsAg positivity rate, 63.0% of the vaccinees had no protective anti-HBs. After the booster, anti-HBs remained undetectable in 28.7% (158/551) of the subjects who had received complete HB vaccination (4 doses) during infancy. We estimated that 10.1% of the total population had lost their HB vaccine-conferred booster response. HBsAg-specific IFN-gamma- or IL-5-secreting PBMCs remained negative in 27.2% (25/92) of subjects after the booster. CONCLUSIONS: A notable proportion of fully vaccinated adolescents had lost immune memory conferred by a plasma-derived HB vaccine 15-18 years later. This decay of immune memory may raise concerns about the need for a booster vaccine for high-risk groups in the long run. PMID- 18444800 TI - Safety and immunogenicity of trivalent inactivated influenza vaccine in infants. AB - BACKGROUND: Trivalent inactivated influenza vaccine (TIV) is not licensed for use in infants <6 months old, the group with the highest influenza hospitalization rates among children. METHODS: In this prospective, open-label study, 2 doses of TIV were administered to healthy infants aged 10-22 weeks. Adverse reactions were assessed, and hemagglutination inhibition (HAI) antibody titers were determined. Weekly telephone surveillance for influenza-like illness was conducted during the influenza season. RESULTS: A total of 42 infants were enrolled and completed the study. Mild local and systemic reactions were noted. In the first season (2004 2005), postvaccination HAI titers >1:32 were noted for 31.6%, 47.4%, and 21.1% of 19 subjects for H1N1, H3N2, and B strains included in the vaccine, respectively. In the second season (2005-2006), postvaccination HAI titers >1:32 were seen in 45.5%, 59.1%, and 0% of 23 subjects for H1N1, H3N2, and B strains included in the vaccine, respectively. Infants who were seronegative before vaccination (titers <1:8) were significantly more likely to have a 4-fold rise in antibody titer after vaccination, compared with infants who had prevaccination titers >1:8 (P<.001). CONCLUSION: Two doses of TIV were found to be safe and moderately immunogenic against some influenza strains. The presence of preexisting maternally derived antibody was associated with significantly lower seroresponse rates to vaccination. Whether vaccination with TIV will prevent influenza in these young children remains to be determined. PMID- 18444801 TI - T cell response to the cytomegalovirus major capsid protein (UL86) is dominated by helper cells with a large polyfunctional component and diverse epitope recognition. AB - T cells are crucial in controlling cytomegalovirus (CMV) infection. The CMV major capsid protein (UL86) is frequently recognized by these cells, but the nature of this response has not been explored in detail. In this study, healthy CMV-exposed individuals were examined, and ex vivo peptide stimulation of peripheral blood mononuclear cells and flow-cytometry were used to obtain data, including response prevalence, magnitude, functional profiles, and recognized epitopes. Of 24 subjects, 19 (79%) had a UL86-specific CD4 T cell response rate between 0.03% and 1.4%. This group of individuals exhibited a similar percentage of polyfunctional T cells in their UL86-specific and pp65-specific responses. A total of 8 CD4 T cell epitopes were identified. In contrast, CD8 T cell responses to UL86 were rare and small. UL86 is of interest for monitoring the response to CMV. PMID- 18444802 TI - Differences in global gene expression in peripheral blood mononuclear cells indicate a significant role of the innate responses in progression of dengue fever but not dengue hemorrhagic fever. AB - BACKGROUND: Dengue virus infection causes an array of symptoms ranging from dengue fever (DF) to dengue hemorrhagic fever (DHF). The pathophysiological processes behind these 2 clinical manifestations are unclear. METHOD: In the present study, genomewide transcriptomes of peripheral blood mononuclear cells (PBMCs) collected from children with acute-phase DF (i.e., DF PBMCs) or acute phase DHF (i.e., DHF PBMCs) were compared using microarray analysis. Results of genome screening were validated at the genomic and proteomics levels. RESULTS: DHF had stronger influences on the gene expression profile than did DF. Of the affected genes, metabolic gene expression was influenced the most. For the immune response category, 17 genes were more strongly up-regulated in DF PBMCs than in DHF PBMCs. Eight of the these 17 genes were categorized as belonging to the interferon (IFN) system. The up-regulation of IFN-related genes was accompanied by strong expression of CD59, a complement inhibitor. DHF PBMCs expressed genes involved in T and B cell activation, cytokine production, complement activation, and T cell apoptosis more strongly than did DF PBMCs. CONCLUSION: We hypothesize that, during DF, genes in the IFN system and complement inhibitor play a role in lowering virus production and reducing tissue damage. In patients with DHF, the dysfunction of immune cells, complement, and cytokines increases viral load and tissue damage. PMID- 18444803 TI - Increased activities of cardiac matrix metalloproteinases matrix metalloproteinase (MMP)-2 and MMP-9 are associated with mortality during the acute phase of experimental Trypanosoma cruzi infection. AB - The strong inflammatory reaction that occurs in the heart during the acute phase of Trypanosoma cruzi infection is modulated by cytokines and chemokines produced by leukocytes and cardiomyocytes. Matrix metalloproteinases (MMPs) have recently emerged as modulators of cardiovascular inflammation. In the present study we investigated the role of MMP-2 and MMP-9 in T. cruzi-induced myocarditis, by use of immunohistochemical analysis, gelatin zymography, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction to analyze the cardiac tissues of T. cruzi-infected C57BL/6 mice. Increased transcripts levels, immunoreactivity, and enzymatic activity for MMP-2 and MMP-9 were observed by day 14 after infection. Mice treated with an MMP inhibitor showed significantly decreased heart inflammation, delayed peak in parasitemia, and improved survival rates, compared with the control group. Reduced levels of cardiac tumor necrosis factor alpha, interferon-gamma, serum nitrite, and serum nitrate were also observed in the treated group. These results suggest an important role for MMPs in the induction of T. cruzi-induced acute myocarditis. PMID- 18444804 TI - Risk factors for acquiring sporadic Campylobacter infection in France: results from a national case-control study. AB - BACKGROUND: To better document the risk factors for sporadic Campylobacter infection in France, we conducted a national case-control study from September 2002 to June 2004. METHODS: Cases with confirmed Campylobacter infection were sampled through the national surveillance laboratory network. Cases and controls who were matched for age, as well as attending physicians, were interviewed about foods consumed, food preparation practices, travel history, contact with cases and animals during the 8 days before the onset of infection, and any antibiotic use occurring during the 30 days before onset. Matched odds ratios [ORs] were calculated using conditional logistic regression and multiple imputation methods. RESULTS: A total of 285 pairs of cases and matched controls were enrolled. "Ate undercooked beef" (OR, 2.86; 95% confidence interval [CI], 1.65-4.95), "ate at restaurant" (OR, 2.20; 95% CI, 1.23-3.93), and "poor utensils hygiene in the kitchen" (OR, 2.12; 95% CI, 1.33-3.37) were the main independent risk factors for infection. Cases infected with a ciprofloxacin-resistant Campylobacter jejuni strain were more likely than controls to have used antibiotics in the month before onset. CONCLUSION: Good hygiene practices in the kitchen remain a strong recommendation to avoid cross-contamination. However, studies are needed to explore the mechanism of contamination throughout the food chain. The use of antibiotics in humans may favor the development of a resistant infection. PMID- 18444806 TI - Use of throat swab or saliva specimens for detection of respiratory viruses in children. AB - BACKGROUND: Nasopharyngeal (NP) specimens are commonly used for the detection of respiratory viruses, but throat and saliva specimens are easier to obtain. The objective of this study was to compare the viral yield of direct fluorescent antigen detection of NP specimens and nucleic acid amplification tests (NAT) of direct fluorescent antigen-negative NP specimens with the viral yield of NAT of throat swab and saliva specimens. METHODS: NP, throat swab, and saliva specimens were obtained from children and adolescents aged 2 days after symptom onset (odds ratio, 2.9; 95% confidence interval, 1.8-4.8). CONCLUSION: NFVIs, especially those due to V. vulnificus, demonstrate high morbidity and mortality. Persons with liver disease should be advised of the risks associated with seawater exposure if a wound is already present or is likely to occur. Clinicians should consider Vibrio species as an etiologic agent in infections occurring in persons with recent seawater exposure, even if the individual was only exposed during recreational marine activities. Immediate antibiotic treatment with aggressive monitoring is advised in suspected cases. PMID- 18444812 TI - Clinical presentation of nipah virus infection in Bangladesh. AB - BACKGROUND: In Bangladesh, 4 outbreaks of Nipah virus infection were identified during the period 2001-2004. METHODS: We characterized the clinical features of Nipah virus-infected individuals affected by these outbreaks. We classified patients as having confirmed cases of Nipah virus infection if they had antibodies reactive with Nipah virus antigen. Patients were considered to have probable cases of Nipah virus infection if they had symptoms consistent with Nipah virus infection during the same time and in the same community as patients with confirmed cases. RESULTS: We identified 92 patients with Nipah virus infection, 67 (73%) of whom died. Although all age groups were affected, 2 outbreaks principally affected young persons (median age, 12 years); 62% of the affected persons were male. Fever, altered mental status, headache, cough, respiratory difficulty, vomiting, and convulsions were the most common signs and symptoms; clinical and radiographic features of acute respiratory distress syndrome of Nipah illness were identified during the fourth outbreak. Among those who died, death occurred a median of 6 days (range, 2-36 days) after the onset of illness. Patients who died were more likely than survivors to have a temperature >37.8 degrees C, altered mental status, difficulty breathing, and abnormal plantar reflexes. Among patients with Nipah virus infection who had well-defined exposure to another patient infected with Nipah virus, the median incubation period was 9 days (range, 6-11 days). CONCLUSIONS: Nipah virus infection produced rapidly progressive severe illness affecting the central nervous and respiratory systems. Clinical characteristics of Nipah virus infection in Bangladesh, including a severe respiratory component, appear distinct from clinical characteristics reported during earlier outbreaks in other countries. PMID- 18444813 TI - High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. AB - BACKGROUND: Artemisinin-based combination therapies are rapidly being adopted for the treatment of malaria in Africa; however, there are limited data on their safety and efficacy among human immunodeficiency virus (HIV)-infected populations. METHODS: We compared malaria treatment outcomes between cohorts of HIV-infected and HIV-uninfected children in Uganda who were observed for 18 and 29 months, respectively. Malaria was treated with artesunate plus amodiaquine, and outcomes were assessed using standardized guidelines. HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis and antiretroviral therapy in accordance with current guidelines. RESULTS: Twenty-six HIV-infected participants experiencing 35 episodes of malaria and 134 HIV-uninfected children experiencing 258 episodes of malaria were included in the study. Twelve HIV-infected children were receiving antiretroviral therapy, 11 of whom were receiving zidovudine. Malaria treatment was highly efficacious in both the HIV-infected and HIV uninfected cohorts (28-day risk of recrudescence, 0% and 3.6%, respectively); however, there was a trend towards increased risk of recurrent malaria among the HIV-uninfected children (2.9% vs. 13.2%; p = .08). Importantly, the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children (45% vs. 6%; p < .001). The severity of all episodes of neutropenia in HIV-uninfected children was mild to moderate, and 16% of episodes of neutropenia in the HIV-infected cohort were severe or life-threatening (neutrophil count, <750 cells/mm(3)). In the HIV-infected cohort, the risk of neutropenia was significantly higher among children who received antiretroviral therapy than among those who did not receive antiretroviral therapy (75% vs. 26%; p < .001). CONCLUSIONS: Artesunate plus amodiaquine was highly efficacious for malaria treatment in HIV-infected children but was associated with a high risk of neutropenia, especially in the context of concurrent antiretroviral use. Our findings highlight an urgent need for evaluation of alternative antimalarial therapies for HIV-infected individuals. PMID- 18444814 TI - Disease and drug interactions: treating malaria with artesunate plus amodiaquine in patients also receiving treatment for concomitant HIV infection. PMID- 18444815 TI - Early repeated infections with Trichomonas vaginalis among HIV-positive and HIV negative women. AB - BACKGROUND: The purpose of the study was to examine whether early repeated infections due to Trichomonas vaginalis among human immunuodeficiency virus (HIV) positive and HIV-negative women are reinfections, new infections, or cases of treatment failure. METHODS: Women attending an HIV outpatient clinic and a family planning clinic in New Orleans, Louisiana, who had culture results positive for T. vaginalis were treated with 2 g of metronidazole under directly observed therapy. At 1 month, detailed sexual exposure and sexual partner treatment information was collected. Isolates from women who had clinical resistance (i.e., who tested positive for a third time after treatment at a higher dose) were tested for metronidazole susceptibility in vitro. RESULTS: Of 60 HIV-positive women with trichomoniasis, 11 (18.3%) were T. vaginalis positive 1 month after treatment. The 11 recurrences were classified as 3 probable reinfections (27%), 2 probable infections from a new sexual partner (18%), and 6 probable treatment failures (55%); 2 of the 6 patients who experienced probable treatment failure had isolates with mild resistance to metronidazole. Of 301 HIV-negative women, 24 (8.0%) were T. vaginalis positive 1 month after treatment. The 24 recurrences were classified as 2 probable reinfections (8%) and 22 probable treatment failures (92%); of the 22 patients who experienced probable treatment failure, 2 had strains with moderate resistance to metronidazole, and 1 had a strain with mild resistance to metronidazole. CONCLUSION: HIV-positive women were more likely to have sexual re-exposure than were HIV-negative women, although the rate of treatment failure was similar in both groups. High rates of treatment failure among both HIV-positive and HIV-negative women indicate that a 2-g dose of metronidazole may not be adequate for treatment of some women and that rescreening should be considered. PMID- 18444816 TI - Impact of routine infectious diseases service consultation on the evaluation, management, and outcomes of Staphylococcus aureus bacteremia. AB - BACKGROUND: Staphylococcus aureus bacteremia causes considerable morbidity and mortality, and strategies to improve management and outcomes of this disease are needed. METHODS: Routine consultation with an infectious diseases specialist for cases of S. aureus bacteremia was mandated at our institution in May 2005. We compared the evaluation, management, and outcomes of cases before and after this policy change. All comparisons are by period (i.e., before or after initiation of the policy of routine consultation). RESULTS: In the year before and the year after after the implementation of routine consultation, 134 and 100 cases of S. aureus bacteremia, respectively, were evaluated. Consultation rates increased from 53% of cases before to 90% of cases after the policy change (p < .001). Echocardiography (57% vs. 73%; p = .01) and radiographic studies (81% vs. 91%; p = .04) were used more frequently during the period of routine consultation, and infective endocarditis or metastatic infections were diagnosed more frequently (33% vs. 46%; p = .04). All 4 standards of care (removal of intravascular foci of infection, obtaining follow-up blood culture samples, use of parenteral beta lactam therapy when possible, and administration of >/=28 days of therapy for complicated infections) were adhered to more frequently with routine consultation (40% vs. 74%; P <.001). Treatment failure (microbiological failure, recurrent bacteremia, late metastatic infection, or death) occurred less often during the intervention year (17% vs. 12%), but this difference was not statistically significant (p = .27). CONCLUSIONS: A policy of routine consultation with an infectious diseases specialist for patients with S. aureus bacteremia resulted in more-detailed evaluation, more-frequent detection of endocarditis and metastatic infection, and improved adherence to standards of care. PMID- 18444817 TI - Timing of antibiotic prophylaxis for primary total knee arthroplasty performed during ischemia. AB - BACKGROUND: There is no clinical trial analyzing the best moment to infuse an antibiotic during knee arthroplasty performed during ischemia. We designed a single-center, randomized, double-blind, placebo-controlled trial to evaluate whether antibiotic therapy should be administered before tourniquet inflation or just before tourniquet deflation. MATERIAL AND METHODS: Patients who underwent a primary knee arthroplasty were randomized to receive (1) 1.5 g of cefuroxime 10 30 min before inflation of the tourniquet and placebo 10 min before release of the tourniquet (standard arm) or (2) placebo 10-30 min before inflation of the tourniquet and 1.5 g of cefuroxime 10 min before release of the tourniquet (experimental arm). In both arms, a postoperative dose of 1.5 g of cefuroxime was given 6 h after the surgical procedure. The main variables associated with the rate of deep-tissue infection after 3 and 12 months of follow-up were gathered. Continuous variables were compared using Student's t test, and categorical variables were compared using the chi(2) test or Fisher's exact test. RESULTS: From September 2004 through December 2005, a total of 908 patients were randomized, 442 and 466 of whom were allocated to the standard and experimental arms, respectively. There were no differences between treatment arms in terms of age, sex, comorbidity, American Society of Anaesthesiologists score, duration of surgery, need of blood transfusion, or fourth-day hematocrit. The rates of deep tissue infection among the standard and experimental groups were 3.4% and 1.9%, respectively, at 3 months of follow-up (P = .21) and 3.6% and 2.6%, respectively, at 12 months of follow-up (P = .44). CONCLUSION: The administration of prophylactic antibiotics just before tourniquet release was not inferior to standard antibiotic prophylaxis. PMID- 18444818 TI - Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory. AB - BACKGROUND: High functional antibody responses, establishment of immunologic memory, and unambiguous efficacy in infants suggest that an initial dose of conjugated pneumococcal polysaccharide (PnC) vaccine may be of value in a comprehensive adult immunization strategy. METHODS: We compared the immunogenicity and safety of 7-valent PnC vaccine (7vPnC) with that of 23-valent pneumococcal polysaccharide vaccine (PPV) in adults >/=70 years of age who had not been previously vaccinated with a pneumococcal vaccine. One year later, 7vPnC recipients received a booster dose of either 7vPnC (the 7vPnC/7vPnC group) or PPV (the 7vPnC/PPV group), and PPV recipients received a booster dose of 7vPnC (the PPV/7vPnC group). Immune responses were compared for each of the 7 serotypes common to both vaccines. RESULTS: Antipolysaccharide enzyme-linked immunosorbent assay antibody concentrations and opsonophagocytic assay titers to the initial dose of 7vPnC were significantly greater than those to the initial dose of PPV for 6 and 5 of 7 serotypes, respectively (P < .01 and P < .05, respectively). 7vPnC/7vPnC induced antibody responses that were similar to those after the first 7vPnC inoculation, and 7vPnC/PPV induced antibody responses that were similar to or greater than antibody responses after administration of PPV alone; PPV/7vPnC induced significantly lower antibacterial responses, compared with those induced by 7vPnC alone, for all serotypes (P < .05). CONCLUSION: In adults, an initial dose of 7vPnC is likely to elicit higher and potentially more effective levels of antipneumococcal antibodies than is PPV. In contrast with PPV, for which the induction of hyporesponsiveness was observed when used as a priming dose, 7vPnC elicits an immunological state that permits subsequent administration of 7vPnC or PPV to maintain functional antipolysaccharide antibody levels. PMID- 18444819 TI - Seasonal and pandemic influenza: a 2007 update on challenges and solutions. AB - The second annual Seasonal and Pandemic Influenza Conference, which took place in February 2007 in Arlington, Virginia, focused on recent progress in basic and clinical research regarding preparedness for outbreaks of influenza. Sporadic outbreaks of avian influenza A in Asia and the Middle East remind us that the threat of another influenza pandemic remains real. Although the exact mechanisms underlying avian influenza A human pathogenicity remain unclear, preclinical studies in animal models provide insights into the mechanisms of avian influenza A virus infection and transmission from bird to human and, rarely, from human to human. With regard to prevention, developmental studies of adjuvant-supplemented vaccines indicate promising immunogenicity and cross-reactivity. The pipeline of new antiviral agents in development is also increasing, including a new neuraminidase inhibitor and agents aimed at completely new targets. Global strategic planning efforts focus on assuring sufficient stocks of vaccines and antiviral agents, as well as timely nonpharmacological interventions to potentially delay or contain spread of an outbreak. These initiatives will also help control outbreaks of seasonal influenza. PMID- 18444820 TI - Current treatment options for community-acquired methicillin-resistant Staphylococcus aureus infection. AB - During the past decade, there has been a marked increase in the prevalence of community-acquired methicillin-resistant Staphylococcus aureus infection in the United States and elsewhere. The most common such infections are those involving the skin and skin structures. Although a number of these lesions (including small furuncles and abscesses) respond well to surgical incision and drainage, oral antimicrobial agents are commonly used to treat these infections in outpatients. Unfortunately, with the exception of linezolid, none of the agents presently being used in this fashion has been subjected to rigorous clinical trial. Thus, current therapy is based largely on anecdotal evidence. For more-serious infections requiring hospitalization, parenteral antimicrobials such as vancomycin, teicoplanin, daptomycin, linezolid, and tigecycline are presently available and have demonstrated effectiveness in randomized, prospective, double blind trials. PMID- 18444821 TI - The importance of the group a streptococcus capsule in the pathogenesis of human infections: a historical perspective. AB - The virulence of group A streptococci (GAS) correlates closely with expression of its surface antigen, M protein, and its hyaluronic acid capsule. In studies of human GAS infection, the former has received considerable attention. For several decades, however, systematic identification of encapsulated virulent strains by the mucoid colonies they produce has been neglected in clinical studies. In part, this may be due to the capsule's evanescent expression on artificial media, its repression during convalescent carriage, lack of expertise in recognizing its colonial morphology, and the growing tendency for clinical laboratories to eschew throat cultures in favor of rapid laboratory tests for group A polysaccharide. Older and more recent studies are reviewed here that emphasize the capsule's basic role in infection. We believe that it is time to refocus newer clinical studies and techniques on achieving early recognition of potentially dangerous, heavily encapsulated strains of GAS for which spread may be prevented. PMID- 18444822 TI - The role of regulatory T cells in chronic and acute viral infections. AB - Regulatory T cells, a subset of CD4(+) T lymphocytes, play a pivotal role in the maintenance of the balance between the tissue-damaging and protective effects of the immune response. These cells have immunosuppressive function and have been intensely studied in the context of autoimmunity, cancer, allergies, asthma, and infectious diseases. Their role in chronic and persistent viral infections is well appreciated. In acute viral infections, the function of these cells is still unclear. The host and pathogen factors that control the generation and activity of regulatory T cells and the role of these cells in modulating expansion, contraction, and development of immune memory in acute respiratory virus infection need to be further elucidated. PMID- 18444823 TI - Destruction of isolates from the Pittsburgh Veterans Affairs Laboratory. AB - The Pittsburgh Veterans Affairs hospital administration closed the research laboratory directed by Victor Yu and Janet Stout and destroyed isolates collected as part of a series of clinical studies over 25 years. This article discusses the implications and protests such destruction as an affront to science and scientific study. A petition signed by 243 individuals accompanies this article. PMID- 18444824 TI - Clostridium difficile-associated diarrhea after antibiotic treatment for traveler's diarrhea. AB - Diarrhea commonly affects international travelers. Episodes are usually short lasting, but in some patients, symptoms may persist. Clostridium difficile infection should be excluded in travelers with prolonged disease. We report what is, to our knowledge, the first reported study of patients with C. difficile associated diarrhea after receipt of antibiotic treatment for traveler's diarrhea. PMID- 18444825 TI - Penicillin G-resistant viridans group streptococcal endocarditis and interpretation of the American Heart Association's Guidelines for the Treatment of Infective Endocarditis. AB - We report a case of endocarditis due to a penicillin-"resistant" Streptococcus parasanguinis, discuss interpretations of the American Heart Association's guidelines for the treatment of viridans group streptococcal infection, and comment on therapy for infective endocarditis due to penicillin-resistant viridans group streptococci. PMID- 18444826 TI - Exophytic tumors on ankles of a patient with psoriasis. PMID- 18444827 TI - Fosfomycin: use beyond urinary tract and gastrointestinal infections. AB - The shortage of new antimicrobial agents has made the scientific community reconsider the potential value of old antibiotics. A search of the literature was performed to compile relevant evidence regarding the effectiveness and safety of fosfomycin for the treatment of patients with gram-positive and/or gram-negative bacterial infections (excluding urinary tract infection and gastrointestinal infection). Of 1311 potentially relevant studies, 62 studies were reviewed in detail. Of 1604 patients with various gram-positive and gram-negative infections of various body sites (including pneumonia and other respiratory infections; osteomyelitis; meningitis; ear, nose, and throat infections; surgical infections; obstetric and gynecological infections; arthritis; septicemia; peritonitis; cervical lymphadenitis; eye infections; diabetic foot infections; and typhoid fever) being treated with fosfomycin alone or in combination with other antibiotics, cure was achieved in 1302 (81.1%) of the patients, and improvement was noted in 47 (2.9%). In comparative perioperative prophylaxis trials that included a total of 1212 patients (mainly patients undergoing colorectal surgery), the fosfomycin-metronidazole combination led to results that were similar to those achieved with the combination of other antibiotics (doxycycline, ampicillin, or cephalothin) and metronidazole. In an era in which there is a shortage of new antibiotics, fosfomycin might be considered to be an alternative treatment agent for infections caused by gram-positive and gram-negative bacteria, in addition to its traditional use in treating uncomplicated urinary tract and gastrointestinal infections. Further research on the in vitro antimicrobial activity of fosfomycin, especially against multidrug-resistant pathogens (such as extended-spectrum beta-lactamase-producing and/or metallo-beta lactamase-producing enterobacteriaceae and Pseudomonas aeruginosa, and on the effectiveness and safety of the drug in the treatment of patients with such infections may be warranted. PMID- 18444828 TI - Biology of immune responses to vaccines in elderly persons. AB - With increasing age, the human immune system undergoes characteristic changes, termed immunosenescence, which lead to increased incidence and severity of infectious diseases and to insufficient protection following vaccination. Functional defects and altered frequencies of innate and adaptive immune cells impair local responses at the site of vaccine injection, hamper the generation of primary responses to neoantigens, prevent the effective induction of memory lymphocytes, and decrease the effect of booster vaccination. As a result, antibody responses of elderly vaccinees are weaker and decline faster, and long term protective effects of vaccination cannot be taken for granted in elderly persons. Improved vaccination strategies, new adjuvants, and new vaccines that specifically target the aged immune system will help to overcome the limitations of immunosenescence and ensure a better protection of the vulnerable elderly population. PMID- 18444829 TI - Do hospitalists or physicians with greater inpatient HIV experience improve HIV care in the era of highly active antiretroviral therapy? Results from a multicenter trial of academic hospitalists. AB - BACKGROUND: Little is known about the effect of provider type and experience on outcomes, resource use, and processes of care of hospitalized patients with human immunodeficiency virus (HIV) infection. Hospitalists are caring for this population with increasing frequency. METHODS: Data from a natural experiment in which patients were assigned to physicians on the basis of call cycle was used to study the effects of provider type-that is, hospitalist versus nonhospitalist-and HIV-specific inpatient experience on resource use, outcomes, and selected measures of processes of care at 6 academic institutions. Administrative data, inpatient interviews, 30-day follow-up interviews, and the National Death Index were used to measure outcomes. RESULTS: A total of 1207 patients were included in the analysis. There were few differences in resource use, outcomes, and processes of care by provider type and experience with HIV-infected inpatients. Patients who received hospitalist care demonstrated a trend toward increased length of hospital stay compared with patients who did not receive hospitalist care (6.0 days vs. 5.2 days; P = .13). Inpatient providers with moderate experience with HIV-infected patients were more likely to coordinate care with outpatient providers (odds ratio, 2.40; P = .05) than were those with the least experience with HIV-infected patients, but this pattern did not extend to providers with the highest level of experience. CONCLUSION: Provider type and attending physician experience with HIV-infected inpatients had minimal effect on the quality of care of HIV-infected inpatients. Approaches other than provider experience, such as the use of multidisciplinary inpatient teams, may be better targets for future studies of the outcomes, processes of care, and resource use of HIV-infected inpatients. PMID- 18444830 TI - Impact of pneumococcal vaccination on the incidence of pneumonia by HIV infection status among patients enrolled in the Veterans Aging Cohort 5-Site Study. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected persons have a high incidence of pneumonia and pneumococcal disease. Benefits of vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV) among these patients continue to be debated. METHODS: The impact of PPV vaccination on the incidence of pneumonia events (i.e., the composite of pneumococcal pneumonia and pneumonia due to nonspecified organisms) was examined among participants in the Veterans Aging Cohort 5-Site Study, an ongoing prospective study of HIV-infected patients matched to an HIV-uninfected control group. Dates of PPV vaccination and pneumonia were determined by retrospective review of electronic medical records. Time to events was measured for up to 2 years from PPV vaccination or from enrollment for vaccinated and unvaccinated patients, respectively. Kaplan-Meier and Cox proportional hazards regression methods were used to examine the incidence of pneumonia by HIV infection and PPV vaccination status. RESULTS: Among 692 HIV-uninfected and 934 HIV-infected study participants, 59% were vaccinated with PPV. The 2-year incidence of pneumonia was 6% (97 participants developed pneumonia). HIV-infected patients had a higher rate of pneumonia (hazard ratio, 5.81; 95% confidence interval, 3.15-10.71); overall, vaccinated patients showed a trend toward lower risk of pneumonia (hazard ratio, 0.75; 95% confidence interval, 0.50-1.13). Among HIV-infected patients, after controlling for HIV-specific and other variables, vaccination significantly reduced the risk of pneumonia (hazard ratio, 0.65; 95% confidence interval, 0.42-1.00); current smoking, low hemoglobin level, and low CD4 cell count significantly increased such risk. The effect of PPV vaccination among HIV-uninfected patients was not significant. CONCLUSIONS: Among HIV-infected patients, PPV vaccination offered protection against pneumonia. Smoking cessation needs to be pursued as an additional strategy for preventing pneumonia. PMID- 18444833 TI - Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: need for international harmonization in terminology. PMID- 18444835 TI - Glycerol and bacterial meningitis: a response to the editorial commentary by Saez Llorens and McCracken. PMID- 18444831 TI - High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. AB - BACKGROUND: Although the human leukocyte antigen (HLA)-B*5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR. This study evaluated the sensitivity of detection of the HLA B*5701 allele as a marker of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical diagnosis. METHODS: White and black patients, identified through chart review, were classified as having received a diagnosis of an ABC HSR based on clinical findings only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially matched subjects who tolerated ABC for >/=12 weeks without experiencing an ABC HSR. Patients and control subjects were tested for the presence of HLA-B*5701. Sensitivity, specificity, and odds ratios for the detection of HLA-B*5701 as a marker for an ABC HSR were calculated for white and black participants. RESULTS: Forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients who met the criteria for clinically suspected HSRs had IC HSRs. All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 1945; 95% confidence interval, 110-34,352). Among all white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested positive for HLA B*5701); specificity among white control subjects was 96%. Five of 5 black patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 900; 95% confidence interval, 38-21,045). Among black patients with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA B*5701); specificity among black control subjects was 99%. CONCLUSIONS: Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races. PMID- 18444836 TI - Increased detection of meningococcal infections in california using a polymerase chain reaction assay. PMID- 18444837 TI - Regression of HIV-associated mucosa-associated lymphoid tissue lymphoma during highly active anti-retroviral therapy. PMID- 18444838 TI - Hypoglycemia and levofloxacin: a case report. PMID- 18444840 TI - Levofloxacin and hypoglycemia. PMID- 18444839 TI - Risk of early virological failure of once-daily tenofovir-emtricitabine plus twice-daily nevirapine in antiretroviral therapy-naive HIV-infected patients. PMID- 18444842 TI - Recurrent bulbar paralysis caused by botulinum toxin type B. AB - Botulism is a rare, potentially lethal paralytic disease characterized by cranial nerve palsies, descending flaccid muscle paralysis, and possible involvement of the diaphragm and other respiratory muscles. Here, we report, to our knowledge, the first case of recurrent botulism type B in the United States, caused by repetitive ingestion of contaminated homemade hot chili pepper in oil from the same jar. PMID- 18444843 TI - Risk of Guillain-Barre syndrome following serogroup C meningococcal conjugate vaccine in Quebec, Canada. AB - To assess the risk of Guillain-Barre syndrome (GBS) following administration of meningococcal serogroup C-CRM(197) conjugate vaccine, provincial immunization records were linked with hospital discharge records, and medical charts were reviewed. In the cohort of 1.9 million individuals (age, 2 months to 20 years), observed postvaccination frequencies of GBS were not higher than expected. PMID- 18444844 TI - CD4+ T cell depletion in an untreated HIV type 1-infected human leukocyte antigen B*5801-positive patient with an undetectable viral load. AB - We report a case of a patient infected with human immunodeficiency virus type 1 (HIV-1) for 20 years who has experienced CD4(+) T cell depletion in spite of maintaining undetectable viral loads. Our data suggest that immune activation can cause CD4(+) T cell depletion even when HIV-1 replication appears to be controlled by host factors. PMID- 18444846 TI - At the threshold: defining clinically meaningful resistance thresholds for antibiotic choice in community-acquired pneumonia. AB - BACKGROUND: Community-acquired pneumonia caused by Streptococcus pneumoniae is a major source of morbidity and mortality. Macrolide antibiotics are recommended as empirical first-line therapy for patients with community-acquired pneumonia. Guidelines suggest a 25% rate of high-level macrolide resistance in the community as the threshold beyond which macrolides should not be used. We evaluated the implications of this threshold for clinical failure rates. METHODS: We developed a theoretical model linking the prevalence of macrolide resistance to patient outcomes, based on the epidemiological concept of risk difference. We estimated the risk of clinical failure as a function of the likelihood and impact of discordant therapy and of the probability of clinical failure even in the presence of optimal therapy. The model was parameterized on the basis of the best available data derived from the published medical literature, and clinical failures were valued monetarily using an expected net benefit approach. RESULTS: Under the proposed 25% resistance threshold, the risk difference for such therapy would be 1.2% (95% credible interval, 0.5%-3.1%) for death, 1.6% (95% credible interval, 0.5%-3.2%) for bacteremia, and 3.3% (95% credible interval, 1.1%-5.7%) for prolonged clinical course; excess risks of death were valued at >$10,000 per empirical treatment of community-acquired pneumonia and were further elevated in high-risk populations. Excluding low-level resistance resulted in a 4-fold underestimation of projected risks. CONCLUSION: A 25% resistance threshold that fails to consider low-level resistance will result in high excess rates of morbidity and mortality because of discordant therapy. Whether projected failure rates are classified as unacceptable is an important health policy question, because risk of clinical failure needs to be weighed against other considerations. PMID- 18444847 TI - Digital decision making: computer models and antibiotic prescribing in the twenty first century. PMID- 18444848 TI - Effects of prior effective therapy on the efficacy of daptomycin and ceftriaxone for the treatment of community-acquired pneumonia. AB - OBJECTIVE: We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). METHODS: Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5-14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. RESULTS: After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, -12.4% to -0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, 13.8% to -3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, -6.1% to 11.5%). CONCLUSIONS: Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment. PMID- 18444849 TI - Reassessing the design, conduct, and analysis of clinical trials of therapy for community-acquired pneumonia. PMID- 18444850 TI - Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. AB - BACKGROUND: Because clarithromycin provided beneficiary nonantibiotic effects in experimental studies, its efficacy was tested in patients with sepsis and ventilator-associated pneumonia (VAP). METHODS: Two hundred patients with sepsis and VAP were enrolled in a double-blind, randomized, multicenter trial from June 2004 until November 2005. Clarithromycin (1 g) was administered intravenously once daily for 3 consecutive days in 100 patients; another 100 patients were treated with placebo. Main outcomes were resolution of VAP, duration of mechanical ventilation, and sepsis-related mortality within 28 days. RESULTS: The groups were well matched with regard to demographic characteristics, disease severity, pathogens, and adequacy of the administered antimicrobials. Analysis comprising 141 patients who survived revealed that the median time for resolution of VAP was 15.5 days and 10.0 days among placebo- and clarithromycin-treated patients, respectively (P = .011); median times for weaning from mechanical ventilation were 22.5 days and 16.0 days, respectively (p = .049). Analysis comprising all enrolled patients showed a more rapid decrease of the clinical pulmonary infection score and a delay for advent of multiple organ dysfunction in clarithromycin-treated patients, compared with those of placebo-treated patients (p = .047). Among the 45 patients who died of sepsis, time to death was significantly prolonged in clarithromycin-treated compared with placebo-treated patients (p = .004). Serious adverse events were observed in 0% and 3% of placebo and clarithromycin-treated patients, respectively (P = .25). CONCLUSIONS: Clarithromycin accelerated the resolution of VAP and weaning from mechanical ventilation in surviving patients and delayed death in those who died of sepsis. The mortality rate at day 28 was not altered. Results are encouraging and render new perspectives on the management of sepsis and VAP. PMID- 18444851 TI - Hospitalization for respiratory syncytial virus infection and invasive pneumococcal disease in Danish children aged <2 years: a population-based cohort study. AB - BACKGROUND: Previous population-based studies have reported a temporal association between respiratory syncytial virus (RSV) infection and invasive pneumococcal disease (IPD). We examined this association at an individual level in the Danish population. METHODS: Using registry information about hospitalization for RSV infection and IPD in Denmark, we conducted a prospective, population-based cohort study and examined the associations between hospitalization for RSV infection and IPD. RESULTS: In our cohort, no persons aged > or =2 years experienced IPD within 30 days after hospitalization for RSV infection. Among children aged <2 years, children who were hospitalized for RSV infection had a significantly increased risk of IPD during the 30 days after hospitalization, compared with those who were not hospitalized for RSV infection (adjusted rate ratio, 7.1; 95% confidence interval, 3.6-14.3). Likewise, hospitalization for a non-RSV respiratory infection increased the risk of IPD during the 30 days after hospitalization (adjusted rate ratio, 4.5; 95% confidence interval, 2.0-10.0). IPD did not increase the risk of hospitalization for RSV infection among children aged <2 years. CONCLUSIONS: Both recent hospitalization for RSV infection and recent hospitalization for non-RSV respiratory infection increased the risk of IPD among Danish children aged <2 years. PMID- 18444852 TI - Mumps vaccine performance among university students during a mumps outbreak. AB - BACKGROUND: The largest reported mumps outbreak at a US college in 19 years occurred in 2006 at a Kansas university with a 2-dose measles-mumps-rubella (MMR) vaccination policy. We assessed vaccine performance and mumps risk factors, including the possibility of waning vaccine protection. METHODS: Case students were compared with a cohort of the university's approximately 19,000 undergraduates. The secondary attack rate for clinical mumps was determined among roommates exposed to case students. Time from receipt of the second dose of MMR vaccine was compared between case students and roommates without mumps. RESULTS: Coverage with > or =2 dose of MMR vaccine was > or =95% among 140 undergraduate case students and 444 cohort students. The secondary attack rate for clinical mumps among roommates who had received 2 doses of vaccine ranged from 2.2% to 7.7%, depending on the case definition. Compared with roommates without mumps, case students were more likely (odds ratio, 2.46; 95% confidence interval, 1.25 4.82) to have received their second dose of MMR vaccine > or =10 years earlier. The odds of being a case student increased with each 1-year increase in time from receipt of the second dose of MMR vaccine (odds ratio, 1.36; 95% confidence interval, 1.10-1.68) among case students and roommates aged 18-19 years but not among those aged > or =20 years. Students aged 18-19 years had a higher risk of mumps (risk ratio, 3.14; 95% confidence interval, 1.60-6.16), compared with students aged > or =22 years; women living in dormitories had increased risk of mumps (risk ratio, 1.95; 95% confidence interval, 1.01-3.76), compared with men not living in dormitories. CONCLUSION: High 2-dose MMR coverage protected many students from developing mumps but was not sufficient to prevent the mumps outbreak. Vaccine-induced protection may wane. Similar US settings where large numbers of young adults from wild-type naive cohorts live closely together may be at particular risk for mumps outbreaks. PMID- 18444853 TI - Outbreak of Mycobacterium abscessus wound infections among "lipotourists" from the United States who underwent abdominoplasty in the Dominican Republic. AB - BACKGROUND: Some US residents travel abroad to undergo cosmetic surgery for fat removal, a practice referred to as "lipotourism." Mycobacterium abscessus can cause postsurgical wound infection. METHODS: US residents who developed M. abscessus wound infection after undergoing cosmetic surgery in the Dominican Republic in 2003 and 2004 were identified using the Emerging Infections Network listserv. RESULTS: Twenty returning US travelers with M. abscessus infection were detected. Eight patients had matching isolates, as determined by pulsed-field gel electrophoresis and repetitive element polymerase chain reaction. All 8 patients, who had previously been healthy Hispanic women, underwent abdominoplasties at the same clinic in the Dominican Republic. Symptoms first developed 2-18 weeks after the procedure (median interval, 7 weeks). Only 2 of the 8 patients received a correct diagnosis at the initial presentation. Most patients presented with painful, erythematous, draining subcutaneous abdominal nodules. Seven patients underwent drainage procedures. Six patients received a combination of antibiotics that included a macrolide plus cefoxitin, imipenem, amikacin, and/or linezolid; 2 received clarithromycin monotherapy. All patients but 1 were cured after a median of 9 months of therapy (range, 2-12 months). Because of a lack of access to the surgical clinic, the cause of the outbreak of infection was not identified. The patients who were infected with nonmatching isolates underwent surgeries in different facilities but otherwise had demographic characteristics and clinical presentations similar to those of the 8 patients infected with matching isolates. CONCLUSIONS: This case series of M. abscessus infection in US "lipotourists" highlights the risks of traveling abroad for surgery and the potential role of the Internet in identifying and investigating outbreaks. PMID- 18444854 TI - Preventing household transmission of Shiga toxin-producing Escherichia coli O157 infection: promptly separating siblings might be the key. AB - BACKGROUND: Preventing household transmission of Shiga toxin-producing Escherichia coli O157 (STEC O157) infection is important because of the ease of interpersonal transmission and the potential disease severity. METHODS: We conducted a retrospective cohort study of households associated with an outbreak of STEC O157 infection in South Wales, United Kingdom, in autumn 2005. We investigated whether characteristics of the primary case patient or the household were predictors for secondary household transmission of STEC O157 infection. Furthermore, we estimated the proportion of cases that might be prevented by isolation (e.g., hospitalization) of the primary case patient immediately after the microbiological diagnosis and the number of patients with STEC O157 who would need to be isolated to prevent 1 case of hemolytic uremic syndrome. Based on dates of symptom onset, case patients in households were classified as having primary, coprimary, or secondary infection. Secondary cases were considered to be preventable if the secondary case patient's symptoms started >1 incubation period (4 days) after the date of microbiological diagnosis of the primary case. RESULTS: Eighty-nine (91%) of 98 eligible households were enrolled. Among 20 households (22%), 25 secondary cases were ascertained. Thirteen secondary cases (56%) occurred in siblings of the primary case patients; hemolytic uremic syndrome developed in 4 of these siblings. Presence of a sibling (risk ratio, 3.8; 95% confidence interval, 0.99-14.6) and young age (<5 years) of the primary case patient (risk ratio, 2.03; 95% confidence interval, 0.99-41.6) were independent predictors for households in which secondary cases occurred. Of the 15 secondary cases for which complete information was available, 7 (46%) might have been prevented. When restricting isolation to primary case patients who were aged <10 years and who had a sibling, we estimated the number of patients who would need to be isolated to prevent 1 case of hemolytic uremic syndrome to be 47 patients (95% confidence interval, 16-78 patients). CONCLUSIONS: Promptly separating pediatric patients with STEC O157 infection from their young siblings should be considered. PMID- 18444855 TI - Isolation of patients acutely infected with Escherichia coli O157:H7: low-tech, highly effective prevention of hemolytic uremic syndrome. PMID- 18444856 TI - Clinical relevance of Mycobacterium szulgai in The Netherlands. AB - BACKGROUND: The clinical relevance of Mycobacterium szulgai isolates is unknown, and available literature focuses on case reports of M. szulgai disease. We assessed the clinical relevance of M. szulgai isolated from patients in The Netherlands. METHODS: We reviewed medical files for all 21 patients in The Netherlands from whom M. szulgai was isolated during 1999-2006, applying the diagnostic criteria of the American Thoracic Society for nontuberculous mycobacterial infection. Random amplified polymorphic DNA genotyping was performed using IS986, OPA-2, and OPA-18 as primers. RESULTS: Of the 21 patients, 16 (76%) met the American Thoracic Society diagnostic criteria and were thus likely to have M. szulgai disease. Pulmonary M. szulgai disease was the most common presentation, with extrapulmonary disease restricted to patients with an impaired systemic immunity. Although treatment regimens varied in content and duration, the outcomes were mostly favorable. Both overtreatment and undertreatment were noticed. Random amplified polymorphic DNA genotyping revealed a higher degree of interpatient variability, with limited intrapatient variability, suggesting persisting monoclonal infection and good reproducibility. No genotype was associated with clinical relevance. CONCLUSIONS: Clinical isolation of M. szulgai generally represents true disease and demands careful follow-up. Extrapulmonary disease occurs in patients with impaired immunity. Adherence to diagnostic guidelines can be improved. PMID- 18444857 TI - Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit. AB - BACKGROUND: Candida albicans has been the most common cause of fungal bloodstream infections (BSIs) in intensive care units (ICUs); however, infections due to non albicans Candida species have been increasing in prevalence. We examined factors associated with BSIs due to non-albicans Candida species, compared with C. albicans BSIs, in an ICU patient population. METHODS: For our case-comparator study, we identified consecutive adult ICU patients with BSIs due to non-albicans Candida species or C. albicans at 2 tertiary care hospitals during the period 1995-2005. Data collected included demographic characteristics, comorbidities, exposure to antibiotics and antifungals, and ICU-related factors, such as total parenteral nutrition, blood product transfusions, invasive procedures, central venous catheter use, hemodialysis, and mechanical ventilation. We built a multivariable logistic regression model that identified variables that differentiate BSIs due to non-albicans Candida species from BSIs due to C. albicans. RESULTS: There were 67 patients with BSIs due to non-albicans Candida species and 79 patients with C. albicans BSIs. Variables were adjusted for time at risk. In multivariable models, factors associated with an increased risk of BSIs due to non-albicans Candida species, compared with C. albicans BSIs, included fluconazole exposure (odds ratio, 11.6; 95% confidence interval, 2.28 58.8), central venous catheter exposure (odds ratio, 1.95; 95% confidence interval, 1.10-3.47), and mean number of antibiotics per day (odds ratio, 2.31; 95% confidence interval, 0.71-7.54). Total parenteral nutrition exposure was associated with a decreased risk (odds ratio, 0.16; 95% confidence interval, 0.05 0.47) of BSIs due to non-albicans Candida species, compared with C. albicans BSIs. Duration of stay in the ICU was not significantly different between the 2 groups. Specific antibiotics, such as vancomycin and piperacillin-tazobactam, were not independently associated with BSI due to non-albicans Candida species. CONCLUSIONS: Receipt of fluconazole and central venous catheter exposure were associated with an increased risk of BSI due to non-albicans Candida species, and total parenteral nutrition was associated with a decreased risk of BSI due to non albicans Candida species, compared with BSI due to C. albicans. Patients without characteristics of infection due to non-albicans Candida species might benefit from empirical antifungal therapy with fluconazole. PMID- 18444858 TI - Relationship between bacterial load, species virulence, and transfusion reaction with transfusion of bacterially contaminated platelets. AB - BACKGROUND: Bacterial contamination is currently the major infectious hazard of platelet transfusion, but associations between bacterial species and quantity and transfusion reactions have not been characterized. METHODS: Patients receiving platelets from July 1991 through December 2006 were observed using active surveillance by quantitative culture of platelets at the time of issue or passive surveillance by investigation of clinical reactions in patients and culture of implicated units. Patient reactions were classified by type and severity and were correlated with bacterial species and number. Endotoxin content of gram-negative contaminants was determined by limulus lysate assay. RESULTS: Fifty-two bacterially contaminated platelet units were detected (50 by active and 2 by passive surveillance). Rates of bacterial contamination and septic transfusion reactions were 32.0-fold and 10.6-fold higher, respectively, as determined by active versus passive surveillance (P < .001). Including 2 index cases, bacterial contaminants included gram-negative bacilli in 4 units (3 of which were associated with fatal reactions), staphylococci in 44 units, streptococci in 4 units, and Bacillus cereus in 2 units. Endotoxin content of the 4 units that were contaminated with gram-negative bacilli ranged from 11,373 to 173,130 endotoxin units. Reaction severity was greater for units with bacterial counts of > or =10(5) colony-forming units/mL and higher bacterial virulence. A detection method with a 10(3) colony-forming units/mL threshold would detect >90% of contaminants. CONCLUSIONS: Active surveillance detected 32-fold more bacterially contaminated platelet units and 10.6-fold more septic reactions than did passive surveillance, and virulent species and bacterial counts of > or =10(5) colony-forming units/mL were associated with more-severe transfusion reactions. Improved detection methods or use of pathogen inactivation technology are needed to eliminate this problem. PMID- 18444859 TI - Treatment of joint prosthesis infection in accordance with current recommendations improves outcome. AB - BACKGROUND: Recently recommended treatment modalities for prosthetic joint infection (PJI) were evaluated. METHODS: A retrospective cohort analysis of 68 patients with PJI of hip or knee who were treated from 1995 through 2004 was conducted at the University Hospital Bern (Bern, Switzerland). RESULTS: A 2-stage exchange was the most frequent (75.0%) surgical strategy, followed by retention and debridement (17.6%), 1-stage exchange (5.9%), and resection arthroplasty or suppressive antimicrobial treatment (1.5%). The chosen strategy was in 88% agreement with the recommendations. Adherence was only 17% for retention and debridement and was 0% for 1-stage exchange. Most PJIs (84%) were treated with an adequate or partially adequate antimicrobial regimen. Recurrence-free survival was observed in 51.5% of PJI episodes after 24 months of follow-up. The risk of treatment failure was significantly higher for PJI treated with a surgical strategy other than that recommended (hazard ratio, 2.34; 95% confidence interval, 1.10-4.70; P = .01) and for PJIs treated with antibiotics not corresponding to recommendations (hazard ratio, 3.45; confidence interval, 1.50 7.60; P = .002). Other risk factors associated with lack of healing were a high infection score at the time of diagnosis (hazard ratio, 1.29; 95% confidence interval, 1.10-1.40; P < .001) and presence of a sinus tract (hazard ratio, 2.35; 95% confidence interval, 1.10-5.0; P = .02). CONCLUSIONS: Our study demonstrates the value of current treatment recommendations. Inappropriate choice of conservative surgical strategies (such as debridement and retention) and inadequate antibiotic treatment are associated with failure. PMID- 18444860 TI - Comprehensive genetic and epigenetic analysis of occult hepatitis B from liver tissue samples. AB - BACKGROUND: Occult infection with hepatitis B virus (HBV) is a type of chronic HBV infection that is characterized by the absence of a detectable hepatitis B surface antigen in the blood and by very low levels of HBV DNA in the blood and liver. The mechanisms leading to occult HBV infection remain poorly understood but include possible genetic mutations and deletions. Recently, it has been shown that HBV has CpG islands that are methylated, raising the possibility that epigenetic changes may also be important. METHODS: The full-length genomes of isolates from 5 cases of occult HBV infection were cloned and analyzed for mutations and deletions. Additional studies were performed to examine for APOBEC3G (1 member of a family of deaminating proteins that are part of the innate immune system's defense against viral infection) hyperediting and methylation of viral DNA. RESULTS: Numerous mutations and deletions were found in the genomes of occult HBV. However, similar types and locations of polymorphisms were also noted in the genome sequences of HBV isolated from control liver tissue samples obtained from individuals with nonoccult HBV infection. Evidence of APOBEC3G hyperediting was found in 1 case of occult HBV infection, but hyperedited sequences made up only a small proportion of the viral sequences. Methylation of HBV CpG islands 1 and 2 was evident in both occult and nonoccult HBV sequences, with island 2 more densely methylated in occult HBV sequences and island 1 more densely methylated in nonoccult HBV sequences. CONCLUSION: Deletions and mutations are common in occult HBV but are also found in control nonoccult HBV, and no unique genetic signature for occult HBV was found. Methylation patterns differ between cases of occult and nonoccult HBV infection, suggesting that epigenetic changes may be relevant to occult HBV. Together, these findings suggest that multiple mechanisms can contribute to occult HBV infection. PMID- 18444861 TI - Epidemiology of Pneumocystis colonization in families. AB - Whether Pneumocystis colonization is transmitted in families with human immunodeficiency virus (HIV)-infected members is unknown. Using nested polymerase chain reaction of oropharyngeal or nasopharyngeal samples, we detected colonization in 11.4% of HIV-infected adults and in 3.3% of their children, but there was no evidence of clustering. PMID- 18444862 TI - Strain-relatedness of methicillin-resistant Staphylococcus aureus isolates recovered from patients with repeated infection. AB - Invasive disease following methicillin-resistant Staphylococcus aureus (MRSA) detection is common, regardless of whether initial detection involves colonization or infection. We assessed the genetic relatedness of isolates obtained > or =2 weeks apart representing either repeated infections or colonization-infection sets to determine if infections are likely to be caused by previously harbored strains. We found that MRSA infection following initial colonization or infection is caused by the same strain in most cases, suggesting that a single successful attempt at decolonization may prevent the majority of later infection. PMID- 18444863 TI - Influence of admission findings on death and neurological outcome from childhood bacterial meningitis. AB - A post hoc analysis of 654 children with bacterial meningitis showed that the level of consciousness is the most important predictor of death and/or neurological sequelae, more than is etiology per se. This finding emphasizes the need of including a measurement of the presenting status in all studies examining treatment efficacy. PMID- 18444864 TI - An african-born man with chronic recurrent hemoptysis. PMID- 18444865 TI - Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. AB - Multidrug-resistant Acinetobacter baumannii is recognized to be among the most difficult antimicrobial-resistant gram-negative bacilli to control and treat. Increasing antimicrobial resistance among Acinetobacter isolates has been documented, although definitions of multidrug resistance vary in the literature. A. baumannii survives for prolonged periods under a wide range of environmental conditions. The organism causes outbreaks of infection and health care-associated infections, including bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection. Antimicrobial resistance greatly limits the therapeutic options for patients who are infected with this organism, especially if isolates are resistant to the carbapenem class of antimicrobial agents. Because therapeutic options are limited for multidrug-resistant Acinetobacter infection, the development or discovery of new therapies, well-controlled clinical trials of existing antimicrobial regimens and combinations, and greater emphasis on the prevention of health care-associated transmission of multidrug-resistant Acinetobacter infection are essential. PMID- 18444866 TI - Emergency care physicians' knowledge, attitudes, and practices related to surveillance for foodborne disease in the United States. AB - During the past decade, the incidence of certain bacterial pathogens that are commonly transmitted through food in the United States has decreased. Concurrently, the emergency department has become an increasingly common setting for health care. Because public health surveillance for bacterial foodborne diseases fundamentally depends on stool cultures, we conducted a survey of physicians who attended an emergency medicine conference to describe knowledge, attitudes, and practices among this provider population. A convenience sample of 162 physicians, representing 34 states, provided responses. Thirty-eight percent reported having ordered a stool culture for the most recent patient with acute diarrheal illness examined in the emergency department, but only 26% of the physicians subsequently received the stool culture results. For only 2 pathogens (Escherichia coli O157:H7 and Salmonella species) did at least one-half of the respondents provide the correct response regarding whether selected diarrheal disease pathogens were reportable in their state. Responses indicated familiarity with the Infectious Diseases Society of America's practice guidelines regarding stool cultures for patients with severe symptoms and a history of travel, but less so with characteristics of public health importance (i.e., attendance at day care and employment as a restaurant cook). We recommend that educational opportunities be made available to emergency care physicians that highlight the public health significance of acute diarrheal illness and that reinforce guidelines regarding culturing stool specimens, making recommendations to prevent further transmission, and reporting to local health authorities. PMID- 18444867 TI - Severe renal dysfunction and risk factors associated with renal impairment in HIV infected adults in Africa initiating antiretroviral therapy. AB - BACKGROUND: We sought to investigate renal function in previously untreated symptomatic human immunodeficiency virus (HIV)-infected adults with CD4(+) cell counts of <200 cells/mm(3) who were undergoing antiretroviral therapy (ART) in Africa. METHODS: The study was an observational analysis within a randomized trial of ART management strategies that included 3316 participants with baseline serum creatinine levels of < or =360 micromol/L. Creatinine levels were measured before ART initiation, at weeks 4 and 12 of therapy, and every 12 weeks thereafter. We calculated estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault formula. We analyzed the incidence of severely decreased eGFR (<30 mL/min/1.73 m(2)) and changes in eGFR to 96 weeks, considering demographic data, type of ART, and baseline biochemical and hematological characteristics as predictors, using random-effects models. RESULTS: Sixty-five percent of the participants were women. Median values at baseline were as follows: age, 37 years; weight, 57 kg; CD4(+) cell count, 86 cells/mm(3); and eGFR, 89 mL/min/1.73 m(2). Of the participants, 1492 (45%) had mild (> or =60 but <90 mL/min/1.73 m(2)) and 237 (7%) had moderate (> or =30 but <60 mL/min/1.73 m(2)) impairments in eGFR. First-line ART regimens included zidovudine-lamivudine plus tenofovir disoproxil fumarate (for 74% of patients), nevirapine (16%), and abacavir (9%) (mostly nonrandomized allocation). After ART initiation, the median eGFR was 89 91 mL/min/1.73 m(2) for the period from week 4 through week 96. Fifty-two participants (1.6%) developed severe reductions in eGFR by week 96; there was no statistically significant difference between these patients and others with respect to first-line ART regimen received (P = .94). Lower baseline eGFR or hemoglobin level, lower body mass index, younger age, higher baseline CD4(+) cell count, and female sex were associated with greater increases in eGFR over baseline, with small but statistically significant differences between regimens (P < .001 for all). CONCLUSIONS: Despite screening, mild-to-moderate baseline renal impairment was relatively common, but these participants had greatest increases in eGFR after starting ART. Severe eGFR impairment was infrequent regardless of ART regimen and was generally related to intercurrent disease. Differences between ART regimens with respect to changes in eGFR through 96 weeks were of marginal clinical relevance, but investigating longer-term nephrotoxicity remains important. PMID- 18444868 TI - Predictors of renal outcome in HIV-associated nephropathy. AB - BACKGROUND: Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is an important cause of end-stage renal disease among African American patients. This study was performed to study the epidemiology of HIVAN in a predominantly black African population and the impact of highly active antiretroviral therapy and other factors on the development of end-stage renal disease. METHODS: We retrospectively identified all patients with HIVAN, defined by biopsy or strict clinical criteria, in 8 clinics in the United Kingdom. Baseline renal function, HIV parameters, renal pathological index of chronic damage, and responses to highly active antiretroviral therapy were analyzed, and factors associated with adverse renal outcome were identified. RESULTS: From 1998 through 2004, we studied 16,834 patients, 61 of whom had HIVAN. HIVAN prevalence in black patients was 0.93%, and HIVAN incidence in those without renal disease at baseline was 0.61 per 1000 person-years. After a median of 4.2 years, 34 patients (56%) had developed end-stage renal disease. There were no significant differences in renal function and HIV parameters at baseline, time to initiation of highly active antiretroviral therapy, and rates of HIV RNA suppression between the 20 patients who developed end-stage renal disease >3 months after receiving the HIVAN diagnosis and the 23 patients who maintained stable renal function. However, the index of chronic damage score was significantly higher in those who developed end stage renal disease (P < .001), and an index of chronic damage score >75 was associated with shorter renal survival (P < .001). CONCLUSIONS: Whereas overall patient survival suggested an important benefit of highly active antiretroviral therapy, no additional renal benefit of early initiation of highly active antiretroviral therapy or viral suppression could be demonstrated in this large cohort of patients with established HIVAN. Severity of chronic kidney damage, as quantified by biopsy, was the strongest predictor of renal outcome. PMID- 18444869 TI - Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study. AB - BACKGROUND: Stavudine is widely used in developing countries. Lipoatrophy and mitochondrial toxicity have been linked to stavudine use, but it is unclear whether switching to a lower dose can reduce these toxicities while maintaining human immunodeficiency virus (HIV) suppression. METHODS: HIV-infected subjects receiving standard-dose stavudine with undetectable HIV type 1 RNA for > or =6 months were randomized (ratio, 3:2) to receive one-half of the stavudine dose (switch arm) or to maintain the dose (continuation arm) while continuing to receive all other prescribed antiretrovirals. The following measurements were obtained at baseline and week 48: fasting lactate, pyruvate, and lipid levels; results of whole-body dual-energy x-ray absorptiometry; and mitochondrial DNA (mtDNA) measurements in fat and peripheral blood mononuclear cells. Change from baseline to week 48 was compared within and between groups. RESULTS: Twenty-four patients (79% of whom were men and 79% of whom were African American; median age, 45 years) were enrolled in the study, 15 were enrolled in the switch arm, and 9 were enrolled in the continuation arm. The median duration of stavudine treatment was 55 months (range, 21-126 months). The median CD4 cell count was 558 cells/mm(3) (range, 207-1698 cells/mm(3)). At baseline, the study arms had similar demographic characteristics and laboratory indices, except for body mass index, total lean body mass, and triglyceride levels (all of which were higher in the switch arm). Three patients (2 in the switch arm) discontinued the study because of study-unrelated reasons. CD4 cell counts remained unchanged. At 48 weeks, 6 patients (4 [27%] in the switch arm and 2 [22%] in the continuation arm) had detectable HIV RNA levels (median, 972 copies/mL; range, 60-49,400 copies/mL). All patients with detectable HIV RNA levels reported significant lapses in treatment adherence; none exhibited mutations in HIV genotype. After the treatment switch, significant changes from study entry to week 48 were noted only for lactate level (median change, -0.27 mmol/L; range, -1.2 to 0.25 mmol/L; P = .02) and fat mtDNA (median change, 40 copies/cell; range, -49 to 261 copies/cell; P = .02). In the continuation arm, a significant loss of bone mineral density was seen at week 48 (median change, -1.7%; range, -6.3% to 0.8%; P = .02). The only significant between-group difference was the change in bone mineral density from baseline (P = .003). CONCLUSIONS: Reducing stavudine dose by one-half increased fat mtDNA and decreased lactate levels, suggesting improvement in mitochondrial indices while preserving HIV suppression in subjects who maintained adherence. A significant loss of bone mineral density was seen in patients receiving standard-dose stavudine but not in those receiving low-dose stavudine. These results suggest that switching to low-dose stavudine may improve mitochondrial indices while maintaining virological suppression. PMID- 18444870 TI - The effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: answers and questions. PMID- 18444871 TI - Factors associated with the emergence of K65R in patients with HIV-1 infection treated with combination antiretroviral therapy containing tenofovir. AB - BACKGROUND: The human immunodeficiency virus type 1 reverse-transcriptase mutation K65R is a single-point mutation that has become more frequent after increased use of tenofovir disoproxil fumarate (TDF). We aimed to identify predictors for the emergence of K65R, using clinical data and genotypic resistance tests from the Swiss HIV Cohort Study. METHODS: A total of 222 patients with genotypic resistance tests performed while receiving treatment with TDF-containing regimens were stratified by detectability of K65R (K65R group, 42 patients; undetected K65R group, 180 patients). Patient characteristics at start of that treatment were analyzed. RESULTS: In an adjusted logistic regression, TDF treatment with nonnucleoside reverse-transcriptase inhibitors and/or didanosine was associated with the emergence of K65R, whereas the presence of any of the thymidine analogue mutations D67N, K70R, T215F, or K219E/Q was protective. The previously undescribed mutational pattern K65R/G190S/Y181C was observed in 6 of 21 patients treated with efavirenz and TDF. Salvage therapy after TDF treatment was started for 36 patients with K65R and for 118 patients from the wild-type group. Proportions of patients attaining human immunodeficiency virus type 1 loads <50 copies/mL after 24 weeks of continuous treatment were similar for the K65R group (44.1%; 95% confidence interval, 27.2%-62.1%) and the wild-type group (51.9%; 95% confidence interval, 42.0%-61.6%). CONCLUSIONS: In settings where thymidine analogue mutations are less likely to be present, such as at start of first-line therapy or after extended treatment interruptions, combinations of TDF with other K65R-inducing components or with efavirenz or nevirapine may carry an enhanced risk of the emergence of K65R. The finding of a distinct mutational pattern selected by treatment with TDF and efavirenz suggests a potential fitness interaction between K65R and nonnucleoside reverse-transcriptase inhibitor induced mutations. PMID- 18444872 TI - CPG 7909 adjuvant plus hepatitis B virus vaccination in HIV-infected adults achieves long-term seroprotection for up to 5 years. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected persons are hyporesponsive to hepatitis B virus (HBV) vaccination. CPG 7909 is an oligodeoxynucleotide containing immunostimulatory CpG motifs that activate human B and plasmacytoid dendritic cells via Toll-like receptor 9. We previously reported that addition of CPG 7909 to a commercial HBV vaccine enhanced the kinetics, magnitude, and longevity of the seroprotective response over 48 weeks. We now report data for the 5-year period following vaccination. METHODS: A randomized, double-blind, controlled trial was conducted to determine clinical safety and immunogenicity of HBV vaccine in adult HIV-infected subjects receiving effective antiretroviral therapy. HBV-susceptible subjects, one-half of whom had experienced previous vaccination failure, were vaccinated at 0, 1, and 2 months with a double adult dose of recombinant HBV vaccine, with or without 1 mg of CPG 7909 (19 subjects per arm). Titers of antibody to HBV surface antigen (anti-HBs) were measured at 6-month intervals for up to 60 months. RESULTS: The proportion of participants achieving and retaining seroprotection (surface antibody titers, > or =10 mIU/mL) was greater in CPG 7909 recipients (P < .05 at all time points). Geometric mean anti-HBs titers were higher in the CPG 7909 group than in the control group (without CPG 7909 adjuvant) at all measured time points. CONCLUSIONS: The immunostimulatory properties of CPG 7909 present an important strategy in achieving long-term protection in HIV-infected patients and other HBV vaccine-hyporesponsive populations. PMID- 18444873 TI - Clinical inertia in the management of low-density lipoprotein abnormalities in an HIV clinic. AB - A retrospective cohort study evaluating the frequency of and factors related to clinical inertia in low-density lipoprotein (LDL) management was performed. Subjects were 90 patients that were not meeting National Cholesterol Education Program Adult Treatment Panel III LDL goals at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic between 1 August 2004 and 1 August 2005. Clinical inertia was observed in 44% of cases. Patients with higher baseline LDL levels were less likely to experience inertia, whereas women and those in the highest coronary heart disease risk category were more likely to be affected. PMID- 18444876 TI - Depression and HIV risk taking. PMID- 18444877 TI - Duration of stool colonization in patients infected with extended-spectrum beta lactamase-producing Escherichia coli and Klebsiella pneumoniae. PMID- 18444878 TI - Antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes. PMID- 18444879 TI - Increased antimicrobial susceptibility profiles among polymyxin-resistant Acinetobacter baumannii clinical isolates. PMID- 18444882 TI - Increased levels of interleukin-10 and IgG3 are hallmarks of Indian post-kala azar dermal leishmaniasis. AB - BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL), an established sequela of visceral leishmaniasis (VL), is proposed to facilitate anthroponotic transmission of VL, especially during interepidemic periods. Immunopathological mechanisms responsible for Indian PKDL are still poorly defined. METHODS: Our study attempted to characterize the immune profiles of patients with PKDL or VL relative to that of healthy control subjects by immunophenotyping, intracellular cytokine staining of peripheral blood mononuclear cells, and enzyme-linked immunosorbent assay for serum cytokines and immunoglobulin G (IgG) subclasses. RESULTS: Patients with PKDL had significantly raised percentages of peripheral CD3+CD8+ cells compared with control subjects, a difference that persisted after cure. Patients with PKDL showed an intact response to phytohemagglutinin, with the percentages of lymphocytes expressing interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and IL-10 being comparable to those in control subjects. Patients with VL had decreased IFN-gamma and IL-2 expression, which was restored after cure, and increased IL-10 expression, which persisted after cure. In their response to Leishmania donovani antigen, patients with PKDL showed a 9.6-fold increase in the percentage of IL-10-expressing CD3+CD8+ lymphocytes compared with control subjects, and this percentage decreased with treatment. Patients with PKDL had raised levels of IgG3 and IgG1 (surrogate markers for IL-10), concomitant with increased serum levels of IL-10. CONCLUSIONS: IL-10-producing CD3+CD8+ lymphocytes are important protagonists in the immunopathogenesis of Indian PKDL. PMID- 18444883 TI - Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects. AB - BACKGROUND: VCL-CB01, a candidate cytomegalovirus (CMV) DNA vaccine that contains plasmids encoding CMV phosphoprotein 65 (pp65) and glycoprotein B (gB) to induce cellular and humoral immune responses and that is formulated with poloxamer CRL1005 and benzalkonium chloride to enhance immune responses, was evaluated in a phase 1 clinical trial. METHODS: VCL-CB01 was evaluated in 44 healthy adult subjects (22 CMV seronegative and 22 CMV seropositive) 18-43 years old. Thirty two subjects received 1- or 5-mg doses of vaccine on a 0-, 2-, and 8-week schedule, and 12 subjects received 5-mg doses of vaccine on a 0-, 3-, 7-, and 28 day schedule. RESULTS: Overall, the vaccine was well tolerated, with no serious adverse events. Local reactions included mild to moderate injection site pain and tenderness, induration, and erythema. Systemic reactions included mild to moderate malaise and myalgia. All reactions resolved without sequelae. Through week 16 of the study, immunogenicity, as measured by enzyme-linked immunosorbant assay and/or ex vivo interferon (IFN)-gamma enzyme-linked immunospot assay, was documented in 45.5% of CMV-seronegative subjects and in 25.0% of CMV-seropositive subjects who received the full vaccine series, and 68.1% of CMV-seronegative subjects had memory IFN-gamma T cell responses at week 32. CONCLUSION: The safety and immunogenicity data from this trial support further evaluation of VCL-CB01. PMID- 18444885 TI - Toward the development of vectored vaccines in compliance with evolutionary medicine. PMID- 18444884 TI - A cytomegalovirus vaccine for transplantation: are we closer? PMID- 18444886 TI - What about cholera vaccines? PMID- 18444888 TI - Immortalized B cells: a neverending source of antigen-presenting cells for vaccines? PMID- 18444890 TI - Cholera in disasters: do vaccines prompt new hopes? AB - Humanitarian aid workers regularly encounter the challenge of setting up functioning surveillance systems immediately after a disaster. Detecting potential outbreaks of diseases, such as cholera, that might arise from disturbed living conditions, displacement and lack of clean water and sanitation is, therefore, extremely difficult. Fears of cholera outbreaks are often rife in such conditions and the pertinence of using cholera vaccines, now available on the market, merit attention. The case of Aceh province, Indonesia, following the 2004 tsunami is examined here: the government of Indonesia decided to carry out a mass vaccination campaign using oral cholera vaccines, a two-dose product that has not been used widely in the particular circumstances of complex emergencies. The preparation and implementation of this campaign faced many hindrances that unfavorably impacted on the time taken to vaccinate the target population and the costs involved. An estimated 69.3% of the target population received immunization. Evidence gathered during the Aceh campaign could be compared with those of a campaign held in another emergency context--Darfur (Sudan). In spite of many dissimilarities, both experiences illustrate the fact that the question of feasibility and relevance of interventions, as well as prioritization of health needs in complex emergencies, remain crucial to alleviate the affected population's suffering in the most efficient way. Following these two campaigns, WHO recommendations on the use of oral cholera vaccines in complex emergencies were issued in 2006. PMID- 18444889 TI - Monovalent virus-like particle vaccine protects guinea pigs and nonhuman primates against infection with multiple Marburg viruses. AB - BACKGROUND: Virus-like particle (VLP)-based vaccines have the advantage of being morphologically and antigenically similar to the live virus from which they are derived. Expression of the glycoprotein and VP40 matrix protein from Lake Victoria marburgvirus (MARV) results in spontaneous production of VLPs in mammalian cells. Guinea pigs vaccinated with Marburg virus VLPs (mVLPs) or inactivated MARV (iMARV) develop homologous humoral and T-cell responses and are completely protected from a lethal homologous MARV challenge. AIMS & METHODS: To determine whether mVLPs based on the Musoke (aka Lake Victoria) isolate of MARV could broadly protect against diverse isolates of MARV, guinea pigs were vaccinated with mVLPs or iMARV-Musoke and challenged with MARV-Musoke, -Ravn or Ci67. RESULTS: Prior to challenge, the mVLP- and iMARV-vaccinated guinea pigs had high levels of homologous MARV-Musoke and heterologous MARV-Ravn and -Ci67 antibodies. The Musoke-based mVLPs and iMARV vaccines provided complete protection in guinea pigs against viremia, viral replication and pathological changes in tissues, and lethal disease following challenge with MARV-Musoke, Ravn or -Ci67. Guinea pigs vaccinated with RIBI adjuvant alone and infected with guinea pig-adapted MARV-Musoke, -Ravn or -Ci67 had histopathologic findings similar to those seen in the nonhuman primate model for MARV infection. Based on the strong protection observed in guinea pigs, we next vaccinated cynomolgus macaques with Musoke-based mVLPs and showed the VLP-vaccinated monkeys were broadly protected against three isolates of MARV (Musoke, Ravn and Ci67). CONCLUSION: Musoke mVLPs are effective at inducing broad heterologous immunity and protection against multiple MARV isolates. PMID- 18444891 TI - Monitoring the impact of vaccines postlicensure: new challenges, new opportunities. AB - Although vaccines are studied intensively before licensure, insight into important aspects of vaccine performance and the effectiveness of immunization programs and policies can only be detected after vaccines enter widespread use. Now that 17 diseases are targeted for prevention through routine immunizations in the USA, reassessment of the nation's vaccine-preventable disease-monitoring efforts is appropriate. Postlicensure disease monitoring has permitted recognition of indirect protection, vaccine effectiveness of various schedules, duration of protection, health disparities, importation patterns and microbial adaptation. The investments in vaccine research, development and regulatory procedures prelicensure, as well as resources devoted to purchase, distribution and delivery of vaccines after introduction, necessitate strategic efforts to monitor the impact of large-scale use of vaccines on disease over time. PMID- 18444892 TI - Microenvironmental impact on lung cell homeostasis and immunity during infection. AB - The lung is a vital organ devoted mainly to gas exchange with an external environment that may be contaminated with various life-threatening pathogens and inert particles. Lung immunity must be permanently balanced between costimulatory and coinhibitory signals, thus controlling potential pathogens while avoiding detrimental inflammation. The lung harbors macrophages and dendritic cells (myeloid and plasmacytoid), which orchestrate the primary defense against microbial invaders. During an infection involving host-microbial synapses, microbes either escape by using host cell physiology or are eliminated by a robust immune response. We thus focus on the dynamics of such cellular interactions within the lung and stress the critical role played by airway epithelial cells in modulating immunity. PMID- 18444893 TI - Age-related decline in immunity: implications for vaccine responsiveness. AB - Aging is associated with declines in immune system function, or 'immunosenescence', leading to progressive deterioration in both innate and adaptive immunity. These changes contribute to the decreased response to vaccines seen in many older adults, and morbidity and mortality from infection. Infections (e.g., influenza, pneumonia and septicemia) appear among the top ten most-common causes of death in adults in the USA aged 55 years and older. As immunosenescence has gathered more attention in the scientific and healthcare communities, investigators have demonstrated more links between immunosenescent changes and morbidity and mortality related to infections and declining vaccine responses. This review summarizes the recent literature on age-dependent defects in adaptive and innate immunity, data linking these defects to poor vaccine response and morbidity and mortality, current recommendations for vaccinations and potential strategies to improve vaccine efficacy in older adults. PMID- 18444894 TI - New drugs and vaccines for drug-resistant Mycobacterium tuberculosis infections. AB - Tuberculosis remains the most common cause of death due to a single infective organism. Despite the availability of a vaccine and chemotherapeutic options, the global disease burden remains relatively unaffected. The ability of the mycobacterial etiological agents to adopt a semidormant, phenotypically drug resistant state requires that chemotherapy is both complex and lengthy. The emergence of drug resistance has raised the possibility of virtually untreatable tuberculosis. Furthermore, the currently used bacillus Calmette-Guerin vaccine has had mixed success in protecting susceptible populations. Given this backdrop, the need for novel anti-infectives and more effective vaccines is clearly evident. Recent progress, described herein, has seen the development and entry into clinical trials of several new drugs and vaccine candidates. PMID- 18444895 TI - Various carrier system(s)- mediated genetic vaccination strategies against malaria. AB - The introduction of vaccine technology has facilitated an unprecedented multiantigen approach to develop an effective vaccine against complex pathogens, such as Plasmodium spp., that cause severe malaria. The capacity of multisubunit DNA vaccines encoding different stage Plasmodium antigens to induce CD8(+) cytotoxic T lymphocytes and IFN-gamma responses in mice, monkeys and humans has been observed. Moreover, genetic vaccination may be multi-immune (i.e., capable of eliciting more than one type of immune response, including cell-mediated and humoral). In the case of malaria parasites, a cytotoxic T-lymphocyte response is categorically needed against the intracellular hepatocyte stage while a humoral response, with antibodies targeted against antigens from all stages of the life cycle, is also needed. Therefore, the key to success for any DNA-based therapy is to design a vector able to serve as a safe and efficient delivery system. This has encouraged the development of nonviral DNA-mediated gene-transfer techniques, such as liposomes, virosomes, microspheres and nanoparticles. Efficient and relatively safe DNA transfection using lipoplexes makes them an appealing alternative to be explored for gene delivery. In addition, liposome-entrapped DNA has been shown to enhance the potency of DNA vaccines, possibly by facilitating uptake of the plasmid by antigen-presenting cells. Another recent technology using cationic lipids has been deployed and has generated substantial interest in this approach to gene transfer. This review comprises various aspects that could be decisive in the formulation of efficient and stable carrier system(s) for the development of malaria vaccines. PMID- 18444897 TI - Chlorophyll fluorescence: a probe of photosynthesis in vivo. AB - The use of chlorophyll fluorescence to monitor photosynthetic performance in algae and plants is now widespread. This review examines how fluorescence parameters can be used to evaluate changes in photosystem II (PSII) photochemistry, linear electron flux, and CO(2) assimilation in vivo, and outlines the theoretical bases for the use of specific fluorescence parameters. Although fluorescence parameters can be measured easily, many potential problems may arise when they are applied to predict changes in photosynthetic performance. In particular, consideration is given to problems associated with accurate estimation of the PSII operating efficiency measured by fluorescence and its relationship with the rates of linear electron flux and CO(2) assimilation. The roles of photochemical and nonphotochemical quenching in the determination of changes in PSII operating efficiency are examined. Finally, applications of fluorescence imaging to studies of photosynthetic heterogeneity and the rapid screening of large numbers of plants for perturbations in photosynthesis and associated metabolism are considered. PMID- 18444898 TI - Seed storage oil mobilization. AB - Storage oil mobilization starts with the onset of seed germination. Oil bodies packed with triacylglycerol (TAG) exist in close proximity with glyoxysomes, the single membrane-bound organelles that house most of the biochemical machinery required to convert fatty acids derived from TAG to 4-carbon compounds. The 4 carbon compounds in turn are converted to soluble sugars that are used to fuel seedling growth. Biochemical analysis over the last 50 years has identified the main pathways involved in this process, including beta-oxidation, the glyoxylate cycle, and gluconeogenesis. In the last few years molecular genetic dissection of the overall process in the model oilseed species Arabidopsis has provided new insight into its complexity, particularly with respect to the specific role played by individual enzymatic steps and the subcellular compartmentalization of the glyoxylate cycle. Both abscisic acid (ABA) and sugars inhibit storage oil mobilization and a substantial degree of the control appears to operate at the transcriptional level. PMID- 18444899 TI - The role of glutathione in photosynthetic organisms: emerging functions for glutaredoxins and glutathionylation. AB - Glutathione, a tripeptide with the sequence gamma-Glu-Cys-Gly, exists either in a reduced form with a free thiol group or in an oxidized form with a disulfide between two identical molecules. We describe here briefly the pathways involved in the synthesis, reduction, polymerization, and degradation of glutathione, as well as its distribution throughout the plant and its redox buffering capacities. The function of glutathione in xenobiotic and heavy metal detoxification, plant development, and plant-pathogen interactions is also briefly discussed. Several lines of evidence indicate that glutathione and glutaredoxins (GRXs) are implicated in the response to oxidative stress through the regeneration of enzymes involved in peroxide and methionine sulfoxide reduction. Finally, emerging functions for plant GRXs and glutathione concern the regulation of protein activity via glutathionylation and the capacity of some GRXs to bind iron sulfur centers and for some of them to transfer FeS clusters into apoproteins. PMID- 18444900 TI - Algal sensory photoreceptors. AB - Only five major types of sensory photoreceptors (BLUF-proteins, cryptochromes, phototropins, phytochromes, and rhodopsins) are used in nature to regulate developmental processes, photosynthesis, photoorientation, and control of the circadian clock. Sensory photoreceptors of algae and protists are exceptionally rich in structure and function; light-gated ion channels and photoactivated adenylate cyclases are unique examples. During the past ten years major progress has been made with respect to understanding the function, photochemistry, and structure of key sensory players of the algal kingdom. PMID- 18444901 TI - Molecular basis of plant architecture. AB - Higher plants display a variety of architectures that are defined by the degree of branching, internodal elongation, and shoot determinancy. Studies on the model plants of Arabidopsis thaliana and tomato and on crop plants such as rice and maize have greatly strengthened our understanding on the molecular genetic bases of plant architecture, one of the hottest areas in plant developmental biology. The identification of mutants that are defective in plant architecture and characterization of the corresponding and related genes will eventually enable us to elucidate the molecular mechanisms underlying plant architecture. The achievements made so far in studying plant architecture have already allowed us to pave a way for optimizing the plant architecture of crops by molecular design and improving grain productivity. PMID- 18444902 TI - Flooding stress: acclimations and genetic diversity. AB - Flooding is an environmental stress for many natural and man-made ecosystems worldwide. Genetic diversity in the plant response to flooding includes alterations in architecture, metabolism, and elongation growth associated with a low O(2) escape strategy and an antithetical quiescence scheme that allows endurance of prolonged submergence. Flooding is frequently accompanied with a reduction of cellular O(2) content that is particularly severe when photosynthesis is limited or absent. This necessitates the production of ATP and regeneration of NAD(+) through anaerobic respiration. The examination of gene regulation and function in model systems provides insight into low-O(2)-sensing mechanisms and metabolic adjustments associated with controlled use of carbohydrate and ATP. At the developmental level, plants can escape the low-O(2) stress caused by flooding through multifaceted alterations in cellular and organ structure that promote access to and diffusion of O(2). These processes are driven by phytohormones, including ethylene, gibberellin, and abscisic acid. This exploration of natural variation in strategies that improve O(2) and carbohydrate status during flooding provides valuable resources for the improvement of crop endurance of an environmental adversity that is enhanced by global warming. PMID- 18444903 TI - Roots, nitrogen transformations, and ecosystem services. AB - This review considers some of the mechanistic processes that involve roots in the soil nitrogen (N) cycle, and their implications for the ecological functions that retain N within ecosystems: 1) root signaling pathways for N transport systems, and feedback inhibition, especially for NO(3)(-) uptake; 2) dependence on the mycorrhizal and Rhizobium/legume symbioses and their tradeoffs for N acquisition; 3) soil factors that influence the supply of NH(4)(+) and NO(3)(-) to roots and soil microbes; and 4) rhizosphere processes that increase N cycling and retention, such as priming effects and interactions with the soil food web. By integrating information on these plant-microbe-soil N processes across scales and disciplinary boundaries, we propose ideas for better manipulating ecological functions and processes by which the environment provides for human needs, i.e., ecosystem services. Emphasis is placed on agricultural systems, effects of N deposition in natural ecosystems, and ecosystem responses to elevated CO(2) concentrations. This shows the need for multiscale approaches to increase human dependence on a biologically based N supply. PMID- 18444904 TI - Auxin: the looping star in plant development. AB - The phytohormone auxin is a key factor in plant growth and development. Forward and reverse genetic strategies have identified important molecular components in auxin perception, signaling, and transport. These advances resulted in the identification of some of the underlying regulatory mechanisms as well as the emergence of functional frameworks for auxin action. This review focuses on the feedback loops that form an integrative part of these regulatory mechanisms. PMID- 18444905 TI - Regulation of cullin RING ligases. AB - The ubiquitin/26S proteasome pathway largely mediates selective proteolysis in the nucleus and cytosol. This pathway catalyzes covalent attachment of ubiquitin (UBQ) to substrate proteins in an E1-E2-E3 cascade. Ubiquitin E3 ligases interact with substrates to catalyze UBQ transfer from E2 to substrate. Within the E3 ligase superfamily, cullin RING ligases (CRLs) are significant in plants because they are linked to hormonal signaling, developmental programs, and environmental responses. Thus, knowledge of CRL regulation is required for a complete understanding of these processes. A major mechanism modulating CRL activity is modification of the cullin subunit by RUB (RELATED TO UBIQUITIN), a ubiquitin like protein, and demodification by the COP9 signalosome (CSN). CULLIN-ASSOCIATED NEDD8-DISSOCIATED 1 (CAND1) interacts with CRLs, affecting both rubylation and derubylation. Described here are the pathways, regulation, and biological function of rubylation and derubylation, as well as future directions and outstanding questions. PMID- 18444906 TI - Coordinating nodule morphogenesis with rhizobial infection in legumes. AB - The formation of nitrogen-fixing nodules on legumes requires an integration of infection by rhizobia at the root epidermis and the initiation of cell division in the cortex, several cell layers away from the sites of infection. Several recent developments have added to our understanding of the signaling events in the epidermis associated with the perception of rhizobial nodulation factors and the role of plant hormones in the activation of cell division leading to nodule morphogenesis. This review focuses on the tissue-specific nature of the developmental processes associated with nodulation and the mechanisms by which these processes are coordinated during the formation of a nodule. PMID- 18444907 TI - Structural and signaling networks for the polar cell growth machinery in pollen tubes. AB - Pollen tubes elongate within the pistil to transport sperms to the female gametophytes for fertilization. Pollen tubes grow at their tips through a rapid and polarized cell growth process. This tip growth process is supported by an elaborate and dynamic actin cytoskeleton and a highly active membrane trafficking system that together provide the driving force and secretory activities needed for growth. A polarized cytoplasm with an abundance of vesicles and tip-focused Ca(2+) and H(+) concentration gradients are important for the polar cell growth process. Apical membrane-located Rho GTPases regulate Ca(2+) concentration and actin dynamics in the cytoplasm and are crucial for maintaining pollen tube polarity. Pollen tube growth is marked by periods of rapid and slow growth phases. Activities that regulate and support this tip growth process also show oscillatory fluctuations. How these activities correlate with the rapid, polar, and oscillatory pollen tube growth process is discussed. PMID- 18444908 TI - Regulation and identity of florigen: FLOWERING LOCUS T moves center stage. AB - The transition from vegetative to reproductive growth is controlled by day length in many plant species. Day length is perceived in leaves and induces a systemic signal, called florigen, that moves through the phloem to the shoot apex. At the shoot apical meristem (SAM), florigen causes changes in gene expression that reprogram the SAM to form flowers instead of leaves. Analysis of flowering of Arabidopsis thaliana placed the CONSTANS/FLOWERING LOCUS T (CO/FT) module at the core of a pathway that promotes flowering in response to changes in day length. We describe progress in defining the molecular mechanisms that activate this module in response to changing day length and the increasing evidence that FT protein is a major component of florigen. Finally, we discuss conservation of FT function in other species and how variation in its regulation could generate different flowering behaviors. PMID- 18444909 TI - Plant aquaporins: membrane channels with multiple integrated functions. AB - Aquaporins are channel proteins present in the plasma and intracellular membranes of plant cells, where they facilitate the transport of water and/or small neutral solutes (urea, boric acid, silicic acid) or gases (ammonia, carbon dioxide). Recent progress was made in understanding the molecular bases of aquaporin transport selectivity and gating. The present review examines how a wide range of selectivity profiles and regulation properties allows aquaporins to be integrated in numerous functions, throughout plant development, and during adaptations to variable living conditions. Although they play a central role in water relations of roots, leaves, seeds, and flowers, aquaporins have also been linked to plant mineral nutrition and carbon and nitrogen fixation. PMID- 18444910 TI - Mechanisms of salinity tolerance. AB - The physiological and molecular mechanisms of tolerance to osmotic and ionic components of salinity stress are reviewed at the cellular, organ, and whole plant level. Plant growth responds to salinity in two phases: a rapid, osmotic phase that inhibits growth of young leaves, and a slower, ionic phase that accelerates senescence of mature leaves. Plant adaptations to salinity are of three distinct types: osmotic stress tolerance, Na(+) or Cl() exclusion, and the tolerance of tissue to accumulated Na(+) or Cl(). Our understanding of the role of the HKT gene family in Na(+) exclusion from leaves is increasing, as is the understanding of the molecular bases for many other transport processes at the cellular level. However, we have a limited molecular understanding of the overall control of Na(+) accumulation and of osmotic stress tolerance at the whole-plant level. Molecular genetics and functional genomics provide a new opportunity to synthesize molecular and physiological knowledge to improve the salinity tolerance of plants relevant to food production and environmental sustainability. PMID- 18444911 TI - Prevalence of GSTT1, GSTM1 and NQO1 (609C>T) in Filipino children with ALL (acute lymphoblastic leukaemia). AB - In the present paper, we examined the incidence of polymorphic genes involved with the detoxification of exogenous chemicals, including carcinogens, namely GSTT1 (glutathione transferase theta1), GSTM1 (glutathione transferase micro1) and NQO1 (NAD(P)H:quinone oxidoreductase 1) in 60 Filipino paediatric patients with ALL (acute lymphoblastic leukaemia). We found a significantly high incidence of the GSTM1 null genotype in ALL children (71.7%) compared with 51.7% in the control group of children (P<0.05). The GSTT1 null genotype was observed in 35.0% and 33.3% of the ALL cases and the control subjects respectively, with no significant difference. Screening for NQO1 (609C>T) mutant alleles showed a high incidence of the NQO1 C/C genotype (NQO1 homozygous wild-type allele genotype) in 60.0% of ALL cases and was significantly higher than in the control group (23.3%) (P<0.01). These GSTM1 null and NQO1 wild-type genotypes are independently associated with the risk of ALL in Filipino patients. When these two genotypes, GSTM1 null and NQO1 C/C, were combined, the hazard rate for childhood leukaemia was significantly increased (P<0.001). We also noticed that the incidences of GSTM1 null mutations and the NQO1 C/C genotype were significantly higher among Filipinos. These findings suggest a possible role of the GSTM1 null and NQO1 C/C genotypes in the susceptibility of paediatric ALL cases in the Philippines. PMID- 18444912 TI - The Banff 2007 working classification of skin-containing composite tissue allograft pathology. AB - Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune-mediated rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La-Coruna, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA-07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin containing CTAs. PMID- 18444913 TI - The number of activating KIR genes inversely correlates with the rate of CMV infection/reactivation in kidney transplant recipients. AB - Viral infection is a common complication after kidney transplantation. The role of natural killer cells (NK cells) in this setting remains unknown. NK cells express activating and inhibitory killer cell immunoglobulin-like receptors (KIR). We analyzed whether activating KIR genes carried by kidney transplant recipients influence the rate of viral infection during the first year after transplantation. In patients with a KIR A/A genotype (n = 40, KIR2DS4 only activating KIR) the rate of cytomegalovirus (CMV) infection and reactivation was 36%, as compared to 20% in transplant recipients with more than one activating KIR gene (KIR B/X genotype, n = 82, p = 0.04). Adjusting for other risk factors in Cox regression, the relative risk of B versus A genotype patients was 0.34 (95% CI 0.15-0.76, p = 0.009). The degree of protection increased with the number of activating KIR genes. Symptomatic CMV disease was only observed in four individuals, all carrying a KIR A/A genotype. As for viral infections other than CMV, and for bacterial infections, no KIR-linked protective effect could be detected. Also, graft function and the rate-rejection episodes were similar in KIR A/A and KIR B/X genotype individuals. This study supports a role for activating KIR in the control of CMV infection after kidney transplantation. PMID- 18444914 TI - Hematopoietic stem cell engraftment and seeding permits multi-lymphoid chimerism in vascularized bone marrow transplants. AB - Vascularized bone marrow transplantation (VBMT) across a MHC barrier under a 7 day alphabeta-TCR mAb and CsA protocol facilitated multiple hematolymphoid chimerism via trafficking of the immature (CD90) bone marrow cells (BMC) between donor and recipient compartments. Early engraftment of donor BMC [BN(RT1(n))] into the recipient BM compartment [LEW(RT1(l))] was achieved at 1 week posttransplant and this was associated with active hematopoiesis within allografted bone and correlated with high chimerism in the hematolymphoid organs. Two-way trafficking between donor and recipient BM compartments was confirmed by the presence of recipient MHC class I cells (RT1(l)) within the allografted bone up to 3 weeks posttransplant. At 10 weeks posttransplant, decline of BMC viability in allografted bone corresponded with bone fibrosis and lack of hematopoiesis. In contrast, active hematopoiesis was present in the recipient bone as evidenced by the presence of donor-specific immature (CD90/RT1(n)) cells, which correlated with chimerism maintenance. Clonogenic activity of donor-origin cells (RT1(n)) engrafted into the host BM compartment was confirmed by colony forming units (CFU) assay. These results confirm that hematolymphoid chimerism is developed early post-VBMT by T-cell lineage and despite allografted bone fibrosis chimerism maintenance is supported by B-cell linage and active hematopoiesis of donor-origin cells in the host BM compartment. PMID- 18444915 TI - High levels of donor CCL2/MCP-1 predict graft-related complications and poor graft survival after kidney-pancreas transplantation. AB - In this study we analyzed the role of CCL2, a member of the chemokine family, in early graft damage. Using simultaneous kidney-pancreas transplantation (SPK) as a model, we showed that brain death significantly increases circulating CCL2 levels in humans. We found that in such situations, high donor CCL2 levels (measured before organ recovery and at the onset of cold preservation) correlate with increased postreperfusion release of CCL2 by both the graft and recipient throughout the week following transplantation (n = 28). In a retrospective study of 77 SPK recipients, we found a significant negative association between high donor levels of CCL2 and graft survival. Decreased survival in these patients is related to early posttransplant complications, including a higher incidence of pancreas thrombosis and delayed kidney function. Taken together our data indicate that high CCL2 levels in the donor serum predict both an increase in graft/recipient CCL2 production and poor graft survival. This suggests that the severity of the inflammatory response induced by brain death influences the posttransplant inflammatory response, independent of subsequent ischemia and reperfusion. PMID- 18444916 TI - Dextran sulfate facilitates anti-CD4 mAb-induced long-term rat cardiac allograft survival after prolonged cold ischemia. AB - Ischemia/reperfusion injury leads to activation of graft endothelial cells (EC), boosting antigraft immunity and impeding tolerance induction. We hypothesized that the complement inhibitor and EC-protectant dextran sulfate (DXS, MW 5000) facilitates long-term graft survival induced by non-depleting anti-CD4 mAb (RIB 5/2). Hearts from DA donor rats were heterotopically transplanted into Lewis recipients treated with RIB 5/2 (20 mg/kg, days-1,0,1,2,3; i.p.) with or without DXS (grafts perfused with 25 mg, recipients treated i.v. with 25 mg/kg on days 1,3 and 12.5 mg/kg on days 5,7,9,11,13,15). Cold graft ischemia time was 20 min or 12 h. Median survival time (MST) was comparable between RIB 5/2 and RIB 5/2+DXS-treated recipients in the 20-min group with >175-day graft survival. In the 12-h group RIB 5/2 only led to chronic rejection (MST = 49.5 days) with elevated alloantibody response, whereas RIB 5/2+DXS induced long-term survival (MST >100 days, p < 0.05) with upregulation of genes related to transplantation tolerance. Analysis of the 12-h group treated with RIB 5/2+DXS at 1-day posttransplantation revealed reduced EC activation, complement deposition and inflammatory cell infiltration. In summary, DXS attenuates I/R-induced acute graft injury and facilitates long-term survival in this clinically relevant transplant model. PMID- 18444917 TI - Primum non nocere and living organ donation: a response to Dr. Klintmalm. PMID- 18444918 TI - Recurrent idiopathic membranous nephropathy after kidney transplantation: a surveillance biopsy study. AB - Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. MN can recur after kidney transplantation causing proteinuria, allograft dysfunction and graft failure. In this study we assessed the incidence of MN recurrence utilizing surveillance graft biopsies. The study included 1310 renal allograft recipients from 2000 to 2006. Glomerular diseases were the cause of kidney failure in 28% of patients and 23 (2%) had idiopathic MN. Recurrent MN was diagnosed in eight of 19 patients included in this analysis (42%) 13 +/- 20 months (median = 4; range 2-61 months) after transplant. The initial clinical manifestations of recurrent MN were mild or absent. Urine protein excretion was 825 +/- 959 (64-2286) mg/day and three patients had no proteinuria. Five of seven patients who did not receive additional immunosuppression for MN had significant increases in proteinuria during follow up and three became nephrotic. At diagnosis, light microscopic changes were subtle or absent. All patients had granular glomerular basement membrane deposits of IgG but little or absent C3 by immunofluorescence. Subepithelial deposits were observed in all cases by electron microscopy. In conclusion, idiopathic MN recurred in 42% of patients after transplantation. The initial clinical and histologic manifestations are subtle but the disease is progressive. PMID- 18444920 TI - Islet transplantation for brittle type 1 diabetes: the UIC protocol. AB - This prospective phase 1/2 trial investigated the safety and reproducibility of allogeneic islet transplantation (Tx) in type I diabetic (T1DM) patients and tested a strategy to achieve insulin-independence with lower islet mass. Ten C peptide negative T1DM subjects with hypoglycemic unawareness received 1-3 intraportal allogeneic islet Tx and were followed for 15 months. Four subjects (Group 1) received the Edmonton immunosuppression regimen (daclizumab, sirolimus, tacrolimus). Six subjects (Group 2) received the University of Illinois protocol (etanercept, exenatide and the Edmonton regimen). All subjects became insulin- independent. Group 1 received a mean total number of islets (EIN) of 1460 080 +/- 418 330 in 2 (n = 2) or 3 (n = 2) Tx, whereas Group 2 became insulin- independent after 1 Tx (537 495 +/- 190 968 EIN, p = 0.028). All Group 1 subjects remained insulin free through the follow-up. Two Group 2 subjects resumed insulin: one after immunosuppression reduction during an infectious complication, the other with exenatide intolerance. HbA1c reached normal range in both groups (6.5 +/- 0.6 at baseline to 5.6 +/- 0.5 after 2-3 Tx in Group 1 vs. 7.8 +/- 1.1 to 5.8 +/- 0.3 after 1 Tx in Group 2). HYPO scores markedly decreased in both groups. Combined treatment of etanercept and exenatide improves islet graft function and facilitates achievement of insulin-independence with less islets. PMID- 18444921 TI - Predictors of long-term survival after liver transplantation for metastatic endocrine tumors: an 85-case French multicentric report. AB - Liver transplantation (LTx) for metastatic endocrine tumors (MET) remains controversial due to the lack of clear selection criteria. From 1989 to 2005, 85 patients underwent LTx for MET. The primary tumor was located in the pancreas or duodenum in 40 cases, digestive tract in 26 and bronchial tree in five. In the remaining 14 cases, primary location was undetermined at the time of LTx. Hepatomegaly (explanted liver > or =120% of estimated standard liver volume) was observed in 53 patients (62%). Extrahepatic resection was performed concomitantly with LTx in 34 patients (40%), including upper abdominal exenteration (UAE) in seven. Postoperative in-hospital mortality was 14%. Overall 5-year survival was 47%. Independent factors of poor prognosis according to multivariate analysis included UAE (relative risk (RR): 3.72), primary tumor in duodenum or pancreas (RR: 2.94) and hepatomegaly (RR: 2.63). After exclusion of cases involving concomitant UAE, the other two factors were combined into a risk model. Five-year survival rate was 12% for the 23 patients presenting both unfavorable prognostic factors versus 68% for the 55 patients presenting one or neither factor (p < 10( 7)). LTx can benefit selected patients with nonresectable MET. Patients presenting duodeno-pancreatic MET in association with hepatomegaly are poor indications for LTx. PMID- 18444922 TI - Expression of B cell and immunoglobulin transcripts is a feature of inflammation in late allografts. AB - To assess the significance of B-cell and plasma cell infiltrates in renal allografts, we compared expression of B-cell-associated transcripts (BATs) and immunoglobulin transcripts (IGTs) to histopathology and function in 177 renal allograft biopsies for clinical indications. BAT and IGT expression correlated with immunostaining for B cells and plasma cells and with expression of B-cell and plasma cell transcription factors. BATs and IGTs were increased in both T cell-mediated and antibody-mediated rejection. BAT and IGT scores were strongly related to time posttransplant: biopsies <5 months expressed less BATs and did not express increased IGTs. In contrast, T-cell-associated transcripts were independent of time posttransplant. In biopsies > or =5 months, BAT and IGT scores correlated with interstitial inflammation, tubular atrophy and interstitial fibrosis. By regression tree analysis, the only variables independently correlated with BATs and IGTs were time and inflammation. Expression of BATs and IGTs correlated with renal function, but this relationship was due to differences in early versus late biopsies: BATs and IGTs were not related to function or future function after correcting for time. PMID- 18444923 TI - Early lung transplantation success utilizing controlled donation after cardiac death donors. AB - Donation-after cardiac death (DCD) donor organs have potential to significantly alleviate the shortage of transplantable lungs. However, only limited data so far describes DCD lung transplantation (LTx) techniques and results. This study aims to describe the Alfred Hospital's early and intermediate outcomes following DCD donor LTx. Following careful experimentation and consultation DCD guidelines were created to utilize Maastricht category III lung donors from either the ICU or operating room(OR), with a warm ischemic time(WIT) of <60 min. Between May 2006 and December 2007, 22 referred DCD donors led to 11 attempted retrievals after withdrawal, resulting in 8 actual bilateral LTx (2 donors did not arrest in prescribed period and 1 donor had nonacceptable lungs). ICU WIT = 38.4 min (range 20-54, OR WIT = 12.7 min (11-15), p < 0.05. Post-LTx, 1 pulmonary hypertensive patient required ECMO for PGD3. The mean group pO2/FiO2 ratio at 24 hours was 307.7 (240-507) with an ICU stay of 9.5 days (2-21) and ward stay of 21.5 days (11-76). All 8 survive at a mean of 311 days (10-573) with good performance status and lung function. In conclusion, the use of Maastricht category III lungs for human LTx is associated with acceptable early clinical outcomes. PMID- 18444924 TI - Combined islet and hematopoietic stem cell allotransplantation: a clinical pilot trial to induce chimerism and graft tolerance. AB - To prevent graft rejection and avoid immunosuppression-related side-effects, we attempted to induce recipient chimerism and graft tolerance in islet transplantation by donor CD34+hematopoietic stem cell (HSC) infusion. Six patients with brittle type 1 Diabetes Mellitus received a single-donor allogeneic islet transplant (8611 +/- 2113 IEQ/kg) followed by high doses of donor HSC (4.3 +/- 1.9 x 10(6) HSC/kg), at days 5 and 11 posttransplant, without ablative conditioning. An 'Edmonton-like' immunosuppression was administered, with a single dose of anti-TNFalpha antibody (Infliximab) added to induction. Immunosuppression was weaned per protocol starting 12 months posttransplant. After transplantation, glucose control significantly improved, with 3 recipients achieving insulin-independence for a short time (24 +/- 23 days). No severe hypoglycemia or protocol-related adverse events occurred. Graft function was maximal at 3 months then declined. Two recipients rejected within 6 months due to low immunosuppressive trough levels, whereas 4 completed 1-year follow-up with functioning grafts. Graft failure occurred within 4 months from weaning (478 +/- 25 days posttransplant). Peripheral chimerism, as donor leukocytes, was maximal at 1-month (5.92 +/- 0.48%), highly reduced at 1-year (0.20 +/- 0.08%), and was undetectable at graft failure. CD25+T-lymphocytes significantly decreased at 3 months, but partially recovered thereafter. Combined islet and HSC allotransplantation using an 'Edmonton-like' immunosuppression, without ablative conditioning, did not lead to stable chimerism and graft tolerance. PMID- 18444925 TI - Liver transplantation for recurrent hepatocellular carcinoma on cirrhosis after liver resection: University of Bologna experience. AB - Liver resection (LR) for patients with small hepatocellular carcinoma (HCC) with preserved liver function, employing liver transplantation (LT) as a salvage procedure (SLT) in the event of HCC recurrence, is a debated strategy. From 1996 to 2005, we treated 227 cirrhotic patients with HCC transplantable: 80 LRs and 147 LTs of 293 listed for transplantation. Among 80 patients eligible for transplantation who underwent LR, 39 (49%) developed HCC recurrence and 12/39 (31%) of these patients presented HCC recurrence outside Milan criteria. Only 10 of the 39 patients underwent LT, a transplantation rate of 26% of patients with HCC recurrence. According to intention-to-treat analysis of transplantable HCC patients who underwent LR (n = 80), compared to all those listed for transplantation (n = 293), 5-year overall survival was 66% in the LR group versus 58% in patients listed for LT, respectively (p = NS); 5-year disease-free survival was 41% in the LR group versus 54% in patients listed for LT (p = NS). Comparable 5-year overall (62% vs. 73%, p = NS) and disease-free (48% vs. 71%, p = NS) survival rates were obtained for SLT and primary LT for HCC, respectively. LR is a valid treatment for small HCC and in the event of recurrence, SLT is a safe and effective procedure. PMID- 18444927 TI - Reversal of cardiac cirrhosis following orthotopic heart transplantation. AB - Irreversible hepatic cirrhosis greatly increases the risks attending heart transplantation (HT), and is accordingly considered to be an absolute contraindication for HT unless combined heart and liver transplantation can be performed. It is now recognized that hepatic cirrhosis can undergo regression if the source of insult is removed, but no cases of post-HT regression of cirrhosis of cardiac origin have hitherto been reported. Here we report a case of cardiac cirrhosis that underwent complete regression following orthotopic HT, and we discuss the implications of this case. PMID- 18444930 TI - The effect of recipient-specific surgical issues on outcome of liver transplantation in biliary atresia. AB - Biliary atresia (BA), the most common reason for orthotopic liver transplantation (OLT) in children, is often accompanied by unique and challenging anatomical variations. This study examines the effect of surgical-specific issues related to the presence of complex vascular anatomic variants on the outcome of OLT for BA. The study group comprised 944 patients who were enrolled in the Studies of Pediatric Liver Transplantation (SPLIT) registry and underwent OLT for BA over an 11-year period. 63 (6.7%) patients met the study definition of complex vascular anomalies (CVA). Patient survival, but not graft survival, was significantly lower in the CVA group, (83 vs. 93 % at 1-year post-OLT). The CVA group had a significantly higher incidence of all reoperations, total biliary tract complications, biliary leaks and bowel perforation. The most frequent cause of death was infection, and death from bacterial infection was more common in the CVA group. Pretransplant portal vein thrombosis and a preduodenal portal vein were significant predictors of patient survival but not graft survival. This study demonstrates that surgical and technical factors have an effect on the outcome of BA patients undergoing OLT. However, OLT in these complex patients is technically achievable with an acceptable patient and graft survival. PMID- 18444931 TI - C5 blockade with conventional immunosuppression induces long-term graft survival in presensitized recipients. AB - We explored whether a functionally blocking anti-C5 monoclonal antibody (mAb) combined with T- and B-cell immunosuppression can successfully prevent antibody mediated (AMR) and cell-mediated rejection (CMR) in presensitized murine recipients of life-supporting kidney allografts. To mimic the urgent clinical features of AMR experienced by presensitized patients, we designed a murine model in which BALB/c recipients were presensitized with fully MHC-mismatched C3H donor skin grafts one week prior to C3H kidney transplantation. Presensitized recipients demonstrated high levels of circulating and intragraft antidonor antibodies and terminal complement activity, rejecting grafts within 8.5 +/- 1.3 days. Graft rejection was predominantly by AMR, characterized by interstitial hemorrhage, edema and glomerular/tubular necrosis, but also demonstrated moderate cellular infiltration, suggesting CMR involvement. Subtherapeutic treatment with cyclosporine (CsA) and LF15-0195 (LF) did not significantly delay rejection. Significantly, however, the addition of anti-C5 mAb to this CsA/LF regimen prevented terminal complement activity and inhibited both AMR and CMR, enabling indefinite (>100 days) kidney graft survival despite the persistence of antidonor antibodies. Long-term surviving kidney grafts expressed the protective proteins Bcl-x(S/L) and A-20 and demonstrated normal histology, suggestive of graft accommodation or tolerance. Thus, C5 blockade combined with routine immunosuppression offers a promising approach to prevent graft loss in presensitized patients. PMID- 18444932 TI - Evaluation of c4d deposition and circulating antibody in small bowel transplantation. AB - Antibody-mediated rejection (AMR) consensus criteria are defined in kidney and heart transplantation by histological changes, circulating donor-specific antibody (DSA), and C4d deposition in affected tissue. AMR consensus criteria are not yet identified in small bowel transplantation (SBTx). We investigated those three criteria in 12 children undergoing SBTx, including one retransplantation and four combined liver-SBTx (SBTx), with a follow-up of 12 days to 2 years. All biopsies (91) were evaluated with a standardized grading scheme for acute rejection (AR), vascular lesions and C4d expression. Sera were obtained at day 0 and during the follow-up. C4d was expressed in 37% of biopsies with or without AR, but in 50% of biopsies with severe vascular lesions. In addition, vascular lesions were always associated with AR and a poor outcome. All children with AR (grade 2 or 3) observed before the third month died or lost the graft. DSA were never found in any studied sera. We found no evidence that C4d deposition was of any clinical relevance to the outcome of SBTx. However, the grading of vascular lesions may constitute a useful marker to identify AR that is potentially resistant to standard treatment, and for which an alternative therapy should be considered. PMID- 18444933 TI - Pharmacokinetics of low and maintenance dose valganciclovir in kidney transplant recipients. AB - Valganciclovir is commonly used for cytomegalovirus (CMV) prophylaxis in renal transplant patients. A fixed dose of 900 mg daily is typically recommended, however, there has never been a formal pharmacokinetic study comparing various doses in renal transplant patients. We therefore compared the pharmacokinetic characteristics of intravenous ganciclovir (IV GCV) and oral ganciclovir (GCV) with two different doses of valganciclovir (VGCV) in an open-label crossover study. Ten adult kidney recipients participated in a four-phase crossover treatment schedule of IV GCV (2.5 mg/kg every 12 h), VGCV (900 mg daily), VGCV (450 mg daily) and oral GCV (1000 mg Q8 H). IV GCV and oral VGCV 900 mg daily achieved similar values for AUC(0-24) (median 60.63 vs. 62.86 microg/h/mL). Oral VGCV 450 mg achieved comparable AUC(0-24) values as oral GCV 1000 mg Q8 H (median AUC(0-24) 35.9 vs. 29.04 microg/h/mL). Oral VGCV 900 mg daily provided systemic GCV exposure similar to IV GCV and confirms PV 16 000 study results. Further, VGCV 450 mg daily provided comparable systemic exposure versus oral GCV. Due to its favorable pharmacokinetic profile, data herein suggest that VGCV can be used in the early post-kidney transplant period, and that 450 mg daily provides ample drug exposure for effective CMV prophylaxis in kidney transplant patients. PMID- 18444934 TI - Use of organs for transplantation from a donor with primary meningoencephalitis due to Naegleria fowleri. AB - Naegleria fowleri is a free-living amebic organism that causes acute meningoencephalitis and brain death in young people. Though this infection is limited to the central nervous system, organ donation is usually ruled out because of the infectious nature of the donor's death. Based on the realization that this organism is limited to the brain, we successfully transplanted organs from a 12-year-old male donor dying of N. fowleri infection. Kidneys, pancreas, a lung and liver were used with no evidence of posttransplant infectious complications. This unusual cause of brain death does not preclude successful organ donation. PMID- 18444935 TI - Refractory hypercalcemia in an infant secondary to talc pleurodesis resolving after renal transplantation. AB - Talc pleurodesis is the definitive therapy of recurrent pneumothorax and has not been associated with metabolic complications. We report an anephric male infant who developed severe hypercalcemia 6 months following talc pleurodesis for recurrent peritoneal dialysis-related hydrothorax. The etiology of hypercalcemia was related to persistently elevated 1,25-dihydroxyvitamin D(3) (1,25[OH]2D) levels. The source appeared to be the extrarenal production of 1,25(OH)2D from macrophages in a large thoracic talc granuloma. Hypercalcemia was controlled with a combination of a low calcium diet, low calcium dialysis, ketoconazole and hydroxychloroquine, but elevated 1,25(OH)2D levels persisted. At 32 months of age the child underwent renal transplantation with alemtuzumab pre-conditioning. The hypercalcemia resolved immediately, with normalization of serum 1,25(OH)2D levels and without hypercalciuria. This case demonstrates that hypercalcemia is a potential complication of talc pleurodesis from the extrarenal production of 1,25(OH)2D and that alemtuzumab, a monoclonal antibody directed against the CD52 antigen (which is expressed on almost all macrophages), may have a role in the treatment of hypercalcemia associated with granulomatous conditions. PMID- 18444936 TI - Acute Page kidney following renal allograft biopsy: a complication requiring early recognition and treatment. AB - The acute Page kidney phenomenon occurs as a consequence of external compression of the renal parenchyma leading to renal ischemia and hypertension. Between January 2000 and September 2007, 550 kidney transplants and 518 ultrasound-guided kidney biopsies were performed. During that time, four recipients developed acute oligo-anuria following ultrasound-guided allograft biopsy. Emergent doppler ultrasounds were performed demonstrating absence of diastolic flow as well as a sub-capsular hematoma of the kidney. Prompt surgical exploration with allograft capsulotomy was performed in all cases. Immediately after capsulotomy, intraoperative Doppler study demonstrated robust return of diastolic flow. Three patients maintained good graft function, and one kidney was lost due to acute antibody-mediated rejection. We conclude that postbiopsy anuria associated with a subcapsular hematoma and acute absence of diastolic flow on doppler ultrasound should be considered pathognomonic of APK. All renal transplant specialists should be able to recognize this complication, because immediate surgical decompression can salvage the allograft. PMID- 18444937 TI - Has time come for new goals in human islet transplantation? AB - The enthusiasm regarding clinical islet transplantation has been dampened by the long-term results. Concerns about the associated risks of life-long immunosuppression and the striking imbalance between potential recipients and available donor pancreata warrant changes in some of the current goals. Islet transplantation will never be a cure of type 1 diabetes in the majority of patients with no secondary complications, but is a valid option for a limited number of patients with brittle diabetes waiting for an organ or after organ transplantation. Furthermore, insulin independence should not be the main goal of islet transplantation, but avoidance of severe hypoglycemia and good glycemic control, which can be achieved with a relatively small functional beta-cell mass. Therefore, initially one islet infusion is sufficient. Retransplantation at a later time point remains an option, if glucose control deteriorates. Efforts to improve islet transplantation should no longer focus on islet isolation and immunosuppression, but rather on the low posttransplant survival rate of islets caused by activation of the coagulation pathway and the limited oxygen delivery to the islets. Transplantation of smaller islets be it naturally small or size tailored reaggregated islets has the potential to facilitate these processes. PMID- 18444938 TI - Ethnocentrism is an unacceptable rationale for health care policy: a critique of transplant tourism position statements. AB - Medical tourism has emerged as a global health care phenomenon, valued at $60 billion worldwide in 2006. Transplant tourism, unlike other more benign forms of medical tourism, has become a flashpoint within the transplant community, underscoring the uneasy relationships among science, religion, politics, ethics and international health care policies concerning the commercialization of transplantation. Numerous professional associations have drafted or issued position statements condemning transplant tourism. Often the criticism is misdirected. The real issue concerns both the source and circumstances surrounding the procurement of donor organs, including commercialization. Unfortunately, many of the position statements circulated to date represent an ethnocentric and decidedly western view of transplantation. As such, the merits of culturally insensitive policy statements issued by otherwise well-intended transplant professionals, and the organizations they represent, must be evaluated within the broader context of foreign relations and diplomacy, as well as cultural and ethical relativity. Having done so, many persons may find themselves reluctant to endorse statements that have produced a misleading social desirability bias, which, to a great extent, has impeded more thoughtful and inclusive deliberations on the issues. Therefore, instead of taking an official position on policy matters concerning the commercial aspects of transplantation, international professional associations should offer culturally respectful guidance. PMID- 18444939 TI - Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel. AB - Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi-disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better- or worse-graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody-mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined. The availability of a simple, reproducible, clinically relevant and internationally accepted schema for grading rejection should improve the level of diagnostic accuracy and facilitate communication between all parties involved in the care of pancreas transplant recipients. PMID- 18444940 TI - Pig thrombomodulin binds human thrombin but is a poor cofactor for activation of human protein C and TAFI. AB - Incompatibility between pig thrombomodulin (TM) and primate thrombin is thought to be an important factor in the development of microvascular thrombosis in rejecting pig-to-primate xenografts. To examine this interaction at the molecular level, we cloned pig TM and measured its ability to bind human thrombin and act as a cofactor for the activation of human protein C and TAFI. The 579-residue pig TM protein showed approximately 69% sequence identity to human TM. Within the EGF domains necessary for binding of thrombin (EGF56), protein C (EGF4) and TAFI (EGF3), all of the amino acids previously identified as critical for the function of human TM, with the exception of Glu-408 in EGF5, were conserved in pig TM. Comparison of transfected cells expressing pig or human TM demonstrated that both proteins bound human thrombin and inhibited its procoagulant activity. However, pig TM was a poor cofactor for the activation of human protein C and TAFI, with domain swapping showing that EGF5 was the most important determinant of compatibility. Thus, while pig TM may be capable of binding thrombin generated in the vicinity of xenograft endothelium, its failure to promote the activation of human protein C remains a significant problem. PMID- 18444941 TI - Skeletal muscle force and functional exercise tolerance before and after lung transplantation: a cohort study. AB - We investigated the impact of lung transplantation and outpatient pulmonary rehabilitation after lung transplantation on skeletal muscle function and exercise tolerance. Skeletal muscle force (Quadriceps force, QF), exercise tolerance (six minute walking distance, 6MWD) and lung function were assessed in 36 patients before and after lung transplantation. Seventeen male and 19 female patients (age 57 +/- 4) showed skeletal muscle weakness before the transplantation. A further 32 +/- 21% reduction was seen 1.2 (interquartile range 0.9 to 2.0) months after LTX. The number of days on the intensive care unit was significantly related to the observed deterioration in muscle force after LTX. At this time point 6MWD was comparable to pre-LTX. Rehabilitation started 37 (IQR 29 to 61) days after LTX. 6MWD and QF improved significantly (140 +/- 91 m, and 35 +/- 48%, respectively; p < 0.05) with rehabilitation. QF remained below pre-LTX values. The evolution of the 6MWD with the transplantation and the subsequent rehabilitation was less in female compared to male subjects. We conclude that muscle strength deteriorates after lung transplantation, particularly in patients with long ICU stay. Outpatient pulmonary rehabilitation is feasible after lung transplantation and leads to recovery of skeletal muscle function. In female patients this recovery is significantly less compared to male recipients. PMID- 18444942 TI - Transmission of lymphoma via organ transplantation. PMID- 18444943 TI - Successful treatment of haemothorax following percutaneous liver biopsy using interventional radiology: importance of arterial anatomical variations. PMID- 18444944 TI - Impact of pulsatile perfusion on postoperative outcome of kidneys from controlled donors after cardiac death. AB - Pulsatile perfusion (PP) might be a cost-effective cold preservation technique to reduce the incidence of delayed graft function (DGF) in kidneys from deceased donors. With the aim to address whether PP can reduce the incidence of DGF in kidneys from controlled donors after cardiac death (cDCD), we compared the clinical outcome of 30 recipients of kidneys from cDCD preserved by static cold storage (cDCD-SCS) with 30 recipients of cDCD kidneys preserved by PP (cDCD-PP). The end-points were the incidence of primary nonfunction (PNF), DGF and acute rejection (AR), the length of hospitalization, 1, 3, 6 and 12-months graft function, graft survival and patient survival. Donor, recipient and preimplantation data were well matched. DGF was significantly lower (53.3% vs. 86.6% P<0.001) and the length of hospitalization shorter (10 vs. 14 days P<0.033) in the cDCD-PP group. Similarly, postoperative and short-term graft function (7 and 30 days and 6 and 12 months, respectively) was statistically better in the cDCD-PP than in the cDCD-SCS. In summary, in this cohort, clinical introduction of PP was associated with a significant reduction of DGF, shorter hospitalization and better graft function than SCS. PMID- 18444945 TI - Association of four DNA polymorphisms with acute rejection after kidney transplantation. AB - Renal transplant outcomes exhibit large inter-individual variability, possibly on account of genetic variation in immune-response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] investigating renal function and biopsy-proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50-6.67]; P=0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42-8.09]; P=0.006). BPAR was almost fivefold more likely in patients homozygous for IL-10 -592A (OR: 4.71, 95% CI [1.52-14.55]; P=0.007) and twice as likely in patients with at least one A allele of TNF-alpha G-308A (OR: 2.18, 95% CI [1.08-4.41]; P=0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant. PMID- 18444946 TI - Preparation of highly concentrated and white cell-poor platelet-rich plasma by plateletpheresis. AB - BACKGROUND AND OBJECTIVES: Contaminating white blood cells (WBC) contribute remarkably to the overall growth factor content of locally applicable platelet rich plasma (PRP) or platelet (PLT) gel and change the relative proportions of the contained growth factors. MATERIALS AND METHODS: To study the independent effects of locally applicated highly concentrated PLTs, the development of preparations is needed that contain large amounts of PLTs and no or at least very few leucocytes. Therefore, 20 plateletpheresis procedures were performed in voluntary blood donors to get highly concentrated and extremely WBC-poor plateletpheresis concentrates. The degree of spontaneous PLT activation, the PLT aggregation response to agonists and the level of the growth factor TGF-beta1 (transforming growth factor beta1) were measured immediately after the donation and 1 day later. RESULTS: The concentrates contained 1.96 +/- 0.36 x 10e11 PLTs per unit in 55.2 +/- 7.9 ml, respectively. In comparison to the donors' blood, the PLT-enrichment factor was 15.3 +/- 5.4. At the same time, the concentrates contained extremely low residual numbers of WBCs (0.8 +/- 3.3 x 10e3/ml). The concentration of the growth factor TGF-beta1 was 743.2 +/- 243.9 ng/ml. On day 1, the PLT concentration and the TGF-beta1 content of the PLT concentrates had not decreased. CONCLUSIONS: In summary, plateletpheresis is suited to provide PRP products with higher concentrations of human platelets and platelet-derived growth factors than previously reported PRP preparation methods but with extremely low numbers of contaminating leucocytes. PMID- 18444947 TI - Complement split products and proinflammatory cytokines in intraoperatively salvaged unwashed blood during hip replacement: comparison between heparin-coated and non-heparin-coated autotransfusion systems. AB - BACKGROUND AND OBJECTIVES: The aim of the present study was to investigate the quality of shed blood collected in a new intraoperative autotransfusion system (Sangvia, AstraTech, Sweden) and to study whether heparin-coated surfaces in the device reduce the production of inflammatory mediators. MATERIAL AND METHODS: The study was randomized and prospective. Twelve total hip arthroplasty patients whose blood was collected with a device having a heparin-coated surface and 12 patients whose blood was collected with a device having a non-heparin-coated surface were included. Venous blood was drawn from the patients preoperatively. Intraoperatively 200 ml salvaged blood was collected and samples were also withdrawn; samples were obtained from the blood bag. RESULTS: Compared to venous blood, elevated concentrations of interleukin 6 (IL-6), IL-8, C3a and polymorphonuclear elastase were found in collected blood. No significant differences in inflammatory mediators were found between the heparin-coated and the non-heparin-coated groups. The median haemoglobin concentration in the salvaged blood was 74 g/l in both groups. Plasma haemoglobin and potassium concentrations were also elevated. There were no significant differences between the groups. CONCLUSION: The present study indicates that the blood salvaged intraoperatively contains elevated levels of complement split product and proinflammatory cytokines and that heparin-coated surfaces of the salvage device do not significantly influence the formation of inflammatory mediators. PMID- 18444948 TI - Dyslipidemia after renal transplantation: a cause for concern? PMID- 18444949 TI - Successful autologous peripheral blood stem cell transplantation with a double conditioning regimen for recurrent hepatoblastoma after liver transplantation. AB - A four-yr-old boy developed a solitary metastasis nine months after living related liver transplantation for unresectable hepatoblastoma. After resection of the metastatic lesion, he received an auto-PBSCT with a double-conditioning regimen consisting of melphalan and thiotepa. Auto-PBSCT could be safely performed without any serious regimen-related toxicity or infection. However, transient cessation of tacrolimus during myelosuppression resulted in graft rejection of the liver just after hematological engraftment, but rejection was resolved by tacrolimus and methylprednisolone. The patient is alive and free from disease two yr after auto-PBSCT without any signs of graft rejection. High-dose chemotherapy using this conditioning regimen may be feasible for recurrent hepatoblastoma after liver transplantation in terms of safety and anti-tumor activity. PMID- 18444951 TI - Beyond cultural competency: Bourdieu, patients and clinical encounters. AB - In response to widely documented racial and ethnic disparities in health, clinicians and public health advocates have taken great strides to implement 'culturally competent' care. While laudable, this important policy and intellectual endeavour has suffered from a lack of conceptual clarity and rigour. This paper develops a more careful conceptual model for understanding the role of culture in the clinical encounter, paying particular attention to the relationship between culture, contexts and social structures. Linking Bourdieu's (1977) notion of 'habitus' and William Sewell's (1992) axioms of multiple and intersecting structures, we theorise patient culture in terms of 'hybrid habitus'. This conceptualisation of patient culture highlights three analytical dimensions: the multiplicity of schemas and resources available to patients, their specific patterns of integration and application in specific contexts, and the constitutive role of clinical encounters. The paper concludes with a discussion of directions for future research as well as reforms of cultural competency training courses. PMID- 18444952 TI - Engaging with sleep: male definitions, understandings and attitudes. AB - Recent literature has highlighted the sociological significance of sleep and has suggested that sleep offers a 'window' onto the gendered nature of our lives. Yet within this body of work men's sleep has been largely ignored. This paper seeks to rectify this omission and situates itself at the intersection between literature on the sociological aspects of sleep and social-constructionist orientated writings on men's health. It draws upon qualitative data from 40 men to investigate male understandings of, and attitudes towards, sleep. At first glance, it could be suggested that men have little regard for sleep, and are prone to taking risks with their dormancy. Viewed in this way sleep becomes an instrument used in the negotiation of status and power and intrinsically bound up with the demonstration of masculinities. Yet, men's relationship with sleep is more complex than this. Amongst other things, the men within the present study were embroiled in a function/non-function dichotomy. Sleep was seen as needed for the praxis of 'father', 'worker', 'husband' and 'mate' but was also considered as something which should not get in the way of performing these roles. PMID- 18444953 TI - Understanding adversity and resilience at older ages. AB - This mixed-methods study looks at the relationship between adversity and resilience. It examines the dynamics of protection in a sub-sample of the Boyd Orr cohort that are aged between 70 and 80 years of age (n = 139). We used a questionnaire and activity diaries to gather a range of quantitative data, and interviews using lifegrids to explore past and present experiences of adversity. Sampling of 32 individuals was based on resilient and vulnerable outcomes (16 cases respectively), measured quantitatively as good or poor quality of life (CASP-19) in the presence of one or more adversities such as ill health or stress. The analysis explored adversity and protection in relationships, retirement, and health. Participants with resilient outcomes drew upon social and individual resources in the face of adversity, in particular resources that stabilised life change by providing continuity. These included: constructing narratives that reinterpreted past adversity in light of recent ones; maintaining social roles and activities that had previously brought pleasure or a sense of mastery; relying on tried and tested coping strategies; support from close ongoing relationships. Participants with vulnerable outcomes, however, described more severe adversities, suggesting that resilience is also dependent on the degree and impact of this experience. PMID- 18444954 TI - Waking up to sleepiness: Modafinil, the media and the pharmaceuticalisation of everyday/night life. AB - This paper examines the social construction of the new wakefulness-promoting drug Modafinil (brand name Provigil) in the British press. Key themes in this newspaper coverage include the potential 'uses' and 'abuses' of this drug in relation to: (i) medical conditions; (ii) lifestyle choices; (iii) military operations; and (iv) sporting competition. The British press, we show, play a dual role in reporting on these trends and developments: on the one hand constructing this as something of a 'wonder drug' in relation to the treatment of a number of medical complaints or conditions, on the other hand articulating and amplifying a range of cultural concerns and anxieties about the non-medical 'uses' and 'abuses' of this drug, both now and in the future. These issues, it is argued, are best interpreted in terms of media concerns over the pharmaceuticalisation rather than the medicalisation of everyday/night life. The paper concludes with some further thoughts and reflections on these issues, including the potential reworking of notions of 'pharmaceutical Calvinism' and the 'elective affinity' between this 'smart' new drug and the spirit of (bio)capitalism. PMID- 18444956 TI - Biomedicine, holism and general medical practice: responses to the 2004 General Practitioner contract. AB - In 2004 a new contract was introduced for General Practitioners in the UK, which introduced a significant element of 'pay-for-performance', including both clinical and organisational targets. The introduction of this contract has caused interest across the world, particularly amongst those responsible for commissioning primary care services. It can be argued that the clinical targets in the contract (known as the Quality and Outcomes Framework, QOF) represent a move towards a more biomedical model of health and illness, which is contrary to the ideal of providing holistic (or biopsychosocial) care that has been traditionally espoused by GPs. This paper reports results from two linked studies (in England and Scotland) investigating the early stages of the new contract. We describe the way in which four practices with different organisational approaches and espoused identities have all changed their practice structures, consultations and clinical care in response to QOF in ways which will result in patients receiving a more biomedical type of care. In spite of these observed changes, respondents continued to maintain discursive claims to holism. We discuss how this disconnection between rhetoric and reality can be maintained, and consider its implications for the future development of GPs' claims to a professional identity. PMID- 18444955 TI - The embryo as moral work object: PGD/IVF staff views and experiences. AB - We report on one aspect of a study that explored the views and experiences of practitioners and scientists on social, ethical and clinical dilemmas encountered when working in the field of preimplantation genetic diagnosis (PGD) for serious genetic disorders. The study produced an ethnography based on observation, interviews and ethics discussion groups with staff from two PGD/IVF Units in the UK. We focus here on staff perceptions of work with embryos that entails disposing of 'affected' or 'spare' embryos or using them for research. A variety of views were expressed on the 'embryo question' in contrast to polarised media debates. We argue that the prevailing policy acceptance of destroying affected embryos, and allowing research on embryos up to 14 days leaves some staff with rarely reported, ambivalent feelings. Staff views are under-researched in this area and we focus on how they may reconcile their personal moral views with the ethical framework in their field. Staff construct embryos in a variety of ways as 'moral work objects'. This allows them to shift attention between micro-level and overarching institutional work goals, building on Casper's concept of 'work objects' and focusing on negotiation of the social order in a morally contested field. PMID- 18444957 TI - Processing of the circumsporozoite protein in infected hepatocytes is not dependent on aspartic proteases. AB - CD8(+) T cells play a major role in the protective immune response against the liver stage of malaria. It was previously shown that the circumsporozoite protein (CSP) is processed and presented to specific T cells by both traversed and infected hepatocytes, but their respective antigen processing requirements were not completely defined. In the present study, we show that in vitro processing of the Plasmodium berghei CSP by infected mouse primary hepatocytes is exclusively dependent on proteasomes, while aspartic proteases are also needed in the case of traversed hepatocytes. PMID- 18444958 TI - Resistance of the Echinococcus granulosus cyst wall to complement activation: analysis of the role of InsP6 deposits. AB - The larva of the cestode Echinococcus granulosus (hydatid cyst) is protected by the acellular laminated layer (LL). The mechanisms that make this thick coat a poor activator of host complement are incompletely understood. The structure binds, through unknown motifs, the host regulator of the alternative complement pathway (ACP), factor H. A second potential mechanism of ACP regulation, the inhibition of factor B activation, was detected in assays employing purified components (Immunopharmacology 42 : 91). The inhibitor was subsequently identified as myo-inositol hexakisphosphate (InsP(6)), which in the form of nano deposits is a major component of the LL (Biochem J 362 : 297; J Cell Biochem 93 : 1272; FEBS J 273 : 3192). In this report we show that colloidal InsP(6 )solids inhibit factor B activation, through adsorption and associated impairment of C3b binding. However, this interaction is not relevant in the presence of serum proteins. In serum, InsP(6) deposits instead bind C1q, and initiate complement activation. This activation is curtailed through efficient C3b inactivation, previously shown to be entirely factor H-dependent, and now observed to be independent of the InsP(6) deposits. Therefore the complement resistance of the LL must be based on functional factor H binding sites present on the mucin-based meshwork that is its other major constituent. PMID- 18444959 TI - Characterization of bovine lymphocytes stimulated in vitro by Dictyocaulus viviparus homogenate. AB - Adult Dictyocaulus viviparus homogenate induced proliferation of lymphocytes from naive cattle. We characterized the responding cells by carboxyfluorescein diacetate succinimidyl ester (CFSE) loading, for detection of proliferation, and antibody labelling for cell surface molecules. Lymphocytes expressing CD4, CD8 and gamma/delta TCR, rather than Ig expressing cells, proliferated after in vitro stimulation with D. viviparus homogenate. Of gamma/delta TCR expressing cells, both CD8, WC1.1 and WC1.2 co-expressing cells proliferated. Moreover, gamma/delta T cells expressing MHC class II proliferated to a higher extent than those negative for MHC class II. Of CD4 and CD8 expressing lymphocytes, both those co expressing CD45R and CD45R0 proliferated. Among CD4 expressing lymphocytes, those that were CD45R0 positive had a larger proportion of proliferated cells than did CD45R positive cells. Compared to stimulation with Con A, the proportion of dividing cells after D. viviparus stimulation was smaller although the cells had divided more times. Furthermore, we also compared in vitro responses of peripheral blood mononuclear cells collected before and after two subsequent infections with D. viviparus, but no clear acquired responses could be detected. Overall, this suggests that most T lymphocytes are stimulated by the D. viviparus homogenate rather than any particular lymphocyte subpopulation. PMID- 18444960 TI - Stomatal and non-stomatal limitations of photosynthesis in trees of a tropical seasonally flooded forest. AB - Trees in the flooded forest of the Mapire River in Venezuela suffer a decrease in photosynthetic rate (A) when flood begins, which is reverted at maximum flood. Changes in A are accompanied by similar changes in stomatal conductance (g(s)), and the possibility of changes in photosynthetic capacity is not ruled out. In order to understand how relative stomatal and non-stomatal limitations of photosynthesis are affected by flooding, we studied the seasonal changes in A and its response to intercellular CO(2) concentration in trees of Campsiandra laurifolia, Symmeria paniculata, Acosmium nitens and Eschweilera tenuifolia. Flooding caused in trees of C. laurifolia and S. paniculata a reduction in A, g(s), carboxylation efficiency and total soluble protein (TSP), whereas gas exchange in A. nitens and E. tenuifolia was more sensitive to drought. Under flooding, relative stomatal limitation (L(s)) was on average half the highest, and relative non-stomatal limitation (L(ns)) increased from the dry season to flooding. Under full flood, A, g(s) and TSP regained high values. A was positively correlated to light-saturated electron transport rate, suggesting that part of the decrease in A under flooding was due to impairment of photosynthetic capacity. Under flooding, not only stomatal closure but also increased L(ns) causes a reduction in photosynthesis of all four species, and a process of acclimation as flooding progresses allows gas exchange and related variables to regain high values. PMID- 18444961 TI - Role of nodal signaling and the microenvironment underlying melanoma plasticity. AB - The incidence of melanoma has increased dramatically over the last 50 yr, and although melanoma accounts for only 10% of all skin cancers, it is responsible for over 80% of skin cancer deaths. Recent studies have uncovered critical molecular events underlying melanocytic transformation and melanomagenesis. Among these noteworthy observations are the acquisition of stem cell-associated proteins, such as the Notch receptors and Nodal, which have also been implicated in melanoma progression. For example, we have demonstrated that Nodal expression is limited to invasive vertical growth phase and metastatic melanoma lesions, and that inhibition of Nodal signaling promotes the reversion of metastatic melanoma cells toward a more differentiated, less invasive non-tumorigenic phenotype. In addition, molecular cross-talk exists between the Notch and Nodal signaling pathways. Interestingly, the acquisition of stem cell-associated plasticity is often acquired via epigenetic mechanisms, and is therefore receptive to reprogramming in response to embryonic microenvironments. Here, we review the concept of melanoma plasticity, with an emphasis on the emerging role of Nodal as a regulator of melanoma tumorigenesis and progression, and present findings related to epigenetic reprogramming. PMID- 18444962 TI - The ACE gene I/ D polymorphism is not associated with generalized vitiligo susceptibility in Gujarat population. PMID- 18444963 TI - TBX3 and its splice variant TBX3 + exon 2a are functionally similar. AB - Tbx3, a member of the conserved family of T-box developmental transcription factors, is a transcriptional repressor required during cardiogenesis for the formation and specification of the sinoatrial node, the pacemaker of the heart. Both the TBX3 and the highly related TBX2 genes are also associated with several cancers, most likely as a consequence of their powerful anti-senescence properties mediated via suppression p14(Arf) and p21(CIP) expression. In melanoma, the TBX2 gene is frequently amplified and inhibition of Tbx2 function leads to senescence and up-regulation of p21(CIP), a Tbx2 target gene. Tbx3 + 2a is a splice variant containing an extra 20 amino acids encoded by exon 2a inserted into the highly conserved T-box DNA-binding domain. We find here that Tbx3 + 2a is evolutionary conserved and that similar insertions are largely absent from the T-box domains of other T-box factors. Tbx3 + 2a has been reported to lack DNA-binding ability and act as a functional antagonist of Tbx3. By contrast, we now demonstrate that both Tbx3 and Tbx3 + 2a bind the consensus T element, the p21(CIP1) promoter, and the Nppa cardiac target gene. Both isoforms also function as repressors of p21(CIP1) and Nppa promoter activity and interact with homeobox factor Nkx2-5. When ectopically expressed in the embryonic heart of mice, Tbx3 and Tbx3 + 2a both suppressed chamber formation and repressed expression of cardiac chamber markers Nppa and Cx40. The results suggest that in the assays used, Tbx3 and Tbx3 + 2a are functionally equivalent and that like Tbx2, Tbx3 may also function as an anti-senescence factor in melanoma. PMID- 18444965 TI - Timeline and distribution of melanocyte precursors in the mouse heart. AB - Apart from the well-studied melanocytes of the skin, eye and inner ear, another population has recently been described in the heart. In this study, we tracked cardiac melanoblasts using in situ hybridization with a dopachrome tautomerase (Dct) probe and Dct-LacZ transgenic mice. Large numbers of melanoblasts were found in the atrioventricular (AV) endocardial cushions at embryonic day (E) 14.5 and persisted in the AV valves into adulthood. The earliest time Dct-LacZ positive cells were observed in the AV endocardial cushions was E12.5. Prior to that, between E10.5 and E11.5, small numbers of melanoblasts traveled between the post-otic area and third somite along the anterior and common cardinal veins and branchial arch arteries with other neural crest cells expressing CRABPI. Cardiac melanocytes were not found in the spotting mutants Ednrb s-l/s-l and Kit w-v/w-v, while large numbers were observed in transgenic mice that overexpress endothelin 3. These results indicate that cardiac melanocytes depend on the same signaling molecules known to be required for proper skin melanocyte development and may originate from the same precursor population. Cardiac melanocytes were not found in zebrafish or frog but were present in quail suggesting an association between cardiac melanocytes and four-chambered hearts. PMID- 18444964 TI - PPAR gamma regulates MITF and beta-catenin expression and promotes a differentiated phenotype in mouse melanoma S91. AB - Melanoma represents one of the most rapidly metastasizing, hence deadly tumors due to its high proliferation rate and invasiveness, characteristics of undifferentiated embryonic tissues. Given the absence of effective therapy for metastatic melanoma, understanding more fully the molecular mechanisms underlying melanocyte differentiation may provide opportunities for novel therapeutic intervention. Here we show that in mouse melanoma S91 cells activation of the peroxisome proliferator activated receptor (PPAR) gamma induces events resembling differentiation, such as growth arrest accompanied by apoptosis, spindle morphology and enhanced tyrosinase expression. These events are preceded by an initial transient increase in expression from the Microphthalmia-associated transcription factor gene, (MITF) promoter, whereas exposure to a PPAR gamma ligand- ciglitazone that exceeds 8 h, causes a gradual decrease of MITF, until by 48 h MITF expression is substantially reduced. Beta-catenin, an MITF transcriptional activator, shows a similar pattern of decline during ciglitazone treatment, consistent with previous reports that activated PPAR gamma inhibits the Wnt/beta-catenin pathway through induction of beta-catenin proteasomal degradation. We suggest that the PPAR gamma-mediated beta-catenin down-regulation is likely to be responsible for changes in MITF levels. The data suggest that PPAR gamma, besides its well-established role in mesenchymal cell differentiation towards adipocytes, might regulate differentiation in the melanocytic lineage. PMID- 18444966 TI - ADHD as a (non) allergic hypersensitivity disorder: a hypothesis. AB - Research data concerning the causal association between attention deficit hyperactivity disorder (ADHD) and allergies are conflicting. Allergic disorders, like asthma and eczema are clinical syndromes in which both genetic predisposition and environmental factors (pets, pollen and foods) contribute to its development. The hypothesis of ADHD, in some children also being an allergic disorder, is postulated based on comparison of the mechanisms underlying the development of ADHD and allergic disorders. According to the accepted terminology, ADHD may comply with the criteria of hypersensitivity, allergy and atopy. This hypothesis has to be thoroughly tested by randomized controlled trials using environmental triggers and immunologic research. As genes related to the immune system may be associated with ADHD, further genetic research is compulsory. Immunotherapeutic approaches, using immunotherapy and probiotics, can subsequently be implicated in the treatment of ADHD. If hypersensitivity to environmental stimuli like foods contributes to the development of ADHD, the assessment and treatment of ADHD will have to be reconsidered, thereby improving the quality of care for these patients. PMID- 18444968 TI - Idiosyncratic differentiation in medulloblastoma--a report of two exceptional cases. PMID- 18444969 TI - Anchorage to the cytosolic face of the endoplasmic reticulum membrane: a new strategy to stabilize a cytosolic recombinant antigen in plants. AB - The levels of accumulation of recombinant vaccines in transgenic plants are protein specific and strongly influenced by the subcellular compartment of destination. The human immunodeficiency virus protein Nef (negative factor), a promising target for the development of an antiviral vaccine, is a cytosolic protein that accumulates to low levels in transgenic tobacco and is even more unstable when introduced into the secretory pathway, probably because of folding defects in the non-cytosolic environment. To improve Nef accumulation, a new strategy was developed to anchor the molecule to the cytosolic face of the endoplasmic reticulum (ER) membrane. For this purpose, the Nef sequence was fused to the C-terminal domain of mammalian ER cytochrome b5, a long-lived, tail anchored (TA) protein. This consistently increased Nef accumulation by more than threefold in many independent transgenic tobacco plants. Real-time polymerase chain reaction of mRNA levels and protein pulse-chase analysis indicated that the increase was not caused by higher transcript levels but by enhanced protein stability. Subcellular fractionation and immunocytochemistry indicated that Nef TA accumulated on the ER membrane. Over-expression of mammalian or plant ER cytochrome b5 caused the formation of stacked membrane structures, as observed previously in similar experiments performed in mammalian cells; however, Nef-TA did not alter membrane organization in tobacco cells. Finally, Nef could be removed in vitro by its tail-anchor, taking advantage of an engineered thrombin cleavage site. These results open up the way to use tail-anchors to improve foreign protein stability in the plant cytosol without perturbing cellular functions. PMID- 18444970 TI - Production of cecropin A in transgenic rice plants has an impact on host gene expression. AB - Expression of the cecropin A gene in rice confers resistance to the rice blast fungus Magnaporthe oryzae. In this study, a polymerase chain reaction-based suppression subtractive hybridization approach was used to generate a cDNA macroarray from the elite japonica rice (Oryza sativa L.) cultivar 'Senia'. Gene expression studies revealed that the expression of components of the protein secretory and vesicular transport machinery is co-ordinately activated at the pre invasive stage of infection of rice by the blast fungus. Comparisons of gene expression between wild-type and cecropin A plants revealed the over-expression of genes involved in protection against oxidative stress in transgenic plants in the absence of the pathogen, which correlated well with the tolerance of these plants to oxidative stress. A subcellular fractionation analysis suggested that cecropin A accumulates in the endoplasmic reticulum in cecropin A rice. Moreover, a large number of genes related to the processes of synthesis, folding and stabilization of proteins that enter into the secretory pathway are over expressed in cecropin A rice, confirming that these plants constitutively express the unfolded protein response. Transgenic expression of cecropin A in rice has an effect on the transcriptional reprogramming that accompanies plant adaptation to fungal infection. Overall, this study provides evidence for transgene-induced changes in gene expression in cecropin A rice under both optimal growth conditions and stress conditions imposed by fungal infection. The data also indicate that resistance to blast in cecropin A rice may be the consequence of a combination of the antifungal activity of cecropin A and cecropin A-mediated over expression of rice genes. PMID- 18444971 TI - Treatment of dermatophyte onychomycosis with three pulses of terbinafine (500 mg day for a week). AB - We assessed the safety and efficacy of pulse therapy with terbinafine tablets in 55 patients with dermatophytic onychomycosis. One pulse consisted of oral terbinafine tablets (500 mg day(-1)) given for 1 week usually followed by a 3 week interval. This regimen was repeated twice. Topical 1% terbinafine cream was applied daily. Efficacy was assessed based on both clinical and mycological examinations 1 year after treatment initiation. We observed a complete cure in 41 patients (74.5%), marked improved in three patients (5.6%), slight improvement in three patients (5.6%) and drop out in six patients (10.7%). Two patients (3.6%) discontinued terbinafine because of gastrointestinal disturbance (one patient) and drug-induced eruption (one patient). No patient had abnormal laboratory findings, including liver function tests. In summary, a regimen of three pulses of terbinafine therapy given daily for 1 week in combination with topical application of terbinafine cream appears to be safe and effective in treating dermatophytic onychomycosis and offers advantages in convenience and cost effectiveness compared with continuous dosing. PMID- 18444972 TI - Confirmed case of feline mycetoma due to Microsporum canis. AB - The first case of feline true mycetoma because of a dermatophyte has been reported in this manuscript, although pseudomycetoma has been described in dogs and cats. The patient was a 9-year-old castrated male Persian cat weighing 4.2 kg with subcutaneous nodules on the dorsal trunk. Physical examination revealed two subcutaneous nodules (2.5 x 5.0 cm and 3.5 x 5.0 cm in size) that drained purulent exudates with cement-like substances containing yellowish granules. The impression smear of the yellowish granules demonstrated by PAS staining that they were masses of fungal septated hyphae (3-4 mum of width). From the nodular inflammation with fibrosis, fistulae draining from deep tissue and many grains containing abundant hyphal filaments, the case was diagnosed as mycetoma, complying with the definitive criteria of mycetoma. The etiologic fungus was molecularly as well as morphologically identified as Microsporum canis. PMID- 18444973 TI - Aspergilloma in a pulmonary hydatid cyst: a case report. AB - The most common predisposing factor for aspergillomas is the presence of a pre existing lung cavity secondary to tuberculosis, bronchial cysts and bullae, neoplasms, and pulmonary infarction. However, Aspergilloma within a hydatid cyst is a rare occurrence. A 52-year-old female was presented with chest pain and shortness of breath. Computerized tomography-guided fine needle aspiration (FNA) showed fragment of lamellated membrane of hydatid cyst in a background of amorphous debris. Surgical enucleation of the cyst revealed lamellated hyaline acellular ectocyst of hydatid cyst and collections of acute angle branching septate hyphae conforming to morphology of Aspergillus. Here we describe this rare entity of aspergilloma in a pulmonary hydatid cyst and discuss its management. PMID- 18444974 TI - The use of glucan as immunostimulant in the treatment of a severe case of chromoblastomycosis. AB - We report the case of an alternative treatment for a patient with a severe form of chromoblastomycosis that responded poorly to the traditional antifungal therapy. We hereby show, in this study, the improvement of lesions after treatment with itraconazole associated with an intramuscular administration of glucan. We observed that the regression of lesions was associated with an improvement of the cellular immune response. This favourable response that we observed suggests that the therapeutic regimen we used might be an option for the treatment of patients with a severe form of chromoblastomycosis. PMID- 18444975 TI - Degradation of 16S rRNA and attributes of viability of viable but nonculturable probiotic bacteria. AB - AIMS: To assess the stability of 16S rRNA of viable but nonculturable (VBNC) probiotics during storage when compared with different attributes of viability. METHODS AND RESULTS: Levels of RNA of the probiotic strains Bifidobacterium longum 46, B. longum 2C and B. animalis subsp. lactis Bb-12 were monitored during storage in fermented and nonfermented foods. Cells which gradually lost their culturability in fermented products retained high level of rRNA, whereas rRNA of acid-killed control cells decreased at faster rate. Furthermore, the viability of B. longum 2C was monitored during storage by measuring changes in reductase activity, cytoplasmic membrane integrity and esterase activity using a flow cytometer. All of the culture-independent viability assays suggested that the cells remained viable during storage. In nonfermented media, the observed losses in culturability were smaller, and the changes in cell counts were comparable with the changes in rRNA levels. CONCLUSIONS: Viable but nonculturable probiotics maintain high levels of rRNA and retain properties of viable bacteria including reductase activity. Quantification of 16S rRNA complements culture-independent viability assays. SIGNIFICANCE AND IMPACT OF THE STUDY: Culture-independent viability assays allow the detection of VBNC probiotics, and can be used parallel to conventional culture-dependent methods to obtain accurate information on probiotic viability. PMID- 18444976 TI - Antifungal effect of gaseous nitric oxide on mycelium growth, sporulation and spore germination of the postharvest horticulture pathogens, Aspergillus niger, Monilinia fructicola and Penicillium italicum. AB - AIM: To evaluate the antifungal activity of nitric oxide (NO) against the growth of the postharvest horticulture pathogens Aspergillus niger, Monilinia fructicola and Penicillium italicum under in vitro conditions. METHODS AND RESULTS: Different volumes of NO gas were injected into the Petri dish headspace to obtain the desired concentrations of 50-500 microl l(-1). The growth of the fungi was measured for 8 days of incubation in air at 25 degrees C. All concentrations of NO were found to produce an antifungal effect on spore germination, sporulation and mycelial growth of the three fungi, with the most effective concentration for A. niger and P. italicum being 100 and 500 microl l(-1) for M. fructicola. CONCLUSIONS: Short-term exposure to a low concentration of NO gas was able to inhibit the subsequent growth of A. niger, M. fructicola and P. italicum. SIGNIFICANCE AND IMPACT OF THE STUDY: NO gas has potential use as a natural fungicide to inhibit microbial growth on postharvest fruit and vegetables. PMID- 18444977 TI - A differential medium for lactic acid-producing bacteria in a mixed culture. AB - AIMS: Modified deMan-Rogosa Sharpe agar containing bromophenol blue (mMRS-BPB) was tested as a medium for counting and differentiation of each lactic acid producing bacterium (LAB), especially in a mixed culture. METHODS AND RESULTS: Type strains of 10 LAB species (Lactobacillus acidophilus, L. brevis, L. bulgaricus, L. gasseri, L. paracasei, L. plantarum, L. reuteri, Weissella confusa, Bifidobacterium bifidum and B. infantis) and five commercial yogurts were inoculated on plate count agar with bromocresol purple, mMRS, and mMRS-BPB. Each type strain showed more clearly formed colonies on the three media under anaerobic conditions than under aerobic conditions. Especially each type strain produced colonies with specific characteristics of each species on mMRS-BPB. Commercial yogurts produced the largest number of colonies with various shapes and colours on mMRS-BPB. CONCLUSIONS: Modified deMan-Rogosa Sharpe agar containing bromophenol blue under anaerobic conditions is appropriate for counting and differentiating each LAB in a mixed culture. SIGNIFICANCE AND IMPACT OF THE STUDY: Modified deMan-Rogosa Sharpe agar containing bromophenol blue will be useful in isolation and enumeration of each LAB from fermented foods as well as intestinal microflora. PMID- 18444978 TI - Sensitivity of the Alternaria infectoria species-group 1 to cycloheximide. AB - AIMS: A possibility of using cycloheximide tolerance and/or sensitivity as an additional diagnostic tool for distinguishing morphologically related species within common small-spored Alternaria has been tested during this study. METHODS AND RESULTS: A total of 33 strains from four Alternaria species-groups, namely Alternaria alternata, Alternaria arborescens, Alternaria infectoria and Alternaria tenuissima were tested for their growth response to 100 microg m(-1) cycloheximide in potato carrot agar. All A. infectoria strains were completely inhibited, showing no growth at all even after prolonged incubation. In contrast, all other strains representing the remnant three species exhibited a high resistance to this antibiotic. CONCLUSIONS: Cycloheximide sensitivity represents a further important physiological character for distinguishing A. infectoria from the three similar species. SIGNIFICANCE AND IMPACT OF THE STUDY: The relevance of these findings corresponds with the potential ability of the Alternaria species produce mycotoxins. Cycloheximide may be in future used in the design of selective media for the isolation of some potentially toxigenic food-borne Alternaria species such as A. alternata, A. tenuissima and/or A. arborescens, for example in screening cereals for toxigenic Alternaria spp. and for their direct separation from nontoxigenic representatives of A. infectoria species-group. PMID- 18444979 TI - Use of suppressive subtractive hybridization to identify Flavobacterium columnare DNA sequences not shared with Flavobacterium johnsoniae. AB - AIMS: To identify specific sequences in the fish pathogen Flavobacterium columnare not shared by Flavobacterium johnsoniae. METHODS AND RESULTS: Suppressive subtractive hybridization (SSH) was used to selectively amplify and clone F. columnare-specific sequences. A highly virulent strain of F. columnare was used as tester and the type strain of F. johnsoniae was used as driver. After library construction, 192 clones were selected and sequenced. From those, 110 clones contained unique F. columnare-specific sequences that were verified using dot blot hybridization. Sequence sizes ranged from 55 to 872 bp with 45,363 bp sequenced in total. CONCLUSIONS: Specific F. columnare sequences representing all but one (motility related) functional categories were annotated. Several putative virulence factors were identified in F. columnare such as a collagenase, a chondroitinase, proteases, as well as drug resistance and iron transport-related genes. SIGNIFICANCE AND IMPACT OF THE STUDY: Suppressive subtractive hybridization is a cost-effective method for identifying genetic differences between Flavobacterium spp. The number of sequences available from F. columnare has been doubled. PMID- 18444980 TI - Coping efficacy and perceived family support: potential factors for reducing stress in premedical students. AB - OBJECTIVE: This study investigated the relationship between perceived family support and coping efficacy in premedical (i.e. prior to entering medical school) students, an understudied subset of undergraduate students who are particularly at risk for academia- related stress. The relationships between students' perceived academic coping abilities and their academic behaviours and experiences of stress have been considered within the vocational literature. However, an understanding of factors that inform coping efficacy beliefs is lacking. METHODS: A total of 238 premedical students provided demographic information regarding themselves and their parents. Students also completed a paper questionnaire containing a coping efficacy scale and items assessing their level of family support. RESULTS: Correlational analyses revealed significant positive relationships between family support and students' perceived abilities to cope with anticipated academic barriers as hypothesised. Bivariate comparisons of mean coping efficacy scores revealed that racial or ethnic minority students reported significantly higher coping efficacy beliefs than did White students. Students with doctor mothers also reported significantly higher coping efficacy than students with mothers employed in other health-related fields. No significant differences in coping efficacy were found when those with doctor fathers versus those with fathers in other health-related fields were compared. CONCLUSIONS: Findings from the present study indicate that perceived family support plays a key role in establishing premedical students' confidence in their ability to cope with the challenges of academic life. These findings have important implications for further studies on coping and stress in premedical students. PMID- 18444981 TI - Outcrossing between an agroforestry plantation and remnant native populations of Eucalyptus loxophleba. AB - Gene dispersal among populations of a species is an important force influencing their genetic structure. Dispersal may also occur between taxa that would normally be isolated when nonendemic, domesticated or transgenic species are planted within the natural range of interfertile taxa. Such a mosaic of populations is typical of many agricultural landscapes, and investigations are needed to assess the risks of genetic contamination of the endemic populations but a combination of approaches may be necessary because of the limitations of research in this landscape. This study used microsatellite markers and a range of analyses (mating system, paternity exclusion, Bayesian assignment) to examine gene dispersal between remnants of the endemic Eucalyptus loxophleba ssp. supralaevis and a plantation of a nonendemic subspecies. Our results indicate that remnant populations are connected by significant dispersal to pollen sources up to 1.94 km away including the plantation. The combined analyses showed that the pollen pool and outcrossing rates of individuals within remnants varied significantly probably because of asynchronous flowering and that the likelihood of paternity was not correlated with spatial proximity. More than half of all progeny had male parents from outside their stand with the largest proportions estimated to come from the plantation by exclusion (42.4%) or Bayesian analyses (18.8-76%). Fragmentation may not be associated with decreased gene dispersal between populations of tree species, natural or planted, so that the distances required to buffer endemic trees in fragmented rural landscapes are likely to be large. PMID- 18444982 TI - Reconstruction of the Sudden Oak Death epidemic in California through microsatellite analysis of the pathogen Phytophthora ramorum. AB - The genetic structure of the clonally reproducing Sudden Oak Death (SOD) pathogen in California was investigated using seven variable microsatellites. A total of 35 multilocus genotypes were identified among 292 samples representative of populations from 14 forest sites and of the nursery trade. amova indicated significant genetic variability both within (44.34%) and among populations (55.66%). Spatial autocorrelation analyses indicated that Moran's index of similarity reached a minimum of 0.1 at 350 m, increased to 0.4 at 1500 m and then decreased to zero at 10 km. These results suggest a bimodal pattern of spread, with medium range dispersal (1500-10,000 m) putatively attributed to the presence of strong winds. Lack of genetic structure was identified for three groups of populations. One group notably included the nurseries' population and two forest populations, both linked to early reports of the pathogen. A neighbour-joining analysis based on pairwise Phi(ST) values indicated that the clade inclusive of the nurseries' populations is basal to all California populations. A network analysis identified three common genotypes as the likely founders of the California infestation and proposes a stepwise model for local evolution of novel genotypes. This was supported by the identification in the same locations of novel genotypes and of their 1- or 2-step parents. We hypothesize that the few undifferentiated population groups indicate historical human spread of the pathogen, while the general presence of genetically structured populations indicates that new infestations are currently generated by rare medium or long range natural movement of the pathogen, followed by local generation of new genotypes. PMID- 18444983 TI - Cryptic speciation in a Holarctic passerine revealed by genetic and bioacoustic analyses. AB - There has been much controversy regarding the timing of speciation events in birds, and regarding the relative roles of natural and sexual selection in promoting speciation. Here, we investigate these issues using winter wrens (Troglodytes troglodytes), an unusual example of a passerine with a Holarctic distribution. Geographical variation has led to speculation that the western North American form Troglodytes troglodytes pacificus might be a distinct biological species compared to those in eastern North America (e.g. Troglodytes troglodytes hiemalis) and Eurasia. We located the first known area in which both forms can be found, often inhabiting neighbouring territories. Each male wren in this area sings either western or eastern song, and the differences in song are as distinct in the contact zone as they are in allopatry. The two singing types differ distinctly in mitochondrial DNA sequences and amplified fragment length polymorphism profiles. These results indicate that the two forms are reproductively isolated to a high degree where they co-occur and are therefore separate species. DNA variation suggests that the initial split between the two species occurred before the Pleistocene, quite long ago for sister species in the boreal forest. Surprisingly, the two forms are similar in morphometric traits and habitat characteristics of territories. These findings suggest that sexual selection played a larger role than habitat divergence in generating reproductive isolation, and raise the possibility that there are other such morphologically cryptic species pairs in North America. PMID- 18444984 TI - Antiviral therapy of hepatitis C in chronic kidney diseases: meta-analysis of controlled clinical trials. AB - Hepatitis C virus (HCV) infection remains frequent in patients with chronic kidney disease and the detrimental role of HCV on survival is well-established in this population. Several authors have reported on efficacy and safety of antiviral therapy for hepatitis C in this polulation but there is no clear consensus on management. To evaluate efficacy and safety of antiviral therapy for hepatitis C in patients with chronic kidney disease, we performed a systematic review of the published medical literature and completed a meta-analysis of controlled clinical trials. The primary outcome was sustained virological response (as a measure of efficacy); the secondary outcome was drop-out rate (as a measure of tolerability). We used the random effects model of Der Simonian and Laird, with heterogeneity and sensitivity analyses. We identified 13 studies including 539 unique patients; 10 (76.9%) concerned patients on maintenance dialysis. Only prospective, controlled clinical trials were included. Pooling of study results showed a significant increase of viral response in study (patients treated with antiviral therapy) than control patients (patients who did not receive therapy), the pooled odds ratio (OR) of failure to obtain a sustained viral response was 0.081 [95% confidence intervals (CI), 0.029-0.230], P = 0.0001. The pooled OR of drop-out rate was significantly increased in study vs control patients, OR = 0.389 (95% CI, 0.155-0.957), P = 0.04. The studies were heterogeneous with regard to viral response and drop-out rate. In the subset of clinical trials (n = 6) involving only dialysis patients receiving interferon (IFN) monotherapy for chronic HCV, there was a significant difference in the risk of failure to obtain a sustained viral response (study vs control patients), OR = 0.054 (95% CI, 0.019; 0.150), P = 0.0001 (random-effects model). No significant (NS) heterogeneity was found (Q = 14.604, P = 1.0). No difference in the drop-out rate between study and control patients was shown, OR = 0.920 (95% CI, 0.367; 2.311), NS. This result being homogeneous (Q = 3.639, P = 0.388). Our meta analysis showed that the viral response was greater in patients with chronic kidney disease who received antiviral therapy than controls. No difference in the drop-out rate between study and control patients occurred in the subgroup of dialysis patients on IFN monotherapy. These results support IFN-based therapy for hepatitis C in patients on maintenance dialysis. PMID- 18444985 TI - A modified version of the Bayley Scales of Infant Development-II for cognitive matching of infants with and without Down syndrome. AB - BACKGROUND: Many measures of infants' early cognitive development, including the BSID-II (The Bayley Scales of Infant Development), mix together test items that assess a number of different developmental domains including language, attention, motor functioning and social abilities, and some items contribute to the assessment of more than one domain. Consequently, the scales may lead to under- or over-estimates of cognitive abilities in some clinical samples and may not be the best measure to use for matching purposes. METHOD: To address this issue we created a modified form of the BSID-II (the BSID-M) to provide a 'purer' assessment of the general cognitive capacities in infants with Down syndrome (DS) from 6 to 18 months of age. We excluded a number of items that implicated language, motor, attentional and social functioning from the original measure. This modified form was administered to 17 infants with Down syndrome when 6, 12 and 18 months old and to 41 typically developing infants at 4, 7 and 10 months old. RESULTS: The results suggested that the modified form continued to provide a meaningful and stable measure of cognitive functioning and revealed that DS infants may score marginally higher in terms of general cognitive abilities when using this modified form than they might when using the standard BSID-II scales. CONCLUSIONS: This modified form may be useful for researchers who need a 'purer' measure with which to match infants with DS and other infants with intellectual disabilities on cognitive functioning. PMID- 18444986 TI - The use of melatonin to treat sleep disorder in adults with intellectual disabilities in community settings - the evaluation of three cases using actigraphy. AB - BACKGROUND: Sleep disorders are known to be very prevalent in adults with intellectual disabilities (ID) but to date there has been limited objective assessment of either sleep disorders or of interventions such as the use of melatonin. METHODOLOGY: A protocol-driven assessment and intervention procedure was followed with three people with moderate to severe ID identified as having a possible sleep disorder. Actigraphic assessment was used to determine the nature of the sleep disorder, after which sleep hygiene advice and then individual treatment with melatonin were provided, following which further actigraphic assessment was carried out. Behavioural disturbance was formally assessed before and after the intervention phase. RESULTS: Following treatment with melatonin, changes in circadian rhythm were noted, together with improvements in challenging behaviour, but no significant effects were noted with regard to either quantity or quality of sleep. CONCLUSIONS: A standardised procedure for assessment and treatment of sleep disorders in people with ID was established. Although no apparent effects on sleep quantity or quality were noted, this may reflect factors inherent in the sample, rather than the relative efficacy of melatonin treatment per se. PMID- 18444987 TI - Adults with intellectual disabilities: prevalence, incidence and remission of self-injurious behaviour, and related factors. AB - BACKGROUND: Self-injurious behaviour (SIB) is a serious condition, with implications for the person, their family and financial costs to the state providing care. The previously reported prevalence of SIB has ranged from 1.7% to 41%, or 1.7%-23.7% in community studies. There has been little study of remission rate, and incidence has not previously been reported. SIB has been reported to be individually associated with lower ability, autism and communication impairments, but given the inter-relationships between these three factors, it is not known whether they are independently associated with SIB. This study investigates the point prevalence, incidence and remission rates of SIB among the adult population with intellectual disabilities (ID), and explores which factors are independently associated with SIB. METHOD: A prospective cohort study design was used in a general community setting. The participants were all adults (16 years and over) with ID in a defined geographical area. Individual assessments were conducted with all participants. RESULTS: The point prevalence of SIB (as defined by DC-LD) was 4.9%, the two-year incidence was 0.6%, and two-year remission rate was 38.2%. Independently related to SIB were: lower ability level, not living with a family carer, having attention deficit hyperactivity disorder, visual impairment, and not having Down syndrome. Other factors, including communication impairment, autism, and level of deprivation of the area resided within, were not related. CONCLUSIONS: SIB is not as enduring and persistent as previously thought; a significant proportion gains remission in this time period. This should provide hope for families, paid carers and professionals, and reduce therapeutic nihilism. Our study is a first tentative step towards identifying risk-markers for SIB, and developing aetiological hypotheses for subsequent testing. The extent to which SIB may be a relapsing-remitting (episodic) condition requires further investigation, so does further hypothesis-based investigation of factors that might be predictive of incidence of, and remission from, SIB. PMID- 18444988 TI - The fragile X continuum: new advances and perspectives. AB - Fragile X syndrome is the world's most common hereditary cause of intellectual disability in men and to a lesser extent in women. The disorder is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation Gene-1. A substantial body of research across the disciplines of molecular genetics, child psychiatry and developmental neuroscience bears testament to a decade of exciting and innovative science that has advanced our knowledge about the fragile X 'signature' or influence across cognitive and social development. The core aims of this review are to first discuss fragile X syndrome and premutation involvement in the context of current advances that demonstrate the dynamic nature of the genotype on phenotypic outcomes. Second, to discuss the implications of these recent advances for the development of clinical and educational interventions and resource tools that target specific phenotypic 'signatures' within the fragile X continuum. PMID- 18444989 TI - Prevalence and risk factors of maladaptive behaviour in young children with Autistic Disorder. AB - BACKGROUND: Children with Autistic Disorder (AD) evidence more co-occurring maladaptive behaviours than their typically developing peers and peers with intellectual disability because of other aetiologies. The present study investigated the prevalence of Clinically Significant maladaptive behaviours during early childhood and identified at-risk subgroups of young children with AD. METHOD: Parents rated their child's maladaptive behaviours on the Child Behaviour Checklist (CBCL) in 169 children with AD aged 1.5 to 5.8 years. RESULTS: One-third of young children with AD had a CBCL Total Problems score in the Clinically Significant range. The highest percentage of Clinically Significant scores were in the Withdrawal, Attention, and Aggression CBCL syndrome scales. There was a high degree of co-morbidity of Clinically Significant maladaptive behaviours. Several subject characteristic risk factors for maladaptive behaviours were identified. CONCLUSIONS: Findings highlight the need to include behavioural management strategies aimed at increasing social engagement, sustained attention and decreasing aggressive behaviour in comprehensive intervention programmes for young children with AD. PMID- 18444990 TI - Artemisia asiatica extracts protect against ethanol-induced injury in gastric mucosa of rats. AB - BACKGROUND AND AIM: Based on our previous studies that Artemisia asiatica extracts exert either antioxidative or cytoprotective actions against non steroidal anti-inflammatory drugs or Helicobacter pylori-induced gastric mucosal injury, or imposes qualified ulcer healing in an acetic acid-induced gastric ulcer model, we investigated the protective effects of Artemisia asiatica extracts against ethanol-induced gastric mucosal injury. METHODS: Sprague-Dawley rats received 4 g/kg body weight (BW) of absolute ethanol intragastrically, which produced visible hemorrhagic gastric lesions 60 min later. RESULTS: In this animal setting, the pretreatment of Artemisia extracts (30 or 100 mg/kg BW), 1 h before ethanol administration, significantly attenuated the source of gastric injury, which was assessed with gross and microscopic analysis (P < 0.01). Protection from alcohol-induced damage with Artemisia pretreatment was associated with significantly decreased lipid peroxidation, protecting gastric mucosa from glutathione depletion, as well as the inhibition of the cytochrome 2E1 ethanol metabolizing enzyme. It attenuated the expressions of ethanol-induced pro inflammatory cytokines, including interleukin (IL)-1beta and interferon-gamma, a weak activation of IL-10, the inhibition of the alcohol-induced overexpression of intercellular adhesion molecule-1, and the considerable induction of heat shock protein-72 expression in gastric mucosal homogenates. CONCLUSION: The data suggest that the ethanol extracts of Artemisia asiatica exerted significant protection from alcohol-induced gastric mucosal injury through bio-regulation, which is essential for cytoprotection and anti-inflammation. PMID- 18444991 TI - Long-term prognosis of cirrhotics with an upper gastrointestinal bleeding episode: does infection play a role? AB - BACKGROUND AND AIM: We evaluated the effect of infection on the short- and long term outcome of cirrhotic patients with upper gastrointestinal bleeding (UGIB), in a series of patients not submitted to antibiotic prophylaxis. METHODS: The cirrhotic patients hospitalized for UGIB were prospectively followed up until the last visit, death, or transplantation. A standard screening protocol was used for bacterial infection at admission. RESULTS: In total, 205 patients were included in the study. Antibiotics were administered in 79 (38.5%) patients and an infection was documented in 64 (31.4%) patients. In total, 130 (63.4%) patients died after a mean (SD) follow up of 23.8 (30.9) months. Six-week mortality was higher in the infected patients (P < 0.0001). The mortality of patients who were alive 6 weeks after admission was not different between the infected and non infected patients. Antibiotic use or bacterial infection, the Child-Pugh score, hepatocellular carcinoma, and creatinine were the independent predictors of 6 week mortality. Age and the Child-Pugh score were the only predictors of mortality of the patients who had survived for more than 6 weeks after acute bleeding. In total, 51 (24.9%) patients rebled, 37 (18.1%) within 5 days of admission. Rebleeding was more frequent (41.8% vs 14.3%, P < 0.0001) in infected patients, mostly due to differences in early rebleeding (31.6% vs 9.5%, P = 0.0001). CONCLUSION: Bacterial infection is associated with failure to control UGIB and early mortality in cirrhotic patients, but does not seem to affect the outcome of patients who overcome the bleeding episode. PMID- 18444992 TI - Novel tumor-ablation device for liver tumors utilizing heat energy generated under an alternating magnetic field. AB - BACKGROUND AND AIMS: We have developed a novel tumor-ablation device for liver tumors utilizing heat energy induced by magnesium ferrite (MgFe(2)O(4)) particles under an alternating magnetic field (AMF) produced by electric currents. This novel device can repeatedly heat liver tumors at lower temperature than usual heating devices, such as radiofrequency ablation therapy, with slight infliction of pain. This study assesses its heating effect on rat liver tumors as local therapy. METHOD: The small needle was manufactured from MgFe(2)O(4) particles by sintering at 1100 degrees C. After a MgFe(2)O(4) needle was inserted into liver tumors comprising of dRLh-84 cells, the tumors were heated for 30 min under an AMF. We examined cellular activity by using nicotinamide adenine dinucleotide (NADH) diaphorase staining and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and evaluated the effect of suppressing tumor growth by sequentially comparing the tumor diameter with that of the control group. RESULTS: The mean temperature of the heated tumors was 60.2 +/- 1.8 degrees C. The tumor cells were constricted, and chromatin of nuclei had shrunk immediately after heating. The heat-injury area that contained the tumors was negative for NADH diaphorase activity. After 3 days, the tumor cells in the heat-injury area became positive for TUNEL staining, which detects cell death. At 7 days, the mean tumor diameters were significantly smaller in the heating group than in the control group (6.15 +/- 0.47 mm vs 16.89 +/- 2.69 mm; P < 0.05). CONCLUSION: This device, utilizing heat energy induced by ferromagnetic metal under an AMF, appears useful as local thermotherapy for human liver cancer. PMID- 18444993 TI - Responses of human sling and clasp fibers to cholecystokinin (CCK) and gastrin through CCK receptors. AB - BACKGROUND AND AIM: Cholecystokinin (CCK) and gastrin exert their influences via CCK receptors. This research was conducted to look at the responses of the sling and clasp fibers forming the human lower esophageal sphincter (LES) to CCK and gastrin, and the role of CCK receptors in the responses. METHODS: Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing subtotal esophagectomy. Isometric tension responses of the strips to CCK-8 and gastrin-17 were studied, and the maximum effect (E(max)) for each agonist was derived. CCK-A receptor antagonist, CR1409 and CCK-B antagonist, CR2945 were applied to sling and clasp fibers and their pK(B) values were calculated. RESULTS: Sling fibers produced significant contractions following exposure to CCK 8 and gastrin-17, while clasp fibers had less responses to the two agents. CR1409 and CR2945 inhibited responses of sling to CCK-8 in a concentration-dependent fashion. The inhibition effects of the two antagonists on clasp fibers were not measurable because there was a mild contraction of the fiber in response to CCK 8. CONCLUSION: The contractions generated by sling fibers following exposure to CCK and gastrin are greater than that produced by clasp fibers. CCK-A receptors are more important for the generation of contractions by the sling fibers, whereas both CCK-A and CCK-B receptors are involved in the functional regulation of the clasp fibers. [Corrections added after online publication 28 April 2008: in the Background and Aims section of the preceding abstract, all instances of 'CKK' were corrected to 'CCK'. In the final sentence of the abstract 'CCKA'was corrected to 'CCK-A'. In the article title '(CKK)' was corrected to '(CCK)'.]. PMID- 18444994 TI - Kinetics of 14carbon dioxide excretion from 14C-urea by oral commensal flora. AB - BACKGROUND AND AIM: Previous studies have shown that while performing the (14)C urea breath test ((14)C-UBT) for the detection of Helicobacter pylori (H. pylori), there is possibility of false-positive results due to the other urease producing bacteria present in oropharynx, if breath samples are obtained within 30 min after administration of non-capsulated (14)C-urea. Therefore, we have exclusively evaluated the kinetics of (14)carbon dioxide ((14)CO(2)) excretion by oral commensal flora to theoretically propose optimum breath collection timings for (14)C-UBT. METHODS: Multiple breath samples up to 15 min were collected in 0.25 mmol benzethonium hydroxide from 25 healthy volunteers after they withheld 37 kBq (1 muCi) of (14)C-urea in their mouths for 15 s and then expectorated the tracer. The test was repeated on the same subjects without and with mouth cleansing protocols. Breath (14)CO(2) content was measured by the Liquid Scintillation Counter (1409; Wallac, Turku, Finland) and results were expressed as (14)CO(2) excretion per mmol breath CO(2) (% administered dose). RESULTS: Peak breath radioactivity at 1 min in the former protocol was 3.53 times higher than the latter which declined subsequently with a half time of 1 min and 2.5 min, and reached baseline levels by 15 and 10 min, respectively. The peak radioactivity (100%) at 1 min declined by 94% and 97.8% in the former and later protocols, respectively, at 15 min. Although magnitude of the peak varied in different subjects, the shape of curve remained almost similar in all cases. CONCLUSIONS: Without mouth cleansing, oral micro flora excreted more (14)CO(2) up to 15 min after administration of non-capsulated (14)C-urea. Therefore, it is proposed that two breath samples may be obtained either at 15 and 20 min without or at 10 and 15 min with mouth cleansing protocols for reliable analysis of (14)C-UBT data for H. pylori detection. PMID- 18444995 TI - Geographically variable selection in Ambystoma tigrinum virus (Iridoviridae) throughout the western USA. AB - We investigated spatially variable selection in Ambystoma tigrinum virus (ATV) which causes frequent and geographically widespread epizootics of the tiger salamander, Ambystoma tigrinum. To test for evidence of selection, we sequenced several coding and noncoding regions from virus strains isolated from epizootics throughout western North America. Three of the sequenced regions contained homologues for genes putatively involved in host immune evasion and virulence: eIF-2alpha, caspase activation and recruitment domain (CARD) and beta-OH-steroid oxidoreductase. Selection analysis showed evidence of very strong purifying selection on eIF-2alpha, purifying selection within certain viral clades on CARD and positive selection on beta-OH-steroid oxidoreductase within certain clades. Analysis using MULTIDIVTIME and Tajima's relative rate tests indicate accelerated rates of evolution within clades associated with anthropogenic movement. These clades also demonstrate greater spatial variability in selection, suggesting a lack of local adaptation (i.e. locally adapted populations should exhibit little to no selection because of absent or reduced variation in fitness once a fitness optimum is reached). Increased transfer of non-native viral strains to naive salamander populations, in conjunction with local maladaptation as a result of local selection pressures, may explain the spread and emergence of ATV epizootics in A. tigrinum in western North America. PMID- 18444996 TI - Habitat-dependent song divergence at subspecies level in the grey-breasted wood wren. AB - Song divergence among populations can theoretically lead to reproductive divergence and speciation. Despite many studies, this theory is still controversial. Habitat differences have been shown to shape songs, but few studies have looked for a link between ecologically driven acoustic and genetic divergence. We tested whether environmental selection has driven song divergence in two genetically distinct, but hybridizing, subspecies of the grey-breasted wood-wren (Henicorhina leucophrys) in Ecuador. Several acoustic features showed significant divergence between the subspecies. Spectral song divergence correlated with ambient noise profiles which differed significantly between the habitats of both subspecies. Temporal song divergence also corresponded as expected to vegetation density. However, in terms of quantified levels of reverberations, we found no significant differences in habitat-dependent sound transmission properties. We conclude that ecological niche segregation may explain acoustic divergence among the two wren subspecies. The resulting habitat dependent song divergence may have contributed to reproductive divergence by guiding assortative mating in parapatric conditions or just currently contribute to maintenance of reproductive isolation upon secondary contact. PMID- 18444997 TI - Production of branched-chain aroma compounds by Propionibacterium freudenreichii: links with the biosynthesis of membrane fatty acids. AB - AIMS: Short branched-chain fatty acids (BCFAs) are cheese flavour compounds, which result from the conversion of branched-chain amino acids (BCAAs). In Swiss cheese, the production of short BCFAs is mainly performed by Propionibacterium freudenreichii and is strain dependent. Our aim was to investigate the possible links between the biosynthesis of short BCFAs and membrane BCFAs in P. freudenreichii. METHODS AND RESULTS: Short and membrane BCFAs were analysed by gas chromatography-mass spectrometry. Two strains differing in their capacities to release short BCFAs were selected. Tri-deuterated-labelled leucine was used in both strains as a precursor of short extracellular iso-BCFAs and of membrane iso BCFAs. The proportions of anteiso : iso BCFAs synthesized varied as function of the BCAAs provided in the growth medium, from 72 : 28 to 100 : 0, with leucine and valine, and with isoleucine as sole BC precursors, respectively. The branching pattern of short BCFAs exactly matched that of membrane BCFAs, whatever the exogenous BCAAs provided. CONCLUSIONS: The biosynthesis of short BCFAs is closely related to that of membrane BCFAs in P. freudenreichii. SIGNIFICANCE AND IMPACT OF THE STUDY: The biosynthesis of short BCFAs in P. freudenreichii depends more on the strain than on the presence of exogenous BC precursors. PMID- 18444998 TI - Genetic analysis of a bile salt hydrolase in Bifidobacterium animalis subsp. lactis KL612. AB - AIMS: To clone, sequence and characterize a new bile salt hydrolase from a bile tolerant strain of Bifidobacterium animalis ssp. lactis KL612, and further analysis of the bsh promoter and an operon-like structure containing the bsh gene in the genus Bifidobacterium. METHODS AND RESULTS: A new type of bile salt hydrolase from a bile tolerant strain of Bifidobacterium was cloned, completely sequenced and characterized. The putative bsh promoter sequence was analysed by primer extension to determine the transcriptional start point by applying the genomic walking-PCR, an operon-like structure containing the bsh gene and two more open reading frames located within a complete set ranging from a promoter to a transcription terminator sequence is reported for the first time in the genus Bifidobacterium. The polycistronic bsh transcript was revealed by reverse transcriptase-PCR (RT-PCR) as well as by Northern hybridization. CONCLUSIONS: Most of bile tolerant strains of bifidobacteria showed a similar genetic organization around the bsh gene. This finding suggests that bile tolerance of those strains is possibly because of the bile salt hydrolase and some transporter proteins, which are functionally related to each other to respond efficiently to the stress from bile salts. SIGNIFICANCE AND IMPACT OF THE STUDY: Knowledge gained through BSH research would provide further insight into the survival of probiotics in the gastrointestinal tract and some physiological functions of this enzyme in relation to the host as well as the enzyme-producing bacteria. PMID- 18444999 TI - Cheetahs of the deep sea: deep foraging sprints in short-finned pilot whales off Tenerife (Canary Islands). AB - 1. Empirical testing of optimal foraging models for breath-hold divers has been difficult. Here we report data from sound and movement recording DTags placed on 23 short-finned pilot whales off Tenerife to study the foraging strategies used to catch deep-water prey. 2. Day and night foraging dives had a maximum depth and duration of 1018 m and 21 min. Vocal behaviour during dives was consistent with biosonar-based foraging, with long series of echolocation clicks interspersed with buzzes. Similar buzzes have been associated with prey capture attempts in other echolocating species. 3. Foraging dives seemed to adapt to circadian rhythms. Deep dives during the day were deeper, but contained fewer buzzes (median 1), than night-time deep dives (median 5 buzzes). 4. In most deep (540 1019 m) daytime dives with buzzes, a downward directed sprint reaching up to 9 m s(-1) occurred just prior to a buzz and coincided with the deepest point in the dive, suggestive of a chase after escaping prey. 5. A large percentage (10-36%) of the drag-related locomotion cost of these dives (15 min long) is spent in sprinting (19-79 s). This energetic foraging tactic focused on a single or few prey items has not been observed previously in deep-diving mammals but resembles the high-risk/high-gain strategy of some terrestrial hunters such as cheetahs. 6. Deep sprints contrast with the expectation that deep-diving mammals will swim at moderate speeds optimized to reduce oxygen consumption and maximize foraging time at depth. Pilot whales may have developed this tactic to target a deep-water niche formed by large/calorific/fast moving prey such as giant squid. PMID- 18445000 TI - Knobloch syndrome: novel intra-oral findings. PMID- 18445001 TI - Oral health research with children. AB - BACKGROUND: There has been a shift towards research with children and the adoption of the concept of child-centred research. However, the majority of oral health research is conducted on children, rather than with them. OBJECTIVE: This study aimed to provide an overview of contemporary approaches to research with children. CONSIDERATIONS: The methodological considerations of such research include: the power relationship between the adult researcher and the child participant, with important factors of language use, the setting for the research, appropriate analysis, and quality of the data; ethical factors such as the purpose and risks of the research, confidentiality, recruitment, funding, information to children and parents, consent, and dissemination; and appropriate methods. Methods suitable for oral health research with children include quantitative techniques such as questionnaires and qualitative approaches including interviews individually or in groups and participatory techniques such as time-lines/life grids, drawings, and vignettes. CONCLUSION: There is considerable scope to access children's perspectives of their oral health and care through actively involving them in research. To conduct such research, however, requires training or collaboration with colleagues from other disciplines. PMID- 18445002 TI - Diet and dental erosion in young people in south-east Brazil. AB - BACKGROUND: The regular consumption of acidic foods and drinks may be associated with dental erosion, and soft drink consumption appears to be increasing both in developed and developing countries. Dentists are aware that an acidic diet can contribute to the development of erosion; however, there may be confusion within the profession concerning the general health message of eating five portions of fruits and vegetables each day. OBJECTIVE: The aim of this study was to investigate associations between dental erosion and the consumption of acidic foods and beverages in schoolchildren in south-east Brazil. The objective was to gather information, by means of a dietary questionnaire, on frequency of intake and patterns of consumption of acidic foods and drinks in a group of schoolchildren. The hypothesis was that the experience of dental erosion among the study sample was associated with the frequency and pattern of consumption of soft drinks, fruit juices, fruits, and yogurt. METHODS: A cross-sectional study was conducted in Tres Coracoes, south-east Brazil. A sample of 458 schoolchildren, mean age 13.8 (SD 0.39) years, completed the study. Information about potential dietary risk factors for dental erosion was collected through a questionnaire survey completed by the schoolchildren. For the dental examinations, the subjects were examined for dental erosion in a school room. Associations between dental erosion and the variables under study were investigated through processes of bivariate and multivariate analyses. The statistical significance level was set at 5%. RESULTS: Analysis of the questionnaire surveys showed that the frequency of consumption of sugared carbonated drinks was the only variable independently associated with the erosive process, with subjects who had a daily consumption of such drinks having a greater likelihood of having erosion (P = 0.015, odds ratio 1.752, 95% confidence interval 1.116-2.750). CONCLUSIONS: Of all tested factors in this sample of schoolchildren the consumption of sugared carbonated drinks is most associated with dental erosion. PMID- 18445003 TI - Deletion of PAX9 and oligodontia: a third family and review of the literature. AB - OBJECTIVE: This study was conducted to report a family affected by benign hereditary chorea in which a large deletion including TTF1, PAX9, and other genes was identified and results in oligodontia. METHODS: Clinical and radiological studies of the two affected members (mother and daughter) were used to describe the oligodontia present in both of them. RESULTS: The missing teeth in both patients are described in detail, and these data are compared with the dental anomalies observed in the only two other families with deletions of PAX9 and with the data available for 12 previously reported families carrying different types of PAX9 mutations. CONCLUSIONS: There is a clinical relevance for recognizing such families, and offering available therapies since childhood is stressed. Some genotype-phenotype correlations between PAX9 mutations and dental anomalies can be drawn. PMID- 18445004 TI - Lymphoid enhancer factor interacts with GATA-3 and controls its function in T helper type 2 cells. AB - GATA-3 is the master transcription factor for T helper 2 (Th2) cell differentiation and is critical for the expression of Th2 cytokines. Little is known, however, about the nature of the functional molecular complexes of GATA-3. We identified a high-mobility group (HMG)-box type transcription factor, lymphoid enhancer factor 1 (LEF-1), in the GATA-3 complex present in Th2 cells using a Flag-calmodulin-binding peptide (CBP)-tag based proteomics method. The interaction between GATA-3 and LEF-1 was confirmed by co-immunoprecipitation experiments using LEF-1-introduced T-cell lineage TG40 cells. The HMG-box domain of LEF-1 and two zinc finger domains of GATA-3 were found to be important for the physical association. The introduction of LEF-1 into developing Th2 cells resulted in the suppression of Th2 cytokine production. The suppression was significantly lower in the cells into which a HMG-box-deleted LEF-1 mutant was introduced. Moreover, LEF-1 inhibited the binding activity of GATA-3 to the interleukin (IL)-5 promoter. These results suggest that LEF-1 is involved in the GATA-3 complex, while also regulating the GATA-3 function, such as the induction of Th2 cytokine expression via the inhibition of the DNA-binding activity of GATA 3. PMID- 18445006 TI - Regulatory T-cell expansion and function do not account for the impaired alloreactivity of ex vivo-expanded T cells. AB - CD3- and CD28-activated T cells expanded for 12 days ex vivo to produce suicide gene-modified T cells are hyporesponsive to alloantigens. To investigate whether this impaired alloreactivity is a result of preferential expansion of regulatory T (Treg) cells, we compared peripheral blood mononuclear cells (PBMC) activated with CD3 and CD28 antibodies co-immobilized on beads and expanded for 12 days with interleukin (IL)-2 (Co(CD3/CD28) cells) to the respective unactivated PBMC in terms of proliferation, cytokine production, and expression of Treg markers [cytotoxic T-lymphocyte antigen 4 (CTLA4), glucocorticoid-induced tumour necrosis factor receptor (GITR) and forkhead box P3 (FoxP3)] after allostimulation. Alloreactive cells were identified by carboxyfluoresceine succinimidyl ester staining dilution. Alloreactive cells in Co(CD3/CD28) cells had a lower proliferative response and a lower potential for IL-2 and interferon-gamma secretion than did those in PBMC, demonstrating a functional impairment of alloreactive cells during ex vivo expansion. Expression of Treg markers transiently increased during ex vivo expansion and was unaffected by depletion of CD25(+) cells (containing Treg cells) before ex vivo PBMC expansion. Such prior CD25(+) depletion did not restore the alloreactivity of Co(CD3/CD28) cells. After allostimulation, expression of Treg markers was restricted to proliferative (alloreactive) cells among PBMC or Co(CD3/CD28) cells. Lastly, CD4(+) CD25(+) cells purified from Co(CD3/CD28) cells lacked suppressive activity when used as a third party, in contrast to CD4(+) CD25(+) cells purified from PBMC. In conclusion, the impaired alloreactivity of T cells expanded ex vivo is not a result of preferential Treg cell expansion and/or enhanced suppressive Treg activity. PMID- 18445005 TI - Widespread natural variation in murine natural killer T-cell number and function. AB - Natural killer T (NKT) cells comprise a novel T-lymphocyte subset that can influence a wide variety of immune responses through their ability to secrete large amounts of a variety of cytokines. Although variation in NKT-cell number and function has been extensively studied in autoimmune disease-prone mice, in which it has been linked to disease susceptibility, relatively little is known of the natural variation of NKT-cell number and function among normal inbred mouse strains. Here, we demonstrate strain-dependent variation in the susceptibility of C57BL/6J and BALB/cJ mice to NKT-mediated airway hyperreactivity, which correlated with significant increases in serum interleukin-4 (IL-4) and IL-13 elicited by the synthetic glycosphingolipid alpha-galactosylceramide. Examination of NKT-cell function revealed a significantly greater frequency of cytokine producing NKT cells in C57BL/6J versus BALB/cJ mice as well as significant differences in the kinetics of NKT-cell cytokine production. Extension of this analysis to a panel of inbred mouse strains indicated that variability in NKT cell cytokine production was widespread. Similarly, an examination of NKT-cell frequency revealed a significantly greater number of liver NKT cells in the C57BL/6J mice versus BALB/cJ mouse livers. Again, examination of a panel of inbred mouse strains revealed that liver NKT-cell numbers were quite variable, spanning over a 100-fold range. Taken together, these results demonstrate the presence of widespread natural variation in NKT-cell number and function among common inbred mouse strains, which may have implications for the examination of the influence of NKT cells in immune responses and disease pathogenesis among different genetic backgrounds. PMID- 18445007 TI - Identification of two subpopulations of purified human blood B cells, CD27- CD23+ and CD27high CD80+, that strongly express cell surface Toll-like receptor 9 and secrete high levels of interleukin-6. AB - B-cell expression of certain Toll-like receptors (TLRs) is important in linking innate and adaptive immune responses in normal and pathological conditions. The expression of TLR9 plays a role in the recognition of conserved pathogen motifs in a manner that is dependent on B-cell localization, deduced from B-cell phenotype. The nature of TLR9 function is unclear. A first step in unravelling the function of this pattern recognition receptor is to discover the precise nature of the cell types that express TLR9. This study used three-colour flow cytometry to characterize the B lymphocytes from human peripheral blood mononuclear cells (PBMCs) that express TLR9 on the surface. We sorted TLR9 positive B and non-B cells from the PBMC population and detected TLR9 expression on naive and memory B cells. Moreover, we identified two discrete subpopulations of B cells: CD19(+) CD27(-) CD23(+) cells and CD19(+) CD27(high) CD80(+) cells. These subpopulations expressed high levels of membrane TLR9 and exhibited a strong in vitro response to binding a relevant CpG motif by secreting high levels of interleukin-6 (compared to controls). Our finding that this pattern recognition receptor is expressed on a variety of cell subsets adds to the current understanding of the functional complexity of B-cell membrane TLR9. PMID- 18445008 TI - Serum lipids regulate dendritic cell CD1 expression and function. AB - Dendritic cells (DCs) are highly potent antigen-presenting cells (APCs) and play a vital role in stimulating naive T cells. Treatment of human blood monocytes with the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 stimulates them to develop into immature dendritic cells (iDCs) in vitro. DCs generated by this pathway have a high capacity to prime and activate resting T cells and prominently express CD1 antigen-presenting molecules on the cell surface. The presence of human serum during the differentiation of iDCs from monocytes inhibits the expression of CD1a, CD1b and CD1c, but not CD1d. Correspondingly, T cells that are restricted by CD1c showed poor responses to DCs that were generated in the presence of human serum, while the responses of CD1d restricted T cells were enhanced. We chemically fractionated human serum to isolate the bioactive factors that modulate surface expression of CD1 proteins during monocyte to DC differentiation. The human serum components that affected CD1 expression partitioned with polar organic soluble fractions. Lysophosphatidic acid and cardiolipin were identified as lipids present in normal human serum that potently modulate CD1 expression. Control of CD1 expression was mediated at the level of gene transcription and correlated with activation of the peroxisome proliferator-activated receptor (PPAR) nuclear hormone receptors. These findings indicate that the ability of human DCs to present lipid antigens to T cells through expression of CD1 molecules is sensitively regulated by lysophosphatidic acid and cardiolipin in serum, which are ligands that can activate PPAR transcription factors. PMID- 18445009 TI - The utility of MDM2 and CDK4 immunohistochemistry in needle biopsy interpretation of lipomatous tumours: a study of 21 Tru-Cut biopsy cases. PMID- 18445010 TI - Acquired von Willebrand syndrome. PMID- 18445011 TI - Thrombelastographic monitoring of recombinant factor VIIa in acquired haemophilia. AB - Monitoring of the global haemostatic capacity is desired to optimize the treatment with bypassing agents in inhibitor patients. Thrombelastographic methods have been used in ex vivo studies and were suggested useful to evaluate the individual response to bypassing agents. This study aimed at assessing changes in thrombelastographic profiles and their association to clinical outcome in patients treated with recombinant factor VIIa (rFVIIa). Ten patients with acquired haemophilia were treated with rFVIIa for acute bleeding. Thrombelastography was performed after activation with a small amount of tissue factor in samples obtained before and after in vivo administration of rFVIIa. In patients studied before and after a first dose, correction of the thrombelastographic profile was observed but did not predict cessation of bleeding. During steady-state dosing, the median Alpha angle tended to be higher in patients with a good clinical treatment response as compared with patients with a partial or poor response. Similar trends were observed for clotting time and clot formation time. A good clinical treatment response was more frequent in patients with a fully corrected trough-level thrombelastographic profile as compared with patients with an abnormal profile. However, a poor treatment response was observed also in a surgical patient with a normal thrombelastographic profile during steady-state dosing. In conclusion, thrombelastographic monitoring was sensitive to haemostatic changes in response to treatment with rFVIIa. In the limited number of patients studied here, a better clotting profile during steady-state dosing was associated with a better clinical treatment response. PMID- 18445012 TI - Successful total hip replacement in a patient with severe haemophilia A with inhibitors using recombinant factor VIIa. PMID- 18445013 TI - Severe hyponatraemia after DDAVP stimulation test in an adult patient. PMID- 18445014 TI - Successful surgical haemostasis in patients with von Willebrand disease with Koate DVI. AB - This report describes our experience with Koate DVI, a factor VIII (FVIII) concentrate containing von Willebrand factor (VWF) for surgery in patients with von Willebrand's disease (VWD). Twenty-one patients underwent 26 procedures, 10 of which were major and 16 were minor. The median age was 27 years (3-55) and the mean weight was 52 kg (16-88). Among the ten patients (type 2-5; type 3-5) who underwent major procedures, the pre-operative dose was 35 IU kg(-1) of FVIII followed by 10-20 IU kg(-1) once daily depending on FVIII:C levels. The mean total dose of FVIII used per procedures was 106 IU kg(-1) (30-190) over a mean duration of 7 days (3-11). In this group, pre-infusion FVIII:C, VWF:Ag and VWF: ristocetin cofactor (RCoF) level that were 19.5% (1-64), 20 U dL(-1) (0-96) and 12% (0-66) increased to 72% (54-198), 131 U dL(-1) (68-206) and 68% (27-108) postinfusion, respectively. Sixteen minor procedures were performed in 11 patients (type 1-3, type 2-6, type 3-2). The preparative dose of FVIII was 10-20 IU kg(-1). The average duration of factor support was 2 days (1-3) for a mean total dose of 23 IU kg(-1) (9-60). The pre-infusion levels of FVIII:C, VWF:Ag and VWF:ristocetin cofactor (RCo) which were 31% (22-64), 25.5 U dL(-1) (0-63) and 21% (0-76), respectively, increased to 76% (27-111), 73 U dL(-1) (30-137) and 45% (2-106) postinfusion. Whereas surgical haemostasis was achieved in all patients, minor postoperative bleeding occurred after one procedure in each group. Both were controlled with additional doses of factor replacement. We conclude that Koate DVI in modest doses provide adequate haemostasis for surgery in patients with VWD. PMID- 18445015 TI - Successful management of Mallory-Weiss syndrome in a haemophilia A patient with inhibitor by recombinant activated factor VII. PMID- 18445016 TI - Applicability and safety of recombinant activated factor VII to control non haemophilic haemorrhage: investigational experience in 265 children. AB - Experience of recombinant activated factor VII (rFVIIa, NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark) to control haemorrhage in non-haemophilic children is limited. The object of this study was to examine the applicability and safety of rFVIIa amongst a group of non-haemophilic paediatric subjects. Details of all non haemophilic children < or =16 years receiving rFVIIa whose data were recorded in the investigational, internet-based registry, haemostasis.com were analysed. A total of 265 children (mean age 7.7 years) were treated with rFVIIa; the median dose administered was 78.4 microg kg(-1) body weight (range 9.0-393.4) and the median total dose received 100.0 microg kg(-1) body weight (range 10.9-1341.2). Therapeutic areas included surgery (34.5%), coagulopathy (including thrombocytopenia; 29.0%), spontaneous bleeding (17.2%), trauma (8.4%) and intracranial haemorrhage (4.5%). Two patients experienced thromboembolic events following administration of rFVIIa. Thirty-nine patients died on account of haemorrhage or complications relating to their underlying condition; neither the thromboembolic events nor the deaths were related to rFVIIa administration. Bleeding stopped in 118/237 (49.8%), markedly decreased in 54/237 (22.8%), decreased in 51/237 (21.5%), remained unchanged in 13/237 (5.5%) and increased in 1/237 (0.4%) patients. These results suggest that rFVIIa is safe and widely applicable in children to control non-haemophilic haemorrhage. PMID- 18445017 TI - From iron oxides to infections. PMID- 18445018 TI - Training the next scientific generation--a tribute to Terrance J. Beveridge. PMID- 18445019 TI - Electron microscopy encounters with unusual thermophiles helps direct genomic analysis of Aciduliprofundum boonei. AB - Terry Beveridge's enthusiasm about the ingenuity of microorganisms has stimulated many new avenues of microbial research. One example where Terry's observations helped direct the scientific process was in the analysis of the draft genome of the thermoacidophilic archaeum, Aciduliprofundum boonei. This deep-sea vent heterotroph ferments peptides as its primary metabolic pathway, using numerous enzymes encoding for proteolytic or peptidolytic activities. An almost complete modified Embden-Meyerhof-Parnas pathway operates in the gluconeogenic direction. Terry was particularly intrigued by the S-layer and flagellum of A. boonei. Although only putative genes for the S-layer protein could be identified, several genes encoding for glycosyl transferases were located in the draft genome that could glycosylate the S-layer proteins and protect the proteins from the acidic environment. Furthermore, A. boonei possesses a unique organization to its flagellum genes and may represent a third organizational type within the Archaea. PMID- 18445020 TI - The activity and stability of cell-associated activity of bovicin HC5, a bacteriocin from Streptococcus bovis HC5. AB - Streptococcus bovis HC5 cultures released a broad spectrum lantibiotic, bovicin HC5, into the cell-fee culture supernatant after they reached stationary phase, but most of the antibacterial activity remained cell-associated. Cell-associated bovicin HC5 was more resistant to degradation by Pronase E than the cell-free activity. Acidic NaCl (pH 2.0, 100 mM) did not release all of the cell-associated activity, and cells that were sequentially treated with acidic NaCl and Pronase E still had antibacterial activity. Cell-associated activity retained after acidic NaCl treatment was still able to catalyze potassium efflux from S. bovis JB1, a sensitive strain. These results indicate that cell-associated bovicin HC5 is more active and stable than cell-free bovicin HC5. PMID- 18445021 TI - Influence of aging on murine neutrophil and macrophage function against Candida albicans. AB - Previous work by our group showed that aged C57BL/6 mice develop an altered innate and adaptive immune response to Candida albicans and are more susceptible to systemic primary candidiasis. In this work, we used young (2-3 months old) and aged (18-20 months old) C57BL/6 mice to study in vitro the influence of aging on (1) the fungicidal activity of neutrophils and macrophages, (2) the production of cytokines by resident peritoneal macrophages in response to C. albicans, and (3) cell surface Toll-like receptor (TLR) 2 expression on resident peritoneal macrophages. Our results indicate that murine phagocytes have a fungicidal activity well preserved with aging. In vitro production of proinflammatory cytokines (IL-6, IL-1beta, and tumor necrosis factor-alpha and chemokines (MIP-2) by purified (CD11b(+)) peritoneal macrophages in response to yeasts and hyphae of C. albicans was significantly lower in aged mice as compared with young mice. However, the production of IL-10 by macrophages, in response to C. albicans, was similar in both young and aged animals. Moreover, baseline TLR2 surface expression level was lower on aged macrophages than on control macrophages. Taken together, these data indicate that the increased susceptibility to C. albicans disseminated infections in aged mice is correlated with defects in TLR2 expression and in cytokine production, but not with an impaired fungicidal activity. PMID- 18445022 TI - Microbial sulphate reduction at a low pH. AB - It is now well established that microbial sulphate-reduction can proceed in environments with a pH<5. This review summarizes existing reports on sulphate reduction at low pH and discusses possible pH effects on sulphate-reducing bacteria. Microbial sulphate reduction has been observed in acidic lakes, wetlands, mesocosms, acidic sulphate soils and bioreactors. Possible inhibitory factors include the metabolites H(2)S and organic acids, which can be toxic depending on pH. Metal sulphide precipitation and competition with other bacteria, namely iron-reducing bacteria, can inhibit sulphate reduction. Theoretical considerations show that normal sulphate reduction rates are too low to maintain a neutral micro niche in an acidic environment. The first acidotolerant sulphate-reducing bacteria have been isolated recently. PMID- 18445023 TI - Genetic susceptibility to keloid scarring: SMAD gene SNP frequencies in Afro Caribbeans. AB - Keloid disease (KD) is a fibroproliferative dermal tumour of unknown aetiology. The increased familial clustering in KD, its increased prevalence in certain races and increased concordance in identical twins suggest a strong genetic predisposition to keloid formation. The highest incidence of keloids is found in the black population, where it has been estimated around 4-6% and up to 16% in random samples of black Africans. SMAD genes 3, 6 and 7 were investigated as candidate genes in Jamaican patients with keloid scars (n = 183) and a matched control population (n = 121) because of their previously reported involvement in fibrotic disorders and to determine if they were associated with keloid disease susceptibility. Thirty Five SNPs across these genes were genotyped using Time-of Flight Mass Spectrometry (MALDI-TOF MS) and iPLEX assay. Linkage disequilibrium (LD) was established between several of the SNPs investigated. In the Jamaican population, the SMAD SNPs investigated for this study were not strongly associated with increased risk of developing KD. Identification of genetic markers in candidate genes such as the SMAD family may be of significant importance in diagnosis, prognosis and development of new therapies in the management of keloid scarring. PMID- 18445024 TI - Adaptive visual memory reorganization in right medial temporal lobe epilepsy. AB - PURPOSE: We investigated functional reorganization mechanisms of the human medial temporal lobe (MTL) for episodic memory, in patients suffering from medial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS). METHODS: We used functional magnetic resonance imaging (fMRI) to measure brain activity changes during matched episodic encoding tasks of abstract words (Verbal) and line drawings (Visual), in patients with unilateral right MTLE undergoing presurgical evaluation and healthy controls. RESULTS: As expected, a significant interaction between material type and the side of MTL activity was present in the control group, with preferential involvement of the left hippocampus in verbal encoding and the right parahippocampal region in visual encoding. When compared with controls, right MTLE patients with intact performance activated a region in the left hippocampus more during visual encoding, which resulted in an interaction between group and hemisphere. Importantly, an effect of memory performance on visual encoding activity was observed in the patients, with greater engagement of the left MTL being associated with higher recognition scores. Interestingly, activity in the left MTL also depended on the epileptic seizure frequency, suggesting a role for this clinical parameter in the recruitment of contralateral regions. DISCUSSION: Taken together, these results indicate functional reorganization of the MTLs in right HS, through transfer of function from the right to the left hemisphere, and strongly suggest an adaptive role for such reorganization mechanism in supporting preserved visual memory. PMID- 18445025 TI - A possible mechanism for the beneficial effect of ethanol in essential tremor. AB - BACKGROUND: Essential tremor is one of the most common movement disorders in elderly people. The hypothesis of a disregulation of N-methyl-D-aspartate (NMDA) pathways has been suggested. It was shown experimentally that infusion of NMDA in cerebellar nuclei down-regulates glutamate release. METHODS: We assessed the effects of intranuclear administration of harmaline on the NMDA-mediated regulation of glutamate in rats using reverse dialysis. We hypothesized that ethanol, which improves essential tremor in the clinic, antagonizes the effect of harmaline upon glutamatergic transmission. We tested the interaction of ethanol and harmaline upon glycerol (a marker of membrane turn-over), lactate, and pyruvate concentrations. RESULTS: Harmaline increased the concentrations of glutamate and impaired the NMDA-mediated regulation of glutamate. Ethanol decreased the concentrations of glutamate during NMDA stimulation in case of pre administration with harmaline. Concentrations of glycerol rose with harmaline. Glycerol levels markedly decreased during NMDA infusion when inhibitors of nitric oxide synthase, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonists or NMDA antagonists were administered. Harmaline increased lactate/pyruvate ratios during NMDA infusion but these ratios returned to normal values in presence of ethanol. DISCUSSION: We provide a possible mechanism for the beneficial effect of ethanol on essential tremor. The concept of glutamatergic disregulation underlying essential tremor is highlighted. Consequences for our understanding of essential tremor are discussed. PMID- 18445026 TI - Biodiversity of polycyclic aromatic hydrocarbon-degrading bacteria from deep sea sediments of the Middle Atlantic Ridge. AB - The bacteria involved in the biodegradation of polycyclic aromatic hydrocarbons (PAHs) in deep sea subsurface environments are largely unknown. In order to reveal their biodiversity, sediments from 2.2 m under the bottom surface at a water depth of 3542 m were sampled on the Middle Atlantic Ridge with a gravity column sampler. The sediments were promptly enriched with either crude oil or a mixture of PAHs (naphthalene, phenanthrene and pyrene) as the sole carbon source, and further enriched with the PAH mixture mentioned above in the lab. The resulting consortia were named C2CO and C2PPN respectively. Their bacterial composition was analysed with plate cultivation, PCR-DGGE and 16S rDNA library analysis. On plates, isolates belonging to Pseudoalteromonas, Halomonas, Marinobacter, Thalassospira and Tistrella dominated the culturable populations. With PCR-DGGE, five major bands closely related to Cycloclasticus, Alteromonas, Thalassospira, Alcanivorax and Rhodospirillaceae were detected in consortium C2CO, while only one major band of Cycloclasticus was detected in consortium C2PPN. In addition, the dynamics of community structure in response to aromatic substrate alterations were examined. As a result, three ribotypes of Cycloclasticus were detected by 16S rDNA library analysis, one which played a key role in phenanthrene degradation; two Alteromonas bacteria dominated the naphthalene reselected consortium. Although bacteria of the two genera grew as the main members of the communities, none of them were isolated, probably owing to their poor cultivability. These results confirm that bacteria of Cycloclasticus are important obligate PAH degraders in marine environments, and coexist with other degrading bacteria that inhabit the deep subsurface sediment of the Atlantic. This supports the view that PAH accumulation and bioattenuation occur in remote areas consistently and continuously. PMID- 18445027 TI - A landscape theory for food web architecture. AB - Ecologists have long searched for structures and processes that impart stability in nature. In particular, food web ecology has held promise in tackling this issue. Empirical patterns in food webs have consistently shown that the distributions of species and interactions in nature are more likely to be stable than randomly constructed systems with the same number of species and interactions. Food web ecology still faces two fundamental challenges, however. First, the quantity and quality of food web data required to document both the species richness and the interaction strengths among all species within food webs is largely prohibitive. Second, where food webs have been well documented, spatial and temporal variation in food web structure has been ignored. Conversely, research that has addressed spatial and temporal variation in ecosystems has generally ignored the full complexity of food web architecture. Here, we incorporate empirical patterns, largely from macroecology and behavioural ecology, into a spatially implicit food web structure to construct a simple landscape theory of food web architecture. Such an approach both captures important architectural features of food webs and allows for an exploration of food web structure across a range of spatial scales. Finally, we demonstrated that food webs are hierarchically organized along the spatial and temporal niche axes of species and their utilization of food resources in ways that stabilize ecosystems. PMID- 18445028 TI - Senescence rates are determined by ranking on the fast-slow life-history continuum. AB - Comparative analyses of survival senescence by using life tables have identified generalizations including the observation that mammals senesce faster than similar-sized birds. These generalizations have been challenged because of limitations of life-table approaches and the growing appreciation that senescence is more than an increasing probability of death. Without using life tables, we examine senescence rates in annual individual fitness using 20 individual-based data sets of terrestrial vertebrates with contrasting life histories and body size. We find that senescence is widespread in the wild and equally likely to occur in survival and reproduction. Additionally, mammals senesce faster than birds because they have a faster life history for a given body size. By allowing us to disentangle the effects of two major fitness components our methods allow an assessment of the robustness of the prevalent life-table approach. Focusing on one aspect of life history - survival or recruitment - can provide reliable information on overall senescence. PMID- 18445029 TI - Mass invariance of population nitrogen flux by terrestrial mammalian herbivores: an extension of the energetic equivalence rule. AB - According to the energetic equivalence rule, energy use by a population is independent of average adult body mass. Energy use can be equated with carbon flux, and it has been suggested that population fluxes of other materials, such as nitrogen and phosphorus, might also be independent of body mass. We compiled data on individual nitrogen deposition rates (via faeces and urine) and average population densities of 26 species of mammalian herbivores to test the hypothesis of elemental equivalence for nitrogen. We found that the mass scaling of individual nitrogen flux was opposite to that of population density for the species in our dataset. By computing the product of individual nitrogen flux and average population density for each species in our dataset, we found that population-level nitrogen flux was independent of species mass, averaging c. 3.22 g N ha(-1) day(-1). Results from this analysis can be used to understand the influence of mammalian herbivore communities on nitrogen cycling in terrestrial ecosystems. PMID- 18445030 TI - A cross-system synthesis of consumer and nutrient resource control on producer biomass. AB - Nutrient availability and herbivory control the biomass of primary producer communities to varying degrees across ecosystems. Ecological theory, individual experiments in many different systems, and system-specific quantitative reviews have suggested that (i) bottom-up control is pervasive but top-down control is more influential in aquatic habitats relative to terrestrial systems and (ii) bottom-up and top-down forces are interdependent, with statistical interactions that synergize or dampen relative influences on producer biomass. We used simple dynamic models to review ecological mechanisms that generate independent vs. interactive responses of community-level biomass. We calibrated these mechanistic predictions with the metrics of factorial meta-analysis and tested their prevalence across freshwater, marine and terrestrial ecosystems with a comprehensive meta-analysis of 191 factorial manipulations of herbivores and nutrients. Our analysis showed that producer community biomass increased with fertilization across all systems, although increases were greatest in freshwater habitats. Herbivore removal generally increased producer biomass in both freshwater and marine systems, but effects were inconsistent on land. With the exception of marine temperate rocky reef systems that showed positive synergism of nutrient enrichment and herbivore removal, experimental studies showed limited support for statistical interactions between nutrient and herbivory treatments on producer biomass. Top-down control of herbivores, compensatory behaviour of multiple herbivore guilds, spatial and temporal heterogeneity of interactions, and herbivore-mediated nutrient recycling may lower the probability of consistent interactive effects on producer biomass. Continuing studies should expand the temporal and spatial scales of experiments, particularly in understudied terrestrial systems; broaden factorial designs to manipulate independently multiple producer resources (e.g. nitrogen, phosphorus, light), multiple herbivore taxa or guilds (e.g. vertebrates and invertebrates) and multiple trophic levels; and - in addition to measuring producer biomass - assess the responses of species diversity, community composition and nutrient status. PMID- 18445031 TI - Scaling of respiration to nitrogen in leaves, stems and roots of higher land plants. AB - Using a database of 2510 measurements from 287 species, we assessed whether general relationships exist between mass-based dark respiration rate and nitrogen concentration for stems and roots, and if they do, whether they are similar to those for leaves. The results demonstrate strong respiration-nitrogen scaling relationships for all observations and for data averaged by species; for roots, stems and leaves examined separately; and for life-forms (woody, herbaceous plants) and phylogenetic groups (angiosperms, gymnosperms) considered separately. No consistent differences in the slopes of these log-log scaling relations were observed among organs or among plant groups, but respiration rates at any common nitrogen concentration were consistently lower on average in leaves than in stems or roots, indicating that organ-specific relationships should be used in models that simulate respiration based on tissue nitrogen concentrations. The results demonstrate both common and divergent aspects of tissue-level respiration nitrogen scaling for leaves, stems and roots across higher land plants, which are important in their own right and for their utility in modelling carbon fluxes at local to global scales. PMID- 18445032 TI - The tropics: cradle, museum or casino? A dynamic null model for latitudinal gradients of species diversity. AB - Several ecological and evolutionary hypotheses have been proposed to explain the latitudinal diversity gradient (LDG), but a general model for this conspicuous pattern remains elusive. Mid-domain effect (MDE) models generate gradients of species diversity by randomly placing the geographic ranges of species in one- or two-dimensional spaces, thus excluding both evolutionary processes and the effect of contemporary climate. Traditional MDE models are statistical and static because they determine the size of ranges either randomly or based on empirical frequency distributions. Here we present a simple dynamic null model for the LDG that simulates stochastic processes of range shifts, extinction and speciation. The model predicts higher species diversity and higher extinction and speciation rates in the tropics, and a strong influence of range movements in shaping the LDG. These null expectations should be taken into consideration in studies aimed at understanding the many factors that generate latitudinal diversity gradients. PMID- 18445033 TI - Switching behavior, coexistence and diversification: comparing empirical community-wide evidence with theoretical predictions. AB - Theory shows that the presence of behavioural switching between alternative resources can contribute to coexistence when competitors differ in trophic related traits. In addition, switching can generate disruptive selection on such traits in a low-diversity community, increasing the number of species. Both of these processes should produce communities in which species differ in their values of the trophic trait, and display corresponding differences in the time course of their switching from one resource to another. Here we present evidence for widespread switching behaviour for a diverse Mediterranean scrubland bird community. We show that species differ in a beak character related to their relative use of insect and fruit resource channels, and that the timing of switching is correlated with the relative use of resources. These patterns are consistent with theoretical predictions, suggesting a possible role of switching behaviour in promoting avian coexistence and diversification. PMID- 18445034 TI - Less lineages - more trait variation: phylogenetically clustered plant communities are functionally more diverse. AB - Functional diversity within communities may influence ecosystem functioning, but which factors drive functional diversity? We hypothesize that communities assembled from many phylogenetic lineages show large functional diversity if assembly is random, but low functional diversity if assembly is controlled by interactions between species within lineages. We combined > 9000 descriptions of Dutch plant communities, a species-level phylogeny, and information on 16 functional traits (including eight dispersal traits). We found that all traits were conserved within lineages, but nevertheless communities assembled from many lineages showed a smaller variation in trait-states of most traits (including dispersal traits) than communities assembled from few lineages. Hence, within lineages, species are not randomly assembled into communities, contradicting Neutral Theory. In fact, we find evidence for evolutionary divergence in trait states as well as present-day mutual exclusion among related, similar species, suggesting that functional diversity of communities increased due to past and present interactions between species within lineages. PMID- 18445035 TI - Coexistence through spatio-temporal heterogeneity and species sorting in grassland plant communities. AB - The effect of spatial heterogeneity on species coexistence relies on the degree of niche heterogeneity in the habitat and the ability of species to exploit the available niche opportunities. We studied species coexistence in a perennial grassland, and tested whether small-scale disturbances create environmental heterogeneity that affects coexistence and whether the functional diversity of species in the species pool affects the ability of community composition to reflect heterogeneity through species sorting. We manipulated the spatio-temporal heterogeneity of disturbance and the functional diversity of species added as seed and measured their impact on the spatial turnover of species composition. Disturbance increased environmental heterogeneity and spatial turnover, and the effect of heterogeneity on turnover was greatest in the presence of a functionally diverse species pool, showing the importance of trait variation among species for exploiting environmental heterogeneity, and suggesting that coexistence occurred due to species sorting among heterogeneous niches. PMID- 18445036 TI - S-nitrosylated proteins of a medicinal CAM plant Kalanchoe pinnata- ribulose-1,5 bisphosphate carboxylase/oxygenase activity targeted for inhibition. AB - Nitric oxide (NO) is a signaling molecule that affects a myriad of processes in plants. However, the mechanistic details are limited. NO post-translationally modifies proteins by S-nitrosylation of cysteines. The soluble S-nitrosoproteome of a medicinal, crassulacean acid metabolism (CAM) plant, Kalanchoe pinnata, was purified using the biotin switch technique. Nineteen targets were identified by MALDI-TOF mass spectrometry, including proteins associated with carbon, nitrogen and sulfur metabolism, the cytoskeleton, stress and photosynthesis. Some were similar to those previously identified in Arabidopsis thaliana, but kinesin-like protein, glycolate oxidase, putative UDP glucose 4-epimerase and putative DNA topoisomerase II had not been identified as targets previously for any organism. In vitro and in vivo nitrosylation of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), one of the targets, was confirmed by immunoblotting. Rubisco plays a central role in photosynthesis, and the effect of S-nitrosylation on its enzymatic activity was determined using NaH14CO3. The NO releasing compound S-nitrosoglutathione inhibited its activity in a dose dependent manner suggesting Rubisco inactivation by nitrosylation for the first time. PMID- 18445037 TI - The evolutionary relationship between the duplicated copies of the zebrafish fabp11 gene and the tetrapod FABP4, FABP5, FABP8 and FABP9 genes. AB - We describe the structure of a fatty acid-binding protein 11 (fabp11b) gene and its tissue-specific expression in zebrafish. The 3.4 kb zebrafish fabp11b is the paralog of the previously described zebrafish fabp11a, with a deduced amino acid sequence for Fabp11B exhibiting 65% identity with that of Fabp11A. Whole mount in situ hybridization of a riboprobe to embryos and larvae showed that zebrafish fabp11b transcripts were restricted solely to the retina and were first detected at 24 h postfertilization. In situ hybridization revealed fabp11b transcripts along the spinal cord in adult zebrafish. However, the highly sensitive RT-PCR assay detected fabp11b transcripts in the brain, heart, ovary and eye in adult tissues. By contrast, fabp11a transcripts had been previously detected in the liver, brain, heart, testis, muscle, ovary and skin of adult zebrafish. Using the LN54 radiation hybrid panel, we assigned zebrafish fabp11b to linkage group 16. Phylogenetic analysis and conserved gene synteny with tetrapod genes indicated that the emergence of two copies of fabp11 in the zebrafish genome may have resulted from a fish-specific whole genome duplication event. Furthermore, we propose that the FABP4-FABP5-FABP8-FABP9 (PERF15) gene cluster on a single chromosome in the tetrapod genome and the fabp11 genes in the zebrafish genome originated from a common ancestral gene, which, following their divergence, gave rise to the fabp11 genes of zebrafish, and the progenitor of the FABP4, FABP5, FABP8 and FABP9 genes in tetrapods after the separation of the fish and tetrapod lineages. PMID- 18445038 TI - Aldo-keto reductase from Helicobacter pylori--role in adaptation to growth at acid pH. AB - Pyridine-linked oxidoreductase enzymes of Helicobacter pylori have been implicated in the pathogenesis of gastric disease. Previous studies in this laboratory examined a cinnamyl alcohol dehydrogenase that was capable of detoxifying a range of aromatic aldehydes. In the present work, we have extended these studies to identify and characterize an aldoketo reductase (AKR) enzyme present in H. pylori. The gene encoding this AKR was identified in the sequenced strain of H. pylori, 26695. The gene, referred to as HpAKR, was cloned and expressed in Escherichia coli as a His-tag fusion protein, and purified using nickel chelate chromatography. The gene product (HpAKR) has been assigned to the AKR13C1 family, although it differs in specificity from the two other known members of this family. The enzyme is a monomer with a molecular mass of approximately 39 kDa on SDS/PAGE. It reduces a range of aromatic aldehyde substrates with high catalytic efficiency, and exhibits dual cofactor specificity for both NADPH and NADH. HpAKR can function over a broad pH range (pH 4-9), and has a pH optimum of 5.5. It is inhibited by sodium valproate. Its substrate specificity complements that of the cinnamyl alcohol dehydrogenase activity in H. pylori, giving the organism the capacity to reduce a wide range of aldehydes. Generation of an HpAKR isogenic mutant of H. pylori demonstrated that HpAKR is required for growth under acidic conditions, suggesting an important role for this enzyme in adaptation to growth in the gastric mucosa. This AKR is a member of a hitherto little-studied class. PMID- 18445039 TI - Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours. AB - Solid tumours are complex structures in which the interdependent relationship between tumour and endothelial cells modulates tumour development and metastasis dissemination. The tumour microenvironment plays an important role in this cell interplay, and changes in its features have a major impact on tumour growth as well as on anticancer therapy responsiveness. Different studies have shown irregular blood flow in tumours, which is responsible for hypoxia and reoxygenation phases, also called intermittent hypoxia. Intermittent hypoxia induces transient changes, the impact of which has been underestimated for a long time. Recent in vitro and in vivo studies have shown that intermittent hypoxia could positively modulate tumour development, inducing tumour growth, angiogenic processes, chemoresistance, and radioresistance. In this article, we review the effects of intermittent hypoxia on tumour and endothelial cells as well as its impacts on tumour development. PMID- 18445040 TI - Hypoxia induces expression of a GPI-anchorless splice variant of the prion protein. AB - The human prion protein (PrP) is a glycoprotein with a glycosylphosphatidylinositol (GPI) anchor at its C-terminus. Here we report alternative splicing within exon 2 of the PrP gene (PRNP) in the human glioblastoma cell line T98G. The open reading frame of the alternatively spliced mRNA lacked the GPI anchor signal sequence and encoded a 230 amino acid polypeptide. Its product, GPI-anchorless PrP (GPI(-) PrPSV), was unglycosylated and soluble in non-ionic detergent, and was found in the cytosolic fraction. We also detected low levels of alternatively spliced mRNA in human brain and non neuronal tissues. When long-term passaged T98G cells were placed in a low-oxygen environment, alternatively spliced mRNA expression increased and expression of normally spliced PrP mRNA decreased. These findings imply that oxygen tension regulates GPI(-) PrPSV expression in T98G cells. PMID- 18445041 TI - Requirements for chromatin reassembly during transcriptional downregulation of a heat shock gene in Saccharomyces cerevisiae. AB - Heat shock genes respond to moderate heat stress by a wave of transcription. The induction phase is accompanied by the massive eviction of histones, which later reassemble with DNA during the ensuing phase of transcription downregulation. In this article, we identify determinants of this reassembly throughout the heat shock protein 104 gene (HSP104) transcription unit. The results show that, although histone H3 lacking amino acids 4-30 of its N-terminal tail (H3Delta4-30) is normally deposited, reassembly of H3Delta4-40 is obliterated with an accompanying sustained transcription. On mutation of the histone chaperones Spt6p and Spt16p, but not Asf1p, reassociation of H3 with DNA is compromised. However, despite a lasting open chromatin structure, transcription ceases normally in the spt6 mutant. Thus, transcriptional downregulation can be uncoupled from histone redeposition and ongoing transcription is not required to prevent chromatin reassembly. PMID- 18445042 TI - Respiratory infection recurrence and passive smoking in early atherosclerosis in children and adolescents with type 1 diabetes. AB - BACKGROUND: Optimal glucose control in juvenile type 1 diabetes mellitus is necessary but not sufficient to reduce the burden of cardiovascular events in later life. This emphasizes the importance of searching for other possible risk factors associated with diabetes. We investigated whether recurrent episodes of acute respiratory infections and exposure to tobacco smoke could influence vascular phenotypes for early atherosclerosis in children and adolescents with type 1 diabetes. MATERIALS AND METHODS: Common carotid artery elasticity and intima-media thickness along with circulating markers of lipid, inflammatory and glycaemic profiles were investigated in up to 98 children and adolescents with type 1 diabetes. The number of clinically manifest acute respiratory tract infections (RTI) during the past year, and the degree of exposure to environmental tobacco smoke (ETS), were assessed by separate questionnaires. RESULTS: Carotid artery compliance (CAC) was decreased in patients with high (>or= 4/year; n = 22) recurrence of RTI compared to the remaining patients (n = 40; P < 0.05). In a multivariate analysis, the number of RTI during the past year and HbA(1C) were independently associated with decreased CAC (P < 0.05 for both). The inverse relationship between RTI recurrence and CAC was strengthened by frequent exposure to ETS. CONCLUSIONS: High recurrence of respiratory infections in young type 1 diabetics is associated with increased stiffening of the carotid artery particularly in those often exposed to tobacco smoke. PMID- 18445044 TI - CHD7 mutation spectrum in 28 Swedish patients diagnosed with CHARGE syndrome. AB - CHARGE syndrome is a disorder characterized by Coloboma, Heart defect, Atresia choanae, Retarded growth and/or development, Genital hypoplasia and Ear anomalies. Heterozygous mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene have been identified in about 60% of individuals diagnosed with CHARGE syndrome. We performed a CHD7 mutation screening by direct exon sequencing in 28 index patients (26 sporadic cases, 1 familial case consisting of a brother and sister and 1 case consisting of monozygotic twins) diagnosed with CHARGE syndrome in order to determine the mutations in a cohort of Swedish CHARGE syndrome patients. The patients without a detectable CHD7 mutation, or with a missense mutation, were further investigated by multiplex ligation-dependent probe amplification (MLPA) in order to search for intragenic deletions or duplications. Thirteen novel mutations and five previously reported mutations were detected. The mutations were scattered throughout the gene and included nonsense, frameshift and missense mutations as well as intragenic deletions. In conclusion, CHD7 mutations were detected in a large proportion (64%) of cases diagnosed with CHARGE syndrome. Screening for intragenic deletions with MLPA is recommended in cases where mutations are not found by sequencing. In addition, a CDH7 mutation was found in an individual without temporal bone malformation. PMID- 18445043 TI - Mixed-lineage eosinophil/basophil crisis in MDS: a rare form of progression. AB - BACKGROUND: Basophilic crisis and eosinophilia are well recognized features of advanced chronic myeloid leukaemia. In other myeloid neoplasms, however, transformation with marked basophilia and eosinophilia is considered unusual. DESIGN: We examined the long-term follow-up of 322 patients with de novo myelodysplastic syndromes (MDS) to define the frequency of basophilic, eosinophilic and mixed lineage (basophilic and eosinophilic) transformation. RESULTS: Of all patients, only one developed mixed lineage crisis (>or= 20% basophils and >or= 20% eosinophils). In this patient, who initially suffered from chronic myelomonocytic leukaemia, basophils increased to 48% and eosinophils up to 31% at the time of progression. Mixed lineage crisis was not accompanied by an increase in blast cells or organomegaly. The presence of BCR/ABL and other relevant fusion gene products (FIP1L1/PDGFRA, AML1/ETO, PML/RAR alpha, CBF beta/MYH11) were excluded by PCR. Myelomastocytic transformation/myelomastocytic leukaemia and primary mast cell disease were excluded by histology, KIT mutation analysis, electron microscopy and immunophenotyping. Basophils were thus found to be CD123+, CD203c+, BB1+, KIT- cells, and to express a functional IgE-receptor. Among the other patients with MDS examined, 4(1.2%) were found to have marked basophilia (>or= 20%) and 7(2.1%) were found to have massive eosinophilia ( >or= 20%), whereas mixed-lineage crisis was detected in none of them. CONCLUSIONS: Mixed basophil/eosinophil crisis may develop in patients with MDS but is an extremely rare event. PMID- 18445045 TI - Knowledge and impressions regarding the concept of mutation among Japanese university students. AB - Although the term mutation is frequently used in genetic counseling, it may carry negative connotations and create misunderstanding. Our objective was to investigate the relationship between the impressions regarding three Japanese terms mutation of gene, change of gene, and lesion of gene as well as to investigate the depth of understanding regarding mutation. A total of 175 university students and auditing students were included and responded to two questionnaires that were Impressions regarding the term in the semantic differential method and Knowledge about the concept of mutation. In factor analysis, three factors (Value, Change Rate, and Intention) were extracted. Participants were divided into three groups depending on their knowledge, and a two-way analysis of variance (Term x Knowledge Group) was conducted on the factor score for each. Results showed that the main effect of the 'Term' was significant for the Value Factor and that interaction was significant for the Change Rate Factor, and that the main effect of Knowledge Group was significant for the Intention Factor. The findings suggest that healthcare professionals should demonstrate an awareness of varying impressions of the different terms used to refer to the identical concepts of mutation. This is of particular importance when communicating with patients and their families. PMID- 18445047 TI - A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2). AB - Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11-q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659-660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations. PMID- 18445046 TI - Enzyme replacement therapy with agalsidase alfa in a cohort of Italian patients with Anderson-Fabry disease: testing the effects with the Mainz Severity Score Index. AB - Anderson-Fabry disease (AFD) is a rare X-linked disorder caused by lysosomal storage of several glycosphingolipids, affecting virtually all organs and systems. Enzyme replacement therapy (ERT) for AFD has been available since 2001. Due to the highly variable nature of clinical manifestations in patients with AFD, it is very difficult to assess disease progression and the effects of therapy. We used the Mainz Severity Score Index (MSSI) as a measure of disease severity to study the effects of ERT in a population of 30 patients treated with agalsidase alfa for a median of 2.9 years (range, 1.0-6.2 years). Our data show that the MSSI captures the correlation between disease severity and both gender and age (1 - males performing worse than females at baseline and 2 - severity of diseases progresses with age in both sex). Furthermore, after at least 1 year of ERT, total MSSI scores were significantly lower than those at baseline (p < 0.001), suggesting a marked clinical improvement under ERT. In conclusion, the MSSI is a sensitive and useful tool for monitoring disease progression and assessing the effects of ERT in a population of patients from different treatment centres. PMID- 18445048 TI - Concurrent microdeletion and duplication of 22q11.2. AB - Microduplication of 22q11.2 has been reported in fewer than 40 cases, all of them including the DiGeorge critical region (DGCR). We here present the characterization of a new duplication that does not include the DGCR. The duplication was initially found by multiplex ligation-dependent probe amplification analysis of 22q11.2 in a young girl with a concurrent deletion of the DGCR in 70% of her peripheral blood lymphocytes. Her phenotype included many of the features of the velocardiofacial syndrome, with velopharyngeal insufficiency, recurrent infections, learning and concentration problems as well as difficulties in social interactions. However, there were no congenital malformations, and her facial appearance was not typical for the syndrome. Further investigations included array comparative genomic hybridization (CGH) to size map the deletion/duplication and interphase fluorescent in situ hybridization to investigate mosaicism and the structure of the rearrangement. An identical duplication of this part of 22q11.2 has not been reported before, and the duplication itself seems to be associated with very mild or no symptoms. This study contributes to the growing knowledge regarding new deletions and duplications of 22q11.2, most of them mediated by the pre-disposing high number of low-copy repeats in the region. PMID- 18445049 TI - Autosomal recessive ichthyosis with hypotrichosis syndrome: further delineation of the phenotype. AB - Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome, which is characterized by congenital ichthyosis, abnormal hair and corneal involvement, has recently been shown in one consanguineous Israeli Arab family to be caused by a mutation in the ST14 gene, which encodes serine protease matriptase. No other families have so far been described since the original report. In this current report we describe a female patient from a second family with ARIH syndrome who carries a homozygous novel mutation, p.M1I. The patient has congenital ichthyosis, light brown, curly, sparse hair, improving with age, and sparse body hair, eyebrows and eyelashes. She does not suffer from photophobia, but has blepharitis. The phenotype of this patient closely resembles that of the affected individuals in the previously reported family, although she does not have tooth abnormalities and the ichthyosis is milder. PMID- 18445050 TI - Mowat-Wilson syndrome: an underdiagnosed syndrome? AB - Mowat-Wilson syndrome (MWS) is an autosomal dominant developmental disorder with mental retardation and variable multiple congenital abnormalities due to mutations of the ZEB2 (ZFHX1B) gene at 2q22. MWS was first described in 1998 and the causative gene was delineated in 2001. Since then, 115 different mutations of ZEB2 have been published in association with this syndrome in 161 individuals. However, recent reports suggest that due to the variability of the congenital abnormalities, this syndrome may still be underdiagnosed. We report two unrelated patients with MWS where the clinical diagnosis was established only after finding of disruption of the ZEB2 gene by a balanced translocation breakpoint and an interstitial microdeletion, respectively. PMID- 18445051 TI - Despite GABAergic neurotransmission, GABAergic innervation does not compensate for the defect in glycine receptor postsynaptic aggregation in spastic mice. AB - In the hypoglossal nucleus of wild-type mice, early mixed glycinergic-GABAergic inhibitory transmission becomes mainly glycinergic during postnatal maturation. In spastic mice (SPA), a model of human hyperekplexic syndrome, an insertion into the gene of the glycine receptor (GlyR) beta subunit results in a decreased accumulation of GlyRs at postsynaptic sites and an impaired glycinergic neurotransmission. In SPA mice displaying a mild phenotype (B6C3Fe strain), a compensatory process involving an increased aggregation of GABA(A) receptors (GABA(A)Rs) at postsynaptic sites was proposed to explain survival of mutant animals until adulthood. However, C57BL/6J strain SPA mice which express a lower amount of GlyR beta subunit die 2-3 weeks after birth, suggesting that GABAergic compensation does not necessarily take place. We performed a morphofunctional study of inhibitory synapses in the developing hypoglossal nucleus of C57BL/6J SPA mice. In this mutant, the inhibitory synaptic activity was mainly GABAergic. Accordingly, we observed a developmental loss of glycinergic presynaptic terminals and an increase in the density of GABAergic presynaptic terminals during the first two postnatal weeks. In addition, while C57BL/6J SPA mice displayed a strong impairment in GlyR aggregation at postsynaptic loci, the proportion of inhibitory presynaptic terminals facing diffuse GABA(A)Rs significantly increased during development. Our results suggest crosstalk between postsynaptic and presynaptic elements, leading to the developmental regulation of the presynaptic terminal neurotransmitter content according to the level of postsynaptic GlyR aggregation. They also indicate that GABAergic neurotransmission does not compensate for defects in GlyR postsynaptic aggregation leading to spastic syndrome in C57BL/6J SPA mice. PMID- 18445052 TI - Calcium-activated potassium currents differentially modulate respiratory rhythm generation. AB - The pre-Botzinger complex (PBC) generates eupnea and sighs in normoxia and gasping during hypoxia through particular mixtures of intrinsic and synaptic properties. Among intrinsic properties, little is known about the role of Ca(2+) activated potassium channels in respiratory rhythms generation. To examine this role, we tested the effects of openers and blockers of the large-conductance (BK) and small-conductance (SK) Ca(2+)-activated potassium channels on the respiratory rhythms recorded both in vitro and in vivo, as well as on the discharge pattern of respiratory neurons in the PBC. Activation of SK channels with 1-ethyl-2 benzimidazolinone (1-EBIO) abolished sigh-like activity and inhibited eupneic like activity, whereas blockade of SK channels with apamine (APA) increased frequency in both rhythms. In hypoxia, APA did not affect the transition to gasping-like activity. At the cellular level, activation of SK channels abolished pacemaker activity and decreased non-pacemaker neurons discharge; opposite effects were observed with SK blockade. In contrast to SK channel modulation, either activation or blockade of BK channels with NS 1619 or iberiotoxin and paxilline, respectively, produced mild effects on eupneic-like and sigh-like bursts during normoxia in vitro. However, BK blockers prevented the changes associated with the transition to gasping-like activity in vitro and perturbed gasping generation and autoresuscitation in vivo. At the cellular level BK channel modulation did not affect respiratory neurons discharge. We conclude that K(Ca) participate in rhythm generation in a state-dependent manner; SK channels are preferentially involved in rhythm generation in normoxia whereas BK channels participate in the transition to gasping generation in hypoxia. PMID- 18445053 TI - Glomerular activation patterns and the perception of odor mixtures. AB - Odor mixtures can produce several qualitatively different percepts; it is not known at which stage of processing these are determined. We asked if activity within the first stage of olfactory processing, the glomerular layer of the olfactory bulb, predicts odor mixture perception. We characterized how mice respond to components after training to five different mixture ratios of pentanal and hexanal, and found two types of responses: elemental perception and overshadowing. We then used intrinsic signal imaging to observe glomerular activity in response to the same mixtures and their components. As has been previously described, glomerular activity patterns produced by mixtures resemble the linear combination of responses to components. Mice trained to identify mixtures with more hexanal than pentanal recognized hexanal but not pentanal when the odorants were presented alone (overshadowing). Consistent with these behavioral responses, the imaged activity pattern in response to mixtures was similar to that produced to hexanal alone. Moreover, there was no significant effect of glomerular inhibition in the imaged response. In contrast, the glomerular activity patterns did not predict elemental perception: when trained to identify mixtures with more pentanal than hexanal, mice recognized both components equally well, even with highly overlapping activation patterns. This suggests that spatial activity patterns within the olfactory bulb are not always sufficient to specify component recognition in mixtures. PMID- 18445054 TI - Altered neurovascular coupling during information-processing states. AB - Brain imaging techniques rely on changes in blood flow, volume and oxygenation to infer the loci and magnitude of changes in activity. Although progress has been made in understanding the link between stimulus-evoked neural activity and haemodynamics, the extent to which neurovascular-coupling relationships remain constant during different states of baseline cortical activity is poorly understood. Optical imaging spectroscopy, laser Doppler flowmetry and electrophysiology were used to measure haemodynamics and neural activity in the barrel cortex of anaesthetized rats. The responses to stimulation of the whisker pad were recorded during quiescence and cortical desynchronization produced by stimulation of the brainstem. Cortical desynchronization was accompanied by increases in baseline blood flow, volume and oxygenation. Haemodynamic responses to low-frequency whisker stimuli (1 Hz) were attenuated during arousal compared with that observed during quiescence. During arousal it was possible to increase stimulus-evoked haemodynamics by increasing the frequency of the stimulus. Neural responses to low-frequency stimuli were also attenuated but to a far lesser extent than the reduction in the accompanying haemodynamics. In contrast, neuronal activity evoked by high-frequency stimuli (40 Hz) was enhanced during arousal, but induced haemodynamic responses of a similar magnitude compared with that observed for the same high-frequency stimulus presented during quiescence. These data suggest that there may be differences in stimulus-evoked neural activity and accompanying haemodynamics during different information-processing states. PMID- 18445055 TI - Riluzole blocks persistent Na+ and Ca2+ currents and modulates release of glutamate via presynaptic NMDA receptors on neonatal rat hypoglossal motoneurons in vitro. AB - The neuroprotective agent riluzole is used for the symptomatic treatment of motoneuron disease, which strongly affects the brainstem nucleus hypoglossus. The mechanism of action of riluzole was investigated using, as a model, patch-clamp recording from hypoglossal motoneurons of the neonatal rat brainstem slice preparation. In the presence of riluzole (10 microm), theta-rhythm oscillations evoked by nicotine continued even though the persistent inward current (comprising sodium and calcium components) was halved, but they disappeared when the high frequency of spontaneous glutamatergic currents waned. Riluzole fully inhibited the persistent sodium current and partly depressed a tetrodotoxin (TTX) insensitive slow current antagonized by Mn(2+) or Cd(2+). Repetitive firing was inhibited by riluzole without changing single action potentials. In the presence of TTX, riluzole depressed miniature glutamatergic currents occurring at high rate. Synaptic transmission with low release probability became sensitive to riluzole if release was stimulated by high potassium solution. Miniature current frequency was depressed by the N-methyl-D-aspartic acid (NMDA) receptor antagonist D-amino-phosphonovaleriate (50 microm), which fully occluded the action of riluzole. As riluzole is a protein kinase C (PKC) inhibitor, the PKC antagonist chelerythrine (2.5 microm) mimicked the effect of riluzole and prevented it. In summary, riluzole blocked the persistent sodium current fully, and the calcium one partly, plus it decreased glutamatergic transmission probably via inhibition of PKC that regulated presynaptic NMDA receptors having a facilitatory effect on glutamate release. Controlling NMDA receptor function and, thus, excitatory transmitter release via modulation of PKC suggests a novel potential target to contrast glutamate excitotoxicity in this motor nucleus. PMID- 18445056 TI - Is there any relationship between metabolic parameters and left ventricular functions in type 2 diabetic patients without evident heart disease? AB - BACKGROUND: The aim of the present study was to evaluate left ventricle (LV) systolic and diastolic function, using tissue Doppler echocardiography (TDE) and color M-mode flow propagation velocity, in relation to blood glucose status in normotensive patients with type 2 diabetes mellitus (T2DM) who had no clinical evidence of heart disease. METHODS: Seventy-two patients with T2DM (mean age 49.1 +/- 9.8 years) without symptoms, signs or history of heart disease and hypertension, and 50 ages matched healthy controls (mean age 46.1 +/- 9.8 years) had echocardiography. Systolic and diastolic LV functions were detected by using conventional echocardiography, TDE and mitral color M-mode flow propagation velocity (V(E)). Fasting blood glucose level (FBG) after 8 hours since eating a meal, postprandial blood glucose level (PPG), and HbA(1C) level were determined. The association of FBG, PPG and HbA(1C) with the echocardiographic parameters was investigated. RESULTS: It was detected that although systolic functions of two groups were similar, diastolic functions were significantly impaired in diabetics. No relation of FBG and PPG with systolic and diastolic functions was determined. However, HbA(1C) was found to be related to diastolic parameters such as E/A, Em/Am, V(E) and E/V(E) (beta=-0.314, P = < 0.05; beta=-0.230, P < 0.05; beta=-0.602, P < 0.001, beta= 0.387, P < 0.005, respectively). In addition to HbA(1C), LV, diastolic functions were also correlated with age and diabetes duration. CONCLUSION: Diastolic LV dysfunction may develop even in absence of ischemia, hypertension, and LVH in T2DM. FBG and PPG have no effect on LV functions, but HbA(1C) levels may affect diastolic parameters. PMID- 18445057 TI - Utility of right ventricular tissue Doppler imaging: correlation with right heart catheterization. AB - OBJECTIVES: The objective of this study was to correlate tissue Doppler imaging of the right ventricle (RV) with pulmonary hemodynamics in patients referred for right heart catheterization. METHODS: Seventy subjects (mean age 54 +/- 13; 35 males) prospectively underwent tissue Doppler imaging of the RV and right heart catheterization within 1 day of each other. Peak systolic velocity and strain were measured at the RV free wall and correlated with pulmonary hemodynamics. RESULTS: RV myocardial velocity demonstrated no correlation with any hemodynamic variable. While RV strain demonstrated significant correlation with cardiac index (r =-0.61; P < 0.001), correlations with transpulmonary gradient (r = 0.26; P < 0.05) and pulmonary vascular resistance (r = 0.30; P < 0.05) were weaker. Subgroup analysis revealed that in patients with left ventricular systolic dysfunction (n = 31), RV strain showed no correlation with any hemodynamic variable. In patients with normal left ventricular systolic function (n = 39), correlations were significant between RV strain and mean pulmonary artery pressure (r = 0.59; P < 0.001), pulmonary vascular resistance (r = 0.60; P < 0.001), and cardiac index (r =-0.67; P < 0.001). CONCLUSIONS: RV myocardial strain correlates significantly with pulmonary hemodynamics in patients with pulmonary hypertension and normal left ventricular function. However, there is no correlation with RV performance in patients with left ventricular dysfunction. PMID- 18445058 TI - Side effects of high-dose dobutamine are not prevented by normal saline infusion in dobutamine stress echocardiography. AB - High-dose dobutamine used in dobutamine stress echocardiography (DSE) has hemodynamically based side effects due to a variable combination of beta1 (inotropic) and beta2 (vasodilator) effects. Of concern is the development of an "empty ventricle syndrome" associated with intracavitary or outflow tract obstruction and resultant symptomatic hypotension. This study was undertaken to determine whether the concurrent administration of normal saline (N/S) would decrease symptoms, limit the development of left ventricular outflow tract (LVOT) obstruction and hypotension by maintaining left ventricular volume. One hundred patients, mean age 66 years +/- 12, presenting for a DSE were randomized into two groups. One group (n = 50) received N/S at a rate of 800 ml/hour during the test, the second group received dobutamine alone. Patients were instructed to report and quantify symptoms on a scale of 1 to 10. Echocardiographic measurements of end systolic volume (ESV) and LVOT gradients were taken prior to dobutamine and at peak dose. There was no difference in symptom scores (3.5 +/- 5.1(N/S) vs. 3.0 +/- 4.7, P = 0.6), change in systolic blood pressure (BP) (-0.74 mmHg +/- 33 (N/S) vs. -0.89 +/- 35, P = 0.9) maximum LVOT gradient at peak (16.4 mmHg +/- 16.1 (N/S) vs. 13.9 mmHg +/- 9, P = 0.4), or ESV at peak (17.9 mL +/- 13.4 (N/S) vs. 15.5 ml +/- 10.6, P = 0.37). Furthermore, there was no difference in the number of patients (10/50 (20%) in both groups) who developed a significant LVOT gradient, defined as greater than 20 mmHg at peak dose. Despite the sound theoretical basis of N/S infusion to protect against "empty ventricle syndrome" during DSE this randomized trial does not demonstrate any symptomatic or hemodynamic benefit. PMID- 18445059 TI - Differences in echocardiographic assessment with standard Doppler and tissue Doppler imaging of left ventricular filling pressure in idiopathic and ischemic dilated cardiomyopathy. AB - BACKGROUND: In idiopathic and ischemic dilated cardiomyopathy (DCM) there are differences in left atrial and ventricular relaxation. We assessed the hypothesis of an influence of these dissimilarities in assessing left ventricular filling pressure (LVFP) in these two DCMs by standard Doppler and tissue Doppler imaging. In particular, we focused on early transmitral flow to early diastolic motion velocity of mitral annulus ratio (E/Ea), useful to estimate normal or elevated LVFP. However, when found in intermediate range (8-15), its role is unclear. METHODS AND RESULTS: We evaluated 26 patients with ischemic and 21 patients with idiopathic DCM. To validate the echocardiographic estimation of LVFP, a sample (12 patients) underwent LVFP assessment by catheterization. In idiopathic DCM, E/Ea directly related to duration of retrograde pulmonary venous flow (ARd) (r = 0.66 P = 0001). In ischemic DCM E/Ea inversely related only to systolic to diastolic velocity ratio of pulmonary venous flow (S/D) (r =-0.56 P = 0002). After a mean follow up of 6 months, by a second echocardiogram we observed a direct relation between E/Ea and ARd percentage variation (r = 0.52 P = 0.02) in idiopathic DCM group, whereas in the ischemic DCM group there was an inverse relation between E/Ea and S/D percentage variation (r =-0.59 P = 0.02). CONCLUSIONS: In conclusion, ARd in idiopathic and S/D in ischemic DCM might be used as specific additional information to estimate LVFP when E/Ea falls within intermediate range. PMID- 18445060 TI - Tissue Doppler derived isovolumic acceleration in patients after atrial repair for dextrotransposition of the great arteries. AB - BACKGROUND: Ventricular dysfunction represents one of the major problems in the long-term follow-up of patients after atrial repair for dextrotransposition of the great arteries. We aimed to study the role of tissue Doppler derived isovolumic acceleration (IVA) to detect early myocardial dysfunction in these patients. METHODS: Twenty-four patients with dextrotransposition of the great arteries (D-TGA) that underwent atrial repair (Senning procedure: n = 12; Mustard procedure: n = 12) in infancy were examined at the age of 21 [12-33] years (median [range]) using tissue Doppler analysis of IVA and peak systolic myocardial velocity at rest and during exercise. 12 age-matched healthy subjects served as controls. RESULTS: At rest, IVA and peak systolic myocardial velocity were reduced in the systemic ventricle (SV) of patients. IVA correlated with peak systolic myocardial velocity (r = 0.76, P < 0.001). During exercise, IVA, but not peak systolic myocardial velocity, increased significantly in the SV of patients (rest: 1.03 +/- 0.44 cm/sec(2); 1 W/kg: 1.80 +/- 1.22 cm/sec(2); 2 W/kg: 2.85 +/- 1.26 cm/sec(2)). In the subpulmonary ventricle, IVA was significantly lower in patients compared to the controls (patients: 1.45 +/- 0.49 cm/sec(2) vs. controls: 2.31 +/- 0.43 cm/sec(2), P < 0.05). IVA but not peak systolic myocardial velocity was able to discriminate between patients and healthy subjects. CONCLUSIONS: IVA is superior to peak systolic myocardial velocity to assess a reduction in functional reserve of both ventricles in patients after atrial repair for D-TGA. PMID- 18445061 TI - Anomalies of left coronary artery origin affecting surgical repair of hypoplastic left heart syndrome and Shone complex. AB - There has traditionally been less concern regarding coronary anomalies with left sided congenital heart lesions such as hypoplastic left heart syndrome (HLHS)or Shone complex than with other lesions. However, coronary anomalies in this setting can profoundly affect surgical intervention, particularly when surgical repair involves the ascending aorta. We describe four patients with congenital left-sided heart lesions in which left coronary artery (LCA) anomalies substantially affected intervention and outcome. In the first two cases, the coronary anomalies were not identified prospectively and resulted in surgical injury directly to the coronary or to its surrounding region. In the latter two cases, successful identification of the coronary anomaly preoperatively allowed for modification of surgical technique and/or intervention. We conclude that detailed coronary artery assessment should be part of the routine echocardiographic evaluation of congenital left-sided heart lesions that require surgery. PMID- 18445062 TI - Value of real time three-dimensional echocardiography in patients with hypertrophic cardiomyopathy: comparison with two-dimensional echocardiography and magnetic resonance imaging. AB - Real time three-dimensional echocardiography (RT3DE) has been demonstrated to be an accurate technique to quantify left ventricular (LV) volumes and function in different patient populations. We sought to determine the value of RT3DE for evaluating patients with hypertrophic cardiomyopathy (HCM), in comparison with cardiac magnetic resonance imaging (MRI). METHODS: We studied 20 consecutive patients with HCM who underwent two-dimensional echocardiography (2DE), RT3DE, and MRI. Parameters analyzed by echocardiography and MRI included: wall thickness, LV volumes, ejection fraction (LVEF), mass, geometric index, and dyssynchrony index. Statistical analysis was performed by Lin agreement coefficient, Pearson linear correlation and Bland-Altman model. RESULTS: There was excellent agreement between 2DE and RT3DE (Rc = 0.92), 2DE and MRI (Rc = 0.85), and RT3DE and MRI (Rc = 0.90) for linear measurements. Agreement indexes for LV end-diastolic and end-systolic volumes were Rc = 0.91 and Rc = 0.91 between 2DE and RT3DE, Rc = 0.94 and Rc = 0.95 between RT3DE and MRI, and Rc = 0.89 and Rc = 0.88 between 2DE and MRI, respectively. Satisfactory agreement was observed between 2DE and RT3DE (Rc = 0.75), RT3DE and MRI (Rc = 0.83), and 2DE and MRI (Rc = 0.73) for determining LVEF, with a mild underestimation of LVEF by 2DE, and smaller variability between RT3DE and MRI. Regarding LV mass, excellent agreement was observed between RT3DE and MRI (Rc = 0.96), with bias of-6.3 g (limits of concordance = 42.22 to-54.73 g). CONCLUSION: In patients with HCM, RT3DE demonstrated superior performance than 2DE for the evaluation of myocardial hypertrophy, LV volumes, LVEF, and LV mass. PMID- 18445063 TI - Role of metalloproteinases at the onset of liver development. AB - At the onset of liver development, the hepatic precursor cells, namely, the hepatoblasts, derive from the ventral foregut endoderm and form a bud surrounded by a basement membrane (BM). To initiate liver growth, the hepatoblasts migrate across the BM and invade the neighboring septum transversum mesenchyme. In the present study, carried out in the mouse embryo, we searched for effectors involved in this process and we examined the role of matrix metalloproteinases (MMPs). We found expression of a broad range of MMPs, among which MMP-2 was predominantly expressed in the septum transversum and MMP-14 in the hepatoblasts. Using a new liver explant culture system we showed that inhibition of MMP activity represses migration of the hepatoblasts. We conclude that MMPs are required to initiate expansion of the liver during development and that our culture system provides a new model to study hepatoblast migration. PMID- 18445064 TI - Human chorionic villous macrophages as a fetal biological shield from maternal chorionic gonadotropin. AB - In addition to its most well characterized biological role in the rescue and maintenance of corpus luteum function, human chorionic gonadotropin (hCG) also stimulates the onset of fetal gonadal steroidogenesis. However, excess hCG is teratogenic to fetal gonadal tissues, and therefore hCG must be tightly regulated. Although there is an anatomical barrier between the fetal vessels and maternal blood, other mechanisms may regulate hCG levels. In the present study, we investigated whether human chorionic villous macrophages degraded maternal hCG. Isolated human macrophages incorporated and degraded hCG in a time-dependent manner. Human placental villous macrophages and phorbol myristate acetate (PMA) treated THP-1 cells expressed the gene encoding an exon 9-deleted form of the luteinizing hormone/chorionic gonadotropin (LH/CG) receptor; expression of the full-length receptor was not determined. While both PMA-treated or untreated THP 1 cells could uptake hCG into their cytoplasms, hCG degradation and excretion of its byproducts only progressed in PMA-treated THP-1 cells. In conclusion, hCG internalization and degradation are different processes in macrophages that protect fetal gonadogenesis from excess hCG. The exon 9-deleted LH/CG receptor, but not the full-length receptor, is involved in the degradation of cytoplasmic hCG by organ-specific, dominant-negative interactions. PMID- 18445065 TI - In vivo DNA electrotransfer into muscle. AB - Naked plasmid DNA injected into skeletal muscle is taken up by muscle cells and the genes in the plasmid are expressed. Among the non-viral techniques for gene transfer in vivo, this method is especially simple, inexpensive, and safe. However, the relatively low expression levels attained by this method have limited its applications for uses other than as a DNA vaccine. We and other groups investigated the applicability of in vivo electroporation for gene transfer into muscle, using plasmid DNA vector. The results demonstrated that gene transfer into muscle by in vivo electroporation is far more efficient than simple intramuscular DNA injection and provides a potential approach to systemically delivering cytokines, growth factors, and other serum proteins for basic research and human gene therapy. PMID- 18445066 TI - Transgenic zebrafish expressing fluorescent proteins in central nervous system neurons. AB - Zebrafish is a powerful model system for investigations of vertebrate neural development. The animal has also become an important model for studies of neuronal function. Both in developmental and functional studies, transgenic zebrafish expressing fluorescent proteins in central nervous system neurons have been playing important roles. We review here the methods for producing transgenic zebrafish. Recent advances in transposon- or bacterial artificial chromosome based transgenesis greatly facilitate the creation of useful lines. We also present our study on alx-positive neurons to reveal how transgenic zebrafish expressing fluorescent proteins in a specific class of neurons can be used to investigate their development and function. PMID- 18445067 TI - Novel two-step Ca2+ increase and its mechanisms and functions at fertilization in oocytes of the annelidan worm Pseudopotamilla occelata. AB - Mature oocytes of the annelidan worm Pseudopotamilla occelata have a wide perivitelline space between the oocyte surface and the vitelline envelope and are arrested at the first metaphase (MI). We found a novel two-step Ca2+ increase in normally fertilized oocytes. The first Ca2+ increase originated at a cortex situated underneath a fertilizing sperm on the vitelline envelope, but failed to propagate beyond the center of the oocyte. The first localized Ca2+ increase was then followed by a larger Ca2+ increase starting from the whole oocyte cortex and spreading inwardly to the center. The first localized Ca2+ increase at fertilization was suppressed by the phospholipase C inhibitor U73122, and a similar Ca2+ change was induced by inositol 1,4,5-trisphosphate (IP3). On the other hand, the second global Ca2+ increase in fertilized oocytes was blocked by removal of external Ca2+ or the voltage-gated Ca2+ channel blocker D-600, and a similar Ca2+ change could be mimicked by addition of excess K+ only when external Ca2+ was present. These results suggest that the first localized Ca2+ increase and the second global Ca2+ increase at fertilization are regulated by Ca2+ release from IP3-sensitive stores and Ca2+ influx via voltage-gated Ca2+ channels, respectively. Our data also demonstrated that the localized Ca2+ increase induces the formation of large cytoplasmic protrusion, which helps the fertilizing sperm to enter the oocyte, whereas the following global Ca2+ increase is a prerequisite for the retraction of the cytoplasmic protrusion and the resumption of meiosis from MI. PMID- 18445068 TI - Retrovirus vector-mediated gene transfer into the chick optic vesicle by in ovo electroporation. AB - Owing to its external position in the embryo, the chick eye has been used as a readily accessible model for studying the molecular mechanisms behind the patterning of the central nervous system. Although methods of genetic analysis have not been established as in the mouse, the chick is convenient for analyzing the functions of genes by in ovo electroporation of retroviral vectors. In this review, we describe the retroviral vector-mediated transfer of genes into the chick optic vesicle by in ovo electroporation. A rapid, efficient, and sustained expression of transgenes is achieved by this approach. PMID- 18445069 TI - Antipruritic effect of cyclosporine microemulsion in prurigo nodularis: results of a case series. AB - BACKGROUND: Prurigo nodularis shows intense itching nodules, which are often persistent and therapy refractory. Histological alterations include fibrosis of collagen fibers and presence of inflammatory infiltrate, which partly explains the clinical persistence of lesions. Inflammatory cells may directly contribute to induction and maintenance of pruritus at nerve fibers. Cyclosporine microemulsion (ME) suppresses the migration and proliferation of inflammatory cells and may thereby interfere with pathogenesis of prurigo nodularis. The aim of this investigation was to assess the antipruritic efficiency of cyclosporine ME in therapy of prurigo nodularis. PATIENTS AND METHODS: 14 patients with prurigo nodularis of diverse origin and failure to previous therapy were treated with oral cyclosporine ME (3 to 5 mg per kg daily). Blood pressure, liver enzymes, renal function and differential blood count were monitored. RESULTS: In 13 of 14 prurigo patients (92.9 %) there was a significant response to monotherapy with cyclosporine ME. The maximal antipruritic effect occurred after 2 weeks to 12 months. Prurigo nodules also healed during therapy. Seven patients (50.0 %) described side effects. In one case the therapy was stopped. CONCLUSIONS: Oral cyclosporine ME is an effective therapy for prurigo nodularis of diverse origin. It appears to function by inhibiting dermal inflammatory cells. PMID- 18445070 TI - Keratoacanthoma with perineural invasion: an indicator for aggressive behavior? AB - Neurotropic invasion of keratoacanthoma (KA) is rare and can easily be missed histologically. A 36-year-old woman developed a KA on the upper lip four weeks after CO(2) laser skin resurfacing; it showed microscopic evidence of perineural invasion. Despite repeated treatment with intralesional methotrexate, the KA recurred after 6 months. She was then treated with ionizing radiation (56 Gy) and has been tumor-free for more than 3 years. Immunohistochemistry showed decreased expression of desmoglein 1 as it is seen in squamous cell carcinomas. In most cases not much importance is attached to perineural invasion which is frequently seen in KA because of the high rate of spontaneous regression. Our case suggests that perineural invasion may be an indicator for aggressive growth of head-and neck KAs so that histologically-controlled excision is recommended. PMID- 18445072 TI - Reporting of informed consent, standard of care and post-trial obligations in global randomized intervention trials: a systematic survey of registered trials. AB - OBJECTIVE: Ethical guidelines are designed to ensure benefits, protection and respect of participants in clinical research. Clinical trials must now be registered on open-access databases and provide details on ethical considerations. This systematic survey aimed to determine the extent to which recently registered clinical trials report the use of standard of care and post trial obligations in trial registries, and whether trial characteristics vary according to setting. METHODS: We selected global randomized trials registered on http://www.clinicaltrials.gov and http://www.controlled-trials.com. We searched for intervention trials of HIV/AIDS, malaria, and tuberculosis from 9 October 2004, the date of the most recent version of the Helsinki Declaration, to 10 April 2007. RESULTS: We collected data from 312 trials. Fifty-eight percent (58%, 95% CI = 53 to 64) of trial protocols report informed consent. Fifty-eight percent (58%, 95% CI = 53 to 64) of trials report active controls. Almost no trials (1%, 95% CI = 0.5 to 3) mention post-trial provisions. Most trials measure surrogate outcomes. Twenty percent (20%, 95% CI = 16 to 25) of trials measure patient-important outcomes, such as death; and the odds that these outcomes are in a low income country are five times greater than for a developed country (odds ratio (OR) 5.03, 95% CI = 2.70 to 9.35, p = < 0.001). Pharmaceutical companies are involved in 28% (CI = 23 to 33) of trials and measure surrogate outcomes more often than nonpharmaceutical companies (OR 2.45, 95% CI = 1.18 to 5.09, p = 0.31). CONCLUSION: We found a large discrepancy in the quality of reporting and approaches used in trials in developing settings compared to wealthier settings. PMID- 18445071 TI - Arterial stiffness, endothelial function and microcirculatory reactivity in healthy young males. AB - Large (C1) and small (C2) arterial stiffness has been suggested to parallel endothelial reactivity and has led researchers to suggest parameters of arterial stiffness may be alternative measures to brachial sonographic assessments of flow mediated dilatation (FMD). However, past studies comparing these measures can be criticized. In addition to %FMD responses, we recorded concurrent hyperaemic responses of the microcirculation and both were compared with C1 and C2. Twenty nine subjects 18-30 years of age were investigated. Radial blood pressure was recorded with a tonometer. Pulse waveform analysis was performed to calculate C1 and C2. These were compared with %FMD responses and responses of finger flux measured by laser Doppler fluxmetry (LDF); pulsatile finger volume measured by photoplethysmography (PPG); and palm skin temperature measured by infrared thermography (Tpalm) (i.e. microcirculatory responses). Responses were determined as % changes from control. We only found weak relationships between C1 and %FMD (r=0.4, P=0.04); C2 and %PPG (r=0.38, P=0.07); and C2 and %LDFdorsal (r=-0.38; P=0.04). Responses of %FMD weakly parallel those of C1. Neither C2 nor C1 are viable indicators of endothelial or microcirculatory reactivity (i.e. hyperaemic or venous constriction) in healthy, resting young males. These findings refute the claims that C1 and C2 are substitute measures to sonographic assessments of brachial FMD. PMID- 18445073 TI - The international dimensions of neuroethics. AB - Neuroethics, in its modern form, investigates the impact of brain science in four basic dimensions: the self, social policy, practice and discourse. In this study, we analyzed a set of 461 peer-reviewed articles with neuroethics content, published by authors from 32 countries. We analyzed the data for: (1) trends in the development of international neuroethics over time, and (2) how challenges at the intersection of ethics and neuroscience are viewed in countries that are considered developed by International Monetary Fund (IMF) standards, and in those that are developing. Our results demonstrate a steady increase in global participation in neuroethics from 1989 to 2005, characterized by an increase in numbers of articles published specifically on neuroethics, journals publishing these articles, and countries contributing to the literature. The focus from all countries was on the practice of brain science and the amelioration of neurological disease. Indicators of technology creation and diffusion in developing countries were specifically correlated with increases in publications concerning policy implications of brain science. Neuroethics is an international endeavor and, as such, should be sensitive to the impact that context has on acceptance and use of technological innovation. PMID- 18445074 TI - Household location choices: implications for biodiversity conservation. AB - Successful conservation efforts require understanding human behaviors that directly affect biodiversity. Choice of household location represents an observable behavior that has direct effects on biodiversity conservation, but no one has examined the sociocultural predictors of this choice relative to its environmental impacts. We conducted a case study of the Teton Valley of Idaho and Wyoming (U.S.A.) that (1) explored relationships between sociodemographic variables, environmental attitudes, and the environmental impact of household location choices, (2) assessed the potential for small household sizes in natural areas to multiply the environmental impacts of household location decisions, and (3) evaluated how length of residency predicted the environmental attitudes of people living in natural areas. We collected sociodemographic data, spatial coordinates, and land-cover information in a survey of 416 households drawn from a random sample of Teton Valley residents (95% compliance rate). Immigrants (respondents not born in the study area) with the lowest education levels and least environmentally oriented attitudes lived in previously established residential areas in disproportionately high numbers, and older and more educated immigrants with the most environmentally oriented attitudes lived in natural areas in disproportionately high numbers. Income was not a significant predictor of household location decisions. Those living in natural areas had more environmental impact per person because of the location and because small households (<3 people/household) were 4 times as likely in natural areas as large households. Longer residency in natural areas predicted less environmentally oriented attitudes, suggesting that living in natural areas does not foster more concern for nature. Because populaces are rapidly aging, growing more educated, and potentially growing more environmentally oriented, these patterns are troubling for biodiversity conservation. Our results demonstrate a need for environmentalists to make household location decisions that reflect their environmental attitudes and future research to address how interactions between education level, environmental attitudes, population aging, and household location choices influence biodiversity conservation. PMID- 18445075 TI - Influence of representation targets on the total area of conservation-area networks. AB - Systematic conservation planning typically requires specification of quantitative representation targets for biodiversity surrogates such as species, vegetation types, and environmental parameters. Targets are usually specified either as the minimum total area in a conservation-area network in which a surrogate must be present or as the proportion of a surrogate's existing spatial distribution required to be in the network. Because the biological basis for setting targets is often unclear, a better understanding of how targets affect selection of conservation areas is needed. We studied how the total area of conservation-area networks depends on percentage targets ranging from 5% to 95%. We analyzed 12 data sets of different surrogate distributions from 5 regions: Korea, Mexico, Quebec, Queensland, and West Virginia. To assess the effect of spatial resolution on the target-area relationship, we also analyzed each data set at 7 spatial resolutions ranging from 0.01 degrees x 0.01 degrees to 0.10 degrees x 0.10 degrees. Most of the data sets showed a linear relationship between representation targets and total area of conservation-area networks that was invariant across changes in spatial resolution. The slope of this relationship indicated how total area increased with target level, and our results suggest that greater surrogate representation requires significantly more area. One data set exhibited a highly nonlinear relationship. The results for this data set suggest a new method for setting targets on the basis of the functional form of target-area relationships. In particular, the method shows how the target-area relationship can provide a rationale for setting targets solely on the basis of distributional information about surrogates. PMID- 18445076 TI - Current trends in plant and animal population monitoring. AB - Animal and plant population monitoring programs are critical for identifying species at risk, evaluating the effects of management or harvest, and tracking invasive and pest species. Nevertheless, monitoring activities are highly decentralized, which makes it difficult for researchers or conservation planners to get a good general picture of what real-world monitoring programs actually entail. We used a Web-based survey to collect information on population monitoring programs. The survey focused on basic questions about each program, including motivations for monitoring, types of data being collected, spatiotemporal design of the program, and reasons for choosing that design. We received responses from 311 people involved in monitoring of various species and used these responses to summarize ongoing monitoring efforts. We also used responses to determine whether monitoring strategies have changed over time and whether they differed among monitoring agencies. Most commonly, monitoring entailed collection of count data at multiple sites with the primary goal of detecting trends. But we also found that goals and strategies for monitoring appeared to be diversifying, that area-occupied and presence-absence approaches appeared to be gaining in popularity, and that several other promising approaches (monitoring to reduce parameter uncertainty, risk-based monitoring, and directly linking monitoring data to management decisions) have yet to become widely established. We suggest that improved communication between researchers studying monitoring designs and those who are charged with putting these designs into practice could further improve monitoring programs and better match sampling designs to the objectives of monitoring programs. PMID- 18445077 TI - The how-much-is-enough myth. PMID- 18445078 TI - Effects of artificial roosts for frugivorous bats on seed dispersal in a neotropical forest pasture mosaic. AB - In the Neotropics ongoing deforestation is producing open and heavily fragmented landscapes dominated by agriculture, mostly plantations and cattle pastures. After some time agriculture often becomes uneconomical and land is abandoned. Subsequent habitat regeneration may be slow because seed inputs are restricted by a lack of incentives--such as suitable roost sites--for seed dispersers to enter deforested areas. Increasing environmental awareness has fostered growing efforts to promote reforestation. Practical and cost-efficient methods for kick-starting forest regeneration are, however, lacking. We investigated whether artificial bat roosts for frugivorous bat species can attract these key seed dispersers to deforested areas, thereby increasing seed rain. We installed artificial bat roosts in a forest-pasture mosaic in the Costa Rican Atlantic lowlands and monitored bat colonization and seed dispersal. Colonization occurred within a few weeks of installation, and 10 species of bats occupied the artificial roosts. Five species of frugivorous or nectarivorous bats colonized artificial roosts permanently in both primary habitat and in deforested areas, in numbers similar to those found in natural roosts. Seed input around artificial roosts increased significantly. Sixty-nine different seed types, mostly of early-successional plant species, were transported by bats to artificial roosts in disturbed habitats. The installation of artificial bat roosts thus successfully attracted frugivorous bats and increased seed inputs into degraded sites. This method is likely to speed up early-vegetation succession, which in turn will attract additional seed dispersers, such as birds, and provide a microhabitat for seeds of mid- and late-successional plants. As well as supporting natural forest regeneration and bat conservation, this cost-efficient method can also increase environmental awareness among landowners. PMID- 18445080 TI - Correlation of the International Prostate Symptom Score bother question with the Benign Prostatic Hyperplasia Impact Index in a clinical practice setting. AB - OBJECTIVE: To evaluate the association between the International Prostate Symptom Score (IPSS) bother question (BQ) and a validated disease-specific quality-of life questionnaire, the Benign Prostatic Hyperplasia (BPH) Impact Index (BPH-II), using the BPH Registry and Patient Survey database. PATIENTS AND METHODS: The BPH Registry and Patient Survey is a multicentre, longitudinal, observational database of management practices and patient outcomes in a population of patients with BPH in the USA, managed with watchful waiting or pharmacotherapy. Men enrolled in the BPH Registry who completed the IPSS BQ and the four-item BPH-II at enrolment were identified. The association between the IPSS BQ score and the BPH Impact Index was assessed using Spearman rank correlation. RESULTS: At baseline (enrolment visit), 6439 men (mean age 66 years) completed the IPSS BQ and the BPH-II. The mean (sd) score of the IPSS BQ was 2.5 (1.4) and of the BPH II was 2.8 (2.8). Based on responses to the BPH-II, at least half the men reported that their urinary symptoms were associated with physical discomfort, worry about their health, and bothersomeness. The IPSS BQ score was significantly correlated (P < 0.001) with the BPH-II (r = 0.68) and each of its four questions (physical discomfort, r = 0.52; worry about health, r = 0.53; bothersomeness of trouble with urination, r = 0.67; and time kept from usual activities, r = 0.44). CONCLUSIONS: The IPSS BQ score has a strong and positive correlation with the BPH II among men enrolled in the BPH Registry. The IPSS BQ is a convenient tool for assessing disease-specific quality of life when determining treatment strategies and evaluating treatment outcomes in men with BPH. PMID- 18445079 TI - Altered adhesive structures and their relation to RhoGTPase activation in merlin deficient Schwannoma. AB - Schwannomas are Schwann cell tumors of the nervous system that occur spontaneously and in patients with neurofibromatosis 2 (NF2) and lack the tumor suppressor merlin. Merlin is known to bind paxillin, beta1 integrin and focal adhesion kinase, members of focal contacts, multi-protein complexes that mediate cell adhesion to the extracellular matrix. Moreover, merlin-deficient Schwannomas show pathological adhesion to the extracellular matrix making the characterization of focal contacts indispensable. Using our Schwannoma in vitro model of human primary Schwann and Schwannoma cells, we here show that Schwannoma cells display an increased number of mature and stable focal contacts. In addition to an involvement of RhoA signaling via the Rho kinase ROCK, Rac1 plays a significant role in the pathological adhesion of Schwannoma cells. The Rac1 guanine exchange factor- beta-Pix, localizes to focal contacts in human primary Schwannoma cells, and we show that part of the Rac1 activation, an effect of merlin-deficiency, occurs at the level of focal contacts in human primary Schwannoma cells. Our results help explaining the pathological adhesion of Schwannoma cells, further strengthen the importance of RhoGTPase signaling in Schwannoma development, and suggest that merlin's role in tumor suppression is linked to focal contacts. PMID- 18445081 TI - Clinical and epidemiological features of patients with genitourinary tract tumour in a blackfoot disease endemic area of Taiwan. AB - OBJECTIVES: To evaluate the clinical and epidemiological characteristics of patients with genitourinary (GU) tract transitional cell carcinoma (TCC) in an endemic area of blackfoot disease (BFD), the arsenic-exposed group, to compare them with characteristics among other non-BFD endemic areas (unexposed group). PATIENTS AND METHODS: In all, 474 patients with pathologically diagnosed GU-TCC were enrolled in the study. All follow-up data were prospectively collected and entered into a database throughout the study period. Statistical analysis was used to determine the association between clinical variables and prognosis, and multivariate regression models were used to assess the association between arseniasis and mortality from GU-TCC. RESULTS: There were no significant differences between the groups in age, sex, tumour stage and grade. However, the exposed group had a significantly higher proportion of females. The overall 5 year survival rate of patients with upper urinary tract (UUT) TCC was 49%, and the two groups had similar 5-year survival rates. The overall 5-year survival rate of patients with urinary bladder (UB) TCC was 68.3%, and there was a statistically significant difference in survival between the groups, with a 5 year survival rate of 58.7% for the exposed and 72.4% for the unexposed group. For patients with early-stage (pTa and pT1) UB cancers, the death rate was five times higher in exposed patients with tumour progression and recurrence after transurethral resection of bladder tumour than in the unexposed group. CONCLUSIONS: There was a significantly higher mortality rate for UB-TCC among exposed patients in the area endemic for arseniasis than in those from other non endemic areas. The arsenic content of artesian-well water might contribute to the increased ratio of female patients with GU-TCC and the unusually high incidence of UUT-TCC in the BFD endemic area in Taiwan. PMID- 18445082 TI - Cluster immunotherapy with a glutaraldehyde-modified mixture of grasses results in an improvement in specific nasal provocation tests in less than 2.5 months of treatment. AB - BACKGROUND: Cluster immunotherapy is becoming increasingly used. It allows for a rapid build up phase and the administration of higher doses of allergen in a shorter period of time. OBJECTIVES: To evaluate the effect of short-term pre seasonal immunotherapy using a glutaraldeyde-modified allergen vaccine in reducing specific nasal hyperreactivity in nasal challenge tests. MATERIALS AND METHODS: Thirty-three patients were selected. All patients had a positive history of allergic rhinitis and skin tests to grass pollen, although most of them (72.7%) were sensitized to other allergens as well. The study was conducted outside of the pollen season and the patients did not receive any pharmacological treatment during this period of time. Two randomized groups of patients were established; Group A: 22 patients (13 females and nine males) and Group B, 11 control patients (seven females and four males). Patients in Group A received immunotherapy with a vaccine containing 50% of the wild grasses Trisetum paniceum and Dactylis glomerata. All patients underwent titrated nasal provocation tests (NPT) before and after completion of the study (2.3 and 2.8 months for Groups A and B, respectively). The administration schedule consisted of 0.1 and 0.2 mL at day 1, followed by 0.3 and 0.5 mL at day 7, 0.5 mL after 2 weeks followed by 0.5 mL monthly. A single vial was used containing an allergen concentration of 10 000 TU/mL (105 microg of total protein and 24.6 microg of Group 1 plus 5 allergens/mL). A mean of 6.5 injections were administered to Group A patients between NPTs. RESULTS: There were no significant differences between both groups at the beginning of the study (P=0.48). At the end, only Group A patients needed significant greater threshold concentrations for a positive NPT than at the beginning (P=0.002). CONCLUSIONS: A short-term cluster pre-seasonal inmunotherapy with a modified vaccine containing a mixture of grass pollen is effective as determined by an objective measure after only a mean 2.3 months of treatment. PMID- 18445083 TI - The investigation of chronic urticaria in childhood: which investigations are being performed and which are recommended? PMID- 18445085 TI - Leukaemia cell lines are robust in vitro models. PMID- 18445086 TI - MEK inhibition induces caspases activation, differentiation blockade and PML/RARalpha degradation in acute promyelocytic leukaemia. AB - The hallmark of acute promyelocytic leukaemia (APL) is the reciprocal translocation t(15;17), which leads to the expression of the promyelocytic leukaemia/retinoic acid receptor alpha (PML/RARalpha) fusion protein and a cell differentiation blockade at the promyelocytic stage. PML/RARalpha is directly targeted by all-trans-retinoic acid (ATRA), which degrades the oncoprotein and induces complete remission of malignancies. The aberrant function of PML/RARalpha, together with the constitutive activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK/ERK) signalling pathway, regulates the ability of haematopoietic cells to proliferate, differentiate, and escape from apoptotic episodes. The role of the MEK/ERK pathway in PML/RARalpha expression, differentiation, proliferation and apoptosis in APL cells was analysed using specific MEK inhibitors. The blockade of MEK/ERK pathway resulted in caspase-dependent degradation of PML/RARalpha, and attenuation of the cell differentiation induction. To our knowledge, this is the first report to show that PML/RARalpha was suppressed by MEK/ERK inhibition, through a mechanism dependent on caspase activation. ATRA co-operated with MEK inhibitor to increase degradation of PML/RARalpha and exhibited a convergence point in caspase activation with MEK inhibitors. Taken together, our data suggest a new role of MEK/ERK pathway in the pathogenesis of APL, thus supporting the use of MEK/ERK inhibitors as an efficient therapeutic strategy for this haematological malignancy. PMID- 18445088 TI - Thrombin generation in whole blood. PMID- 18445089 TI - Enhancements, easy shortcuts, and the richness of human activities. AB - One argument that is frequently invoked against the technological enhancement of human functioning is that it is morally suspect, or even wrong, to take an easy shortcut. Some things that usually take effort, endurance or struggle can come easily with the use of an enhancer. This paper analyses the various arguments that circle round the idea that enhancement of human functioning is problematic because of the 'easy shortcut' that it offers. It discusses the concern that quick fixes lead to corrosion of character and the idea that suffering, pain, hard work and effort are essential for real and worthy achievements, and argues that these views are largely mistaken. Next, the paper argues that the core worry about taking an easy shortcut is that it makes us lose sight of the complexities of our means and ends; in other words, the argument warns against reducing the richness of human activities. A vocabulary of 'practices', 'internal goods' and 'focal engagement' will be used to articulate this argument further. The conclusion is that the easy shortcut argument has no general validity as an argument against enhancement 'as such'. The paper urges us, however, to evaluate enhancement technologies not only in terms of their efficiency in reaching certain goals but also in terms of their contribution to intrinsically worthwhile human activities. It can point out some of the caveats, as well as the opportunities, of the use of enhancement technologies. PMID- 18445090 TI - Medical confidentiality: legal and ethical aspects in Greece. AB - Respect for confidentiality is firmly established in codes of ethics and law. Medical care and the patients' trust depend on the ability of the doctors to maintain confidentiality. Without a guarantee of confidentiality, many patients would want to avoid seeking medical assistance The principle of confidentiality, however, is not absolute and may be overridden by public interests. On some occasions (birth, death, infectious disease) there is a legal obligation on the part of the doctor to disclose but only to the appropriate authorities. Permissible disclosure can be granted by the patients' consent, for example, for the purpose of insurance they may wish to take out. Moreover, there are some ambivalent situations (such as criminal acts, or notification of sexual partner in case of a patient with AIDS) for which Greek law does not include relevant provisions, and the Codes of Medical Ethics do not offer clear guidelines. Therefore, the Greek doctor is called to estimate the situation and assume full responsibility for his decision. Finally, new considerations have arisen in the context of the recent advances in the field of telemedicine and electronic archiving. The paper discusses the current situation and legislation in Greece. PMID- 18445091 TI - Free riders and pious sons--why science research remains obligatory. AB - John Harris has previously proposed that there is a moral duty to participate in scientific research. This concept has recently been challenged by Iain Brassington, who asserts that the principles cited by Harris in support of the duty to research fail to establish its existence. In this paper we address these criticisms and provide new arguments for the existence of a moral obligation to research participation. This obligation, we argue, arises from two separate but related principles. The principle of fairness obliges us to support the social institutions which sustain us, of which research is one; while the principle of beneficence, or the duty of rescue, imposes upon us a duty to prevent harm to others, including by supporting potentially beneficial, even life-saving research. We argue that both these lines of argument support the duty to research, and explore further aspects of this duty, such as to whom it is owed and how it might be discharged. PMID- 18445092 TI - Why we are not morally required to select the best children: a response to Savulescu. AB - The purpose of this paper is to review critically Julian Savulescu's principle of 'Procreative Beneficence,' which holds that prospective parents are morally obligated to select, of the possible children they could have, those with the greatest chance of leading the best life. According to this principle, prospective parents are obliged to use the technique of pre-implantation genetic diagnosis (PGD) to select for the 'best' embryos, a decision that ought to be made based on the presence or absence of both disease traits and non-disease traits such as intelligence. While several articles have been written in response to Savulescu's principle, none has systematically explored its philosophical underpinnings to demonstrate where it breaks down. In this paper I argue that the examples that Savulescu employs to support his theory in fact fail to justify it. He presents these examples as analogous to PGD, when in fact they differ from it in subtle but morally relevant ways. Specifically, Savulescu fails to acknowledge the fact that his examples evoke deontological and virtue ethics concerns that are absent in the context of PGD. These differences turn out to be crucial, so that, in the end, the analogies bear little support for his theory. Finally, I lay out the implications of this analysis for reproductive ethics. PMID- 18445093 TI - Procreative reasons-relevance: on the moral significance of why we have children. AB - Advances in reproductive technologies - in particular in genetic screening and selection - have occasioned renewed interest in the moral justifiability of the reasons that motivate the decision to have a child. The capacity to select for desired blood and tissue compatibilities has led to the much discussed 'saviour sibling' cases in which parents seek to 'have one child to save another'. Heightened interest in procreative reasons is to be welcomed, since it prompts a more general philosophical interrogation of the grounds for moral appraisal of reasons-to-parent, and of the extent to which such reasons are relevant to the moral assessment of procreation itself. I start by rejecting the idea that we can use a distinction between 'other-regarding' and 'future-child-regarding' reasons as a basis on which to distinguish good from bad procreative reasons. I then offer and evaluate three potential grounds for elucidating and establishing a relationship between procreative motivation and the rightness/wrongness of procreative conduct: the predictiveness, the verdictiveness, and the expressiveness of procreative reasons. PMID- 18445094 TI - The moral importance of selecting people randomly. AB - This article discusses some ethical principles for distributing pandemic influenza vaccine and other indivisible goods. I argue that a number of principles for distributing pandemic influenza vaccine recently adopted by several national governments are morally unacceptable because they put too much emphasis on utilitarian considerations, such as the ability of the individual to contribute to society. Instead, it would be better to distribute vaccine by setting up a lottery. The argument for this view is based on a purely consequentialist account of morality; i.e. an action is right if and only if its outcome is optimal. However, unlike utilitarians I do not believe that alternatives should be ranked strictly according to the amount of happiness or preference satisfaction they bring about. Even a mere chance to get some vaccine matters morally, even if it is never realized. PMID- 18445095 TI - Characteristics of symptomatic reflux episodes on Acid suppressive therapy. AB - BACKGROUND: Persistent symptoms on acid suppressive therapy are due to either acid or nonacid gastroesophageal reflux (GER) episodes or are not related to reflux. AIM: To compare physical and chemical characteristics of GER episodes associated with symptoms in patients on acid suppressive therapy. METHODS: Patients with persistent symptoms on acid suppressive therapy underwent combined impedance-pH monitoring. Reflux episodes were classified as acid if nadir pH was <4.0, and nonacid if it remained at >/=4.0, separated into liquid-only or mixed (liquid-gas), and considered to reach the proximal esophagus if liquid was present 15 cm above the lower esophageal sphincter (LES). Reflux episodes were considered symptomatic if patients recorded a symptom within 5 min after the reflux episode. Risk factors of symptomatic reflux episodes were identified using multivariable generalized estimating equations (GEEs). RESULTS: One hundred twenty patients (85 women, median age 54 yr, range 18-85 yr) recorded 3,547 reflux episodes (84.3% nonacid, 50.6% mixed), of which 468 (13.2%) were symptomatic. Based on multivariable GEE analysis with episode-level symptom status (symptomatic vs nonsymptomatic) as the outcome variable, reflux episode acidity was not significantly associated with symptoms (P= 0.40). Mixed reflux episodes were significantly associated with symptoms relative to liquid-only episodes (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.19-1.87, P= 0.0005), as were reflux episodes reaching the proximal esophagus compared with those reaching the distal esophagus only (OR 1.28, 95% CI 1.06-1.55, P= 0.012). CONCLUSION: The majority of reflux episodes on acid suppressive therapy are asymptomatic. Reflux episodes extending proximally and having a mixed (liquid gas) composition are significantly associated with symptoms, irrespective of whether pH is acid (<4) or nonacid (>/=4). PMID- 18445097 TI - Management of Barrett's esophagus in the UK: overtreated and underbiopsied but improved by the introduction of a national randomized trial. AB - OBJECTIVES: To assess the variation in practice of Barrett's esophagus (BE) management in comparison with accepted international guidelines before and after the introduction of a large BE randomized controlled trial (RCT) with protocols including those of tissue sampling. DESIGN: A validated anonymized questionnaire was sent to 401 senior attending gastroenterologists asking for details of their current management of BE, especially histological sampling. Of the 228 respondents, 57 individuals (each from a different center) were in the first group to enter the ASPirin Esomeprazole (BE) Chemoprevention Trial (AspECT), and we assessed change in practice in these centers. RESULTS: Ninety percent of specialists did not take adequate biopsies for histological diagnosis. Furthermore, 74% would consider aggressive surgical resection for prevalent cases of high-grade dysplasia in BE as their first-line choice despite the associated perioperative mortality. Ninety-two percent claim their lack of adherence to guidelines is because there is a need for stronger evidence for surveillance and medical interventions. Effect of the AspECT trial: Those clinicians in centers where the AspECT trial has started have improved adherence to ACG guidelines compared with their previous practice (P < 0.05). BE patients now get 18.8% more biopsies compared with previous practice, and 37.7% if the patient is entered into the AspECT trial (P < 0.01). CONCLUSIONS: This large study indicates both wide variation in practice and poor compliance with guidelines. Because optimal histology is arguably the most important facet of BE management, the improvement in practice in centers taking part in the AspECT trial indicates an additional value of large international RCTs. PMID- 18445098 TI - Effect of a community screening for Helicobacter pylori: a 5-Yr follow-up study. AB - BACKGROUND: Helicobacter pylori (H. pylori) screening and eradication may reduce the incidence of gastric cancer, AND AIMS: peptic ulcer, and ulcer complications, and it may reduce symptoms in a small proportion of individuals with functional dyspepsia. This study aimed to assess the effect of community H. pylori screening and treatment on the prevalence of dyspepsia, and as secondary outcomes, the effect on dyspepsia-related health-care consumption and quality of life over 5 yr. METHODS: In 1998-1999, individuals aged 40-65 yr were randomized to H. pylori screening and treatment or to the control group. Five years later, the participants were sent a questionnaire to assess the prevalence of dyspepsia and quality of life. In addition, we obtained information from registers on the use of endoscopies and prescription medication. An economic evaluation was done alongside the randomized trial. RESULTS: Of 12,530 participants attending the study at baseline, 11,065 (88%) were traced and contacted at the 5-yr follow-up. The response rate was 94%. At baseline, 17.5% in the screened group were H. pylori-positive. The absolute reduction in dyspepsia during the first year was 4% in the screened group, whereas no change was observed in the unscreened group; this rate remained constant during the next 4 yr. Quality of life did not change. A small effect was found for dyspepsia-related consultations and sick leave days, but not on the prescription rate of ulcer drugs. A 33% lower ulcer incidence (107 ulcers vs 148 ulcers) was seen in the screened group compared to the unscreened group. CONCLUSION: A population H. pylori screening and treatment program in an H. pylori low-prevalence area had only a modest, but insignificant, effect on the rate of dyspepsia, and a modest, significant effect on the consultation rate and sick leave days for dyspepsia, but resulted in a decreased ulcer incidence. The intervention resulted in an increased cost due to H. pylori screening and treatment. PMID- 18445099 TI - Endoscopic-guided versus cotton-tipped applicator methods of nasal anesthesia for transnasal esophagogastroduodenoscopy: a randomized, prospective, controlled study. AB - BACKGROUND: Ultrathin transnasal esophagogastroduodenoscopy (UT-EGD) is well tolerated by patients, but the methods of nasal anesthesia are various. AIM: To compare patient tolerance, safety, and adverse events between the endoscopic guided (EGNA) and cotton-tipped applicator (CTNA) methods of nasal anesthesia. METHODS: Between September 2005 and September 2006, we conducted a prospective, randomized, controlled study in a large tertiary referral hospital in eastern Taiwan. In total, 235 consecutive patients were randomly assigned to the CTNA group or EGNA group before unsedated UT-EGD. We compared demographic data, procedural discomfort using a validated 5-point visual analog scale, optical quality, total procedure time, and adverse events between the two groups. RESULTS: After randomization and exclusion, 101 (43 men and 58 women) and 103 (44 men and 59 women) patients were allocated to the CTNA and EGNA groups, respectively. Baseline characteristics and periprocedural hemodynamics of patients in the two groups were similar. There was no statistical difference in insertion failure rates between the two methods (CTNA 10.9%vs EGNA 7.7%, P= 0.59). Pain scores during both anesthesia (2.3 +/- 0.4 vs 3.5 +/- 0.6, P < 0.001) and insertion (2.8 +/- 1.2 vs 3.8 +/- 1.8, P < 0.001) were significantly lower in the EGNA group; however, the sensation of bad taste was significantly worse in the EGNA group (2.3 +/- 1.3 vs 1.9 +/- 1.4, P= 0.040). Less epistaxis happened in the EGNA group than in the CTNA group. The EGNA method had a significantly better visual capacity and shorter procedure time. More patients in the EGNA group said they would like to receive the same procedure the next time. CONCLUSION: Compared with the CTNA method, in which the taste of lidocaine gel was more acceptable, EGNA appeared to be more tolerable, caused less epistaxis, improved visualization capacity, and reduced procedure time. PMID- 18445096 TI - Technical performance of colonoscopy: the key role of sedation/analgesia and other quality indicators. AB - BACKGROUND: It is essential to identify the factors in clinical practice that influence the technical performance of colonoscopy as a basis for quality improvement programs. AIMS: To assess the factors linked to two key indicators of colonoscopy performance, i.e., cecal intubation and polyp diagnosis. DESIGN AND SETTING: Consecutives colonoscopies performed over a 2-wk period in 278 unselected practice sites throughout Italy were prospectively evaluated. A multivariate model was developed to identify determinants of the performance indicators of colonoscopy. RESULTS: In total, 12,835 patients (mean age 60.5 yr, standard deviation [SD] 15.1, 53% men) were studied. Sedation and/or analgesia was administered in 55.3% of procedures: 28.8% of patients received intravenous (IV) benzodiazepines, 15.4% received benzodiazepines in combination with narcotics, 3.1% received propofol, and 7.5% received other sedation regimens. Overall, cecal intubation was achieved in 80.7% of procedures, and the polyp detection rate was 27.3%. Multivariate analysis showed that the strongest predictors of cecal intubation were the quality of bowel preparation (inadequate vs excellent: odds ratio [OR] 0.013, 95% confidence interval [CI] 0.009-0.018; fair vs excellent: OR 0.246, 95% CI 0.209-0.290; and good vs excellent: OR 0.586, 95% CI 0.514-0.667) and the use of sedation (IV benzodiazepines vs no sedation: OR 1.460, 95% CI 1.282-1.663; IV benzodiazepines and narcotics vs no sedation: OR 2.128, 95% CI 1.776-2.565; and propofol vs no sedation: OR 2.355, 95% CI 1.590 3.488). The colonoscopy setting (workload and organizational complexity of the center) and the endoscopist colonoscopy volume were other factors independently correlated with completion of the procedure. Detection of polyps partially depended on the quality of bowel cleansing (inadequate vs excellent: OR 0.511, 95% CI 0.404-0.647) and use of sedation (OR 1.172, 95% CI 1.074-1.286). CONCLUSION: In usual clinical practice, the use of sedation/analgesia, the colon cleansing quality, the endoscopist experience, and some features related to the colonscopy setting decisively influence the quality of colonoscopy. These factors indicate the targets of future corrective measures to boost the quality of this examination. PMID- 18445101 TI - Tolerance to disulfiram induced by chronic alcohol intake in the rat. AB - BACKGROUND: Disulfiram, an inhibitor of aldehyde dehydrogenase used in the treatment of alcoholism, is an effective medication when its intake is supervised by a third person. However, its therapeutic efficacy varies widely, in part due to the fact that disulfiram is a pro-drug that requires its transformation into an active form and because it shows a wide range of secondary effects which often prevent the use of doses that ensure full therapeutic effectiveness. In this preclinical study in rats we report the development of tolerance to disulfiram induced by the chronic ingestion of ethanol, an additional source of variation for the actions of disulfiram with possible therapeutic significance, We also addresses the likely mechanism of this effect. METHODS: Wistar-derived rats bred for generations as high ethanol drinkers (UChB) were trained for either 3 days (Group A) or 30 days (Group B) to choose between ethanol (10% v/v) or water, which were freely available from 2 bottles on a 24-hour basis. Subsequently, animals in both groups were administered disulfiram or cyanamide (another inhibitor of aldehyde dehydrogenase) and ethanol intake in this free choice paradigm was determined. Animals were also administered a standard dose of 1 g ethanol/kg (i.p) and arterial blood acetaldehyde was measured. RESULTS: Disulfiram (12.5 and 25 mg/kg) and cyanamide (10 mg/kg) markedly inhibited ethanol intake (up to 60 to 70%) in animals that had ethanol access for only 3 days (Group A). However both drugs were inactive in inhibiting ethanol intake in animals that had consumed ethanol for 30 days (Group B). Following the injection of 1 g ethanol/kg, arterial blood acetaldehyde levels reached levels of 150 and 300 microM for disulfiram and cyanamide respectively, values which were virtually identical regardless of the length of prior ethanol intake of the animals. CONCLUSIONS: Chronic ethanol intake in high-drinker rats leads to marked tolerance to the aversive effects of disulfiram and cyanamide on ethanol intake despite the presence of consistently high levels of blood acetaldehyde. These findings may have implications for the use of disulfiram for the treatment of alcoholism in humans. PMID- 18445102 TI - The relative contribution of genes and environment to alcohol use in early adolescents: are similar factors related to initiation of alcohol use and frequency of drinking? AB - BACKGROUND: The present study assessed the relative contribution of genes and environment to individual differences in initiation of alcohol use and frequency of drinking among early adolescents and examined the extent to which the same genetic and environmental factors influence both individual differences in initiation of alcohol use and frequency of drinking. METHODS: Questionnaire data collected by the Netherlands Twin Register were available for 694 twin pairs aged of 12 to 15 years. Bivariate genetic model fitting analyses were conducted in mx. We modeled the variance of initiation of alcohol use and frequency of drinking as a function of three influences: genetic effects, common environmental effects, and unique environmental effects. Analyses were performed conditional on sex. RESULTS: Findings indicated that genetic factors were most important for variation in early initiation of alcohol use (83% explained variance in males and 70% in females). There was a small contribution of common environment (2% in males, 19% in females). In contrast, common environmental factors explained most of the variation in frequency of drinking (82% in males and females). In males the association between initiation and frequency was explained by common environmental factors influencing both phenotypes. In females, there was a large contribution of common environmental factors that influenced frequency of drinking only. There was no evidence that different genetic or common environmental factors operated in males and females. CONCLUSION: Different factors were involved in individual differences in early initiation of alcohol use and frequency of drinking once adolescents have started to use alcohol. PMID- 18445103 TI - Immunological detection of in vitro formed phosphatidylethanol--an alcohol biomarker--with monoclonal antibodies. AB - BACKGROUND: Phosphatidylethanol (PEth) is a promising new marker for detecting long-term alcohol abuse with excellent sensitivity and specificity. Current methods are based on the high performance liquid chromatography-mass spectrometric method and therefore require high levels of expertise and expensive instrumentation. This study was designed to generate PEth-specific monoclonal antibodies for PEth immunoassay development. METHODS: C57/BL6 mice were immunized with PEth in 3 different carriers, mouse serum albumin, mouse high-density lipoproteins, and human low-density lipoprotein (LDL). Mouse splenocytes were fused with a mouse myeloma cell line using the hybridoma technique. Mouse IgM producing cell lines were selected by limiting dilutions. Binding characteristics of the anti-PEth antibodies were studied using luminometric immunoassays and sequence analysis of the variable region mRNA sequences of the antibodies. Produced antibodies were purified by chromatographic methods. PEth was detected with these antibodies in fluorescence immunoassay and flow cytometric analysis. RESULTS: We generated monoclonal cell lines (2B1 and 2E9) that produce IgM antibodies binding specifically to PEth but not to structurally or chemically similar phospholipids, such as phosphatidylcholine, phosphatidic acid, and cardiolipin. We show here that these anti-PEth antibodies can be used to detect PEth in a fluorescent PEth assay and FACS analysis of human red blood cell samples spiked with PEth. CONCLUSIONS: The present study shows that PEth-specific monoclonal antibodies can be generated using traditional hybridoma technique. Immunogenicity of PEth was enhanced using human LDL as an immunization carrier. The generated monoclonal anti-PEth antibodies, 2B1 and 2E9 bind to PEth in fluid phase and in biological membranes. PMID- 18445104 TI - The association between alcohol consumption and biomarkers of alcohol exposure with total serum immunoglobulin E levels. AB - BACKGROUND: A number of studies have shown that self-reported alcohol intake is positively associated with total serum immunoglobin E (IgE) levels. The purpose of the present study was to investigate the association of self-reported alcohol consumption and different biomarkers of alcohol exposure to total serum IgE levels in a general adult population. METHODS: A total of 3,443 subjects aged 20 to 79 years from the population-based cross-sectional Study of Health in Pomerania (SHIP) were included in the analyses. Information on alcohol consumption and serum carbohydrate-deficient transferrin (CDT), gamma-glutamyl transferase (GGT), aspartate-amino transferase (ASAT), andalanine-amino transferase (ALAT) levels were measured. Multivariable linear regression models were performed separately in atopic and nonatopic subjects. RESULTS: In nonatopic subjects positive associations between self-reported alcohol consumption as well as all considered biomarkers of alcohol exposure and total serum IgE levels were found. Further the results also suggested positive associations between alcohol consumption as well as alcohol biomarkers and total serum IgE level in atopic subjects, even though not all tests for linear trend reached statistical significance. CONCLUSIONS: In conclusion, biomarkers of alcohol exposure were positively associated with total serum IgE levels supporting that the positive association between self-reported alcohol intake and IgE levels observed in previous studies is real and not due to misclassification of alcohol intake or confounding by other factors that may be linked to both alcohol intake and total serum IgE levels. PMID- 18445105 TI - No role of matrixmetalloproteinase-3 genetic promoter polymorphism 1171 as a risk factor for cirrhosis in alcoholic liver disease. AB - BACKGROUND: As only a minority of alcoholics develop cirrhosis, polymorphic genes, whose products are involved in fibrosis development were suggested to confer individual susceptibility. We tested whether a functional promoter polymorphism in the gene encoding matrix metalloproteinase-3 (MMP-3; 1171 5A/6A) was associated liver cirrhosis in alcoholics. METHODS: Independent cohorts from the UK and Germany were studied. (i) UK cohort: 320 alcoholic cirrhotics and 183 heavy drinkers without liver damage and (ii) German cohort: 149 alcoholic cirrhotics, 220 alcoholic cirrhotics who underwent liver transplantation and 151 alcoholics without liver disease. Patients were genotyped for MMP-3 variants by restriction fragment length polymorphism, single strand confirmation polymorphism, and direct sequencing. In addition, MMP-3 transcript levels were correlated with MMP-3 genotype in normal liver tissues. RESULTS: Matrix metalloproteinase-3 genotype and allele distribution in all 1023 alcoholic patients were in Hardy-Weinberg equilibrium. No significant differences in MMP-3 genotype and allele frequencies were observed either between alcoholics with or without cirrhosis. There were no differences in hepatic mRNA transcription levels according to MMP-3 genotype. CONCLUSIONS: Matrix metalloproteinase-3 1171 promoter polymorphism plays no role in the genetic predisposition for liver cirrhosis in alcoholics. Stringently designed candidate gene association studies are required to exclude chance observations. PMID- 18445106 TI - Ethanol and pain sensitivity: effects in healthy subjects using an acute pain paradigm. AB - BACKGROUND: The primary objective of this study was to determine whether healthy subjects without a history of heavy alcohol use or a family history of alcoholism exhibit a concentration-dependent analgesic effect of ethanol. In a preliminary fashion, we also compared this sample to a group of subjects with a strong positive family history for alcoholism (FHP) to test the secondary hypothesis that FHP individuals will be more sensitive to the analgesic effects of alcohol compared to healthy subjects who are negative for a family history of alcoholism (FHN). METHODS: Forty-one healthy FHN subjects and 19 FHP subjects participated. Test days included an ethanol high concentration (breathalyzer = 0.100 g/dl), ethanol low concentration (breathalyzer = 0.040 g/dl) or placebo. The infusion of ethanol was via computerized pump to achieve a steady-state ("clamp") ethanol concentration. Noxious electrical stimulation and pain assessments were performed prior to start of placebo/ethanol infusion and at the 60-min infusion mark. The applied current was progressively increased until the pain was reported as 5 or higher on an 11-point Verbal Numeric Scale (VNS). Outcome variables included measures of pain threshold and tolerance and Visual Analog Scales of mood states. RESULTS: Among FHN subjects there was a significant ethanol concentration effect on pain tolerance (F = 3.0, p = 0.05). The average change in pain stimuli required to reach a VNS of 5 or greater were (-2.4, -1.0, and 2.2 mAmps respectively) for high concentration, low concentration, and placebo. There were no ethanol concentration related differences in pain threshold. The analgesic effect of ethanol was not correlated with changes in mood states, suggesting an independent analgesic effect of the drug. A comparison of FHP to FHN subjects produced no differences on pain responses. CONCLUSION: The findings support the hypothesis that in healthy subjects intravenous ethanol administration has a concentration effect on pain tolerance but not on pain threshold. Additional studies are planned to further elucidate the mechanisms of ethanol's analgesic effects. PMID- 18445107 TI - Consistent, high-level ethanol consumption in pig-tailed macaques via a multiple session, limited-intake, oral self-dosing procedure. AB - BACKGROUND: Alcohol abuse is a major public health burden that can lead to many adverse health effects such as impaired hepatic, gastrointestinal, central nervous system and immune system function. Preclinical animal models of alcohol abuse allow for experimental control over variables often difficult to control in human clinical studies (e.g., ethanol exposure before or during the study, history of other drug use, access to medical care, nutritional status, etc). Nonhuman primate models in particular provide increased genetic, anatomic and physiologic similarity to humans, relative to rodent models. A small percentage of macaques will spontaneously consume large quantities of ethanol; however, most nonhuman primate models of "voluntary" ethanol intake produce relatively low daily ethanol intake in the majority of monkeys. METHODS: To facilitate study of chronic exposure to high levels of ethanol intake, a macaque model has been developed that induces consistent, daily high-level ethanol consumption. This multiple-session procedure employed 4 drinking sessions per day, with sessions occurring once every 6 hours. RESULTS: The group average alcohol consumption was 4.6 g/kg/d (SEM 0.4), roughly twice the group average consumption of previous reports. Ethanol drinking sessions produced group mean blood ethanol levels of 95 mg/dl after 60 minutes, and fine motor control was impaired up to 90 minutes after a drinking session. CONCLUSION: This model of multiple-session, limited access, oral ethanol self-dosing produced consistent, high-level ethanol consumption with each session qualifying as a "binge" drinking session using the definition of "binge" provided by the NIAAA (>80 mg/dl/session). This model of ethanol drinking in macaques will be of great utility in the study of immunological, physiological and behavioral effects of ethanol in nonhuman primates. PMID- 18445108 TI - Ethnic differences in positive alcohol expectancies during childhood: the Pittsburgh Girls Study. AB - BACKGROUND: Positive expectancies about alcohol's effects are more likely to be endorsed with increasing age through adolescence, and the strength of positive alcohol expectancies in children appears to differ by ethnicity. Little is known about the extent to which differences in a measure's psychometric properties as a function of development and ethnicity may account for changes that are observed over time and ethnic differences. This study used measurement invariance methods to examine ethnic differences in the development of alcohol expectancies, and examined risk factors associated with girls' positive expectancies. METHODS: African-American (56%) and Caucasian (44%) girls (n = 570) in the age 7 cohort of the Pittsburgh Girls Study, and the girl's primary caretaker, were followed annually for 4 years (ages 7-10). Girls reported on alcohol expectancies at each wave, and physical aggression at Year 1. In Year 1, caretakers reported on neighborhood drug use, their own substance-related problems, and depression in the girl. Structural equation modeling was used to examine measurement invariance of positive alcohol expectancies, and to test associations of risk factors to initial level and change in expectancies. RESULTS: Five of 8 positive alcohol expectancy items showed measurement equivalence for African-American and Caucasian girls in cross-sectional, but not longitudinal, analyses. Measurement equivalence over ages 7-10 was demonstrated for Caucasian girls, and over ages 7 8 and 9-10 (i.e., a two-part model) for African-American girls. Risk factor analyses indicated that, for Caucasian girls, greater physical aggression was associated with higher initial positive expectancies. CONCLUSIONS: Some developmental change and ethnic differences in the performance of positive expectancy items were identified, highlighting the utility of measurement invariance methods. Risk factor analyses suggest the potential benefit of targeted alcohol prevention interventions for certain girls. PMID- 18445109 TI - Innate differences in the expression of brain-derived neurotrophic factor in the regions within the extended amygdala between alcohol preferring and nonpreferring rats. AB - BACKGROUND: Animal lines such as alcohol-preferring (P) and nonpreferring (NP) rats appear to be suitable animal models to investigate the biological basis of alcohol-drinking behaviors. The extended amygdala serves as a neuroanatomical substrate for alcohol-drinking behaviors. Brain-derived neurotrophic factor (BDNF) in the amygdala has been implicated in alcohol-drinking behaviors; however, its expression in the extended amygdala of P and NP rats is unknown. Therefore, we examined the basal expression of BDNF in the extended amygdala of alcohol naive P and NP rats. METHODS: We determined the basal mRNA and protein levels of BDNF by in situ RT-PCR and immuno-histochemical procedure, respectively, in the amygdaloid [central nucleus of amygdala (CeA), medial nucleus of amygdala (MeA), and basolateral amygdala (BLA)], nucleus accumbal (NAc shell and core), and bed nucleus of stria terminalis (BNST) [lateral BNST (lBNST), medial BNST (mBNST), and ventral BNST (vBNST)] brain structures of P and NP rats. In addition, we examined the localization of BDNF in neurons using double-immunofluorescence labeling of BDNF with neuron-specific nuclear protein (NeuN) and also determined the number of NeuN-positive neurons in the amygdaloid structures of P and NP rats. RESULTS: The mRNA and protein levels of BDNF were found to be significantly lower in both the CeA and MeA, but not in the BLA, of P compared with NP rats. We also found that BDNF was expressed in neurons in the amygdaloid structures of P and NP rats. In addition, we found that the number of NeuN-positive neurons was similar in the amygdaloid structures of P and NP rats. Interestingly, the mRNA and protein levels of BDNF were also significantly lower in the lBNST, mBNST, and vBNST of P compared with NP rats. On the other hand, mRNA and protein levels of BDNF were similar in the NAc shell and core structures of P and NP rats. CONCLUSIONS: P and NP rats are selectively bred for higher and lower alcohol preference, respectively; therefore it is possible that lower BDNF levels in the amygdaloid and BNST structures may be associated with the excessive alcohol-drinking behaviors of P rats. PMID- 18445110 TI - Age and gender differences in response to neonatal ethanol withdrawal and polyamine challenge in organotypic hippocampal cultures. AB - BACKGROUND: Polyamines are synthesized and released in high concentrations during CNS development. These agents can potentiate N-methyl-D-aspartate receptor (NMDAR) function and appear to play an important role in CNS development. Previous work has shown that polyamine release is increased during ethanol withdrawal (EWD). This likely promotes NMDAR overactivity and contributes to neurotoxicity during EWD, however, little is known regarding such effects in early neonatal brain. The present study compared the effects of EWD and polyamine exposure on toxicity in hippocampal slice cultures derived from postnatal day 2 (PND 2) or postnatal day 8 (PND 8) day-old rats. Due to changes in NMDAR subtypes and response to polyamines, we predicted that slices taken from PND 2 pups would be more sensitive to EWD and polyamine challenge. METHODS: Organotypic hippocampal slice cultures were obtained from neonatal rats either 2 or 8 days of age (PND 2 or PND 8). Five days after explantation, cultures were exposed to ETOH (50 mM- typically subthreshold for EWD induced cell death) for 10 days and then withdrawn from ETOH for 24-hour in the presence of 100 microM of the polyamine spermidine and/or 100 microM ifenprodil, an NMDAR antagonist that blocks the NMDAR that is the most sensitive to polyamine modulation. Cytotoxicity was measured after 24-hour by visualization of propidium iodide (PI) fluorescence. RESULTS: There were clear age and gender-dependent differences in response to EWD and to polyamines. EWD produced significant increases in PI uptake in all subregions (CA1, CA3 and DG) of cultures derived from PND 2 pups, but not PND 8 pups. Exposure of cultures to spermidine for 24-hour also produced significant increases in cytotoxicity in all 3 regions of PND 2 cultures with no gender differences. In contrast, there were both gender and region-specific differences in response to spermidine in cultures from PND 8. While the CA1 region of both sexes displayed increased cytotoxicity following spermidine exposure, only females showed increased cytotoxicity in the CA3 region while the DG appeared relatively insensitive to spermidine. Exposure to spermidine during EWD produced enhanced toxicity in all 3 hippocampal subregions in tissue from both PND 2 and PND 8 rats and this was reduced or prevented by co-exposure to ifenprodil. Of interest, the PND 2 hippocampus was significantly more sensitive than the PND 8 hippocampus to the toxic effects of EWD and to spermidine during EWD in the DG and CA3 regions. CONCLUSIONS: Hippocampal slice cultures derived from PND 2 rats were more sensitive to the toxic effects of both EWD and EWD + spermidine exposure than were those derived from PND 8 rats. These findings are similar to recent behavioral data collected from our lab showing greater sensitivity to ETOH's behavioral teratogenic effects when ETOH exposure in vivo occurred during the first postnatal week relative to the second postnatal week. Ifenprodil's ability to block the toxic effects of spermidine during EWD suggests that excess activity of NR2B subunits of the NMDAR contributed to the excitatory and cytotoxic effects of EWD plus spermidine. While no sex differences in toxicity were observed in cultures taken from pups during the first postnatal week, these data do suggest that later in neonatal life (i.e., the second postnatal week), the female hippocampus may be more sensitive to polyamine-induced neurotoxicity than males. PMID- 18445111 TI - The subjective, rather than the disinhibiting, effects of alcohol are related to binge drinking. AB - BACKGROUND: Evidence suggests that alcohol-related problems are associated with impulsivity and disinhibited behavior. Less certain is whether disinhibited behavior is due to an impulsive disposition or alcohol's ability to disinhibit some people more than others. There are a range of disinhibited behaviors associated with alcohol, including excessive alcohol consumption, bingeing. The study tested whether nondependent alcohol bingers showed more disinhibition after placebo and/or alcohol relative to nonbingers and whether this was related to enhanced motivation to drink following a priming dose of alcohol. METHODS: Twenty participants (10 bingers) attended the laboratory twice. Baseline measures included impulsivity, alcohol-related cognitions, alcohol urge, and mood. Participants were preloaded with alcohol (male: 0.6 g/kg, female: 0.5 g/kg) and placebo (counterbalanced). After a 20-minute rest, participants completed 2 impulsivity tasks (Two Choice & Time Estimation) separated by second urge and mood ratings. RESULTS: Bingers did not show greater impulsivity characteristics but were more concerned about their drinking (p = 0.02) and ability to control drinking (p = 0.04). A priming effect was found: alcohol urge increased after alcohol but not placebo (p = 0.006). Bingers reported greater tolerance to the sedative (p = 0.05) and lightheaded (p = 0.04) effects of alcohol, relative to nonbingers. Binge status was not associated with impulsivity task performance, while preload type (alcohol/placebo) supported only marginal associations. CONCLUSIONS: Risk of binge drinking in nondependent individuals is not strongly affected by impulsive personality characteristics or alcohol's ability to induce behavioral disinhibition. However, alcohol did lead to a priming effect and bingers were more tolerant to the sedative and lightheaded effects of alcohol relative to placebo. Risk of binge drinking is associated with the subjective effects of a priming dose of alcohol. PMID- 18445112 TI - Elevated cerebrospinal fluid tau protein levels in Wernicke's encephalopathy. AB - OBJECTIVE: Limited neuronal cell loss is seen in the neuropathology of Wernicke's encephalopathy (WE), but the extent of neuronal damage has not been well studied. Moreover, there is still a debate as to whether alcohol itself causes brain damage in humans. Although, it is difficult to examine the extent of neuronal damage in living patients, recent studies have revealed that total tau protein levels in the cerebrospinal fluid (CSF) reflect the rate of neuronal degeneration. Therefore, we hypothesized that the elevated CSF total tau in patients with WE was due to neuronal damage and thus we examined CSF total tau protein in patients with WE, as well as in those with alcohol withdrawal delirium (WD) and Korsakoff syndrome (KS). We also examined CSF total tau in nonalcohol dependent patients with Alzheimer's disease (AD) as a disease control. METHODS: CSF samples were obtained from 13 acute WE patients with alcohol dependence, 9 WD patients with alcohol dependence and 16 KS patients with alcohol dependence, and from 20 nonalcohol dependent AD patients. CSF was also obtained from 10 of the WE patients after their disease had progressed to the chronic stage. CSF tau protein levels in all samples were determined by sandwich enzyme-linked immunosorbent assay. Tau phosphorylated at threonine 181 (p-tau(181)) and amyloid beta-protein ending at amino acid 42 (A beta 42) in CSF were also determined for comparison between acute WE with AD. RESULTS: Total tau was significantly elevated in acute WE and decreased on long-term follow-up, but was not elevated in WD or KS. The patterns of p-tau(181) and A beta 42 differed between acute WE and AD. CONCLUSIONS: Intense neuronal cell death occurs transiently in WE, and the mechanism differs from that in AD. Neuronal damage is generally unaccompanied in WD. These results suggest that CSF total tau is a useful biological marker for WE. PMID- 18445113 TI - Upregulation of beta-catenin levels in superior frontal cortex of chronic alcoholics. AB - BACKGROUND: Chronic and excessive alcohol misuse results in neuroadaptive changes in the brain. The complex nature of behavioral, psychological, emotional, and neuropathological characteristics associated with alcoholism is likely a reflection of the network of proteins that are affected by alcohol-induced gene expression patterns in specific brain regions. At the molecular level, however, knowledge remains limited regarding alterations in protein expression levels affected by chronic alcohol abuse. Thus, novel techniques that allow a comprehensive assessment of this complexity will enable the simultaneous assessment of changes across a group of proteins in the relevant neural circuitry. METHODS: A proteomics analysis was performed using antibody microarrays to determine differential protein levels in superior frontal cortices between chronic alcoholics and age- and gender-matched control subjects. Seventeen proteins related to the catenin signaling pathway were analyzed, including alpha-, beta-, and delta-catenins, their upstream activators cadherin-3 (type I cadherin) and cadherin-5 (type II cadherin), and 5 cytoplasmic regulators c-Src, CK1 epsilon, GSK-3beta, PP2A-C alpha, and APC, as well as the nuclear complex partner of beta-catenin CBP and 2 downstream genes Myc and cyclin D1. ILK, G(alpha1), G(beta1), and G(beta2), which are activity regulators of GSK 3beta, were also analyzed. RESULTS: Both alpha- and beta-catenin showed significantly increased levels, while delta-catenin did not change significantly, in chronic alcoholics. In addition, the level of the beta-catenin downstream gene product Myc was significantly increased. Average levels of the catenin regulators c-Src, CK1 epsilon, and APC were also increased in chronic alcoholics, but the changes were not statistically significant. CONCLUSION: Chronic and excessive alcohol consumption leads to an upregulation of alpha- and beta-catenin levels, which in turn increase downstream gene expressions such as Myc that is controlled by beta-catenin signaling. This study showed that the beta-catenin signal transduction pathway was upregulated by chronic alcohol abuse, and prompts further investigation of mechanisms underlying the upregulation of alpha- and beta-catenins in alcoholism, which may have considerable pathogenic and therapeutic relevance. PMID- 18445114 TI - A longitudinal analysis of alcohol outlet density and assault. AB - BACKGROUND: The majority of studies that have examined the local-level relationship between alcohol outlet density and violence have utilized cross sectional data. These studies have consistently demonstrated that there is a spatial link between outlets and violence, but because of their design they have not been able to determine whether changes in outlet density result in changes in rates of violence. The few studies that have examined this question over time have found that the violence rates are related to changes in outlet density. This study provides further evidence of this link and examines the characteristics of regions in which changes in outlet density are most strongly associated with changes in violence rates. METHODS: The study examined 9 years of data measuring alcohol outlet density (using liquor licensing records) and alcohol-related violence (using police recorded night-time assaults) from 186 postcodes in the metropolitan area of Melbourne, Australia. The relationships between 3 types of alcohol outlet density and alcohol-related violence were assessed using fixed effects models. The postcodes were then grouped into 5 clusters based on their socio-demographic profile and separate fixed-effects models were fitted to assess whether the relationships between outlets and violence differed based on the type of region being examined. RESULTS: The initial models found overall positive relationships between all 3 types of alcohol outlets and violence. When separate models were developed for postcode clusters, they demonstrated that the link between outlet density and violence was significant in all neighborhood types, but the specific relationships varied substantially. CONCLUSIONS: Changes in the number of alcohol outlets in a community are linked to changes in the amount of violence the community experiences. This relationship varies across the clusters of suburbs examined, with packaged liquor outlets consistently associated with violence in suburban areas and general (hotel) and on-premise (nightclubs, restaurants, and bars) licenses associated with violence in inner-city and inner suburban areas. PMID- 18445115 TI - Validity of the obsessive compulsive drinking scale in a heavy drinking population. AB - BACKGROUND: The Obsessive Compulsive Drinking Scale [OCDS; Anton et al., Alcohol Clin Exp Res 19 (1995), 92] is the most widely used measure of alcohol craving. There are no studies which comprehensively investigate the construct and concurrent validity of the OCDS in a severe alcohol dependent population. METHODS: Three hundred and seventy alcohol-dependent patients were referred to a hospital-based alcohol treatment program. All participants completed the OCDS, the Alcohol Use Disorders Identification Test [AUDIT; Saunders et al., Addiction 88 (1993), 791] and provided demographic and alcohol consumption data. RESULTS: The sample was randomly split into 2. Exploratory factor analysis and confirmatory factor analysis were conducted on these subsamples. Both analyses identified a 4-factor solution (compulsions, interference, obsessions and resisting obsessions). All factors showed sound internal consistency. Neither the factor scores nor the total OCDS score was related to baseline alcohol problems (AUDIT) or consumption. CONCLUSIONS: There was some support for the construct validity of the OCDS in this clinical group. Concurrent validity of the scale was not supported by these cross-sectional data. Future research should examine the predictive utility of the OCDS over time. PMID- 18445116 TI - Enhanced ethanol inhibition of recombinant N-methyl-D-aspartate receptors by magnesium: role of NR3A subunits. AB - BACKGROUND: The effects of ethanol on brain function are thought to be partly because of altered activity of ion channels that regulate synaptic activity. Results from previous studies from this lab and others have shown that ethanol inhibits the function of the N-methyl-D-aspartate (NMDA) receptors, a calcium permeable ion channel activated by the neurotransmitter glutamate. Factors that influence the acute sensitivity of NMDA receptors to ethanol may be critical in determining how neurons and neuronal networks respond to the presence of ethanol. In this study, we have examined the effect of physiologically relevant concentrations of magnesium on the ethanol sensitivity of recombinant NMDA receptors and how ethanol inhibition under these conditions is influenced by the NR3A subunit. METHODS: Recombinant cDNAs encoding NMDA receptor subunits were expressed in human embryonic kidney 293 cells. Whole-cell patch-clamp electrophysiology was used to measure currents induced by rapid application of glutamate in the absence and presence of ethanol. RESULTS: In magnesium-free recording solution, ethanol inhibited glutamate-mediated currents in cells transfected with NMDA receptor subunits. The magnitude of ethanol inhibition was significantly enhanced when recordings were carried out in media containing 1 mM magnesium. This effect was reversible and required magnesium-sensitive receptors. Magnesium did not enhance ethanol inhibition of glycine-activated NR1/NR3A/NR3B receptors. However, NR3A co-expression prevented the enhancement of ethanol's inhibitory effect on receptors composed of NR2A but not NR2B subunits. CONCLUSIONS: These results suggest that under physiological conditions, NR3A may be an important regulator of the acute ethanol sensitivity of brain NMDA receptors. PMID- 18445117 TI - Comparison between idiopathic deep vein thrombosis of the upper and lower extremity regarding risk factors and recurrence. AB - BACKGROUND: The pathogenesis and natural course of idiopathic upper extremity deep vein thrombosis (UEDVT) are unclear. OBJECTIVE: To compare patients with UEDVT and with idiopathic lower extremity deep vein thrombosis (LEDVT) regarding risk factors and recurrence. METHODS: We followed 50 patients with first idiopathic UEDVT and 841 patients with first idiopathic LEDVT for an average of 59 and 46 months, respectively. We excluded patients with natural inhibitor deficiency, lupus anticoagulant, cancer, pregnancy, isolated pulmonary embolism (PE), or long-term antithrombotic treatment. The endpoint was recurrent venous thromboembolism (VTE). RESULTS: In comparison to LEDVT patients, UEDVT patients were younger (38 +/- 13 years vs. 49 +/- 16 years, P < 0.001), slimmer (body mass index: 24 +/- 4 vs. 27 +/- 5, P < 0.001), less frequently had a family history of VTE (18% vs. 31%, P = 0.06) or concomitant PE (8% vs. 31%, P =0.001), were less frequently carriers of factor V Leiden (12% vs. 30%, P = 0.009), and had lower thrombin generation marker levels (D-dimer, 283 +/- 361 ng mL(-1) vs. 456 +/- 446 ng mL(-1), P < 0.001; peak thrombin, 298 +/- 101 nm vs. 363 +/- 111 nm, P = 0.001). Recurrence occurred in two of 50 patients with UEDVT (4%) and in 129 of 841 patients with LEDVT (15%). After 5 years, the likelihood of recurrence was 2% [95% confidence interval (CI) 0-6] among UEDVT patients and 19% (95% CI 16-22; P = 0.02) among LEDVT patients. As compared to LEDVT patients, the adjusted risk of recurrence was 0.26 (95% CI 0.06-1.05; P = 0.059) in UEDVT patients. CONCLUSION: The pathogenesis and natural course of the disease differ between patients with idiopathic UEDVT and LEDVT. PMID- 18445118 TI - Hospital-based costs associated with venous thromboembolism treatment regimens. AB - INTRODUCTION: Venous thromboembolism (VTE) poses a significant health and economic burden in US hospitals. Clinical guidelines for acute VTE treatment recommend antithrombotic therapy (at least 5 days) with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). With upcoming US national performance measures requiring successful implementation of evidence-based therapy, cost considerations for anticoagulant choice are of increasing importance to hospitals. METHODS: This retrospective cohort analysis utilizes discharge records from a large real-world US population (January 2002 to December 2006) to provide total, direct, inpatient medical costs associated with LMWH and UFH for acute VTE treatment. Furthermore, for both LMWH and UFH discharges, we compare VTE-related readmission rates at 30 and 90 days after discharge. RESULTS: In total, 57 131 discharges were identified (57.7% LMWH; 42.3% UFH). After adjustment for covariates, including age, severity of illness, and length of stay, total direct medical costs per hospital discharge for UFH were $3476.22 vs. $3056.42 for LMWH (P < 0.0001; difference $420). Costs were significantly higher in the UFH group for most cost categories. Notably, drug acquisition cost was higher for LMWH. LMWH treatment was 12% [odds ratio (OR) 0.876; P < 0.001] and 10% (OR 0.895; P = 0.0006) less likely to result in VTE readmission within 30 and 90 days, respectively. CONCLUSIONS: This study provides the first large, real world analysis of the total direct medical costs of treating VTE in-hospital. It confirms that, despite higher drug acquisition costs, LMWH is cost-saving compared with UFH in the inpatient setting, and is associated with a lower VTE readmission rate at 30 and 90 days than is UFH. PMID- 18445119 TI - Rab5 activation by Toll-like receptor 2 is required for Trypanosoma cruzi internalization and replication in macrophages. AB - Trypanosoma cruzi can infect and replicate in macrophages. During invasion, T. cruzi interacts with different macrophage receptors to induce its own phagocytosis. However, the nature of those receptors and the molecular mechanisms involved are poorly understood. In this study, we demonstrate that T. cruzi metacyclic trypomastigotes but not epimastigotes were able to induce Rab5 activation and binding to the early endosomes in peritoneal macrophages. In this process, active Rab5 colocalized with parasites in the phagosome and with the Rab5A effector molecule early endosomal antigen 1. Phagosome formation and T. cruzi internalization were inhibited in Raw 264.7 macrophages expressing a dominant-negative form of Rab5 [(S34N)Rab5]. Using T. cruzi membrane extracts, we verified that the Rab5 activation depends on the interaction between parasite surface molecules and macrophages surface molecule. In addition, during infection of macrophages, phosphatidylinositol 3-kinase (PI3K) pathway was activated. Assays carried out using a selective PI3K inhibitor (LY294002) showed that the PI3K activation is essential for Rab5 activation by T. cruzi infection and for the entrance and intracellular replication of T. cruzi in macrophages. Moreover, using macrophages from knockout mice, we found that activation of Rab5, fusion of early endosomes and phagocytosis induced by T. cruzi infection involved Toll-like receptor (TLR)2 but were independent of TLR4 receptors. PMID- 18445120 TI - Vesicle docking in regulated exocytosis. AB - In electron micrographs, many secretory and synaptic vesicles are found 'docked' at the target membrane, but it is unclear why and how. It is generally assumed that docking is a necessary first step in the secretory pathway before vesicles can acquire fusion competence (through 'priming'), but recent studies challenge this. New biophysical methods have become available to detect how vesicles are tethered at the target membrane, and genetic manipulations have implicated many genes in tethering, docking and priming. However, these studies have not yet led to consistent working models for these steps. In this study, we review recent attempts to characterize these early steps and the cellular factors to orchestrate them. We discuss whether assays for docking, tethering and priming report on the same phenomena and whether all vesicles necessarily follow the same linear docking-priming-fusion pathway. We conclude that most evidence to date is consistent with such a linear pathway assuming several refinements that imply that some vesicles can be nonfunctionally docked ('dead-end' docking) or, conversely, that the linear pathway can be greatly accelerated (crash fusion). PMID- 18445121 TI - For better or for worse: complexins regulate SNARE function and vesicle fusion. AB - In contrast to constitutive secretion, SNARE-mediated synaptic vesicle fusion is controlled by multiple regulatory proteins, which determine the Ca(2+) sensitivity of the vesicle fusion process and the speed of excitation-secretion coupling. Complexins are among the best characterized SNARE regulators known to date. They operate by binding to trimeric SNARE complexes consisting of the vesicle protein synaptobrevin and the plasma membrane proteins syntaxin and SNAP 25. The question as to whether complexins facilitate or inhibit SNARE-mediated fusion processes is currently a matter of significant controversy. This is mainly because of the fact that biochemical experiments in vitro and studies on vertebrate complexins in vivo have yielded apparently contradictory results. In this review, I provide a summary of available data on the role of complexins in SNARE-mediated vesicle fusion and attempt to define a model of complexin function that incorporates evidence for both facilitatory and inhibitory roles of complexins in SNARE-mediated fusion. PMID- 18445122 TI - Going with the flow: trafficking-dependent and -independent regulation of serotonin transport. AB - Antidepressant-, cocaine- and 3,4-methylenedioxymethamphetamine-sensitive serotonin (5-hydroxytryptamine, 5-HT) transporters (SERTs) are expressed on presynaptic membranes of 5-HT-secreting neurons to provide efficient uptake of the biogenic amine after release. SERTs also support 5-HT transport across platelet, placental, gastrointestinal and pulmonary membranes and thus play a critical role in central nervous system and peripheral nervous system 5-HT signaling. SERTs are subject to multiple levels of posttranslational regulation that can rapidly alter 5-HT uptake and clearance rates. Specific cell surface receptors are now known to regulate SERT trafficking and/or catalytic function, with pathways activating protein kinase C, protein kinase G and p38 mitogen activated protein kinase receiving the greatest attention. Remarkably, disease associated mutations in SERT not only impact basal SERT activity but also selectively impact one or more SERT regulatory pathway(s). In this review, we describe both trafficking-dependent and trafficking-independent modes of SERT regulation and also the suspected roles played in regulation by SERT-associated proteins. Elucidation of the SERT 'regulome' provides important depth to our understanding of the likely origins of 5-HT-associated disorders and may help orient research to develop novel therapeutics. PMID- 18445123 TI - Regulation of hypophysiotrophic corticotrophin-releasing hormone- and thyrotrophin-releasing hormone-synthesising neurones by brainstem catecholaminergic neurones. AB - Hypophysiotrophic corticotrophin-releasing hormone (CRH)- and thyrotrophin releasing hormone (TRH)-synthesising neurones are the principal hypothalamic regulators of glucocorticoid and thyroid hormone secretion, respectively. These two neuroendocrine cell populations are closely situated in the hypothalamic paraventricular nucleus and are targets of neuronal afferent pathways that convey important signals for adapting the neurosecretory activity of CRH and TRH neurones to actual demands. The catecholaminergic afferents of CRH and TRH neurones originate from both noradrenaline- and adrenaline-synthesising cell groups located in the brainstem, and collectively represent one of the most well studied neural inputs of these neurones. The present review summarises the data obtained in recent years concerning the functional significance of the catecholaminergic innervation of hypophysiotrophic CRH and TRH neurones in rats. PMID- 18445124 TI - Oestrogen influences on mitochondrial gene expression and respiratory chain activity in cortical and mesencephalic astrocytes. AB - The regulation of mitochondrial energy metabolism plays an essential role in the central nervous system (CNS). Abnormalities of the mitochondrial respiratory chain often accompany neurodegenerative diseases. This makes mitochondria a perfect target for strategies of cellular protection against toxic compounds and pathological conditions. Steroid hormones, such as oestrogen, are well-known to fulfil a protective role in the brain during ischaemic and degenerative processes. Because astrocytes function as the major energy supplier in the CNS, we have analysed oestrogen effects on the mitochondrial respiratory chain of this cell type. In our studies, we applied semi- and quantitative polymerase chain reaction analysis of gene expression and polarographic measurements of the respiratory chain activity of mitochondria. We observed that structural and functional properties were regulated dependent on the oestrogen exposure time and the brain region, but independent of the nuclear oestrogen receptors. We could demonstrate that long-term oestrogen exposure increases the subunit gene expression of respiratory chain complexes and the mitochondrial DNA content, thereby indicating an up-regulation of the amount of mitochondria per cell together with an increase of mitochondrial energy production. This could represent an important indirect mechanism by which long-term oestrogen exposure protects neurones from cell death under neurotoxic conditions. On the other hand, we observed short-term effects of oestrogen on the activity of mitochondrial, proton-pumping respiratory chain complexes. In astrocytes from the cortex, respiratory chain activity was decreased, whereas it was increased in astrocytes from the mesencephalon. An increased production of reactive oxygen species would be the consequence of an increased respiratory chain activity in mesencephalic astrocytes. This could explain the different efficiencies of oestrogen-mediated short-term protection in distinct brain regions, but also indicates the limitations for a therapeutic short-term application of oestrogen. PMID- 18445125 TI - Temporal and spatial regulation of CRE recombinase expression in gonadotrophin releasing hormone neurones in the mouse. AB - Gonadotrophin-releasing hormone (GnRH) neurones located within the brain are the final neuroendocrine output regulating the reproductive hormone axis. Their small number and scattered distribution in the hypothalamus make them particularly difficult to study in vivo. The Cre/loxP system is a valuable tool to delete genes in specific cells and tissues. We report the production of two mouse lines that express the CRE bacteriophage recombinase in a GnRH-specific manner. The first line, the GnRH-CRE mouse, contains a transgene in which CRE is under the control of the murine GnRH promoter and targets CRE expression specifically to GnRH neurones in the hypothalamus. The second line, the GnRH-CRETeR mouse, uses the same murine GnRH promoter to target CRE expression to GnRH neurones, but is modified to be constitutively repressed by a tetracycline repressor (TetR) expressed from a downstream tetracycline repressor gene engineered within the transgene. GnRH neurone-specific CRE expression can therefore be induced by treatment with doxycycline which relieves repression by TetR. These GnRH-CRE and GnRH-CRETeR mice can be used to study the function of genes expressed specifically in GnRH neurones. The GnRH-CRETeR mouse can be used to study genes that may have distinct roles in reproductive physiology during the various developmental stages. PMID- 18445127 TI - Melatonin activates brain dopaminergic systems in the eel with an inhibitory impact on reproductive function. AB - In the eel, a deficit in gonadotrophin-releasing hormone (GnRH) and a strong dopaminergic (DA) inhibition are responsible for the blockade of gonad development if silver eels are prevented from their reproductive migration. Environmental factors that eels encounter during their oceanic reproductive migration are thought to play an important role in the stimulation of eel pubertal development. We investigated the potential role of melatonin, a known mediator of the effects of external factors on reproductive function in vertebrates. We demonstrated that a long-term melatonin treatment increased brain tyrosine hydroxylase (TH, the rate limiting enzyme of DA synthesis) mRNA expression in a region-dependent way. Melatonin stimulated the dopaminergic system of the preoptic area, which is involved in the inhibitory control of gonadotrophin [luteinising hormone (LH) and follicle-stimulating hormone (FSH)] synthesis and release. Moreover, we showed that the increased TH expression appeared to be consistent with melatonin binding site distribution as shown by 2[(125)I]-melatonin labelling studies. On the other hand, melatonin had no effects on the two eel native forms of GnRH (mGnRH and cGnRH-II) mRNA expression. Concerning the pituitary-gonad axis, we showed that melatonin treatment decreased both gonadotrophin beta-subunit (LHbeta, FSHbeta) mRNA expression and reduced sexual steroid (11-ketotestosterone, oestradiol) plasma levels. This indicates that melatonin treatment had a negative effect on eel reproductive function. To our knowledge, the results of the present study provide the first evidence that melatonin enhances TH expression in specific brain regions in a non-mammalian species. By this mechanism melatonin could represent one pathway by which environmental factors could modulate reproductive function in the eel. PMID- 18445126 TI - Role of AMP-activated protein kinase in the control of appetite. AB - AMP-activated protein kinase is a key enzyme in the regulation of energy metabolism. Its activation has pleiotropic effects in multiple tissues, including increased fatty acid oxidation, glucose uptake and glycolysis, as well as the inhibition of fatty acid and glycogen synthesis and gluconeogenesis, and stimulation of mitochondrial biogenesis. Recently, the AMP-activated protein kinase (AMPK) has also emerged as a regulator of appetite, contributing to the control of energy metabolism at both cell and the whole body levels. Pharmacological and genetic activation or inhibition of hypothalamic AMPK lead to increased or reduced food intake, respectively. AMPK appears to play a role in hypothalamic glucose and nutrient sensing and numerous studies have suggested a role for AMPK in mediating the orexigenic or anorexigenic effects of various endogenous and exogenous substances. PMID- 18445129 TI - Differential appetite-related responses to central neuropeptide S in lines of chickens divergently selected for low or high body weight. AB - The anorexigenic 20 amino acid neuropeptide S (NPS) has not been studied in an animal model of hypo- or hyperphagia. The present study aimed to elucidate whether central NPS appetite-related effects are different in lines of chickens that had undergone long-term divergent selection for low (LWS) or high (HWS) body weight and that were hypo- and hyperphagic, respectively. It took a longer time for food intake to be reduced in LWS than HWS chicks administered the lowest dose of NPS tested (0.14 nmol) and, at the highest dose tested (0.56 nmol), they had a greater reduction in food intake than did HWS chicks. HWS chicks responded with a similar magnitude of food intake reduction that was independent of NPS dose. Although water intake was reduced concurrently with food intake after central NPS in both lines, blood glucose concentrations were not affected. Hypothalamic signalling was different between the lines. Although both lines respond to central NPS with decreased c-Fos immunoreactivity in the lateral hypothalamus, the periventricular nucleus had increased c-Fos immunoreactivity in LWS but not HWS chicks. After central NPS treatment, there was increased c-Fos immunoreactivity in the paraventricular nucleus in HWS but not LWS chicks. These data support the notion of differences in the central NPS system between the LWS and HWS lines and infer that central NPS may differentially affect appetite related processes in other species that contain hypo- and hyperphagic individuals. PMID- 18445128 TI - Oestrogen receptor alpha localisation in the prefrontal cortex of three mammalian species. AB - Oestrogen modulates cognitive function and affective behaviours subserved by the prefrontal cortex (PFC). Identifying and localising oestrogen receptor (ER)alpha, in human PFC will contribute to our understanding of the molecular mechanism of oestrogen action in this region. Inferences about the site of action of oestrogen in human brain are derived largely from studies performed in nonhuman mammalian species; however, the congruence of findings across species has not been demonstrated. Furthermore, the laminar, cellular, and subcellular localisation of ERalpha in the cortex is debated. Therefore, we compared the distribution of ERalpha in human dorsolateral prefrontal cortex (DLPFC) with that of monkey DLPFC and rat medial PFC. Immunohistochemistry performed on frontal cortex from the three species demonstrated ERalpha positive cells throughout all layers of the PFC, in pyramidal and nonpyramidal neurones, with both nuclear and cytoplasmic immunoreactivity. Western blot analyses and preabsorption studies confirmed that the antibody used recognised ERalpha and not ERbeta. A strong ERalpha immunoreactive band corresponding to the full-length ERalpha protein (65-67 kDa) in the frontal cortex of all three species matched the size of the predominant immunoreactive band detected in breast cancer cell lines known to express ERalpha. Additionally, other ERalpha immunoreactive proteins of varying molecular weight in breast cancer cells, rat ovary and mammalian brain were detected, suggesting that ERalpha may exist in more than one form in the mammalian frontal cortex. The present study provides evidence that ERalpha protein exists in neurones in mammalian PFC and that ERalpha is anatomically well-positioned to directly mediate oestrogen action in these neurones. PMID- 18445130 TI - Isoprene emission is not temperature-dependent during and after severe drought stress: a physiological and biochemical analysis. AB - SUMMARY: Black poplar (Populus nigra L.) plants grown at 25 and 35 degrees C were subjected to drought stress to assess the combined impact of two consequences of global climate change--rising temperature and drought--on isoprene biosynthesis and emission. At both temperatures, photosynthesis was inhibited by moderate drought, but isoprene emission only decreased when drought was prolonged. The mRNA transcript level, protein concentration and activity of isoprene synthase (ISPS) changed in concert with isoprene emission during drought stress. However, ISPS activity decreased before isoprene emission during drought development, indicating a tighter control of the emission at a transcriptional or post transcriptional level under moderate drought stress, and at both temperatures. A residual isoprene emission was measured when photosynthesis was totally inhibited after 35 days of drought. This photosynthesis-independent emission of isoprene was probably dependent on a cytosolic carbon supply as all the properties of ISPS were drastically inhibited. Isoprene emission was associated with dark respiration during the entire drought stress period, and at both temperatures, indicating that the two processes are sustained by, but do not compete for, the same carbon source. Isoprene emission was directly related to phosphoenolpyruvate carboxylase activity in plants grown at 25 degrees C and inversely related in plants grown at 35 degrees C, suggesting a strong temperature control on the regulation of the pyruvate flowing from the cytosol to the plastidic isoprenoid biosynthetic pathway under drought stress and recovery. In re-watered plants, the temperature control on isoprene emission was suppressed, despite complete recovery of photosynthesis and ISPS activity similar to levels in plants subjected to mild drought stress. Our results reveal the overriding effects of drought on isoprene emission, possibly affecting protein level or substrate supply. These effects may largely offset the predicted impact of rising temperatures on the emission of isoprene in terrestrial ecosystems. PMID- 18445131 TI - Vascular-related NAC-DOMAIN7 is involved in the differentiation of all types of xylem vessels in Arabidopsis roots and shoots. AB - SUMMARY: The Arabidopsis thaliana NAC domain transcription factor, vascular related NAC-DOMAIN7 (VND7), plays a pivotal role in regulating the differentiation of root protoxylem vessels. In order to understand the mechanisms underscoring the function of VND7 in vessel differentiation in more detail, we conducted extensive molecular analyses in yeast (Saccharomyces cerevisiae), Arabidopsis, and Nicotiana tabacum L. cv. Bright Yellow 2 (tobacco BY-2) cells. The transcriptional activation activity of VND7 was confirmed in yeast and Arabidopsis, and the C-terminal region was shown to be required for VND7 transcriptional activation. Expression of the C-terminus-truncated VND7 protein under the control of the native VND7 promoter resulted in inhibition of the normal development of metaxylem vessels in roots and vessels in aerial organs, as well as protoxylem vessels in roots. The expression pattern of VND7 overlapped that of VND2 to VND5 in most of the differentiating vessels. Furthermore, a yeast two-hybrid assay revealed the ability of VND7 to form homodimers and heterodimers with other VND proteins via their N-termini, which include the NAC domain. The heterologous expression of VND7 in tobacco BY-2 cells demonstrated that the stability of VND7 could be regulated by proteasome-mediated degradation. Together these data suggest that VND7 regulates the differentiation of all types of vessels in roots and shoots, possibly in cooperation with VND2 to VND5 and other regulatory proteins. PMID- 18445132 TI - AtCYP38 ensures early biogenesis, correct assembly and sustenance of photosystem II. AB - SUMMARY: AtCYP38 is a thylakoid lumen protein comprising the immunophilin domain and the phosphatase inhibitor module. Here we show the association of AtCYP38 with the photosystem II (PSII) monomer complex and address its functional role using AtCYP38-deficient mutants. The dynamic greening process of etiolated leaves failed in the absence of AtCYP38, due to specific problems in the biogenesis of PSII complexes. Also the development of leaves under short-day conditions was severely disturbed. Detailed biophysical and biochemical analysis of mature AtCYP38-deficient plants from favorable growth conditions (long photoperiod) revealed: (i) intrinsic malfunction of PSII, which (ii) occurred on the donor side of PSII and (iii) was dependent on growing light intensity. AtCYP38 mutant plants also showed decreased accumulation of PSII, which was shown not to originate from impaired D1 synthesis or assembly of PSII monomers, dimers and supercomplexes as such but rather from the incorrect fine-tuning of the oxygen evolving side of PSII. This, in turn, rendered PSII centers extremely susceptible to photoinhibition. AtCYP38 deficiency also drastically decreased the in vivo phosphorylation of PSII core proteins, probably related to the absence of the AtCYP38 phosphatase inhibitor domain. It is proposed that during PSII assembly AtCYP38 protein guides the proper folding of D1 (and CP43) into PSII, thereby enabling the correct assembly of the water-splitting Mn(4)-Ca cluster even with high turnover of PSII. PMID- 18445133 TI - Concomitant degradation of beta-catenin and GSK-3 beta potently contributes to glutamate-induced neurotoxicity in rat hippocampal slice cultures. AB - Increasingly, published evidence links glutamate with the pathogenesis of Alzheimer's disease. We investigated the molecular mechanism underlying glutamate induced neurotoxicity in hippocampus, which is primarily linked to cognitive dysfunction in Alzheimer's disease. Acute exposure of rat hippocampal slices to glutamate significantly induced cell death, as determined by media lactate dehydrogenase levels and PI staining. Moreover, this was accompanied by Ca2+ influx and calpain-1 activation, as confirmed by the proteolytic pattern of spectrin. Notably, glutamate-induced calpain-1 activation decreased the level of beta-catenin, and this process appeared to be independent of glycogen synthase kinase 3beta (GSK-3beta), since glutamate also led to loss of GSK-3beta. Calpeptin, a calpain inhibitor, attenuated the glutamate-mediated degradations of spectrin, synaptophysin, and beta-catenin except GSK-3beta and modestly increased cell survival. In contrast, the NMDA receptor antagonist 2-amino-5 phosphonopentanoic acid (APV) effectively reduced all glutamate-evoked responses, i.e., the breakdowns of spectrin, synaptophysin, beta-catenin and GSK-3beta, and cell death. Pharmacological studies and in vitro calpain-1 proteolysis confirmed that in the glutamate-treated hippocampus, calpain-1-mediated decrease of beta catenin could occur independently of GSK-3beta and of proteasome, and that GSK 3beta degradation is independent of calpain-1. These findings together provide the first direct evidence that glutamate promotes the down-regulations of beta catenin and GSK-3beta, which potently contribute to neurotoxicity in hippocampus during excitotoxic cell death, and a molecular basis for the protection afforded by calpeptin and APV from the neurotoxic effect of glutamate. PMID- 18445134 TI - Conformational change of the transmembrane helices II and IV of metabotropic glutamate receptor involved in G protein activation. AB - G protein-coupled receptors are classified into several families on the basis of their amino acid sequences and the members of the same family exhibit sequence similarity but those of different families do not. In family 1 GPCRs such as rhodopsin and adrenergic receptor, extensive studies have revealed the stimulus dependent conformational change of the receptor: the rearrangement of transmembrane helices III and VI is essential for G protein activation. In contrast, in family 3 GPCRs such as metabotropic glutamate receptor (mGluR), the inter-protomer relocation upon ligand binding has been observed but there is much less information about the structural changes of the transmsmbrane helices and the cytoplasmic domains. Here we identified constitutively active mutation sites at the cytoplasmic borders of helices II and IV of mGluR8 and successfully inhibited the G protein activation ability by engineering disulfide cross-linking between these cytoplasmic regions. The analysis of all possible single substitution mutants of these residues revealed that some steric interactions around these sites would be important to keep the receptor protein inactive. These results provided the model that the conformational changes at the cytoplasmic ends of helices II and IV of mGluR are involved in the efficient G protein coupling. PMID- 18445135 TI - Transcriptional regulation of the human CYP46A1 brain-specific expression by Sp transcription factors. AB - Brain defective cholesterol homeostasis has been associated with neurologic diseases, such as Alzheimer's and Huntington's disease. The elimination of cholesterol from the brain involves its conversion into 24(S)-hydroxycholesterol by CYP46A1, and the efflux of this oxysterol across the blood-brain barrier. Herein, we identified the regulatory elements and factors involved the human CYP46A1 expression. Functional 5'deletion analysis mapped a region spanning from nucleotides -236/-64 that is indispensable for basal expression of this TATA-less gene. Treatment of SH-SY5Y cells with mithramycin A resulted in a significant reduction of promoter activity, suggesting a role of Sp family of transcription factors in CYP46A1 regulation. Combination of Sp1, Sp3, and Sp4 over-expression studies in Drosophila SL-2 cells, and systematic promoter mutagenesis identified Sp3 and Sp4 binding to four GC-boxes as required and sufficient for high levels of promoter activity. Moreover, Sp3 and Sp4 were demonstrated to be the major components of the protein-DNA complexes observed in primary rat cortical extracts. Our results suggest that the cell-type specific expression of Sp transcription factors - substitution of Sp1 by Sp4 in neurons - is responsible for the basal expression of the CYP46A1 gene. This study delineates for the first time the mechanisms underlying the human CYP46A1 transcription and thereby elucidates potential pathways underlying cholesterol homeostasis in the brain. PMID- 18445136 TI - Partial inhibition of complex I activity increases Ca-independent glutamate release rates from depolarized synaptosomes. AB - Mitochondria have been implicated in the pathogenesis of several neurodegenerative disorders and, in particular, complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3) activity has been shown to be partially reduced in postmortem studies of the substantia nigra of Parkinson's disease patients. The present study examines the effect of partial inhibition of complex I activity on glutamate release from rat brain synaptosomes. Following a 40% inhibition of complex I activity with rotenone, it was found that Ca(2+)-independent release of glutamate increased from synaptosomes depolarized with 4-aminopyridine. Highest rates of glutamate release were found to occur between 60-90% complex I inhibition. A similar pattern of increase was shown to occur in synaptosomes depolarized with KCl. The increase in glutamate release was found to correlate to a significant decrease in ATP. Inhibition of complex I activity by 40% was also shown to cause a significant collapse in mitochondrial membrane potential (Deltapsi(m)). These results suggest that partial inhibition of complex I activity in in situ mitochondria is sufficient to significantly increase release of glutamate from the pre-synaptic nerve terminal. The relevance of these results in the context of excitotoxicity and the pathogenesis of neurodegenerative disorders is discussed. PMID- 18445137 TI - CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region. AB - Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as cognitive-enhancing effect. We previously showed that nefiracetam potentiates NMDA-induced currents in cultured rat cortical neurons. To address questions whether nefiracetam affects NMDA receptor-dependent synaptic plasticity in the hippocampus, we assessed effects of nefiracetam on NMDA receptor-dependent long-term potentiation (LTP) by electrophysiology and LTP induced phosphorylation of synaptic proteins by immunoblotting analysis. Nefiracetam treatment at 1-1000 nM increased the slope of fEPSPs in a dose dependent manner. The enhancement was associated with increased phosphorylation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) without affecting synapsin I phosphorylation. In addition, nefiracetam treatment increased PKCalpha activity in a bell-shaped dose-response curve which peaked at 10 nM, thereby increasing phosphorylation of myristoylated alanine-rich protein kinase C substrate and NMDA receptor. Nefiracetam treatment did not affect protein kinase A activity. Consistent with the bell-shaped PKCalpha activation, nefiracetam treatment enhanced LTP in the rat hippocampal CA1 region with the same bell-shaped dose-response curve. Furthermore, nefiracetam-induced LTP enhancement was closely associated with CaMKII and PKCalpha activation with concomitant increases in phosphorylation of their endogenous substrates except for synapsin I. These results suggest that nefiracetam potentiates AMPA receptor mediated fEPSPs through CaMKII activation and enhances NMDA receptor-dependent LTP through potentiation of the post-synaptic CaMKII and protein kinase C activities. Together with potentiation of nicotinic acetylcholine receptor function, nefiracetam-enhanced AMPA and NMDA receptor functions likely contribute to improvement of cognitive function. PMID- 18445138 TI - Functional variation in the 3' untranslated region of the serotonin transporter in human and rhesus macaque. AB - The serotonin system underlies a wide variety of behavioral traits and its dysregulation is the cause of numerous neuropsychiatric disorders. Among genes involved in the system, the serotonin transporter (SERT) is integral and has been repeatedly shown to be associated with disease as well as being a primary drug target. In addition to promoter region variation, we identify here variation in a regulatory region in the 3' untranslated region (UTR) of the SERT gene in both humans and rhesus macaques. We comprehensively survey the 3' UTR of SLC6A4 in Indian-origin rhesus macaques to identify three single nucleotide polymorphisms (SNPs) creating two haplotypes, both derived from an ancestral sequence, that represent the vast majority of the alleles in the population. Through the use of a luciferase reporter gene assay, we are able to show that not only do these alleles have differential effects on gene expression, modulated through changes in messenger RNA stability, but that different commonly occurring SNPs in the human 3' UTR also have similar effects. This finding not only offers additional insight into the regulation, and thus dysregulation, of SERT expression, but also suggests the role of natural selection in maintaining both high and low SERT expression levels broadly across populations of multiple primate species. PMID- 18445139 TI - Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision. AB - BACKGROUND: The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma. OBJECTIVE: To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour. SUBJECTS AND METHODS: FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data. RESULTS: Si was lower in insulinoma patients before, compared with after surgery (3.37 +/- 0.62 vs. 6.24 +/- 1.09 SE [x10(-4)] min(-1)microU(-1) ml, P < 0.05). Sg was similar in patients pre- and post-surgery (3.0 +/- 0.67 vs. 2.4 +/- 0.6 [x10(-2)] min(-1), NS). CONCLUSIONS: Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia. PMID- 18445140 TI - A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations. AB - CONTEXT: Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22-24. There is little phenotype genotype correlation known to date. OBJECTIVE: To study the genotype-phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC. DESIGN: The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family. PATIENTS: The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC. RESULTS: The PRKAR1A-inactivating mutation c.502 +1G > A in the intron 5 splice-donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means. CONCLUSIONS: A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC. PMID- 18445141 TI - Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904-Z. AB - BACKGROUND: AGN 201904-Z is a new, slowly absorbed, acid-stable pro-proton pump inhibitor (pro-PPI) rapidly converted to omeprazole in the systemic circulation giving a prolonged residence time. AIM: To investigate pharmacodynamics and pharmacokinetics of AGN 201904-Z compared to esomeprazole. METHODS: A randomized, open-label, parallel group, investigator-blinded intragastric pH study was conducted in 24 healthy Helicobacter pylori negative male volunteers. AGN 201904 Z enteric-coated capsules (600 mg/day) or esomeprazole delayed-release tablets (40 mg/day) were administered for 5 days. Twenty-four-hour intragastric pH recordings were acquired at baseline, days 1, 3 and 5 with blood levels of omeprazole, AGN 201904-Z and gastrin. RESULTS: On day 1, median nocturnal pH and proportion of nocturnal time with pH >or=4 and 24-h and nocturnal time pH >or=5 were significantly higher with AGN 201904-Z than esomeprazole. At day 5, 24-h and median nocturnal pH were significantly higher for AGN 201904-Z than esomeprazole (P < 0.0001). There was also a marked reduction in periods of nocturnal pH <4.0. Area under curve of the AGN 201904-Z active metabolite (omeprazole) in the blood was twice that of esomeprazole at day 5. CONCLUSIONS: AGN 201904-Z produced a significantly greater and more prolonged acid suppression than esomeprazole, and nocturnal acid suppression was more prolonged over all 5 days. AGN 201904-Z should provide true once-a-day treatment and better clinical efficacy than current PPIs. PMID- 18445142 TI - Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. AB - BACKGROUND: Currently, although only a few therapies normalize the liver test abnormalities with/without improving the liver histology, no pharmacologic therapy has proved to be effective for the treatment of non-alcoholic steatohepatitis. AIM: To investigate the role of insulin sensitizers in the treatment of individuals with non-alcoholic steatohepatitis (NASH). METHODS: A total of 74 individuals with NASH (male/female, 44/30; mean age, 47.2 +/- 9.0 years) were enrolled. Participants were divided into two distinct groups: group 1 (n = 25) participants were administered a conventional diet and exercise programme while those in group 2 (n = 49) were administered the diet and exercise programme plus insulin sensitizers. RESULTS: With respect to baseline metabolic, biochemical and histological parameters, no significant differences were observed between the two groups (P > 0.05). Insulin sensitizers significantly improved metabolic parameters (homeostasis model assessment-insulin resistance score, P < 0.05), serum aminotransferase levels [aspartate aminotransferase (AST): 45.9 +/- 24.2 to 33.3 +/- 17.7 IU/L, P < 0.01; alanine aminotransferase (ALT): 78.2 +/- 46.3 to 47.3 +/- 34.5 IU/L, P < 0.001] and histological features (median non alcoholic fatty liver disease activity score: 5.0-3.0, P = 0.01), while diet and exercise improved serum aminotransferase levels (AST: 39.3 +/- 11.1 to 30.0 +/- 8.6 IU/L, P < 0.01; ALT: 66.9 +/- 28.9 to 42.0 +/- 16.2 IU/L, P < 0.001) at the end of the 48 weeks when compared to baseline. Insulin sensitizers improved the high-sensitivity C-reactive protein levels (P < 0.01). No serious adverse effects of insulin sensitizers were observed. CONCLUSION: Insulin sensitizers can lead to improvement in metabolic, biochemical and histological abnormalities of NASH as a result of improved insulin sensitivity. PMID- 18445144 TI - Compression and crevasses in vitreous sections under different cutting conditions. AB - Compression and crevasses are common cutting artefacts in cryo-ultramicrotomy of vitreous sections. They can be reduced or suppressed under optimal cutting conditions. In the present study, compression and thickness were measured for different cutting speeds and knife angles. It was found that compression decreased with feed and that crevasses appeared only above a certain thickness. The optimal feed for vitreous sections was between 50 and 80 nm. The thickness, calculated by two independent methods, was quantitatively related to feed and compression. PMID- 18445145 TI - Selective detection of luminescence from semiconductor quantum dots by nanosecond time-gated imaging with a colour-masked CCD detector. AB - Quantum dots are of considerable interest as highly detectable labels with broad absorption, narrow spectral emission and good quantum yields. The luminescence emission has a longer decay time than that of the most common fluorophores, leading to facile rejection of much background emission (such as autofluorescence from biological samples) by means of gated detection. Here, it is shown that a new technique, true-colour nanosecond time-gated luminescence imaging, can be used for selective detection of quantum dot luminescence and should prove valuable for multiplexed detection on the basis of both spectral emission profile and luminescence decay time. PMID- 18445146 TI - Constraint factor graph cut-based active contour method for automated cellular image segmentation in RNAi screening. AB - Image-based, high throughput genome-wide RNA interference (RNAi) experiments are increasingly carried out to facilitate the understanding of gene functions in intricate biological processes. Automated screening of such experiments generates a large number of images with great variations in image quality, which makes manual analysis unreasonably time-consuming. Therefore, effective techniques for automatic image analysis are urgently needed, in which segmentation is one of the most important steps. This paper proposes a fully automatic method for cells segmentation in genome-wide RNAi screening images. The method consists of two steps: nuclei and cytoplasm segmentation. Nuclei are extracted and labelled to initialize cytoplasm segmentation. Since the quality of RNAi image is rather poor, a novel scale-adaptive steerable filter is designed to enhance the image in order to extract long and thin protrusions on the spiky cells. Then, constraint factor GCBAC method and morphological algorithms are combined to be an integrated method to segment tight clustered cells. Compared with the results obtained by using seeded watershed and the ground truth, that is, manual labelling results by experts in RNAi screening data, our method achieves higher accuracy. Compared with active contour methods, our method consumes much less time. The positive results indicate that the proposed method can be applied in automatic image analysis of multi-channel image screening data. PMID- 18445147 TI - Cluster identification in AA5754 aluminium sheets using mathematical morphology analysis. AB - Quantitative image analysis of particle distribution in the microstructure of continuous cast (CC) and direct chill cast (DC) AA5754 aluminium alloy sheets have been conducted. This information can be used as an input for modelling mechanical deformation and instability in these materials. The quantitative analysis reveals that there are significant differences in the microstructure of the two materials even though the total content of second-phase particles is statistically similar. Qualitative observation shows the second-phase particles to be arranged in the form of streaks parallel to the rolling direction in the CC sheets and in a uniform random manner in the DC sheets. The main difference in the geometric microstructure of the CC and DC material is the spatial arrangement of the second-phase particles. A new mathematical technique called proximity analysis is developed to identify clusters and group of particles belonging to a cluster. Quantification through proximity analysis reveals that the particle clusters in CC sheet are in the form of long clusters (streaks) parallel to the rolling direction and are significantly longer than those in DC sheets (with the largest cluster in CC being four times larger than DC), and also have anisotropic angular orientation parallel to the rolling direction. The lower value of fracture strain observed in the CC sheets compared to DC sheets is attributed to a combination of large sizes of clusters and their preferential alignment along the rolling direction in the CC microstructure. PMID- 18445148 TI - Single wavelength micro-endoscopy in non-surgical vascular lesion diagnosis & characterization. AB - Malignant and dysplastic epithelial lesions have often been reported to excite vascular responses by histopathological characterization. Little is reported concerning in vivo real-time imaging of vascular patterns and flow in health or disease but the development of miniature imaging instrumentation has now allowed such developments. We describe the application of a selective wavelength (540 nm) epi-illumination Hopkins pattern endoscopic imaging system to image vascular tissues and capillary blood flow in vivo. The contrast mechanism in such imaging was characterized, haemoglobin acting as a chromatic transmission filter despite endoscopy being a non-invasive and therefore principally reflection mode imaging system. In vivo adrenergic vascular responses, capillary flow rate variations over time and variations in normal capillary architecture around the oral cavity were recorded; demonstrating that simple imaging systems can be used for non surgical diagnosis and characterization of vascular lesions, tumours and treatment responses. PMID- 18445149 TI - Correction for non-perpendicularity of beam and tilt axis in tomographic reconstructions with the IMOD package. AB - A correction for non-perpendicularity between the beam axis and the tilt axis in electron tomographic tilt series has been implemented in the IMOD software package and its value and limitations have been explored. Correction for this effect can provide a significant improvement in the alignment error and the reconstruction quality in some cases. However, when the projection model being fit includes an anisotropic shrinkage (i.e. stretch) in the plane of the specimen, adding a variable for the beam tilt does not produce a lower alignment error; it is thus not possible to distinguish between the effects of stretch and beam tilt. Test reconstructions indicate that an alignment solution that includes stretch will adequately correct for the effects of a beam tilt. For specimens subject to deformation under the beam, an alignment solution that accounts for stretch is preferable to one that accounts for beam tilt instead, provided that the markers used for alignment are sufficiently well distributed. Otherwise, a correction for beam tilt should be used. PMID- 18445150 TI - AFM for diagnosis of nanocrystallization of steels in hardening processes. AB - INTRODUCTION: The aim of this study is to investigate the nanocrystallization of steels caused by the transformation from the austenitic to the martensitic phase induced by a severe plastic deformation (SPD) treatment. In this framework, we applied an air blast shot peening treatment, which is a simple protocol widely used for industrial purposes. METHODS: AISI 286 and AISI 316 specimens were peened for different times and polished using diamond pastes in order to remove corrugations higher than 1 mum. The characterization of the steel surfaces was performed by atomic force microscopy (AFM) operating in contact mode. Additional EDXD measurements were performed to confirm the phase transition. RESULTS AND DISCUSSION: An AFM-based characterization at nanometric level of the steel surfaces is provided. When the peening exceeds a threshold time that, as expected, depends on the steel composition, a uniform nanostructuration is detected. It is well known that such rearrangement is associated to the growth of a martensitic phase. To date, AFM has been employed in this field only for few applications and to solve specific problems. On the other hand, our results demonstrate that this is a useful technique for the characterization of hardened surfaces, especially when non-destructive sample preparation treatments are required. Moreover, we show that AFM can be a useful tool also for in situ industrial diagnostics of metallic parts. PMID- 18445151 TI - Atomic force microscopy to characterize the molecular size of prion protein. AB - The conformational transition of alpha-helix-rich cellular prion protein (PrP(C)) to an isomer with high beta-sheet content is associated with transmissible spongiform encephalopathies. With the ultimate long-term goal of using imaging techniques to study PrP aggregation, we report the results of initial experiments to determine whether PrP molecules could be visualized as single molecules, and if the observed size corresponded to the calculated size for PrP. The investigation of single molecules, and not those embedded into larger aggregates, was the key in our experimental approach. Using atomic force microscopy (AFM) as an imaging method, the immobilization of recombinant histidine (His)10-tagged PrP on mica was performed in the presence of different heavy metal ions. The addition of Cu2+ resulted in an enhanced PrP immobilization, whereas Ni2+ reduced coverage of the surface by PrP. High-resolution data from dried PrP preparations provided a first approximation to geometrical parameters of PrP precipitates, which indicated that the volume of a single PrP molecule was 30 nm3. Molecular dynamics simulations performed to complement the structural aspects of the AFM investigation yielded a calculated molecular volume of 33 nm3 for PrP. These experimentally observed and theoretically expected values provide basic knowledge for further studies on the size and composition of larger amyloidal PrP aggregates, PrP isoforms or mutants such as PrP molecules without octarepeats. PMID- 18445152 TI - Comparative study using scanning electron techniques for imaging of micro architecture and antigen appearance. AB - We have used various scanning electron microscopy technologies for the analysis of structures and the appearance of antigen on eukaryotic cells. Various scanning electron microscopy including conventional scanning electron microscopy, high resolution scanning electron microscopy and environmental scanning electron microscopy applied for cell surface analysis allow obtaining sub-micrometre surface features on cell membranes. We used cell systems for imaging along with molecular localization of a cell surface antigen, SVEP1 protein. SVEP1 was studied using the immuno-gold technique for the identification of cell surface features and protein localization. We used an antibody to SVEP1 molecule that was labelled with secondary antibody conjugated with gold particles. The comparison between scanning electron methods enabled the visualization of surface structures and the molecular imaging for the distribution of SVEP1. PMID- 18445153 TI - Evolution of residual stress and crack morphologies during 3D FIB tomographic analysis of alumina. AB - Three-dimensional focused ion beam (FIB) tomography is increasingly being used for 3D characterization of microstructures in the 50 nm-20 microm range. FIB tomography is a destructive, invasive process, and microstructural changes may potentially occur during the analysis process. Here residual stress and crack morphologies in single-crystal sapphire samples have been concurrently analyzed using Cr3+ fluorescence spectroscopy and FIB tomography. Specifically, maps of surface residual stress have been obtained from optically polished single-crystal alumina [surface orientation (1 i 0 2)], from FIB milled surface trenches, from Vickers micro-indentation sites (loads 50 g-300 g), and from Vickers micro indentation sites during FIB serial sectioning. The residual stress maps clearly show that FIB sputtering generates residual stress changes. For the case of the Vickers micro-indentations, FIB sputtering causes significant changes in residual stress during the FIB tomographic serial sectioning. 3D reconstruction of the crack distribution around micro-indentation sites shows that the cracks observed are influenced by the location of the FIB milled surface trenches due to localized stress changes. PMID- 18445154 TI - New developments in high-pressure freezing. Introduction. PMID- 18445155 TI - Pseudovacuoles--immobilized by high-pressure freezing--are associated with blebbing in walker carcinosarcoma cells. AB - By applying high pressure freezing and freeze-substitution, we observed large inclusions of homogeneous appearance in the front of locomoting Walker carcinosarcoma cells that have not been described earlier. Live cell imaging revealed that these inclusions were poor in lipids and nucleic acids but had a high lysine (and hence protein) content. Usually one such structure 2-5 mum in size was present at the front of motile Walker cells, predominantly in the immediate vicinity of newly forming blebs. By correlating the lysine-rich areas in fixed and embedded cells with electron microscopic pictures, inclusions could be assigned to confined, faintly stained cytoplasmic areas that lacked a surrounding membrane; they were therefore called pseudovacuoles. After high pressure freezing and freeze substitution, pseudovacuoles appeared to be filled with 20 nm large electron-transparent patches surrounded by 12 and 15 nm large particles. The heat shock protein Hsp90 was identified by peptide sequencing as a major fluorescent band on SDS-PAGE of lysine-labelled Walker cell extracts. By immunofluorescence, Hsp90 was found to be enriched in pseudovacuoles. Colocalization of the lysine with a potassium-specific dye in living cells revealed that pseudovacuoles act as K+ stores in the vicinity of forming blebs. We propose that pseudovacuoles might support blebbing by locally regulating the intracellular hydrostatic pressure. PMID- 18445156 TI - Silver enhancement of Nanogold particles during freeze substitution for electron microscopy. AB - Recent advances in rapid freezing and fixation by freeze substitution have allowed structural cell biologists to apply these reliable modes of sample preparation to a wide range of specimens and scientific problems. Progress in electron tomography has produced cellular images with resolution approaching 4 nm in 3D, but our ability to localize macromolecules in these well-fixed, well resolved samples has remained limited. When light fixation and low temperature embedding are employed with appropriate resins, immuno-localizations can recognize antigens at a section's surface, but labelling is therefore confined, not throughout the section's depth. Small, electron-dense markers, like Nanogold(R), will often enter a living cell, serving as reliable tracers for endocytic activity, but these markers are usually too small to be visible in the context of a cell. We have developed a method for the silver enhancement of Nanogold particles that works during freeze substitution in organic solvents at low temperature. Here, we describe the development of this method, based on in vitro tests of reagents and conditions. We then show results from application of the method to an in vivo system, using Nanogold to track the internalization of immunoglobulin by neonatal murine intestinal epithelium, a specific example of receptor-mediated membrane traffic. PMID- 18445157 TI - Freeze-substitution: the addition of water to polar solvents enhances the retention of structure and acts at temperatures around -60 degrees C. AB - High-pressure freezing followed by freeze substitution and plastic embedding is becoming a more widely used method for TEM sample preparation. Here, we have investigated the influence of solvents, fixative concentrations and water content in the substitution medium on the sample quality of high-pressure frozen, freeze substituted and plastic embedded mammalian cell culture monolayers. We found that the visibility of structural details was optimal with acetone and that extraction increased with both increasing and decreasing solvent polarity. Interestingly, the addition of water to polar solvents increased the sample quality, while being destructive when added to apolar solvents. The positive effect of water addition is saturable in acetone and ethanol at 5%(v/v), but even addition of up to 20% water has no negative effect on the sample structure. Therefore, a medium based on acetone containing fixatives and 5% water is most optimal for the substitution of mammalian cell cultures. In addition, our results suggest that the presence of water is critical for the retention of structure at temperatures around -60 degrees C. PMID- 18445159 TI - Microcarriers for high-pressure freezing and cryosectioning of adherent cells. AB - A method is described employing microcarrier spheres of cross-linked dextran for obtaining ultra- and semithin vitreous sections from high-pressure frozen anchorage-dependent (mammalian) cells. Avoiding trypsination or scraping cells off from the culture surface, the presented approach allows for cryoimmobilization, cryosectioning and cryoelectron microscopy/tomography of frozen-hydrated cells in an unperturbed manner which is important to preserve the native state of, for instance, the cytoskeleton. Furthermore, our studies on the 'life cycle' of Herpes simplex virus in Vero cells demonstrate that cell monolayers on microcarrier beads are well suited for fluorescence microscopic characterization of the sample prior to high-pressure freezing. PMID- 18445158 TI - Controlled microaspiration for high-pressure freezing: a new method for ultrastructural preservation of fragile and sparse tissues for TEM and electron tomography. AB - High-pressure freezing is the preferred method to prepare thick biological specimens for ultrastructural studies. However, the advantages obtained by this method often prove unattainable for samples that are difficult to handle during the freezing and substitution protocols. Delicate and sparse samples are difficult to manipulate and maintain intact throughout the sequence of freezing, infiltration, embedding and final orientation for sectioning and subsequent transmission electron microscopy. An established approach to surmount these difficulties is the use of cellulose microdialysis tubing to transport the sample. With an inner diameter of 200 microm, the tubing protects small and fragile samples within the thickness constraints of high-pressure freezing, and the tube ends can be sealed to avoid loss of sample. Importantly, the transparency of the tubing allows optical study of the specimen at different steps in the process. Here, we describe the use of a micromanipulator and microinjection apparatus to handle and position delicate specimens within the tubing. We report two biologically significant examples that benefit from this approach, 3D cultures of mammary epithelial cells and cochlear outer hair cells. We illustrate the potential for correlative light and electron microscopy as well as electron tomography. PMID- 18445160 TI - Electron microscopy of the early Caenorhabditis elegans embryo. AB - The early Caenorhabditis elegans embryo is currently a popular model system to study centrosome assembly, kinetochore organization, spindle formation, and cellular polarization. Here, we present and review methods for routine electron microscopy and 3D analysis of the early C. elegans embryo. The first method uses laser-induced chemical fixation to preserve the fine structure of isolated embryos. This approach takes advantage of time-resolved fixation to arrest development at specific stages. The second method uses high-pressure freezing of whole worms followed by freeze-substitution (HPF-FS) for ultrastructural analysis. This technique allows staging of developing early embryos within the worm uterus, and has the advantage of superior sample preservation required for high-resolution 3D reconstruction. The third method uses a correlative approach to stage isolated, single embryos by light microscopy followed by HPF-FS and electron tomography. This procedure combines the advantages of time-resolved fixation and superior ultrastructural preservation by high-pressure freezing and allows a higher throughput electron microscopic analysis. The advantages and disadvantages of these methods for different applications are discussed. PMID- 18445161 TI - Golgi apparatus studied in vitreous sections. AB - Cryo-electron microscopy of vitrified specimen is the method of choice to explore cellular ultrastructure at high resolution as close as possible to the native state and environment. In this study, we investigated the Golgi apparatus - the main organelle of the secretory pathway. Cultured mammalian cells were fixed by high-pressure freezing, sectioned in vitreous ice and subjected to cryo-electron microscopy and cryo-electron tomography. Although the overall morphology of Golgi stacks was comparable to well prepared and plastic-embedded samples, in detail we reached much higher resolution in terms of distinction between biological structures based on their native density. On cisternal buds and peri-Golgi vesicles--some associated with microtubules--we detected two different subtypes of COPI coats: (1) a homogenous coat and (2) an inhomogeneous spiky coat, providing an 8-9 nm regularity, clearly distinct from clathrin coat. Next, we monitored the secretion of cargo, namely, procollagen I, through the Golgi complex. Temporally correlated with fluorescence microscopy, we performed three dimensional cryo-electron tomography analysis and detected Golgi cisternae enlarged to saccules, containing cargo and showing inter-cisternal connections. Our work provides a first step towards the high-resolution description of the secretory pathway in native vitrified samples and describes the challenges associated with this attempt. PMID- 18445162 TI - Moving EM: the Rapid Transfer System as a new tool for correlative light and electron microscopy and high throughput for high-pressure freezing. AB - In this paper, the Rapid Transfer System (RTS), an attachment to the Leica EMPACT2 high-pressure freezer, is described as a new tool for special applications within the cryofixation field. The RTS is an automated system that allows for fast processing of samples (<5 s) that make it possible for the first time to use high-pressure freezing in combination with high time resolution correlative light and electron microscopy. In addition, with a working cycle of 30 s this rapid turn over time allows one to acquire more samples of biopsy material before it deteriorates than with other HPF machines with longer cycle times. With the use of the RTS it was possible to obtain three samples each of four different tissues in 6 min. Together with the finding that 90% of samples of cells grown on sapphire discs were well frozen, the RTS was both fast and reliable. Most important, together with other newly developed accessories, the RTS made it possible to capture specific events occurring live in the cell as observed by light microscopy, to cryofix that sample/event within 4 s, and then to analyze that event at high resolution in the electron microscope with excellent preservation of ultra-structure. These developments should give us the tools to unravel intracellular processes that can be observed by live cell imaging but are too rare or fast to be picked up by routine EM methods or where the history of a structure is necessary to be able to discern its nature. PMID- 18445163 TI - Evaluation of the diagnostic reliability of different RBC indices and formulas in the differentiation of the beta-thalassaemia minor from iron deficiency in Palestinian population. AB - Beta-thalassaemia minor and iron deficiency are the most common causes of microcytosis and/or hypochromasia. The present study evaluates the diagnostic reliability of different RBC indices and formulas, as well as our proposed formula, in the differentiation of the beta-thalassaemia minor from iron deficiency in Palestinian population. Complete blood count (CBC) parameters of 2196 certainly diagnosed (1272 beta-thalassaemia minor and 924 iron deficiency) samples were used to evaluate the following indices and formulas: Bessman index (RDW), Mentzer formula (MCV/RBC), England and Fraser formula (MCV - RBC - 5 x Hb- 3.4), Shine and Lal formula (MCV2 x MCH/100), Ehsani formula (MCV-10 x RBC), Srivastava formula (MCH/RBC), Green and King formula (MCV2 x RDW/Hb x 100), red distribution width index RDWI (RDW x MCV/RBC), RDW/RBC, as well as our formula (MCV-RBC -3 x Hb). For each index and formula, the receiver operative characteristic (ROC) curve was constructed to calculate the area under the curve (AUC), in addition, sensitivity, specificity, and likelihood ratios were calculated. No significant differences were reported between our formula, Green King formula and the RDWI (P > 0.05) in discriminating beta-thalassaemia minor from iron deficiency (AUC = 0.914, 0.909 and 0.907 respectively). However, the three indices and formula showed the highest efficiencies and they were significantly (P < 0.05) better than the others in the discrimination efficiency . It was concluded that our formula, Green-King formula and the RDWI provided the highest reliabilities in differentiating beta-thalassaemia minor from iron deficiency in Palestinian population while Bessman index was poor and ineffective for that purpose. PMID- 18445164 TI - An overview of study design. PMID- 18445166 TI - The BSAVA policy statement on vaccination strongly supports the science behind vaccination. PMID- 18445167 TI - Effect of growth conditions on poly-N-acetylglucosamine expression and biofilm formation in Escherichia coli. AB - Escherichia coli contains a four-gene operon, pgaABCD, which encodes the proteins necessary for the synthesis of polymeric N-acetylglucosamine, or PGA. Poly-N acetyl-glucosamine was first described in Staphylococcus aureus and Staphylococcus epidermidis and was found to have important roles in biofilm formation and immune evasion. PGA also plays a role in biofilm formation in E. coli, but its role in immune evasion has not been thoroughly studied. We previously reported that E. coli PGA cross-reacts with an opsonic-antibody raised against S. aureus PNAG and this is the basis for an ongoing investigation regarding the development of a vaccine against both pathogens. In this paper we investigated pga expression in wild type and csrA or nhaR deletion mutant strains during different growth phases and temperatures, and in response to chemical stimuli using a pga promoter-reporter fusion construct, real-time reverse transcriptase-PCR, immunoblotting, and biofilm assays. Expression of pga and polysaccharide synthesis were induced by glucose, NaCl, and ethanol, but only glucose augmented biofilm formation. The regulatory factor NhaR was required for NaCl-induced pga expression, whereas the effects of glucose and ethanol were independent of CsrA and NhaR. PMID- 18445169 TI - The high prevalence of unrecognized anaemia in patients with diabetes and chronic kidney disease: a population-based study. AB - BACKGROUND: Anaemia occurs early in the course of diabetes-related chronic kidney disease (CKD). There is little evidence about the prevalence of anaemia in people with diabetes. The aim of this study was to assess the prevalence of anaemia, by stage of CKD, in the general diabetic population. METHODS: Haemoglobin (Hb) was measured on all glycated haemoglobin (HbA1c) samples and the most recent (< 4 months) estimated glomerular filtration rate (eGFR) was obtained. Anaemia (at treatment level) was defined as Hb < 110 g/l or the use of erythropoetic stimulating agents (ESA). RESULTS: Twelve per cent (10-14%) of people had Hb < 110 g/l. The prevalence of anaemia increased progressively with worsening CKD. People with CKD stage 3 accounted for the largest number of people with anaemia; 18% (95% CI 13-24%) had Hb < 110 g/l. Those with eGFR < 60 ml/min/1.73 m2 and not on ESA or dialysis were four (2-7) times more likely than patients with better renal function to have Hb < 110 g/l. The relation between Hb and eGFR became approximately linear below an eGFR of 83 ml/min/1.73 m2, where, for every 1 ml/min/1.73 m2 fall in eGFR, there was a 0.4 (0.3-0.5) g/l fall in haemoglobin. CONCLUSIONS: This study demonstrates that anaemia, at levels where treatment is indicated, occurs commonly in people with diabetes and CKD stage 3 or worse. The screening for anaemia in current diabetes management should be extended. PMID- 18445168 TI - Offspring birth weight, gestational age and maternal characteristics in relation to glucose status at age 53 years: evidence from a national birth cohort. AB - AIMS: We investigated pathways linking offspring birth weight to maternal diabetes risk in later life by taking into account a range of prospective early life and adult maternal factors. METHODS: In a national birth cohort study, we examined the relationship between offspring birth weight and maternal glycated haemoglobin (HbA1c) at age 53 years in 581 mothers who had a first birth between age 19 and 25 years, and had data on potential confounders or mediators. RESULTS: Mean age at first birth was 21.5 years. After adjustment for maternal body mass index (BMI), mean percentage change in maternal HbA1c per kilogram increase in offspring birth weight was -1.8%[95% confidence interval (CI) -3.5, -0.1; P = 0.03]. This relationship was mostly accounted for by gestational age that was inversely related to maternal HbA1c (-0.9%; 95% CI -1.5, -0.4; P = 0.001). Other risk factors for high HbA1c were smoking and high BMI at 53 years. There was a significant interaction between offspring birth weight and maternal childhood social class (P = 0.01). Mothers from a manual background with higher birth weight offspring had lower HbA1c (BMI adjusted: -3.1%; 95% CI -5.0, -1.1); this was not observed for mothers from a non-manual background (BMI adjusted: 1.9%; 95% CI -1.3, 5.0). CONCLUSIONS: Short gestational age and low offspring birth weight may be part of a pathway linking impaired early maternal growth to diabetes risk in later life. A second possible pathway linking higher offspring birth weight to later maternal glucose status was also identified. These potential pathways require further investigation in cohorts with a wider maternal age range so that the early targeting of public health initiatives can be assessed. PMID- 18445170 TI - Upper abdominal symptoms in patients with Type 1 diabetes: unrelated to impairment in gastric emptying caused by autonomic neuropathy. AB - AIMS: Diabetic gastroparesis is a common condition occurring in some 30-50% of patients with long-term diabetes. Some studies have found a relationship between autonomic neuropathy and diabetic gastroparesis. In addition to autonomic neuropathy, acute changes in plasma glucose concentration can also affect gastric emptying. The objective was to examine the relationship between autonomic nerve function, glucose concentration, gastric emptying, and upper abdominal symptoms in Type 1 diabetic patients. METHODS: Gastric emptying of solids and liquids was measured with scintigraphy in 27 patients with longstanding Type 1 diabetes with upper abdominal symptoms. Autonomic nerve function was examined by standardized cardiovascular tests, and plasma glucose concentrations were measured during scintigraphy. Severity of abdominal symptoms and quality of life were explored by validated questionnaires. RESULTS: Seven patients (26%) had delayed gastric emptying of solids and three (11%) of liquids. Mean gastric half-emptying time of solids was 128 +/- 116 min and of liquids 42 +/- 30 min. Of the 26 patients undergoing tests, 16 (62%) had autonomic nerve dysfunction. Autonomic neuropathy score (1.6 +/- 1.7) correlated positively with the gastric emptying rate of solids (P = 0.006), a rate unrelated to symptom scores or plasma glucose concentrations during scintigraphy. Quality of life in patients with abdominal symptoms was lower than in the normal Finnish population. CONCLUSIONS: Impaired gastric emptying of solids in patients with Type 1 diabetes is related to autonomic neuropathy, but not to actual glycaemic control. The upper abdominal symptoms observed in these patients cannot be explained, however, by impaired gastric emptying. PMID- 18445171 TI - Road traffic accidents and diabetes: insulin use does not determine risk. AB - AIMS: Progressive restrictions placed on insulin-treated patients with diabetes exclude them from driving group 2 and class C1 and D1 vehicles. This reflects an assumption that an increased risk of hypoglycaemia in these patients will cause road traffic accidents. These restrictions have been implemented without any consistent evidence that this is the case. The aim of the study was therefore to investigate whether the rate of road traffic collisions in insulin-treated patients was higher than that of the non-diabetic population using a population register-based study. METHODS: A historical cohort study combined information from the Devon and Cornwall Constabulary database on road traffic collisions with the district wide retinal screening database, to provide an anonymized matched database of road traffic collisions in the diabetic population. Accident rates were calculated in the diabetic population and compared to rates in the non diabetic population using relative risks. RESULTS: The estimated overall annual accident rate for the non-diabetic population was 1469 per 100,000 vs. 856 per 100,000 for the diabetic population as a whole (Chi-squared, P < 0.001). On stratification of the groups by age, within the insulin-treated group there was no significant difference in the accident rate compared to the non-diabetic population, with relative risks between 0.51 [confidence interval (CI) 0.25-1.05] and 1.13 (CI 0.88-1.46). CONCLUSIONS: Our findings suggest that insulin-treated patients as a group do not pose an increased risk to road safety. They reiterate the need for an individualized risk-based assessment when considering driving restrictions. PMID- 18445172 TI - Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in Type 2 diabetes. AB - AIMS: To compare insulin and glucose profiles during basal continuous subcutaneous infusion of a rapid-acting insulin analogue and once daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes. METHODS: Twenty-one patients with Type 2 diabetes treated with oral glucose lowering agents were randomized in this two-period crossover study to an equivalent 24-h dose of continuous subcutaneous infusion of insulin aspart and subsequently once-daily bedtime subcutaneous injection of insulin glargine, or vice versa, for eight consecutive days. Plasma profiles of insulin and glucose were recorded. RESULTS: On the last day of each treatment period, the area under the curve (AUC) for glucose was 10% lower on the continuous subcutaneous infusion regimen compared with the insulin injection regimen (P = 0.002). This was accomplished by a flat exogenous insulin infusion profile compared with a peaking profile with injected insulin (AUC was 74% higher after injection compared with pre-injection levels (P = 0.001)). During the last 6 days in each treatment period, the intra-subject variability of exogenous fasting insulin levels in the mornings was 41% lower during insulin infusion compared with insulin injection (P = 0.012). The corresponding intra-subject variability for fasting glucose only showed a tendency to be lower during infusion as compared to the injection regimen (28%; P = 0.104). Thirteen symptomatic-only or minor hypoglycaemic episodes were recorded during the entire infusion period compared with three episodes during the injection period. CONCLUSIONS: Basal continuous subcutaneous infusion of a rapid-acting insulin analogue improved plasma insulin (more flat insulin profile with a lower variability) and glucose (lower AUC) profiles compared with once-daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes. PMID- 18445173 TI - Flexible, intensive insulin therapy and dietary freedom in adolescents and young adults with Type 1 diabetes: a prospective implementation study. AB - AIMS: To assess the outcome of a Diabetes Treatment and Teaching Programme (DTTP) on glycated haemoglobin (HbA1c), severe hypoglycaemia (SH) and severe ketoacidosis (SKA) in adolescents and young adults with Type 1 diabetes. METHODS: Quality-assurance project with assessment of participants 1 year after participation in a DTTP (5-day inpatient course, groups < or = 10 patients, fixed curriculum of education/training, introduction of dietary freedom). Before-after analyses of participants aged 12-15, 15-18, 18-21 and 21-24 years. Main outcome measures were HbA1c, SH and SKA. RESULTS: For the 1592 participants, aged 12 to 24 years, mean age at enrolment was 19 +/- 3 years, mean duration of diabetes was 7.3 +/- 5.4 (range 0.3-24) years, mean baseline HbA1c declined from 8.8 +/- 2.3% to 8.1 +/- 2.0%. The incidence of SH was 0.31 vs. 0.11 events/patient/year; the incidence of SKA 0.17 vs. 0.07 events/patient/year. In mixed effects models taking into account effects of centres, age and diabetes duration, the mean difference was -0.64%[P < 0.001, 95% confidence interval (CI) -0.79 to -0.5] for HbA1c, -0.2 events/patient/year (P < 0.0001, 95% CI -0.28 to -0.12) for SH and 0.1 events/patient/year (P < 0.0001, 95% CI -0.14 to -0.06) for SKA. CONCLUSIONS: Adolescents and young adults with Type 1 diabetes benefit from participation in a standard DTTP for flexible, intensive insulin therapy and dietary freedom. PMID- 18445174 TI - Impact of 3-year lifestyle intervention on postprandial glucose metabolism: the SLIM study. AB - OBJECTIVE: To determine the effect of a 3-year diet and exercise lifestyle intervention, based on general public health recommendations, on glucose tolerance, insulin resistance and metabolic cardiovascular risk factors in Dutch subjects with impaired glucose tolerance (IGT). METHODS: The study was a randomized controlled lifestyle intervention over 3 years. A total of 147 IGT subjects (75 male, 72 female) were randomized to the intervention (INT) group or control (CON) group; 106 subjects (52 INT, 54 CON) completed 3 years of intervention. Annually, glucose, insulin and free fatty acid (FFA) concentrations were determined fasting and after an oral glucose tolerance test. Measurements of body weight, serum lipids, blood pressure and maximal aerobic capacity were also performed. RESULTS: Analysis of those who completed the 3-year trial, showed that the lifestyle intervention improved body weight (INT -1.08 +/- 4.30 kg; CON +0.16 +/- 4.91 kg, P = 0.01), homeostatis model assessment index for insulin resistance and 2-h FFA. Two-hour glucose concentrations improved in the INT group, the difference being most pronounced after 1 year, with a return to baseline values after 3 years, from 8.59 +/- 1.55 to 8.55 +/- 0.34 mm; in contrast, 2-h glucose deteriorated in the CON group-from 8.46 +/- 1.84 to 9.35 +/- 2.50 mm (P = 0.02). In the INT group, diabetes incidence was reduced by 58% (P = 0.025). CONCLUSION: Our lifestyle intervention showed a sustained beneficial effect on 2-h glucose concentrations, insulin resistance and 2-h FFA, even after 3 years. Our lifestyle intervention is effective, but for implementation more information is needed about factors influencing adherence. PMID- 18445175 TI - An effective system of nurse-led diabetes care in rural Africa. AB - AIMS: Delivering adequate diabetes care is difficult in rural Africa because of drug and equipment shortages; as well as lack of trained medical expertise. We aimed to set up and evaluate a nurse-led protocol and education-based system in rural Kwazulu Natal in South Africa. METHODS: A treatment algorithm and education system adapted from previously validated methods was used; care was devolved to primary health clinics and was delivered by two nurses. Glycaemic control was assessed by glycated haemoglobin (HbA1c), assayed off site and not available for clinical use during the study. Results A total of 284 patients were enrolled, with 197 followed for 18 months (13 died and 26% lapsed during the period). HbA1c was 11.6 +/- 4.5% (sd) at baseline, 8.7 +/- 2.3% at 6 months and 7.7 +/- 2.0% at 18 months. There was a small associated increase in weight but no increase in hypoglycaemia. Subgroup analysis showed that education alone, without drug type or dose changes, also improved control (HbA1c 10.6 +/- 4.2% baseline and 7.6 +/- 2.3% at 18 months). The service was very popular with patients, families and other health workers. CONCLUSIONS: We conclude that a simple protocol and education-based diabetes care system can be successfully introduced and run by nurses in rural Africa. Medium-term glycaemic improvements are excellent and the service has been very well received. PMID- 18445176 TI - Service quality for Type 2 diabetes in Australia: the patient perspective. AB - AIMS: To assess the service quality of care as perceived by people with Type 2 diabetes mellitus. METHODS: A cross-sectional survey using a self-administered questionnaire was carried out among members of Diabetes Australia-Queensland with Type 2 diabetes. For 12 aspects of service quality derived from a literature review and focus group research, patients scored the relative importance of the aspects and their perception of quality of received care. A measure of service quality was derived by combining the relative importance and actual performance. RESULTS: A total of 603 people with Type 2 diabetes participated. Of the 12 aspects of care, communication, availability of support group, safety and prevention had the highest scores for importance; support group and basic amenities had the highest average performance values; but the highest service quality values were for support group, basic amenities, dignity and confidentiality. Younger participants had lower service quality scores (P = 0.001) and participants with good control of their diabetes had higher scores (P < 0.001). Compared with the reference population, our sample had 8.7% fewer people under 65 years old. CONCLUSIONS: From the perspective of people with Type 2 diabetes, there is a notable gap between their expectations and what they have actually received in most aspects of provided care. In addition, overall service quality and six aspects of service quality (choice of care provider, accessibility, prevention, continuity, timeliness and safety) were identified to be of inadequate quality. Hence, this study demonstrates a significant opportunity to improve quality of healthcare services. PMID- 18445177 TI - Pancreatic exocrine insufficiency is not common in HNF-1alpha MODY. AB - AIMS: Exocrine pancreatic insufficiency has been described in Type 1 and Type 2 diabetes. The hepatocyte nuclear factor (HNF)-1alpha gene associated with maturity-onset diabetes of the young (MODY3) is expressed in several organs, including the exocrine pancreas. The aim of this study was to determine the prevalence of exocrine pancreas dysfunction in HNF-1alpha MODY patients. METHODS: Thirty-one diabetic HNF-1alpha MODY patients (mean age 37.2 +/- 14.6 years) and 35 healthy control subjects (39.1 +/- 13.9 years) participated. In addition, 25 Type 1 diabetic (T1DM) subjects were also examined (mean age 30.6 +/- 10.1 years). Exocrine pancreas function was assessed by measurement of stool elastase 1 (E1) activity. All diabetic patients and control subjects completed a gastrointestinal (GI) symptoms questionnaire. RESULTS: In all but two individuals, stool E1 levels were normal (> 200 microg/g). The only case of severely impaired pancreas exocrine function (E1 = 47.5 microg/g) was observed in the MODY3 group. The mean stool E1 elastase level in the HNF-1alpha MODY group was significantly lower than in the control subjects (401.0 +/- 118.4 vs. 482.7 +/- 151.1 microg/g, P = 0.001). Similarly, E1 levels in T1DM were lower than in control subjects (344.8 +/- 132.1 microg/g, P = 0.001); one patient with a moderate enzyme decrease was identified in this group. In addition, more frequent GI complaints were reported by HNF-1alpha MODY patients when compared with control subjects and also with T1DM patients. CONCLUSION: Pancreatic exocrine insufficiency is not common in HNF-1alpha MODY diabetic patients, although their stool E1 levels are lower than in healthy control subjects. PMID- 18445178 TI - Comparison of effects of combined ACE inhibitor and low-dose thiazide diuretic with ACE inhibitor alone on insulin action in patients with hypertension and Type 2 diabetes: a double-blind crossover study. AB - AIMS: To establish the safety in terms of insulin sensitivity of a low dose thiazide/ACE inhibitor combination. METHODS: We examined the effects on insulin sensitivity of captopril either alone or in combination with low-dose bendroflumethiazide (1.25 mg) in 15 hypertensive Type 2 diabetic patients. Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomised, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendroflumethiazide (CB) (1.25 mg). RESULTS: Blood pressure was lower following CB compare to C (138/83 vs. 144/85 mmHg; P < 0.05) and both were lower than baseline (153/92 mmHg; P < 0.01). CB resulted in a significant increase in fasting plasma glucose compared to C (9.6 +/- 2.6 vs. 8.5 +/- 1.6 mmol/l; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (25.1 +/- 13.3 vs. 34.2 +/- 16.8 micromol/kg/min; P < 0.01) as were isotopically determined glucose utilisation rates (29.0 +/- 12.4 vs. 36.6 +/- 17.3 micromol/kg/min; P < 0.05). There was no significant difference in fasting endogenous glucose production between treatments (CB 9.3 +/- 3.3 vs. C 8.6 +/- 1.6 micromol/kg/min), nor between suppression following insulin (CB 4.0 +/- 2.1 vs. C 4.3 +/- 3.1 micromol/kg/min). CONCLUSIONS: Combination of low-dose bendroflumethiazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone. PMID- 18445179 TI - The relationship between clinic and ambulatory blood pressure measurement in patients with both Type 2 diabetes and hypertension. PMID- 18445180 TI - In Allergy, 'A new day has begun'. PMID- 18445181 TI - Finnish Allergy Programme 2008-2018--time to act and change the course. AB - BACKGROUND: The prevalence of allergic diseases has grown in Finland, similarly to many other western countries. Although the origin of allergy remains unresolved, increasing body of evidence indicates that the modern man living in urban built environment is deprived from environmental protective factors (e.g. soil microorganisms) that are fundamental for normal tolerance development. The current dogma of allergen avoidance has not proved effective in halting the 'epidemic', and it is the Finnish consensus that restoring and strengthening tolerance should more be in focus. AIM: The national 10-year programme is aimed to reduce burden of allergies. The main goals are to (i) prevent the development of allergic symptoms; (ii) increase tolerance against allergens; (iii) improve the diagnostics; (iv) decrease work-related allergies; (v) allocate resources to manage and prevent exacerbations of severe allergies and (vi) decrease costs caused by allergic diseases. METHODS: For each goal, specific tasks, tools and evaluation methods are defined. Nationwide implementation acts through the network of local co-ordinators (primary care physicians, nurses, pharmacists). In addition, three nongovernmental organizations (NGOs) take care of the programme implementation. The 21 central hospital districts carry out a three step educational process: (i) healthcare personnel; (ii) representatives and educators of NGOs and (iii) patients and the general population. For outcome evaluation, repeated surveys are performed and healthcare registers employed at the beginning, at 5 years, and at the end of the programme. The process will be evaluated by an independent external body. CONCLUSION: The Finnish initiative is a comprehensive plan to reduce burden of allergies. The aim is to increase immunological tolerance and change attitudes to support health instead of medicalizing common and mild allergy symptoms. It is time to act, when allergic individuals are becoming a majority of western populations and their numbers are in rapid increase worldwide. The Programme is associated with the Global Alliance of Chronic Respiratory Diseases (GARD), WHO. PMID- 18445182 TI - House dust mite control measures for asthma: systematic review. AB - The major allergen in house dust comes from mites. We performed a systematic review of the randomized trials that had assessed the effects of reducing exposure to house dust mite antigens in the homes of people with mite-sensitive asthma, and had compared active interventions with placebo or no treatment. Fifty four trials (3002 patients) were included. Thirty-six trials assessed physical methods (26 mattress covers), 10 chemical methods and eight a combination of chemical and physical methods. Despite the fact that many trials were of poor quality and would be expected to exaggerate the reported effect, we did not find an effect of the interventions. For the most frequently reported outcome, peak flow in the morning (1565 patients), the standardized mean difference was 0.00 (95% confidence interval (CI) -0.10 to 0.10). There were no statistically significant differences in number of patients improved (relative risk 1.01, 95% CI 0.80-1.27), asthma symptom scores (standardized mean difference -0.04, 95% CI 0.15 to 0.07) or in medication usage (standardized mean difference -0.06, 95% CI 0.18 to 0.07). Chemical and physical methods aimed at reducing exposure to house dust mite allergens cannot be recommended. PMID- 18445183 TI - ARIA-suggested drugs for allergic rhinitis: what impact on quality of life? A GA2LEN review. AB - Allergic diseases constitute a global health problem, as they have an increasing economic and social impact and, especially, they can deeply interfere with the patients' daily life, being a cause of physical and emotional discomfort. This is why the health-related quality-of-life (HRQoL) has become increasingly important in health care research; in fact, the assessment of the impact the disease and its treatment have on patients, provides a more comprehensive approach in outcome evaluation. Numerous validated questionnaires are available and many studies have been performed evaluating HRQoL in people affected by allergic rhinitis (AR), thus testifying a great interest in this topic. The aims of the present review are: to examine the scientific literature of the last 3 years dealing with the impact of AR treatments suggested by allergic rhinitis and its impact on asthma guidelines on patients' QoL, and to identify the unexplored or not-fully investigated areas concerning this issue. PMID- 18445185 TI - Mechanisms of asthma in Olympic athletes--practical implications. AB - Athletes' symptoms may only occur in extreme conditions, which are far from normal. Exercise may increase ventilation up to 200 l/min for short periods in speed and power athletes, and for longer periods in endurance athletes such as swimmers and cross-country skiers. Increasing proportions of young athletes are atopic, i.e. they show signs of IgE-mediated allergy which is, along with the sport event (endurance sport), a major risk factor for asthma and respiratory symptoms. Mechanisms in the etiology and clinical phenotypes vary between disciplines and individuals, and it may be an oversimplification to discuss athlete's asthma as a distinct and unambiguous disease. Nevertheless, the experience on Finnish Olympic athletes suggests at least two different clinical phenotypes, which may reflect different underlying mechanisms. The pattern of 'classical asthma' is characterized by early onset childhood asthma, methacholine responsiveness, atopy and signs of eosinophilic airway inflammation, reflected by increased exhaled nitric oxide levels. Another distinct phenotype includes late onset symptoms (during sports career), bronchial responsiveness to eucapnic hyperventilation test, but not necessarily to inhaled methacholine, and a variable association with atopic markers and nitric oxide. A mixed type of eosinophilic and neutrophilic airway inflammation seems to affect especially swimmers, ice-hockey players, and cross-country skiers. The inflammation may represent a multifactorial trauma, in which both allergic and irritant mechanisms play a role. There is a significant problem of both under- and overdiagnosing asthma in athletes and the need for objective testing is emphasized. Follow-up studies are needed to assess the temporal relationship between asthma and competitive sporting, taking better into account individual disposition, environmental factors (exposure), intensity of training and potential confounders. PMID- 18445184 TI - An evaluation of the cost-effectiveness of omalizumab for the treatment of severe allergic asthma. AB - Omalizumab is the first licensed anti-immunoglobulin (Ig) E antibody shown to be effective for treatment of allergic (IgE-mediated) asthma. Recent international guidelines recommend omalizumab as add-on treatment to fixed dose inhaled corticosteroid (ICS) and long-acting beta(2)-agonist (LABA) combination therapy. However, omalizumab is more expensive than other current asthma treatments and health and reimbursement authorities are increasingly demanding evidence of economic benefit to support pricing and formulary listing. The aims of this article are to (i) summarize data on the human and economic burden of severe asthma, (ii) summarize the efficacy data obtained for omalizumab in clinical trials in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA, and (iii) discuss the cost-effectiveness evidence published for omalizumab in this patient population. A wealth of evidence exists highlighting that the health, economic and societal burden of asthma is considerable and is highly skewed towards patients with severe asthma, particularly when asthma is inadequately controlled. Omalizumab is clinically beneficial in patients with severe persistent allergic asthma despite high-dose ICS plus a LABA, particularly in a subgroup of patients who respond to therapy. In patients who respond to therapy, the cost-effectiveness of omalizumab compares well with other biologic treatments for chronic illness. PMID- 18445186 TI - Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy? AB - BACKGROUND: Sublingual immunotherapy (SLIT) represents an alternative to subcutaneous immunotherapy. While antigen-presenting cells such as Langerhans cells (LCs) are thought to contribute to the effectiveness of SLIT, mast cells (MCs) most likely account for adverse reactions such as sublingual edema. As little is known about LCs and MCs within the oral cavity, we investigated their distribution in search for mucosal sites with highest LCs and lowest MCs density. METHODS: Biopsies were taken simultaneously from human vestibulum, bucca, palatum, lingua, sublingua, gingiva, and skin. Immunohistochemistry and flow cytometry were used to detect MCs, LCs and high affinity receptor for IgE (FcepsilonRI) expression of LCs. Mixed lymphocyte reactions were performed to assess their stimulatory capacity. RESULTS: Highest density of MCs was detected within the gingiva, while the lowest density of MCs was found within the palatum and lingua. However, sublingual MCs were located within glands, which might explain swelling of sublingual caruncle in some SLIT patients. Highest density of LCs was detected within the vestibular region with lowest density in sublingual region. Highest expression of FcepsilonRI was detected on LCs within the vestibulum. Furthermore LCs from different regions displayed similar stimulatory capacity towards allogeneic T cells. CONCLUSIONS: In view of our data, different mucosal regions such as the vestibulum might represent alternative SLIT application sites with potent allergen uptake. Our data might serve as a basis for new application strategies for SLIT to enhance efficiency and reduce local adverse reactions. PMID- 18445187 TI - Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism. AB - BACKGROUND: Atopic dermatitis (AD) is often complicated by an enhanced susceptibility to bacterial skin infections, especially with Staphylococcus aureus. Toll-like receptors (TLR), especially TLR-2 recognizes cell wall components of S. aureus, e.g. lipoteichoic acid (LTA) and peptidoglycan (PGN). A heterozygous TLR-2 R753Q polymorphism occurs in a frequency of 11.5% in adult AD patients and has been shown to be associated with a severe phenotype of AD. METHODS: The aim of this study was to investigate the impact of TLR-2 agonists (LTA, PGN and Pam3Cys) on cytokine production in human monocytes from AD patients with the TLR-2 R753Q polymorphism compared with that of AD patients with 'wild type' TLR-2 and control individuals to elucidate the functional role of the TLR-2 R753Q polymorphism. RESULTS: Monocytes from AD patients with the TLR-2 R753Q mutation produced significantly more IL-6 and IL-12 compared with that of AD patients with nonmutated TLR-2 upon stimulation with TLR-2 agonists. CONCLUSION: We show for the first time functional differences in TLR-2 responsiveness of monocytes from AD patients with the TLR-2 R753Q mutation compared with wild type AD patients in a ligand-dependent manner. CLINICAL IMPLICATION: Our data support the emerging concept that AD patients have a dysbalance in innate and acquired immunity. TLR-2 may be essential in the pathogenesis and maintenance of AD and may be involved in the enhanced susceptibility to skin infections with S. aureus and in a higher inflammatory response in patients with AD carrying the TLR-2 polymorphism. PMID- 18445188 TI - Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. AB - BACKGROUND: Long-term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent relapses. This 12-month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE). METHODS: During the initial open-label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of < or =2 was achieved, the patient entered the disease control period (DCP) and was randomized to either proactive tacrolimus (n = 116) or vehicle ointment (n = 108) twice weekly for 12 months. Exacerbations were treated with 0.1% tacrolimus ointment b.i.d. until an IGA < or =2 was regained, then randomized treatment was restarted. The primary endpoint was the number of DEs during the DCP that required a substantial therapeutic intervention. RESULTS: Proactive tacrolimus 0.1% ointment application significantly reduced the number of DEs requiring substantial therapeutic intervention (median difference 2; P < 0.001; Wilcoxon rank sum test), the percentage of DE treatment days (median difference: 15.2%; P < 0.001; Wilcoxon rank sum test) and increased the time to first DE (median 142 vs 15 days; P < 0.001; stratified log-rank test). The adverse event profile was similar for the two treatment approaches. CONCLUSION: A 12-month, twice weekly proactive tacrolimus ointment application was an effective treatment in most study patients which prevented, delayed and reduced the occurrence of AD exacerbations. PMID- 18445189 TI - Treatment of skin swellings with C1-inhibitor concentrate in patients with hereditary angio-oedema. AB - BACKGROUND: Skin swellings are the most frequent symptoms in hereditary angio oedema (HAE) arising out of C1-inhibitor (C1-INH) deficiency. They may be painful and impact daily activities of patients. Detailed clinical data concerning the treatment of skin swellings by C1-INH concentrate have not been reported yet. METHODS: From 1976 through 2007, a total of 2104 skin-swelling attacks in 47 patients with HAE were treated with the C1-INH concentrate. Time to relief and duration of the swellings were documented during personal interviews using standardized questionnaires. The results were compared with 9046 untreated skin swellings in the same patients. RESULTS: The first clinical sign of efficacy was a slowdown of progress of symptoms accompanied by a decreased feeling of tension and pain in the swollen area. The mean time to the first relief of symptoms was 1.1 +/- 1.4 h in treated skin swellings and 50.4 +/- 33 h in untreated skin swellings. Improvement of facial skin swellings took longer than swellings of the extremities, genitals or trunk. The duration of treated skin swellings was 1.7 day in treated and 3.2 day in untreated ones. In treated swellings, there was long-lasting control and no rebound within the 48 h following the drug administration and no laryngeal oedema following facial oedema were observed. No severe side-effects occurred. CONCLUSIONS: The C1-INH concentrate has proven to be highly effective and safe for treating skin swellings in patients with HAE arising out of C1-INH deficiency. PMID- 18445190 TI - Characterization of Der p 21, a new important allergen derived from the gut of house dust mites. AB - BACKGROUND: The house dust mite (HDM) Dermatophagoides pteronyssinus is a major allergen source eliciting allergic asthma. The aim of the study was to identify new important HDM allergens associated with allergic asthma. METHODS: A cDNA coding for a new mite allergen, designated Der p 21, was isolated using immunoglobulin E (IgE) antibodies from patients with allergic asthma out of a D. pteronyssinus expression cDNA library and expressed in Escherichia coli. RESULTS: Circular dichroism analysis of the purified allergen showed that rDer p 21 (14 726 Da) is one of the few mite allergens with an alpha-helical secondary structure. The protein exhibited high thermal stability and refolding capacity, and, as determined by small angle X-ray scattering, formed a dimer consisting of two flat triangles. rDer p 21 bound high levels of patients' IgE antibodies and showed high allergenic activity in basophil activation experiments. Rabbit anti Der p 21 IgG antibodies inhibited mite-allergic patients' IgE binding and allowed the ultrastructural localization of the allergen in the midgut (epithelium, lumen and faeces) of D. pteronyssinus by immunogold electron microscopy. Der p 21 revealed sequence homology with group 5 mite allergens, but IgE and IgG reactivity data and cross-inhibition studies identified it as a new mite allergen. CONCLUSIONS: Der p 21 is a new important mite allergen which is liberated into the environment via faecal particles and hence may be associated with allergic asthma. PMID- 18445191 TI - Identification of a serine protease as a major allergen (Per a 10) of Periplaneta americana. AB - BACKGROUND: Cockroach allergens are associated with the development of asthma, but none of these has been characterized for proteolytic activity. This study was undertaken to isolate and characterize a protease from Periplaneta americana and determine its allergenicity. METHODS: A serine protease was isolated from P. americana extract using benzamidine sepharose column and characterized by immunobiochemical methods. Allergenicity of the protease was assessed by enzyme linked immunosorbent assay, immunoblot, intradermal testing, histamine release and peripheral blood mononuclear cells (PBMCs) proliferation. RESULTS: Affinity purified protein of approximately 28 kDa (Per a 10) showed a single band of activity in gelatin zymogram and agarose plate assay. N-terminal sequence (IVGGRPAQI) revealed similarity with mite serine protease allergens and insect trypsins. It demonstrated proteolytic activity with azocollagen > gelatin > defatted-milk > casein including serine protease specific substrate, N-benzoyl arginine-ethyl-ester-hydrochloride. It was inhibited by serine protease inhibitors, namely aprotinin > pefabloc > AEBSF > PMSF > benzamidine > antipain > leupeptin and trypsin-specific inhibitor (tosyl-lysyl-chloromethyl-ketone) suggesting it to be a trypsin-like serine protease. Per a 10 was recognized as a major allergen, showing IgE reactivity with >80% of cockroach sensitized patients by skin tests and immunoblot. It could induce significant histamine release (P < 0.05) in blood and secretion of interleukin-4 (IL-4) (P < 0.05) and IL-5 (P < 0.05) in culture supernatant of PBMCs from cockroach hypersensitive patients, suggesting a strong allergenic potency. CONCLUSION: A serine protease isolated from P. americana was demonstrated to be a major allergen (Per a 10). It has a potential for component-based diagnosis of allergy and will be useful in elucidating the mechanism of allergy. PMID- 18445192 TI - How to assess disease activity in patients with chronic urticaria? AB - BACKGROUND: The current EAACI/GA(2)LEN/EDF guidelines recommend assessing disease activity in chronic urticaria (CU) by using an established and well-defined symptom score, i.e. the urticaria activity score (UAS), which combines daily wheal numbers and pruritus intensity. However, this UAS has never been formally tested for its suitability in assessing CU activity. AIM: To determine the UAS correlation with quality of life (QoL) in CU patients and to compare the UAS to other symptom scores. METHODS: Chronic urticaria symptoms (wheals, erythema, angioedema, pruritus) were assessed on seven consecutive days in 111 CU patients for their numbers, duration, size, and/or intensity. Quality of life was assessed by using the Dermatology Life Quality Index. Both, urticaria activity and QoL were determined before and after a 3-week period, in which the patients followed a pseudoallergen-low diet. RESULTS: Urticaria activity score values correlated positively, albeit weakly, with QoL impairment in CU patients (r(2) = 0.31, P < 0.05). Also, changes in QoL following a pseudoallergen-low diet were reflected by the changes observed in the UAS (r(2) = 0.30, P < 0.05). No significant differences were found comparing the QoL correlation of the UAS and other symptom scores combining up to four CU symptom qualities. Quality of life correlation with UAS values increased with the number of days the UAS was assessed and plateaued starting from the fourth consecutive day. CONCLUSIONS: Our findings back the current guideline recommendations to use the UAS for monitoring disease activity in CU patients. Urticaria activity score mean values of at least four consecutive days should be used. PMID- 18445193 TI - Do we have to recommend not using oat-containing emollients in children with atopic dermatitis? PMID- 18445194 TI - Response to Campbell, Spackman, Sullivan letter to Allergy. PMID- 18445195 TI - Anaphylactic shock after intradermal testing with betalactam antibiotics. PMID- 18445196 TI - DRESS syndrome induced by sodium meglumine ioxitalamate. PMID- 18445197 TI - Delayed hypersensitivity to acylureidopenicillins: a case report. PMID- 18445198 TI - Localized cold-induced urticaria associated with specific immunotherapy for tree pollen allergy. PMID- 18445199 TI - Omalizumab in persistent severe bakers' asthma. PMID- 18445200 TI - Perioperative thromboprophylaxis in children: development of a guideline for management. AB - BACKGROUND: Venous thromboembolic (VTE) events can occur in children at the time of surgery where a patient has associated prothrombotic risk factors. There is currently little advice available to anesthetists on how to assess the risks and provide prophylaxis. AIM/OBJECTIVE: To increase awareness of thrombosis in the perioperative pediatric patient, and to give some guidance when considering prophylaxis in this group. METHOD/RESULTS: A guideline outlining risk factors for venous thromboembolism in patients presenting for surgery was written as a flowchart. Recommendations for low risk patients was early mobilization and good hydration; for moderate risk patients having major general surgery to include physical prophylaxis where size permits, i.e. elastic stockings and compression devices; for high-risk patients undergoing major orthopaedic or general surgery to also receive prophylactic low molecular weight heparin enoxaparin 0.5 mg x kg( 1) b.d. CONCLUSION: Children with multiple risk factors for VTE should be considered for prophylactic measures when presenting for prolonged major surgery. PMID- 18445201 TI - Paraplegia after thoracotomy under combined general and epidural anesthesia in a child. AB - A 9-year-old boy underwent a thoracotomy for excision of his right third rib under combined general and epidural anesthesia for a Ewings sarcoma. Postoperatively, he was found to have a complete T2-3 paraplegia. Permanent paraplegia was described as a rare complication of thoracotomy in adults, and very rarely after epidural analgesia in adults and babies. This was the first report in a child. PMID- 18445202 TI - Society for Pediatric Sedation reply to Dr Cote's editorial. PMID- 18445205 TI - Anesthetic management of children with pulmonary arterial hypertension. PMID- 18445206 TI - Cost of dexmedetomidine in MRI. PMID- 18445208 TI - Postoperative upper extremity hemiplegia in a toddler following general anesthesia for drainage of a subgaleal fluid collection. PMID- 18445209 TI - Effect of pediatric simulation training on candidate's confidence. PMID- 18445210 TI - Anesthetic considerations in the child with Costello syndrome: risks of cardiac arrest upon induction of anesthesia. PMID- 18445211 TI - Displacement of helex atrial septal occluder: a rare complication of percutaneous occlusion of atrial septal defect. PMID- 18445212 TI - Airway complication related to an electromyography tracheal tube. PMID- 18445213 TI - Undiagnosed tracheal stenosis in a patient with Down's syndrome. PMID- 18445214 TI - Medial orbitofrontal cortex codes relative rather than absolute value of financial rewards in humans. AB - Functional imaging studies in recent years have confirmed the involvement of orbitofrontal cortex (OFC) in human reward processing and have suggested that OFC responses are context-dependent. A seminal electrophysiological experiment in primates taught animals to associate abstract visual stimuli with differently valuable food rewards. Subsequently, pairs of these learned abstract stimuli were presented and firing of OFC neurons to the medium-value stimulus was measured. OFC firing was shown to depend on the relative value context. In this study, we developed a human analogue of this paradigm and scanned subjects using functional magnetic resonance imaging. The analysis compared neuronal responses to two superficially identical events, which differed only in terms of the preceding context. Medial OFC response to the same perceptual stimulus was greater when the stimulus predicted the more valuable of two rewards than when it predicted the less valuable. Additional responses were observed in other components of reward circuitry, the amygdala and ventral striatum. The central finding is consistent with the primate results and suggests that OFC neurons code relative rather than absolute reward value. Amygdala and striatal involvement in coding reward value is also consistent with recent functional imaging data. By using a simpler and less confounded paradigm than many functional imaging studies, we are able to demonstrate that relative financial reward value per se is coded in distinct subregions of an extended reward and decision-making network. PMID- 18445215 TI - A local signature of LTP- and LTD-like plasticity in human NREM sleep. AB - Paired associative stimulation (PAS) repeatedly pairs electrical nerve stimulation with transcranial magnetic stimulation of the contralateral motor hand area (M1(HAND)). Depending on the interstimulus interval, PAS can induce a long-term potentiation (LTP)-like facilitation or long-term depression (LTD)-like suppression of cortical excitability. In three experimental sessions, 12 awake men received PAS of the right median nerve and left M1(HAND) in the evening before sleep. To optimize the timing of paired stimulation in M1(HAND), the interstimulus interval of PAS was adjusted to the individual N20-latency of the somatosensory evoked potential to induce LTP-like effects (PAS(N20+2ms)), LTD like effects (PAS(N20-5ms)), or no timing-dependent after-effects (PAS(control)). Motor-evoked potentials (MEPs) showed high interindividual variations in the conditioning effects of PAS(N20+2ms) and PAS(N20-5ms) on cortical excitability. However, PAS(control) allowed us to adjust for any unspecific stimulation effects and the MEP increase after PAS(N20+2ms) differed significantly from the MEP decrease after PAS(N20-5ms). PAS(N20+2ms) and PAS(N20-5ms) also had a differential effect on regional expression of slow waves and slow spindle activity during the first hour of subsequent non-rapid eye movement (NREM) sleep. At the electrode sites overlying the conditioned M1(HAND) and the adjacent premotor cortex, local expression of slow spindle activity was significantly correlated with interindividual differences in the efficacy of PAS(N20+2ms) and PAS(N20-5ms) to potentiate or suppress cortical excitability. This correlation indicates that PAS shapes the local regulation of slow sleep spindles during subsequent NREM sleep. PMID- 18445216 TI - Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor. AB - In the present study, we established and characterized an animal model of vulnerability to repeated stress. We found that control Sprague-Dawley (SD) rats showed a gradual decrease in the HPA axis response following 14 days of repeated restraint stress, whereas Fischer 344 (F344) rats did not show such HPA axis habituation. Similar habituation was observed in the expression of c-fos mRNA, corticotropin-releasing hormone hnRNA, and phospho-CREB and phospho-ERK proteins in the hypothalamic paraventricular nucleus (PVN) of SD rats, but not in the F344 rats. In addition, repeatedly restrained F344 rats exhibited decreased cell proliferation in the dentate gyrus of the hippocampus and increased anxiety related behaviours, while repeatedly restrained SD rats exhibited a selective enhancement of hippocampal cell proliferation in the ventral area. Moreover, we found a lower expression of glucocorticoid receptor (GR) protein, but not mRNA, in the PVN of F344 rats compared to SD rats. We also identified that microRNA (miR)-18a inhibited translation of GR mRNA in cultured neuronal cells and that increased expression of miR-18a in the PVN was observed in F344 rats compared with SD rats. These strain differences in GR protein levels were not found in the hippocampus and prefrontal cortex, and the expression of miR-18a was much lower in these brain regions than in the PVN. Our results suggest that F344 rats could be a useful animal model for studying vulnerability to repeated stress, and that miR-18a-mediated down-regulation of GR translation may be an important factor to be considered in susceptibility to stress-related disorders. PMID- 18445217 TI - Emergence of spatial impairment in rats following specific cholinergic depletion of the medial septum combined with chronic stress. AB - A consistent finding in patients suffering from Alzheimer's disease is a loss of the cholinergic neurons of the basal forebrain that project to the hippocampus. However, the role this depletion plays in the development of Alzheimer's disease remains unclear. The loss of this ascending neurotransmitter system could potentially render hippocampal neurons more susceptible to further insult, such as chronic stress, ultimately resulting in neuronal death and memory loss. We explored this possibility by using the highly specific toxin 192 IgG-Saporin to destroy the majority of cholinergic activity in the septo-hippocampal pathway in rats. Following depletion, rats were subjected to 2 weeks of restraint stress. Rats were divided into two groups and were tested either on a hippocampal dependent (water maze) task or a hippocampal-independent task (fear conditioning to tone and context). We showed that cholinergic depletion or stress alone had no effect on the successful performance of either of the tasks. However, rats with a combination of cholinergic depletion and stress were significantly impaired on the water-maze task. No deficits were apparent in the combined group that was tested on fear conditioning to tone or context, suggesting that this impairment is specific to spatial working memory. These rats had no obvious hippocampal neuronal loss or damage; however, there were likely subtle changes in hippocampal processing that led to the observed deficit on the hippocampal-dependent task. These findings support our theory that cholinergic depletion of the medial septum increases hippocampal vulnerability to further insults such as stress. PMID- 18445219 TI - A primitive social circuit: vasotocin-substance P interactions modulate social behavior through a peripheral feedback mechanism in goldfish. AB - At its core, the polyvagal theory proposes that peptides affect simple social behaviors through influences on hindbrain autonomic processes. To test this mechanism, we compared the effects of fore- and hindbrain infusions of vasotocin (VT) on social approach behavior in goldfish. VT infusions into the 4th ventricle, which ink infusions verified did not move rostrally to the forebrain, inhibited social approach at a lower dose than did infusions into the 3rd ventricle, which did diffuse to the hindbrain. Thus, VT actions in the hindbrain appear to modulate this simple social behavior. We then identified a population of substance P (SP)-immunoreactive cells in the hindbrain that are encapsulated by putative VT terminals, and determined that those cells project to the periphery. Injecting SP peripherally, as with infusing VT centrally, inhibited social approach, and peripheral injections of an SP antagonist, but not central infusions, abolished the behavioral effects of central VT infusions. We therefore propose that VT inhibits social approach by activating SP cells in the hindbrain, which then induce changes in body state that feed back to the brain. Central VT infusions did not inhibit feeding, suggesting that this VT mechanism selectively affects appetitive social responses. Because VT projections to the hindbrain are highly conserved in vertebrates, influences on peripheral feedback processes like the one we have described in goldfish may reflect how VT affected simple social behaviors in ancestral vertebrates and thus preadapted members of this peptide family to play increasingly complex roles in social and emotional regulation in modern animals. PMID- 18445218 TI - Long-lasting alteration in mesocorticolimbic structures after repeated social defeat stress in rats: time course of mu-opioid receptor mRNA and FosB/DeltaFosB immunoreactivity. AB - Social defeat stress is a salient stressor that induces neuroadaptive changes in the mesocorticolimbic dopaminergic system. Substantial evidence indicates that mu opioid receptors (MORs) modulate dopamine transmission in the ventral tegmental area (VTA). FosB/DeltaFosB protein accumulation in dopaminergic projections during repeated treatments is thought to be involved in long-term neuroplasticity. In this study we characterize the magnitude and time-course of MOR mRNA expression and FosB/DeltaFosB immunoreactivity in mesocorticolimbic regions following repeated social defeat stress. Effects of brief repeated social defeat stress or control handling procedures were studied in rats either 2 h after the last exposure, or 3, 7, 14, 21 and 28 days later. We found that MOR mRNA expression in the VTA doubled after the last stress compared with handling, and remained 30-70% higher until day 21. The number of FosB/DeltaFosB-labeled neurons in regions of the frontal cortex, nucleus accumbens (NAc) shell and core, and in the medial, central and basolateral amygdala increased significantly immediately after the last stress episode, and remained enhanced for 21 days. Another group of rats received bilateral intra-VTA infusion of the MOR agonist, DAMGO, 7 days after the last stress. Prior social defeat stress augmented DAMGO induced Fos expression in the NAc shell, suggesting that Fos expression in this region might be the direct result of MOR activity in the VTA. Social defeat stress leads to an increased capacity for MOR activation in the VTA, which may be relevant to enduring FosB/DeltaFosB expression in mesocorticolimbic areas and to the behaviorally sensitized response to psychostimulant drugs. PMID- 18445220 TI - Motor learning affects visual movement perception. AB - In the present study we investigated whether imitation of artificial movement trajectories of meaningless objects has an effect on how these trajectories are later perceptually processed within the human brain. During observation of a sequence of artificial object movements 10 participants (experimental group) actively imitated the trajectories during motor training and 10 participants (control group) solved a working memory task without motor training. The haemodynamic responses were recorded before and after the intervention while participants observed the movements and either had to detect colour changes of one of the objects (colour task, motor-irrelevant) or had to judge whether the movement pattern could be imitated with the hands (simulation judgement task, motor-relevant). The between-group comparison of the post-intervention haemodynamic responses revealed stronger activity for the motor training than for the control group during the simulation judgement task. This activity appeared in motor-related areas (supplementary motor area and inferior parietal lobe) and in the occipito-temporal area. During the colour task, the motor training group showed stronger activity in the occipital lobe. The control group did not reveal any stronger activity than the motor training group for either task. The results suggest that motor training has task-specific effects on neural processes that are involved in perception of movements. Furthermore, they indicate that motor related areas are triggered by observed artificial object movements, but only if a motor-relevant task is pursued. PMID- 18445221 TI - Changes in effective connectivity of human superior parietal lobule under multisensory and unisensory stimulation. AB - Previous event-related potential (ERP) studies have identified the superior parietal lobule (SPL) as actively multisensory. This study compares effective, or contextually active, connections to this region under unisensory and multisensory conditions. Effective connectivity, the influence of one brain region over another, during unisensory visual, unisensory auditory and multisensory audiovisual stimulation was investigated. ERPs were recorded from subdural electrodes placed over the parietal lobe of three patients while they conducted a rapid reaction-time task. A generative model of interacting neuronal ensembles for ERPs was inverted in a scheme allowing investigation of the connections from and to the SPL, a multisensory processing area. Important features of the ensemble model include inhibitory and excitatory feedback connections to pyramidal cells and extrinsic input to the stellate cell pool, with extrinsic forward and backward connections delineated by laminar connection differences between ensembles. The framework embeds the SPL in a plausible connection of distinct neuronal ensembles mirroring the integrated brain regions involved in the response task. Bayesian model comparison was used to test competing feed forward and feed-backward models of how the electrophysiological data were generated. Comparisons were performed between multisensory and unisensory data. Findings from three patients show differences in summed unisensory and multisensory ERPs that can be accounted for by a mediation of both forward and backward connections to the SPL. In particular, a negative gain in all forward and backward connections to the SPL from other regions was observed during the period of multisensory integration, while a positive gain was observed for forward projections that arise from the SPL. PMID- 18445222 TI - Intratelencephalic corticostriatal neurons equally excite striatonigral and striatopallidal neurons and their discharge activity is selectively reduced in experimental parkinsonism. AB - Striatonigral and striatopallidal neurons form distinct populations of striatal projection neurons. Their discharge activity is imbalanced after dopaminergic degeneration in Parkinson's disease. Striatal projection neurons receive massive cortical excitatory inputs from bilateral intratelencephalic (IT) neurons projecting to both the ipsilateral and contralateral striatum and from collateral axons of ipsilateral neurons that send their main axon through the pyramidal tract (PT). Previous anatomical studies in rats suggested that IT and PT inputs preferentially excite striatonigral and striatopallidal neurons, respectively. Here we used electrophysiological criteria to identify them with antidromic stimulations. We show that the spontaneous discharge activity of IT neurons is depressed, whereas that of PT neurons is not affected in the rat cortex ipsilateral to 6-hydroxydopamine injection. However, our functional experiments do not support the hypothesis of a differential cortical input to striatal pathways. Firstly, although the conduction velocity of PT neurons is 4.6 times faster than that of IT neurons, identified striatopallidal and striatonigral neurons exhibit identical latencies of their spike responses to electrical stimulation of the ipsilateral cortex. Secondly, although PT neurons are ipsilateral, both striatal populations exhibit similar sensitivity to the stimulation of the ipsilateral and contralateral cortex. We suggest that IT neurons provide the main excitatory input to both striatal populations and that the corticostriatal PT input is weaker. Therefore, our functional data do not support our previous hypothesis that the deficit of IT neurons associated with the dopaminergic depletion might contribute to the striatal imbalance. This imbalance might rather result from intrinsic striatal mechanisms. PMID- 18445223 TI - Functional similarities between the P1 component and alpha oscillations. AB - The present study attempts to demonstrate functional similarities between the P1 component of event-related potentials and alpha oscillations that are predicted by the 'alpha inhibition-timing' hypothesis. On the basis of findings showing that the frequency characteristic of the P1 component lies in the alpha range and that alpha oscillation is functionally associated with inhibition, we predict that the P1 component also reflects inhibitory processes. This hypothesis is tested in two experiments, a spatial-cuing task and a visual-semantic categorization task. The results of the cuing task demonstrate that in a similar way as alpha power, the P1 component is larger over task-irrelevant ipsilateral sites. For the categorization task, we found that the P1 component, in a similar way to alpha oscillations, is larger for task-irrelevant, distorted pictures. We conclude that the P1 component may be generated at least in part by evoked alpha oscillations and reflects inhibition in the sense of suppressing task-irrelevant processes. PMID- 18445224 TI - Disentangling neural structures for processing of high- and low-speed visual motion. AB - Human psychophysical and electrophysiological evidence suggests at least two separate visual motion pathways, one tuned to a lower and one tuned to a broader and partly overlapping range of higher speeds. It remains unclear whether these two different channels are represented by different cortical areas or by sub populations within a single area. We recorded evoked potentials at 59 scalp locations to the onset of a slow (3.5 degrees /s) and fast (32 degrees /s) moving test pattern, preceded by either a slow or fast adapting pattern that moved in either the same direction or opposite to the test motion. Baseline potentials were recorded for slow and fast moving test patterns after adaptation to a static pattern. Comparison of adapted responses with baseline responses revealed that the N2 peak around 180 ms after test stimulus onset was modulated by the preceding adaptation. This modulation depended on both direction and speed. Source localization of baseline potentials as well as direction-independent motion adaptation revealed cortical areas activated by fast motion to be more dorsal, medial and posterior compared with neural structures underlying slow motion processing. For both speeds, the direction-dependent component of this adaptation modulation occurred in the same area, located significantly more dorsally compared with neural structures that were adapted in a direction independent manner. These results demonstrate for the first time the cortical separation of more ventral areas selectively activated by visual motion at low speeds (and not high speeds) and dorsal motion-sensitive cortical areas that are activated by both high and low speeds. PMID- 18445225 TI - Cortex- and striatum- derived neural stem cells produce distinct progeny in the olfactory bulb and striatum. AB - Neural stem cells can be isolated from the mouse embryonic cortex but do not persist in the adult cortex. In contrast, neural stem cells from the striatal embryonic germinal zone persist in the adult subependyma. Emx1-lineage analysis revealed that cortex-derived neural stem cells survive and migrate ventrally into the subependyma where they intermix with the host striatal neural stem cells [S. Willaime-Morawek et al. (2006)J. Cell Biol. 175, 159-168]. Cortex-derived cells proliferate faster in the subependyma and reach the olfactory bulb earlier than striatum-derived cells. In the olfactory bulb, cortex-derived cells produce more cells and more dopaminergic neurons in the glomerular layer than striatum-derived cells. Cortex-derived cells also give rise to more astrocytes and less neurons in the striatum than striatum-derived cells. Thus, history matters; cortex-derived neural stem cells in the subependyma give rise to progeny in the olfactory bulb and striatum but in different proportions than striatum-derived neural stem cells. PMID- 18445226 TI - 13-cis-retinoic acid alters the cellular morphology of slice-cultured serotonergic neurons in the rat. AB - Retinoids influence cellular processes such as differentiation, proliferation and apoptosis via retinoic acid receptor (RAR) and retinoid X receptor (RXR), and have therapeutic applications in several cancers and dermatologic diseases. Recent reports indicate that depression occasionally occurs in patients using the acne drug Accutane, the active component of which is 13-cis-retinoic acid (13-cis RA). Although impairment of serotonin (5-HT)-expressing neurons, including morphologic changes, is thought to be associated with depressive symptoms, the effects of 13-cis-RA on 5-HT neurons have not been examined. The present study demonstrated that 13-cis-RA alters the morphology of 5-HT neurons in cultured rat midbrain slices. The 13-cis-RA-induced changes were partially blocked by RXR and RAR antagonists. Furthermore, cotreatment with RAR and RXR agonists altered the morphology of 5-HT neurons to a greater extent than the individual application of each agonist. The morphologic changes were completely blocked by RXR antagonist, whereas RAR antagonist partially blocked the effects. These results suggest that 13-cis-RA exerts its action on slice-cultured 5-HT neurons, at least in part, through specific retinoid receptors. Moreover, RXR has a greater influence on the morphology of 5-HT neurons than RAR. The receptor-mediated actions of 13-cis-RA presented here may provide a clue for further research on depression associated with the use of 13-cis-RA. PMID- 18445227 TI - The role of RNA editing of the serotonin 2C receptor in a rat model of oro-facial neuropathic pain. AB - We examined whether infraorbital nerve injury affected the RNA editing efficiency of the serotonin (5HT) 2C receptor in the cervical spinal cord, in association with increased pain thresholds, and whether a 5HT reuptake inhibitor (fluvoxamine; Depromel, Meiji Seika, Tokyo, Japan) altered this editing. Accordingly, we injured rats with an infraorbital nerve loose ligation and examined the pain thresholds, mRNA and mRNA editing of the 5HT2C receptor. We evaluated changes in mRNA editing and 5HT2C mRNA expression using cloning along with sequence analysis and quantitative reverse transcription-polymerase chain reaction to compare samples taken at post-injury day 28 from spinal cord sites, including the trigeminal nucleus caudalis, in naive, sham and injured rats (groups of each type had also received fluvoxamine). 5HT2C receptor expression was maintained post-injury. The RNA editing efficiency was statistically significantly lower at molecular sites A and B in ipsilateral spinal cord samples from injured rats than in bilateral samples from naive and sham rats, and in contralateral samples from injured rats. After injury, the proportional presence of two receptor isoforms changed, i.e. statistically significantly less VNV and significantly more INV and ISV. The proportions reverted after fluvoxamine administration. The post-injury change might be evidence of a functional adaptation mechanism that increases the expression of 5HT2C mRNA isoforms that encode receptors that are more sensitive to 5HT. This would activate the brainstem-spinal descending 5HT systems and, in effect, suppress nociceptive signals from primary afferent neurons to the spinal trigeminal nucleus caudalis. PMID- 18445228 TI - Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3(R427C) and A3(R563C). AB - Mutations in the CNGA3 gene have been associated with complete and incomplete forms of total colour blindness (achromatopsia), a disorder characterized by reduced visual acuity, lack of colour discrimination, photophobia and nystagmus. CNGA3 encodes the A-subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel, an essential component of the phototransduction cascade. Here we report the identification of three new CNGA3 mutations in patients with achromatopsia. To assess the pathogenicity of these newly identified and four previously reported mutations, mutant CNGA3 channels were heterologously expressed in a human embryonic kidney cell line (HEK293 cells) and functionally analysed using calcium imaging. Channels with the mutations R427C and R563C showed a response in imaging experiments and were subsequently characterized in depth with the patch-clamp technique. The mutant channels were analysed as homooligomers and also as heterooligomers with the wild-type B-subunit present in native channels. Overall, cyclic guanosine monophosphate (cGMP) maximum currents of mutant channels were profoundly reduced in homo- and heteromers. Treatment with the chemical chaperone glycerol effectively increased macroscopic currents, presumably by enhancing surface expression of mutant channels as confirmed by immunocytochemistry. These results suggest decreased channel density in the cell membrane due to impaired folding or trafficking of the channel protein as the main pathogenic effect of the mutations R427C and R563C. Moreover, A3(R427C) homomers showed distinctly increased cGMP and cyclic adenosine monophosphate (cAMP) sensitivities as well as cAMP fractional currents that were raised to over 90% of cGMP maximum currents. Co-expression of A3(R427C) with the B3 subunit compensated for most of these aberrant properties, apart from the reduced cGMP maximum currents. PMID- 18445229 TI - Membrane properties of excitatory and inhibitory neurons in the rat prepositus hypoglossi nucleus. AB - The prepositus hypoglossi nucleus (PHN) is thought to be a neural structure involved in transforming eye or head velocity signals into eye position signals for horizontal eye movements. In this study, we investigated the relationship between electrophysiological membrane properties and expression patterns of cellular markers for excitatory and inhibitory neurons by whole-cell patch clamp recordings followed by reverse transcription polymerase chain reaction (RT-PCR) analysis in rat brainstem slices. Three types of voltage response properties, namely afterhyperpolarization (AHP), firing pattern, and response to hyperpolarizing current pulses, were characterized in each neuron. Following RT PCR analysis, we identified PHN neurons as either glutamatergic (n = 22) or GABAergic (n = 43), although a small number of cholinergic (n = 2) and glycinergic neurons (n = 1) were also identified. Both glutamatergic and GABAergic neurons showed a wide variety of membrane properties; however, we found several characteristic relationships between neuronal type and membrane properties. Most neurons exhibiting (i) AHP without a slow component, (ii) a firing pattern with a delay in the generation of the first spike, (iii) a firing pattern with a transient burst and (iv) a firing pattern with a prolonged initial interspike interval were GABAergic. On the other hand, glutamatergic neurons were primarily characterized by a low firing rate. These results indicate that there is a close relationship between specific electrophysiological membrane properties and expression of chemical markers in some types of glutamatergic and GABAergic PHN neurons. PMID- 18445230 TI - Down-regulation of insulin-degrading enzyme by presenilin 1 V97L mutant potentially underlies increased levels of amyloid beta 42. AB - Amyloid beta (Abeta)42 plays a pivotal role in Alzheimer's disease. We previously reported a novel presenilin (PS)1 mutant (V97L) that was expressed in related patients with early onset Alzheimer's disease. We found that patients with the V97L mutation had increased levels of extracellular and intracellular Abeta42. Here we found that the increased extracellular level of Abeta42 was always accompanied by a reduction of insulin-degrading enzyme (IDE) activity on the plasma membranes. However, increase of intracellular Abeta42 was associated with decreased expression and activity of IDE in the cytosol and endoplasmic reticulum in the PS1 V97L mutant-transfected human SH-SY5Y cell line. These studies indicate that pathological levels of Abeta42 may be caused by the negative effects of PS1 (V97L) on IDE expression and activity. Our findings provide evidence for the molecular basis of familial Alzheimer's disease pathogenesis. PMID- 18445231 TI - Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia. AB - Striatal enriched protein tyrosine phosphatase (STEP) acts in the central nervous system to dephosphorylate a number of important proteins involved in synaptic function including ERK and NMDA receptor subunits. These proteins are also linked to stroke, in which cerebral ischemia triggers a complex cascade of events. Here we demonstrate that STEP is regulated at both the transcriptional and the post transcriptional levels in rat models of cerebral ischemia and that its regulation may play a role in the outcome of ischemic insults. After transient middle cerebral artery occlusion, there are profound decreases in the levels of STEP mRNA, whilst in global ischemia STEP mRNA is selectively down-regulated in areas susceptible to ischemic damage. In a neuroprotective preconditioning paradigm, and in regions of the brain that are relatively resistant to ischemic damage, STEP mRNA levels are increased. Furthermore, there is a significant processing of STEP after ischemia to generate a novel species, STEP(33), resulting in a redistribution of STEP from membrane-bound to soluble compartments. Concomitant with the cleavage of mature forms of STEP, there are changes in the phosphorylation state of ERK. We show that the cleavage of STEP leads to a catalytically active form, but this cleaved form no longer binds to and dephosphorylates its substrate pERK. Therefore, in response to ischemic insults, there are profound reductions in both the amount and the activity of STEP, its localization, as well as the activity of one of its key substrates, pERK. These changes in STEP may reflect a critical role in the outcomes of ischemic brain injury. PMID- 18445232 TI - Mechanical lesion activates newly identified NFATc1 in primary astrocytes: implication of ATP and purinergic receptors. AB - Ca2+-dependent calcineurin is upregulated in reactive astrocytes in neuroinflammatory models. Therefore, the fact that the nuclear factor of activated T cells (NFAT) is activated in response to calcineurin qualifies this family of transcription factors with immune functions as candidates to mediate astrogliosis. Brain trauma induces a neuroinflammatory state in which ATP is released from astrocytes, stimulating calcium signalling. Our goal here is to characterize NFATc1 and NFATc2 in mouse primary astrocyte cultures, also exploring the implication of NFAT in astrocyte activation by mechanical lesion. Quantitative reverse transcriptase-polymerase chain reaction, Western blot analysis and immunofluorescence microscopy identified NFATc1 in astrocytes, but not NFATc2. Moreover, NFATc1 was expressed in the cytosol of resting astrocytes, whereas activation of the Ca2+-calcineurin pathway by ionomycin translocated NFATc1 to the nucleus, which is a requirement for activation. The implication of astrocytic NFAT in brain trauma was analysed using an in vitro scratch lesion model. Mechanical lesion caused a rapid NFATc1 translocation that progressed throughout the culture as a gradient and was maintained for at least 4 h. We also demonstrate that ATP, released by lesion, is a potent inducer of NFATc1 translocation and activation. Moreover, the use of P2Y receptor modulators showed that such ATP action is mediated by stimulation of several G(q)-protein-coupled P2Y purinergic receptors, among which P2Y(1) and P2Y(6) are included. In conclusion, this work provides evidence that newly identified NFATc1 is translocated in astrocytes in response to lesion following a pathway that involves ATP release and activation of metabotropic purinergic receptors. PMID- 18445233 TI - Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat. AB - The present study re-evaluated an existing notion that serotonin (5 hydroxytryptamine; 5-HT) could not cross the brain to the circulating blood via the blood-brain barrier (BBB). To elevate brain 5-HT alone, 5-hydroxytryptophan (5-HTP; 30-75 mg/kg) was administrated intravenously to anaesthetized rats that had undergone gastrointestinal and kidney resections along with liver inactivation (organs contributing to increasing blood 5-HT after 5-HTP administration). A microdialysis method and HPLC system were used to determine the brain 5-HT levels in samples collected from the frontal cortex. Blood 5-HT levels were determined from whole blood, not platelet-poor plasma, collected from the central vein. We found that blood 5-HT levels showed a significant augmentation whenever brain 5-HT levels were significantly elevated after the administration of 5-HTP in those rats with the abdominal surgical procedures. This elevation was abolished after pretreatment with a selective serotonin reuptake inhibitor (fluoxetine; 10 mg/kg i.v.), although brain 5-HT levels remained augmented. These results indicate that augmented brain 5-HT can cross the BBB through the 5-HT transporter from the brain to the circulating blood. PMID- 18445234 TI - Neonatal stimulation of 5-HT(2) receptors reduces androgen receptor expression in the rat anteroventral periventricular nucleus and sexually dimorphic preoptic area. AB - Masculinization of the brain is dependent upon a perinatal surge in testosterone. It also requires a transient decrease in hypothalamic 5-HT concentration and turnover and an increase in androgen receptor (AR) expression during the second postnatal week. We have previously shown that increasing 5-HT activity over this period in male or androgenized female rats feminizes their adult behaviour and also feminizes the size of their anteroventral periventricular nucleus (AVPV) and sexually dimorphic nucleus of the preoptic area (SDN-POA). To investigate the role of 5-HT in sexual differentiation of the brain, 5-HT activity was raised over postnatal days 8-16 in male, female and androgenized female rats by daily administration of the 5-HT(2) receptor agonist (-)[2,5 dimethoxy-4-iodophenyl]-2 amino propane hydrochloride [(-)DOI]. By postnatal day 18, the size of the AVPV and SDN-POA was sexually dimorphic; their sizes were feminized by (-)DOI treatment. In the absence of (-)DOI treatment, there were significantly more AR immunoreactive cells in the AVPV of males, and in the SDN-POA of males and androgenized females, than in those of females on postnatal day 18. (-)DOI treatment reduced the number of AR-immunoreactive cells in the AVPV and SDN-POA of males and androgenized females, but not of females, by postnatal day 18. These results suggest that 5-HT(2) receptor activation can influence sexual differentiation of the brain by controlling AR expression. PMID- 18445237 TI - [The founding of the European Skin Research Foundation (ESRF)]. PMID- 18445238 TI - Current therapeutic options of chronic leg ulcers. AB - Wound treatment is continually becoming more complex and difficult. In the following review, we focus on the different options of wound debridement, stimulation of granulation tissue, different wound dressings, and therapeutic strategies in hard-to-heal-wounds. We also present some future treatment options for chronic wounds. PMID- 18445239 TI - [Circumscribed congenital hypertrichosis. Congenital smooth muscle hamartoma- CSMH. Congenital pili arrector hamartoma]. PMID- 18445240 TI - [Removal of a finger ring with a suture technique]. PMID- 18445241 TI - [Munro's microabscess--before Munro]. PMID- 18445243 TI - [In Memoriam: Alan Lyell 1917-2007]. PMID- 18445248 TI - Osseous metaplasia in an ulcerating tubular adenoma of the colon: a case report. AB - INTRODUCTION: Heterotopic bone is rarely found in the gastrointestinal tract. Here we report a rare case of metaplastic ossification within a benign ulcerating adenoma and review the literature concerning the aetiology. CASE PRESENTATION: A 63-year-old woman, who presented with a history of melaena, was found at colonoscopy to have a pedunculated ulcerating polyp. Histological examination demonstrated multiple areas of osseous metaplasia within the polyp stroma. CONCLUSION: Heterotopic ossification in colonic adenomas is a particularly rare phenomenon, with the majority of cases occurring within malignant lesions. The suggested mechanisms for its aetiology still remain unclear. PMID- 18445249 TI - Ethnomedicinal plant knowledge and practice of the Oromo ethnic group in southwestern Ethiopia. AB - An ethnomedicinal study was conducted to document the indigenous medicinal plant knowledge and use by traditional healers in southwestern Ethiopia from December 2005 to November 2006. Data were collected from 45 randomly selected traditional healers using semi-structured interviews and observations. Sixty-seven ethnomedicinal plant species used by traditional healers to manage 51 different human ailments were identified and documented. Healers' indigenous knowledge was positively correlated with their reported age but not with their educational level. High degree of consensus was observed among traditional healers in treating tumor (locally known as Tanacha), rabies (Dhukuba Seree) and insect bite (Hadhaa). The use of more than one species was significantly cited for remedy preparations. The reported abundance of the ethnomedicinal plant species varied significantly with respect to the presence of multiple uses of the reported species. Our results showed that ethnomedicinal plant species used by healers are under serious threat due to several factors, which indicates the need for urgent attention towards their conservation and sustainable utilization. PMID- 18445250 TI - Optimized haemostasis in nephron-sparing surgery using small-intestine submucosa. AB - BACKGROUND: The indications for nephron-sparing surgery are expanding constantly. One major contributing fact for this development is the improvement of haemostatic techniques following excision of the tumor. Nevertheless, postoperative bleeding complications still occur. To prevent this, we prospectively studied the effect of application of small-intestine submucosa (SIS) over the renal defect. METHODS: We performed 55 nephron-sparing surgeries applying SIS between 08/03 and 10/06 in 53 pts. (mean age: 59 yrs., range 29 - 79 yrs.). After resection of the renal tumor and application of a haemostyptic agent, we used SIS to secure and apply compression on the defect. RESULTS: The final pathology revealed clear-cell and papillary carcinoma, papillary adenoma, oncocytoma, and angiomyolipoma in 39 (70.9%), 6 (10.9), 1 (1.8%), 2 (3.6%) and 7 (12.7%) patients, respectively. The 45 malignant lesions (81.8%) were classified as pT1a and pT1b in 35 (77.8%) and 10 (22.2%) patients, respectively. The median tumor size was 4.5 cm (range: 1.3 - 13 cm). The median operating time was 186 min (range: 90 - 260 min). 18 (32.7%) procedures were performed without ischemia. 23 (41.8%) and 14 (25.5%) cases were operated in in-situ cold and warm ischemia, respectively. The median intraoperative blood loss was 730 cc (range: 100 - 2500 cc). No open operative revision was indicated due to postoperative bleeding complications. Furthermore, there was no necessity to substitute persistent blood loss from the drains postoperatively. No urinoma occurred. CONCLUSION: SIS is a highly effective and easy-to-use instrument for preventing postoperative bleeding and urinary fistula complications in nephron-sparing surgery. PMID- 18445251 TI - Differences in mtDNA haplogroup distribution among 3 Jewish populations alter susceptibility to T2DM complications. AB - BACKGROUND: Recent genome-wide association studies searching for candidate susceptibility loci for common complex diseases such as type 2 diabetes mellitus (T2DM) and its common complications have uncovered novel disease-associated genes. Nevertheless these large-scale population screens often overlook the tremendous variation in the mitochondrial genome (mtDNA) and its involvement in complex disorders. RESULTS: We have analyzed the mitochondrial DNA (mtDNA) genetic variability in Ashkenazi (Ash), Sephardic (Seph) and North African (NAF) Jewish populations (total n = 1179). Our analysis showed significant differences (p < 0.001) in the distribution of mtDNA genetic backgrounds (haplogroups) among the studied populations. To test whether these differences alter the pattern of disease susceptibility, we have screened our three Jewish populations for an association of mtDNA genetic haplogroups with T2DM complications. Our results identified population-specific susceptibility factors of which the best example is the Ashkenazi Jewish specific haplogroup N1b1, having an apparent protective effect against T2DM complications in Ash (p = 0.006), being absent in the NAF population and under-represented in the Seph population. We have generated and analyzed whole mtDNA sequences from the disease associated haplogroups revealing mutations in highly conserved positions that are good candidates to explain the phenotypic effect of these genetic backgrounds. CONCLUSION: Our findings support the possibility that recent bottleneck events leading to over-representation of minor mtDNA alleles in specific genetic isolates, could result in population specific susceptibility loci to complex disorders. PMID- 18445252 TI - Biological treatment of tannery wastewater by using salt-tolerant bacterial strains. AB - BACKGROUND: High salinity (1-10% w/v) of tannery wastewater makes it difficult to be treated by conventional biological treatment. Salt tolerant microbes can adapt to these saline conditions and degrade the organics in saline wastewater. RESULTS: Four salt tolerant bacterial strains isolated from marine and tannery saline wastewater samples were identified as Pseudomonas aeruginosa, Bacillus flexus, Exiguobacterium homiense and Staphylococcus aureus. Growth factors of the identified strains were optimized. Tannery saline wastewater obtained from a Common Effluent Treatment Plant (CETP) near Chennai (southern India) was treated with pure and mixed consortia of four salt tolerant bacterial strains. Experiments with optimized conditions and varying salt content (between 2 and 10% (w/v) were conducted. Salt inhibition effects on COD removal rate were noted. Comparative analysis was made by treating the tannery saline wastewater with activated sludge obtained from CETP and with natural habitat microbes present in raw tannery saline wastewater. CONCLUSION: Salt tolerant bacterial mixed consortia showed appreciable biodegradation at all saline concentrations (2%, 4%, 6%, 8% and 10% w/v) with 80% COD reduction in particular at 8% salinity level the consortia could be used as suitable working cultures for tannery saline wastewater treatment. PMID- 18445253 TI - Pruritus is a common feature in sheep infected with the BSE agent. AB - BACKGROUND: The variability in the clinical or pathological presentation of transmissible spongiform encephalopathies (TSEs) in sheep, such as scrapie and bovine spongiform encephalopathy (BSE), has been attributed to prion protein genotype, strain, breed, clinical duration, dose, route and type of inoculum and the age at infection. The study aimed to describe the clinical signs in sheep infected with the BSE agent throughout its clinical course to determine whether the clinical signs were as variable as described for classical scrapie in sheep. The clinical signs were compared to BSE-negative sheep to assess if disease specific clinical markers exist. RESULTS: Forty-seven (34%) of 139 sheep, which comprised 123 challenged sheep and 16 undosed controls, were positive for BSE. Affected sheep belonged to five different breeds and three different genotypes (ARQ/ARQ, VRQ/VRQ and AHQ/AHQ). None of the controls or BSE exposed sheep with ARR alleles were positive. Pruritus was present in 41 (87%) BSE positive sheep; the remaining six were judged to be pre-clinically infected. Testing of the response to scratching along the dorsum of a sheep proved to be a good indicator of clinical disease with a test sensitivity of 85% and specificity of 98% and usually coincided with weight loss. Clinical signs that were displayed significantly earlier in BSE positive cases compared to negative cases were behavioural changes, pruritic behaviour, a positive scratch test, alopecia, skin lesions, teeth grinding, tremor, ataxia, loss of weight and loss of body condition. The frequency and severity of each specific clinical sign usually increased with the progression of disease over a period of 16-20 weeks. CONCLUSION: Our results suggest that BSE in sheep presents with relatively uniform clinical signs, with pruritus of increased severity and abnormalities in behaviour or movement as the disease progressed. Based on the studied sheep, these clinical features appear to be independent of breed, affected genotype, dose, route of inoculation and whether BSE was passed into sheep from cattle or from other sheep, suggesting that the clinical phenotype of BSE is influenced by the TSE strain more than by other factors. The clinical phenotype of BSE in the genotypes and breed studied was indistinguishable from that described for classical scrapie cases. PMID- 18445254 TI - Solitary colonic polypoid ganglioneuroma. AB - This short report discusses a case of solitary colonic polypoid ganglioneuroma associated with melanosis coli in a woman with no systemic manifestations. To our knowledge this is the first ganglioneuroma reported in the literature in association with melanosis coli. The nature and significance of this event remains unclear, although this may be coincidental due to the laxative intake. Further investigation is necessary to clarify this point. The interest of this case lies moreover in the rarity of this entity and its endoscopic and histologic resemblance to sessile polyps frequent in the clinical practice. PMID- 18445255 TI - Cost-effectiveness analysis of insecticide-treated net distribution as part of the Togo Integrated Child Health Campaign. AB - BACKGROUND: To evaluate the cost-effectiveness of the first nationwide delivery of long-lasting insecticide-treated nets (LLITNs) as part of the 2004 measles vaccination campaign in Togo to all children between nine months and five years. METHODS: An incremental approach was used to calculate the economic costs and effects from a provider perspective. Effectiveness was estimated in terms of malaria cases averted, deaths averted and Disability-Adjusted Life Years (DALYs) averted. Malaria cases were modelled using regional estimates. Programme and treatment costs were derived through reviews of financial records and interviews with key stakeholders. Uncertain variables were subjected to a univariate sensitivity analysis. RESULTS: Assuming equal attribution of shared costs between the LLITN distribution and the measles vaccination, the net costs per LLITN distributed were 4.41 USD when saved treatment costs were taken into account. Assuming a constant utilization of LLITNs by the target group over three years, 1.2 million cases could be prevented at a net cost per case averted of 3.26 USD. The net costs were 635 USD per death averted and 16.39 USD per DALY averted, respectively. CONCLUSION: The costs per case, death and DALY averted are well within commonly agreed benchmarks set by other malaria prevention studies. Varying transmission levels are shown to have a significant impact on cost effectiveness ratios. Results also suggest that substantial efficiency gains may be derived from the joint delivery of vaccination campaigns and malaria interventions. PMID- 18445256 TI - Comparison of two self-reported measures of physical work demands in hospital personnel: a cross-sectional study. AB - BACKGROUND: Low back pain (LBP) is a frequent health complaint among health care personnel. Several work tasks and working postures are associated with an increased risk of LBP. The aim of this study was to compare two self-reported measures of physical demands and their association with LBP (the daily number of patient handling tasks and Hollmann's physical load index). METHODS: A questionnaire was distributed to 535 hospital employees in a psychiatric and an orthopedic ward in a Danish hospital. Of these 411 (77%) filled in and returned the questionnaire. Only the 373 respondents who had non-missing values on both measures of physical demands were included in the analyses. The distribution of physical demands in different job groups and wards are presented, variance analysis models are employed, and logistic regression analysis is used to analyze the association between measures of physical demands and LBP. RESULTS: In combination, hospital ward and job category explained 56.6% and 23.3% of the variance in the self-reported physical demands measured as the daily number of patient handling tasks and as the score on the physical load index, respectively. When comparing the 6% with the highest exposure the prevalence odds ratio (POR) for LBP was 5.38 (95% CI 2.03-14.29) in the group performing more than 10 patient handling tasks per day and 2.29 (95% CI 0.93-5.66) in the group with the highest score on the physical load index. CONCLUSION: In specialized hospital wards the daily number of patient handling tasks seems to be a more feasible measure of exposure when assessing the risk of LBP compared to more advanced measures of physical load on the lower lumbar spine. PMID- 18445257 TI - Bilateral sternoclavicular joint septic arthritis secondary to indwelling central venous catheter: a case report. AB - INTRODUCTION: Septic arthritis of the sternoclavicular joint is rare, comprising approximately 0.5% to 1% of all joint infections. Predisposing causes include immunocompromising diseases such as diabetes, HIV infection, renal failure and intravenous drug abuse. CASE PRESENTATION: We report a rare case of bilateral sternoclavicular joint septic arthritis in an elderly patient secondary to an indwelling right subclavian vein catheter. The insidious nature of the presentation is highlighted. We also review the literature regarding the epidemiology, investigation and methods of treatment of the condition. CONCLUSION: SCJ infections are rare, and require a high degree of clinical suspicion. Vague symptoms of neck and shoulder pain may cloud the initial diagnosis, as was the case in our patient. Surgical intervention is often required; however, our patient avoided major intervention and settled with parenteral antibiotics and washout of the joint. PMID- 18445258 TI - Impact of five years of peer-mediated interventions on sexual behavior and sexually transmitted infections among female sex workers in Mombasa, Kenya. AB - BACKGROUND: Since 2000, peer-mediated interventions among female sex workers (FSW) in Mombasa Kenya have promoted behavioural change through improving knowledge, attitudes and awareness of HIV serostatus, and aimed to prevent HIV and other sexually transmitted infection (STI) by facilitating early STI treatment. Impact of these interventions was evaluated among those who attended peer education and at the FSW population level. METHODS: A pre-intervention survey in 2000, recruited 503 FSW using snowball sampling. Thereafter, peer educators provided STI/HIV education, condoms, and facilitated HIV testing, treatment and care services. In 2005, data were collected using identical survey methods, allowing comparison with historical controls, and between FSW who had or had not received peer interventions. RESULTS: Over five years, sex work became predominately a full-time activity, with increased mean sexual partners (2.8 versus 4.9/week; P < 0.001). Consistent condom use with clients increased from 28.8% (145/503) to 70.4% (356/506; P < 0.001) as well as the likelihood of refusing clients who were unwilling to use condoms (OR = 4.9, 95%CI = 3.7-6.6). In 2005, FSW who received peer interventions (28.7%, 145/506), had more consistent condom use with clients compared with unexposed FSW (86.2% versus 64.0%; AOR = 3.6, 95%CI = 2.1-6.1). These differences were larger among FSW with greater peer-intervention exposure. HIV prevalence was 25% (17/69) in FSW attending > or = 4 peer-education sessions, compared with 34% (25/73) in those attending 1-3 sessions (P = 0.21). Overall HIV prevalence was 30.6 (151/493) in 2000 and 33.3% (166/498) in 2005 (P = 0.36). CONCLUSION: Peer-mediated interventions were associated with an increase in protected sex. Though peer mediated interventions remain important, higher coverage is needed and more efficacious interventions to reduce overall vulnerability and risk. PMID- 18445259 TI - The validity, reliability and normative scores of the parent, teacher and self report versions of the Strengths and Difficulties Questionnaire in China. AB - BACKGROUND: The Strengths and Difficulties Questionnaire (SDQ) has become one of the most widely used measurement tools in child and adolescent mental health work across the globe. The SDQ was originally developed and validated within the UK and whilst its reliability and validity have been replicated in several countries important cross cultural issues have been raised. We describe normative data, reliability and validity of the Chinese translation of the SDQ (parent, teacher and self report versions) in a large group of children from Shanghai. METHODS: The SDQ was administered to the parents and teachers of students from 12 of Shanghai's 19 districts, aged between 3 and 17 years old, and to those young people aged between 11 and 17 years. Retest data was collected from parents and teachers for 45 students six weeks later. Data was analysed to describe normative scores, bandings and cut-offs for normal, borderline and abnormal scores. Reliability was assessed from analyses of internal consistency, inter-rater agreement, and temporal stability. Structural validity, convergent and discriminant validity were assessed. RESULTS: Full parent and teacher data was available for 1965 subjects and self report data for 690 subjects. Normative data for this Chinese urban population with bandings and cut-offs for borderline and abnormal scores are described. Principle components analysis indicates partial agreement with the original five factored subscale structure however this appears to hold more strongly for the Prosocial Behaviour, Hyperactivity - Inattention and Emotional Symptoms subscales than for Conduct Problems and Peer Problems. Internal consistency as measured by Cronbach's alpha coefficient were generally low ranging between 0.30 and 0.83 with only parent and teacher Hyperactivity - Inattention and teacher Prosocial Behaviour subscales having alpha > 0.7. Inter rater correlations were similar to those reported previously (range 0.23 - 0.49) whilst test retest reliability was generally lower than would be expected (range 0.40 - 0.79). Convergent and discriminant validity are supported. CONCLUSION: We report mixed findings with respect the psychometric properties of the Chinese translation of the SDQ. Reliability is a particular concern particularly for Peer Problems and self ratings by adolescents. There is good support for convergent validity but only partial support for structural validity. It may be possible to resolve some of these issues by carefully examining the wording and meaning of some of the current questions. PMID- 18445260 TI - Proteomic analysis of differential proteins in pancreatic carcinomas: Effects of MBD1 knock-down by stable RNA interference. AB - BACKGROUND: Methyl-CpG binding domain protein 1 (MBD1), a suppressor of gene transcription, may be involved in inactivation of tumor suppressor genes during tumorigenesis. Over-expression of MBD1 has been reported in human pancreatic carcinomas. METHODS: In this study, we established a MBD1-knock-down pancreatic cancer cell line (BxPC-3) using stable RNA interference, to compare the proteomic changes between control and MBD1-knock-down cells using two-dimensional gel electrophoresis and mass spectrometry. RESULTS: We identified five proteins that were up-regulated and nine proteins that were down-regulated. Most of the identified proteins are involved in tumorigenesis, some are prognostic biomarkers for human malignant tumors. CONCLUSION: Our data suggest that these differential proteins may be associated with the function of MBD1, and provide some insight into the functional mechanism of MBD1 in the development of pancreatic cancer. PMID- 18445261 TI - Clinical research without consent in adults in the emergency setting: a review of patient and public views. AB - BACKGROUND: In emergency research, obtaining informed consent can be problematic. Research to develop and improve treatments for patients admitted to hospital with life-threatening and debilitating conditions is much needed yet the issue of research without consent (RWC) raises concerns about unethical practices and the loss of individual autonomy. Consistent with the policy and practice turn towards greater patient and public involvement in health care decisions, in the US, Canada and EU, guidelines and legislation implemented to protect patients and facilitate acute research with adults who are unable to give consent have been developed with little involvement of the lay public. This paper reviews research examining public opinion regarding RWC for research in emergency situations, and whether the rules and regulations permitting research of this kind are in accordance with the views of those who ultimately may be the most affected. METHODS: Seven electronic databases were searched: Medline, Embase, CINAHL, Cochrane Database of Systematic Reviews, Philosopher's Index, Age Info, PsychInfo, Sociological Abstracts and Web of Science. Only those articles pertaining to the views of the public in the US, Canada and EU member states were included. Opinion pieces and those not published in English were excluded. RESULTS: Considering the wealth of literature on the perspectives of professionals, there was relatively little information about public attitudes. Twelve studies employing a range of research methods were identified. In five of the six questionnaire surveys around half the sample did not agree generally with RWC, though paradoxically, a higher percentage would personally take part in such a study. Unfortunately most of the studies were not designed to investigate individuals' views in any depth. There also appears to be a level of mistrust of medical research and some patients were more likely to accept an experimental treatment 'outside' of a research protocol. CONCLUSION: There are too few data to evaluate whether the rules and regulations permitting RWC protects - or is acceptable to - the public. However, any attempts to engage the public should take place in the context of findings from further basic research to attend to the apparently paradoxical findings of some of the current surveys. PMID- 18445262 TI - Do quality of life, participation and environment of older adults differ according to level of activity? AB - BACKGROUND: Activity limitation is one of the most frequent geriatric clinical syndromes that have significant individual and societal impacts. People living with activity limitations might have fewer opportunities to be satisfied with life or experience happiness, which can have a negative effect on their quality of life. Participation and environment are also important modifiable variables that influence community living and are targeted by health interventions. However, little is known about how quality of life, participation and environment differ according to activity level. This study examines if quality of life, participation (level and satisfaction) and perceived quality of the environment (facilitators or obstacles in the physical or social environment) of community dwelling older adults differ according to level of activity. METHODS: A cross sectional design was used with a convenience sample of 156 older adults (mean age = 73.7; 76.9% women), living at home and having good cognitive functions, recruited according to three levels of activity limitations (none, slight to moderate and moderate to severe). Quality of life was estimated with the Quality of Life Index, participation with the Assessment of Life Habits and environment with the Measure of the Quality of the Environment. Analysis of variance (ANOVA) or Welch F-ratio indicated if the main variables differed according to activity level. RESULTS: Quality of life and satisfaction with participation were greater with a higher activity level (p < 0.001). However, these differences were clinically significant only between participants without activity limitations and those with moderate to severe activity limitations. When activity level was more limited, participation level was further restricted (p < 0.001) and the physical environment was perceived as having more obstacles (p < 0.001). No differences were observed for facilitators in the physical and social environment or for obstacles in the social environment. CONCLUSION: This study suggests that older adults' participation level and obstacles in the physical environment differ according to level of activity. Quality of life and satisfaction with participation also differ but only when activity level is sufficiently disrupted. The study suggests the importance of looking beyond activity when helping older adults live in the community. PMID- 18445263 TI - Large asymptomatic left atrial myxoma with ossification: case report. AB - BACKGROUND: Atrial myxomas are the most common primary cardiac tumors. They are usually small or moderate in size by the time of the diagnosis, exhibiting non specific cardiac or systemic symptoms, and are most frequently soft and friable without microscopic signs of ossification. We describe herein an extremely rare case of an asymptomatic giant left atrial myxoma with angiographic neovascularization and ossification. CASE PRESENTATION: An asymptomatic 58-year old male with a giant left atrial tumor, was transferred to our Unit for surgical treatment. The tumor was an incidental finding during a work-up for hemoptysis due to bronchectasis. The coronary angiogram showed tumor vessels originating from the RCA. The tumor macroscopically did not resemble a myxoma, considering its dimensions (12 x 10 cm) and its solid substance. The mass was excised together with the interatrial septum and the right lateral LA wall close to the right pulmonary veins orifices. The defect was closed with Dacron patches in order to prevent malformation of both atria. The pathology study revealed a benign myxoma with excessive osteoid (mature bone) content. CONCLUSION: We consider our case as extremely rare because of the asymptomatic course despite the large size of the tumor, the blood supply from the right coronary artery and the bone formation. PMID- 18445264 TI - Epidemiology of foot-and-mouth disease in Landhi Dairy Colony, Pakistan, the world largest Buffalo colony. AB - BACKGROUND: Foot-and-mouth disease (FMD) is endemic in Pakistan and causes huge economic losses. This work focus on the Landhi Dairy Colony (LDC), located in the suburbs of Karachi. LDC is the largest Buffalo colony in the world, with more than 300,000 animals (around 95% buffaloes and 5% cattle, as well as an unknown number of sheep and goats). Each month from April 2006 to April 2007 we collected mouth-swabs from apparently healthy buffaloes and cattle, applying a convenient sampling based on a two-stage random sampling scheme, in conjunction with participatory information from each selected farm. Furthermore, we also collected epithelium samples from animals with clinical disease, as well as mouth-swabs samples from those farms. In addition, we analysed a total of 180 serum samples randomly collecting 30 samples each month at the local slaughterhouse, from October 2006 to March 2007. Samples have been screened for FMDV by real-time RT PCR and the partial or full 1D coding region of selected isolates has been sequenced. Serum samples have been analysed by applying serotype-specific antibody ELISA and non-structural proteins (NSP) antibody ELISA. RESULTS: FMDV infection prevalence at aggregate level shows an endemic occurrence of FMDV in the colony, with peaks in August 2006, December 2006 and February 2007 to March 2007. A significant association of prevalence peaks to the rainy seasons, which includes the coldest time of the year and the muslimic Eid-festival, has been demonstrated. Participatory information indicated that 88% of all questioned farmers vaccinate their animals. Analysis of the serum samples showed high levels of antibodies for serotypes O, A, Asia 1 and C. The median endpoint-titre for all tested serotypes, except serotype C, in VNT titration is at a serum dilution of equal or above 1/100. All 180 serum samples collected have been tested for antibodies against the non-structural proteins and all but four have been found positive. Out of the 106 swab-samples from apparently healthy and affected animals positive in real-time RT-PCR, we sequenced the partial or full 1D coding region from 58 samples. In addition we sequenced the full 1D coding region of 17 epithelium samples from animals with clinical signs of FMD. From all sequenced samples, swabs and epithelium, 19 belong to the regional PanAsia II lineage of serotype O and 56 to the A/Iran/2005 lineage of serotype A. CONCLUSION: For an effective and realisable FMD control program in LDC, we suggest to introduce a twice annually mass vaccination of all buffaloes and cattle in the colony. These mass vaccinations should optimally take place shortly before the beginning of the two rainy periods, e.g. in June and September. Those vaccinations should, in our opinion, be in addition to the already individually performed vaccinations of single animals, as the latter usually targets only newly introduced animals. This suggested combination of mass vaccination of all large ruminants with the already performed individually vaccination should provide a continuous high level of herd immunity in the entire colony. Vaccines used for this purpose should contain the matching vaccine strains, i.e. as our results indicate antigens for A/Iran/2005 and the regional type of serotype O (PanAsia II), but also antigens of the, in this world region endemic, Asia 1 lineage should be included. In the long term it will be important to control the vaccine use, so that subclinical FMD will be avoided. PMID- 18445265 TI - Distribution of knock-down resistance mutations in Anopheles gambiae molecular forms in west and west-central Africa. AB - BACKGROUND: Knock-down resistance (kdr) to DDT and pyrethroids in the major Afrotropical vector species, Anopheles gambiae sensu stricto, is associated with two alternative point mutations at amino acid position 1014 of the voltage-gated sodium channel gene, resulting in either a leucine-phenylalanine (L1014F), or a leucine-serine (L1014S) substitution. In An. gambiae S-form populations, the former mutation appears to be widespread in west Africa and has been recently reported from Uganda, while the latter, originally recorded in Kenya, has been recently found in Gabon, Cameroon and Equatorial Guinea. In M-form populations surveyed to date, only the L1014F mutation has been found, although less widespread and at lower frequencies than in sympatric S-form populations. METHODS: Anopheles gambiae M- and S-form specimens from 19 sites from 11 west and west-central African countries were identified to molecular form and genotyped at the kdr locus either by Hot Oligonucleotide Ligation Assay (HOLA) or allele specific PCR (AS-PCR). RESULTS: The kdr genotype was determined for about 1,000 An. gambiae specimens. The L1014F allele was found at frequencies ranging from 6% to 100% in all S-form samples (N = 628), with the exception of two samples from Angola, where it was absent, and coexisted with the L1014S allele in samples from Cameroon, Gabon and north-western Angola. The L1014F allele was present in M-form samples (N = 354) from Benin, Nigeria, and Cameroon, where both M- and S-forms were sympatric. CONCLUSION: The results represent the most comprehensive effort to analyse the overall distribution of the L1014F and L1014S mutations in An. gambiae molecular forms, and will serve as baseline data for resistance monitoring. The overall picture shows that the emergence and spread of kdr alleles in An. gambiae is a dynamic process and that there is marked intra- and inter-form heterogeneity in resistance allele frequencies. Further studies are needed to determine: i) the importance of selection pressure exerted by both agricultural and public health use of pyrethroid insecticides, ii) the phenotypic effects, particularly when the two mutations co-occur; and iii) the epidemiological importance of kdr for both pyrethroid- and DDT-based malaria control operations, particularly if/when the two insecticides are to be used in concert. PMID- 18445266 TI - Lack of c-kit receptor promotes mammary tumors in N-nitrosomethylurea-treated Ws/Ws rats. AB - BACKGROUND: c-kit is expressed in various cell types during development and it has been linked to the promotion of cellular migration, proliferation and/or survival of melanoblasts, hematopoietic progenitors and primordial germ cells. Several reports have proposed a role for the c-kit gene on carcinogenesis. Gain of-function mutations are associated with diseases such as mastocytosis and gastrointestinal stromal tumors among others. However, very little is known about pathologies associated with loss-of-function mutations. Regarding breast cancer, c-kit protein and mRNA are highly expressed in normal breast but their expression decreases or is absent in the presence of breast cancer. We studied the role of c kit in mammary carcinogenesis in the Ws/Ws rats carrying spontaneous lack-of function mutation in the c-kit gene. Fifty day-old virgin female Ws/Ws rats and their wild type counterparts were injected with either 50 mg/kg body weight of the chemical carcinogen N-nitrosomethylurea or with vehicle. The animals were followed-up for 6 months. Fisher 344 rats were used as positive controls for tumor development. RESULTS: Eleven weeks after treatment, palpable tumors were detected in the Ws/Ws rats. The tumor incidence was 80% in Ws/Ws rats, while no tumors were observed in the wild type rats (p = 0.006). Our data show that the lack of c-kit is permissive for the development of mammary tumor in Ws/Ws rats treated with carcinogen. CONCLUSION: We conclude that the lack of c-kit may contribute to an imbalanced homeostatic state in the mammary gland either by affecting signaling between stroma and epithelium, or through the lack of mast cells. PMID- 18445267 TI - A high sensitivity assay for the inflammatory marker C-Reactive protein employing acoustic biosensing. AB - C-Reactive Protein (CRP) is an acute phase reactant routinely used as a biomarker to assess either infection or inflammatory processes such as autoimmune diseases. CRP also has demonstrated utility as a predictive marker of future risk of cardiovascular disease. A new method of immunoassay for the detection of C Reactive Protein has been developed using Resonant Acoustic Profilingtrade mark (RAPtrade mark) with comparable sensitivity to a high sensitivity CRP ELISA (hsCRP) but with considerable time efficiency (12 minutes turnaround time to result). In one method, standard solutions of CRP (0 to 231 ng/mL) or diluted spiked horse serum sample are injected through two sensor channels of a RAPtrade mark biosensor. One contains a surface with sheep antibody to CRP, the other a control surface containing purified Sheep IgG. At the end of a 5-minute injection the initial rate of change in resonant frequency was proportional to CRP concentration. The initial rates of a second sandwich step of anti-CRP binding were also proportional to the sample CRP concentration and provided a more sensitive method for quantification of CRP. The lower limit of detection for the direct assay and the homogenous sandwich assay were both 20 ng/mL whereas for the direct sandwich assay the lower limit was 3 ng/mL. In a step towards a rapid clinical assay, diluted horse blood spiked with human CRP was passed over one sensor channel whilst a reference standard solution at the borderline cardiovascular risk level was passed over the other. A semi-quantities ratio was thus obtained indicative of sample CRP status. Overall, the present study revealed that CRP concentrations in serum that might be expected in both normal and pathological conditions can be detected in a time-efficient, label-free immunoassay with RAPtrade mark detection technology with determined CRP concentrations in close agreement with those determined using a commercially available high sensitivity ELISA. PMID- 18445268 TI - Similarity of DMD gene deletion and duplication in the Chinese patients compared to global populations. AB - BACKGROUND: DNA deletion and duplication were determined as the major mutation underlying Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). METHOD: Applying multiplex ligation-dependent probe amplification (MLPA), we have analyzed 179 unrelated DMD/BMD subjects from northern China. RESULTS: Seventy three percent of the subjects were found having a deletion (66.25%) or duplication (6.25%). Exons 51-52 were detected as the most common fragment deleted in single-exon deletion, and the region of exons 45-50 was the most common exons deleted in multi-exon deletions. About 90% of DMD/BMD cases carry a small size deletion that involves 10 exons or less, 26.67% of which carry a single-exon deletion. Most of the smaller deletions resulted in an out-of-frame mutation. The most common exons deleted were determined to be between exon 48 and exon 52, with exon 50 was the model allele. Verifying single-exon deletion, one sample with a deletion of exon 53 that was initially observed from MLPA showed that there was a single base deletion that abolished the ligation site in MLPA. Confirmation of single-exon deletion is recommended to exclude single base deletion or mutation at the MLPA ligation site. CONCLUSION: The frequency of deletion and duplication in northern China is similar to global ethnic populations. PMID- 18445269 TI - Highly accurate sigmoidal fitting of real-time PCR data by introducing a parameter for asymmetry. AB - BACKGROUND: Fitting four-parameter sigmoidal models is one of the methods established in the analysis of quantitative real-time PCR (qPCR) data. We had observed that these models are not optimal in the fitting outcome due to the inherent constraint of symmetry around the point of inflection. Thus, we found it necessary to employ a mathematical algorithm that circumvents this problem and which utilizes an additional parameter for accommodating asymmetrical structures in sigmoidal qPCR data. RESULTS: The four-parameter models were compared to their five-parameter counterparts by means of nested F-tests based on the residual variance, thus acquiring a statistical measure for higher performance. For nearly all qPCR data we examined, five-parameter models resulted in a significantly better fit. Furthermore, accuracy and precision for the estimation of efficiencies and calculation of quantitative ratios were assessed with four independent dilution datasets and compared to the most commonly used quantification methods. It could be shown that the five-parameter model exhibits an accuracy and precision more similar to the non-sigmoidal quantification methods. CONCLUSION: The five-parameter sigmoidal models outperform the established four-parameter model with high statistical significance. The estimation of essential PCR parameters such as PCR efficiency, threshold cycles and initial template fluorescence is more robust and has smaller variance. The model is implemented in the qpcR package for the freely available statistical R environment. The package can be downloaded from the author's homepage. PMID- 18445270 TI - Altered gene expression in the superior temporal gyrus in schizophrenia. AB - BACKGROUND: The superior temporal gyrus (STG), which encompasses the primary auditory cortex, is believed to be a major anatomical substrate for speech, language and communication. The STG connects to the limbic system (hippocampus and amygdala), the thalamus and neocortical association areas in the prefrontal cortex, all of which have been implicated in schizophrenia. RESULTS: To identify altered mRNA expression in the superior temporal gyrus (STG) in schizophrenia, oligonucleotide microarrays were used with RNA from postmortem STG tissue from 7 individuals with schizophrenia and 7 matched non-psychiatric controls. Overall, there was a trend towards down-regulation in gene expression, and altered expression of genes involved in neurotransmission, neurodevelopment, and presynaptic function was identified. To confirm altered expression identified by microarray analysis, the mRNA expression levels of four genes, IPLA2gamma, PIK31R1, Lin-7b and ATBF1, were semi-quantitatively measured using relative real time PCR. A number of genes with altered expression in the STG were also shown to have similar changes in expression as shown in our previous study of peripheral blood lymphocytes in schizophrenia. CONCLUSION: This study has identified altered expression of genes in the STG involved in neurotransmission and neurodevelopment, and to a lesser extent presynaptic function, which further support the notion of these functions playing an integral role in the development of schizophrenia. PMID- 18445271 TI - A GATA4/WT1 cooperation regulates transcription of genes required for mammalian sex determination and differentiation. AB - BACKGROUND: In mammals, sex determination is genetically controlled. The SRY gene, located on Y chromosome, functions as the dominant genetic switch for testis development. The SRY gene is specifically expressed in a subpopulation of somatic cells (pre-Sertoli cells) of the developing urogenital ridge for a brief period during gonadal differentiation. Despite this tight spatiotemporal expression pattern, the molecular mechanisms that regulate SRY transcription remain poorly understood. Sry expression has been shown to be markedly reduced in transgenic mice harboring a mutant GATA4 protein (a member of the GATA family of transcription factors) disrupted in its ability to interact with its transcriptional partner FOG2, suggesting that GATA4 is involved in SRY gene transcription. RESULTS: Although our results show that GATA4 directly targets the pig SRY promoter, we did not observe similar action on the mouse and human SRY promoters. In the mouse, Wilms' tumor 1 (WT1) is an important regulator of both Sry and Mullerian inhibiting substance (Amh/Mis) expression and in humans, WT1 mutations are associated with abnormalities of sex differentiation. GATA4 transcriptionally cooperated with WT1 on the mouse, pig, and human SRY promoters. Maximal GATA4/WT1 synergism was dependent on WT1 but not GATA4 binding to their consensus regulatory elements in the SRY promoter and required both the zinc finger and C-terminal regions of the GATA4 protein. Although both isoforms of WT1 synergized with GATA4, synergism was stronger with the +KTS rather than the -KTS isoform. WT1/GATA4 synergism was also observed on the AMH promoter. In contrast to SRY, WT1/GATA4 action on the mouse Amh promoter was specific for the -KTS isoform and required both WT1 and GATA4 binding. CONCLUSION: Our data therefore provide new insights into the molecular mechanisms that contribute to the tissue specific expression of the SRY and AMH genes in both normal development and certain syndromes of abnormal sex differentiation. PMID- 18445272 TI - Lsa21, a novel leptospiral protein binding adhesive matrix molecules and present during human infection. AB - BACKGROUND: It has been well documented over past decades that interaction of pathogens with the extracellular matrix (ECM) plays a primary role in host cell attachment and invasion. Adherence to host tissues is mediated by surface-exposed proteins expressed by the microorganisms during infection. The mechanisms by which pathogenic leptospires invade and colonize the host remain poorly understood since few virulence factors contributing to the pathogenesis of the disease have been identified. Whole-genome sequencing analysis of L. interrogans allowed identification of a repertoire of putative leptospiral surface proteins. RESULTS: Here, we report the identification and characterization of a new leptospiral protein that exhibits extracellular matrix-binding properties, called as Lsa21 (leptospiral surface adhesin, 21 kDa). Compatible with its role in adhesion, the protein was shown to be surface-exposed by indirect immunofluorescence. Attachment of Lsa21 to laminin, collagen IV, and plasma fibronectin was specific and dose dependent. Laminin oxidation by sodium metaperiodate reduced the protein-laminin interaction in a concentration dependent manner, indicating that laminin sugar moieties are crucial for this interaction. The gene coding for Lsa21 is present in pathogenic strains belonging to the L. interrogans species but was not found in the saprophytic L. biflexa serovar Patoc strain Patoc 1. Loss of gene expression occurs upon culture attenuation of pathogenic strains. Environmental factors such as osmolarity and temperature affect Lsa21 expression at the transcriptional level. Moreover, anti Lsa21 serum labeled liver and kidney tissues of human fatal cases of leptospirosis. CONCLUSION: Our data suggest a role of Lsa21 in the pathogenesis of leptospirosis. PMID- 18445273 TI - 14-3-3 theta binding to cell cycle regulatory factors is enhanced by HIV-1 Vpr. AB - BACKGROUND: Despite continuing advances in our understanding of AIDS pathogenesis, the mechanism of CD4+ T cell depletion in HIV-1-infected individuals remains unclear. The HIV-1 Vpr accessory protein causes cell death, likely through a mechanism related to its ability to arrest cells in the G2,M phase. Recent evidence implicated the scaffold protein, 14-3-3, in Vpr cell cycle blockade. RESULTS: We found that in human T cells, 14-3-3 plays an active role in mediating Vpr-induced cell cycle arrest and reveal a dramatic increase in the amount of Cdk1, Cdc25C, and CyclinB1 bound to 14-3-3 theta during Vprv-induced G2,M arrest. By contrast, a cell-cycle-arrest-dead Vpr mutant failed to augment 14-3-3 theta association with Cdk1 and CyclinB1. Moreover, G2,M arrest caused by HIV-1 infection strongly correlated with a disruption in 14-3-3 theta binding to centrosomal proteins, Plk1 and centrin. Finally, Vpr caused elevated levels of CyclinB1, Plk1, and Cdk1 in a complex with the nuclear transport and spindle assembly protein, importin beta. CONCLUSION: Thus, our data reveal a new facet of Vpr-induced cell cycle arrest involving previously unrecognized abnormal rearrangements of multiprotein assemblies containing key cell cycle regulatory proteins. PMID- 18445274 TI - Polymorphism at the apical membrane antigen 1 locus reflects the world population history of Plasmodium vivax. AB - BACKGROUND: In malaria parasites (genus Plasmodium), ama-1 is a highly polymorphic locus encoding the Apical Membrane Protein-1, and there is evidence that the polymorphism at this locus is selectively maintained. We tested the hypothesis that polymorphism at the ama-1 locus reflects population history in Plasmodium vivax, which is believed to have originated in Southeast Asia and is widely geographically distributed. In particular, we tested for a signature of the introduction of P. vivax into the New World at the time of the European conquest and African slave trade and subsequent population expansion. RESULTS: One hundred and five ama-1 sequences were generated and analyzed from samples from six different Brazilian states and compared with database sequences from the Old World. Old World populations of P. vivax showed substantial evidence of population substructure, with high sequence divergence among localities at both synonymous and nonsynonymous sites, while Brazilian isolates showed reduced diversity and little population substructure. CONCLUSION: These results show that genetic diversity in P. vivax AMA-1 reflects population history, with population substructure characterizing long-established Old World populations, whereas Brazilian populations show evidence of loss of diversity and recent population expansion. NOTE: Nucleotide sequence data reported is this paper are available in the GenBanktrade mark database under the accession numbers EF031154 - EF031216 and EF057446 - EF057487. PMID- 18445276 TI - Simultaneous determination of eight major bioactive compounds in Dachengqi Tang (DT) by high-performance liquid chromatography. AB - BACKGROUND: Dachengqi Tang (DT) is a common traditional Chinese medicine formula for expelling neire ('internal heat') in the stomach and intestines. There was no reliable analytical method available for the quality control of DT. METHODS: A high-performance liquid chromatography (HPLC) method with a reverse phase C18 column (150 x 4.6 mm) was developed. The mobile phase was methanol with 0.2% acetic acid. Eight markers including naringin, hesperidin, aloe emodin, rhein, honokiol, magnolol, emodin and chrysophanol were determined. RESULTS: Regression analysis revealed a linear relationship between the concentrations of the markers and the peak area ratio of the standards and internal standard. The limit of detection (S/N = 3) and the limit of qualification (RSD < 20%) ranged from 0.21 to 0.43 ng/microl and 0.76 to 1.74 ng/microl respectively. The recovery was between 95.6% and 103.4%. The tests on the samples from three batches of DT showed that the profiles of the markers did not vary significantly among batches. CONCLUSION: A reliable HPLC method for simultaneous determination of the eight markers in DT was developed. PMID- 18445275 TI - Evaluation of biological pathways involved in chemotherapy response in breast cancer. AB - INTRODUCTION: Our goal was to examine the association between biological pathways and response to chemotherapy in estrogen receptor-positive (ER+) and ER-negative (ER-) breast tumors separately. METHODS: Gene set enrichment analysis including 852 predefined gene sets was applied to gene expression data from 51 ER- and 82 ER+ breast tumors that were all treated with a preoperative paclitaxel, 5 fluoruracil, doxorubicin, and cyclophosphamide chemotherapy. RESULTS: Twenty seven (53%) ER- and 7 (9%) ER+ patients had pathologic complete response (pCR) to therapy. Among the ER- tumors, a proliferation gene signature (false discovery rate [FDR] q = 0.1), the genomic grade index (FDR q = 0.044), and the E2F3 pathway signature (FDR q = 0.22, P = 0.07) were enriched in the pCR group. Among the ER+ tumors, the proliferation signature (FDR q = 0.001) and the genomic grade index (FDR q = 0.015) were also significantly enriched in cases with pCR. Ki67 expression, as single gene marker of proliferation, did not provide the same information as the entire proliferation signature. An ER-associated gene set (FDR q = 0.03) and a mutant p53 gene signature (FDR q = 0.0019) were enriched in ER+ tumors with residual cancer. CONCLUSION: Proliferation- and genomic grade-related gene signatures are associated with chemotherapy sensitivity in both ER- and ER+ breast tumors. Genes involved in the E2F3 pathway are associated with chemotherapy sensitivity among ER- tumors. The mutant p53 signature and expression of ER-related genes were associated with lower sensitivity to chemotherapy in ER+ breast tumors only. PMID- 18445278 TI - The Mycobacterium tuberculosis Rv2540c DNA sequence encodes a bifunctional chorismate synthase. AB - BACKGROUND: The emergence of multi- and extensively-drug resistant Mycobacterium tuberculosis strains has created an urgent need for new agents to treat tuberculosis (TB). The enzymes of shikimate pathway are attractive targets to the development of antitubercular agents because it is essential for M. tuberculosis and is absent from humans. Chorismate synthase (CS) is the seventh enzyme of this route and catalyzes the NADH- and FMN-dependent synthesis of chorismate, a precursor of aromatic amino acids, naphthoquinones, menaquinones, and mycobactins. Although the M. tuberculosis Rv2540c (aroF) sequence has been annotated to encode a chorismate synthase, there has been no report on its correct assignment and functional characterization of its protein product. RESULTS: In the present work, we describe DNA amplification of aroF-encoded CS from M. tuberculosis (MtCS), molecular cloning, protein expression, and purification to homogeneity. N-terminal amino acid sequencing, mass spectrometry and gel filtration chromatography were employed to determine identity, subunit molecular weight and oligomeric state in solution of homogeneous recombinant MtCS. The bifunctionality of MtCS was determined by measurements of both chorismate synthase and NADH:FMN oxidoreductase activities. The flavin reductase activity was characterized, showing the existence of a complex between FMNox and MtCS. FMNox and NADH equilibrium binding was measured. Primary deuterium, solvent and multiple kinetic isotope effects are described and suggest distinct steps for hydride and proton transfers, with the former being more rate-limiting. CONCLUSION: This is the first report showing that a bacterial CS is bifunctional. Primary deuterium kinetic isotope effects show that C4-proS hydrogen is being transferred during the reduction of FMNox by NADH and that hydride transfer contributes significantly to the rate-limiting step of FMN reduction reaction. Solvent kinetic isotope effects and proton inventory results indicate that proton transfer from solvent partially limits the rate of FMN reduction and that a single proton transfer gives rise to the observed solvent isotope effect. Multiple isotope effects suggest a stepwise mechanism for the reduction of FMNox. The results on enzyme kinetics described here provide evidence for the mode of action of MtCS and should thus pave the way for the rational design of antitubercular agents. PMID- 18445277 TI - Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat. AB - BACKGROUND: The Adhesion G protein-coupled receptors (GPCRs) are membrane-bound receptors with long N termini. This family has 33 members in humans. Several Adhesion GPCRs are known to have important physiological functions in CNS development and immune system response mediated by large cell surface ligands. However, the majority of Adhesion GPCRs are still poorly studied orphans with unknown functions. RESULTS: In this study we performed the extensive tissue localization analysis of the entire Adhesion GPCR family in rat and mouse. By applying the quantitative real-time PCR technique we have produced comparable expression profile for each of the members in the Adhesion family. The results are compared with literature data and data from the Allen Brain Atlas project. Our results suggest that the majority of the Adhesion GPCRs are either expressed in the CNS or ubiquitously. In addition the Adhesion GPCRs from the same phylogenetic group have either predominant CNS or peripheral expression, although each of their expression profile is unique. CONCLUSION: Our findings indicate that many of Adhesion GPCRs are expressed, and most probably, have function in CNS. The related Adhesion GPCRs are well conserved in their structure and interestingly have considerable overlap in their expression profiles, suggesting similarities among the physiological roles for members within many of the phylogenetically related clusters. PMID- 18445279 TI - Effectiveness of computer-tailored Smoking Cessation Advice in Primary Care (ESCAPE): a randomised trial. AB - BACKGROUND: Smoking remains a major public health problem; developing effective interventions to encourage more quit attempts, and to improve the success rate of self-quit attempts, is essential to reduce the numbers of people who smoke. Interventions for smoking cessation can be characterised in two extremes: the intensive face-to face therapy of the clinical approach, and large-scale, public health interventions and policy initiatives. Computer-based systems offer a method for generating highly tailored behavioural feedback letters, and can bridge the gap between these two extremes. Proactive mailing and recruitment can also serve as a prompt to motivate smokers to make quit attempts or to seek more intensive help. The aim of this study is to evaluate the effect of personally tailored feedback reports, sent to smokers identified from general practitioners lists on quit rates and quitting activity. The trial uses a modified version of a computer-based system developed by two of the authors to generate individually tailored feedback reports. METHOD: A random sample of cigarette smokers, aged between 18 and 65, identified from GP records at a representative selection of practices registered with the GPRF are sent a questionnaire. Smokers returning the questionnaire are randomly allocated to a control group to receive usual care and standard information, or to an intervention group to receive usual care and standard information plus tailored feedback reports. Smoking status and cognitive change will be assessed by postal questionnaire at 6-months. DISCUSSION: Computer tailored personal feedback, adapted to reading levels and motivation to quit, is a simple and inexpensive intervention which could be widely replicated and delivered cost effectively to a large proportion of the smoking population. Given its recruitment potential, a modest success rate could have a large effect on public health. The intervention also fits into the broader scope of tobacco control, by prompting more quit attempts, and increasing referrals to specialised services. The provision of this option to smokers in primary care can complement existing services, and work synergistically with other measures to produce more quitters and reduce the prevalence of smoking in the UK. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05385712. PMID- 18445280 TI - Validity and reliability of a home environment inventory for physical activity and media equipment. AB - BACKGROUND: Little is known about how the home environmental supports physical activity and screen media usage. The purpose of this study was to develop and test the reliability and validity of a self-report instrument to comprehensively reflect the availability and accessibility of physical activity and screen media equipment in the home environment. METHODS: Ten families participated in the initial field testing to provide feedback for instrument development. Thirty one adult participants, each of whom had at least one child 10-17 years old, completed two Physical Activity and Media Inventory (PAMI) instruments. The first PAMI was completed simultaneously, but independently, with a research assistant to assess validity. A second PAMI was completed by the participant one week later to assess reliability. RESULTS: The adult participants were mostly mothers/female guardians, mean age 38 +/- 7.2 years, mostly Caucasian (52%), college educated (65%), living in single family homes (74%). Test-retest reliability was acceptable to strong for all summary variables (physical activity equipment, ICC = 0.76 to 0.99; media equipment, ICC = 0.72 to 0.96). For validation, reports from participants and research assistants were strongly correlated (physical activity, 0.67 - 0.98; media, 0.79 - 0.96). Compared to participants, research assistants reported a greater percentage of physical activity equipment as "in plain view and easy to get to" and a smaller percentage of items as "put away and difficult to get to". CONCLUSION: Our results indicate strong evidence for the reliability and validity of the variables calculated from the PAMI. This self report inventory may be useful in assessing the availability of physical activity and screen media equipment in the home environment and could be used in conjunction with other home assessment tools (food availability, parenting styles and feeding practices) to identify obesogenic home environments. PMID- 18445281 TI - Thyroglossal duct cyst carcinoma with concurrent thyroid carcinoma: a case report. AB - INTRODUCTION: Thyroglossal duct carcinoma is a very rare finding and its presentation is similar to that of a benign cyst, which is a relatively common developmental abnormality that may manifest as a midline, neck mass. In general the diagnosis of thyroglossal duct carcinoma is based on the pathologic examination of the mass, but needle aspiration cytology, ultrasound and computed tomography play a role in the differential diagnosis of malignancy. CASE PRESENTATION: A further case of thyroglossal duct carcinoma and concurrent thyroid carcinoma with locoregional lymph node metastases affecting a 40-year-old woman followed up for 4 years is presented and discussed. CONCLUSION: Sistrunk's surgical technique must always be the initial treatment, but in case of carcinoma further surgery, that is, thyroidectomy with or without lymph node dissection, and treatment with radioactive iodine have to be considered according to the microscopic and clinical findings. Accurate pre-operative clinical and radiological evaluation should be performed in order to plan surgical strategy. PMID- 18445282 TI - Whole tumor antigen vaccination using dendritic cells: comparison of RNA electroporation and pulsing with UV-irradiated tumor cells. AB - Because of the lack of full characterization of tumor associated antigens for solid tumors, whole antigen use is a convenient approach to tumor vaccination. Tumor RNA and apoptotic tumor cells have been used as a source of whole tumor antigen to prepare dendritic cell (DC) based tumor vaccines, but their efficacy has not been directly compared. Here we compare directly RNA electroporation and pulsing of DCs with whole tumor cells killed by ultraviolet (UV) B radiation using a convenient tumor model expressing human papilloma virus (HPV) E6 and E7 oncogenes. Although both approaches led to DCs presenting tumor antigen, electroporation with tumor cell total RNA induced a significantly higher frequency of tumor-reactive IFN-gamma secreting T cells, and E7-specific CD8+ lymphocytes compared to pulsing with UV-irradiated tumor cells. DCs electroporated with tumor cell RNA induced a larger tumor infiltration by T cells and produced a significantly stronger delay in tumor growth compared to DCs pulsed with UV-irradiated tumor cells. We conclude that electroporation with whole tumor cell RNA and pulsing with UV-irradiated tumor cells are both effective in eliciting antitumor immune response, but RNA electroporation results in more potent tumor vaccination under the examined experimental conditions. PMID- 18445283 TI - Specific detection of fungal pathogens by 18S rRNA gene PCR in microbial keratitis. AB - BACKGROUND: The sensitivity and specificity of 18S rRNA polymerase chain reaction (PCR) in the detection of fungal aetiology of microbial keratitis was determined in thirty patients with clinical diagnosis of microbial keratitis. METHODS: Corneal scrapings from patients were used for Gram stain, culture and PCR analysis. PCR was performed with primer pairs targeted to the 18S rRNA gene. The result of the PCR was compared with conventional culture and Gram staining method. The PCR positive samples were identified by DNA sequencing of the internal transcribed spacer (ITS) region of the rRNA gene. Main outcome measures were sensitivity and specificity of PCR in the detection of fungus in corneal keratitis. RESULTS: Combination of microscopy and culture gave a positive result in 11 of 30 samples of microbial keratitis. PCR detected 10 of 11 samples that were positive by conventional method. One of the 19 samples that was negative by conventional method was positive by PCR. Statistical analysis revealed that the PCR to have a sensitivity of 90.9% and specificity of 94.7% in the detection of a fungal aetiology in microbial keratitis. CONCLUSION: PCR is a rapid, sensitive and useful method to detect fungal aetiology in microbial keratitis. PMID- 18445284 TI - Stable transformation of an episomal protein-tagging shuttle vector in the piscine diplomonad Spironucleus vortens. AB - BACKGROUND: Diplomonads are common free-living inhabitants of anoxic aquatic environments and are also found as intestinal commensals or parasites of a wide variety of animals. Spironucleus vortens is a putatively commensal diplomonad of angelfish that grows to high cell densities in axenic culture. Genomic sequencing of S. vortens is in progress, yet little information is available regarding molecular and cellular aspects of S. vortens biology beyond descriptive ultrastructural studies. To facilitate the development of S. vortens as an additional diplomonad experimental model, we have constructed and stably transformed an episomal plasmid containing an enhanced green fluorescent protein (GFP) tag, an AU1 epitope tag, and a tandem affinity purification (TAP) tag. This construct also contains selectable antibiotic resistance markers for both S. vortens and E. coli. RESULTS: Stable transformants of S. vortens grew relatively rapidly (within 7 days) after electroporation and were maintained under puromycin selection for over 6 months. We expressed the enhanced GFP variant, eGFP, under transcriptional control of the S. vortens histone H3 promoter, and visually confirmed diffuse GFP expression in over 50% of transformants. Next, we generated a histone H3::GFP fusion using the S. vortens conventional histone H3 gene and its native promoter. This construct was also highly expressed in the majority of S. vortens transformants, in which the H3::GFP fusion localized to the chromatin in both nuclei. Finally, we used fluorescence in situ hybridization (FISH) of the episomal plasmid to show that the transformed plasmid localized to only one nucleus/cell and was present at roughly 10-20 copies per nucleus. Because S. vortens grows to high densities in laboratory culture, it is a feasible diplomonad from which to purify native protein complexes. Thus, we also included a TAP tag in the plasmid constructs to permit future tagging and subsequent purification of protein complexes by affinity chromatography via a two-step purification procedure. CONCLUSION: Currently, progress in protistan functional and comparative genomics is hampered by the lack of free-living or commensal protists in axenic culture, as well as a lack of molecular genetic tools with which to study protein function in these organisms. This stable transformation protocol combined with the forthcoming genome sequence allows Spironucleus vortens to serve as a new experimental model for cell biological studies and for comparatively assessing protein functions in related diplomonads such as the human intestinal parasite, Giardia intestinalis. PMID- 18445285 TI - The somatically preoccupied patient in primary care: use of attachment theory to strengthen physician-patient relationships. AB - BACKGROUND: Individuals with somatic preoccupation constitute a substantial number of primary care patients. Somatically preoccupied patients are challenging to primary care physicians for several reasons including patient complaints consuming a great deal of physician time, expense to diagnose and treat and strain on the physician-patient relationship. This paper examines and discusses how disruptions in early attachment relationships such as often occurs when a female is a victim of child sexual abuse may result in somatic preoccupation in adulthood. TREATMENT UTILIZING ATTACHMENT THEORY: Attachment theory provides a useful framework for primary care physicians to conceptualize somatic preoccupation. Utilization and containment techniques grounded in an understanding of attachment dynamics aid the physician in developing a sound physician-patient relationship. Successfully engaging the patient in treatment prevents misunderstandings that frequently derail medical care for somatically preoccupied patients. PMID- 18445286 TI - Myocardial dysfunction in the periinfarct and remote regions following anterior infarction in rats quantified by 2D radial strain echocardiography: an observational cohort study. AB - BACKGROUND: Heart failure from adverse ventricular remodeling follows myocardial infarction, but the contribution of periinfarct and remote myocardium to the development of cardiomyopathy remains poorly defined. 2D strain echocardiography (2DSE) is a novel and sensitive tool to measure regional myocardial mechanics. The aim is to quantify radial strain in infarcted (I), periinfarct (PI) and remote (R) myocardial regions acutely and chronically following anterior infarction in rats. METHODS: The left anterior coronary artery of male Sprague Dawley rats (270-370 g) were occluded for 20-30 minutes and 2DSE was performed in the acute setting (n = 10; baseline and 60 minutes post-reperfusion) and in the chronic setting (n = 14; baseline, 1, 3 and 6 weeks). Using software, radial strain was measured in the mid-ventricle in short axis view. The ventricle was divided into 3 regions: I (anteroseptum, anterior and anterolateral), PI - (inferoseptum and inferolateral) and R - (inferior). Infarct size was measured using triphenyl tetrazolium chloride in the acute group. RESULTS: Following infarct, adverse remodeling occurred with progressive increase in left ventricular size, mass and reduced fractional shortening within 6 weeks. Radial strain decreased not only in the infarct but also in the periinfarct and remote regions acutely and chronically (I, PI, R, change vs. baseline, 60 minutes -32.7 +/- 8.7, -17.4 +/- 9.4, -13.5 +/- 11.6%; 6 weeks -24.4 +/- 8.2, -17.7 +/- 8.3, 15.2 +/- 8.4% respectively, all p < 0.05). Reduced radial strain in periinfarct and remote regions occurred despite minimal or absent necrosis (area of necrosis I, PI, R: 48.8 +/- 23, 5.1 +/- 6.6, 0 +/- 0%, p < 0.001 vs. I). CONCLUSION: Following left anterior coronary occlusion, radial strain decreased at 60 minutes and up to 6 weeks in the periinfarct and remote regions, similar to the reduction in the infarct region. This demonstrates early and chronic myopathic process in periinfarct and remote regions following myocardial infarction that may be an under recognized but important contributor to adverse left ventricular remodeling and progression to ischemic cardiomyopathy. PMID- 18445287 TI - Genome sequence surveys of Brachiola algerae and Edhazardia aedis reveal microsporidia with low gene densities. AB - BACKGROUND: Microsporidia are well known models of extreme nuclear genome reduction and compaction. The smallest microsporidian genomes have received the most attention, but genomes of different species range in size from 2.3 Mb to 19.5 Mb and the nature of the larger genomes remains unknown. RESULTS: Here we have undertaken genome sequence surveys of two diverse microsporidia, Brachiola algerae and Edhazardia aedis. In both species we find very large intergenic regions, many transposable elements, and a low gene-density, all in contrast to the small, model microsporidian genomes. We also find no recognizable genes that are not also found in other surveyed or sequenced microsporidian genomes. CONCLUSION: Our results demonstrate that microsporidian genome architecture varies greatly between microsporidia. Much of the genome size difference could be accounted for by non-coding material, such as intergenic spaces and retrotransposons, and this suggests that the forces dictating genome size may vary across the phylum. PMID- 18445288 TI - Accelerated intimal hyperplasia in aortocoronary internal mammary vein grafts in minipigs. AB - BACKGROUND: More than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is the initial critical step in the progression toward occlusion. Internal mammary veins, which are physiologically prone to less hydrostatic pressure, may undergo an accelerated progression to intimal hyperplasia and thus be suitable for investigation of the mechanisms of aortocoronary vein graft disease. METHODS: Six minipigs underwent aortocoronary bypass grafting using standard cardiopulmonary bypass and cardioplegic arrest. Mammary vein were grafted in a reversed manner from ascending aorta to left anterior descending coronary artery (LAD). The proximal LAD was ligated, rendering the anterior left ventricle vein graft-dependent. Minipigs were killed after 4 weeks, and vein grafts were harvested. Histological and immunohistological investigation were performed with respect to morphometric analysis, endothelial damage/dysfunction (v-Willebrand-factor (vWF)), smooth muscle cells (alpha-smooth actin) and proliferation rate (proliferation marker Ki 67). RESULTS: Mean intimal area of vein grafts was increased compared to ungrafted mammary veins. Intimal hyperplasia in vein grafts was characterized by massive accumulation of smooth muscle cells with a high proliferation rate and endothelial perturbation. Significant (p = 0.001) intimal hyperplasia of the grafted mammary vein compared to the ungrafted mammary vein was found. These changes were absent in ungrafted mammary veins. CONCLUSION: The present study demonstrates a pig model of aortocoronary vein graft intimal hyperplasia which is characterized by an accelerated progression within internal mammary veins. The model is suitable to investigate the pathophysiology of aortocoronary vein graft intimal hyperplasia as well as therapeutic approaches. PMID- 18445289 TI - An efficient method for the prediction of deleterious multiple-point mutations in the secondary structure of RNAs using suboptimal folding solutions. AB - BACKGROUND: RNAmute is an interactive Java application which, given an RNA sequence, calculates the secondary structure of all single point mutations and organizes them into categories according to their similarity to the predicted structure of the wild type. The secondary structure predictions are performed using the Vienna RNA package. A more efficient implementation of RNAmute is needed, however, to extend from the case of single point mutations to the general case of multiple point mutations, which may often be desired for computational predictions alongside mutagenesis experiments. But analyzing multiple point mutations, a process that requires traversing all possible mutations, becomes highly expensive since the running time is O(nm) for a sequence of length n with m-point mutations. Using Vienna's RNAsubopt, we present a method that selects only those mutations, based on stability considerations, which are likely to be conformational rearranging. The approach is best examined using the dot plot representation for RNA secondary structure. RESULTS: Using RNAsubopt, the suboptimal solutions for a given wild-type sequence are calculated once. Then, specific mutations are selected that are most likely to cause a conformational rearrangement. For an RNA sequence of about 100 nts and 3-point mutations (n = 100, m = 3), for example, the proposed method reduces the running time from several hours or even days to several minutes, thus enabling the practical application of RNAmute to the analysis of multiple-point mutations. CONCLUSION: A highly efficient addition to RNAmute that is as user friendly as the original application but that facilitates the practical analysis of multiple-point mutations is presented. Such an extension can now be exploited prior to site directed mutagenesis experiments by virologists, for example, who investigate the change of function in an RNA virus via mutations that disrupt important motifs in its secondary structure. A complete explanation of the application, called MultiRNAmute, is available at [1]. PMID- 18445290 TI - Concomitant ablation of atrial fibrillation in octogenarians: an observational study. AB - BACKGROUND: Cardiac surgery is increasingly required in octogenarians. These patients frequently present atrial fibrillation (AF), a significant factor for stroke and premature death. During the last decade, AF ablation has become an effective procedure in cardiac surgery. Because the results of concomitant AF ablation in octogenarians undergoing cardiac surgery are still not clear, we evaluated the outcome in these patients. METHODS: Among 200 patients undergoing concomitant AF ablation (87% persistent AF), 28 patients were >/= 80 years (82 +/ 2.4 years). The outcome was analysed by prospective follow up after 3, 6, 12 months and annually thereafter. Freedom from AF was calculated according to the Kaplan-Meier method. RESULTS: Octogenarians were similar to controls regarding AF duration (48 +/- 63.2 versus 63 +/- 86.3 months, n.s.) and left atrial diameter (49 +/- 6.1 versus 49 +/- 8.8 mm, n.s.), but differed in EuroSCORE (17.3 +/- 10.93 versus 7.4 +/- 7.31%, p < 0.001), prevalence of paroxysmal AF (25.0 versus 11.0%, p = 0.042) and aortic valve disease (67.8 versus 28.5%, p < 0.001). ICU stay (8 +/- 16.9 versus 4 +/- 7.2 days, p = 0.027), hospital stay (20 +/- 23.9 versus 14 +/- 30.8 days, p < 0.05), and 30-d-mortality (14.3 versus 4.6%, p = 0.046) were increased. After 12 +/- 6.1 months of follow-up (95% complete), 14 octogenarians (82%) and 101 controls (68%, n.s.) were in sinus rhythm; 59% without antiarrhythmic drugs in either group (n.s.). Sinus rhythm restoration was associated with improved NYHA functional class and renormalization of left atrial size. Cumulative freedom from AF demonstrated no difference between groups. Late mortality was higher in octogenarians (16.7 versus 6.1%, p = 0.065). CONCLUSION: Sinus rhythm restoration rate and functional improvement are satisfactory in octogenarians undergoing concomitant AF ablation. Hence, despite an increased perioperative risk, this procedure should be considered even in advanced age. PMID- 18445291 TI - Vehicle emissions and consumer information in car advertisements. AB - BACKGROUND: The advertising of vehicles has been studied from a safety perspective but not in terms of vehicle air pollutants. We aimed to examine the content and trends of greenhouse gas emissions and air pollution-related information, in light passenger vehicle advertisements. METHODS: Content analysis of the two most popular current affairs magazines in New Zealand for the five year period 2001-2005 was undertaken (n = 514 advertisements). This was supplemented with vehicle data from official websites. RESULTS: The advertisements studied provided some information on fuel type (52%), and engine size (39%); but hardly any provided information on fuel efficiency (3%), or emissions (4%). Over the five-year period the reported engine size increased significantly, while fuel efficiency did not improve. For the vehicles advertised, for which relevant official website data could be obtained, the average "greenhouse rating" for carbon dioxide (CO2) emissions was 5.1, with a range from 0.5 to 8.5 (on a scale with 10 being the best and 0.5 being the most polluting). The average CO2 emissions were 50% higher than the average for cars made by European manufacturers. The average "air pollution" rating for the advertised vehicles was 5.4 (on the same 1-10 scale). The yearly averages for the "greenhouse" or "air pollution" ratings did not change significantly over the five-year period. One advertised hybrid vehicle had a fuel consumption that was under half the average (4.4 versus 9.9 L/100 km), as well as the best "greenhouse" and "air pollution" ratings. CONCLUSION: To enhance informed consumer choice and to control greenhouse gas and air pollution emissions, governments should introduce regulations on the content of vehicle advertisements and marketing (as started by the European Union). Similar regulations are already in place for the marketing of many other consumer products. PMID- 18445292 TI - In vivo consequences of deleting EGF repeats 8-12 including the ligand binding domain of mouse Notch1. AB - BACKGROUND: Notch signaling is highly conserved in the metazoa and is critical for many cell fate decisions. Notch activation occurs following ligand binding to Notch extracellular domain. In vitro binding assays have identified epidermal growth factor (EGF) repeats 11 and 12 as the ligand binding domain of Drosophila Notch. Here we show that an internal deletion in mouse Notch1 of EGF repeats 8 12, including the putative ligand binding domain (lbd), is an inactivating mutation in vivo. We also show that maternal and zygotic Notch1(lbd/lbd) mutant embryos develop through gastrulation to mid-gestation. RESULTS: Notch1(lbd/lbd) embryos died at mid-gestation with a phenotype indistinguishable from Notch1 null mutants. In embryonic stem (ES) cells, Notch1(lbd) was expressed on the cell surface at levels equivalent to wild type Notch1, but Delta1 binding was reduced to the same level as in Notch1 null cells. In an ES cell co-culture assay, Notch signaling induced by Jagged1 or Delta1 was reduced to a similar level in Notch1(lbd) and Notch1 null cells. However, the Notch1(lbd/lbd) allele was expressed similarly to wild type Notch1 in Notch1(lbd/lbd) ES cells and embryos at E8.75, indicating that Notch1 signaling is not essential for the Notch1 gene to be expressed. In addition, maternal and zygotic Notch1 mutant blastocysts developed through gastrulation. CONCLUSION: Mouse Notch1 lacking the ligand binding domain is expressed at the cell surface but does not signal in response to the canonical Notch ligands Delta1 and Jagged1. Homozygous Notch1(lbd/lbd) mutant embryos die at approximately E10 similar to Notch1 null embryos. While Notch1 is expressed in oocytes and blastocysts, Notch1 signaling via canonical ligands is dispensable during oogenesis, blastogenesis, implantation and gastrulation. PMID- 18445293 TI - PCR-based gene synthesis to produce recombinant proteins for crystallization. AB - BACKGROUND: Gene synthesis technologies are an important tool for structural biology projects, allowing increased protein expression through codon optimization and facilitating sequence alterations. Existing methods, however, can be complex and not always reproducible, prompting researchers to use commercial suppliers rather than synthesize genes themselves. RESULTS: A PCR based gene synthesis method, referred to as SeqTBIO, is described to efficiently assemble the coding regions of two novel hyperthermophilic proteins, PAZ (Piwi/Argonaute/Zwille) domain, a siRNA-binding domain of an Argonaute protein homologue and a deletion mutant of a family A DNA polymerase (PolA). The gene synthesis procedure is based on sequential assembly such that homogeneous DNA products can be obtained after each synthesis step without extensive manipulation or purification requirements. Coupling the gene synthesis procedure to in vivo homologous recombination techniques allows efficient subcloning and site-directed mutagenesis for error correction. The recombinant proteins of PAZ and PolA were subsequently overexpressed in E. coli and used for protein crystallization. Crystals of both proteins were obtained and they were suitable for X-ray analysis. CONCLUSION: We demonstrate, by using PAZ and PolA as examples, the feasibility of integrating the gene synthesis, error correction and subcloning techniques into a non-automated gene to crystal pipeline such that genes can be designed, synthesized and implemented for recombinant expression and protein crystallization. PMID- 18445294 TI - Splenic rupture as the presenting manifestation of primary splenic angiosarcoma in a teenage woman: a case report. AB - INTRODUCTION: Primary splenic angiosarcoma is a rare neoplasm of vascular origin carrying a very poor prognosis, partly due to its high metastatic potential. This disease presents frequently with splenic rupture and hemorrhage. We report the case of a 17-year-old woman who presented with rupture of a primary splenic angiosarcoma. CASE PRESENTATION: The patient presented with diffuse abdominal pain and distention. Clinical examination revealed severe tenderness in the left upper abdominal quadrant, a palpable abdominal mass, and hemodynamic instability with a systolic arterial blood pressure of 75 mmHg and heart rate of 135 beats per minute. Blood tests revealed anemia (hemoglobin 7.0 g/dl) and thrombocytopenia (platelets 70 x 109/liter). After initial fluid resuscitation and stabilization, abdominal ultrasound and computed tomography were performed, revealing a large quantity of intraperitoneal free fluid, an enlarged spleen, and a heterogeneous low-density signal within the splenic parenchyma, which showed varying degrees of contrast enhancement. At laparotomy a huge (weight 1530 g, diameter 19 cm) actively bleeding spleen was identified and splenectomy was performed. Histopathology showed a primary splenic angiosarcoma. After an uneventful recovery, the patient was discharged on the sixth postoperative day. CONCLUSION: Primary splenic angiosarcoma is rare. Although this malignancy is usually encountered in advanced age, there have been a few reported cases among younger patients. The case reported here presented with splenic rupture, was treated by laparotomy and splenectomy, and the patient is disease free 16 months after surgery. PMID- 18445296 TI - Predictive factors for beneficial application of high-frequency electromagnetics for tumour vaporization and coagulation in neurosurgery. AB - OBJECTIVE: To identify preoperative and intraoperative factors and conditions that predicts the beneficial application of a high-frequency electromagnetic field (EMF) system for tumor vaporization and coagulation. METHODS: One hundred three subsequent patients with brain tumors were microsurgically treated using the EMF system in addition to the standard neurosurgical instrumentarium. A multivariate analysis was performed regarding the usefulness (ineffective/useful/very helpful/essential) of the new technology for tumor vaporization and coagulation, with respect to tumor histology and location, tissue consistency and texture, patients' age and sex. RESULTS: The EMF system could be used effectively during tumor surgery in 83 cases with an essential contribution to the overall success in 14 cases. In the advanced category of effectiveness (very helpful/essential), there was a significant difference between hard and soft tissue consistency (50 of 66 cases vs. 3 of 37 cases). The coagulation function worked well (very helpful/essential) for surface (73 of 103 cases) and spot (46 of 103 cases) coagulation when vessels with a diameter of less than one millimeter were involved. The light-weight bayonet hand piece and long malleable electrodes made the system especially suited for the resection of deep-seated lesions (34 of 52 cases) compared to superficial tumors (19 of 50 cases). The EMF system was less effective than traditional electrosurgical devices in reducing soft glial tumors. Standard methods where also required for coagulation of larger vessels. CONCLUSION: It is possible to identify factors and conditions that predict a beneficial application of high-frequency electromagnetics for tumor vaporization and coagulation. This allows focusing the use of this technology on selective indications. PMID- 18445295 TI - Delayed sleep phase cases and controls. AB - BACKGROUND: Delayed sleep phase disorder (DSPD) is a condition in which patients have difficulty falling asleep before the early morning hours and commonly have trouble awakening before late morning or even early afternoon. Several studies have suggested that variations in habitual bedtime are 40-50% heritable. METHODS: We recruited a case series of 205 participants, along with 221 controls (DSPD-C) with normal sleep, roughly matched for age, gender, and ancestry. A representative sample of San Diego adults recruited some years before was already available to confirm the control group. Both DSPD and DSPD-C provided blood or saliva samples for DNA and completed extensive questionnaires about sleep habits, sleep history, family history, sleep quality, morningness-eveningness traits, depression, mania, and seasonality of symptoms. The DSPD group wore wrist actigraphs for a median of 13.2 days. The representative sample collected previously had undergone actigraphic recordings, from which 48 hours of data were generally available. RESULTS: The DSPD and DSPD-C samples showed almost no overlap on morningness-eveningness scores. DSPD cases went to bed and arose about 3 hours later than the DSPD-C and the representative sample. DSPD cases reported more difficulties with sleep, poorer sleep quality, and more depression, but there was no significant difference in a history of mania. DSPD cases reported more family history of late bedtimes, but female DSPD reported that their fathers' bedtimes were later than the fathers of male DSPD. CONCLUSION: These results indicate a DSPD phenotype is familial and associated with unipolar depression. PMID- 18445297 TI - Assessing midwives' breastfeeding knowledge: properties of the Newborn Feeding Ability questionnaire and Breastfeeding Initiation Practices scale. AB - BACKGROUND: There are few reliable and valid tools to assess lactation and infant feeding knowledge and practices. This study tested the psychometric properties of two new scales, the Newborn Feeding Ability (NFA) questionnaire and Breastfeeding Initiation Practices (BIP) scale to assess midwives' breastfeeding knowledge and practices specific to breastfeeding initiation. METHODS: A national postal survey of Australian midwives (n = 3500) was conducted in October 2001. Reliability was determined through Cronbach's alpha coefficient and stability determined by a test-retest. Content validity was established through a critical review of literature and review by an expert panel. Construct validity was informed by an exploratory factor analysis and principle component analysis with varimax rotation. Correlations between NFA and BKQ knowledge subscale scores and BIP and BKQ practice subscale scores assessed criterion validity. A multiple hierarchical regression analysis determined predictive validity of the NFA and BIP. RESULTS: A response rate of 31.6% (n = 1107) was achieved. Adequate internal consistency was established for both instruments. Five factors on the NFA questionnaire were congruent with knowledge about effects of skin-to-skin contact, physiological stability, newborn innate abilities, work practices and effective breastfeeding. The BIP revealed three factors related to observing pre-feeding behavior, mother/baby care and attachment and positioning practices. Predictive validity of knowledge was moderate (r = 0.481, p < 0.01) and contributed to 31.5% of variance in reported practice. Midwives with high knowledge scores were more likely to report best practice when assisting mothers to initiate breastfeeding. Midwives with more personal breastfeeding experience scored higher on all scales. CONCLUSION: The Newborn Feeding Ability questionnaire and the Breastfeeding Initiation Practices scale can contribute to practice development by assessing lactation and infant feeding knowledge and practice deficits. Individual learning needs can be identified, and effectiveness of education interventions evaluated using these tools. Further testing is required with other samples of midwives and health professionals involved in the promotion of breastfeeding. PMID- 18445298 TI - Factors influencing the use of public dental services: an application of the Theory of Planned Behaviour. AB - BACKGROUND: There is limited evidence of the influence of psychosocial factors and health beliefs on public dental patient's patterns of service use in Australia. The research aims were to examine associations between dental attitudes and beliefs of public dental service users and dental visiting intention and behaviour using the Theory of Planned Behaviour. METHODS: 517 randomly selected adult public dental patients completed a questionnaire assessing dental attitudes and beliefs which was matched with electronic records for past and future dental service use. A questionnaire measured intentions, attitudes, subjective norms and perceptions of behavioural control and self efficacy in relation to visiting public dentists. A measure of dental attendance at public dental clinics was obtained retrospectively (over 3 1/2 years) and prospectively (over a one year period following the return of the questionnaire) by accessing electronic patient clinical records. RESULTS: Participants had positive attitudes, subjective norms and self-efficacy beliefs towards dental visiting but perceived a lack of control over visiting the dentist. Attitudes, subjective norms, self-efficacy and perceived control were significant predictors of intention (P < 0.05). Intentions, self-efficacy and past dental attendance were significant predictors of actual dental attendance (P < 0.05). CONCLUSION: Public dental patients held favourable attitudes and beliefs but perceived a lack of control towards dental visiting. Reducing structural barriers may therefore improve access to public dental services. PMID- 18445299 TI - Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia. AB - BACKGROUND: Honeybee's sting on human skin can induce ongoing pain, hyperalgesia and inflammation. Injection of bee venom (BV) into the intraplantar surface of the rat hindpaw induces an early onset of spontaneous pain followed by a lasting thermal and mechanical hypersensitivity in the affected paw. The underlying mechanisms of BV-induced thermal and mechanical hypersensitivity are, however, poorly understood. In the present study, we investigated the role of mitogen activated protein kinase (MAPK) in the generation of BV-induced pain hypersensitivity. RESULTS: We found that BV injection resulted in a quick activation of p38, predominantly in the L4/L5 spinal dorsal horn ipsilateral to the inflammation from 1 hr to 7 d post-injection. Phosphorylated p38 (p-p38) was expressed in both neurons and microglia, but not in astrocytes. Intrathecal administration of the p38 inhibitor, SB203580, prevented BV-induced thermal hypersensitivity from 1 hr to 3 d, but had no effect on mechanical hypersensitivity. Activated ERK1/2 was observed exclusively in neurons in the L4/L5 dorsal horn from 2 min to 1 d, peaking at 2 min after BV injection. Intrathecal administration of the MEK inhibitor, U0126, prevented both mechanical and thermal hypersensitivity from 1 hr to 2 d. p-ERK1/2 and p-p38 were expressed in neurons in distinct regions of the L4/L5 dorsal horn; p-ERK1/2 was mainly in lamina I, while p-p38 was mainly in lamina II of the dorsal horn. CONCLUSION: The results indicate that differential activation of p38 and ERK1/2 in the dorsal horn may contribute to the generation and development of BV-induced pain hypersensitivity by different mechanisms. PMID- 18445300 TI - Varicella-zoster virus ORF 58 gene is dispensable for viral replication in cell culture. AB - BACKGROUND: Open reading frame 58 (ORF58) of varicella-zoster virus (VZV) lies at the 3'end of the Unique long (UL) region and its functional is unknown. In order to clarify whether ORF58 is essential for the growth of VZV, we constructed a deletion mutant of ORF58 (pOka-BACDelta58) from the Oka parental genome cloned into a bacterial artificial chromosome (pOka-BAC). RESULTS: The ORF58-deleted virus (rpOkaDelta58) was reconstituted from the pOka-BACDelta58 genome in MRC-5 cells, indicating that the ORF58 gene is non-essential for virus growth. Comparison of the growth rate of rpOkaDelta58 and recombinant wild-type virus by assessing plaque sizes revealed no significant differences between them both in MRC-5 cells and malignant melanoma cells. CONCLUSION: This study shows that the ORF58 gene is dispensable for viral replication and does not affect the virus' ability to form plaques in vitro. PMID- 18445301 TI - Morphologically and immunohistochemically undifferentiated gastric neoplasia in a patient with multiple metastatic malignant melanomas: a case report. AB - INTRODUCTION: Malignant melanoma is a neoplasia which frequently involves the gastrointestinal tract (GIT). GIT metastases are difficult to diagnose because they often recur many years after treatment of the primary cutaneous lesion and also manifest clinically at an advanced stage of the neoplasia. Furthermore, GIT metastases can appear in various morphological forms, and therefore immunohistochemistry is often useful in distinguishing between a malignant melanoma and other malignancies. CASE PRESENTATION: We report the case of a 60 year-old man with a multiple metastatic melanoma who underwent an upper endoscopy to clarify the possible involvement of the gastric wall with a mass localized in the upper abdomen involving the pancreas and various lymph nodes, which was previously described with computed tomography. Clinically, the patient reported a progressive loss of appetite, nausea and vomiting. The upper endoscopy and histological examination revealed a gastric location of an undifferentiated neoplasm with an absence of immunohistochemical characteristics referable to the skin malignant melanoma that was removed previously. CONCLUSION: The present case report shows the difficulty in diagnosing a metastatic melanoma in the GIT and therefore, it seems worthwhile to consider metastatic malignant melanoma in the differential diagnosis of undifferentiated neoplasia. PMID- 18445303 TI - Associations of serum carotenoid concentrations with the metabolic syndrome: interaction with smoking. AB - Recent epidemiological studies show the associations of serum antioxidant status with the metabolic syndrome. Oxidative stress may play an important role in the pathogenesis of diabetes and CVD. Actually, smoking is a potent oxidative stressor in man, but little is known about the interaction of serum carotenoids and the metabolic syndrome with smoking status. In this study, the associations of the serum carotenoids with the metabolic syndrome stratified by smoking habit were evaluated cross-sectionally. A total of 1073 subjects (357 male and 716 female) who had received health examinations in the town of Mikkabi, Shizuoka Prefecture, Japan, participated in the study. Among total subjects, the OR for the metabolic syndrome in the highest tertile of serum beta-carotene was 0.41 (95 % CI 0.18, 0.92) after adjusting confounders. In current smokers, significantly lower OR were observed in the middle (OR 0.10; 95 % CI 0.01, 0.72) and highest (OR 0.06; 95 % CI 0.01, 0.73) tertiles of serum beta-carotene. Furthermore, lower OR were observed in accordance with tertiles of serum alpha-carotene and beta cryptoxanthin in current smokers (P for trend 0.042 and 0.036, respectively). In contrast, in non-smokers, a significantly lower OR was observed in the highest tertile of serum beta-carotene (OR 0.30; 95 % CI 0.10, 0.89) after multiple adjustment. Inverse associations of serum carotenoids with the metabolic syndrome were more evident among current smokers than non-smokers. These results support that antioxidant carotenoids may have a protective effect against development of the metabolic syndrome, especially in current smokers who are exposed to a potent oxidative stress. PMID- 18445302 TI - Treatment with pioglitazone induced significant, reversible mitral regurgitation. AB - There has in recent years been great concern about possible cardiac side effects of thiazolidinediones (TZDs). We present a case-report of a 60 year-old male who developed significant mitral regurgitation during six months treatment with pioglitazone in parallel with laboratory indications of fluid retention. Echocardiography six months after discontinuation of medication showed regression of mitral regurgitation and the laboratory parameters were also normalized. It is noteworthy that six months treatment with pioglitazone could induce significant valve dysfunction, which was reversible, and this underlines the importance of carefully monitoring patients when placing them on treatment with TZDs. PMID- 18445304 TI - Fasting heat production and energy cost of standing activity in veal calves. AB - Metabolic body size of veal calves is still calculated by using the 0.75 exponent and no data were available to determine energy cost of physical activity during the whole fattening period. Data from two trials focusing on protein and/or energy requirements were used to determine the coefficient of metabolic body size and the energy cost of standing activity in male Prim'Holstein calves. Total heat production was measured by indirect calorimetry in ninety-five calves weighing 60 265 kg and was divided using a modelling approach between components related to the BMR, physical activity and feed intake. The calculation of the energy cost of standing activity was based on quantifying the physical activity by using force sensors on which the metabolism cage was placed and on the interruption of an IR beam allowing the determination of standing or lying position of the calf. The best exponent relating zero activity fasting heat production (FHP 0) to metabolic body size was 0.85, which differed significantly from the traditionally used 0.75. Per additional kJ metabolizable energy (ME) intake, FHP 0 increased by 0.28 kJ; at a conventional daily 650 kJ/kg body weight (BW)0.85 ME intake, daily FHP 0 averaged 310 kJ/kg BW 0.85. Calves stood up sixteen times per day; total duration of standing increased from 5.1 to 6.4 h per day as animals became older. The hourly energy cost of standing activity was proportional to BW 0.65 and was estimated as 12.4 kJ/kg BW 0.65. These estimates allow for a better estimation of the maintenance energy requirements in veal calves. PMID- 18445305 TI - Beneficial or harmful influence of phytosterols on human cells? AB - So far, a protective influence of phytosterols on the human organism and atherogenesis has been suggested. Most studies have concentrated on the cytotoxic efficacy of phytosterols on cancer cells. However, there are only a few reports showing their influence on normal cells. The aim of the present study was to determine whether dietary plant sterols and their thermal processing products could influence the viability of normal, abdominal endothelial cells that play a crucial role in atherogenesis. Thus, we studied the effect of rapeseed oil extract components, beta-sitosterol, cholesterol and their epoxy-derivatives, 5 alpha,6 alpha-epoxy-beta-sitosterol and 5 alpha,6 alpha-epoxycholesterol, on the proliferation and viability of human abdominal aorta endothelial cells HAAE-2 in vitro. We showed strong cytotoxic properties of beta-sitosterol in HAAE-2 cells (half maximal inhibitory concentration (IC50) = 1.99 (SEM 0.56) microm) and, interestingly, a weaker cytotoxic effect of 5 alpha,6 alpha-epoxy-beta-sitosterol (IC50>200 microm). Moreover, we observed a significantly stronger cytotoxic activity of beta-sitosterol than cholesterol (IC50 = 8.99 (SEM 2.74) microm). We also revealed that beta-sitosterol as well as cholesterol caused apoptosis, inducing caspase-3 activity in the cells (60 % increase compared with control cells) that corresponded to the DNA fragmentation analysis in a terminal uridine deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) study. Although absorption of plant sterols is low compared with cholesterol, they can still influence other physiological functions. Since they effectively reduce serum LDL-cholesterol and atherosclerotic risk but also decrease the viability of cancer cells as well as normal cells in a time- and dose-dependent manner in vitro, their influence on other metabolic processes remains to be elucidated. PMID- 18445306 TI - Hypolipidaemic effects of fenofibrate and fasting in the herbivorous grass carp ( Ctenopharyngodon idella) fed a high-fat diet. AB - We investigated whether the hypolipidaemic effect of fenofibrate and fasting observed in most omnivorous mammals may also apply to herbivorous fish. Grass carp (Ctenopharyngodon idella) fed a high-fat (8 %) diet exhibited a marked increase in blood lipids and body fat after 6 weeks. They were then treated with fenofibrate (100 mg/kg body weight) in the same high-fat diet for 2 weeks, followed by fasting for 1 week. Plasma lipid concentration, body fat amount, fatty acid composition, plasma thiobarbituric acid-reactive substances and some parameters related to hepatic fatty acid oxidation were measured, and liver samples were stained for histological examination. Fenofibrate treatment decreased TAG and cholesterol concentrations in plasma, total lipids of the whole body and liver, and EPA and DHA contents in tissues. Further, a mobilisation of mesenteric fat concomitant with an increase in hepatic peroxisomal fatty acid oxidation and lipid peroxidation was observed. Compared with fenofibrate treatment, fasting decreased body weight and plasma TAG, but not plasma cholesterol. It also reduced the fat content of the whole body and increased the EPA and DHA contents in the liver and other tissues. Fatty acid oxidation was stimulated by fasting in mitochondria, but not in peroxisomes. These data suggest that fenofibrate and fasting regulate the lipid metabolism in grass carp through different metabolic pathways. The grass carp is moderately responsive to a fibrate derivative in comparison with the well-known excess responsiveness of the rat model, and so it could be used for the study of lipid abnormalities as a herbivorous model. PMID- 18445307 TI - Evaluation of the preventative effects exerted by Lactobacillus fermentum in an experimental model of septic shock induced in mice. AB - The preventative effects of the probiotic Lactobacillus fermentum CECT5716 were evaluated in the lipopolysaccharide (LPS) model of septic shock in mice. The probiotic was administered suspended in drinking water at the final concentration of 108 colony-forming units/ml for 2 weeks before the induction of an endotoxic shock by an intraperitoneal injection of LPS (400 microg/200 microl per mouse). Blood and different organs were collected after 24 h to evaluate the severity of the endotoxic shock and the preventative effects of the probiotic. L. fermentum reduced TNF-alpha levels in blood, which promotes the major alterations observed during septic shock, as well as the infiltration of activated neutrophils into the lungs. Furthermore, free radical overproduction and oxidative stress were associated with a significant decrease in hepatic glutathione levels in septic mice, and with an excessive NO production attributed to the induction of the inducible isoform of NO synthase (iNOS). In fact, hepatic glutathione levels were significantly increased in the group of mice receiving the probiotic, and the increased iNOS expression both in the colon and lungs was down-regulated in those mice treated with L. fermentum. Finally, pre-treatment with L. fermentum may also exert its protective action modulating the expression of different cytokines in splenocyte-derived T cells such us IL-2, IL-5, IL-6 or IL-10. In conclusion, pre treatment with L. fermentum may exert its protective action against LPS-induced organ damage in mice by a combination of several actions including its antioxidant properties and by reduction of the synthesis of the pro-inflammatory TNF-alpha and IL-6. PMID- 18445308 TI - Interactions of ethanol drinking with n-3 fatty acids in rats: potential consequences for the cardiovascular system. AB - Moderate ethanol drinking (ED) and n-3 fatty acids have both been associated with low cardiac mortality. However, there are few data evaluating the interactions of ED with n-3. We recently reported that moderate ED results in increased n-3 in cardiac patients. The main aim of the present study was, through a well controlled experimental model, to confirm that chronic ED actually results in increased n-3. Secondary aims were to examine the effects of chronic ED on cardiac mitochondria, cardiac function and experimental myocardial infarction. We studied the fatty acid profiles of plasma, cell membranes and cardiac mitochondria phospholipids in a rat model of chronic ED. In plasma and cell membranes, ED actually resulted in higher n-3 (P = 0.005). In mitochondria phospholipids of ED rats, n-3 were also increased (P < 0.05) but quite modestly. Cardiac mitochondrial function and left ventricular function were not significantly different in ED and control rats, while infarct size after 30 min ischaemia and reperfusion was smaller (P < 0.0001) in ED rats. This is the first animal study confirming interaction of alcohol drinking with n-3. We found no harmful effect of chronic ED on the heart in that model but a significant cardioprotection. Further studies are warranted to investigate the mechanisms by which moderate ED alters the metabolism of n-3 and whether n-3 are the mediators of the ED-induced cardioprotection. PMID- 18445309 TI - A risk model for lung resection: data from the European Thoracic Database Project. AB - The development, application and interpretation of risk models is becoming an important activity in a number of surgical disciplines. In this paper, we discuss the many issues that arise when constructing a risk model, with particular reference to the development of a risk model for thoracic surgery. First, we briefly revisit the origins of risk modelling in cardiothoracic surgery. PMID- 18445310 TI - Effects of castration and testosterone replacement on the antioxidant defense system in rat left ventricle. AB - There is strong evidence that oxidative stress plays a key role in the pathophysiology of several cardiovascular diseases. On the other hand, the presence of specific receptors for androgens and estrogens in the myocardium implies that sex hormones play a physiological role in cardiac function, myocardial injury, and the regulation of the redox state in the heart. The present study was designed to determine whether castration and androgen replacement result in changes in the capacity of the antioxidant defense system in the left ventricle (LV) of adult male rats. To assess this, the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione peroxidase [GPX], catalase [CAT], and glutathione reductase [GR]), concentrations of nonenzymatic antioxidants (reduced glutathione [GSH] and alpha- and gamma-tocopherols), and oxidative stress biomarkers (tissue sulfhydryl groups, protein nitrotyrosine levels, and lipid peroxidation) were measured in castrated animals (CAS), castrates replaced with testosterone (CAS+T), and sham-operated controls (Sham). Testosterone was not detectable in serum from gonadectomized rats. The results indicate that castration significantly and negatively affected the antioxidant status of rat LV, as evidenced by a significant decline in activities of all antioxidant enzymes, by a tendency toward lower levels of GSH and protein thiol groups, and by enhanced lipid peroxidation and higher nitrotyrosine concentrations in left ventricular tissue. Increases in LV tissue concentrations of alpha- and gamma-tocopherols seem to be a compensatory response to enhanced oxidative stress induced by gonadectomy. The reestablishment of physiological serum testosterone level by androgen replacement resulted in a tendency toward a further decrease in the antioxidant defense status in the LV tissue. PMID- 18445311 TI - Political disagreement in intergroup terms: contextual variation and the influence of power. AB - In two studies we examined justified attributions made in the face of political disagreement. Study 1 showed that Australian supporters and opponents of Australian involvement in the 2003 invasion of Iraq made stereotypical attributions that justified the superiority of the in-group over the out-group. Stereotypical attributions were consistent with the justification that the supporters of the war had been misled by dishonest political leaders. Study 2 replicated this pattern with supporters and opponents of Australia's policy of mandatory detention of asylum seekers. It also identified pragmatism as a dimension that dominant, government-aligned, groups may use to justify the superiority of the in-group over the out-group. In both studies political leaders were seen as more competent than members of the public. The results show the influence of intergroup power and within-group leader/supporter distinctions on people's attributions about political disagreement. They point to the power of social psychological theory to help analyse important contemporary political concerns. PMID- 18445312 TI - [Selection of bak siRNA sequences and its influence on Al-induced apoptosis of SH SY5Y cell line]. AB - OBJECTIVE: To find the optimal design of small interfering RNA compounds, transfection concentration and transfection time to reduce the Al-induced apoptosis in SH-SY5Y cells. METHODS: Three siRNA sequences on bak gene were designed and transfected into SH-SY5Y cells, which were treated at various concentrations of aluminum. Cell viability was detected by CCK-8 kit on different siRNA sequences, various transfection concentrations, and diverse transfection courses. Transfection efficiency was determined by fluorescent staining of CY3, and interference efficiency was measured by QRT-PCR. Besides, immunohistochemical staining was used to express Bak protein content. Finally, apoptotic rate and necrotic rate in Al treated SH-SY5Y cells transfecting by the selected bak siRNA 1 were detected. RESULTS: Based on the viability of siRNA sequences, siRNA 1 was selected as the optimal siRNA sequences. The optimal transfection concentration was 10 nmol/L, and the optimal time course was 24 h after transfection. The transfection efficiency was above 90% and the interference efficiency with bak gene was 57.76%. Furthermore, there was significant transfection effect on Bak protein. The apoptotic rate in Al treated SH-SY5Y cells were significantly decreased by bak siRNA 1 transfection. CONCLUSION: Apoptosis is one of the major cell death pathways in SH-SY5Y cells induced by aluminum. When chemically synthesized siRNA is inducted to neural cells, it can significantly reduce bak gene level, decrease Bak protein expression and apoptotic rate, which may serve as the basis for preventing neural cells apoptosis and inhibiting the development of neurodegenerative diseases. PMID- 18445313 TI - [Activated protein 1-cyclin D1/E2F 1 pathways involved in cell cycle changes induced by benzo (a) pyrene]. AB - OBJECTIVE: To investigate the roles of activated protein 1 (AP-1) in cell cycle changes on human embryo lung fibroblasts (HELF) induced by benzo (a) pyrene [B (a) P], and relationships between AP-1 and cyclin D1/CDK4-E2F-1/4. METHODS: Cells transfected with AP-1 luciferase reporter plasmid (AP-H) were cultured with serum free RPMI1640 for 48 h, and treated with 2 micromol/L B (a) P for 24 h. AP-1 relative activity was detected by luciferase assay. Changes of cell cycle and the expression of cyclin D1, CDK4 and E2F-1/4 were checked using the flow cytometer and Western blot assay. RESULTS: After B (a) P was treated for 24 h, the ratio of G1 phase cells (71 +/- 2)% was decreased to (48 +/- 3)% (P < 0.05), and an increase was observed in the ratio of S phase. AP-1 activity and cyclin D1/E2F-1 expression were increased significantly, but CDK4/E2F-4 expression did not change after B (a) P treatment. When AP-1 activity was inhibited by curcumin, decreases of G1 phase in response to B (a) P treatment were blocked, and overexpression of cyclin D1/E2F-1 was attenuated, but CDK4/E2F-4 expression was not changed significantly. CONCLUSION: AP-1 is involved in B (a) P induced cell cycle changes, and is the upstream signals of cyclin D1/E2F-1, but not CDK4/E2F-4. PMID- 18445314 TI - [Quantitative method of health risk assessment for occupational exposure to benzene based on dose-response models]. AB - OBJECTIVE: To study a quantitative method of health risk assessment for occupational exposure to benzene, and to provide theoretical basis for occupational health risk research in our country. METHODS: The probability of the occurrence of cancer during the lifetime of individual exposed to an agent at dose D during lifetime was estimated by using dose-response models. The relationships between internal dose of substance in question and the probability of occurrence of a tumor could be formulated by probit model, logit model, Weibull model, one hit model, multi-hit model, or multistage model. The functions between internal dose and exposure concentrations could be obtained by pharmacokinetic analysis or human epidemiological data fitting. Then, by incorporating these functions into dose-response models, the risk at various exposure levels of exposed populations could be estimated. RESULTS: The risk of workers exposed to benzene in a plant was estimated by two-stage model, one hit model and Weibull model respectively, given the concentrations of benzene. The dose-response curves obtained from three models were all linear. The risk at mean concentration 7.25 mg/m3 were 7.50 x 10(-4), 1.83 x 10(-4), 2.31 x 10(-6) respectively. The value by two-stage model was maximal and the value by Weibull model was minimum. CONCLUSION: This method can be used to assess the risk of exposure to hazardous substances in the workplace, and lifetime cancer risk of exposed populations can be estimated. PMID- 18445315 TI - [MicroRNA profiles of malignantly transformed cells induced by anti-benzo-a pyrene-trans-7, 8-dihydrodiol-9, 10-epoxide]. AB - OBJECTIVE: To screen microRNA (miRNA) profiles of malignantly transformed cells induced by anti-benzo-a-pyrene-trans-7, 8-dihydrodiol-9, 10-epoxide (BPDE) and to look for miRNAs which is expressed differently between malignantly transformed cells and normal human bronchial epithelial cells 16HBE. METHODS: Experimental group was the malignantly transformed 16HBE which was induced by cultured with final concentration 2.0 micromol/L of BPDE which was dissolved in dimethyl sulphoxide. The control group was 16HBE that was cultured with minimal essential medium including dimethyl sulphoxide. 327 miR-NAs were tested be-tween those two groups with miRNA microarray analysis. MiR-10a that was down expressed and miR 320 that was overexpressed were selected to be validated by miRNA specific quantitative real-time reverse transcriptase chain reaction (miR qRT-PCR). RESULTS: 327 human miRNAs were tested with miRNA microarray analysis. 55 miRNAs were found expressing differently between those two groups and of which 46 were overexpressed and 9 were down expressed. Some data were validated by quantitative RT-PCR. CONCLUSION: miRNAs expressed significantly between malignantly transformed 16HBE and normal cells and this helps us look for unique miRNAs of malignantly transformed cells induced by BPDE, but there should have more sufficient evidences to prove their functions in malignant cells. PMID- 18445316 TI - [Detection of binding of three aldehyde compounds with DNA using high performance liquid chromatograph]. AB - OBJECTIVE: To detect the binding sites and characteristics of the adduct from the reaction of formaldehyde, acetaldehyde, acrolein with DNA. METHODS: Formaldehyde, acetaldehyde, acrolein were reacted with four kinds of deoxyribonucleoside monophosphate (dNMP) in buffered solutions with neutral pH. The reaction products were separated by high performance liquid chromatograph (HPLC) and characterized by UV spectroscopy. RESULTS: The reaction of formaldehyde, acetaldehyde with dG was separated and detected by HPLC. The reaction of acrolein, formate, acetic acid, Mercapturic acid with dG was not separated and detected by HPLC, while the dominant dNMP binding with formaldehyde, acetaldehyde was also determined. CONCLUSION: Formaldehyde, acetaldehyde could bind with dGMP to express genotoxic effects. PMID- 18445318 TI - [Survey of psychological status of nursing workers in a hospital]. PMID- 18445317 TI - [Cyto-genotoxicity induced by 2, 2', 4, 4'-tetrabromodiphenyl ethers combined with 2, 2', 4, 4', 5-hexachlorobiphenyl treatment in SH-SY5Y cells]. AB - OBJECTIVE: To investigate the cyto-genotoxicity of 2, 2', 4, 4' tetrabromodiphenyl ethers (PBDE-47) combined with 2, 2', 4, 4', 5 hexachlorobiphenyl (PCB153) treatment in SH-SY5Y cells. METHODS: Exponentially growing SH-SY5Y cells were exposed to different concentrations of PBDE-47 or/and PCB153 for 24 h in vitro. Cell viability, DNA damage, chromosome abnormalities, and DNA-protein crosslinks (DPC) were measured using MTT, comet assay, cytokinesis-block micronucleus (CBMN) test, and SDS-KCl assay respectively. RESULTS: Compared to the each single PBDE-47 groups, the nuclear division index (NDI) was significantly lower (P < 0.05) and the frequencies of micronuclei (MNI), percentage of DNA in the tail, Olive tail moment and DPC were significantly increased (P < 0.05) in the PBDE-47 combined with PCB153 groups. There was a statistical decrease in cell viability in groups of 4 micromol/L PBDE 47 and above combined with PCB153 than that in contrast to the same dose of PBDE 47 group or PCB153 alone (P < 0.05). Significant increase was found in MNI frequency and DPC in 2 micromol/L PBDE-47 and above combined with PCB153 than those in the single PCB153 group (P < 0.05). In the groups of 4 micromol/L PBDE 47 and above combined with PCB153, the cell NDI were significantly lower than that of the single PCB153 group (P < 0.05). Compared to the single PCB153 group, the percentage of DNA in the tail and Olive tail moment was significantly increased in the 8 micromol/L PBDE-47 combined with 5 micromol/L PCB153. Factorial analysis showed that interactions between PBDE-47 and PCB153 existed in inhibiting cell viability, inducing DNA damage, MNI, and DPC formation (P < 0.01), and possessing synergistic effects. CONCLUSION: Some dose of PBDE-47 combined with PCB153 can inhibit cell viability, induce DNA damage, DPC formation, and chromosome abnormalities. The pattern of the combined effect is synergistic in cyto-genotoxicity. PMID- 18445321 TI - [Analysis and strategy of current condition of occupational diseases prevention in labor employment organizations]. PMID- 18445319 TI - [Relation between genetic polymorphism of hMSH2 and genetic predisposition of chronic occupational benzene poisoning]. PMID- 18445322 TI - [Preliminary investigation on occupational hygiene archives information management]. PMID- 18445323 TI - [Survey of current condition of occupational hygiene technology service organizations in Guangxi Province]. PMID- 18445324 TI - [Gas chromatography for determination of naphthalene in air of working places]. PMID- 18445325 TI - [Pumpless individual sampling gas chromatography for determination of dichloromethane in air of working places]. PMID- 18445326 TI - [Thermal desorption gas chromatography for determination of diisobutyl ketone in air of working places]. PMID- 18445327 TI - [Gas chromatography for determination of paraquat derivatives in blood]. PMID- 18445328 TI - [Ion chromatography for determination of iodine in air of working places]. PMID- 18445329 TI - [One patient with multiple organ impairment induced by acute severe benzene poisoning]. PMID- 18445331 TI - [An accident of group lead poisoning]. PMID- 18445332 TI - [Experience of prevention of dispute in diagnosis of occupational disease]. PMID- 18445334 TI - [Problems and suggestions for occupational health education in farmer workers]. PMID- 18445335 TI - [Clinical characteristics and treatment of explosive injury of lungs caused by burn in gas explosion]. PMID- 18445336 TI - [Chest X-ray manifestation in hydrogen sulfide poisoning combined with drowning]. PMID- 18445337 TI - Interleukin-7 receptor signaling network: an integrated systems perspective. AB - Interleukin-7 (IL-7) is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor (IL-7R), activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstalk, shared interaction domains, feedback loops, integrated gene regulation, multimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7 receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology. PMID- 18445338 TI - Salmonella typhi: from a human pathogen to a vaccine vector. AB - Salmonella (S.) typhi is an important intracellular pathogen. Among the more than 2,300 closely-related Salmonella serovars bacteria recognized, S. typhi is the only one that is pathogenic exclusively for humans, in whom it causes typhoid or enteric fever. The pathogen has been around for many years and many studies have been done in an effort to combat it. Molecular and biologic features of S. typhi and host factors and immune responses involved in Salmonella invasion have been extensively studies. Vaccines that have been developed most notably are Vi polysaccharide and Ty21a. However, as the results show, there is still a long way to go. It is also shown that multi-drug resistance has occurred to the few available antibiotics. More and more studies have shown that Salmonella can be used as a vaccine vector carrying antigens of other pathogens. This has been promising in that the immune system can be elicited in response to both the Salmonella bacteria and the antigen of the pathogen in question. This review aims to highlight some of the milestones attained in the fight against the disease from the time S. typhi was seen as a pathogen causing typhoid fever to the use of Salmonella as a vaccine vector. PMID- 18445339 TI - Human TSLP-educated DCs. AB - Thymic stromal lymphopoietin (TSLP), an IL-7-related cytokine, is widely expressed by epithelial cells in many tissues with different biological effects. Human TSLP (hTSLP) has been shown to play an important role in promoting T cell homeostasis, developing nondeletional central tolerance, amplifying epithelium induced class switching, inducing atopic diseases and maintaining intestinal noninflammatory environment. Among diverse cells responding to hTSLP, dendritic cells (DCs) are the most obviously characterized target cells. In this review, we attempt to outline an effect of the functional versatility of hTSLP-activated DCs (hTSLP-DCs) on T cells. PMID- 18445340 TI - Stem cell niche, the microenvironment and immunological crosstalk. AB - The concept of stem cells, their physiological existence, the intricate anatomical localization, the known and the unknown functions, and their exclusive utility for the purpose of regenerative medicine, are all now encompassed within an emergent question, 'how compatible these cells are immunologically?' Indeed, the medical aspects of stem cells are dependent on a large number of queries based on the basic properties of the cells. It has greatly been emphasized to probe into the basic research on stem cells before any successful therapeutic attempts are made. One of the intricate aspects of the adult stem cells is its immunological behavior in relation to the microenvironmental associates, the stromal cells in the presence of a suitable target. PMID- 18445341 TI - Apoptosis and proinflammatory cytokine responses of primary mouse microglia and astrocytes induced by human H1N1 and avian H5N1 influenza viruses. AB - Patients with an influenza virus infection can be complicated by acute encephalopathy and encephalitis. To investigate the immune reactions involved in the neurocomplication, mouse microglia and astrocytes were isolated, infected with human H1N1 and avian H5N1 influenza viruses, and examined for their immune responses. We observed homogeneously distributed viral receptors, sialic acid (SA)-alpha2,3-Galactose (Gal) and SA-alpha2,6-Gal, on microglia and astrocytes. Both viruses were replicative and productive in microglia and astrocytes. Virus induced apoptosis and cytopathy in infected cells were observed at 24 h post infection (p.i.). Expression of IL-1beta, IL-6 and TNF-alpha mRNA examined at 6 h and 24 h p.i. was up-regulated, and their expression levels were considerably higher in H5N1 infection. The amounts of secreted proinflammatory IL-1beta, IL-6 and TNF-alpha at 6 h and 24 h p.i. were also induced, with greater induction by H5N1 infection. This study is the first demonstration that both human H1N1 and avian H5N1 influenza viruses can infect mouse microglia and astrocytes and induce apoptosis, cytopathy, and proinflammatory cytokine production in them in vitro. Our results suggest that the direct cellular damage and the consequences of immunopathological injury in the CNS contribute to the influenza viral pathogenesis. PMID- 18445342 TI - Distinct effect of CD40 and TNF-signaling on the chemokine/chemokine receptor expression and function of the human monocyte-derived dendritic cells. AB - A key and limiting step in the process of human monocyte-derived dendritic cells (mDCs) for clinical use is their in vitro maturation and in vivo migration. We previously observed that CD40 signal facilitated human mDC growth and maturation. To further explore this process, mDCs generated with GM-CSF and IL-4 were co cultured with apoptotic tumor cells for 24 hours, followed by incubating with anti-CD40 monoclonal antibody or TNF-alpha for 48 hours to generate mature DCs. The chemokine/chemokine receptor expression and functions of mature DCs upon various stimuli were determined. The expression of costimulatory molecules on apoptotic tumor cell-loaded mature DCs co-cultured with either anti-CD40 antibody (anti-CD40-DCs) or TNF-alpha (TNF-DCs) were up-regulated compared to immature DCs, consistent with the abilities of these cytokine to drive DC maturation in vitro. The mRNA levels of chemokines such as stromal cell-derived factor-1alpha (SDF-1alpha), EBV-induced molecule 1 ligand chemokine (ELC), and IFN inducible protein-10 (IP-10) in anti-CD40 activated DCs were increased and the dendritic cell-specific chemokine 1 (DC-CK1) was moderately up-regulated as compared with other mature DCs. The corresponding chemokine receptors CXCR4 and CCR7 of anti CD40-DCs were significantly expressed. The CXCR3 expression on activated T cells stimulated by anti-CD40-DCs was also increased. Moreover, the anti-CD40-DCs had a stronger ability to stimulate T cell proliferation than any other DCs. The NF kappaB activity was much higher in anti-CD40-DCs than that of TNF-DCs. These results offer further evidence of the importance of the CD40 signal in developing efficient human DC vaccines for cancer immune therapy. PMID- 18445344 TI - Activity after site-directed mutagenesis of CD59 on complement-mediated cytolysis. AB - CD59 may inhibit the cytolytic activity of complement by binding to C8/C9 and protect host cell membranes against homologous membrane attack complex (MAC). However, CD59 is widely overexpressed on tumor cells, which has been implicated in tumorigenesis. The active site of CD59 relative to MAC is still confused. As reported the MAC binding site is located in the vicinity of a hydrophobic groove on the membrane distal face of the protein centered around residue W40. Here two site-directed mutagenesis were performed by overlapping extension PCR to delete residue W40 site (Mutant 1, M1) or to change C39W40K41 to W39W40W41 (Mutant 2, M2). Then we constructed mutant CD59 eukaryotic expression system and investigated their biological function on CHO cells compared with wild-type CD59. Stable populations of CHO cells expressing recombinant proteins were screened by immunotechnique. After 30 passages culturing, proteins could be tested. Dye release assays suggest that M1CD59 loses the activity against complement, while M2CD59 increases the anti-complement activity slightly. Results indicate that W40 of human CD59 is important to its activity, and prohibition of this site may be a potential way to increase complement activity and to treat tumors. PMID- 18445343 TI - Dysfunction of murine dendritic cells induced by incubation with tumor cells. AB - In vivo studies showed that dendritic cell (DC) dysfunction occurred in tumor microenvironment. As tumors were composed of many kinds of cells, the direct effects of tumor cells on immature DCs (imDCs) are needed for further studies in vitro. In the present study, bone marrow-derived imDCs were incubated with lymphoma, hepatoma and menaloma cells in vitro and surface molecules in imDCs were determined by flow cytometry. Then, imDCs incubated with tumor cells or control imDCs were further pulsed with tumor lysates and then incubated with splenocytes to perform mixed lymphocyte reaction. The DC-dependent tumor antigen specific T cell proliferation, and IL-12 secretion were determined by flow cytometry, and enzyme-linked immunosorbent assay respectively. Finally, the DC dependent tumor-associated antigen-specific CTL was determined by enzyme-linked immunospot assay. The results showed that tumor cell-DC incubation down-regulated the surface molecules in imDCs, such as CD80, CD54, CD11b, CD11a and MHC class II molecules. The abilities of DC-dependent antigen-specific T cell proliferation and IL-12 secretion were also decreased by tumor cell incubation in vitro. Most importantly, the ability for antigenic-specific CTL priming of DCs was also decreased by incubation with tumor cells. In the present in vitro study demonstrated that the defective abilities of DCs induced by tumor cell co incubation and the co-incubation system might be useful for future study of tumor immune cells direct interaction and for drug screen of immune-modulation. PMID- 18445345 TI - Defect of CD8+ memory T cells developed in absence of IL-12 priming for secondary expansion. AB - IL-12 priming plays an important role in stimulation of CD8+ effector T cells and development of CD8+ memory T (Tm) cells. However, the functional alteration of CD8+ Tm cells developed in the absence of IL-12 priming is elusive. In this study, we investigated the capacity of secondary expansion of CD8+ Tm cells developed from transgenic OT I CD8+ T cells. The latter cells were in vitro and in vivo stimulated by ovalbumin (OVA)-pulsed dendritic cells [DCOVA and (IL-12-/ )DCOVA] derived from wild-type C57BL/6 and IL-12 gene knockout mice, respectively. We demonstrated that IL-12 priming is important not only in CD8+ T cell clonal expansion, but also in generation of CD8+ Tm cells with the capacity of secondary expansion upon antigen re-encounter. However, IL-12 signaling is not involved in CD8+ Tm cell survival and recall responses. Therefore, this study provides useful information for vaccine design and development. PMID- 18445346 TI - cAMP modulates macrophage development by suppressing M-CSF-induced MAPKs activation. AB - M-CSF is a key cytokine in macrophage development by inducing MAPKs activation, and cAMP can inhibit MAPKs activation induced by inflammatory stimuli. To explore the effects of cAMP on M-CSF-induced MAPKs activation and on macrophage development, the model of bone marrow-derived murine macrophages (BMMs) was used. The effects of cAMP on M-CSF-induced MAPKs activation were analyzed by Western blotting assay, and the effects of cAMP on CD14 and F4/80 expression during macrophage development were examined by FACS analysis. Macrophage morphology showed the successful establishment of the model of macrophage development. Western blotting assay revealed that M-CSF activated ERK, JNK and p38 in both mature and immature macrophages, and cAMP inhibited M-CSF-induced ERK, JNK and p38 activation in a time-dependent manner. FACS analysis revealed that macrophage development was impaired with cAMP pretreatment. In conclusion, cAMP modulates macrophage development by suppressing M-CSF-induced MAPKs activation. PMID- 18445347 TI - A much-anticipated FDA reform bill is signed into law: progress and compromise. PMID- 18445348 TI - Inflammation at the islets of langerhans and its role for the pathogenesis of type 2 diabetes. PMID- 18445350 TI - Latent (slowly progressing) autoimmune diabetes in adults. AB - About 10% of patients with the clinical presentation of type 2 diabetes suffer from an autoimmune form of diabetes associated with a rapid decline of residual beta-cell mass and subsequent development of insulin dependency. In this condition, called latent autoimmune diabetes in adults (LADA), there are clinical and metabolic features intermediate between type 1 and type 2 diabetes. Recent studies provide novel information on the immune markers associated with progressive beta-cell loss in LADA patients. However, LADA pathogenesis is still poorly understood; further studies are needed to establish general recommendation for preventing and treating this subtype of autoimmune diabetes. PMID- 18445349 TI - Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization. AB - Mucosal administration of insulin represents an attractive antigen-specific therapeutic approach to preventing type 1 diabetes. It can prevent autoimmune diabetes in animal models, but although it has been shown to be safe, it has not yet been proven effective in human studies. Efficacy may depend on the dose and route at which insulin is administered, the stage in type 1 diabetes pathogenesis at which treatment is initiated, and the study cohort that is treated. We have proposed Pre-POINT (Primary Oral/intranasal INsulin Trial), a dose-finding safety and immune efficacy pilot study for primary mucosal insulin therapy in islet autoantibody-negative children at high genetic risk for type 1 diabetes who naturally first develop autoimmunity to insulin. Pre-POINT aims to identify an optimal insulin dose and route of application (orally or intranasally) that is well tolerated and can induce an immune response to insulin for additional use in a phase II/III primary prevention trial in children at risk. PMID- 18445351 TI - T cells in the pathogenesis of type 1 diabetes. AB - T lymphocytes' crucial role in the autoimmune process leading to insulin dependent type 1 diabetes is now universally recognized. Research focuses on identifying pathogenic and nonpathogenic T cells, understanding how they are primed and expanded, characterizing their antigen specificity, and ultimately on devising strategies to blunt their autoaggressive action. In this review, we focus on recent progress identified in three different areas. Results obtained with transgenic mice acknowledge proinsulin's unique role in triggering autoimmunity and suggest that other beta-cell proteins are recognized as a result of epitope spreading, at least in the nonobese diabetic mouse. Progress has also been achieved by developing and validating reliable CD4+ and CD8+ T-cell tests that may prove valuable for diagnostic and prognostic purposes in the near future. Finally, recent results provide novel and important guidance for manipulating autoreactive T-cell responses against beta-cell antigens. PMID- 18445353 TI - Intensive diabetes treatment and cognition: no long-lasting effects of recurrent hypoglycemia. PMID- 18445352 TI - Immunomodulation of autoimmune diabetes by dendritic cells. AB - The biology and properties of dendritic cells (DCs) have been intensely studied in the research areas of infectious diseases, tumor immunology, and vaccine development. This unique subset of immune cells has recently also moved to the center of interest for basic and clinical research in autoimmunity, owing not only to the extraordinary importance of DCs in the initiation and sustenance of adaptive immune responses, but also to more recent discoveries about their profound ability to control and downregulate ongoing T-cell responses. We review current progress of using DCs in mice for induction and propagation of autoimmune T-cell responses and their therapeutic potential to dampen or even stop beta-cell specific autoimmunity. Finally, we offer our perspective on how basic research progress in DC technology, mostly from mouse models, may translate into emerging diagnostic and therapeutic applications for human type 1 diabetes. PMID- 18445354 TI - Psychosocial and behavioral aspects of diabetic foot lesions. AB - This article reviews key findings from recently conducted and ongoing studies into how patients adapt to diabetic foot complications by focusing on two areas. These areas include the role of psychological factors in guiding preventive foot self-care and the impact of diabetic foot ulceration and amputations on an individual's emotional state and quality of life. PMID- 18445355 TI - Behavioral aspects of weight loss in type 2 diabetes. AB - Recent research has clearly shown that lifestyle intervention can reduce the risk of diabetes in those with impaired glucose tolerance; weight reduction appears to be the primary determinant of this effect. Weight loss can also improve glycemic control and cardiovascular risk factors in those with diabetes; however, the long term impact of weight loss on cardiovascular morbidity and mortality is still under investigation. An important finding is that modest weight losses of just 5% to 10% of initial body weight appear sufficient to produce these benefits for diabetes prevention and cardiovascular risk reduction. PMID- 18445356 TI - Cognition and brain imaging in type 1 diabetes. AB - Type 1 diabetes has mild effects on cognition that are influenced by age of onset, hyperglycemia, and hypoglycemic episodes. Some of these changes occur quite early in the disease course. Studies using relatively new brain imaging techniques have also shown brain changes in adults and children that appear to be influenced by metabolic abnormalities present in diabetes. Early detections of brain changes may be early indicators of subsequent cognitive abnormalities. PMID- 18445357 TI - Genetics of metabolic syndrome. AB - Metabolic syndrome (MetS) is a common phenotype, affecting about 24% of the US population. It is associated with an increased risk for type 2 diabetes and cardiovascular disease. Although there is no universally accepted definition for MetS, affected individuals commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidemia, and dysglycemia. Recently, there has been extensive interest in potential genetic contributions to MetS. At present, no single gene or cluster of genes has been consistently replicated for MetS among different populations, likely due to the complex interplay between gene and environment necessary for expression of this phenotype. We review recent studies regarding the genetic contributions to MetS. PMID- 18445359 TI - Genes and nonalcoholic fatty liver disease. AB - Whereas most individuals with nonalcoholic fatty liver disease (NAFLD) will have steatosis, only a minority will ever develop progressive disease. Family studies and interethnic variations in susceptibility suggest that genetic factors may be important in determining disease risk. Although no genetic associations with advanced NAFLD have been replicated in large studies, preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, tumor necrosis factor-alpha, transforming growth factor-beta, and angiotensinogen may be associated with steatohepatitis and/or fibrosis. With the advent of high throughput gene analyses and the reduced cost of whole genome-wide scans, it seems likely that genes contributing to inherited susceptibility to this common disease will be identified in the near future. PMID- 18445360 TI - Bicarbonate supplementation as a preventive way in statins-induced muscle damage. AB - PURPOSE: The aim of this study was to evaluate the bicarbonate-induced improvement of statins, cerivastatin, simvastatin acid and lovastatin acid induced apoptosis using rat myoblast cell line (L6) as a model of in vitro skeletal muscle and of cerivastatin-induced muscle damage in vivo study. METHODS: Statin-induced reduction of cell viability and apoptosis was measured by 3-(4,5 dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay and caspase assay. In vivo, we evaluated plasma creatine phosphokinase (CPK) level in cerivastatin-treated rat. RESULTS: Bicarbonate prevented cerivastatin-, simvastatin- acid and lovastatin acid -induced reduction of cell viability, morphological change and caspase activation in L6 cells. Moreover, in the in vivo study, bicarbonate prevented cerivastatin-induced increase in CPK concentrations. CONCLUSIONS: These results from in vitro and in vivo studies support that bicarbonate supplementation prevented statin-induced muscle damage. PMID- 18445358 TI - TCF7L2 genetic defect and type 2 diabetes. AB - After two decades of limited success, the genetic architecture of type 2 diabetes (T2D) is finally being revealed. Within only 2 years, an avalanche of studies identified several genes expressed in pancreatic beta cells and involved in the control of insulin secretion, such as transcription factor 7-like 2 (TCF7L2), a key element of the Wnt signaling pathway. In Europeans, genome-wide association scans showed that TCF7L2 has been the most important locus predisposing to T2D so far. For the first time, a gene is consistently involved in T2D susceptibility in all major ethnic groups. At the individual level, carrying the TCF7L2 risk allele increases T2D risk 50%. However, at the population level, the attributable risk is lower than 25% and varies with the allele frequency. The presence of the TCF7L2 rs7903146 risk allele increases TCF7L2 gene expression in beta cells, possibly impairing glucagon-like peptide-1-induced insulin secretion and/or the production of new mature beta cells. The tremendous association of TCF7L2 polymorphisms with T2D provides new insights into future genetic predisposition tests but remains the tip of the T2D genetic iceberg. PMID- 18445361 TI - Effect of malnutrition on the pharmacokinetics of cefuroxime axetil in young rats. AB - PURPOSE: To determine the pharmacokinetics of cefuroxime axetil in malnourished rats using a diet with a restriction in energy and nutrients (group M), a diet with a low quality protein (group K) and a good quality diet (group C) as a control. METHODS: The rats were fed with the corresponding diet during 21 days. After this period a single oral dose of cefuroxime axetil (equivalent to a 2.2 mg dose of cefuroxime) was administered, and plasma samples were taken at 0, 5, 10, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes; samples were assayed using an HPLC assay. Biochemical parameters were also measured an a microscopy study of the small intestine was done. After a 21 day period of recovery of the malnourished groups a second pharmacokinetic study was performed using the same sample times as in the first study. RESULTS: In malnourished animals of group K the levels of plasma proteins were low, and showed higher concentrations of fat in the liver. The relative bioavailability of cefuroxime was 78.2% for group M and 64.4% for group K. Groups M and K presented lower values of area under the curve, which means that the amount of antibiotic absorbed was lower than group C. In the second pharmacokinetic study although the animals received a good quality diet, it was observed that the area under the curve of group K was lower, and the relative bioavailability was 54.3%, while group M had similar pharmacokinetic values than control group. CONCLUSIONS: The pharmacokinetics of cefuroxime was affected by malnutrition, suggesting that the absorption process via the transporter was modified in the malnourished groups, specially in the group fed with a low quality protein. PMID- 18445362 TI - Effects of pioglitazone on erectile dysfunction in sildenafil poor-responders: a randomized, controlled study. AB - PURPOSE: The effects of pioglitazone on sildenafil responsiveness in men with erectile dysfunction(ED) and a history of poor response to sildenafil were assessed. METHODS: In a double-blinded study,38 men aged 47 +/- 1.5 years with moderate-to severe ED and poor response to sildenafil were randomly assigned to take a premedication of pioglitazone 30 mg (n=19) or placebo (n=19) once daily for 9 weeks along with on-demand use of sildenafil during the last month of pioglitazone treatment.Erectile function (EF) scores, assessed by EF domain of International Index of Erectile Function (IIEF), along with responses to Global Assessment Questions (GAQs) were major outcome measures. Serum levels of total testosterone (T),dehydroepiandrosterone sulfate (DHEAS), glucose,lipid profile and liver function test were minor outcome measures. RESULTS: Pioglitazone significantly improved major outcome measures compared with placebo. The decrease from baseline of total cholesterol level was more in pioglitazone than in placebo treated groups. In 84% (32 out of 38) of the sildenafil poor-responders, at least one of the associated risk factors of ED was found. There was undiagnosed hypercholesterolemia in 34% of the subjects. Serum levels of T, DHEAS, glucose and other parameters remained unchanged in both groups. The intervention was well tolerated. CONCLUSIONS: Pioglitazone increased sildenafil response to improve ED of men with prior sildenafil failure and seems to be safe based on the present preliminary study. This improvement is likely regardless of fasting glucose and sex hormones levels. PMID- 18445363 TI - Review of the cosolvency models for predicting solubility of drugs in water cosolvent mixtures. AB - The cosolvency models presented from 1960 to 2007 were reviewed and their accuracies for correlating and/or predicting the solubility of drugs in water cosolvent mixtures were discussed. The cosolvency models could be divided into theoretical, semi-empirical and empirical models, the first group of models provide basic information from the solution, while the last group of models are good suitable for solubility correlation studies. The simplest cosolvency model, i.e. the log-linear model of Yalkowsky, provides an estimate of drug solubility in water-cosolvent mixtures using aqueous solubility of the drug, whereas the Jouyban-Acree model predicts the solubility with an acceptable error with the cost of one more data point (the solubility in neat cosolvent) which is required as input value in the prediction process. A number of error terms used in the literature was also discussed with a brief comments on the acceptable prediction error for pharmaceutical applications. PMID- 18445364 TI - Oral immunization against hepatitis B using bile salt stabilized vesicles (bilosomes). AB - PURPOSE: Most of the presently available vaccines including hepatitis B vaccines administered through parenteral route, fail to induce a mucosal antibody response. Therefore, oral immunization appears to be an effective and attractive alternative to parenteral immunization. However, the problem of degradation of antigen in the harsh and hostile environment of the gastrointestinal tract consequently requires larger doses and more frequent dosing of antigen. Furthermore, much larger doses can induce antigen tolerance. Therefore the purpose of the present study was firstly to overcome these problems by the use of bile salt stabilized vesicles (bilosomes) and HBsAg as the model antigen,which could provide both protection to the antigen as well as enable transmucosal uptake and subsequent immunization. Another purpose of this study was to determine the dose that could produce serum antibody titres against hepatitis B via the oral route compared to those following intramuscular immunization. METHODS: In the present study bilosomes containing recombinant hepatitis B surface antigen were prepared by a lipid cast film method. HBsAg loaded bilosomeswere characterized in vitro for their shape, size, percent antigen entrapment and stability. Fluorescence microscopy was carried out to confirm the uptake of bilosomes by gut associated lymphoid tissues (GALT). The in vivo part of the study comprised estimation of anti-HBsAg IgG response in serum and anti HBsAg sIgA in various body secretions using specific ELISA techniques following oral immunization with low dose loaded bilosomes (B1, 10 microg), intermediate dose loaded bilosomes (B2, 20 microg) and high dose loaded bilosomes (B3, 50 microg) in BALB/c mice. RESULTS: Fluorescence microscopy suggested that there was an increase in fluorescence intensity following the uptake of bilosomes entrapped FITC-BSA in gut associated lymphoid tissues. The high dose HBsAg bilosomes (B3, 50 microg) produced comparable anti-HBsAg IgG levels in serum to those observed in the case of intramuscular administration of alum adsorbed HBsAg (10 microg). In addition, the bilosomal preparations elicited measurable sIgA in mucosal secretions, where the highest responses were observed with high dose HBsAg bilosomes (B3,50 microg) and as expected, intramuscular administered alum adsorbed HBsAg (10 microg) failed to elicit such responses. CONCLUSIONS: HBsAg loaded bilosomes produced both systemic as well as mucosal antibody responses upon oral administration. Furthermore, bilosomes with a five times higher dose upon oral administration produced comparable serum antibody titres to those obtained after intramuscular immunization without the induction of systemic tolerance. PMID- 18445365 TI - Evolutionary artificial neural networks as tools for predicting the internal structure of microemulsions. AB - PURPOSE: The purpose of this study was to predict microemulsion structures by creating two artificial evolutionary neural networks (ANN) combined with a genetic algorithm. The first ANN would be able to determine the type of microemulsion from the desired composition, and the second to determine the type of microemulsion directly from a differential scanning calorimetry (DSC) curve. METHODS: The algorithms and the structures for each ANN were constructed and programmed in C++ computer language. The ANNs had a feedforward structure with one hidden level and were trained using a genetic algorithm. DSC was used to determine the microemulsion type. RESULTS: The ANNs showed very encouraging accuracy in predicting the microemulsion type from its composition and also directly from the DSC curve. The percentage success, calculated over the tested data, was over 90%. This enabled us, with satisfactory accuracy, to construct several pseudoternary diagrams that could facilitate the selection of the microemulsion composition to obtain the optimal desired drug carrier. CONCLUSIONS: The ANN constructed here, enhanced with a genetic algorithm, is an effective tool for predicting the type of microemulsion. These findings provide the basis for reducing research time and development cost for characterizing microemulsion properties. Its application would stimulate the further development of such colloidal drug delivery systems, exploit their advantages and, to a certain extent, avoid their disadvantages. PMID- 18445366 TI - Validation of a HPLC method for flavonoid biomarkers in skullcap (Scutellaria) and its use to illustrate wide variability in the quality of commercial tinctures. AB - PURPOSE: To compare the flavonoid biomarker content (baicalin, baicalein and wogonin) of eleven commercial tinctures derived from Scutellaria lateriflora aerial parts (n=7) and Scutellaria baicalensis root (n=4). S. lateriflora tinctures are used in by western herbal practitioners to treat anxiety whereas S. baicalensis tinctures are used to treat inflammatory disease. METHODS: Baicalin and baicalein were purchased from Aldrich Chemical Co. and Wogonin was purchased from ChromaDex. The internal standard (4-hydroxybenzoic acid) was obtained from Acros Organics. The column used was a Luna C18, 5 m (150 x 4.6 mm, Phenomenex) maintained at ambient room temperature. A HP1050 HPLC system was used, comprising a gradient pump with degasser, a variable wavelength UV detector set to 270 nm, and an autosampler. Gradient elution was performed using 0.1% formic acid (eluent A) and methanol (eluent B). The gradient elution initial conditions were 45% B with linear gradient to 60% from 2 to 10 min, followed by linear gradient to 70% B at 30 min, and then linear gradient to 99% B at 31 min, this proportion being maintained for 1 min. The mobile phase was then returned to initial conditions at 33 min and maintained until the end of the run at 35 min. The flow rate was 1 mL/min. The assay was validated for sensitivity, accuracy and reproducibility. RESULTS: The concentration range of biomarkers (baicalin, baicalein and wogonin) in commercial tinctures is reported for S. lateriflora (baicalin: 0-12.66 mg/mL; baicalein: 0-0.63 mg/mL; wogonin: 0-0.16 mg/mL) and for S. baicalensis (baicalin: 0.12-10.61 mg/mL; baicalein: 0.52-5.88 mg/mL; wogonin: 0.08-1.61 mg/mL). CONCLUSION: The wide variability in biomarker concentrations between commercial tinctures has important implications for the manufacturers of commercial tinctures, for herbal practitioners in the choice of tinctures and not least for pharmacology and clinical researchers. PMID- 18445367 TI - Effects of diabetes mellitus induced by alloxan on the pharmacokinetics of metformin in rats: restoration of pharmacokinetic parameters to the control state by insulin treatment. AB - PURPOSE: To test the effect of insulin treatment on the pharmacokinetics of metformin in rats with diabetes mellitus induced by alloxan (DMIA rats). The following results were reported from other studies. Metformin was metabolized via hepatic CYP2C11, 2D1, and 3A1/2 in rats. In DMIA rats, the protein expression and mRNA levels of hepatic CYP2C11 and 3A1/2 decreased and increased, respectively. In rat model of diabetes mellitus induced by streptozotocin, the protein expression of hepatic CYP2D1 was not changed. The increase in hepatic CYP1A2, 2B1, and 2E1, and decrease in hepatic CYP2C11 in DMIA rats was returned to the controls by insulin treatment. METHODS: Metformin (100 mg/kg) was administered intravenously and orally to the control rats, DMIA rats, and DMIA rats with insulin treatment for 3 weeks (DMIA rats with insulin). RESULTS: After intravenous administration of metformin to the DMIA rats, the CLR and CLNR of the drug were significantly slower than the controls. After oral administration of metformin to the DMIA rats, the AUC of the drug was also significantly greater than the controls. After intravenous administration of metformin to the DMIA rats with insulin, the significantly slower CLNR of the drug in the DMIA rats was returned to the controls. The altered pharmacokinetic indices observed following intravenous and oral administration of metformin to DMIA rats returned to the control values in the DMIA rats with insulin. CONCLUSIONS: The significantly slower CLNR of metformin in the DMIA rats could be due to the decrease in hepatic CYP2C11 than the controls. The comparable CLNR of metformin between the DMIA rats with insulin and the control rats could be due to restoration of hepatic CYP enzyme changes in DMIA rats to the controls. PMID- 18445368 TI - The tape-stripping technique as a method for drug quantification in skin. AB - Quantification of drugs within the skin is essential for topical and transdermal delivery research. Over the last two decades, horizontal sectioning, consisting of tape stripping throughout the stratum corneum, has become one of the traditional investigative techniques. Tape stripping of human stratum corneum is widely used as a method for studying the kinetics and penetration depth of drugs. This paper shows the applications of the tape stripping technique to quantify drug penetration through the skin, underlining its versatile application in the area of topical and transdermal drugs. PMID- 18445369 TI - The impact of electronic prescribing on the professionalization of community pharmacists: a qualitative study of pharmacists' perception. AB - PURPOSE: To understand how the technology of electronic prescription (e Rx) can transform the community pharmacist's role through its effects on professionalization. We define professionalization as a pharmaceutical practice centred on clinical activities and made possible by the establishment of professional pharmaceutical services. METHODS: We asked 12 community pharmacists who had participated in an e Rx pilot project in the Canadian province of Quebec to fill out a qualitative survey on their experience. We then analyzed the pharmacists' perceptions of this new technology using a conceptual framework based on the Davenport typology that presents an exhaustive list of mechanisms, specific to Information Technologies, and thus e-Rx, that can potentially modify information management process and then the role of pharmacists. RESULTS: The pharmacists identified five main mechanisms by which e Rx could affect the professionalization of community pharmacists: analytical capabilities of the pharmacist and physician, dissemination of knowledge, integration of process tasks, process automation and elimination of intermediaries. These mechanisms can assist pharmacists in exercising their professional judgement by improving the quality of available information and facilitate the execution of prescriptions by improving the quality of orders. E Rx technology can also strengthen pharmacists' credibility as medication specialists in the eyes of both patients and physicians. Thus, e Rx can become a collaborative technology to the extent that it improves collaboration between community pharmacists and prescribing physicians. However, the potential benefits of this technology would appear to depend on its characteristics and how prescribing physicians use it. CONCLUSIONS: E-Rx proposes ways of working and communicating that were previously unimaginable. These new possibilities pave the way for transformations that can significantly increase the professionalization of community pharmacists. The results of this study indicate that community pharmacists have a favourable opinion of e Rx, believing it can be an ally in their professionalization. PMID- 18445370 TI - The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole. AB - PURPOSE: To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ). METHODS: Some important CYP isoenzymes (rat CYP1A1, 1A2, 2C6, 2C11, 2D1, 2D2, and 3A1 and human CYP1A1, 1A2, 2D6 and 3A4) were spiked with various concentrations of AM to determine the relative kinetic parameters for formation of DEA in the presence and absence of various concentrations of KTZ. RESULTS: The formation of DEA was observed when AM was exposed to each of the CYP tested, although the rates were varied. Human CYP1A1 followed by 3A4 had the highest intrinsic clearance (CLint) for DEA formation whereas in rat, CYP2D1 followed by CYP2C11 had the highest CLint. Human and rat CYP1A2 seemed to have the lowest CLint. At high concentrations of AM and KTZ, near those expected in vivo, significant inhibition of all isoforms except for rat CYP1A2 was observed. At lower concentration ranges of both drugs, the inhibitory constant was determined. At these levels, KTZ was found to potently inhibit human CYP1A1 and 3A4 and rat 2D2 and 1A1. CONCLUSION: Human CYP1A1 and 3A4 and rat CYP2D1 and 2C11 were most efficient in converting AM to DEA. For DEA formation, the in vivo administration of KTZ could inhibit other CYP isoforms besides CYP3A in human and rat. PMID- 18445371 TI - Bioequivalence assessment of topical clobetasol propionate products using visual and chromametric assessment of skin blanching. AB - PURPOSE: The assessment of the degree of skin blanching following the application of a formulation containing a topical corticosteroid has been established as a surrogate method for the determination of bioequivalence. In this study, both visual and chromametric assessments have been carried out on two topical creams containing clobetasol propionate (0.05%) and the results from both methods are compared. METHODS: Human subjects (volunteers) were screened using a cream containing 0.05%clobetasol propionate, in order to identify appropriate subjects for inclusion in the study. The study was implemented according to the FDA guidance using both visual and chromameter assessment techniques. Blanching responses were assessed visually by three trained, independent observers and instrumentally using a Chromameter. An ED50 of 36 min was used as the dose duration based upon data previously obtained from a pilot study using the same topical corticosteroid reference product. A visual rating scale of 0-4 and the a scale readings from the chromameter were used. RESULTS: The visual and chromameter blanching profiles showed similar blanching responses with good correspondence. The 90% confidence intervals for the data from both methods were calculated using Locke's method. When only the data obtained from 23 subjects who were identified as"detectors" (as per FDA guidance) were used, the products fell within the bioequivalence acceptance range of 80-125% using the visual assessment method (99.3-111.6%) whereas the data using a chromameter (86.5-129.3%) were just outside the acceptance limits. However, when all subjects (n=34) were included in the calculations, both the visual (97.9-109.2) and chromameter (90.2-120.7) data fell within the bioequivalence acceptance range. CONCLUSIONS: Whereas visual data indicated bioequivalence using either data from "detectors" or data from all subjects, the chromameter data from "detectors" only indicated bioinequivalence but inclusion of all subject data fell within the acceptance range to be declared bioequivalent. PMID- 18445373 TI - Continuing importation of falciparum malaria from Goa into Europe. PMID- 18445374 TI - Public health response to an avian influenza A (H5N1) poultry outbreak in Suffolk, United Kingdom, in November 2007. PMID- 18445375 TI - Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. PMID- 18445376 TI - Observed oseltamivir resistance in seasonal influenza viruses in Europe interpretation and potential implications. AB - In this weeks issue of Eurosurveillance, Zambon and colleagues describe the first findings of the European Union-funded European Surveillance Network for Vigilance Against Viral Resistance (VIRGIL) of some seasonal influenza viral isolates resistant to the antiviral drug oseltamivir in Europe. PMID- 18445380 TI - Chikungunya virus in north-eastern Italy: a consequence of seasonal synchronicity. PMID- 18445381 TI - Ongoing measles outbreak in southern Bavaria, Germany. PMID- 18445382 TI - Eurosurveillance moves on... PMID- 18445384 TI - Unusual brain disease death in the United Kingdom: possible implications for variant Creutzfeldt-Jacob disease. PMID- 18445385 TI - Trends in hepatitis B incidence in Romania, 1989-2005. AB - In the early 1990s, Romania had a high incidence of hepatitis B, with over 30 cases per 100,000 population annually. The disease represented a serious public health problem, especially for children. As a result, public health measures were introduced during the 1990s such as the enforcement of the use of single-use needles and a routine vaccination programme for children and health workers. This paper describes the change in incidence of HBV infection in Romania from the late 1980s until 2005, and demonstrates the impact of those measures. They have lead to a dramatic decrease in hepatitis B incidence across the country: overall, the incidence has decreased from 43 per 100,000 in 1989 to 8.5 per 100,000 in 2004. The decrease has been most prominent in children under 15, dropping from 81 to 11 per 100,000 population and year during that period. PMID- 18445386 TI - First confirmed cases of Clostridium difficile PCR ribotype 027 in Norway. PMID- 18445387 TI - An interactive central database of vaccinations in Iceland. PMID- 18445388 TI - Food-borne viruses in Europe network report: the norovirus GII.4 2006b (for US named Minerva-like, for Japan Kobe034-like, for UK V6) variant now dominant in early seasonal surveillance. PMID- 18445389 TI - Outbreak of serogroup C meningococcal disease in Veneto region, Italy. PMID- 18445390 TI - Fatal case of human rabies (Duvenhage virus) from a bat in Kenya: The Netherlands, December 2007. PMID- 18445392 TI - Analysis of the surveillance situation for viral encephalitis and meningitis in Europe. AB - Infective processes in the brain, spinal cord and meninges are considered to be the main causes of encephalitis, myelitis and meningitis. However, most cases remain unexplained. The incidence of different viral aetiologies (zoonotic and non-zoonotic) is especially poorly estimated, due to the lack of a standard case definition and of agreed diagnostic algorithms, including harmonised diagnostic methods and sample collection. It is important to clarify the incidence of viral encephalitis/meningitis and to optimise the diagnosis of infectious neurological illness, particularly to ensure early recognition of outbreaks or emerging infectious such a West Nile encephalitis. The European Network for Diagnostics of 'Imported' Viral Diseases (ENIVD) has analysed the present surveillance situation for viral encephalitis/meningitis in Europe. Here we give an overview of the existing epidemiological sources of information in European Union (EU) Member States, mapping the laboratory capacity and identifying key requirements for a possible future surveillance study at European level. The data presented will help design a harmonised/standardised Europe-wide surveillance study investigating patients with encephalitis and/or meningitis in order to obtain more information on the role of infections in these rarely analysed syndromes, both from a clinical and an epidemiological perspective. PMID- 18445393 TI - Creating an online atlas of Salmonella serotypes in Europe. PMID- 18445394 TI - Autochthonous chikungunya virus transmission may have occurred in Bologna, Italy, during the summer 2007 outbreak. PMID- 18445395 TI - Multidrug-resistant methicillin-resistant Staphylococcus aureus (MRSA) strain in a men-who-have-sex-with-men (MSM) community in the United States: comment. PMID- 18445396 TI - HIV testing in Europe: from policies to effectiveness some highlights from the meeting. PMID- 18445397 TI - High rates of metallo-beta-lactamase-producing Klebsiella pneumoniae in Greece--a review of the current evidence. AB - For the last four years Greece has faced a large number of infections, mainly in the intensive care units (ICU), due to carbapenem-resistant, VIM-1-producing Klebsiella pneumoniae. The proportion of imipenem-resistant K. pneumoniae has increased from less than 1% in 2001, to 20% in isolates from hospital wards and to 50% in isolates from ICUs in 2006. Likewise, in 2002, these strains were identified in only three hospitals, whereas now they are isolated in at least 25 of the 40 hospitals participating in the Greek Surveillance System. This situation seems to be due to the spread of the blaVIM-1 cassette among the rapidly evolving multiresistant plasmids and multiresistant or even panresistant strains of mainly K. pneumoniae and also other enterobacterial species. However, the exact biological basis of this phenomenon and the risk factors that facilitate it are not yet fully understood. Moreover, the fact that most strains display minimum inhibitory concentration (MIC) values below or near the Clinical Laboratory Standard Institute (CLSI) resistance breakpoint create diagnostic and therapeutic problems, and possibly obstruct the assessment of the real incidence of these strains. An evidence-based consensus on the therapeutic strategy for these infections is urgently needed. The problem of VIM-producing K. pneumoniae was timely recognized by the Greek System for the Surveillance of Antimicrobial Resistance and various guidelines, including advice on antibiotic policy and infection control, were developed by the National Centre for Disease Control and Prevention. However, these measures have yet had a relatively small impact on the situation. The best way to handle the problem of antibiotic resistance would be the development and implementation of a national integrated strategic action plan (currently under development) affirming the political commitment of the public health administration in confronting this issue. PMID- 18445398 TI - European Centre for Disease Prevention and Control issues guidance for the introduction of human papillomavirus (HPV) vaccines in European Union countries. PMID- 18445399 TI - The influenza season has started in a number of European countries. PMID- 18445400 TI - A secondary case of meningococcal disease in an ambulance worker, Berkshire, November 2007. PMID- 18445404 TI - Looking for tips to find icebergs--surveillance of haemolytic uraemic syndrome to detect outbreaks of Shiga toxin-producing E. coli infection. PMID- 18445405 TI - The first report on Campylobacter coli family outbreak detected in Poland in 2006. AB - A family outbreak of gastroenteritis caused by Campylobacter coli occurred in May 2006 in Bielsko-Biala, in the south of Poland. Four members of a family had non bloody diarrhea and abdominal cramps. C. coli were isolated in three of the four patients. PFGE and PCR-RFLP-flaA patterns confirmed the link between cases, showing the usefulness of these methods in outbreak investigation. At the same time, the epidemiological and environmental investigations of this outbreak were very limited and did not provide enough evidence to identify the source of infection, and thus to support the hypothesis formulated by the local epidemiologist. It is necessary to improve surveillance of campylobacteriosis mainly by multidisciplinary training of epidemiologists, microbiologists and general practitioners. PMID- 18445406 TI - First outbreak of methicillin-resistant Staphylococcus aureus ST398 in a Dutch hospital, June 2007. PMID- 18445407 TI - A cluster of measles cases in Denmark following importation, January and February 2008. PMID- 18445410 TI - Progressive inflammatory neuropathy (PIN) among swine slaughterhouse workers in Minnesota, United States, 2007-2008. PMID- 18445411 TI - The introduction of the SENTINEL influenza surveillance system in Poland- experiences and lessons learned from the first three epidemic seasons. AB - Influenza surveillance provides information on virus activity and is necessary for the selection of vaccine strains and early warning. To improve this surveillance in Poland, a sentinel surveillance system was introduced in 2004-5 influenza season (SENTINEL). This paper presents results from SENTINEL during three seasons of its existence. Voivodship Sanitary-Epidemiological Stations (VSESs), physicians and the National Influenza Center (NIC) participate in SENTINEL. Laboratory course was performed by the NIC for VSESs. Stations were provided with procedures, report forms, etc. Physicians register number of influenza-like illnesses (ILI) and collect swabs. VSESs perform diagnostic tests. On the basis of information from VSESs, the NIC prepares weekly reports for the entire country. In 2004-5 epidemiological reports were received from 50% of VSESs, while in 2005-6 and 2006-7 from all VSESs. Virological reports were obtained from 37.5% of VSESs (2004-5), 75% (2005-6) and 94% (2006-7). Weekly number of reporting physicians ranged in three consecutive seasons from 165 to 219, 98 to 949 and 696 to 1,054. A total of 399 specimens were tested during the 2004-5 winter; 63 (16%) were positive for influenza and 21 (5%) for other respiratory viruses. In 2005-6, 949 specimens were tested. Influenza infections were confirmed in 47 cases (5%) and infections with other respiratory viruses in 36 cases (4%). A total of 1,195 specimens were tested during the 2006-7 winter; 37 (3%) were positive for influenza and 26 (2%) for other respiratory viruses. SENTINEL provided improvement of influenza surveillance when compared with seasons before 2004. Nevertheless, due to decreasing rate of positive specimens, virological surveillance is the most important part to improve in the next years. PMID- 18445412 TI - An outbreak of measles in an ultra-orthodox Jewish community in Jerusalem, Israel, 2007--an in-depth report. AB - Measles elimination in Europe is hindered by recurrent outbreaks, typically in non-immunised specific sub-populations. In 2003 and 2004, two measles outbreaks occurred in Jewish ultra-orthodox communities in Jerusalem, Israel. In 2007, another measles outbreak emerged in Jerusalem. Epidemiological investigation and control activities were initiated. Three measles cases (15 years old, 22 years old and an infant; all unvaccinated) were diagnosed in Jerusalem in August 2007. All three belonged to Jewish ultra-orthodox communities in London, United Kingdom, and had had contact with patients in London. The epidemiological investigation did not reveal any connection between these cases other than their place of origin. The disease spread rapidly in extremely ultra-orthodox sub groups in Jerusalem. Until 8 January 2008, 491 cases were reported. Most patients (70%) were young children (0-14 years old), 96% unimmunized. Frequently, all the children in a large family were infected; two thirds of the cases belonged to family clusters of more than two patients per family (in part due to non compliance with post-exposure prophylaxis recommendations). The high age-specific incidence among infants 0-1-year- (408.5/100,000) and 1-4-year-olds (264.1/100,000) is a cause for concern. The hospitalisation rate was 15% (71/491), mainly due to fever, patients (26.7%) presented with pneumonitis or pneumonia and two patients presented with encephalitis. There have not been any deaths to date. The outbreak was apparently caused by measles importation into unprotected groups. Despite a high national immunisation coverage (94-95%), programmes to increase and maintain immunisation coverage are essential, with special focus on specific sub-populations. PMID- 18445413 TI - Measles in south-west Germany imported from Switzerland--a preliminary outbreak description. PMID- 18445414 TI - Measles outbreak in Switzerland--an update relevant for the European football championship (EURO 2008). PMID- 18445415 TI - Mumps outbreak in young adults following a festival in Austria, 2006. AB - Mumps is not a mandatorily notifiable disease in Austria. However, in the first week of May 2006, a sudden increase in serologically confirmed cases of mumps, confined to three public health districts of the southern Austrian province of Carinthia, was identified by the Austrian Reference laboratory for MMR. An epidemiological investigation of this cluster of mumps cases was performed. A total of 214 cases fulfilled the outbreak case definition; 143 cases were laboratory confirmed and 71 cases were epidemiologically linked and fulfilled the clinical picture of the case definition. The vaccination status was known for 169 patients. Nearly half of the cases for whom the vaccination status was known occurred in non-vaccinated persons, another 40% were vaccinated with one dose of the vaccine and 11% had received two doses. Only four mumps cases occurred in children aged 14 years or younger, indicating that the vaccination coverage and the acceptance of the recommended childhood vaccinations have strongly improved within the past 15 years. Vaccination scheme failure but not vaccine failure is primarily to blame for this mumps outbreak. PMID- 18445416 TI - Outbreak of verocytotoxin-producing E. coli O145 and O26 infections associated with the consumption of ice cream produced at a farm, Belgium, 2007. AB - In October 2007, an outbreak of verocytotoxin-producing Escherichia coli (VTEC) O145 and E. coli O26 occurred among consumers of ice cream produced and sold in September 2007 at a farm in the province of Antwerp (Belgium). The ice cream was consumed at two birthday parties and also eaten at the farm. Five children, aged between two and 11 years, developed haemolytic uraemic syndrome (HUS), and seven other co-exposed persons contracted severe diarrhoea. In three of the five HUS cases VTEC O145 infections were laboratory confirmed, one in association with VTEC O26. Identical isolates of E. coli O145 and O26 were detected with PCR and PFGE in faecal samples of patients and in ice cream leftovers from one of the birthday parties, in faecal samples taken from calves, and in samples of soiled straw from the farm at which the ice cream was produced. Ice cream was made from pasteurised milk and most likely contaminated by one of food handlers. PMID- 18445417 TI - Vector-related risk mapping of the introduction and establishment of Aedes albopictus in Europe. PMID- 18445418 TI - Excess mortality as an epidemic intelligence tool in chikungunya mapping. PMID- 18445419 TI - Imported schistosomiasis in Europe: preliminary data for 2007 from TropNetEurop. PMID- 18445420 TI - Three cases of tularaemia in southern Baden-Wuerttemberg, Germany, November 2007. PMID- 18445422 TI - Swiss study suggests condom use not necessary for some HIV-positive patients. PMID- 18445423 TI - Strengthening Europe's epidemic intelligence capacity: the first collaboration between a European Union Member State and the European Centre for Disease Prevention and Control. PMID- 18445424 TI - The value of ProMED-mail for the Early Warning Committee in the Netherlands: more specific approach recommended. AB - This article describes a retrospective and descriptive study into the added value of ProMED-mail--the global electronic reporting system for outbreaks of emerging infectious diseases and toxins maintained by the International Society for Infectious Diseases--as an early warning system for The Netherlands Early Warning Committee (NEWC). Information about infectious disease events in foreign countries originating from ProMED-mail was retrieved from the reports of the NEWC between May 2006 and June 2007. Each event was analysed in depth in order to determine if it could have been a possible threat to public health in The Netherlands. It was determined whether these events were mentioned in other sources of information used by the NEWC besides ProMED-mail. In addition, we assessed the possible consequences of missing an event when not reading ProMED mail or of being informed of the event with a time delay. Semi-structured interviews with stakeholders were conducted to explore other functions of ProMED mail besides early warning. Five out of 25 events reported in ProMED-mail were assessed as a potential threat to The Netherlands, mainly because of the known vulnerability of The Netherlands for vaccine preventable diseases: an outbreak of measles in the United Kingdom and Japan, a case of poliomyelitis in Kenya, and two events concerning Highly Pathogenic Avian Influenza (HPAI) H5N1. The outbreak of measles in Japan and one case of HPAI H5N1 infection in a bird in Germany were only reported by ProMED-mail; the other potential threats were mentioned in other sources with a time delay. ProMED-mail has a limited but real added value over other sources in the early warning of threats. A more specific approach of using ProMED-mail by defining vulnerabilities of a country would be useful and efficient. ProMED-mail is appreciated for providing background and preliminary outbreak information. PMID- 18445425 TI - Oseltamivir resistance in human seasonal influenza viruses (A/H1N1) in EU and EFTA countries: an update. PMID- 18445426 TI - High rates of fluoroquinolone-resistant Campylobacter in Portugal--need for surveillance. PMID- 18445429 TI - Human Listeria monocytogenes infections in Europe--an opportunity for improved European surveillance. AB - The 2006 Community Summary Report from the European Food Safety Authority (EFSA) and the European Centre for Disease Prevention and Control (ECDC) was published recently with the latest trends and figures on the occurrence of zoonotic infections and agents, antimicrobial resistance and foodborne outbreaks in the then 25 European Union (EU) Member States and five non-EU countries. This article seeks to expand further upon reports of human listeriosis (Listeria monocytogenes infections) and changes in the epidemiology of this disease, in order to inform of important developments as they relate to an opportunity for the establishment of a formalized listeriosis surveillance network in Europe. PMID- 18445427 TI - Epidemic intelligence in the European Union: strengthening the ties. PMID- 18445430 TI - Increase in the spread of human immunodeficiency virus in Sweden, 2007. PMID- 18445431 TI - Community-associated methicillin-resistant Staphylococcus aureus ST8 ("USA300") in an HIV-positive patient in Cologne, Germany, February 2008. PMID- 18445432 TI - Mumps outbreak ongoing since October 2007 in the Republic of Moldova. PMID- 18445433 TI - An outbreak of measles in Reims, eastern France, January-March 2008--a preliminary report. PMID- 18445438 TI - Meningococcal disease in an ambulance worker. PMID- 18445439 TI - A European survey on public health policies for managing cases of meningococcal disease and their contacts. AB - In 2007, a European survey was conducted to compare national policies on public health management of cases of meningococcal disease and their contacts. The results revealed differences in definitions of close contacts and prophylactic regimens between countries. These differences can be attributed to a lack of evidence on optimal prevention and treatment strategies. The development of guidance for best practice in priority areas, based on evidence or consensus, is therefore recommended. PMID- 18445440 TI - The detection of meningococcal household clusters and their prophylaxis in the changing epidemiological situation of invasive meningococcal disease in Poland, 2003-2006. PMID- 18445441 TI - Asian tiger mosquito (Aedes albopictus) - a threat for Switzerland? PMID- 18445442 TI - Is there room for improving case management for contacts of meningococcal disease in the European Union? PMID- 18445445 TI - The measles situation in Austria: a rapid risk assessment by an ECDC team and the outcome of an International Meeting in Vienna, Austria. PMID- 18445446 TI - A survey on cases of tick-borne encephalitis in European countries. AB - The European Network for Diagnostics of "Imported" Viral Diseases (ENIVD) is finalising a project to improve the diagnostic and monitoring of encephalitis viruses in Europe. Part of this study was to analyse the present surveillance situation for tick-borne encephalitis (TBE), which is the most important flavivirus infection of the central nervous system in the European Union (EU) and Russia. A questionnaire was mailed to contact points in all Member States of the EU and three non-EU countries (Norway, Russia and Switzerland) to summarise their TBE surveillance and prevention activities. Information was requested on case definition, type of laboratory tests for TBE diagnostics, investigations regarding tick-transmitted diseases, mapping of endemic foci, vaccination programmes, and recommendations for travellers. The survey gives an overview of the existing epidemiological and laboratory sources of information and the number of TBE cases from 2004 until 2007, but also showed that, in particular, case definitions, diagnostic assays for confirmation, and methods/indicators for mapping risk areas differ widely across the participating countries. The data will help to develop recommendations for the standardisation and quality control or TBE surveillance and diagnostics. PMID- 18445447 TI - Web-based questionnaires - a tool used in a Campylobacter outbreak investigation in Stockholm, Sweden, October 2007. AB - Campylobacteriosis is the most common reported bacterial gastrointestinal disease in Sweden. Food-borne outbreaks of campylobacteriosis in Sweden are rather rare except for, usually rather small, family outbreaks. Water-borne outbreaks of campylobacteriosis, however, have affected several thousand persons in the past. PMID- 18445448 TI - An increase in reported cases of haemorrhagic fever with renal syndrome in Slovenia in early 2008. AB - Haemorrhagic fever with renal syndrome (HFRS) is an acute zoonotic viral disease, caused by hantaviruses. Hantaviruses infect rodents worldwide. They are transmitted to humans by aerosol from rodent excreta. Several hantaviruses are known to infect humans with varying severity. PMID- 18445449 TI - Probable cases of Crimean-Congo-haemorrhagic fever in Bulgaria: a preliminary report. PMID- 18445450 TI - Tick-borne encephalitis: rounding out the picture. PMID- 18445453 TI - Evaluation prompting transition from enhanced to routine surveillance of lymphogranuloma venereum (LGV) in the Netherlands. AB - In 2004, a lymphogranuloma venereum (LGV) epidemic among men who have sex with men in the Netherlands motivated the introduction of enhanced surveillance. We evaluated the acceptability of the enhanced LGV surveillance in the Netherlands in 2004-2005 to provide recommendations for future surveillance. Completeness of requested patient information was analysed. All 12 sexually transmitted infection (STI) health services participating in the 2004-2005 STI surveillance completed evaluation questionnaires and rated surveillance system features from 1="very poor" to 5="very good". Information from enhanced LGV surveillance was available for 34 (33%) of 104 cases. For these 34 cases, median proportions of response decreased successively for clinical information (100%), sexual anamnesis (71%) and details about the last sex partners (44%). A median score of 4 ("good") was assigned to simplicity, required resources and surveillance information requested and distributed. Seven respondents favoured continuation of LGV surveillance, whereof six preferred modifications, usually meaning less extensive surveillance. In conclusion, the enhanced LGV surveillance was generally regarded as adequate. However, it was limited by low completeness, underlining the need to keep requested information to a minimum. The routine STI surveillance now includes LGV diagnosis and, following this evaluation, the additional enhanced surveillance was discontinued. However, occasional cases justify alertness and LGV remains under routine STI surveillance in the Netherlands. PMID- 18445454 TI - EURO 2008--preparations for the football championship in Austria. PMID- 18445455 TI - Continuing high levels of HIV diagnoses in men who have sex with men in the United Kingdom. PMID- 18445456 TI - Emerging high-level mupirocin resistance among MRSA isolates in Ireland. PMID- 18445458 TI - Workshop on European behavioural indications for men who have sex with men. PMID- 18445460 TI - (Yet) another human A/H5N1 influenza case and cluster - when should Europe be concerned? PMID- 18445459 TI - Survey of European programmes for the epidemiological surveillance of congenital toxoplasmosis. AB - The objective of this investigation was to describe systems for the epidemiological surveillance of congenital toxoplasmosis implemented in European countries. In September 2004, a questionnaire, adapted from the evaluation criteria published by the United States Centers for Disease Control and Prevention, was sent to a panel of national correspondents in 35 countries in the European geographical area with knowledge of the epidemiological surveillance systems implemented in their countries. Where necessary, we updated the information until July 2007. Responses were received from 28 countries. Some 16 countries reported routine surveillance for toxoplasmosis. In 12 countries (Bulgaria, Cyprus, Czech Republic, England and Wales, Estonia, Ireland, Latvia, Lithuania, Malta, Poland, Scotland and Slovakia), surveillance was designed to detect only symptomatic toxoplasmosis, whether congenital or not. Four countries reported surveillance of congenital toxoplasmosis, on a regional basis in Italy and on a national basis in Denmark, France and Germany. In conclusion, epidemiological surveillance of congenital toxoplasmosis needs to be improved in order to determine the true burden of disease and to assess the effectiveness of and the need for existing prevention programmes. PMID- 18445461 TI - Emergence of high-level azithromycin resistance in Neisseria gonorrhoeae in England and Wales. PMID- 18445462 TI - Two cases of variant Creutzfeldt-Jakob disease reported in Spain in 2007 and 2008. PMID- 18445464 TI - Measles outbreaks in London, United Kingdom - a preliminary report. PMID- 18445463 TI - Reptile-associated Salmonellosis in residents in the South East of Ireland 2005 - 2007. PMID- 18445465 TI - Determination of uric acid in human urine and serum by capillary electrophoresis with chemiluminescence detection. AB - A simple and sensitive method based on capillary electrophoresis (CE) with chemiluminescence (CL) detection has been developed for the determination of uric acid (UA). The sensitive detection was based on the enhancement effect of UA on the CL reaction between luminol and potassium ferricyanide (K3[Fe(CN)6]) in alkaline solution. A laboratory-built reaction flow cell and a photon counter were deployed for the CL detection. Experimental conditions for CL detection were studied in detail to achieve a maximum assay sensitivity. Optimal conditions were found to be 1.0 x 10(-4) M luminol added to the CE running buffer and 1.0 x 10( 4) M K3[Fe(CN)6] in 0.2 M NaOH solution introduced postcolumn. The proposed CE-CL assay showed good repeatability (relative standard deviation [RSD]=3.5%, n=11) and a detection limit of 3.5 x 10(-7) M UA (signal/noise ratio [S/N]=3). A linear calibration curve ranging from 6.0 x 10(-7) to 3.0 x 10(-5) M UA was obtained. The method was evaluated by quantifying UA in human urine and serum samples with satisfactory assay results. PMID- 18445466 TI - Design of selective substrates of proteinase 3 using combinatorial chemistry methods. AB - In this study, chemical synthesis of the selective chromogenic/fluorogenic substrates for proteinase 3 is described. The substrates' sequence was obtained using combinatorial chemistry methods. Deconvolution of the tripeptide library against proteinase 3 with general formula ABZ-X3-X2-X1-ANB-NH2 yielded the active sequence. Selected peptide was further modified on its C terminus to investigate the impact of chromophore moiety modification on enzyme-substrate interaction. To determine specificity, activity of selected substrates was characterized against proteinase 3 and neutrophil elastase. Finally, the peptide ABZ-Tyr-Tyr-Abu-ANB NH2 displayed the highest value of specificity constant (k(cat)/K(M)=189 x 10(3) M(-1) s(-1)) for proteinase 3. To the best of our knowledge, this is the first short peptide that undergoes selective proteolysis by proteinase 3 and displays no significant hydrolysis in the presence of human neutrophil elastase and cathepsin G. PMID- 18445467 TI - Mineral oil-, glycerol-, and Vaseline-coated plates as matrix-assisted laser desorption/ionization sample supports for high-throughput peptide analysis. AB - A novel protocol for rapid and high-quality sample preparation prior to matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been developed by coating bare stainless steel plates with one of three adhesives: mineral oil, glycerol, or Vaseline. The advantages of these three adhesive coats are that they take little time to both prepare and wipe away, hold the matrices to prevent them from flying from the support, reduce the background matrix, and affect neither the resolution of the peptide peaks nor the accuracy of their determined molecular masses. Consequently, the signal intensity, detection limit, and tolerance of the analytes to contaminants on the three adhesive-coated plates are improved. In the two strategies of on-plate desalting and concentration of the peptide mixture, all three adhesives reduced the loss of peptides, especially in the case of larger molecular mass peptides. The microscope and stereomicroscope images of the deposited droplets showed that after dropping onto the adhesive coats, the droplets formed a reduced spot size, were more homogeneous, and showed sticky crystallization. Therefore, this is an easy-to-use, reproducible, highly sensitive, tolerant (to salts), and high throughput method of peptide sample preparation for MALDI-TOF MS analysis. PMID- 18445468 TI - Folding strategy to prepare Co(II)-substituted metallo-beta-lactamase L1. AB - In an effort to overcome previous problems with the preparation of Co(II) substituted metallo-beta-lactamase L1, two strategies were undertaken. Attempts to prepare Co(II)-substituted L1 using biological incorporation resulted in an enzyme that contained only 1 Eq of cobalt and exhibited no catalytic activity. Co(II)-substituted L1 could be prepared by refolding metal-free L1 in the presence of Co(II), and the resulting enzyme contained 1.8 Eq of cobalt, yielded a UV-Vis spectrum consistent with 5-coordinate Co(II), and exhibited a k(cat) of 63 s(-1) and K(m) of 20 microM when using nitrocefin as the substrate. Pre-steady state fluorescence and UV-Vis studies demonstrated that refolded, Co(II) substituted L1 uses the same kinetic mechanism as Zn(II)-containing L1, in which a reaction intermediate is formed when using nitrocefin as substrate. The described refolding strategy can be used to prepare other Co(II)-substituted Zn(II)-metalloenzymes, particularly those that contain a solvent-exposable disulfide, which often causes oxidation of Co(II) to Co(III). PMID- 18445469 TI - Immunoblotting conditions for human hemoglobin chains. AB - Immunoblotting to analyze low-molecular-weight proteins like calmodulin and metallothioneins is challenging and requires modifications for reproducible detection. Human globin chains are 17-kDa proteins and are not detectable by conventional immunoblotting using nitrocellulose membranes. Here we describe an immunoblotting method using nitrocellulose membranes that allows quantitative analyses of globin chains. Although previous studies have demonstrated that the fixation of blotted membranes with glutaraldehyde improves immunodetection of low molecular-weight proteins, we found that the detection sensitivity for human globins is increased markedly by fixation with paraformaldehyde, but not glutaraldehyde. This immunoblotting procedure facilitates studies of posttranscriptional mechanisms for globin gene expression. PMID- 18445470 TI - An enzyme cycling method for measurement of allantoin in human serum. AB - Current conventional measurement of allantoin levels in human serum uses an HPLC method. However, performing this assay is time-consuming and sample-intensive, and it requires expensive equipment. We have developed a novel enzyme cycling method for measuring allantoin concentrations in human serum. In the first step, serum allantoin is converted to allantoate by the action of allantoinase (EC 3.5.2.5), and endogenous ammonia is simultaneously removed by the action of glutamine synthetase II (EC 6.3.1.2). In the second step, l-methionine sulfoximine is used to inhibit glutamine synthetase II, and ammonia is liberated from allantoate by the activity of allantoate amidohydrolase (EC 3.5.3.9). In the final step, the ammonia is then converted to NAD by NAD synthetase (EC 6.3.1.5). Subsequent action of glucose dehydrogenase (EC 1.1.1.47) and diaphorase (EC 1.6.99.2) in the presence of glucose and 2-(4-iodophenyl)-3-(4-nitrophenyl)-5 (2,4-disulfophenyl)-2H-tetrazolium (WST-1) acts to cycle the formed NAD between its oxidized and reduced forms, resulting in the production of WST-1 formazan, which is monitored at 450 nm. The assay standard curve is linear from 0 to 70 muM allantoin. The level of allantoin in healthy subjects was measured to be 8.2+/ 3.1 microM (n=30). PMID- 18445471 TI - Biogenesis of cytochrome c oxidase--in vitro approaches to study cofactor insertion into a bacterial subunit I. AB - Biogenesis of cytochrome c oxidase is a complex process involving more than 30 known accessory proteins in yeast for the regulation of transcription and translation, membrane insertion and protein processing, cofactor insertion, and subunit assembly. Here, we focus on the process of cofactor insertion into subunit I of cytochrome c oxidase using the soil bacterium Paracoccus denitrificans as a model organism. The use of bacterial systems facilitates biogenesis studies, as the number of required assembly factors is reduced to a minimum. Both, co- and posttranslational cofactor insertion scenarios are discussed, and several approaches to shed light on this aspect of biogenesis are presented. CtaG, the Paracoccus homolog of yeast Cox11 which is involved in copper delivery to the Cu(B) center, has been purified and characterized spectroscopically. A previously unreported signal at 358 nm allows monitoring copper transfer from copper-loaded CtaG to an acceptor. Both CtaG and apo-subunit I were purified after expression in Escherichia coli to develop an in vitro copper transfer system, probing the posttranslational insertion hypothesis. To mimic a potential cotranslational insertion process, cell-free expression systems using E. coli and P. denitrificans extracts have been established. Expression of subunit I in the presence of the detergent Brij-35 produces high amounts of "solubilized" subunit I which can be purified in good yield. With this system it may be feasible to trap and purify assembly intermediates after adding free cofactors, purified assembly proteins, or P. denitrificans membranes. PMID- 18445472 TI - Competitive inhibition of electron donation to photosystem 1 by metal-substituted plastocyanin. AB - The electron transfer from wild-type spinach plastocyanin (Pc) to photosystem 1 has been studied by flash-induced absorption changes at 830 nm. The decay kinetics of photo-oxidized P700 are drastically slower in the presence of Ag(I) substituted Pc, while addition of Zn(II)-substituted Pc has a weaker effect. The metal-substituted forms of Pc act as competitive inhibitors of the reaction between normal, Cu-containing, Pc and P700. The inhibition constants obtained from an analysis of the kinetic data were 30 and 410 microM for Ag(I)- and Zn(II) substituted Pc, respectively. When the Gly8Asp mutant form of Pc was used instead of the wild-type form, the corresponding values were found to be 77 and 442 microM. If the Ag- and Zn-derivatives can be considered as structural mimics of reduced and oxidized CuPc, respectively, our results imply that there is a redox induced decrease in the affinity between Pc and photosystem 1 that follows the electron donation to P700. Our data also imply that the Gly8Asp mutation can diminish the magnitude of this change. The findings reported here are consistent with a reaction mechanism where the electron transfer in the complex between Pc and photosystem 1 is assumed to be reversible. PMID- 18445473 TI - Dipalmitoylphosphatidylcholine membranes modified with carotenoid pigment lutein: experiment versus Monte Carlo simulation study of the membrane organization. AB - Organization of bilayer lipid membrane formed with dipalmitoylphosphatidylcholine and containing a xanthophyll pigment lutein was studied by both the Monte Carlo simulation and UV-Vis absorption spectroscopy. The simulations were based on ten state Pink model. The proposed model consisted of two monolayers represented by a two-dimensional triangular lattice with vacancies. The orientation and aggregation state of lutein, obtained from the analysis of the spectroscopic measurements, were used to calibrate intermolecular interactions in the model. In accordance with the experimental data, the model allows two orientations of lutein molecules: one spanning the membrane and the other parallel to its plane. The influence of the intermolecular interactions on the main phase transition as well as on the aggregation of lutein molecules is discussed. The analysis of the model enables us to learn about molecular mechanisms that govern the effects of lutein on the membrane properties as well as the effects of the lipid matrix on lutein organization in the membrane. A concept is discussed according to which increasing domination of parallel lutein orientation, observed at high temperatures, can protect the membrane against penetration by water molecules and reactive oxygen species and against loss of the membrane compactness, especially in the regions of oxidized acyl chains. PMID- 18445474 TI - Degradation of lyophilized lipid/DNA complexes during storage: the role of lipid and reactive oxygen species. AB - The presence of trace amounts of metal ions in nonviral vector formulations can significantly affect the stability of lipid/DNA complexes (lipoplexes) during acute freeze-drying. The goal of the present study was to evaluate the generation of reactive oxygen species (ROS) in dried formulations of lipoplexes and in their individual components (lipid or naked DNA). The experiments were conducted in the presence or absence of a transition metal (Fe2+). Lipoplexes and their individual components were formulated in trehalose and subjected to lyophilization and stored for a period of up to 2 months at +60 degrees C. Physico-chemical characteristics and biological activity were evaluated at different time intervals. Generation of ROS during storage was determined by adding a fluorescence probe to the formulations prior to freeze-drying. We also monitored the formation of thiobarbituric reactive substances (TBARS). Our results show that ROS and TBARS form during storage in the dried state. Our findings also suggest that degradation is more rapid in the presence of lipid, even in the absence of metal. We also showed that dried naked DNA formulations are more stable without the lipid component. Effective strategies are then needed to minimize the formation and accumulation of oxidative damage of lipoplexes during storage. PMID- 18445475 TI - Fungicidal effect and the mode of action of piscidin 2 derived from hybrid striped bass. AB - Piscidin 2 (P2), a 22-residue cationic peptide isolated from the mast cells of hybrid striped bass, has potent antibacterial activities. However, its antifungal properties are not completely understood. In the current study, we investigated the antifungal effects and mode of action of P2. P2 exhibited potent antifungal activity against human pathogenic fungi. To understand the fungicidal properties of P2, we focused on a membrane-active mechanism of the peptide by in vivo and in vitro testing. Flow cytometric analysis using bis-(1,3-dibutylbarbituric acid) trimethine oxonol [DiBAC(4)(3)] and protoplast regeneration experiments showed that P2 caused fungal membrane damage. Furthermore, fluorescence analysis using 1,6-diphenyl-1,3,5-hexatriene (DPH) revealed that P2 created pores in fungal membranes. These results were confirmed with dye leakage tests by using liposomes composed of phosphatidylcholine/phosphatidylserine (3:1, w/w), which mimicked fungal membranes. The present study indicated that P2 exerts its fungicidal effects by perturbing membrane activities. PMID- 18445476 TI - Trans-encapsidation of hepatitis C virus subgenomic replicon RNA with viral structure proteins. AB - A trans-packaging system for hepatitis C virus (HCV) subgenomic replicon RNAs was developed. HCV subgenomic replicon was efficiently encapsidated by the HCV structural proteins that were stably expressed in trans under the control of a mammalian promoter. Infectious HCV-like particles (HCV-LPs), established a single round infection, were produced and released into culture medium in titers of up to 10(3) focus forming units/ml. Expression of NS2 protein with structural proteins (core, E1, E2, and p7) was shown to be critical for the infectivity of HCV-LPs. Anti-CD81 treatment decreased the number of infected cells, suggesting that HCV-LPs infected cells in a CD81-dependent manner. The packaging cell line should be useful both for the production of single-round infectious HCV-LPs to elucidate the mechanisms of HCV assembly, particle formation and infection to host cells, and for the development of HCV replicon-based vaccines. PMID- 18445477 TI - An association between RBMX, a heterogeneous nuclear ribonucleoprotein, and ARTS 1 regulates extracellular TNFR1 release. AB - The type I, 55-kDa tumor necrosis factor receptor (TNFR1) is released to the extracellular space by two mechanisms, the constitutive release of TNFR1 exosome like vesicles and the inducible proteolytic cleavage of TNFR1 ectodomains. Both pathways appear to be regulated by an interaction between TNFR1 and ARTS-1 (aminopeptidase regulator of TNFR1 shedding). Here, we sought to identify ARTS-1 interacting proteins that modulate TNFR1 release. Co-immunoprecipitation identified an association between ARTS-1 and RBMX (RNA-binding motif gene, X chromosome), a 43-kDa heterogeneous nuclear ribonucleoprotein. RNA interference attenuated RBMX expression, which reduced both the constitutive release of TNFR1 exosome-like vesicles and the IL-1beta-mediated inducible proteolytic cleavage of soluble TNFR1 ectodomains. Reciprocally, over-expression of RBMX increased TNFR1 exosome-like vesicle release and the IL-1beta-mediated inducible shedding of TNFR1 ectodomains. This identifies RBMX as an ARTS-1-associated protein that regulates both the constitutive release of TNFR1 exosome-like vesicles and the inducible proteolytic cleavage of TNFR1 ectodomains. PMID- 18445478 TI - Activation of AMP-activated protein kinase by kainic acid mediates brain-derived neurotrophic factor expression through a NF-kappaB dependent mechanism in C6 glioma cells. AB - AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis. Kainic acid (KA), a prototype excitotoxin is known to induce brain-derived neurotrophic factor (BDNF) in brain. In this study, we examined the role of AMPK in KA-induced BDNF expression in C6 glioma cells. We showed that KA and KA receptor agonist induced activation of AMPK and KA-induced AMPK activation was blocked by inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK) beta. We then showed that inhibition of AMPK by compound C, a selective inhibitor of AMPK, or small interfering RNA of AMPKalpha1 blocked KA-induced BDNF mRNA and protein expression. Inhibition of AMPK blocked KA-induced phosphorylation of CaMKII and I kappaB kinase (IKK) in C6 cells. Finally, we showed that inhibition of AMPK reduced DNA binding and transcriptional activation of nuclear factor-kappaB (NF-kappaB) in KA-treated cells. These results suggest that AMPK mediates KA-induced BDNF expression by regulating NF-kappaB activation. PMID- 18445479 TI - A potential acyltransferase regulates swarming in Serratia marcescens. AB - Swarming in Serratia marcescens is a specialized form of bacterial populational surface migration behavior. A precocious swarming mutant S. marcescens O6 whose rssC is interrupted by mini-Tn5 transposon was obtained. The 364 amino-acid RssC showed a high identity to members of acyltransferase family. Characterization of the rssC knock-out mutant S. marcescens PC105 showed aberrant and hypervirulent phenotypes including precocious swarming behavior, reduced cell attachment ability and increase in swimming motility, flagellin synthesis, capsular polysaccharide (CPS) production, hemolysin activity, and cytotoxicity activity. Besides a more intense pattern of O-antigen sugar unit ladder, S. marcescens PC105 also showed an altered cell surface topology. A potential FlhDC binding site was identified at the rssC promoter region. In accordance, rssC transcriptional activity was up-regulated by FlhDC(Sm). Briefly, rssC is hierarchically classified as class II members in FlhDC(Sm) regulon, and reciprocally defect in rssC results in aberrant swarming and hypervirulence in S. marcescens. PMID- 18445480 TI - Dipeptide synthesis by L-amino acid ligase from Ralstonia solanacearum. AB - Despite its utility, dipeptides have not been widely used due to the absence of an efficient manufacturing method. Recently, a novel method for effective production of dipeptides using l-amino acid alpha-ligase (Lal) is presented. Lal, which is only identified in Bacillus subtilis, catalyzes dipeptide synthesis from unprotected amino acids in an ATP-dependent manner. However, not all the dipeptide can be synthesized by Lal from B. subtilis (BsLal) due to its substrate specificity. Here, we attempted to find a novel Lal exhibiting different substrate specificity from BsLal. By in silico screening based on the amino acid sequence of BsLal, RSp1486a an unknown protein from Ralstonia solanacearum was found to show the Lal activity. RSp1486a exhibited different substrate specificity from BsLal, and preferably synthesized hetero-dipeptides where more bulky amino acid was placed at N terminus and less bulky amino acid was placed at C terminus in opposition to those synthesized by BsLal. PMID- 18445481 TI - Renal press-mediated transfection method for plasmid DNA and siRNA to the kidney. AB - Gene and oligonucleotides transfection methods to the kidney are required for the progress of biomedical research and the therapy of renal diseases. In this study, we found that siRNA as well as plasmid DNA can be transfected to the kidney by a simple method including lightly and once pressing the kidney after intravenous injection of siRNA or plasmid DNA (renal press-mediated transfection method). Using luciferase as the reporter, gene expression and silencing properties were evaluated. Plasmid DNA is efficiently and widely transfected to the periphery of the pressed kidney, and also siRNA is transfected into the kidney and significant suppression of gene expression can be achieved. Additively, serum creatinine and blood urea nitrogen levels, that are indices of renal function, exhibited no marked changes after transfection by this method. Therefore, it appears that plasmid DNA and siRNA could be transfected to the kidney without renal dysfunction by renal press-mediated transfection method. PMID- 18445482 TI - Compensatory binding of an asparagine residue to the coordination-unsaturated type I Cu center in bilirubin oxidase mutants. AB - Met467, the axial ligand to type I Cu in a multicopper oxidase, Myrothecium verrucaria bilirubin oxidase was substituted with a non-coordinating Phe and Leu to transform the spectral and magnetic properties and oxidase activities of the enzyme into those of fungal laccases, but the mutated type I Cu center showed properties characteristic of phytocyanins, blue copper proteins with an axial coordination of Gln, due to compensatory binding of the distal Asn459 as evidenced by a double mutation. PMID- 18445483 TI - Tityus serrulatus Hypotensins: a new family of peptides from scorpion venom. AB - Using a proteomic approach, a new structural family of peptides was put in evidence in the venom of the yellow scorpion Tityus serrulatus. Tityus serrulatus Hypotensins (TsHpt) are random-coiled linear peptides and have a similar bradykinin-potentiating peptide (BPP) amino acid signature. TsHpt-I (2.7kDa), the first member of this family, was able to potentiate the hypotensive effects of bradykinin (BK) in normotensive rats. Using the C-terminal of this peptide as a template, a synthetic analog peptide (TsHpt-I([17-25])) was designed to held the BK-potentiating effect. A relevant hypotensive effect, independent on BK, was also observed on both TsHpt (native and synthetic). To better evaluate this hypotensive effect, we examined the vasorelaxation of aortic rings from male Wistar rats and the peptides were able to induce endothelium-dependent vasorelaxation dependent on NO release. Both TsHpt could not inhibit ACE activity. These peptides appear to exert their anti-hypertensive effect through NO-dependent and ACE-independent mechanisms. PMID- 18445484 TI - Cytokines and anticytokines in psoriasis. AB - BACKGROUND: Psoriasis is a chronic autoimmune hyperproliferative skin disease of varying severity affecting approximately 2-3% of the general population in the USA and Europe. Although the pathogenesis of psoriasis has not been fully elucidated, an immunologic-genetic relationship is likely. Cutaneous and systemic overexpression of various proinflammatory cytokines (TNF, interleukins, interferon-gamma) has been demonstrated in psoriatic patients. METHODS: We reviewed the current database literature and summarized the involvement of cytokines and their receptors in the pathogenesis and treatment of psoriasis. RESULTS: Although many cytokine/anti-cytokine therapies have been conducted, TNF antagonists in the treatment of both psoriasis arthropatica and vulgaris appear to be the most widely used clinically. Interestingly, the efficacy and tolerability of some cytokines (rhIL-11 or ABX-IL-8,) were found to be much lower than expected. CONCLUSIONS: Preliminary results obtained with cytokine and anti cytokine therapies appear promising and as such continued research is clearly indicated. PMID- 18445485 TI - Knockdown of cytosolic 5'-nucleotidase II (cN-II) reveals that its activity is essential for survival in astrocytoma cells. AB - IMP preferring cytosolic 5'-nucleotidase (cN-II) is an ubiquitous nucleotide hydrolysing enzyme. The enzyme is widely distributed and its amino acid sequence is highly conserved among vertebrates. Fluctuations of cN-II activity have been associated with the pathogenesis of neurological disorders. The enzyme appears to be involved in the regulation of the intracellular availability of the purine precursor IMP and also of GMP and AMP, but the contribution of this activity and of its regulation to cell metabolism and to CNS cell functions remains uncertain. To address this issue, we used a vector based short hairpin RNA (shRNA) strategy to knockdown cN-II activity in human astrocytoma cells. Our results demonstrated that 53 h after transduction, cN-II mRNA was reduced to 17.9+/-0.03% of control cells. 19 h later enzyme activity was decreased from 0.7+/-0.026 mU/mg in control ADF cells to 0.45+/-0.046 mU/mg, while cell viability (evaluated by the MTT reduction assay) decreased up to 0.59+/-0.01 (fold vs control) and caspase 3 activity increased from 136+/-5.8 pmol min(-1) mg(-1) in control cells to 639+/ 37.5 pmol min(-1) mg(-1) in silenced cells, thus demonstrating that cN-II is essential for cell survival. The decrease of enzyme activity causes apoptosis of the cultured cells without altering intracellular nucleotide and nucleoside concentration or energy charge. Since cN-II is highly expressed in tumour cells, our finding offers a new possible therapeutical approach especially against primary brain tumours such as glioblastoma, and to ameliorate chemotherapy against leukemia. PMID- 18445487 TI - RecJ nuclease is required for SOS induction after introduction of a double-strand break in a RecA loading deficient recB mutant of Escherichia coli. AB - The SOS response is an important mechanism which allows Escherichia coli cells to maintain genome integrity. Two key proteins in SOS regulation are LexA (repressor) and RecA (coprotease). The signal for SOS induction is generated at the level of a RecA filament. Depending on the type of DNA damage, a RecA filament is produced by specific activities (helicase, nuclease and RecA loading) of either RecBCD, RecF or a hybrid recombination pathway. It was recently demonstrated that RecA loading activity is essential for the induction of the SOS response after UV-irradiation. In this paper we studied the genetic requirements for SOS induction after introduction of a double-strand break (DSB) by the I-SceI endonuclease in a RecA loading deficient recB mutant (recB1080). We monitored SOS induction by assaying beta-galactosidase activity and compared induction of the response between strains having one or more inactivated mechanisms of RecA loading and their derivatives. We found that simultaneous inactivation of both RecA loading functions (in recB1080 recO double mutant) partially impairs SOS induction after introduction of a DSB. However, we found that the RecJ nuclease is essential for SOS induction after the introduction of a DSB in the recB1080 mutant. This result indicates that RecJ is needed to prepare ssDNA for subsequent loading of RecA protein. It implies that an additional type of RecA loading could exist in the cell. PMID- 18445486 TI - Chronological aging-induced apoptosis in yeast. AB - Saccharomyces cerevisiae is the simplest among the major eukaryotic model organisms for aging and diseases. Longevity in the chronological life span paradigm is measured as the mean and maximum survival period of populations of non-dividing yeast. This paradigm has been used successfully to identify several life-regulatory genes and three evolutionary conserved pro-aging pathways. More recently, Schizosaccharomyces pombe has been shown to age chronologically in a manner that resembles that of S. cerevisiae and that depends on the activity of the homologues of two pro-aging proteins previously identified in the budding yeast. Both yeast show features of apoptotic death during chronological aging. Here, we review some fundamental aspects of the genetics of chronological aging and the overlap between yeast aging and apoptotic processes with particular emphasis on the identification of an aging/death program that favors the dedifferentiation and regrowth of a few better adapted mutants generated within populations of aging S. cerevisiae. We also describe the use of a genome-wide screening technique to gain further insights into the mechanisms of programmed death in populations of chronologically aging S. cerevisiae. PMID- 18445488 TI - Antiapoptotic role of S-adenosyl-l-methionine against hydrochloric acid induced cell death in Saccharomyces cerevisiae. AB - Exposure of stationary phase cells of Saccharomyces cerevisiae to 10 mM HCl (pH approximately 2) resulted in cell death as a function of time (up to 6 h) with most (about 40%-65%) of the cells showing apoptotic features including chromatin condensation along the nuclear envelope, exposure of phosphatidylserine on the outer leaflet of cytoplasmic membrane, and DNA fragmentation. During the first 2 h of acid exposure there was an increase in reactive oxygen species (ROS) level inside cells, with subsequent elevation in the level of lipid peroxidation and decrease in reducing equivalents culminating in loss of mitochondrial membrane potential (DeltaPsi(m)). An initial (1 h) event of mitochondrial hyper polarization with subsequent elevation of ROS level of the acid treated cells was also observed. S-adenosyl-l-methionine (AdoMet; 1 mM) treatment increased the cell survival of the acid stressed cells. It partially scavenged the increased intracellular ROS level by supplementing glutathione through the transsulfuration pathway. It also inhibited acid mediated lipid peroxidation, partially recovered acid evoked loss of DeltaPsi(m) and protected the cells from apoptotic cell death. S-adenosyl di-aldehyde, an indirect inhibitor of the AdoMet metabolic pathway, increased mortality of the acid treated cells. Incubation of acid stressed cells with the antioxidant, N-acetyl-cysteine (1 mM), decreased the cellular mortality, but the same concentration of AdoMet offered more protection by scavenging the free radicals. The ability of AdoMet to scavenge ROS mediated apoptosis may be an important function of this molecule in responding to cellular stress. The study could open a new avenue for detailed investigation on the curative potential of AdoMet against gastric ulcer. PMID- 18445489 TI - Interaction between previous beliefs and cue predictive value in covariation based causal induction. AB - The main aim of this work was to show the impact of preexisting causal beliefs on causal induction from cause-effect co-occurrence information, when several cues compete with each other for predicting the same effect. Two different causal scenarios -- one social (a), the other medical (b) -- were used to check the generality of the effects. In Experiments 1a and 1b, participants were provided information on the co-occurrence of a two-cause compound and an effect, but not about the potential relationship between each cause by its own and the effect. As expected, prior beliefs -- induced by means of instructions -- strongly modulated the causal strength assigned to each element of the compound. In Experiments 2a and 2b, covariation evidence was provided, not only about the predictive value of the two-cause compound, but also about one of the elements of the compound. When this evidence was available, prior beliefs had less impact on judgments, and these were mostly guided by the relative predictive value of the cue. These results demonstrate the involvement of inferential integrative mechanisms in the generation of causal knowledge and show that single covariation detection mechanisms -- either rule-based or associative -- are insufficient to account for human causal judgment. At the same time, the fact that the power of new covariational evidence to change prior beliefs depended on the availability of information on the relative (conditional) predictive value of the target candidate cause suggests that causal knowledge derived from information on causal mechanisms and from covariation probably share a common representational basis. PMID- 18445490 TI - Human gaze behaviour during action execution and observation. AB - Gaze shifts and fixations appear to be proactive in both action execution and observation. We investigated a dependency of anticipatory gaze behaviour by using a block stacking task. Blocks were rectangles depicted on a computer screen and the stacking movements were controlled via computer mouse. Subjects either had to execute the task or had to observe it made by the experimenter, or by the computer. The dependency of gaze behaviour on the visibility of a virtual effector, the visibility of the actor, and the nature of the actor was tested by measuring eye movements. Anticipatory eye movements were predominant when the subjects themselves executed the task. During action observation, gaze behaviour did neither depend on the visibility nor depend on the nature of the actor. However, big variability was found between the subjects suggesting the use of two different strategies in action observation: some subjects were mainly tracking the blocks during stacking movements; others were strongly anticipating. We suggest that gaze behaviour during action observation is not predetermined by rigid neural circuitry, but strongly depends on the context. The possibility to explain the causal mechanism, as well as the ownership of the action may be crucial preconditions for anticipatory gaze behaviour. PMID- 18445491 TI - Attenuation of progressive hearing loss in a model of age-related hearing loss by a heat shock protein inducer, geranylgeranylacetone. AB - Mechanisms of age-related hearing loss (ARHL) have not been elucidated as aging processes are extremely complex. Although oxidative stress and apoptotic cell death are involved in progression of ARHL, number of trial to treat ARHL is limited. Heat shock response is characterized by induction of heat shock proteins (HSPs) in response to stresses such as heat shock, which diminishes during aging. HSPs act as molecular chaperones, and some HSPs also inhibit apoptotic pathways. Here, we examined age-related expression of HSPs in the cochlea of ARHL model DBA/2J mice and control CBA/N mice. Western blot assay revealed that CBA/N mice showed constant expression of Hsp70 and Hsp110 with age, but not in DBA/2J mice. The result suggests that pharmacological upregulation of HSPs might attenuate ARHL. We administered DBA/2J mice with food containing geranylgeranylacetone (GGA) that induces HSPs in the cochlea, and found that its administration suppresses ARHL examined by ABR test and histological examination though protection is specific for the apical part of the cochlea. These results demonstrate that dietary supplementation of GGA could be an effective therapeutic strategy for treatment of ARHL. PMID- 18445492 TI - Administration of angiotensin II in the paraventricular nucleus protects gastric mucosa from ischemia-reperfusion injury. AB - Our previous study demonstrated that electrical stimulation of the hypothalamic paraventricular nucleus (PVN) protects against gastric ischemia-reperfusion (GI R) injury, but it is still unknown whether angiotensin II (Ang II) in the PVN plays a role in the development of GI-R. The purpose of this study was to investigate the effect of Ang II in the PVN on GI-R injury. GI-R injury was induced in rats by clamping the celiac artery for 30 min, and then reperfusing for 30 min, 1 h, 3 h, 6 h or 24 h, respectively. A cannula was inserted into the unilateral PVN for microinjection of Ang II. The extent of gastric mucosal damage was determined by gross and histological methods. We found that microinjection of pharmacological doses of Ang II (3, 30, and 300 ng) into the PVN dose-dependently inhibited GI-R injury, and that Ang II (30 ng) markedly attenuated GI-R injury at 1 h and 3 h after reperfusion. The effect of Ang II was prevented by pretreatment with the Ang II AT1 receptor antagonist losartan (5 microg) into the lateral cerebral ventricle. Furthermore, the protective effect of Ang II on GI-R injury was abolished by propranolol (1 mg/kg, i.v.) or disconnection of the nerves innervating the adrenal glands, was augmented by sympathectomy or phentolamine (1 mg/kg, i.v.), and was not affected by subdiaphragmatic vagotomy or atropine (1 mg/kg, i.v.). These results indicate that the PVN is a responsive site for central Ang II-induced protection against GI-R injury. The central effects of Ang II are mediated by AT1 receptors in the PVN, and the peripheral effects by a sympathetic-adrenal gland/beta-adrenoceptor pathway. PMID- 18445493 TI - PET O-15 cerebral blood flow and metabolism after acute stroke in spontaneously hypertensive rats. AB - Hypertension is a major stroke risk factor and is correlated with worse outcome after stroke. Thus, the effects of hypertension on cerebral hemodynamics and metabolism within an hour after stroke must be evaluated in detail. Cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate for oxygen (CMRO2) and cerebral metabolic rate for glucose (CMRglc) were measured 1 h after the occlusion of the right middle cerebral artery (MCA) in male spontaneously hypertensive rats (SHR) and male normotensive Wistar Kyoto rats (WKY). Physiological responses were determined by positron emission tomography (PET) using 15O-H2O and radiolabeled 15O-O2 blood (methodology previously developed in this laboratory) and by autoradiography (ARG) using 18F-FDG. The right hemisphere of SHR showed lower CBF values than the left hemisphere after stroke (right: 0.17+/-0.07 mL/min/g; left: 0.29+/-0.08 mL/min/g), CMRO2 (right: 2.55+/-0.80 mL/min/100 g; left: 4.11+/- 0.84 mL/min/100 g) and CMRglc (right: 52.4+/-16.2 mg/min/100 g; left: 65.6+/-10.2 mg/min/100 g). WKY rats exhibited significant decreases only in CBF and CMRO2. These results suggest greater underlying physiologic disturbances in SHR. Also, the occlusion significantly reduced CBF in both hemispheres of SHR compared with WKY, suggesting a disturbance of the autoregulatory mechanism in SHR. In summary, our results indicate that hypertension intensifies metabolic disturbances after the onset of stroke, at least in the first hour. Therefore, we suggest that hypertension not only increases the incidence of stroke but also exacerbates stroke-mediated damage. PMID- 18445494 TI - Non-reducing end alpha-mannosylated glycolipids as potent activators for invariant Valpha19 TCR-bearing natural killer T cells. AB - A novel invariant Valpha19-Jalpha33 T cell receptor alpha chain, first found in mammalian blood cells, was primarily expressed by natural killer T cell repertoire (Valpha19 NKT cell). Attempts have been made to find specific antigens for Valpha19 NKT cells. A series of alpha- and beta-glycosyl ceramides were synthesized and tested whether they had potential to stimulate the cells isolated from invariant Valpha19-Jalpha33 TCR transgenic mice (where the development of Valpha19 NKT cells is facilitated). Comprehensive examinations revealed substantial antigenic activity in alpha-ManCer that was presented by MR1, one of the MHC class Ib molecules. Next, naturally occurring and synthetic alpha mannosyl glycolipids were further analyzed to determine structural requirements for natural ligands for Valpha19 NKT cells. As a result, alpha-mannosyl phosphatidyl inositols (PI) such as (alpha-Man)(2)-PI and alpha-Man-alpha GlcNH(2)-PI (a partial structure of mycobacterial lipoarabinomannan and GPI anchors) as well as alpha-ManCer derivatives were found to activate Valpha19 NKT cells in vivo and in vitro. Thus, Valpha19 NKT cells are possibly responsive to certain alpha-mannosyl glycolipids and may have roles in the innate and adaptative immune systems to protect against various antigens expressing alpha mannosyl glycolipids and to regulate the adaptive immune system responding to the intracellular ligands. PMID- 18445495 TI - LRRK2 regulates synaptic vesicle endocytosis. AB - The leucine-rich repeat kinase 2 (LRRK2) has been identified as the defective gene at the PARK8 locus causing the autosomal dominant form of Parkinson's disease (PD). Although several LRRK2 mutations were found in familial as well as sporadic PD patients, its physiological functions are not clearly defined. In this study, using yeast two-hybrid screening, we report the identification of Rab5b as an LRRK2-interacting protein. Indeed, our GST pull down and co immunoprecipitation assays showed that it specifically interacts with LRRK2. In addition, subcellular fractionation and immunocytochemical analyses confirmed that a fraction of both proteins co-localize in synaptic vesicles. Interestingly, we found that alteration of LRRK2 expression by either overexpression or knockdown of endogenous LRRK2 in primary neuronal cells significantly impairs synaptic vesicle endocytosis. Furthermore, this endocytosis defect was rescued by co-expression of functional Rab5b protein, but not by its inactive form. Taken together, we propose that LRRK2, in conjunction with its interaction with Rab5b, plays an important role in synaptic function by modulating the endocytosis of synaptic vesicles. PMID- 18445496 TI - Seasonal covariation in progesterone and odorant emissions among breeding crested auklets (Aethia cristatella). AB - Crested auklets emit a citrus-like odorant that is seasonally modulated, suggesting that it is a secondary sexual trait. We hypothesized that expression of the chemical odorant is facilitated by steroid hormones, similar other secondary sexual traits in birds. Therefore we examined variation in concentrations of hormones in blood plasma and odor production during incubation and early chick rearing. A novel method was used to obtain and measure chemical emissions of crested auklets. Blood plasma samples were analyzed by radioimmunoassay. Progesterone was detected in all birds, and it varied during the breeding season. Octanal emissions covaried with progesterone levels in males but not in females. No seasonal patterns were detected in testosterone, estrogen or DHT, and these hormones were not detected in all breeding adults. Covariance of progesterone and octanal emissions in males suggests there could be at least an indirect relationship between odor emissions and steroid hormones in this species. Thus expression of the citrus-like odorant of crested auklets, like other secondary sexual traits in birds, could be regulated by steroid hormones. PMID- 18445497 TI - Transcriptional regulation of corticotrophin releasing factor gene by furocoumarins isolated from seeds of Psoralea corylifolia. AB - Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system plays a causal role in the development and course of depression. Clinically effective antidepressant drugs normalize the disturbed activity of the HPA axis by inhibition of corticotrophin releasing factor gene promoter activity. Furocoumarins from Psoralea corylifolia have been demonstrated to possess potent antidepressant properties. In order to ascertain whether these coumarin components directly regulate corticotrophin releasing factor (CRF) gene transcription, we studied their effect on CRF promoter activity using the luciferase reporter assay in Neuro-2A cells. CRF promoter was cloned into firefly luciferase reporter vector and co-transfected into Neuro-2A cells with Renilla luciferase plasmid as internal control. CRF promoter transcription activity was induced by forskolin. We found that one of the components of P. corylifolia, psoralidin, strongly inhibited forskolin-induced CRF promoter activity. We further confirmed that psoralidin suppressed CRF gene transcription by quantitative reverse transcription polymerase chain reaction. Hence, down regulation of CRF gene transcription by psoralidin may be involved in the molecular mechanism underlying its potent antidepressant effect. PMID- 18445498 TI - Do malnutrition and fluoxetine neonatal treatment program alterations in heart morphology? AB - Growth and development events are observed in all organisms and can be modified by exogenous factors such as nutritional changes. Drastic morphological and functional alterations may occur during a vulnerable stage of development. The aim of this study was to investigate if malnutrition and/or fluoxetine neonatal treatment program alterations in heart morphology during the postnatal period. The sample consisted of 48 albino Wistar male rats. The rats were divided into two groups: nourished and malnourished. Pharmacologic manipulation was performed during the suckling period. The animals of each group were divided into two subgroups: saline-nourished and saline-malnourished, treated with sodium chloride solution, and fluoxetine-nourished and fluoxetine-malnourished, treated with fluoxetine. Half of the individuals in each subgroup were weighed and sacrificed on day 30 and the other half on day 71. Myocardial perfusion was performed and the heart subsequently weighed. The ventricles were cross-sectioned into two parts, which were fixed, dehydrated and sectioned. There were differences in body weight, heart weight, cross-sectional area and perimeter of the heart and in the cross-sectional area and perimeter of the cardiac cells among the groups at the different ages. Malnutrition appears to program alterations in heart morphology. However, malnourished animals that had undergone drug treatment did not exhibit the same changes. PMID- 18445499 TI - The probability of HIV infection in a new host and its reduction with microbicides. AB - We use a simple mathematical model to estimate the probability and its time dependence that one or more HIV virions successfully infect target cells. For the transfer of a given number of virions to target cells we derive expressions for the probability P(inf), of infection. Thus, in the case of needlestick transfer we determine P(inf) and an approximate time window for post-exposure prophylaxis (PEP). For heterosexual transmission, where the transfer process is more complicated, a parameter gamma is employed which measures the strength of the infection process. For the smaller value of gamma, P(inf) is from 6 x 10(-5) to 0.93 or from 7.82 x 10(-6) to 0.29, where the lower figures are for the transfer of 100 virions and the upper figures are for the transfer of 4.4 million virions. We estimate the reductions in P(inf) which occur with a microbicide of a given efficacy. It is found that reductions may be approximately as stated when the number of virions transferred is less than about 10(5), but declines to zero for viral loads above that number. It is concluded that PEP should always be applied immediately after a needlestick incident. Further, manufacturers of microbicides should be encouraged to investigate and report their effectiveness at various transferred viral burdens. PMID- 18445500 TI - The AOC promoter of tomato is regulated by developmental and environmental stimuli. AB - The allene oxide cyclase (AOC) catalyzes the formation of cis-(+)-12 oxophytodienoic acid, an intermediate in jasmonate biosynthesis and is encoded by a single copy gene in tomato. The full length AOC promoter isolated by genome walk contains 3600 bp. Transgenic tomato lines carrying a 1000 bp promoter fragment and the full length promoter, respectively, in front of the beta glucuronidase (GUS)-encoding uidA gene and several tobacco lines carrying the full length tomato AOC promoter before GUS were used to record organ- and tissue specific promoter activities during development and in response to various stimuli. High promoter activities corresponding to immunocytochemically detected occurrence of the AOC protein were found in seeds and young seedlings and were confined to the root tip, hypocotyl and cotyledons of 3-d-old seedlings. In 10-d old seedlings promoter activity appeared preferentially in the elongation zone. Fully developed tomato leaves were free of AOC promoter activity, but showed high activity upon wounding locally and systemically or upon treatment with JA, systemin or glucose. Tomato flowers showed high AOC promoter activities in ovules, sepals, anthers and pollen. Most of the promoter activity patterns found in tomato with the 1000 bp promoter fragment were also detected with the full length tomato AOC promoter in tobacco during development or in response to various stimuli. The data support a spatial and temporal regulation of JA biosynthesis during development and in response to environmental stimuli. PMID- 18445501 TI - Quantitative 1H NMR-analysis of technical octabrominated diphenylether DE-79 and UV spectra of its components and photolytic transformation products. AB - A quantitative analysis of the technical octabromo diphenylether mixture DE-79 is performed by (1)H NMR, avoiding any separation technique. The mass fractions are 36% BDE183, 19% BDE197, 13.1% BDE207, 9.1% BDE196, 7.3% BDE153, 6.2% BDE203, 2.2% BDE180, 1.6% BDE171, 1.2% BDE154 and 0.7% BDE206, considering an additional mass fraction of 1.3% BDE209 determined by HPLC analysis with a diode array detector (DAD). HPLC chromatograms of the BDEs in commercial decaBDE, octaBDE DE-79 and pentaBDE DE-71 and UV spectra of the components of DE-79 are presented. The photolysis of the octaBDE mixture DE-79, dissolved in tetrahydrofuran, by simulated sunlight is monitored by HPLC-DAD and observed to proceed mainly via debromination. Polybrominated dibenzofurans are identified from their UV spectra as significant intermediates. PMID- 18445502 TI - Sensitivity study of an OCDD environmental fate screening model in soils in the presence of PCP wood-preserving oil. AB - In order to better understand the fate of polychloro dibenzo-p-dioxins and furans (PCDD/Fs) in soils around pentachlorophenol (PCP) treated poles, a model was developed to assess the influence of wood-preserving oil and PCP on the vertical migration of octachloro-dibenzo-p-dioxin (OCDD). Simulations were performed for three soil types: sand, clay and organic. OCDD fate was modeled in the absence of co-contaminant and in the presence of oil with or without 5% (w/w) PCP. A variance propagation study was conducted to evaluate the model sensitivity to a small variation in input parameters, to determine the uncertainty on the migration depth modeled for each soil, and to understand the variability of this migration observed between different soil types. The model predicts a different OCDD fate depending on the soil type with a significant migration in the case of sand and an absence of migration in the case of organic soil. No migration is predicted in the absence of co-contaminants and a migration depth of 7-600 cm is predicted in the presence of oil (with and without PCP). Model sensitivity also depends on the soil type: the predicted OCDD migration depth is, respectively, 22 cm+/-10 cm for organic soils, 71 cm+/-20 cm for clay and 566 cm+/-200 cm for sand after 60 days of emissions from a class 3, 12.2m long pole. Even if the input parameters have a significant uncertainty due to the lack of available data, the model results seem reliable as a first approximation to screen an eventual PCDD/F migration. PMID- 18445504 TI - Atmospheric input of POPs into Lake Maggiore (Northern Italy): PCDD/F and dioxin like PCB profiles and fluxes in the atmosphere and aquatic system. AB - The delivery and accumulation of PCDD/Fs and dioxin-like PCBs (DL-PCBs) as recorded in sediments from the Lake Maggiore (LM) in Northern Italy and the influence of the atmosphere in contaminating this subalpine ecosystem were studied. PCDD/Fs (17 congeners) and DL-PCBs (12 congeners) concentrations, congener profiles and fluxes in air, bulk deposition, aquatic settling material and surface sediments are presented. Our strategy was to obtain surface sediment from areas near riverine inputs and in the depositional basins, settling material in sediment traps at one site and air, aerosol and bulk deposition profiles. PCDD/F concentrations in air of 25 WHO-TEQ fg m(-3) and DL-PCBs of 7 WHO-TEQ fg m(-3) were measured. Bulk atmospheric deposition yielded 140 and 28 WHO-TEQ pg m( 2) per week for dioxins/furans and DL-PCBs, respectively. Aquatic settling material exhibited concentrations of 11 WHO-TEQ pg g(-1) for PCDD/Fs and 2 WHO TEQ pg g(-1) for DL-PCBs. Weekly settling material fluxes of 50 WHO-TEQ pg m(-2) and 10 WHO-TEQ pg m(-2) were obtained for PCDD/Fs and DL-PCBs, respectively. PCDD/Fs concentrations in surface sediments varied from 0.1 to 17 WHO-TEQ pg g( 1) whereas values ranged from 0.03 to 6 WHO-TEQ pg g(-1) for DL-PCBs. The concentrations obtained in the environmental compartments studied suggest a situation of low level contamination. PCDD/Fs and DL-PCBs congener profiles in atmospheric air, bulk deposition, aquatic settling matter and surface sediment point to an important if not dominant contribution from atmospheric deposition to Lake Maggiore, especially derived from wet deposition of aerosol-bound PCDD/Fs and DL-PCBs. Flux estimates support this hypothesis. PMID- 18445505 TI - The utility of preoperative endometrial sampling for the detection of uterine sarcomas. AB - OBJECTIVE: Uterine sarcomas are aggressive cancers, often not recognized prior to surgical exploration. The goal of this study was to determine the utility of endometrial sampling in detecting uterine sarcomas and to examine factors associated with diagnostic inaccuracy. METHODS: All uterine tumors identified at hysterectomy from 1990 to 2006 were reviewed. Included patients underwent preoperative endometrial sampling reviewed at our center. Pathologic data was documented through review of hospital records. Statistical analysis was performed using Chi square test. RESULTS: 938 patients were identified. Preoperative sampling was available for review in 730 (78%) subjects. Uterine sarcomas occurred in 142 patients; 72 (51%) underwent preoperative sampling. Overall, endometrial sampling identified an invasive tumor in 84% (600/713), and the correct histology in 79% (564/713). Among women with sarcomas, preoperative sampling suggested an invasive tumor in 86% (62/72) and predicted the correct histologic diagnosis in 64% (46/72). The rate of detection of an invasive cancer by preoperative sampling was not statistically different among sarcomas and epithelial tumors (86% vs. 84%, p=0.76). Preoperative sampling was significantly less reliable in predicting the correct histology for uterine sarcomas (64% vs. 81%, p<0.0001). Similar trends were seen when sarcoma patients were compared to low-grade and high-grade epithelial cancers. Both biopsy and curettage had similar accuracy in diagnosing sarcomas (p=0.84). CONCLUSIONS: Endometrial sampling has a significantly lower predictive value in diagnosing uterine sarcomas compared to epithelial uterine malignancies. Biopsy and curettage have similar accuracy. Novel diagnostic techniques are needed to accurately identify uterine sarcomas preoperatively. PMID- 18445507 TI - Prevalence of transportation and leisure walking among U.S. adults. AB - OBJECTIVE: This paper aims to contrast the demographic correlates of leisure and transportation walking. METHODS: Using data from the 2005 National Health Interview Survey (n=31,482), this paper reports on the prevalence of transportation walking and leisure walking for U.S. adults and examines the variation in prevalence across different socio-demographic groups. The prevalence of transportation walking and leisure walking for U.S. adults (> or =5 days/week for > or =30 min/day) was calculated using data from the 2005 National Health Interview Survey. RESULTS: In the United States, 41.5% of adults walked for leisure and 28.2% walked for transportation in intervals of at least 10 min. The highest prevalence of transportation walking was among black non-Hispanic men (36.0%) and Asian/Native Hawaiian/Pacific Islander women (40.5%). The highest prevalence of leisure walking was among Asian/Native Hawaiian/Pacific Islander men (42.0%) and white non-Hispanic women (46.6%). Leisure walking was most prevalent among respondents with higher incomes and education levels, whereas transportation walking increased in prevalence with education level but decreased with income level. Based on the findings, 6% of U.S. adults were considered regularly active (> or =5 days/week for > or =30 min/day) by walking for transportation and 9% were regularly active by walking for leisure. CONCLUSION: Leisure and transportation walking have distinctly different demographic correlates. These differences should guide interventions aimed at influencing walking for different purposes. PMID- 18445506 TI - The effects of novelty-seeking phenotypes and sex differences on acquisition of cocaine self-administration in selectively bred High-Responder and Low-Responder rats. AB - Individual differences in exploratory behavior can predictably influence psychostimulant self-administration behavior. Male rats that exhibit a high degree of locomotor activity in a novel environment (High Responders, HR) will self-administer cocaine more readily than males exhibiting low levels of novelty induced locomotion (Low Responders, LR). The present experiment investigates the combined influences of the sex of an individual and individual phenotypes in novelty-induced locomotion to predispose animals to acquire cocaine self administration behavior, in male and female rats selectively bred for the HR-LR phenotypes. We first established that HR females, like their male counterparts, exhibit a dramatically greater locomotor response to novelty and less anxiety like behavior than do LR females. While locomotor behavior was subtly influenced by estrous stage, with both HR and LR females showing increased activity during metestrus and diestrus compared to proestrus and estrus, the effect did not obscure HR-LR differences. When male and female HR-LR animals were trained to self-administer cocaine (2 h/day, 5 days/wk x 3 wk, 0.2 mg cocaine/kg/infusion), HR males and females acquired cocaine self-administration significantly faster than their LR counterparts. Furthermore, HR females self-administered significantly more cocaine than all other groups. In conclusion, female rats, like males, exhibit HR-LR phenotypes that predict rapidity of acquiring cocaine self-administration. Moreover, HR females self-administer more cocaine than HR males and both LR groups. PMID- 18445508 TI - Borderline personality disorder and mood spectrum. AB - Several lines of evidence have raised the question of whether Borderline Personality Disorder (BPD) is an independent disease entity or it might be better conceptualized as belonging to the spectrum of mood disorders. This study explores a wide array of lifetime mood features (mood, cognitions, energy, and rhythmicity and vegetative functions) in patients with BP and mood disorders. The sample consisted of 25 BPD patients who did not meet the criteria for bipolar disorders, 16 bipolar disorders patients who did not meet the criteria for BPD, 19 unipolar patients who did not meet the criteria for BPD, and 30 non-clinical subjects. Clinical diagnoses were determined by administering the structured clinical interviews for DSM-IV disorders. The Mood Spectrum Self-Report (MOODS SR) was used for measuring lifetime mood phenomenology. Clinical subjects displayed higher mean scores than normal subjects in all domains of the MOODS-SR, and BPD patients displayed higher scores than unipolar patients in the Mood and Cognition depressive subdomains. Differences between patients with BP and bipolar disorders on MOODS psychopathology did not attain statistical significance for any (sub)domain considered. The results of this study are consistent with previous findings suggesting the importance of mood dysregulations in patients with BPD. PMID- 18445509 TI - Lack of TRPV1 inhibits cystitis-induced increased mechanical sensitivity in mice. AB - Transient receptor potential vanilloid 1 (TRPV1) is highly expressed in primary afferent neurons. Tissue damage generates an array of chemical mediators that activate and sensitize afferent nerve fibers, and sensitization of afferent nerve fibers plays an important role in development of visceral pain. We investigated participation of TRPV1 in visceral pain associated with bladder inflammation induced in mice by systemic treatment with cyclophosphamide or intravesical instillation of acrolein. The effects of experimental cystitis on bladder function (an indicator of visceral pain) and the threshold of response to mechanical or thermal stimuli of the hind paws were investigated using TRPV1 knock-out (KO) and congenic wild-type (WT) mice. We found that cystitis induced bladder mechanical hyperreactivity and increased mechanical sensitivity of hind paws in WT, but not in TRPV1 KO mice. Lack of functional TRPV1 did not inhibit development of histological evidence of bladder inflammation, or increased expression of mRNAs for nerve growth factor, endothelial nitric oxide synthase, cyclooxygenase-2 and bradykinin receptors in urothelium. Cystitis did not affect the threshold of response to thermal stimuli in WT or KO mice. These results suggest that TRPV1 is essential for cystitis-induced bladder mechanical hyperreactivity. Also, TRPV1 participates in development of visceral pain, as reflected by referred increased mechanosensitivity in peripheral tissues in the presence of visceral inflammation. PMID- 18445510 TI - Comment on "Helicobacter pylori infection may improve the survival of patients with carcinomas". PMID- 18445511 TI - Inhibition of RANK/RANKL signal transduction pathway: a promising approach for osteoporosis treatment. AB - Osteoporosis is a bone disease causing impaired bone strength. It is characterized by increased osteoclast formation or enhanced bone resorption, leading to an increased risk of fragility fractures. Its prevalence increases with age. The advent of an aging population suggests that progressively more individuals will develop this disease in the aging population. A number of drugs for the prevention and treatment of osteoporosis act by inhibiting bone resorption. However, the effectiveness of osteoporosis treatment in clinical practice is limited. Since the osteoclast is the only cell in the body that is capable of resorbing bone, understanding its biology will be necessary for developing a new therapeutic approach for osteoporosis. Recently, it was discovered that the receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system is an important signal transduction pathway that regulates osteoclast formation. The binding of OPG to RANKL inhibits the binding between RANKL and RANK; this, in turn, prevents osteoclast precursors from differentiating and fusing to form mature osteoclasts. Therefore, the inhibition of the RANK/RANKL pathway inhibits osteoclast formation, differentiation, activation, and bone resorption. A potential clinical antiresorptive therapy can be developed by using an anti-RANKL monoclonal antibody, such as denosumab, that binds to RANKL with high affinity and specificity and blocks RANKL-RANK interactions. PMID- 18445512 TI - Parasympathetic nervous system: a silent killer in the early morning hours? PMID- 18445513 TI - Perspectives on microbes as oncogenic infectious agents and implications for breast cancer. AB - Cancer management is partly based on weighing risk factors attributed to noninfectious agents, human genes and epigenetic factors. Infectious disease causation has largely been restricted to genes directly responsible for causing cancer after sustaining damage i.e. oncogenes. Lately, evidence has emerged linking infectious agents to a number of chronic diseases. These studies have recognized the influence that acute, atypical, latent and chronic infections may play in tricking the immune system and affecting disease etiology. Similar evidence is emerging in model systems with respect to the role of infectious agents in gastrointestinal, liver and lung cancers. Although viruses have been found in association with breast cancer, skepticism remains about a role for other infectious agents, notably microbes in the disease etiology. Improved experimental designs employed in different cancer studies and a less rigid definition of infectious causation may aid in confirming or refuting a microbe breast cancer connection. Cancer recurrence could potentially be minimized and treatment options further tailored on a case by case basis if microbes/microbial components/strain variants associated with breast cancer are identified; probiotics are employed to reduce treatment side-effects and if microbes could effectively be harnessed in immunotherapy. PMID- 18445514 TI - Steroid protection in aging and age-associated diseases. AB - Neuroactive steroids are secretory products of peripheral endocrine glands that modulate a variety of brain functions. A close relationship between neuroactive steroid structure and function becomes most evident under pathological circumstances. On one side, overproduction of glucocorticoid and mineralocorticoid neuroactive steroids may be detrimental to the hippocampus, which is enriched in glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). Thus, a dysfunction of the adrenocortical system in aging and age associated diseases (diabetes, hypertension) is able to cause hippocampal damage. Whereas aging and uncontrolled diabetes show a predominant GR overdrive, a MR overdrive characterizes hypertensive animals. Some abnormalities commonly found in the hippocampus of aging, diabetic and hypertensive animals include decreased neurogenesis, astrogliosis and neuronal loss in the hilus of the dentate gyrus (DG). On the other side, and in contrast to adrenal gland-derived steroids, estrogens qualify as hippocampal neuroprotectants. Given to middle-age mice, estrogens stimulated proliferation and differentiation of newborn cells in the DG, decreased astrogliosis and increased hilar neuronal number. Similar estrogen effects were obtained in mice with streptozotocin-induced diabetes and in spontaneously hypertensive rats (SHR). The results suggest that in aging and age associated diseases, adrenocortical steroid overdrive sensitizes the hippocampus to the pathological milieu imposed by a pre-existing degeneration or illness. In this setting, estradiol neuroprotection rescues hippocampal parameters previously altered by the pathological environment. PMID- 18445515 TI - Age-dependent effects of treadmill exercise during a period of inactivity. AB - The objective of this study was to investigate the effect of a treadmill exercise protocol to prevent muscle weakness, atrophy and alterations in calcium regulation in adult, old and very old rats. Adult (7-12 months), old (29-30 months) and very old (34-36 months) F344BNF(1) rats were randomly assigned to weight bearing (WB), weight bearing exercise (WBX), non-weight bearing (NWB) and non-weight bearing exercise (NWBX) groups. The WB group was considered the sedentary-control animals. NWB rats were hindlimb unweighted for 14 days. WBX and NWBX groups were exercised on a treadmill for approximately 15 min four times daily. The contractile properties [diameter, peak active force (P(0)), specific tension (P(0)/CSA)] of single myosin heavy chain type II fibers and Ca regulation [Ca(2+) dependent ATPase activity] were determined. Fiber diameter reduced by 24% in the very old rats with NWB. P(0) and P(0)/CSA declined in the young adult and very old rats with NWB. NWBX attenuated these changes in the young and very old rats. Ca(2+) dependent ATPase activity increased with treadmill exercise during non-weight bearing in the young animals. In conclusion, the treadmill exercise is beneficial in attenuating the non-weight bearing-induced changes in the individual MHC type II muscle fibers of the gastrocnemius muscle. PMID- 18445517 TI - Environmental assessment of solid waste landfilling technologies by means of LCA modeling. AB - By using life cycle assessment (LCA) modeling, this paper compares the environmental performance of six landfilling technologies (open dump, conventional landfill with flares, conventional landfill with energy recovery, standard bioreactor landfill, flushing bioreactor landfill and semi-aerobic landfill) and assesses the influence of the active operations practiced on these performances. The environmental assessments have been performed by means of the LCA-based tool EASEWASTE, whereby the functional unit utilized for the LCA is "landfilling of 1ton of wet household waste in a 10m deep landfill for 100 years". The assessment criteria include standard categories (global warming, nutrient enrichment, ozone depletion, photo-chemical ozone formation and acidification), toxicity-related categories (human toxicity and ecotoxicity) and impact on spoiled groundwater resources. Results demonstrate that it is crucially important to ensure the highest collection efficiency of landfill gas and leachate since a poor capture compromises the overall environmental performance. Once gas and leachate are collected and treated, the potential impacts in the standard environmental categories and on spoiled groundwater resources significantly decrease, although at the same time specific emissions from gas treatment lead to increased impact potentials in the toxicity-related categories. Gas utilization for energy recovery leads to saved emissions and avoided impact potentials in several environmental categories. Measures should be taken to prevent leachate infiltration to groundwater and it is essential to collect and treat the generated leachate. The bioreactor technologies recirculate the collected leachate to enhance the waste degradation process. This allows the gas collection period to be reduced from 40 to 15 years, although it does not lead to noticeable environmental benefits when considering a 100 years LCA-perspective. In order to more comprehensively understand the influence of the active operations (i.e., leachate recirculation, waste flushing and air injection) on the environmental performance, the time horizon of the assessment has been split into two time periods: years 0-15 and 16-100. Results show that if these operations are combined with gas utilization and leachate treatment, they are able to shorten the time frame that emissions lead to environmental impacts of concern. PMID- 18445516 TI - Large-insert genome analysis technology detects structural variation in Pseudomonas aeruginosa clinical strains from cystic fibrosis patients. AB - Large-insert genome analysis (LIGAN) is a broadly applicable, high-throughput technology designed to characterize genome-scale structural variation. Fosmid paired-end sequences and DNA fingerprints from a query genome are compared to a reference sequence using the Genomic Variation Analysis (GenVal) suite of software tools to pinpoint locations of insertions, deletions, and rearrangements. Fosmids spanning regions that contain new structural variants can then be sequenced. Clonal pairs of Pseudomonas aeruginosa isolates from four cystic fibrosis patients were used to validate the LIGAN technology. Approximately 1.5 Mb of inserted sequences were identified, including 743 kb containing 615 ORFs that are absent from published P. aeruginosa genomes. Six rearrangement breakpoints and 220 kb of deleted sequences were also identified. Our study expands the "genome universe" of P. aeruginosa and validates a technology that complements emerging, short-read sequencing methods that are better suited to characterizing single-nucleotide polymorphisms than structural variation. PMID- 18445518 TI - Survival of selected pathogens in diluted sludge of a thermophilic waste treatment plant and in NaCl-solution under aerobic and anaerobic conditions. AB - Decimal reduction times (DRT or D-value) of Campylobacter jejuni, Salmonella enterica (formerly Salmonella choleraesuis) serovar Senftenberg, Escherichia coli, and Listeria monocytogenes were determined in two different matrices, diluted fermenter sludge (DFS) and 0.95% NaCl-solution (NaCl) at 50 degrees C, both under aerobic and anaerobic conditions. Depending on aeration, matrix composition, and the respective organism, the D-values varied between 10min and more than 15h. Generally the viability of bacteria decreased faster in DFS compared to NaCl-solution and under aerobic compared to anaerobic conditions. After 24h no viable cells could be detected in DFS, both under aerobic as well as under anaerobic conditions, whereas viable cells were still found in NaCl solutions. In both matrices the detection limits determined by means of PCR-based and classical microbiological methods were compared and pointed to lower detection limits of the latter methods. Results of the present investigation show that test organisms were far from surviving several days in DFS whereas hydraulic retention times normally used for thermophilic anaerobic digestion are in the range of 2 weeks. However, an underestimation of survival rates of the test organisms seems probable when applying aerobic standard methods. PMID- 18445519 TI - Discussion of "effect of inoculation in composting processes: modifications in lignocellulosic fraction" Waste Management 27 (2007) 1099-1107. PMID- 18445520 TI - Inhibition of insulin-like growth factor-I receptor (IGF-IR) using NVP-AEW541, a small molecule kinase inhibitor, reduces orthotopic pancreatic cancer growth and angiogenesis. AB - The insulin-like growth factor-I receptor (IGF-IR) is frequently overexpressed and constitutively activated in pancreatic cancer, thus representing a promising target for therapy. We investigated the impact of a novel inhibitor of IGF-IR (NVP-AEW541) on signalling and growth of pancreatic cancer. Human pancreatic cancer cells and endothelial cells were employed, and effects of NVP-AEW541 on signalling pathways investigated by Western blotting. NVP-AEW541 diminished the activation of IGF-IR, IRS-1, Erk, Akt and STAT3. Furthermore, NVP-AEW541 reduced cancer cell proliferation and abrogated migratory effects of IGF-I. NVP-AEW541 elicited a direct effect on endothelial cells in terms of reducing endothelial cell migration. In vivo, treatment of mice with NVP-AEW541 significantly reduced orthotopic pancreatic tumour growth, vascularisation, and VEGF expression. Interestingly, NVP-AEW541 lowered serum levels of IGF-binding-protein-3 (IGFBP 3). In conclusion, the IGF-IR inhibitor NVP-AEW541 effectively disrupts IGF-I signalling and reduces pancreatic tumour growth. Hence, blocking IGF-IR could prove valuable for targeted therapy of pancreatic cancer. PMID- 18445521 TI - Intracellular accumulation and DNA damage persistence as determinants of human squamous cell carcinoma hypersensitivity to the novel camptothecin ST1968. AB - ST1968, a novel hydrophilic camptothecin analogue of the 7-oxyiminomethyl series, is characterised by the formation of stable DNA-topoisomerase I cleavable complex and by a promising profile of antitumour activity. The present study was designed to extend preclinical evaluation of the novel camptothecin in human squamous cell carcinoma (SCC) models. ST1968 exhibited an impressive activity with a high cure rate in SCC models. ST1968 produced 100% of complete response without evidence of regrowth in tumours characterised by susceptibility to drug-induced apoptosis (FaDu, A431 and A2780). In contrast to irinotecan, ST1968 still showed an excellent, persisting activity in models less susceptible to apoptosis induction (KB, Caski and SiHa), in which drug treatment elicited a persistent DNA damage response, as documented by phosphorylation of p53, RPA-2 and histone H2AX, resulting in delayed apoptosis and senescence. This behaviour was associated with a marked cellular/tumour drug accumulation. In conclusion, ST1968 exhibited an outstanding antitumour activity superior to that of irinotecan against SCC. A high intracellular accumulation, resulting in fast apoptosis or DNA damage persistence, appeared to be a critical determinant of SCC sensitivity to ST1968. PMID- 18445522 TI - Biofiltration of ethyl acetate and amyl acetate using a composite bead biofilter. AB - Biodegradation kinetic behaviors of ethyl acetate and amyl acetate in a composite bead biofilter were investigated. The composite bead was the spherical PVA/peat/KNO3/GAC composite bead which was prepared in our previous works. Both microbial growth rate and biochemical reaction rate were inhibited at higher inlet concentration. For the microbial growth process, the microbial growth rate of ethyl acetate was greater than that of amyl acetate in the inlet concentration range of 100-400ppm. The degree of inhibitive effect was almost the same for ethyl acetate and amyl acetate in this concentration range. The half-saturation constant Ks values of ethyl acetate and amyl acetate were 16.26 and 12.65ppm, respectively. The maximum reaction rate Vm values of ethyl acetate and amyl acetate were 4.08 and 3.53gCh(-1)kg(-1) packed material, respectively. Zero-order kinetic with the diffusion limitation could be regarded as the most adequate biochemical reaction model. For the biochemical reaction process, the biochemical reaction rate of ethyl acetate was greater than that of amyl acetate in the inlet concentration range of 100-400ppm. The inhibitive effect for ethyl acetate was more pronounced than that for AA in this concentration range. The maximum elimination capacity of ethyl acetate and amyl acetate were 82.3 and 37.93gCh( 1)m(-3) bed volume, respectively. Ethyl acetate degraded by microbial was easier than amyl acetate did. PMID- 18445523 TI - Free radical scavenging of grape pomace extracts from Cabernet sauvingnon (Vitis vinifera). AB - Pressed grape pomace obtained from the wine production of Cabernet sauvignon (Vitis vinifera) vintage was dried until 9.8% moisture content, ground and submitted to extraction of soluble components from different extraction techniques. Low pressure extractions were performed with ethanol maceration followed by fractionation with n-hexane, dichloromethane, butanol and ethyl acetate. These solvents were furthermore applied for soxhlet extraction. Supercritical fluid extraction (SFE) was also performed to obtain grape pomace extracts by using pure CO2 and CO2 with ethanol as co-solvent in concentrations of 10, 15 and 20%w/w. The operating condition used in high pressure extractions was 150bar and 40 degrees C. The antioxidant activity of the grape pomace extracts was determined considering the free radical scavenging assay using 1,1 Diphenyl-2-picrylhydrazyl (DPPH) and was correlated with the total phenol content determined according to the Folin-Ciocalteu method. The results obtained in DPPH tests indicate the highest antioxidant activity of 96.6+/-0.3%AA, with an IC50 value of 13+/-1, for the extracts obtained with ethyl acetate in solid-liquid extraction. The highest yield values were achieved in soxhlet extraction with ethanol (13.2%w/w) and with butanol (12.2%w/w), and also by SFE with 15% ethanol (9.2%w/w). The lipophilic composition of grape pomace extracts was evaluated by gas chromatography-mass spectrometry with the identification of components like linoleic acid and ethyl linoleate, with important therapeutic activities. PMID- 18445524 TI - Thermodynamic characterization of a highly thermoactive extracellular pectate lyase from a new isolate Bacillus pumilus DKS1. AB - An extracellular pectate lyase (EC 4.2.2.2) was purified from the culture filtrate of a newly isolated Bacillus pumilus DKS1 grown in pectin containing medium. Using ion-exchange and gel filtration chromatography, this enzyme was purified and found to have a molecular weight of around 35kDa. The purified enzyme exhibited maximal activity at a temperature of 75 degrees C and pH 8.5. The presence of 1mM calcium and manganese enhanced pectate lyase activity and was strongly inhibited by zinc, nickel and EDTA. The thermal inactivation studies revealed an entropy-enthalpy compensation pattern below a critical temperature. The alkaliphilicity and high thermostability of this pectate lyase may have potential implications in fibre degumming. PMID- 18445525 TI - Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors. AB - A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II. PMID- 18445526 TI - Arylethynyltriazole acyclonucleosides inhibit hepatitis C virus replication. AB - Novel acyclic triazole nucleosides with various ethynyl moieties appended on the triazole nucleobase were synthesized efficiently using a convenient one-step Sonogashira reaction in aqueous solution and under microwave irradiation. One of the compounds, 1f, inhibited HCV subgenomic replication with a 50% effective concentration (EC(50)) of 22 microg/ml and did not inhibit proliferation of the host cell at a concentration of 50 microg/ml. A preliminary SAR study suggests that the appended phenyl ring as well as the rigid triple bond linker contributes importantly to the anti-HCV activity. PMID- 18445527 TI - P2Y1 receptor antagonists as novel antithrombotic agents. AB - The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable. PMID- 18445528 TI - Efficient synthesis and evaluation of bimodal ligand NETA. AB - The efficient and short synthetic route to the structurally novel bimodal ligand NETA for antibody-targeted radiation therapy (radioimmunotherapy, RIT) of cancer was developed. The structure of NETA was determined by X-ray crystallography. The arsenazo-based UV spectroscopic complexation kinetics data suggest that NETA is a promising chelator for use in RIT applications of (212)Bi, (213)Bi, and (177)Lu. PMID- 18445529 TI - The significance of persistent newly developed autoantibodies in JIA patients under long-term anti-TNF treatment. AB - OBJECTIVE: To study the significance of persistent (12 months) new autoantibodies, in Juvenile Idiopathic Arthritis (JIA) patients treated with either Infliximab (INFL) or Etanercept (ET) for 2 years. PATIENTS-METHODS: 26 children under INFL (n=12) or ET (n=14) were prospectively studied. A large panel of autoantibodies was tested using indirect immunofluorescence (ANA, anti-dsDNA, anti-ENA, SMA, LKM, AMA, PCA, anti-R1, ATA), ELISA (ANA, anti-ENA, anti cardiolipin, ANCA), immunoblotting assay (anti-ENA: anti-Ro, anti-La, anti-Sm, anti-URNP, anti-Jo, anti-Scl70, anti-centromere, anti-ribosomal and anti-histone) and rate nephelometry (RF). RESULTS: Apart from the positive patients for ANA (13/26) and RF (2/26) prior to anti-TNF treatment, 6/26 patients (23%) developed new autoantibodies (SMA, anti-R1, ATA) which persisted for 12-50 months. None developed antibodies to nuclear antigens. In only one case, ATA was associated with the development of Hashimoto's thyroiditis. CONCLUSIONS: These findings indicate that in JIA patients in contrast to adult RA patients, development of new autoantibodies to various nuclear antigens is rare. Other non relevant to rheumatic diseases autoantibodies, may appear and persist for >12 months, but very rarely they may be related to clinical entities, especially in the presence of a positive family history of autoimmunity. PMID- 18445530 TI - Differentiating shame from guilt. AB - How does shame differ from guilt? Empirical psychology has recently offered distinct and seemingly incompatible answers to this question. This article brings together four prominent answers into a cohesive whole. These are that (a) shame differs from guilt in being a social emotion; (b) shame, in contrast to guilt, affects the whole self; (c) shame is linked with ideals, whereas guilt concerns prohibitions and (d) shame is oriented towards the self, guilt towards others. After presenting the relevant empirical evidence, we defend specific interpretations of each of these answers and argue that they are related to four different dimensions of the emotions. This not only allows us to overcome the conclusion that the above criteria are either unrelated or conflicting with one another, it also allows us to tell apart what is constitutive from what is typical of them. PMID- 18445532 TI - Thinner prefrontal cortex in veterans with posttraumatic stress disorder. AB - Structural neuroimaging studies in posttraumatic stress disorder (PTSD) have focused primarily on structural alterations in the medial temporal lobe, and only a few have examined grey matter reductions in the cortex. Recent advances in computational analysis provide new opportunities to use semi-automatic techniques to determine cortical thickness, but these techniques have not yet been applied in PTSD. Twenty-five male veterans with PTSD and twenty-five male veterans without PTSD matched for age, year and region of deployment were recruited. All the subjects were scanned using MRI. Subjects' brains were aligned using cortex based alignment in a region of interest based approach. Individual cortical thickness maps were calculated from the MR images. Regions of interest examined included the bilateral superior frontal gyri, bilateral middle frontal gyri, bilateral inferior frontal gyri, bilateral superior temporal gyri, and bilateral middle temporal gyri. In a large number of patients and controls, IQ scores and memory scores were also obtained. Individual cortical thickness maps were calculated from the MR images. Veterans with PTSD revealed reduced cortical thickness in the bilateral superior and middle frontal gyri, the left inferior frontal gyrus, and the left superior temporal gyrus. Veterans with PTSD performed significantly worse on memory measures compared to control veterans. Cortical thickness correlated with memory measures in the veterans without PTSD, but not in the veterans with PTSD. Cortical thinning in these regions may thus correspond to functional abnormalities observed in patients with PTSD. PMID- 18445531 TI - Feedback signals in the caudate reflect goal achievement on a declarative memory task. AB - The striatum has been shown to be a key region in the processing of reward related information. The head of the caudate nucleus has been implicated in processing performance feedback, or in other words, information about the outcomes of one's actions. However, feedback provides multiple types of information, and it is not clear which of these types of information drive a caudate response. We sought to determine whether the signal in the caudate differed when feedback was informative but only arbitrarily related to performance versus when it provided information about goal achievement. To do this, we used functional magnetic resonance imaging (fMRI) to examine caudate activation during a feedback-based paired associate word-learning task. During an initial round of 60 distinct trials, participants chose one of two responses on each trial and received feedback about whether their responses were correct. On the subsequent two rounds, the 60 trials were repeated and participants chose their responses based on their memory of the correct answer. The caudate nuclei were strongly engaged only during the second two rounds, when feedback reflected the accuracy of memory. These results support the idea that feedback-based caudate activation is context dependent: the caudate can be engaged in feedback based declarative memory tasks, but it is more strongly engaged when feedback is "earned" by performance than when it is informative but not tied to goal achievement. PMID- 18445533 TI - Reproducible imaging of rat corticothalamic pathway by longitudinal manganese enhanced MRI (L-MEMRI). AB - Manganese-enhanced MRI (MEMRI) has been described as a powerful tool to depict the architecture of neuronal circuits. The aim of the present study was to optimize the experimental conditions of MEMRI that permits the study of insult induced alterations of the somatosensory pathway in a longitudinal way, and to provide functional information on rat corticothalamic connectivity or disturbances thereof. A guidance screw was implanted in the skull of the rats, over the forelimb representation area of the primary somatosensory cortex (S1fl), allowing repetitive injections at the same stereotactic coordinates. MnCl2 (200 nL, 0.3 M) was injected 1.5 mm below the dura using a calibrated microcapillary. Animals received MnCl2 injections 3 times at 15 day intervals. Spatiotemporal patterns showed a significant hyperintensity on T1-weighted images induced by manganese transport in structures related to the somatosensory pathway, i.e. globus pallidus, caudate putamen, thalamus and substantia nigra. 7 days after MnCl2 injection hyperintensity was only evident at some points surrounding the injection site. Complete loss of manganese-induced contrast was achieved after 15 days after injection. Functional MRI (fMRI) experiments were performed under the same conditions, 24 h after MnCl2 injection. Activation of S1fl was observed showing that fMRI and MEMRI studies are compatible and can be performed in parallel in the same animals. The present study shows, for the first time, a robust and reproducible technique to perform longitudinal MEMRI (L-MEMRI) experiments and to study the time course of alterations of the corticothalamic connections following stroke in the rat. PMID- 18445534 TI - Mossy fiber sprouting in pilocarpine-induced status epilepticus rat hippocampus: a correlative study of diffusion spectrum imaging and histology. AB - Mossy fiber sprouting (MFS) is the main characteristic of temporal lobe epilepsy (TLE), which is highly correlated with the frequencies of recurrent seizures as well as degrees of severity of TLE. A recent MRI technique, referred to as diffusion spectrum imaging (DSI), can resolve crossing fibers and investigate the intravoxel heterogeneity of water molecular diffusion. Being able to achieve higher accuracy in depicting the complex fiber architecture, DSI may help improve localization of the seizure-induced epileptic foci. In this study, two indices of DSI, which represented the mean diffusivity (MSL) and diffusion anisotropy (DA), were proposed. A correlative study between diffusion characteristics and the severity of MFS was investigated in the pilocarpine-induced status epilepticus (SE) rat model. Nine SE rats and five control rats were studied with MRI and histological Timm's staining. For MSL, no significant correlation was found in the dentate gyrus (DG), r=-0.36; p=0.2017, and positive correlation was found in cornu ammonis (CA3), r=0.62; p=0.0174. The correlation between DA and Timm's score showed positive correlation in DG, r=0.71; p=0.0047, and negative correlation in CA3, r=-0.63; p=0.0151. Our results were compatible with the previous reports on fiber architecture alterations in DG and CA3 subregions. In conclusion, the histological correspondence of DSI indices was demonstrated. With DSI indices, longitudinal follow-up of hippocampal fiber architecture can be achieved to elucidate the pathophysiology of TLE, which might be helpful in disease localization. PMID- 18445535 TI - The first report of Histophilus somni pneumonia in Nigerian dairy cattle. AB - Clinical signs of severe bronchopneumonia, including anorexia, coughing, nasal discharge, dyspnoea, diarrhoea, distension of the neck, lethargy, recumbency, lameness preceding collapse, and death were observed among a herd of Holstein Friesian dairy cattle. The outbreak occurred over a 30-day period, and attack and case-fatality rates were 0.4% and 50%, respectively. At necropsy, extensive consolidation in the cranioventral parts of the lungs was observed. Histologically, a severe acute bronchopneumonia with slight pleuritis was present. Both pathological and bacteriological evaluation of the lungs incriminated Histophilus somni (heavy growth). Supplementary laboratory investigations also isolated Clostridium and Klebsiella species (scanty growth) from the lungs. Histophilosis in cattle was confirmed for the first time in Nigeria. PMID- 18445536 TI - Diagnostic imaging of the equine fetlock region using radiography and ultrasonography. Part 1: Soft tissues. AB - The equine fetlock is the joint most commonly associated with lameness. Although the fetlock is regarded as a simple joint, diagnosis of a fetlock disorder can be a challenge and various imaging modalities are routinely used to arrive at an accurate diagnosis. This review describes the principal disorders affecting the soft tissues of the fetlock region and addresses some of the technical aspects involved in taking radiographic and ultrasonographic images of the different soft tissue lesions. A combination of radiography and ultrasonography is still the most commonly used diagnostic approach in clinical practice. PMID- 18445537 TI - Echocardiographic evaluation including tissue Doppler imaging in New Zealand white rabbits sedated with ketamine and midazolam. AB - Limited data are available on the use of more recent echocardiographic parameters in the rabbit. Echocardiographic examination, including conventional echocardiography and tissue Doppler imaging (TDI), was performed on 26 male New Zealand white rabbits under ketamine-midazolam sedation. Particular emphasis was placed on the more recent systolic and diastolic parameters, such as myocardial performance index (Tei index) and mitral annular motion (from septal and lateral sides of the left ventricle) obtained using pulsed TDI. Parameters that assessed systolic and diastolic function (fractional shortening, Tei index, and maximal mitral E- and A-wave velocities) were comparable to those reported in the literature for rabbits in the awake state. The less cardiodepressive anaesthetic protocol could offer a good alternative in performing echocardiographic evaluation whenever such caution is necessary. TDI is feasible in healthy rabbits and potentially suitable for the investigation of left ventricle systolic and diastolic function. PMID- 18445538 TI - Upstream transcription factor 1 (USF1) in risk of type 2 diabetes: association study in 2000 Dutch Caucasians. AB - Type 2 diabetes shares substantial genetic and phenotypic overlap with familial combined hyperlipidemia. Upstream stimulatory factor 1 (USF1), a well-established susceptibility gene for familial combined hyperlipidemia, is postulated to be such a shared genetic determinant. We evaluated two established variants in familial combined hyperlipidemia (rs2073658 and rs3737787) for association with type 2 diabetes in two Dutch case-control samples (N=2011). The first case control sample comprised 501 subjects with type 2 diabetes from the Breda cohort and 920 healthy blood bank donors of Dutch Caucasian origin. The second case control sample included 211 subjects with type 2 diabetes, and 379 normoglycemic controls. SNP rs2073658 and SNP rs3737787 were in perfect linkage disequilibrium. In the first case-control sample, prevalence of the major allele was higher in patients than in controls (75% versus 71%, OR=1.25, p=0.018). A similar effect size and -direction was observed in the second case-control sample (76% versus 72%, OR=1.22, p=0.16). A combined analysis strengthened the evidence for association (OR=1.23, p=0.006). Notably, the increased risk for type 2 diabetes could be ascribed to the major allele, and its high frequency translated to a substantial population attributable risk of 14.5%. In conclusion, the major allele of rs2073658 in the USF1 gene is associated with a modestly increased risk to develop type 2 diabetes in Dutch Caucasians, with considerable impact at the population level. PMID- 18445539 TI - Mechanisms underlying the limited injectability of hydraulic calcium phosphate paste. AB - Calcium phosphate (CaP) cements are being increasingly used for minimally invasive hard tissue implantation. Possible approaches to improve the bad injectability of hydraulic calcium phosphate pastes have been discussed and investigated in a number of recent publications. However, the liquid-phase separation mechanism leading to the limited injectability has not yet been addressed. Liquid-phase separation means that the liquid-to-powder ratio (LPR) of the extruded paste is higher than the LPR of the paste left in the syringe. The goal of this paper was to remedy this situation by looking at the liquid-phase migration occurring during the injection of a paste from a syringe through a cannula. Experimentally, it was seen that the liquid content of both the syringe paste and the extrudate decreased during the paste injection. Moreover, a high extrusion velocity, small syringe size, short cannula and high LPR favored a good injectability. These results could be partly explained in light of rheological measurements performed with the investigated paste. PMID- 18445540 TI - Perspectives on the pathogenesis and therapy of hemophagocytic syndrome. PMID- 18445541 TI - Antimicrobial resistance of rapidly growing mycobacteria in western Taiwan: SMART program 2002. AB - BACKGROUND/PURPOSE: To understand the resistance patterns of rapidly growing mycobacteria (RGM) in Taiwan, antimicrobial resistance of clinical isolates was determined as part of the SMART (Surveillance from Multicenter Antimicrobial Resistance in Taiwan) program. METHODS: During the period from January 2002 to December 2003, clinical isolates were collected from eight hospitals located on the west side of Taiwan and one reference laboratory. Broth microdilution minimum inhibitory concentrations of 11 antimicrobial agents were determined for 312 clinical isolates of RGM, including the Mycobacterium fortuitum group (110 isolates), Mycobacterium abscessus group (168 isolates), and Mycobacterium chelonae group (34 isolates). RESULTS: Nearly all of the RGM were susceptible to amikacin and ofloxacin (= 90%) and resistant to doxycycline (less than 3% susceptible). Tobramycin showed similar in vitro activity against the M. fortuitum and M. chelonae (77%) groups, but was less active against the M. abscessus group (58%). Ciprofloxacin was active mainly against M. fortuitum (95%). Nearly all RGM were resistant to erythromycin and doxycycline. However, around half of the RGM isolates remained susceptible to minocycline (50-54%). Clarithromycin was active against the M. abscessus group (53% susceptible), with a high rate of resistance in the M. chelonae (38% susceptible) and M. fortuitum (15% susceptible) group. Cefoxitin was more active against the M. fortuitum group (65%) than the other two RGM (40-44%), and les than 40% of the RGM isolates remained susceptible to imipenem (21-38%). CONCLUSION: The resistance of RGM in Taiwan is not as high as previously reported (notably for tobramycin, ciprofloxacin and cefoxitin), but reduction in the susceptibility rates of clarithromycin and imipenem for the M. fortuitum and M. abscessus groups demonstrates the importance of in vitro susceptibility testing of clinically important isolates, as susceptibility may differ in different geographical areas, even regionally, and over time. PMID- 18445542 TI - Central ossifying fibroma: a clinicopathologic study of 28 cases. AB - BACKGROUND/PURPOSE: Central ossifying fibroma (COF) is the most common benign fibro-osseous lesion of the jaw. This retrospective study evaluated the clinical and histopathologic features of 28 COFs in Taiwanese patients. METHODS: Twenty eight consecutive cases of COF were collected from 1988 to 2006. The clinical data and microscopic features of these cases were reviewed and analyzed. RESULTS: The mean age of patients at the time of diagnosis was 34 years. There were six male and 22 female patients. Twenty-six (93%) cases were found in the mandible and two (7%) in the maxilla. The most common sites for COFs were the molar region (17 cases, 61%), followed by the premolar (8 cases, 28%), and incisor/canine (3 cases, 11%) regions. Bone swelling or expansion (96%, 26/27) was the most frequent clinical presentation. Six (21%) COFs presented as a radiolucent lesion, 17 (61%) as a mixed lesion, and five (18%) as a radio-opaque lesion. No recurrence of the lesion was found after surgical excision in this series. Microscopically, COFs showed trabeculae of woven bone (25 cases) and/or lamellar bone (5 cases) and/or spherules of cementoid (19 cases) in a cellular fibrous connective tissue stroma. The stromal component was highly cellular in 21 cases, moderately cellular in seven cases, prominently vascular in 11, and collagenous in six. CONCLUSION: COFs occur more frequently in female patients and in those in the second to fourth decades of life. The most commonly affected site is the mandible, especially the molar region. The majority of COF lesions present as a well-defined, mixed lesion radiographically. Most COFs can be treated by conservative surgical excision without subsequent recurrence. PMID- 18445543 TI - Astrovirus gastroenteritis in children in Taipei. AB - BACKGROUND/PURPOSE: A prospective study was initiated to study astroviral infections in Taiwan. METHODS: A total of 415 stool samples were collected and assayed for astrovirus antigen using an enzyme immunoassay. RESULTS: Twelve (2.9%) stool samples from 12 patients were positive for astrovirus antigen. Most patients (8/12) had watery diarrhea which lasted for 2-6 days. The majority of patients recovered without specific treatment, except for two patients who were treated with antibiotics for possible bacterial infections. One patient developed chronic diarrhea and two episodes were nosocomially acquired. A clustering in the autumn and winter, with a peak in December (5/12), was noted. Growth on Caco-2 cells was performed for four specimens with positive astroviral RT-PCR results, and a characteristic cytopathic effect was observed after 4 days. Astroviral RNA was detected in six stool samples using RT-PCR. Five of six strains were serotype 1 and one strain was serotype 3. Sequence homology among the six strains was between 80.5% and 100%. A higher degree of homology (89.9-100%) was noted in the five strains of serotype 1. A phylogenetic study demonstrated two clusters in our strains and Oxford reference strain types 1 and 2. CONCLUSION: Our study results provide further information about the prevalence and span of clinical spectra associated with astroviral infections in Taiwan. The current study showed that infection with astroviruses may be an important cause of gastroenteritis, as well as respiratory symptoms, in infants and children in Taipei. PMID- 18445544 TI - Impact on neonatal outcome and anthropometric growth in very low birth weight infants with histological chorioamnionitis. AB - BACKGROUND/PURPOSE: Chorioamnionitis (CAM) is one of the main causes of preterm labor. The specific aim of our study was to evaluate neonatal outcome and anthropometric growth at the corrected age of 2 years after exposure to an adverse intrauterine event of CAM in very low birth weight (VLBW, less than 1500 g) infants. METHODS: One hundred and nineteen VLBW infants had adequate placental histological data available for the study. Maternal and perinatal characteristics and neonatal morbidity were determined. The infants were followed up prospectively and their anthropometric growth was recorded in the neonatal follow up clinic for 2 years. RESULTS: Histological CAM was evident in 64 cases (53.8%, CAM group). Patients with histological CAM delivered earlier (27.8 +/- 2.9 vs. 29.6 +/- 3.6 weeks, p = 0.003), and they had higher incidence of preterm premature rupture of membranes (PPROM, p less than 0.001) and longer ventilation days (p = 0.001). After adjusting for gestational age, sepsis (aOR, 3.355), bronchopulmonary dysplasia (aOR, 3.018) and mechanical ventilation (aOR, 4.094) had a higher incidence in the CAM group. At the corrected ages of 6, 12, 18 and 24 months, anthropometric measurements, including body weight, body height and head circumference, were similar for the study and control infants. CONCLUSION: Histological CAM was associated with a higher incidence of PPROM, sepsis, bronchopulmonary dysplasia, more mechanical ventilation and longer ventilation days. However, at the age of 2 years, CAM had no impact on anthropometric growth. PMID- 18445545 TI - High frequency oscillatory ventilation in children: experience of a medical center in Taiwan. AB - BACKGROUND/PURPOSE: Data about the effectiveness of high frequency oscillatory ventilation (HFOV) in children with respiratory failure are limited. This study investigated the efficacy and prognostic factors of this treatment. METHODS: Children between 2 months and 18 years of age who received HFOV between January 2000 and September 2006 in a tertiary care center were enrolled in this retrospective study. RESULTS: Thirty-six HFOV treatments were given to 33 patients (twice in one patient and three times in another patient) at a mean age of 5.4 +/- 5.0 years. HFOV was used as a rescue after conventional mechanical ventilation (CMV) for 4.4 +/- 4.2 days. The mean duration of HFOV was 7.6 +/- 7.9 days. The most common indication for HFOV was oxygenation failure, which was due to pneumonia with acute respiratory distress syndrome in 15 (45.5%), severe lobar pneumonia in nine (27.3%), pulmonary hemorrhage in eight (24.2%) and pneumothorax in one (3%). PaCO2 was significantly improved 4 hours after HFOV and the PaO2/FiO2 ratio increased significantly 12 hours later. The oxygenation index and alveolar-arterial oxygen difference P(A-a)O2, however, did not change markedly. Four (12%) patients needed further extracorporeal life support and two of these survived. The overall survival rate was 45.5%. Patients with heavier body weight (p less than 0.05) and of the male gender (p less than 0.05) had a higher risk of mortality. CONCLUSION: As a relatively late rescue therapy after failure of CMV, HFOV may improve PaCO2 and PaO2/FiO2 in children with respiratory failure. However, it carries an increased mortality rate in patients with heavier body weight and male gender. PMID- 18445546 TI - Radiographic assessment of skeletal maturation stages for orthodontic patients: hand-wrist bones or cervical vertebrae? AB - BACKGROUND/PURPOSE: The skeletal maturation status of a growing patient can influence the selection of orthodontic treatment procedures. Either lateral cephalometric or hand-wrist radiography can be used to assess skeletal development. In this study, we examined the correlation between the maturation stages of cervical vertebrae and hand-wrist bones in Taiwanese individuals. METHODS: The study group consisted of 330 male and 379 female subjects ranging in age from 8 to 18 years. A total of 709 hand-wrist and 709 lateral cephalometric radiographs were analyzed. Hand-wrist maturation stages were assessed using National Taiwan University Hospital Skeletal Maturation Index (NTUH-SMI). Cervical vertebral maturation stages were determined by the latest Cervical Vertebral Maturation Stage (CVMS) Index. Spearman's rank correlation was used to correlate the respective maturation stages assessed from the hand-wrist bones and the cervical vertebrae. RESULTS: The values of Spearman's rank correlation were 0.910 for males and 0.937 for females, respectively. These data confirmed a strong and significant correlation between CVMS and NTUH-SMI systems (p less than 0.001). After comparison of the mean ages of subjects in different stages of CVMS and NTU-SMI systems, we found that CVMS I corresponded to NTUH-SMI stages 1 and 2, CVMS II to NTUH-SMI stage 3, CVMS III to NTUHSMI stage 4, CVMS IV to NTUH-SMI stage 5, CVMS V to NTUH-SMI stages 6, 7 and 8, and CVMS VI to NTUH-SMI stage 9. CONCLUSION: Our results indicate that cervical vertebral maturation stages can be used to replace hand-wrist bone maturation stages for evaluation of skeletal maturity in Taiwanese individuals. PMID- 18445547 TI - Effects of a multimodule curriculum of palliative care on medical students. AB - BACKGROUND/PURPOSE: The objective of this study was to investigate the effects of educational intervention using a multimodule curriculum of palliative care on medical students, and to explore significant factors that influence improvement in beliefs of ethical decision-making. METHODS: A total of 259 medical students enrolled in the "Family, Society and Medicine" course, and accepted a multimodule palliative care curriculum that included a 1-hour lecture, 1 hour of patient contact, 1 hour of literature reading, and 1 hour of discussion. A questionnaire was administered before and after the course to evaluate improvements in medical students' knowledge (principles and clinical management) of palliative care and their beliefs concerning ethical decision-making in palliative care. RESULTS: The students showed significant improvements after the course in their knowledge of the principles of palliative care (pretest 58.4% vs. posttest 73.1%; p less than 0.01) and clinical management of palliative care (pretest 58.8% vs. posttest 67.9%; p less than 0.01). Although their beliefs about ethical decision-making were also improved after the course, the medical students did not have a positive belief of "artificial nutrition and hydration is not always beneficial for terminal cancer patients", with a mean score of only 3.15 and 3.51 (pretest and posttest, respectively; range, 1-5). The logistic regression model showed that improvement in knowledge of either principles or clinical management did not significantly improve beliefs about ethical decision-making. CONCLUSION: A multimodule curriculum of palliative care for medical students can significantly improve their knowledge on principles of clinical management and beliefs about ethical decision-making in palliative care. As for changes in beliefs about ethical decision-making in palliative care, continued ethical and clinical training is required. PMID- 18445548 TI - Dynamic effects of axial loading on the lumbar spine during magnetic resonance imaging in patients with suspected spinal stenosis. AB - BACKGROUND: Previous studies have shown that axial compression in extension (ACE) of the spine during magnetic resonance imaging (MRI) has revealed unexpected pathological features compared with the conventional psoas-relaxed position (PRP) used in imaging. The purpose of this study was to evaluate the dynamic effect of axial loading on lumbar spinal stenosis using MRI in patients with spinal stenosis. METHODS: A total of 14 women and 11 men with lumbar spinal stenosis were examined in both PRP and ACE positions. We calculated the dural-sac cross sectional area (DCSA) to evaluate severity of spinal canal stenosis. DCSA, as well as the dural-sac anteroposterior diameter (DAPD) and dural-sac transverse diameter (DTD) in both positions were measured using a digital image view station. A paired t test determined the differences in DCSA, DAPD and DTD between the two positions at each intervertebral disc level. RESULTS: Axial loading increased severity of lumbar spinal stenosis during MRI, as demonstrated by a decrease in DCSA from 20.5% to 6.3% (mean, 11.40 +/- 3.66%) between the PRP and ACE positions (p less than 0.01). Significant differences were also noted in DAPD and DTD between the PRP and ACE positions (p less than 0.01). A significant correlation was found between the decrease in mean DCSA and that in DAPD and DTD. The decrease in mean DCSA, DAPD and DTD following axial compression was greatest at the L4/5 and L5/S1 levels. CONCLUSION: Axial loading increases severity of lumbar canal stenosis and the effect of axial loading on MRI examination is greatest at the L4/5 and L5/S1 levels. PMID- 18445549 TI - Association of extremely skewed X-chromosome inactivation with Taiwanese women presenting with recurrent pregnancy loss. AB - X-chromosome inactivation (XCI) is a phenomenon that occurs in female mammals. Typically, maternally and paternally-derived X chromosomes are inactivated at approximately the same frequency. If preferential inactivation occurs, the person is considered to have skewed XCI. Skewed XCI has been reported to occur more frequently in women who experience recurrent pregnancy loss (RPL). In this study, we sought to investigate if there is an association between skewed XCI and unexplained RPL in Taiwanese women. A total of 194 women who had experienced unexplained RPL were recruited into the study. Human androgen receptor or DXS6673E and DX15-134 loci were used in the XCI assay. The results of our study suggested that a cut-off point less than 90% may not be justified for skewed XCI. Only extremely skewed (more than 95%) XCI is associated with RPL. Extremely skewed XCI occurs in a subset of Taiwanese women with RPL. PMID- 18445550 TI - Primary synovial sarcoma of the kidney. AB - Primary synovial sarcoma arising from the kidney is extremely rare. We report two cases with primary renal synovial sarcoma. Both were initially diagnosed as renal cell carcinoma. The first case was a 30-year-old woman who presented with right flank soreness. Ultrasonography disclosed a multiloculated cystic tumor measuring 9 x 7 cm. She underwent hand-assisted laparoscopic radical nephrectomy; there was no recurrence during 15 months of follow-up. The second case was a 49-year-old woman who presented with a palpable mass in the left upper quadrant of the abdomen of 1 month's duration. Computed tomography showed a heterogeneously enhanced tumor measuring 13 x 11 cm at the left retroperitoneum with displacement of the pancreas and the left kidney. Hand-assisted retroperitoneoscopic radical nephrectomy was performed. She had no evidence of recurrence after 27 months of follow-up. Pathology of the two cases showed histologic and immunochemical features of synovial sarcoma with coexisting spindle and epithelial cells. Physicians should be aware of the possibility of malignancy in cystic renal masses and that synovial sarcoma is one of the possibilities. PMID- 18445551 TI - Ruptured pseudoaneurysm of the external iliac artery in an advanced cervical cancer patient treated by endovascular covered stent placement. AB - The formation of pseudoaneurysms in patients with gynecologic malignancies is rare. We describe a patient with locally advanced cervical cancer who had life threatening rectal bleeding due to a ruptured pseudoaneurysm of the right external iliac artery, which was successfully treated by emergent endovascular covered stent placement. This 56-year-old woman had received concurrent chemoradiation, salvage hysterectomy and systemic chemotherapy for advanced cervical cancer. About 25 months after her diagnosis of cervical cancer, she suffered from acute life-threatening rectal bleeding. Angiography revealed active extravasation from a pseudoaneurysm of the right external iliac artery. A covered stent was placed across the pseudoaneurysm via an endovascular approach to stop the bleeding. The patient recovered well without any sequelae. We believe that this technique might also be useful in other irradiated gynecologic cancer patients, especially when direct surgical repair is difficult to perform due to pelvic irradiation or tumor recurrence. PMID- 18445552 TI - Adaptive dynamics with a single two-state protein. AB - An important step towards understanding biological systems is to relate simple biochemical elements to dynamics. Here, we present the arguably simplest dynamical element in biochemical networks. It consists of a single protein with two states (active and inactive) and an external signal that catalyses the conversion between these two states. Further, there is steady synthesis and degradation of the inactive and active forms, respectively. As this element captures both structural and dynamical features of biochemical networks at the lowest level, we refer to it as a biochemical network unit (BioNetUnit). Using both simulations and mathematical analysis, we find that BioNetUnit shows perfect adaptation that leads to temporal responses to step changes in the incoming signal. Compared with a well-described adaptive system, which is found in bacterial chemotaxis, BioNetUnit has lower sensitivity and its adaptation time is less robust to the base signal levels. We show that these dynamical limitations lead to 'once-and-only-once' responses for certain signal sequences. These findings demonstrate that BioNetUnit is relevant in adaptive and cyclic processes. In particular, it could be seen as a generic representation for ligand activated receptors that are desensitized upon continuous activation. The analysis of coupled BioNetUnits will show how the presented dynamics at single unit will change upon increased system complexity and how such systems would mediate biological functions. PMID- 18445553 TI - Mapping protein electron transfer pathways with QM/MM methods. AB - Mixed quantum mechanics/molecular mechanics (QM/MM) methods offer a valuable computational tool for understanding the electron transfer pathway in protein substrate interactions and protein-protein complexes. These hybrid methods are capable of solving the Schrodinger equation on a small subset of the protein, the quantum region, describing its electronic structure under the polarization effects of the remainder of the protein. By selectively turning on and off different residues in the quantum region, we are able to obtain the electron pathway for short- and large-range interactions. Here, we summarize recent studies involving the protein-substrate interaction in cytochrome P450 camphor, ascorbate peroxidase and cytochrome c peroxidase, and propose a novel approach for the long-range protein-protein electron transfer. The results on ascorbate peroxidase and cytochrome c peroxidase reveal the importance of the propionate groups in the electron transfer pathway. The long-range protein-protein electron transfer has been studied on the cytochrome c peroxidase-cytochrome c complex. The results indicate the importance of Phe82 and Cys81 on cytochrome c, and of Asn196, Ala194, Ala176 and His175 on cytochrome c peroxidase. PMID- 18445554 TI - Environment-contingent sexual selection in a colour polymorphic fish. AB - Sexual selection could be a driving force in the maintenance of intraspecific variation, but supporting observations from nature are limited. Here, we test the hypothesis that spatial heterogeneity of the visual environment can influence sexual selection on colourful male secondary traits such that selective advantage is environment contingent. Using a small fish endemic to Sulawesi, Indonesia (Telmatherina sarasinorum) that has five male colour morphs varying in frequency between two visually distinct mating habitats, we used direct behavioural observations to test the environment-contingent selection hypothesis. These observations were combined with measurements of the visual environment, fish coloration and the sensitivity of visual photopigments to determine whether differential morph conspicuousness was associated with reproductive success across habitats. We found that blue and yellow males are most conspicuous in different habitats, where they also have the highest reproductive fitness. A less conspicuous grey morph also gained high reproductive success in both habitats, raising the possibility that alternative behaviours may also contribute to reproductive success. In a comprehensive analysis, conspicuousness was strongly correlated with reproductive success across morphs and environments. Our results suggest an important role for spatially heterogeneous environments in the maintenance of male colour polymorphism. PMID- 18445555 TI - Variation in contributions to teaching by meerkats. AB - Recent evidence from cooperative insect, bird and mammal societies has challenged the assumption that teaching is restricted to humans. However, little is known about the factors affecting the degree to which individuals in such societies contribute to teaching. Here, I examine variation in contributions to teaching in meerkats, where older group members teach pups to handle difficult prey. I show that investment in teaching varies with characteristics of pups, helpers, groups and ecological conditions. Although prior experience in caring for pups did not significantly influence teaching behaviour, younger helpers, which were still investing in growth, contributed less to teaching than older individuals. This suggests that, in common with other cooperative activities, contributions to teaching vary with the costs experienced by individual group members. However, in contrast to other forms of helping in meerkats, I detected no effects of nutritional state on teaching, suggesting that it carries relatively low costs. In species where individuals can potentially gain direct or indirect fitness benefits from facilitating learning in others, low costs divided among multiple group members may help tip the balance towards selection for teaching. PMID- 18445556 TI - Global patterns in marine dispersal estimates: the influence of geography, taxonomic category and life history. AB - We examine estimates of dispersal in a broad range of marine species through an analysis of published values, and evaluate how well these values represent global patterns through a comparison with correlates of dispersal. Our analysis indicates a historical focus in dispersal studies on low-dispersal/low-latitude species, and we hypothesize that these studies are not generally applicable and representative of global patterns. Large-scale patterns in dispersal were examined using a database of correlates of dispersal such as planktonic larval duration (PLD, 318 species) and genetic differentiation (FST, 246 species). We observed significant differences in FST (p<0.001) and PLD (p<0.001) between taxonomic groups (e.g. fishes, cnidarians, etc.). Within marine fishes (more than 50% of datasets), the prevalence of demersal eggs was negatively associated with PLD (R2=0.80, p<0.001) and positively associated with genetic structure (R2=0.74, p<0.001). Furthermore, dispersal within marine fishes (i.e. PLD and FST) increased with latitude, adult body size and water depth. Of these variables, multiple regression identified latitude and body size as persistent predictors across taxonomic levels. These global patterns of dispersal represent a first step towards understanding and predicting species-level and regional differences in dispersal, and will be improved as more comprehensive data become available. PMID- 18445557 TI - Pheromones enhance somatosensory processing in newt brains through a vasotocin dependent mechanism. AB - We tested whether the sex pheromones that stimulate courtship clasping in male roughskin newts do so, at least in part, by amplifying the somatosensory signals that directly trigger the motor pattern associated with clasping and, if so, whether that amplification is dependent on endogenous vasotocin (VT). Female olfactory stimuli increased the number of action potentials recorded in the medulla of males in response to tactile stimulation of the cloaca, which triggers the clasp motor reflex, as well as to tactile stimulation of the snout and hindlimb. That enhancement was blocked by exposing the medulla to a V1a receptor antagonist before pheromone exposure. However, the antagonist did not affect medullary responses to tactile stimuli in the absence of pheromone exposure, suggesting that pheromones amplify somatosensory signals by inducing endogenous VT release. The ability of VT to couple sensory systems together in response to social stimulation could allow this peptide to induce variable behavioural outcomes, depending on the immediate context of the social interaction and thus on the nature of the associated stimuli that are amplified. If widespread in vertebrates, this mechanism could account for some of the behavioural variability associated with this and related peptides both within and across species. PMID- 18445558 TI - Community extinction patterns in coloured environments. AB - Understanding community responses to environmental variation is a fundamental aspect of ecological research, with direct ecological, conservation and economic implications. Here, we examined the role of the magnitude, correlation and autocorrelation structures of environmental variation on species' extinction risk (ER), and the probability of actual extinction events in model competitive communities. Both ER and probability increased with increasing positive autocorrelation when species responded independently to the environment, yet both decreased with a strong correlation between species-specific responses. These results are framed in terms of the synchrony between--and magnitude of variation within--species population sizes and are explained in terms of differences in noise amplification under different conditions. The simulation results are robust to changes in the strength of interspecific density dependence, and whether noise affects density-independent or density-dependent population processes. Similar patterns arose under different ranges of noise severity when these different model assumptions were examined. We compared our results with those from an analytically derived solution, which failed to capture many features of the simulation results. PMID- 18445559 TI - Subtle cues of predation risk: starlings respond to a predator's direction of eye gaze. AB - For prey animals to negotiate successfully the fundamental trade-off between predation and starvation, a realistic assessment of predation risk is vital. Prey responses to conspicuous indicators of risk (such as looming predators or fleeing conspecifics) are well documented, but there should also be strong selection for the detection of more subtle cues. A predator's head orientation and eye-gaze direction are good candidates for subtle but useful indicators of risk, since many predators orient their head and eyes towards their prey as they attack. We describe the first explicit demonstration of a bird responding to a live predator's eye-gaze direction. We present wild-caught European starlings (Sturnus vulgaris) with human 'predators' whose frontal appearance and gaze direction are manipulated independently, and show that starlings are sensitive to the predator's orientation, the presence of eyes and the direction of eye-gaze. Starlings respond in a functionally significant manner: when the predator's gaze was averted, starlings resumed feeding earlier, at a higher rate and consumed more food overall. By correctly assessing lower risk and returning to feeding activity earlier (as in this study), the animal gains a competitive advantage over conspecifics that do not respond to the subtle predator cue in this way. PMID- 18445560 TI - Viability of brown trout embryos positively linked to melanin-based but negatively to carotenoid-based colours of their fathers. AB - 'Good-genes' models of sexual selection predict significant additive genetic variation for fitness-correlated traits within populations to be revealed by phenotypic traits. To test this prediction, we sampled brown trout (Salmo trutta) from their natural spawning place, analysed their carotenoid-based red and melanin-based dark skin colours and tested whether these colours can be used to predict offspring viability. We produced half-sib families by in vitro fertilization, reared the resulting embryos under standardized conditions, released the hatchlings into a streamlet and identified the surviving juveniles 20 months later with microsatellite markers. Embryo viability was revealed by the sires' dark pigmentation: darker males sired more viable offspring. However, the sires' red coloration correlated negatively with embryo survival. Our study demonstrates that genetic variation for fitness-correlated traits is revealed by male colour traits in our study population, but contrary to predictions from other studies, intense red colours do not signal good genes. PMID- 18445562 TI - Local resource competition and local resource enhancement shape primate birth sex ratios. AB - Sex ratio theory provides a powerful source of testable predictions about sex allocation strategies. Although studies of invertebrates generally support predictions derived from the sex ratio theory, evidence for adaptive sex ratio biasing in vertebrates remains contentious. This may be due to the fact that most studies of vertebrates have focused on facultative adjustment in relation to maternal condition, rather than processes that might produce uniform sex biases across individuals. Here, we examine the effects of local resource enhancement (LRE) and local resource competition (LRC) on birth sex ratios (BSRs). We also examine the effects of sex differences in the costs of rearing male and female offspring on BSRs. We present data from 102 primate species and show that BSRs are skewed in favour of the dispersing sex in species that do not breed cooperatively, as predicted by the LRC model. In accordance with the LRE model, BSRs are generally skewed in favour of the more beneficial sex in cooperatively breeding primate species. There is no evidence that BSRs reflect the extent of sexual size dimorphism, an indirect measure of the costs of rearing male and female offspring. These analyses suggest that adaptive processes may play an important role in the evolution of BSRs in vertebrates. PMID- 18445561 TI - Phylogeny and geography predict pathogen community similarity in wild primates and humans. AB - In natural systems, host species are often co-infected by multiple pathogen species, and recent work has suggested that many pathogens can infect a wide range of host species. An important question therefore is what determines the host range of a pathogen and the community of pathogens found within a given host species. Using primates as a model, we show that infectious diseases are more often shared between species that are closely related and inhabit the same geographical region. We find that host relatedness is the best overall predictor of whether two host species share the same pathogens. A higher frequency of pathogen host shifts between close relatives or inheritance of pathogens from a common ancestor may explain this result. For viruses, geographical overlap among neighbouring primate hosts is more important in determining host range. We suggest this is because rapid evolution within viral lineages allows host jumps across larger evolutionary distances. We also show that the phylogenetic pattern of pathogen sharing with humans is the same as that between wild primates. For humans, this means we share a higher proportion of pathogens with the great apes, including chimpanzees and gorillas, because these species are our closest relatives. PMID- 18445564 TI - Can prey exhibit threat-sensitive generalization of predator recognition? Extending the Predator Recognition Continuum Hypothesis. AB - Despite the importance of predator recognition in mediating predator-prey interactions, we know little about the specific characteristics that prey use to distinguish predators from non-predators. Recent experiments indicate that some prey who do not innately recognize specific predators as threats have the ability to display antipredator responses upon their first encounter with those predators if they are similar to predators that the prey has recently learned to recognize. The purpose of our present experiment is to test whether this generalization of predator recognition is dependent on the level of risk associated with the known predator. We conditioned fathead minnows to chemically recognize brown trout either as a high or low threat and then tested the minnows for their responses to brown trout, rainbow trout (closely related predator) or yellow perch (distantly related predator). When the brown trout represents a high-risk predator, minnows show an antipredator response to the odour of brown trout and rainbow trout but not to yellow perch. However, when the brown trout represents a low-risk predator, minnows display antipredator responses to brown trout, but not to the rainbow trout or yellow perch. We discuss these results in the context of the Predator Recognition Continuum Hypothesis. PMID- 18445563 TI - The impact of dietary restriction, intermittent feeding and compensatory growth on reproductive investment and lifespan in a short-lived fish. AB - While dietary restriction usually increases lifespan, an intermittent feeding regime, where periods of deprivation alternate with times when food is available, has been found to reduce lifespan in some studies but prolong it in others. We suggest that these disparities arise because in some situations lifespan is reduced by the costs of catch-up growth (following the deprivation) and reproductive investment, a factor that has rarely been measured in studies of lifespan. Using three-spined sticklebacks, we show for the first time that while animals subjected to an intermittent feeding regime can grow as large as continuously fed controls that receive the same total amount of food, and can maintain reproductive investment, they have a shorter lifespan. Furthermore, we show that this reduction in lifespan is linked to rapid skeletal growth rate and is due to an increase in the instantaneous risk of mortality rather than in the rate of senescence. By contrast, dietary restriction caused a reduction in reproductive investment in females but no corresponding increase in longevity. This suggests that in short-lived species where reproduction is size dependent, selection pressures may lead to an increase in intrinsic mortality risk when resources are diverted from somatic maintenance to both growth and reproductive investment. PMID- 18445565 TI - Introduction. Stochastic physics and climate modelling. AB - Finite computing resources limit the spatial resolution of state-of-the-art global climate simulations to hundreds of kilometres. In neither the atmosphere nor the ocean are small-scale processes such as convection, clouds and ocean eddies properly represented. Climate simulations are known to depend, sometimes quite strongly, on the resulting bulk-formula representation of unresolved processes. Stochastic physics schemes within weather and climate models have the potential to represent the dynamical effects of unresolved scales in ways which conventional bulk-formula representations are incapable of so doing. The application of stochastic physics to climate modelling is a rapidly advancing, important and innovative topic. The latest research findings are gathered together in the Theme Issue for which this paper serves as the introduction. PMID- 18445566 TI - Comparison of stochastic parametrization approaches in a single-column model. AB - We discuss and test the potential usefulness of single-column models (SCMs) for the testing of stochastic physics schemes that have been proposed for use in general circulation models (GCMs). We argue that although single-column tests cannot be definitive in exposing the full behaviour of a stochastic method in the full GCM, and although there are differences between SCM testing of deterministic and stochastic methods, SCM testing remains a useful tool. It is necessary to consider an ensemble of SCM runs produced by the stochastic method. These can be usefully compared with deterministic ensembles describing initial condition uncertainty and also with combinations of these (with structural model changes) into poor man's ensembles. The proposed methodology is demonstrated using an SCM experiment recently developed by the GCSS (GEWEX Cloud System Study) community, simulating transitions between active and suppressed periods of tropical convection. PMID- 18445567 TI - Stochastic theories for the irregularity of ENSO. AB - The El Nino/Southern Oscillation (ENSO) phenomenon is the dominant climatic fluctuation on interannual time scales. It is an irregular oscillation with a distinctive broadband spectrum. In this article, we discuss recent theories that seek to explain this irregularity. Particular attention is paid to explanations that involve the stochastic forcing of the slow ocean modes by fast atmospheric transients. We present a theoretical framework for analysing this picture of the irregularity and also discuss the results from a number of coupled ocean atmosphere models. Finally, we briefly review the implications of the various explanations of ENSO irregularity to attempts to predict this economically significant phenomenon. PMID- 18445568 TI - Stochastic models of the meridional overturning circulation: time scales and patterns of variability. AB - The global meridional overturning circulation (MOC) varies over a wide range of space and time scales in response to fluctuating 'weather' perturbations that may be modelled as stochastic forcing. This study reviews model studies of the effects of climate noise on decadal to centennial MOC variability, on transitions between the MOC regimes and on the dynamics of Dansgaard-Oeschger events characteristic of glacial periods. PMID- 18445569 TI - Stochastic parametrization of multiscale processes using a dual-grid approach. AB - Some speculative proposals are made for extending current stochastic sub gridscale parametrization methods using the techniques adopted from the field of computer graphics and flow visualization. The idea is to emulate sub-filter-scale physical process organization and time evolution on a fine grid and couple the implied coarse-grained tendencies with a forecast model. A two-way interaction is envisaged so that fine-grid physics (e.g. deep convective clouds) responds to forecast model fields. The fine-grid model may be as simple as a two-dimensional cellular automaton or as computationally demanding as a cloud-resolving model similar to the coupling strategy envisaged in 'super-parametrization'. Computer codes used in computer games and visualization software illustrate the potential for cheap but realistic simulation where emphasis is placed on algorithmic stability and visual realism rather than pointwise accuracy in a predictive sense. In an ensemble prediction context, a computationally cheap technique would be essential and some possibilities are outlined. An idealized proof-of-concept simulation is described, which highlights technical problems such as the nature of the coupling. PMID- 18445570 TI - Impact of a quasi-stochastic cellular automaton backscatter scheme on the systematic error and seasonal prediction skill of a global climate model. AB - The impact of a nonlinear dynamic cellular automaton (CA) model, as a representation of the partially stochastic aspects of unresolved scales in global climate models, is studied in the European Centre for Medium Range Weather Forecasts coupled ocean-atmosphere model. Two separate aspects are discussed: impact on the systematic error of the model, and impact on the skill of seasonal forecasts. Significant reductions of systematic error are found both in the tropics and in the extratropics. Such reductions can be understood in terms of the inherently nonlinear nature of climate, in particular how energy injected by the CA at the near-grid scale can backscatter nonlinearly to larger scales. In addition, significant improvements in the probabilistic skill of seasonal forecasts are found in terms of a number of different variables such as temperature, precipitation and sea-level pressure. Such increases in skill can be understood both in terms of the reduction of systematic error as mentioned above, and in terms of the impact on ensemble spread of the CA's representation of inherent model uncertainty. PMID- 18445571 TI - A stochastic dynamical systems view of the Atlantic Multidecadal Oscillation. AB - We provide a dynamical systems framework to understand the Atlantic Multidecadal Oscillation and show that this framework is in many ways similar to that of the El Nino/Southern Oscillation. A so-called minimal primitive equation model is used to represent the Atlantic Ocean circulation. Within this minimal model, we identify a normal mode of multidecadal variability that can destabilize the background climate state through a Hopf bifurcation. Next, we argue that noise is setting the amplitude of the sea surface temperature variability associated with this normal mode. The results provide support that a stochastic Hopf bifurcation is involved in the multidecadal variability as observed in the North Atlantic. PMID- 18445572 TI - An applied mathematics perspective on stochastic modelling for climate. AB - Systematic strategies from applied mathematics for stochastic modelling in climate are reviewed here. One of the topics discussed is the stochastic modelling of mid-latitude low-frequency variability through a few teleconnection patterns, including the central role and physical mechanisms responsible for multiplicative noise. A new low-dimensional stochastic model is developed here, which mimics key features of atmospheric general circulation models, to test the fidelity of stochastic mode reduction procedures. The second topic discussed here is the systematic design of stochastic lattice models to capture irregular and highly intermittent features that are not resolved by a deterministic parametrization. A recent applied mathematics design principle for stochastic column modelling with intermittency is illustrated in an idealized setting for deep tropical convection; the practical effect of this stochastic model in both slowing down convectively coupled waves and increasing their fluctuations is presented here. PMID- 18445573 TI - Effects of stochastic parametrization on conceptual climate models. AB - Conceptual climate models are very simple mathematical representations of climate processes, which are especially useful because their workings can be readily understood. The usual procedure of representing effects of unresolved processes in such models using functions of the prognostic variables (parametrizations) that include no randomness generally results in these models exhibiting substantially less variability than do the phenomena they are intended to simulate. A viable yet still simple alternative is to replace the conventional deterministic parametrizations with stochastic parametrizations, which can be justified theoretically through the central limit theorem. The result is that the model equations are stochastic differential equations. In addition to greatly increasing the magnitude of variability exhibited by these models, and their qualitative fidelity to the corresponding real climate system, representation of unresolved influences by random processes can allow these models to exhibit surprisingly rich new behaviours of which their deterministic counterparts are incapable. PMID- 18445574 TI - Type I Brugada electrocardiogram pattern during the recovery phase of exercise testing. PMID- 18445575 TI - Trends in antimicrobial susceptibility of Gram-negative isolates from a paediatric intensive care unit in Warsaw: results from the MYSTIC programme (1997 2007). AB - OBJECTIVES: The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programme is a longitudinal global surveillance study to monitor in vitro data on microbial susceptibility in centres that prescribe meropenem. This overview provides data on the susceptibility of Gram-negative bacteria (n = 1300) isolated from clinical specimens of children hospitalized in a paediatric intensive care unit (ICU) during 1997-2007. METHODS: MICs of meropenem and eight other antibiotics were determined using the CLSI agar dilution method. RESULTS: Meropenem, imipenem and ciprofloxacin were most active (>90% susceptibility) against the tested isolates. A greater proportion of Pseudomonas aeruginosa isolates was susceptible to meropenem compared with imipenem. Antibiotic susceptibility of Enterobacteriaceae and Acinetobacter baumannii showed an increase in 2007. Only susceptibility of P. aeruginosa to ceftazidime and cefepime increased. The incidence of extended-spectrum beta-lactamase (ESBL) producers among Enterobacteriaceae isolates decreased from 37% in 1997 to 21.8% in 2007, and AmpC beta-lactamase producers decreased from 24.6% to 5.7%. Consumption of cephalosporins remained the same and piperacillin/tazobactam increased 3-fold. During 11 years, despite an increase in carbapenem consumption, meropenem and imipenem have retained excellent activity against the majority of isolates studied. CONCLUSIONS: The comparison of antibiotic susceptibility of Gram-negative isolates in 1997 and 2007 showed a trend of increase, and the number of beta-lactamase-producing isolates among Enterobacteriaceae showed a trend of decrease possibly related to changes in antibiotic policy. PMID- 18445576 TI - Efficacy and pharmacodynamics of linezolid, alone and in combination with rifampicin, in an experimental model of methicillin-resistant Staphylococcus aureus endocarditis. AB - OBJECTIVES: To evaluate the efficacy of oral linezolid, with or without rifampicin, on valve vegetations and secondary foci of infection compared with vancomycin, in the absence or presence of rifampicin, in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus. METHODS: Treatment groups were controls (n = 16), linezolid (n = 15), vancomycin (n = 15), linezolid and rifampicin (n = 15), vancomycin and rifampicin (n = 13), linezolid relapse (n = 11) and vancomycin relapse (n = 9). Therapy lasted 5 days in all groups, with survival of animals in the linezolid relapse and vancomycin relapse groups being recorded for an additional 5 days. Blood was drawn to determine the linezolid concentration, and valve vegetations, and kidney, liver, lung and spleen segments were collected for culture. RESULTS: Survival in each individual group was higher than that in the control group; bacterial load in valve vegetations was reduced by all treatment regimens, with linezolid exhibiting bactericidal effects. Bactericidal activity of linezolid was noted in all secondary foci of infection except the lung, where only the combination of rifampicin with linezolid was bactericidal. CONCLUSIONS: Orally administered linezolid is effective in limiting bacterial growth in the secondary foci of endocarditis. Co-administration of rifampicin favoured the suppression of bacterial growth in the lung. PMID- 18445577 TI - Guidelines for the management of hospital-acquired pneumonia in the UK: report of the working party on hospital-acquired pneumonia of the British Society for Antimicrobial Chemotherapy. AB - These evidence-based guidelines have been produced after a systematic literature review of a range of issues involving prevention, diagnosis and treatment of hospital-acquired pneumonia (HAP). Prevention is structured into sections addressing general issues, equipment, patient procedures and the environment, whereas in treatment, the structure addresses the use of antimicrobials in prevention and treatment, adjunctive therapies and the application of clinical protocols. The sections dealing with diagnosis are presented against the clinical, radiological and microbiological diagnosis of HAP. Recommendations are also made upon the role of invasive sampling and quantitative microbiology of respiratory secretions in directing antibiotic therapy in HAP/ventilator associated pneumonia. PMID- 18445578 TI - GABIE and Perkin Elmer passive sampler performance under fluctuating concentration conditions. AB - Passive sampling is an approved and accurate method for the assessment of organic compound exposure over long sampling time. This method could be very convenient for the short-time exposure assessment, but passive samplers have to be validated for this use. In this article, the behaviour of two commercial passive samplers (GABIE and Perkin Elmer) under fluctuant concentration conditions is studied. Artificial atmospheres were produced in the laboratory and passive samplers were exposed to different concentration profiles. Both theoretical and experimental results detailed in the paper underline the capability of these two samplers to assess pollutant exposure either when the concentration is unsteady or when the sampling time is short. Then, a suitable sampling strategy is proposed for the assessment of short-term exposure, based on the association of a direct reading photoionization device and passive sampler. PMID- 18445579 TI - Unraveling molecular complexity of phosphorylated human cardiac troponin I by top down electron capture dissociation/electron transfer dissociation mass spectrometry. AB - Cardiac troponin I (cTnI), the inhibitory subunit of the thin filament troponin tropomyosin regulatory complex, is required for heart muscle relaxation during the cardiac cycle. Expressed only in cardiac muscle, cTnI is widely used in the clinic as a serum biomarker of cardiac injury. In vivo function of cTnI is influenced by phosphorylation and proteolysis; therefore analysis of post translational modifications of the intact protein should greatly facilitate the understanding of cardiac regulatory mechanisms and may improve cTnI as a disease biomarker. cTnI (24 kDa, pI approximately 9.5) contains twelve serine, eight threonine, and three tyrosine residues, which presents a challenge for unequivocal identification of phosphorylation sites and quantification of positional isomers. In this study, we used top down electron capture dissociation and electron transfer dissociation MS to unravel the molecular complexity of cTnI purified from human heart tissue. High resolution MS spectra of human cTnI revealed a high degree of heterogeneity, corresponding to phosphorylation, acetylation, oxidation, and C-terminal proteolysis. Thirty-six molecular ions of cTnI were detected in a single ESI/FTMS spectrum despite running as a single sharp band on SDS-PAGE. Electron capture dissociation of monophosphorylated cTnI localized two major basal phosphorylation sites: a well known site at Ser(22) and a novel site at Ser(76)/Thr(77), each with partial occupancy (Ser(22): 53%; Ser(76)/Thr(77): 36%). Top down MS(3) analysis of diphosphorylated cTnI revealed occupancy of Ser(23) only in diphosphorylated species consistent with sequential (or ordered) phosphorylation/dephosphorylation of the Ser(22/23) pair. Top down MS of cTnI provides unique opportunities for unraveling its molecular complexity and for quantification of phosphorylated positional isomers thus allowing establishment of the relevance of such modifications to physiological functions and disease status. PMID- 18445582 TI - Control of invasive hosts by generalist parasitoids. AB - This article was motivated by the invasion of leaf-mining microlepidopteron attacking horse chestnut trees in Europe and the need for a biological control. Following Owen & Lewis (2001, Bull. Math. Biol., 63, 655-684), we consider predation of leafminers by a generalist parasitoid with a Holling Type II functional response. We first identified six equilibrium points and discussed their stabilities in the non-spatial model. The model always predicts persistence of the parasitoid. Depending on the parameter values, the model may predict that the host persists and goes extinct or there is something like an Allee effect where the outcome depends on the initial host density. Special cases were also studied for small carrying capacities leading to complex dynamical behaviours. Then, numerical simulations of the spatial reaction--diffusion model enabled us to identify the conditions for which the leafminer's advance can be stopped and reversed by parasitoids. Compared to the ordinary differential equation model, the incorporation of space, combined with the polyphagy of the parasitoid, leads to a decrease of the parameter domain of coexistence. This is in stark to several other models in which space promotes coexistence by enabling hosts to escape. PMID- 18445580 TI - Integration of metabolomic and proteomic phenotypes: analysis of data covariance dissects starch and RFO metabolism from low and high temperature compensation response in Arabidopsis thaliana. AB - Statistical mining and integration of complex molecular data including metabolites, proteins, and transcripts is one of the critical goals of systems biology (Ideker, T., Galitski, T., and Hood, L. (2001) A new approach to decoding life: systems biology. Annu. Rev. Genomics Hum. Genet. 2, 343-372). A number of studies have demonstrated the parallel analysis of metabolites and large scale transcript expression. Protein analysis has been ignored in these studies, although a clear correlation between transcript and protein levels is shown only in rare cases, necessitating that actual protein levels have to be determined for protein function analysis. Here, we present an approach to investigate the combined covariance structure of metabolite and protein dynamics in a systemic response to abiotic temperature stress in Arabidopsis thaliana wild-type and a corresponding starch-deficient mutant (phosphoglucomutase-deficient). Independent component analysis revealed phenotype classification resolving genotype-dependent response effects to temperature treatment and genotype-independent general temperature compensation mechanisms. An observation is the stress-induced increase of raffinose-family-oligosaccharide levels in the absence of transitory starch storage/mobilization in temperature-treated phosphoglucomutase plants indicating that sucrose synthesis and storage in these mutant plants is sufficient to bypass the typical starch storage/mobilization pathways under abiotic stress. Eventually, sample pattern recognition and correlation network topology analysis allowed for the detection of specific metabolite-protein co regulation and assignment of a circadian output regulated RNA-binding protein to these processes. The whole concept of high-dimensional profiling data integration from many replicates, subsequent multivariate statistics for dimensionality reduction, and covariance structure analysis is proposed to be a major strategy for revealing central responses of the biological system under study. PMID- 18445583 TI - Routine glutamic acid decarboxylase autoantibody (GADA) testing: patients' perspective. AB - BACKGROUND: Latent autoimmune diabetes in adults (LADA) is a form of type 1 diabetes which in the UK is often diagnosed and treated as type 2 diabetes (T2D). People with LADA show slow progression to insulin dependence and can be distinguished from T2D by blood tests for glutamic acid decarboxylase autoantibodies (GADA). Aims. This study explores the views and experiences of patients who are newly diagnosed with LADA, with particular reference to (i) routine GADA testing; (ii) whether this diagnosis has any influence on the self management of their diabetes; and (iii) the information needs of patients newly diagnosed with LADA. METHODS: Ten consecutive patients newly diagnosed with LADA (GADA positive) were invited to participate in individual qualitative semi structured interviews. Their views and experiences were analysed into codes and categories, using a constant comparative method. FINDINGS: Participants supported routine GADA testing in all patients with diabetes because the provision of a correct diagnosis has an empowering effect on patients, as it encourages the consideration of treatment options early on in the condition. Participants preferred to rely on future Hba(1c) levels and their doctor's opinion to determine a change in treatment to insulin. Some participants had difficulty distinguishing between the different types of diabetes, including LADA. Others needed to ask questions about LADA in addition to written information. CONCLUSIONS: Participants were supportive of routine GADA testing, would prefer not to start insulin immediately following a diagnosis of LADA and needed to discuss treatment options with health professionals who were knowledgeable on LADA. PMID- 18445584 TI - Reporting of research data by GPs: a cautionary tale for primary care researchers. AB - BACKGROUND: Given the importance of community-based research, there is a need to ensure the quality of data obtained from such studies. However, research has been considered a low priority for most GPs. OBJECTIVES: To assess the quality of data reported by GPs in a large community-based study. METHODS: Men were recruited as part of a population-based study on prostate-specific antigen (PSA) testing. Those with elevated initial PSA levels in the mid-1990s and no investigation in the intervening period were invited for repeat PSA testing. The GP of each included man was contacted and asked to report basic clinical information. Trained data extractors independently reviewed each man's GP medical notes and recorded data relating to prostate problems. Data provided by GPs were rematched with data extracted from medical notes. RESULTS: A total of 758 men with 379 GPs were included. In all, 366 (96.6%) GPs agreed to participate. Of 698 men suitable for follow-up, GP and note review data were available in 505 (72.3%) cases (287 GPs). Overall, 245 (85.4%) GPs provided completely accurate data. Male GPs, compared to female GPs, were found to have a higher level of inaccurate reporting (P = 0.008). CONCLUSIONS: We found that when GPs were asked to record basic clinical information, for the purposes of a primary care-based study, there was a significant level of inaccurate reporting. The results from our study confirm the importance of quality control in primary care research, especially in studies that involve GPs' reporting data. PMID- 18445585 TI - The Clostridium cellulolyticum dockerin displays a dual binding mode for its cohesin partner. AB - The plant cell wall degrading apparatus of anaerobic bacteria includes a large multienzyme complex termed the "cellulosome." The complex assembles through the interaction of enzyme-derived dockerin modules with the multiple cohesin modules of the noncatalytic scaffolding protein. Here we report the crystal structure of the Clostridium cellulolyticum cohesin-dockerin complex in two distinct orientations. The data show that the dockerin displays structural symmetry reflected by the presence of two essentially identical cohesin binding surfaces. In one binding mode, visualized through the A16S/L17T dockerin mutant, the C terminal helix makes extensive interactions with its cohesin partner. In the other binding mode observed through the A47S/F48T dockerin variant, the dockerin is reoriented by 180 degrees and interacts with the cohesin primarily through the N-terminal helix. Apolar interactions dominate cohesin-dockerin recognition that is centered around a hydrophobic pocket on the surface of the cohesin, formed by Leu-87 and Leu-89, which is occupied, in the two binding modes, by the dockerin residues Phe-19 and Leu-50, respectively. Despite the structural similarity between the C. cellulolyticum and Clostridium thermocellum cohesins and dockerins, there is no cross-specificity between the protein partners from the two organisms. The crystal structure of the C. cellulolyticum complex shows that organism-specific recognition between the protomers is dictated by apolar interactions primarily between only two residues, Leu-17 in the dockerin and the cohesin amino acid Ala-129. The biological significance of the plasticity in dockerin-cohesin recognition, observed here in C. cellulolyticum and reported previously in C. thermocellum, is discussed. PMID- 18445586 TI - Oxidative stress and covalent modification of protein with bioactive aldehydes. AB - The term "oxidative stress" links the production of reactive oxygen species to a variety of metabolic outcomes, including insulin resistance, immune dysfunction, and inflammation. Antioxidant defense systems down-regulated due to disease and/or aging result in oxidatively modified DNA, carbohydrates, proteins, and lipids. Increased production of hydroxyl radical leads to the formation of lipid hydroperoxides that produce a family of alpha,beta-unsaturated aldehydes. Such reactive aldehydes are subject to Michael addition reactions with the side chains of lysine, histidine, and cysteine residues, referred to as "protein carbonylation." Although not widely appreciated, reactive lipids can accumulate to high levels in cells, resulting in extensive protein modification leading to either loss or gain of function. The use of mass spectrometric methods to identify the site and extent of protein carbonylation on a proteome-wide scale has expanded our view of how oxidative stress can regulate cellular processes. PMID- 18445587 TI - Adenosine receptors control a new pathway of Fas-associated death domain protein expression regulation by secretion. AB - FADD is the key adaptor transmitting the apoptotic signal mediated by death receptors. We have previously shown that FADD protein expression could be lost in vivo in cancerous cells, in mice and humans, and be used as prognostic factor. Furthermore, loss of FADD could contribute to tumor progression and aggressiveness. However, the mechanism accounting for the loss of FADD was unknown. Using in vitro-cultured mouse organ models, we demonstrated that loss of FADD occurred through a new regulatory pathway of FADD expression by secretion. The secretion of FADD is an active release following shedding of microvesicles derived from the plasma membrane. In our experimental settings, this phenomenon was restricted to 6 of 12 FADD-expressing organs. This process is calcium- and adenosine-dependent. Moreover, we identified the two receptors with low affinity to adenosine, namely A(2B) and A(3) adenosine receptors, as regulators of the FADD secretion process. Furthermore, we showed that modulating A(3) adenosine receptor can convert a nonsecreting organ into a FADD-secreting one. Finally, we reported that mouse FADD release occurred in vivo during tumor disease. These results demonstrate the existence of a new localization site (in microvesicles) and regulatory mechanism (by secretion) of the FADD protein, and the implication of adenosine receptors in this process. These data open a new field of investigation consisting of the possibility to regulate FADD expression via the modulation of adenosine receptors, which constitutes a therapeutic target in diseases in which FADD-mediated signaling is impaired. PMID- 18445588 TI - Impact of phosphorylation on structure and thermodynamics of the interaction between the N-terminal domain of enzyme I and the histidine phosphocarrier protein of the bacterial phosphotransferase system. AB - The structural and thermodynamic impact of phosphorylation on the interaction of the N-terminal domain of enzyme I (EIN) and the histidine phosphocarrier protein (HPr), the two common components of all branches of the bacterial phosphotransferase system, have been examined using NMR spectroscopy and isothermal titration calorimetry. His-189 is located at the interface of the alpha and alphabeta domains of EIN, resulting in rather widespread chemical shift perturbation upon phosphorylation, in contrast to the highly localized perturbations seen for HPr, where His-15 is fully exposed to solvent. Residual dipolar coupling measurements, however, demonstrate unambiguously that no significant changes in backbone conformation of either protein occur upon phosphorylation: for EIN, the relative orientation of the alpha and alphabeta domains remains unchanged; for HPr, the backbone /Psi torsion angles of the active site residues are unperturbed within experimental error. His --> Glu/Asp mutations of the active site histidines designed to mimic the phosphorylated states reveal binding equilibria that favor phosphoryl transfer from EIN to HPr. Although binding of phospho-EIN to phospho-HPr is reduced by a factor of approximately 21 relative to the unphosphorylated complex, residual dipolar coupling measurements reveal that the structures of the unphosphorylated and biphosphorylated complexes are the same. Hence, the phosphorylation states of EIN and HPr shift the binding equilibria predominantly by modulating intermolecular electrostatic interactions without altering either the backbone scaffold or binding interface. This facilitates highly efficient phosphoryl transfer between EIN and HPr, which is estimated to occur at a rate of approximately 850 s(-1) from exchange spectroscopy. PMID- 18445589 TI - Identification of the major cysteine protease of Giardia and its role in encystation. AB - Giardia lamblia is a protozoan parasite and the earliest branching clade of eukaryota. The Giardia life cycle alternates between an asexually replicating vegetative form and an infectious cyst form. Encystation and excystation are crucial processes for the survival and transmission of Giardia. Cysteine proteases in Giardia have been implicated in proteolytic processing events that enable the continuance of the life cycle throughout encystation and excystation. Using quantitative real-time PCR, the expression of twenty-seven clan CA cysteine protease genes in the Giardia genome was measured during both vegetative growth and encystation. Giardia cysteine protease 2 was the most highly expressed cysteine protease during both life cycle stages measured, with a dramatic expression increase during encystation. The mRNA transcript for Giardia cysteine protease 2 was 7-fold up-regulated during encystation and was greater than 3-fold higher than any other Giardia protease gene product. Recombinant Giardia cysteine protease 2 was expressed, purified, and biochemically characterized. The activity of the recombinant cysteine protease 2 protein was confirmed to be identical to the dominant cysteine protease activity found in G. lamblia lysates. Giardia cysteine protease 2 was co-localized with cyst wall protein in encystation specific vesicles during encystation and processed cyst wall protein 2 to the size found in Giardia cyst walls. These data suggest that Giardia cysteine protease 2 is not only the major cysteine endoprotease expressed in Giardia, but is also central to the encystation process. PMID- 18445590 TI - Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance. AB - Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of obesity. p21(WAF1/CIP1), a cyclin dependent kinase inhibitor, is induced during adipocyte differentiation; however, its precise contribution to this process is unknown. Using both in vitro and in vivo systems, we show that p21 is crucial for maintaining adipocyte hypertrophy and obesity-induced insulin resistance. The absence of p21 in 3T3-L1 fibroblasts by RNA-mediated interference knockdown or in embryonic fibroblasts from p21(-/-) mice impaired adipocyte differentiation, resulting in smaller adipocytes. Despite normal adipose tissue mass on a normal diet, p21(-/-) mice fed high energy diets had reduced adipose tissue mass and adipocyte size accompanied by a marked improvement in insulin sensitivity. Knockdown of p21 in enlarged epididymal fat of diet-induced obese mice and also in fully differentiated 3T3-L1 adipocytes caused vigorous apoptosis by activating p53. Thus, p21 is involved in both adipocyte differentiation and in protecting hypertrophied adipocytes against apoptosis. Via both of these mechanisms, p21 promotes adipose tissue expansion during high fat diet feeding, leading to increased downstream pathophysiological consequences such as insulin resistance. PMID- 18445591 TI - Aldose reductase regulates hepatic peroxisome proliferator-activated receptor alpha phosphorylation and activity to impact lipid homeostasis. AB - Aldose reductase (AR) is implicated in the development of a number of diabetic complications, but the underlying mechanisms remain to be fully elucidated. We performed this study to determine whether and how AR might influence hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) activity and lipid metabolism. Our results in mouse hepatocyte AML12 cells show that AR overexpression caused strong suppression of PPARalpha/delta activity (74%, p < 0.001) together with significant down-regulation of mRNA expression for acetyl CoA oxidase and carnitine palmitoyltransferase-1. These suppressive effects were attenuated by the selective AR inhibitor zopolrestat. Furthermore, AR overexpression greatly increased the levels of phosphorylated PPARalpha and ERK1/2. Moreover, AR-induced suppression of PPARalpha activity was attenuated by treatment with an inhibitor for ERK1/2 but not that for phosphoinositide 3 kinase, p38, or JNK. Importantly, similar effects were observed for cells exposed to 25 mm glucose. In streptozotocin-diabetic mice, AR inhibitor treatment or genetic deficiency of AR resulted in significant dephosphorylation of both PPARalpha and ERK1/2. With the dephosphorylation of PPARalpha, hepatic acetyl-CoA oxidase and apolipoprotein C-III mRNA expression was greatly affected and that was associated with substantial reductions in blood triglyceride and nonesterified fatty acid levels. These data indicate that AR plays an important role in the regulation of hepatic PPARalpha phosphorylation and activity and lipid homeostasis. A significant portion of the AR-induced modulation is achieved through ERK1/2 signaling. PMID- 18445592 TI - Role of Bacillus subtilis RNase J1 endonuclease and 5'-exonuclease activities in trp leader RNA turnover. AB - The 140-nucleotide trp leader RNA, which is formed by transcription termination under conditions of high intracellular tryptophan, was used to study RNA turnover in Bacillus subtilis. We showed in vivo that the amount of endonuclease cleavage at approximately nucleotide 100 is decreased under conditions where RNase J1 concentration is reduced. In addition, under these conditions the level of 3' terminal RNA fragments, which contain the strong transcription terminator structure, increases dramatically. These results implicated RNase J1 in the initiation of trp leader RNA decay as well as in the subsequent steps leading to complete turnover of the terminator fragment. To confirm a direct role for RNase J1, experiments were performed in vitro with various forms of trp leader RNA and 3'-terminal RNA fragments. Specific endonuclease cleavages, which were restricted to single-stranded regions not bound by protein, were observed. Degradation of the 3'-terminal fragment by the 5' to 3'-exonuclease activity of RNase J1 was also demonstrated, although the presence of strong secondary structure impeded RNase J1 processivity to some extent. These results are consistent with a model for mRNA decay in Bacillus subtilis whereby the downstream products of RNase J1 endonucleolytic cleavage become substrates for the 5' to 3'-exoribonuclease activity of the enzyme. PMID- 18445593 TI - Control of excitatory synaptic transmission by C-terminal Src kinase. AB - The induction of long-term potentiation at CA3-CA1 synapses is caused by an N methyl-d-aspartate (NMDA) receptordependent accumulation of intracellular Ca(2+), followed by Src family kinase activation and a positive feedback enhancement of NMDA receptors (NMDARs). Nevertheless, the amplitude of baseline transmission remains remarkably constant even though low frequency stimulation is also associated with an NMDAR-dependent influx of Ca(2+) into dendritic spines. We show here that an interaction between C-terminal Src kinase (Csk) and NMDARs controls the Src-dependent regulation of NMDAR activity. Csk associates with the NMDAR signaling complex in the adult brain, inhibiting the Src-dependent potentiation of NMDARs in CA1 neurons and attenuating the Src-dependent induction of long-term potentiation. Csk associates directly with Src-phosphorylated NR2 subunits in vitro. An inhibitory antibody for Csk disrupts this physical association, potentiates NMDAR mediated excitatory postsynaptic currents, and induces long-term potentiation at CA3-CA1 synapses. Thus, Csk serves to maintain the constancy of baseline excitatory synaptic transmission by inhibiting Src kinase-dependent synaptic plasticity in the hippocampus. PMID- 18445594 TI - Plasma membrane cholesterol content affects nitric oxide diffusion dynamics and signaling. AB - Nitric oxide (NO) signaling is inextricably linked to both its physical and chemical properties. Due to its preferentially hydrophobic solubility, NO molecules tend to partition from the aqueous milieu into biological membranes. We hypothesized that plasma membrane ordering provided by cholesterol further couples the physics of NO diffusion with cellular signaling. Fluorescence lifetime quenching studies with pyrene liposome preparations showed that the presence of cholesterol decreased apparent diffusion coefficients of NO approximately 20-40%, depending on the phospholipid composition. Electrochemical measurements indicated that the diffusion rate of NO across artificial bilayer membranes were inversely related to cholesterol content. Sterol transport defective Niemann-Pick type C1 (NPC1) fibroblasts exhibited increased plasma membrane cholesterol content but decreased activation of both intracellular soluble guanylyl cyclase and vasodilator-stimulated phosphoprotein (VASP) phosphorylation at Ser(239) induced by exogenous NO exposure relative to their normal human fibroblast (NHF) counterparts. Augmentation of plasma membrane cholesterol in NHF diminished production of both cGMP and VASP phosphorylation elicited by NO to NPC1-comparable levels. Conversely, decreasing membrane cholesterol in NPC1 resulted in the augmentation in both cGMP and VASP phosphorylation to a level similar to those observed in NHF. Increasing plasma membrane cholesterol contents in NHF, platelets, erythrocytes and tumor cells also resulted in an increased level of extracellular diaminofluorescein nitrosation following NO exposure. These findings suggest that the impact of cholesterol on membrane fluidity and microdomain structure contributes to the spatial heterogeneity of NO diffusion and signaling. PMID- 18445595 TI - G13-dependent activation of MAPK by thyrotropin. AB - Stimulation of the thyrotropin receptor (TSHR) activates G proteins of all four subfamilies (G(s), G(i/o), G(q/11), and G(12/13)). Whereas G(s)/cAMP-dependent cellular responses upon TSHR stimulation are well established, other signaling pathways are less characterized. We evaluated TSH-elicited cellular responses in human follicular thyroid carcinoma cells stably expressing the TSHR and in primary, nonneoplastic human thyrocytes. In these cellular models, stimulation with TSH caused activation of p44/42 MAPK and subsequent induction of c-Fos. MAPK stimulation occurred independently of G(s), G(i/o), and G(q/11) signaling. Dominant negative constructs of G(12) or G(13) as well as shRNA-mediated suppression of Galpha(12) or Galpha(13) revealed that MAPK activation was dependent on G(13) but not on G(12) signaling. Furthermore, G(13)-dependent transactivation of the epidermal growth factor receptor was necessary for MAPK activation in follicular carcinoma cells, whereas EGFR was not involved in MAPK activation in nonneoplastic primary thyrocytes. The use of bacterial inhibitors of monomeric GTPases revealed that MAPK activation proceeded independently of Rho proteins but was clostridial toxin B-sensitive, suggesting involvement of Cdc42 or Rac. Thus, our data shed new light on cAMP-independent TSHR signaling and identify the first G(13)-dependent TSHR signaling pathway in human thyrocytes. PMID- 18445596 TI - Structure, function, and evolution of biogenic amine-binding proteins in soft ticks. AB - Two highly abundant lipocalins, monomine and monotonin, have been isolated from the salivary gland of the soft tick Argas monolakensis and shown to bind histamine and 5-hydroxytryptamine (5-HT), respectively. The crystal structures of monomine and a paralog of monotonin were determined in the presence of ligands to compare the determinants of ligand binding. Both the structures and binding measurements indicate that the proteins have a single binding site rather than the two sites previously described for the female-specific histamine-binding protein (FS-HBP), the histamine-binding lipocalin of the tick Rhipicephalus appendiculatus. The binding sites of monomine and monotonin are similar to the lower, low affinity site of FS-HBP. The interaction of the protein with the aliphatic amine group of the ligand is very similar for the all of the proteins, whereas specificity is determined by interactions with the aromatic portion of the ligand. Interestingly, protein interaction with the imidazole ring of histamine differs significantly between the low affinity binding site of FS-HBP and monomine, suggesting that histamine binding has evolved independently in the two lineages. From the conserved features of these proteins, a tick lipocalin biogenic amine-binding motif could be derived that was used to predict biogenic amine-binding function in other tick lipocalins. Heterologous expression of genes from salivary gland libraries led to the discovery of biogenic amine-binding proteins in soft (Ornithodoros) and hard (Ixodes) tick genera. The data generated were used to reconstruct the most probable evolutionary pathway for the evolution of biogenic amine-binding in tick lipocalins. PMID- 18445597 TI - The C-terminal region of human adipose triglyceride lipase affects enzyme activity and lipid droplet binding. AB - Adipose triglyceride lipase (ATGL) catalyzes the first step in the hydrolysis of triacylglycerol (TG) generating diacylglycerol and free fatty acids. The enzyme requires the activator protein CGI-58 (or ABHD5) for full enzymatic activity. Defective ATGL function causes a recessively inherited disorder named neutral lipid storage disease that is characterized by systemic TG accumulation and myopathy. In this study, we investigated the functional defects associated with mutations in the ATGL gene that cause neutral lipid storage disease. We show that these mutations lead to the expression of either inactive enzymes localizing to lipid droplets (LDs) or enzymatically active lipases with defective LD binding. Additionally, our studies assign important regulatory functions to the C-terminal part of ATGL. Truncated mutant ATGL variants lacking approximately 220 amino acids of the C-terminal protein region do not localize to LDs. Interestingly, however, these mutants exhibit substantially increased TG hydrolase activity in vitro (up to 20-fold) compared with the wild-type enzyme, indicating that the C terminal region suppresses enzyme activity. Protein-protein interaction studies revealed an increased binding of truncated ATGL to CGI-58, suggesting that the C terminal part interferes with CGI-58 interaction and enzyme activation. Compared with the human enzyme, the C-terminal region of mouse ATGL is much less effective in suppressing enzyme activity, implicating species-dependent differences in enzyme regulation. Together, our results demonstrate that the C-terminal region of ATGL is essential for proper localization of the enzyme and suppresses enzyme activity. PMID- 18445599 TI - The human TRPV6 channel protein is associated with cyclophilin B in human placenta. AB - Transcellular calcium transport in the kidney, pancreas, small intestine, and placenta is partly mediated by transient receptor potential (TRP) channels. The highly selective TRPV6 calcium channel protein is most likely important for the calcium transfer in different specialized epithelial cells. In the human placenta the protein is expressed in trophoblast tissue, where it is implicated in the transepithelial calcium transfer from mother to the fetus. We enriched the TRPV6 channel protein endogenously expressed in placenta together with annexin A2 and cyclophilin B (CypB), which is a member of the huge immunophilin family. In the human placenta TRPV6 and CypB are mainly located intracellularly in the syncytiotrophoblast layer, but a small amount of the mature glycosylated TRPV6 channel protein and CypB is also expressed in microvilli apical membranes, the fetomaternal barrier. To understand the role of CypB on the TRPV6 channel function, we evaluated the effect of CypB co-expression on TRPV6-mediated calcium uptake into Xenopus laevis oocytes expressing TRPV6. A significant increase of TRPV6-mediated calcium uptake was observed after CypB/TRPV6 co-expression. This stimulatory effect of CypB was reversed by the immunosuppressive drug cyclosporin A, which inhibits the enzymatic activity of CypB. Cyclosporin A had no significant effect on TRPV6 and CypB protein expression levels in the oocytes. In summary, our results establish CypB as a new TRPV6 accessory protein with potential involvement in TRPV6 channel activation through its peptidyl-prolyl cis/trans isomerase activity. PMID- 18445598 TI - Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane. AB - HFE2 (hemochromatosis type 2 gene) is highly expressed in skeletal muscle and liver hepatocytes. Its encoded protein, hemojuvelin (HJV), is a co-receptor for the bone morphogenetic proteins 2 and 4 (BMP2 and BMP4) and enhances the BMP induced hepcidin expression. Hepcidin is a central iron regulatory hormone predominantly secreted from hepatocytes. HJV also binds neogenin, a membrane protein widely expressed in many tissues. Neogenin is required for the processing and release of HJV from cells. The role that neogenin plays in HJV trafficking was investigated, using HepG2 cells, a human hepatoma cell line. Knockdown of endogenous neogenin markedly suppresses HJV release but has no evident effect on HJV trafficking to the plasma membrane. The addition of a soluble neogenin ectodomain to cells markedly inhibits HJV release, indicating that the HJV shedding is not processed before trafficking to the cell surface. At the plasma membrane it undergoes endocytosis in a dynamin-independent but cholesterol dependent manner. The additional findings that HJV release is coupled to lysosomal degradation of neogenin and that cholesterol depletion by filipin blocks both HJV endocytosis and HJV release suggest that neogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surface. PMID- 18445601 TI - Derepression of RNA polymerase III transcription by phosphorylation and nuclear export of its negative regulator, Maf1. AB - Maf1 is the global repressor of RNA polymerase III (Pol III) in yeast Saccharomyces cerevisiae. Transcription regulation by Maf1 is important under stress conditions and during the switch between fermentation and respiration. Under repressive conditions on nonfermentable carbon sources, Maf1 is dephosphorylated and located predominantly in the nucleus. When cells were shifted to glucose medium, Maf1 became phosphorylated and concomitantly relocated to the cytoplasm. This relocation was dependent on Msn5, a carrier responsible for export of several other phosphoproteins out of the nucleus. Using coimmunoprecipitation, Maf1 was found to interact with Msn5. When msn5-Delta cells were transferred to glucose, Maf1 remained in the nucleus. Remarkably, despite constitutive presence in the nucleus, Maf1 was dephosphorylated and phosphorylated normally in the msn5-Delta mutant, and Pol III was under proper regulation. That phosphorylation of Maf1 and Pol III derepression are tightly linked was shown by studying tRNA transcription in Maf1 mutants with an altered pattern of phosphorylation. In summary, we conclude that phosphorylation of Maf1 inside the nucleus acts both directly by decreasing of Maf1-mediated repression of Pol III and indirectly by stimulation of Msn5 binding and export of nuclear Maf1 to the cytoplasm. PMID- 18445602 TI - Functional dissociation in right inferior frontal cortex during performance of go/no-go task. AB - The contribution of the right inferior frontal cortex to response inhibition has been demonstrated by previous studies of neuropsychology, electrophysiology, and neuroimaging. The inferior frontal cortex is also known to be activated during processing of infrequent stimuli such as stimulus-driven attention. Response inhibition has most often been investigated using the go/no-go task, and the no go trials are usually given infrequently to enhance prepotent response tendency. Thus, it has not been clarified whether the inferior frontal activation during the go/no-go task is associated with response inhibition or processing of infrequent stimuli. In the present functional magnetic resonance imaging study, we employed not only frequent-go trials but also infrequent-go trials that were presented as infrequently as the no-go trials. The imaging results demonstrated that the posterior inferior frontal gyrus (pIFG) was activated during response inhibition as revealed by the no-go vs. infrequent-go trials, whereas the inferior frontal junction (IFJ) region was activated primarily during processing of infrequent stimuli as revealed by the infrequent-go versus frequent-go trials. These results indicate that the pIFG and IFJ within the inferior frontal cortex are spatially close but are associated with different cognitive control processes in the go/no-go paradigm. PMID- 18445600 TI - Elimination of KATP channels in mouse islets results in elevated [U-13C]glucose metabolism, glutaminolysis, and pyruvate cycling but a decreased gamma aminobutyric acid shunt. AB - Pancreatic beta cells are hyper-responsive to amino acids but have decreased glucose sensitivity after deletion of the sulfonylurea receptor 1 (SUR1) both in man and mouse. It was hypothesized that these defects are the consequence of impaired integration of amino acid, glucose, and energy metabolism in beta cells. We used gas chromatography-mass spectrometry methodology to study intermediary metabolism of SUR1 knock-out (SUR1(-/-)) and control mouse islets with d-[U (13)C]glucose as substrate and related the results to insulin secretion. The levels and isotope labeling of alanine, aspartate, glutamate, glutamine, and gamma-aminobutyric acid (GABA) served as indicators of intermediary metabolism. We found that the GABA shunt of SUR1(-/-) islets is blocked by about 75% and showed that this defect is due to decreased glutamate decarboxylase synthesis, probably caused by elevated free intracellular calcium. Glutaminolysis stimulated by the leucine analogue d,l-beta-2-amino-2-norbornane-carboxylic acid was, however, enhanced in SUR1(-/-) and glyburide-treated SUR1(+/+) islets. Glucose oxidation and pyruvate cycling was increased in SUR1(-/-) islets at low glucose but was the same as in controls at high glucose. Malic enzyme isoforms 1, 2, and 3, involved in pyruvate cycling, were all expressed in islets. High glucose lowered aspartate and stimulated glutamine synthesis similarly in controls and SUR1(-/-) islets. The data suggest that the interruption of the GABA shunt and the lack of glucose regulation of pyruvate cycling may cause the glucose insensitivity of the SUR1(-/-) islets but that enhanced basal pyruvate cycling, lowered GABA shunt flux, and enhanced glutaminolytic capacity may sensitize the beta cells to amino acid stimulation. PMID- 18445603 TI - The human brain distinguishes between single odorants and binary mixtures. AB - Single odors are processed differently from odor mixtures in the cortex of rodents. We investigated whether single and binary odor mixtures activate different regions also in the human brain. We analyzed data from positron emission tomography scans using pyridine, citral, and 5 mixtures of pyridine and citral in proportions varying from 10/90 to 90/10, with 50/50 being the most impure. Comparing mixtures with single odorants gave activation in the left cingulate and right parietal and superior frontal cortices and bilateral activation in the anterior and lateral orbitofrontal cortices. We also found that brain activity in the lateral orbitofrontal cortex (OFC) increased with odorant impurity, whereas the anterior OFC was activated for binary odor mixtures and deactivated for single components. We conclude that binary odor mixtures and their individual components are processed differently by the human brain. The lateral portion of the OFC responds to mixture impurity in a graded fashion, whereas the anterior portion acts like an on-off detector of odor mixtures. PMID- 18445604 TI - Activation of endothelial cells to pathological status by down-regulation of connexin43. AB - AIMS: We investigated the effects of connexin43 (Cx43) down-regulation on endothelial function. METHODS AND RESULTS: We used two different sequences of Cx43-specific small interference RNA (siRNA) to reduce de novo synthesis of Cx43 in human aortic endothelial cells and then examined the expression profiles, proliferation activity and viability, and angiogenic potential. The involvement of mitogen-activated protein kinase signalling pathways was analysed. In parallel, the effect of inhibition of gap-junctional communication by connexin mimetic peptides was evaluated. During the down-regulation of Cx43 by the siRNA, the cells exhibited impaired gap-junctional communication, proliferation, viability, and angiogenic potential. In addition, plasminogen activator inhibitor 1 (PAI-1) and von Willebrand factor were up-regulated. Furthermore, c-jun N terminal kinase (JNK) and its downstream target c-jun were activated, while caspase-3, p38, and extracellular signal-regulated kinase remained unchanged. Inhibition of JNK by SP600125 blocked the siRNA-induced increased expression of PAI-1 and partially recovered the impaired angiogenic potential. Short-term inhibition of Cx43 channels by connexin-mimetic peptides did not activate JNK. CONCLUSION: Down-regulation of Cx43 inhibits gap-junctional communication and activates endothelial cells to pathological status, as characterized by up regulation of coagulatory molecules and impairment of proliferation, viability, and angiogenesis. The processes are associated with activation of JNK signalling pathways and rectified by inhibition of the activation. These results suggest that inadequate expression of Cx43 per se impairs endothelial function by the activation of stress-activated protein kinase. PMID- 18445605 TI - Cytoscape ESP: simple search of complex biological networks. AB - SUMMARY: Cytoscape enhanced search plugin (ESP) enables searching complex biological networks on multiple attribute fields using logical operators and wildcards. Queries use an intuitive syntax and simple search line interface. ESP is implemented as a Cytoscape plugin and complements existing search functions in the Cytoscape network visualization and analysis software, allowing users to easily identify nodes, edges and subgraphs of interest, even for very large networks. Availabiity: http://chianti.ucsd.edu/cyto_web/plugins/ CONTACT: ashkenaz@agri.huji.ac.il. PMID- 18445606 TI - jSquid: a Java applet for graphical on-line network exploration. AB - jSquid is a graph visualization tool for exploring graphs from protein-protein interaction or functional coupling networks. The tool was designed for the FunCoup web site, but can be used for any similar network exploring purpose. The program offers various visualization and graph manipulation techniques to increase the utility for the user. AVAILABILITY: jSquid is available for direct usage and download at http://jSquid.sbc.su.se including source code under the GPLv3 license, and input examples. It requires Java version 5 or higher to run properly. CONTACT: erik.sonnhammer@sbc.su.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 18445607 TI - nuScore: a web-interface for nucleosome positioning predictions. AB - Sequence-directed mapping of nucleosome positions is of major biological interest. Here, we present a web-interface for estimation of the affinity of the histone core to DNA and prediction of nucleosome arrangement on a given sequence. Our approach is based on assessment of the energy cost of imposing the deformations required to wrap DNA around the histone surface. The interface allows the user to specify a number of options such as selecting from several structural templates for threading calculations and adding random sequences to the analysis. AVAILABILITY: The nuScore interface is freely available for use at http://compbio.med.harvard.edu/nuScore. CONTACT: peter_park@harvard.edu; tolstorukov@gmail.com SUPPLEMENTARY INFORMATION: The site contains user manual, description of the methodology and examples. PMID- 18445608 TI - Withdrawal forces of lumbar spinal catheters: no dependence on body position. AB - BACKGROUND: Spinal catheters, because of their smaller diameter, have lower tensile strength than epidural catheters. This study was designed to measure the withdrawal forces needed to remove lumbar spinal catheters and to determine whether patient position affects withdrawal forces. METHODS: Eighty-two patients with a 24-gauge spinal catheter placed midline at the lumbar L3/4 or L4/5 level were randomly assigned to catheter removal either in flexed lateral or sitting position. Withdrawal forces were measured using a tension spring balance. RESULTS: Mean withdrawal force was 0.91 N (95% CI: 0.73, 1.09) with extremes up to 5 N. Withdrawal force in the flexed lateral position was 1.04 N (95% CI: 0.73, 1.34) or in the sitting position was 0.78 N (95% CI: 0.59, 0.97). The 95% CI for the difference of the means was -0.62 N, 0.10 N. Thus, the absolute mean difference between the positions can be assumed to be smaller than 0.62 N. Neither the length of the spinal catheter under the skin or in the subarachnoid space, nor BMI influenced withdrawal force. CONCLUSION: Withdrawal force of spinal catheters is not influenced by body position during catheter removal, length of catheter under skin, or BMI. PMID- 18445609 TI - Association of angiotensin-converting enzyme gene 2350G>A polymorphism with myocardial infarction in a Chinese population. AB - Angiotensin-converting enzyme (ACE) gene 2350G>A polymorphism has the most significant effect on plasma ACE concentrations. But the association between this polymorphism and myocardial infarction (MI) is presently unknown. We carried out a case-control study in the Chinese Han population. ACE2350G>A genotypes of 231 patients with MI and 288 healthy controls were detected by PCR-RFLP. Differences in frequencies of ACE genotypes and alleles and their associations with clinical features were assessed. The distribution of the ACE2350G>A genotypes (GG, GA, and AA) was 20.78%, 51.08%, and 28.14% in the MI group and 31.60%, 46.53%, and 21.87% in controls, respectively (P = .0167).The frequency of the A allele in the MI group was significantly higher than that in controls (53.68% vs 45.14%, P = .0062). The A allele carriers (GA + AA genotypes) had approximately 2-fold increased risk of MI when compared with the GG genotype (odds ratio = 1.76; 95% confidence interval = 1.24-3.52). There were no significant differences among the 3 genotypes in plasma levels of lipids, apolipoproteins, high-sensitivity C reactive protein, and soluble CD40 ligand in either the MI group or the control group (P > .05). No statistical difference was observed between ACE2350G>A polymorphism and severity of the coronary lesions (P > .05). These results suggest that ACE2350G>A polymorphism is associated with acute MI, and A allele carrier is an independent risk factor for acute MI in the Chinese Han population. PMID- 18445611 TI - Issues raised in systematic reviews of complex multisectoral and community based interventions. PMID- 18445610 TI - The effect of tirofiban on fibrinogen/agonist-induced platelet shape change and aggregation. AB - There is evidence linking raised plasma fibrinogen (fib) and platelet hyperactivity with vascular events. One way to inhibit platelets is to block the platelet membrane glycoprotein (GP) IIb/IIIa receptor, which binds circulating fib or von Willebrand factor and cross-links platelets at the final common pathway to platelet aggregation. Tirofiban is a potent and specific fib receptor antagonist, used in the treatment of unstable angina. The authors assessed the effect of tirofiban on spontaneous platelet aggregation (SPA), fib-induced, serotonin (5HT)-induced, and adenosine diphosphate (ADP)-induced aggregation in whole blood by calculating the percentage free platelet count. These various agonists were used alone and in combination. The authors also measured the effect of tirofiban on agonists-induced (ADP, 5HT) platelet shape change (PSC). The effect of fib on PSC was also evaluated in platelet-rich plasma using a high resolution (0.07 fL) channelyzer. Tirofiban significantly inhibited SPA, fib (2, 4, 8 g/L), ADP, ADP + fib combination, and 5HT-induced aggregation. Tirofiban had no effect on agonist-induced PSC. There was no apparent change in platelet volume with fib. In conclusion, tirofiban does not appear to have an effect on PSC, an early phase of platelet activation. Tirofiban seems to be a nonspecific and an effective inhibitor of platelet aggregation (a later phase of platelet activation) in whole blood. The clinical significance of these findings remains to be established. PMID- 18445612 TI - Gender differences in colorectal cancer incidence, mortality, hospitalizations and surgical procedures in Canada. AB - BACKGROUND: Over the past few decades there have been changes in incidence and mortality of colorectal cancer. OBJECTIVE: To examine gender differences in incidence, hospitalization, hospital-based procedures and mortality for colorectal cancer. METHODS: Data were derived from the Hospital Morbidity Database, Canadian Cancer Registry and the Canadian Mortality Database. RESULTS: Overall incidence and mortality rates for colorectal cancer are decreasing, but remain substantially higher for males. Absolute numbers of cases are similar for men and women. The top subsite for men was rectal cancer, which was third highest for women, whereas right colon cancer was highest for women. Male/female ratios for incidence and surgeries were highest for distal cancer and are increasing with time. CONCLUSIONS: Although overall incidence rates have shown a decline, absolute numbers of new colorectal cancer cases have increased. While men have higher colorectal cancer rates, women have similar numbers and screening should target both equally. Over the years, colorectal cancer subsites are showing a rightward shift, i.e. an increase in proximal subsites, but a leftward shift in male/female ratios, i.e. a greater decrease for the more distal subsites in females. The lower rates for women for distal cancer are compatible with a degree of hormonal protection based on oral contraceptive and hormone replacement therapy. Colorectal cancer will continue to be a considerable public health problem in the foreseeable future. PMID- 18445613 TI - Coronary collaterals in obese patients: impact of metabolic syndrome. AB - Obesity is a growing pandemic. Among obese patients with significant coronary artery stenosis, development of coronary collaterals was investigated. Consecutive 104 obese patients with stable angina pectoris were enrolled. Coronary collaterals were assessed according to the Cohen and Rentrop grading system and classified into 2 as those with poor collaterals (grade 0-1, Group 1) and those with good collaterals (grade 2-3, Group 2). Group 1 had higher body mass index, shorter duration of angina pectoris than Group 2. Poor collaterals were present in 82.3% and 59.5% of patients with and without (P = .019) metabolic syndrome, respectively. Metabolic syndrome score (sum of each component) was found to be negatively correlated with Rentrop score (r = -691; P < .001). After controlling for symptom duration and body mass index, metabolic syndrome kept independent association with poor collaterals among obese patients (P = .043, B = 1.8). Metabolic syndrome appears to influence the development of coronary collaterals among obese patients with stable coronary artery disease. PMID- 18445614 TI - Glycoprotein IIb/IIIa inhibitor (tirofiban) in acute ST-segment elevation myocardial infarction. AB - Studies have shown conflicting results for glycoprotein IIb/IIIa inhibitor (tirofiban) use in ST-segment elevation myocardial infarction (STEMI). The authors aimed to determine if an upstream conventional dose of tirofiban in addition to a standard treatment regimen improved coronary patency and clinical outcomes in patients with STEMI. A retrospective analysis of consecutive patients with STEMI, who underwent emergent percutaneous coronary intervention (PCI) in the authors' hospital from July 2000 to April 2006 was performed. All patients received loading doses of aspirin, clopidogrel or ticlopidine, and unfractionated heparin with or without tirofiban in the emergency department prior to PCI. It was found that adding a conventional dose of tirofiban to the standard treatment regimen prior to PCI did not improve coronary patency in STEMI patients. Tirofiban also failed to show favorable outcomes for 90 days of follow-up, but there was a favorable trend for short-term 30-day survival. PMID- 18445615 TI - Analysis of left ventricular changes after acute myocardial infarction using transthoracic real-time three-dimensional echocardiography. AB - BACKGROUND: Little information is available regarding the relationship between three-dimensional (3-D) echocardiographic parameters in acute stage of acute myocardial infarction (AMI) and subsequent left ventricular (LV) remodeling after AMI. METHODS: Consecutive patients with AMI were analyzed for echocardiographic predictors of subsequent LV remodeling after AMI using two-dimensional (2-D) echocardiography and real-time 3-D echocardiography at baseline and month 3 of follow-up. LV adverse and favorable remodeling were defined as a >10% and 42 mL/m(2) of 75%, 71%, 75%, and 71%, respectively. CONCLUSIONS: LVESVI assessed by 3-D echocardiography was the most predictive parameter indicating favorable LV remodeling after AMI. LV shape on contraction changed from elliptical shape to more globular in the adverse remodeling process after AMI. PMID- 18445616 TI - Effect of Duplex Arteriography in the Management of Acute Limb-Threatening Ischemia From Thrombosed Popliteal Aneurysms. AB - The role of routine use of duplex arteriography to diagnose thrombosis of popliteal artery aneurysm as a cause of acute lower extremity ischemia is investigated. In all, 109 patients (group 1) from 1994 to 1997 and 201 patients from 1998 to 2001(group 2) presenting with acute limb-threatening ischemia were studied. None of the group 1 patients underwent preoperative duplex arteriography, and no diagnosis of acute popliteal artery aneurysm thrombosis was made. Ten patients with acute ischemia due to thrombosed popliteal artery aneurysm were identified in group 2 when preoperative duplex arteriography was routinely performed. Urgent revascularization was performed based on the results of duplex arteriography. Six patients had functioning bypasses with a mean follow up of 15.6 months. There were 3 deaths, 2 within 30 days and 1 after 2(1/2) years with functioning grafts. One patient was lost to follow-up. Routine use of duplex arteriography may provide the diagnosis and may identify the available outflow vessels for popliteal artery aneurysm. PMID- 18445617 TI - Effect of antihypertensive therapy on serum lipids in newly diagnosed essential hypertensive men. AB - The effect of antihypertensives on serum lipids in newly diagnosed male essential hypertensive patients was studied. The participants (n = 99) were randomly allocated to receive amlodipine, atenolol, enalapril, hydrochlorothiazide, and a combination of amlodipine and atenolol. Lipid parameters were estimated before and after 8 weeks of therapy. The atenolol and thiazide group showed a significant increase in triglycerides (TGs) and very-low-density lipoprotein cholesterol (VLDL-C). High-density lipoprotein cholesterol (HDL-C) and HDL-C to low-density lipoprotein cholesterol (LDL-C) ratio were significantly increased and TC to HDL-C ratio was significantly decreased in the amlodipine and amlodipine- atenolol combination groups. In the enalapril group, we found a significant reduction in TC, TGs, VLDL-C, non-HDL-C, and TG to HDL-C ratio after treatment. It can be concluded from the present study that some drugs have beneficial effects on the lipid status, whereas others adversely affect the lipid status in hypertension. PMID- 18445618 TI - Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. AB - Proteolysis of mutant huntingtin is crucial to the development of Huntington disease (HD). Specifically preventing proteolysis at the capase-6 (C6) consensus sequence at amino acid 586 of mutant huntingtin prevents the development of behavioural, motor and neuropathological features in a mouse model of HD. However, the mechanism underlying the selective toxicity of the 586 amino acid cleavage event is currently unknown. We have examined the subcellular localization of different caspase proteolytic fragments of huntingtin using neo epitope antibodies. Our data suggest that the nucleus is the primary site of htt cleavage at amino acid 586. Endogenously cleaved 586 amino acid fragments are enriched in the nucleus of immortalized striatal cells and primary striatal neurons where they co-localize with active C6. Cell stress induced by staurosporine results in the nuclear translocation and activation of C6 and an increase in 586 amino acid fragments of huntingtin in the nucleus. In comparison, endogenous caspase-2/3-generated huntingtin 552 amino acid fragments localize to the perinuclear region. The different cellular itineraries of endogenously generated caspase products of huntingtin may provide an explanation for the selective toxicity of huntingtin fragments cleaved at amino acid 586. PMID- 18445619 TI - Two-generation reproductive toxicity study of dietary bisphenol A in CD-1 (Swiss) mice. AB - Dietary bisphenol A (BPA) was evaluated in a mouse two-generation study at 0, 0.018, 0.18, 1.8, 30, 300, or 3500 ppm (0, 0.003, 0.03, 0.3, 5, 50, or 600 mg BPA/kg/day, 28 per sex per group). A concurrent positive control group of dietary 17beta-estradiol (0.5 ppm; 28 per sex) confirmed the sensitivity of CD-1 mice to an endogenous estrogen. There were no BPA-related effects on adult mating, fertility or gestational indices, ovarian primordial follicle counts, estrous cyclicity, precoital interval, offspring sex ratios or postnatal survival, sperm parameters or reproductive organ weights or histopathology (including the testes and prostate). Adult systemic effects: at 300 ppm, only centrilobular hepatocyte hypertrophy; at 3500 ppm, reduced body weight, increased kidney and liver weights, centrilobular hepatocyte hypertrophy, and renal nephropathy in males. At 3500 ppm, BPA also reduced F1/F2 weanling body weight, reduced weanling spleen and testes weights (with seminiferous tubule hypoplasia), slightly delayed preputial separation (PPS), and apparently increased the incidence of treatment related, undescended testes only in weanlings, which did not result in adverse effects on adult reproductive structures or functions; this last finding is considered a developmental delay in the normal process of testes descent. It is likely that these transient effects were secondary to (and caused by) systemic toxicity. Gestational length was increased by 0.3 days in F1/F2 generations; the toxicological significance, if any, of this marginal difference is unknown. At lower doses (0.018-30 ppm), there were no treatment-related effects and no evidence of nonmonotonic dose-response curves for any parameter. The systemic no observable effect level (NOEL) was 30 ppm BPA (approximately 5 mg/kg/day); the reproductive/developmental NOEL was 300 ppm (approximately 50 mg/kg/day). Therefore, BPA is not considered a selective reproductive or developmental toxicant in mice. PMID- 18445620 TI - Evolutionary dynamics of segmental duplications from human Y-chromosomal euchromatin/heterochromatin transition regions. AB - Human chromosomal regions enriched in segmental duplications are subject to extensive genomic reorganization. Such regions are particularly informative for illuminating the evolutionary history of a given chromosome. We have analyzed 866 kb of Y-chromosomal non-palindromic segmental duplications delineating four euchromatin/heterochromatin transition regions (Yp11.2/Yp11.1, Yq11.1/Yq11.21, Yq11.23/Yq12, and Yq12/PAR2). Several computational methods were applied to decipher the segmental duplication architecture and identify the ancestral origin of the 41 different duplicons. Combining computational and comparative FISH analysis, we reconstruct the evolutionary history of these regions. Our analysis indicates a continuous process of transposition of duplicated sequences onto the evolving higher primate Y chromosome, providing unique insights into the development of species-specific Y-chromosomal and autosomal duplicons. Phylogenetic sequence comparisons show that duplicons of the human Yp11.2/Yp11.1 region were already present in the macaque-human ancestor as multiple paralogs located predominantly in subtelomeric regions. In contrast, duplicons from the Yq11.1/Yq11.21, Yq11.23/Yq12, and Yq12/PAR2 regions show no evidence of duplication in rhesus macaque, but map to the pericentromeric regions in chimpanzee and human. This suggests an evolutionary shift in the direction of duplicative transposition events from subtelomeric in Old World monkeys to pericentromeric in the human/ape lineage. Extensive chromosomal relocation of autosomal-duplicated sequences from euchromatin/heterochromatin transition regions to interstitial regions as demonstrated on the pygmy chimpanzee Y chromosome support a model in which substantial reorganization and amplification of duplicated sequences may contribute to speciation. PMID- 18445621 TI - Bacterioferritin from Mycobacterium smegmatis contains zinc in its di-nuclear site. AB - Bacterioferritins, also known as cytochrome b (1), are oligomeric iron-storage proteins consisting of 24 identical amino acid chains, which form spherical particles consisting of 24 subunits and exhibiting 432 point-group symmetry. They contain one haem b molecule at the interface between two subunits and a di nuclear metal binding center. The X-ray structure of bacterioferritin from Mycobacterium smegmatis (Ms-Bfr) was determined to a resolution of 2.7 A in the monoclinic space group C2. The asymmetric unit of the crystals contains 12 protein molecules: five dimers and two half-dimers located along the crystallographic twofold axis. Unexpectedly, the di-nuclear metal binding center contains zinc ions instead of the typically observed iron ions in other bacterioferritins. PMID- 18445622 TI - Toward chaperone-assisted crystallography: protein engineering enhancement of crystal packing and X-ray phasing capabilities of a camelid single-domain antibody (VHH) scaffold. AB - A crystallization chaperone is an auxiliary protein that binds to a target of interest, enhances and modulates crystal packing, and provides high-quality phasing information. We critically evaluated the effectiveness of a camelid single-domain antibody (V(H)H) as a crystallization chaperone. By using a yeast surface display system for V(H)H, we successfully introduced additional Met residues in the core of the V(H)H scaffold. We identified a set of SeMet-labeled V(H)H variants that collectively produced six new crystal forms as the complex with the model antigen, RNase A. The crystals exhibited monoclinic, orthorhombic, triclinic, and tetragonal symmetry and have one or two complexes in the asymmetric unit, some of which diffracted to an atomic resolution. The phasing power of the Met-enriched V(H)H chaperone allowed for auto-building the entire complex using single-anomalous dispersion technique (SAD) without the need for introducing SeMet into the target protein. We show that phases produced by combining SAD and V(H)H model-based phases are accurate enough to easily solve structures of the size reported here, eliminating the need to collect multiple wavelength multiple-anomalous dispersion (MAD) data. Together with the presence of high-throughput selection systems (e.g., phage display libraries) for V(H)H, the enhanced V(H)H domain described here will be an excellent scaffold for producing effective crystallization chaperones. PMID- 18445623 TI - Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with tumour necrosis factor blocking agents in patients with rheumatoid arthritis. AB - OBJECTIVE: To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). METHODS: IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated fibrinogen (ACF) and IgG1 : IgG4 ACPA ratios were calculated. A pilot study was performed in 28 ACF positive patients treated with infliximab for one year. Confirmation of the results was obtained using a cohort of 180 consecutive patients treated with adalimumab for 28 weeks. RESULTS: The median reduction in ACF levels was 31% for total IgG, 29% for IgG1, 40% for IgG4 and 22% for the IgG4 : IgG1 ACF ratio in the infliximab cohort. In adalimumab-treated patients, ACF levels declined 14% for total IgG and IgG1, and 36% for IgG4 ACF; the IgG4 : IgG1 ratio was reduced by 24% (all percentage values p<0.05). The decrease in antibody levels was correlated with the clinical response; European League Against Rheumatism good responders had the greatest decline in antibody levels and this effect was most pronounced for IgG4 (48% reduction). The IgG4 : IgG1 ACF ratio preferentially decreased in patients with adequate therapeutic adalimumab levels. CONCLUSION: ACPA subclass distribution is modulated by effective anti-inflammatory treatment. The preferential decline of IgG4 ACPA, reflected by the decreased IgG4 : IgG1 ratio, suggests a beneficial effect of anti-TNF treatment on chronic antigenic stimulation by citrullinated proteins. This effect may be directly anti-TNF mediated or the result of effective dampening of the inflammation in the rheumatoid joint. PMID- 18445624 TI - The -670G>A polymorphism in the FAS gene promoter region influences the susceptibility to systemic sclerosis. AB - OBJECTIVE: To evaluate the role of the single-nucleotide polymorphism (SNP) at position -670 in the FAS gene promoter (FAS-670G>A) in influencing the susceptibility, clinical features and severity of systemic sclerosis (SSc). METHODS: 350 white Italian SSc patients (259 with limited cutaneous SSc (lcSSc) and 91 with diffuse cutaneous SSc (dcSSc)) and 232 healthy individuals were studied. Patients were assessed for the presence of autoantibodies (anticentromere, anti-topoisomerase I (anti-Scl-70) antibodies), interstitial lung disease (ILD), pulmonary arterial hypertension and scleroderma renal crisis. FAS-670G>A SNP was genotyped by PCR restriction fragment length polymorphism assay. Serum levels of soluble FAS (sFAS) were analysed by ELISA. RESULTS: A significant difference in FAS-670 genotype distribution was observed between SSc patients and healthy individuals (p = 0.001). The frequency of the FAS-670A allele was significantly greater in SSc than in controls (p = 0.001). No significant difference in genotype distribution and allele frequencies was observed between lcSSc and dcSSc, although a greater frequency of the FAS-670A allele was found in dcSSc. The FAS-670AA genotype significantly influenced the predisposition to SSc (OR 1.97, 95% CI 1.35 to 2.88, p = 0.001) and to both lcSSc (OR 1.84, 95% CI 1.23 to 2.75, p = 0.003) and dcSSc (OR 2.37, 95% CI 1.41 to 3.99, p = 0.001). FAS-670A allele frequency was greater, although not significantly, in anti-Scl-70 antibody-positive dcSSc and ILD dcSSc. sFAS was significantly higher in patients and controls carrying the FAS-670AA genotype compared with those carrying the FAS-670GG genotype (p = 0.003 in SSc, p = 0.004 in controls). CONCLUSION: The FAS-670A allele is significantly associated with susceptibility to SSc, suggesting a role for a genetic control of apoptosis in the pathogenesis of the disease. PMID- 18445625 TI - Development and initial validation of a screening questionnaire for psoriatic arthritis: the Toronto Psoriatic Arthritis Screen (ToPAS). AB - OBJECTIVE: To develop and validate a psoriatic arthritis (PsA) screening questionnaire: the Toronto Psoriatic Arthritis Screen (ToPAS). METHODS: The ToPAS was developed through review of items seen in patients with PsA and evaluation by patients with PsA and patients with other rheumatological conditions, and was administered to consecutive consenting patients attending five clinics: PsA, psoriasis, general dermatology, general rheumatology (excluding PsA patients) and family medicine. All patients were assessed by a rheumatologist according to a standard protocol. A three-step analysis strategy was adopted: a stepwise logistic regression to identify the questions most important in discriminating between those with and without PsA; a logistic model was fitted to three clinically relevant domains for PsA: skin, joints and nails; and a simpler weighting of each of the domains used in step 2. Receiver operating characteristic (ROC) curves were obtained based on these various models. RESULTS: In all, there were 134 patients from the PsA clinic, 123 with psoriasis, 118 from dermatology, 135 from rheumatology and 178 from family medicine. A simplified discriminatory score based on the skin, joint and nail domains gave results comparable to other methods with an observed overall sensitivity and specificity, based on a single cut point, of 86.8% and 93.1%. When the patients with PsA were compared with each of the other four patient groups individually, the sensitivity and specificity of the ToPAS were: psoriasis 89.1%, 86.3%; dermatology 91.9%, 95.2%; rheumatology 92.6%, 85.7%; and family medicine 90.4%, 100%. CONCLUSION: Our simplified index is very good at classifying those who are not diagnosed with PsA and those who are diagnosed with PsA. PMID- 18445626 TI - Infliximab efficacy and safety against refractory systemic necrotising vasculitides: long-term follow-up of 15 patients. AB - BACKGROUND: Results of uncontrolled studies have suggested that infliximab is efficacious against systemic necrotising vasculitides (SNV) refractory to conventional treatment. However, its safety and ability to induce and maintain remission over the long term remain unknown. OBJECTIVES: To report the use of infliximab to treat refractory SNV, focusing on patients' longer-term outcomes. METHODS: The medical charts of patients given adjunctive infliximab for refractory SNV >/=2 years before this evaluation were reviewed retrospectively. RESULTS: The 15 patients (median age 46 (range 20-69) years, median follow-up 35 (24-41) months) included 10 with Wegener's granulomatosis, 1 microscopic polyangiitis, 3 rheumatoid arthritis-associated and 1 cryoglobulinaemia-related vasculitides. Infliximab was taken for a median time of 8 (2-31) months; 2 patients are still being treated. By day 45, 11 patients had entered remission (Birmingham Vasculitis Activity Score (BVAS) = 0) and 4 others had responded (BVAS decrease >/=50%). Five patients achieved sustained remissions (>/=6 months, corticosteroids 2-fold changes in the expression of 402 genes including 55 linked to cell-cycle regulation, cell growth or apoptosis during 48 h treatment. Computational search predicted that 250 transcriptional regulatory factors (TRFs) could recognize the proximal upstream regions of any of the 55 genes. Expression of 61 TRF genes was significantly changed during ATRA incubation, providing many potential regulatory edges. We focused on six TRFs that could regulate many of the 55 genes and found a total of 160 potential edges in which the expression of each of the genes was changed later than the expression change of the corresponding regulator. RNAi knockdown of the selected TRFs caused perturbation of the respective potential targets. The genes showed an opposite regulation pattern by ATRA and specific siRNA treatments were selected as strong candidates for direct TRF targets. Finally, 36 transcriptional regulatory edges were validated by chromatin immunoprecipitation. These analyses enabled us to depict a part of the transcriptional regulatory cascades closely linked to ATRA-induced cell growth arrest. PMID- 18445635 TI - Failure of cefoxitin and doxycycline to eradicate endometrial Mycoplasma genitalium and the consequence for clinical cure of pelvic inflammatory disease. AB - OBJECTIVES: As Mycoplasma genitalium is associated with pelvic inflammatory disease (PID), we examined the efficacy of a commonly used PID antimicrobial in treating M genitalium upper genital tract infection. METHODS: In the PID Evaluation and Clinical Health study of inpatient versus outpatient treatment, 682 women treated with cefoxitin and doxycycline for clinically suspected PID had stored cervical and endometrial specimens available for analysis. In the current sub study, we compared baseline endometritis, short term treatment failure (continued endometritis and pelvic pain 30 days following treatment) and sequelae among women with and without M genitalium, identified using PCR. RESULTS: Endometrial M genitalium was associated with baseline endometritis (adjusted OR 3.0, 95% CI 1.5 to 6.1). Among women with a positive baseline M genitalium test, 41% tested positive again 30 days following treatment. Women testing positive compared to those testing negative for M genitalium at baseline had an increased risk of short-term treatment failure (RR 4.6, 95% CI 1.1 to 20.1). Rates of sequelae, including infertility (22%), recurrent PID (31%) and chronic pelvic pain (42%), were high among women testing positive for endometrial M genitalium at baseline. There was a non-significant trend towards increased infertility, chronic pelvic pain and recurrent PID, and decreased pregnancy and live birth following M genitalium infection. CONCLUSIONS: M genitalium is associated with endometritis and short-term PID treatment failure. Cefoxitin and doxycycline, a Centers for Disease Control and Prevention recommended PID treatment regimen, is ineffective for the treatment of M genitalium upper genital tract infection. PMID- 18445637 TI - Network-guided genetic screening: building, testing and using gene networks to predict gene function. AB - A challenge facing nearly all biologists is to identify the complete set of genes that are important for a process or disease. This applies to scientists investigating fundamental pathways in model organisms, but also to clinicians trying to understand human disease. There are many different types of experimental data that can be used to predict the genes that are important for a process, but these data are normally dispersed across numerous publications and databases, and are of varying and unknown quality. Integrated functional gene networks aim to gather functional information from all of these data into a single intuitive graph model that can be used to predict gene functions. In this approach, the ability of each data set to predict functional associations between genes is first measured using a standard benchmark, and then the scored predictions by each data set are combined. The resulting integrated probabilistic gene network can be used by all researchers to predict gene function, with much greater coverage and accuracy than any individual data set. In this review, we discuss how such integrated gene networks are constructed, how their predictive power for gene function can be tested, and how experimental biologists can use these networks to guide their research. We pay particular attention to such networks constructed for Caenorhabditis elegans, because in this complex multicellular model system functional predictions for genes can be rapidly tested in vivo using RNAi. The approach is, however, widely applicable to any system, and might soon be a common method used to dissect the genetics of human complex diseases. PMID- 18445636 TI - Intention of parents to have male children vaccinated with the human papillomavirus vaccine. AB - BACKGROUND: Although already approved for use in males in some jurisdictions, there is little information about parental attitudes toward having their sons receive the human papillomavirus (HPV) vaccine. The goal of this study was to ascertain parental intentions to vaccinate their sons with an HPV vaccine and to determine factors that predict this intention. METHODS: Parents of children aged 8-18 years were recruited from across Canada through random digit dialling. Participants were asked to respond to a series of questions in the context of a Grade 6 (age 11/12 years old), publicly funded school-based HPV vaccine programme, including their intention to vaccinate their sons with the HPV vaccine. Parents were also asked about a series of characteristics thought to predict intention to vaccinate as well as demographic characteristics. Backwards logistic regression was conducted to calculate adjusted odds ratios (AOR) to identify the factors that are predictive of parents' intention to vaccinate their son(s) against HPV. RESULTS: Of the 1381 respondents with male children, 67.8% (95% CI 65.3 to 70.3) intend to vaccinate their son(s) against HPV. Parents who had positive attitudes toward vaccines and the HPV vaccine in particular (AOR 41.5, 95% CI 9.5 to 181.7), parents who were influenced by subjective norms (AOR 7.8, 95% CI 5.8 to 10.5), parents who felt that the vaccine had limited influence on sexual behaviour (AOR 2.3, 95% CI 1.6 to 3.3) and parents who were aware of HPV (AOR 1.4, 95% CI 1.1 to 2.0) were significantly more likely to report an intention to vaccinate boys against HPV. In contrast, residence in British Columbia compared to Atlantic Canada (AOR 0.4, 95% CI 0.2 to 0.8) and higher education (AOR 0.7, 95% CI 0.5 to 0.9) were negatively associated with intention to vaccinate. Parents who reported an intention to vaccinate their daughters were also highly likely to report an intention to vaccinate their sons (kappa = 0.9, p<0.001). DISCUSSION: The majority of Canadian parents would intend to have their male children receive the HPV vaccine in the context of a publicly funded school based immunisation programme. Overall attitudes toward vaccine, recommendations from health professionals and impact of the vaccine on sexual practices are important predictors of intention to have a male child receive the HPV vaccine. PMID- 18445638 TI - Patients' priorities for health research: focus group study of patients with chronic kidney disease. AB - BACKGROUND: The inclusion of consumer preferences in prioritizing research topics is widely advocated, but prioritization is driven largely by professional agendas. METHODS: Patients with chronic kidney disease (CKD) were purposively sampled from four kidney dialysis and transplant centres in Australia to participate in nine focus groups (three each for pre-dialysis, dialysis and transplant patients), which were conducted from July 2006 to September 2006. Each involved 6-8 participants. Transcripts were coded and thematically analysed to identify recurrent research topics and the participants' reasons for their choices. RESULTS: Participants suggested eight research priorities: prevention of kidney disease, better access to and improvement in kidney transplantation, reduction of symptoms of CKD and complications associated with treatment, new technological therapies, psychosocial aspects of living with CKD, whole body not organ-specialized care, and improvement in dialysis and caregiver support. Five major reasons for the selections were identified: normalization of life (developing therapies and regimens that fit into daily living), altruism (considering the welfare of others before personal needs), economic efficiency (channelling resources for maximum economic gain), personal needs (preferences based on feelings, values, personal needs) and clinical outcomes (improving health states and the physiological condition of patients with CKD). CONCLUSIONS: A patient-focused research agenda is possible to elicit for CKD, and by inference for other healthcare issues. Unlike researchers who focus on specific interventions and questions, consumers think in terms of broad themes and quality of life outcomes. Effective methods for translating a patient-focused agenda into research priority setting and resource allocation are now needed. PMID- 18445639 TI - Conclusion of recent 'osmolality trials' in preventing contrast-induced nephropathy by NAC--what is the standard? PMID- 18445640 TI - Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice. AB - BACKGROUND: Rapamycin is a potent immunosuppressive drug with proven efficacy in rejection prophylaxis in solid organ transplantation. By virtue of its immunosuppressive properties, rapamycin might also be useful in the treatment of autoimmune diseases. The aim of this study was to determine the effect of rapamycin on the severity of established nephritis in lupus-prone New Zealand Black/White F(1) (NZB/W F(1)) mice. METHODS: Six-month-old female NZB/W F(1) mice with active nephritis (albuminuria >100 mg/dL) were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 4 months. The effect of rapamycin on the severity of nephritis was evaluated by clinical manifestations, biochemical parameters, renal histology, immunohistochemistry and semi-quantitative gene expression studies. RESULTS: Treatment with rapamycin significantly decreased albuminuria, improved survival, diminished splenomegaly, preserved renal function and reduced serum anti-dsDNA antibody levels. Kidney sections from saline-treated mice revealed marked mesangial proliferation, tubular dilation with intra-tubular protein cast deposition and leukocytic infiltration of the interstitium. The rapamycin-treated mice, in contrast, had relatively mild histological changes in their kidneys. Rapamycin treatment also significantly reduced the amount of immune complex deposition in the glomeruli, suppressed the interstitial infiltration by T-cells, B-cells and macrophages as well as down-regulated the intra-renal expression of RANTES. CONCLUSIONS: We conclude that rapamycin is effective in attenuating the severity of established nephritis in NZB/W F(1) mice. The beneficial effects of rapamycin are mediated, at least in part, through inhibition of lymphoproliferation, reduced RANTES expression and decreased inflammatory cell infiltration in the kidneys. Rapamycin could be of therapeutic value in the treatment of human lupus nephritis. PMID- 18445641 TI - Biodiversity informatics: the challenge of linking data and the role of shared identifiers. AB - A major challenge facing biodiversity informatics is integrating data stored in widely distributed databases. Initial efforts have relied on taxonomic names as the shared identifier linking records in different databases. However, taxonomic names have limitations as identifiers, being neither stable nor globally unique, and the pace of molecular taxonomic and phylogenetic research means that a lot of information in public sequence databases is not linked to formal taxonomic names. This review explores the use of other identifiers, such as specimen codes and GenBank accession numbers, to link otherwise disconnected facts in different databases. The structure of these links can also be exploited using the PageRank algorithm to rank the results of searches on biodiversity databases. The key to rich integration is a commitment to deploy and reuse globally unique, shared identifiers [such as Digital Object Identifiers (DOIs) and Life Science Identifiers (LSIDs)], and the implementation of services that link those identifiers. PMID- 18445642 TI - Will generalist physician supply meet demands of an increasing and aging population? AB - We predict that population growth and aging will increase family physicians' and general internists' workloads by 29 percent between 2005 and 2025. We expect a 13 percent increased workload for care of children by pediatricians and family physicians. However, the supply of generalists for adult care, adjusted for age and sex, will increase 7 percent, or only 2 percent if the number of graduates continues to decline through 2008. We expect deficits of 35,000-44,000 adult care generalists, although the supply for care of children should be adequate. These forces threaten the nation's foundation of primary care for adults. PMID- 18445643 TI - An evidence-based alcohol policy. PMID- 18445644 TI - Mechanisms of extrahepatic vasodilation in portal hypertension. AB - In liver cirrhosis, abnormal persistent extrahepatic vasodilation leads to hyperdynamic circulatory dysfunction which essentially contributes to portal hypertension. Since portal hypertension is a major factor in the development of complications in cirrhosis, the mechanisms underlying this vasodilation are of paramount interest. Extensive studies performed in cirrhotic patients and animals revealed that this vasodilation is associated on the one hand with enhanced formation of vasodilators, and on the other hand with vascular hyporesponsiveness to vasoconstrictors. The latter phenomenon has been termed "vascular hypocontractility". It is caused by a combination of different mechanisms and factors described in this review. PMID- 18445645 TI - Development of a multiplex quantitative fluorescent PCR assay for identification of rearrangements in the AZFb and AZFc regions. AB - The azoospermia factor b (AZFb) and azoospermia factor c (AZFc) regions in the human Y chromosome consist of five palindromes constructed from six distinct families of amplicons and are prone to rearrangement. Partial deletion and duplication in the region can cause azoospermia or oligozoospermia and male infertility. The aim of the study was to establish a quantitative fluorescent PCR (QF-PCR) assay to classify AZFb and AZFc rearrangements. A single pair of fluorescent primers was designed to amplify simultaneously the amplicon in AZFc and the length-variant homologous sequences outside of the region as control. Since the copy number of the control sequences is fixed in the human genome, dosage of the target could be easily obtained through comparing the height of the fluorescent peaks between the target and the control after amplification with limited PCR cycles. Most types of rearrangements in AZFb and AZFc regions could be classified with QF-PCR containing four such primer pairs. Eleven types of rearrangement in AZFb and AZFc regions were well discriminated with QF-PCR. In conclusion, QF-PCR is a simple and reliable method to detect rearrangements in AZFb and AZFc. PMID- 18445646 TI - Attributions of teacher reactions to diabetes self-care behaviors. AB - OBJECTIVE: This study had two objectives: examine relationships among negative attributions of teacher reactions, anticipated adherence difficulties, teacher support, diabetes stress, and metabolic control; and develop questionnaires to test these relationships. METHODS: One hundred and two youths with type 1 insulin dependent diabetes completed instruments measuring attribution of teacher reactions, anticipated adherence, teacher support, and diabetes stress. Metabolic control was measured by percentage of hemoglobin A(1c). RESULTS: Structural equation modeling demonstrated that negative attributions had direct effects on anticipated adherence difficulties and diabetes stress. Diabetes stress had a direct effect on metabolic control. Negative attributions had a significant indirect effect on metabolic control through associations with diabetes stress. Teacher support moderated the path between negative attributions and anticipated adherence difficulties. CONCLUSIONS: Youths making negative attributions about teacher's reactions are likely to find adherence difficult in school situations and have increased stress. Results are discussed in terms of a social information processing model of adjustment and practical applications. PMID- 18445647 TI - Brief report: illness factors and child behavior before and during pediatric hospitalization. AB - OBJECTIVE: Little is known about factors predicting in-hospital adjustment in children with chronic illnesses or about risk/protective factors for in-hospital behavior compared to out-of-hospital behavior. This study investigated the relationship between illness factors (chronicity and severity) and child adjustment in and out of the hospital. METHODS: Parents and nurses completed questionnaires about in-hospital and home behavior for a sample of 85 hospitalized children. RESULTS: In the hospital, children with acute illnesses demonstrated more internalizing behavior problems than children with chronic illnesses. Children with life-threatening illnesses had more internalizing and externalizing problems than children with non-life-threatening illnesses. Out of the hospital, children with chronic illnesses demonstrated more internalizing problems and a trend toward more externalizing problems than healthy children who later developed acute illnesses. Out of hospital behavior problems were unrelated to illness severity. CONCLUSIONS: Results suggest that different illness factors may predict in-hospital as compared to out-of-hospital behavioral adjustment. PMID- 18445648 TI - The fetal liver is a niche for maturation of primitive erythroid cells. AB - Primitive erythroid cells (EryP) are the earliest differentiated cell type of the mammalian embryo. They appear in the yolk sac by embryonic day 7.5, begin to enter the embryonic circulation 2 days later and continue to mature in a stepwise and synchronous fashion. Like their adult counterparts, EryP enucleate. However, EryP circulate throughout the embryo for several days before the first enucleated forms can be identified in the blood. We have used transgenic mouse lines in which GFP marks EryP to investigate this seemingly long lag and have identified a previously unrecognized developmental niche for EryP maturation. After exiting the yolk sac, EryP begin to express cell adhesion proteins, including alpha4, alpha5, and beta1 integrins, on their surface and migrate into the fetal liver (FL), where they interact with macrophages within erythroblastic islands. Binding of EryP to FL macrophages in vitro is stage-specific and partly depends on VCAM 1. The ability to tag and track EryP nuclei using a transgenic mouse line expressing an H2B-EGFP fusion allowed us to identify and characterize extruded EryP nuclei and to demonstrate that molecules such as alpha4, alpha5, and beta1 integrins are redistributed onto the plasma membrane surrounding the extruding nucleus. FL macrophages engulf extruded EryP nuclei in cocultures and in the native FL in vivo. We conclude that EryP home to, complete their maturation, and enucleate within the FL, a tissue that is just developing as EryP begin to circulate. Our observations suggest a simple solution for a puzzling aspect of the development of the primitive erythroid lineage. PMID- 18445650 TI - Phenotypic transcription factors epigenetically mediate cell growth control. AB - Ribosomal RNA (rRNA) genes are down-regulated during osteogenesis, myogenesis, and adipogenesis, necessitating a mechanistic understanding of interrelationships between growth control and phenotype commitment. Here, we show that cell fate determining factors [MyoD, myogenin (Mgn), Runx2, C/EBPbeta] occupy rDNA loci and suppress rRNA expression during lineage progression, concomitant with decreased rRNA expression and reciprocal loss of occupancy by c-Myc, a proliferation specific activator of rRNA transcription. We find interaction of phenotypic factors with the polymerase I activator upstream binding factor UBF-1 at interphase nucleoli, and this interaction is epigenetically retained on mitotic chromosomes at nucleolar organizing regions. Ectopic expression and RNA interference establish that MyoD, Mgn, Runx2, and C/EBPbeta each functionally suppress rRNA genes and global protein synthesis. We conclude that epigenetic control of ribosomal biogenesis by lineage-specific differentiation factors is a general developmental mechanism for coordinate control of cell growth and phenotype. PMID- 18445649 TI - Design of protein function leaps by directed domain interface evolution. AB - Most natural proteins performing sophisticated tasks contain multiple domains where an active site is located at the domain interface. Comparative structural analyses suggest that major leaps in protein function occur through gene recombination events that connect two or more protein domains to generate a new active site, frequently occurring at the newly created domain interface. However, such functional leaps by combination of unrelated domains have not been directly demonstrated. Here we show that highly specific and complex protein functions can be generated by joining a low-affinity peptide-binding domain with a functionally inert second domain and subsequently optimizing the domain interface. These directed evolution processes dramatically enhanced both affinity and specificity to a level unattainable with a single domain, corresponding to >500-fold and >2,000-fold increases of affinity and specificity, respectively. An x-ray crystal structure revealed that the resulting "affinity clamp" had clamshell architecture as designed, with large additional binding surface contributed by the second domain. The affinity clamps having a single-nanomolar dissociation constant outperformed a monoclonal antibody in immunochemical applications. This work establishes evolutionary paths from isolated domains with primitive function to multidomain proteins with sophisticated function and introduces a new protein engineering concept that allows for the generation of highly functional affinity reagents to a predefined target. The prevalence and variety of natural interaction domains suggest that numerous new functions can be designed by using directed domain interface evolution. PMID- 18445651 TI - The crystal structure and dimerization interface of GADD45gamma. AB - Gadd45 proteins are recognized as tumor and autoimmune suppressors whose expression can be induced by genotoxic stresses. These proteins are involved in cell cycle control, growth arrest, and apoptosis through interactions with a wide variety of binding partners. We report here the crystal structure of Gadd45gamma, which reveals a fold comprising an alphabetaalpha sandwich with a central five stranded mixed beta-sheet with alpha-helices packed on either side. Based on crystallographic symmetry we identified the dimer interface of Gadd45gamma dimers by generating point mutants that compromised dimerization while leaving the tertiary structure of the monomer intact. The dimer interface comprises a four helix bundle involving residues that are the most highly conserved among Gadd45 isoforms. Cell-based assays using these point mutants demonstrate that dimerization is essential for growth inhibition. This structural information provides a new context for evaluation of the plethora of protein-protein interactions that govern the many functions of the Gadd45 family of proteins. PMID- 18445652 TI - Beta-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic beta cells. AB - Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted from enteroendocrine L cells and potentiates glucose-dependent insulin secretion in pancreatic beta cells. Recently the GLP-1 receptor (GLP-1 R) has been a focus for new anti-diabetic therapy with the introduction of GLP-1 analogues and DPP-IV inhibitors, and this has stimulated additional interest in the mechanisms of GLP 1 signaling. Here we identify a mechanism for GLP-1 action, showing that the scaffold protein beta-arrestin-1 mediates the effects of GLP-1 to stimulate cAMP production and insulin secretion in beta cells. Using a coimmunoprecipitation technique, we also found a physical association between the GLP-1 R and beta arrestin-1 in cultured INS-1 pancreatic beta cells. beta-Arrestin-1 knockdown broadly attenuated GLP-1 signaling, causing decreased ERK and CREB activation and IRS-2 expression as well as reduced cAMP levels and impaired insulin secretion. However, beta-arrestin-1 knockdown did not affect GLP-1 R surface expression and ligand-induced GLP-1 R internalization/desensitization. Taken together, these studies indicate that beta-arrestin-1 plays a role in GLP-1 signaling leading to insulin secretion, defining a previously undescribed mechanism for GLP-1 action. PMID- 18445653 TI - Extreme polyploidy in a large bacterium. AB - Cells rely on diffusion to move metabolites and biomolecules. Diffusion is highly efficient but only over short distances. Although eukaryotic cells have broken free of diffusion-dictated constraints on cell size, most bacteria and archaea are forced to remain small. Exceptions to this rule are found among the bacterial symbionts of surgeonfish; Epulopiscium spp. are cigar-shaped cells that reach lengths in excess of 600 mum. A large Epulopiscium contains thousands of times more DNA than a bacterium such as Escherichia coli, but the composition of this DNA is not well understood. Here, we present evidence that Epulopiscium contains tens of thousands of copies of its genome. Using quantitative, single-cell PCR assays targeting single-copy genes, we have determined that copy number is positively correlated with Epulopiscium cell size. Although other bacteria are known to possess multiple genomes, polyploidy of the magnitude observed in Epulopiscium is unprecedented. The arrangement of genomes around the cell periphery may permit regional responses to local stimuli, thus allowing Epulopiscium to maintain its unusually large size. Surveys of the sequences of single-copy genes (dnaA, recA, and ftsZ) revealed genetic homogeneity within a cell consistent with only a small amount ( approximately 1%) of the parental DNA being transferred to the next generation. The results also suggest that the abundance of genome copies in Epulopiscium may allow for an unstable genetic feature, a long mononucleotide tract, in an essential gene. With the evolution of extreme polyploidy and large cell size, Epulopiscium has acquired some of the advantages of eukaryotic cells. PMID- 18445654 TI - Release of hydrophobic molecules from polymer micelles into cell membranes revealed by Forster resonance energy transfer imaging. AB - It is generally assumed that polymeric micelles, upon administration into the blood stream, carry drug molecules until they are taken up into cells followed by intracellular release. The current work revisits this conventional wisdom. The study using dual-labeled micelles containing fluorescently labeled copolymers and hydrophobic fluorescent probes entrapped in the polymeric micelle core showed that cellular uptake of hydrophobic probes was much faster than that of labeled copolymers. This result implies that the hydrophobic probes in the core are released from micelles in the extracellular space. Forster resonance energy transfer (FRET) imaging and spectroscopy were used to monitor this process in real time. A FRET pair, DiIC(18(3)) and DiOC(18(3)), was loaded into monomethoxy poly(ethylene glycol)-block-poly(d,l-lactic acid) micelles. By monitoring the FRET efficiency, release of the core-loaded probes to model membranes was demonstrated. During administration of polymeric micelles to tumor cells, a decrease of FRET was observed both on the cell membrane and inside of cells, indicating the release of core-loaded probes to the cell membrane before internalization. The decrease of FRET on the plasma membrane was also observed during administration of paclitaxel-loaded micelles. Taken together, our results suggest a membrane-mediated pathway for cellular uptake of hydrophobic molecules preloaded in polymeric micelles. The plasma membrane provides a temporal residence for micelle-released hydrophobic molecules before their delivery to target intracellular destinations. A putative role of the PEG shell in the molecular transport from micelle to membrane is discussed. PMID- 18445655 TI - Assembly mechanism of recombinant spider silk proteins. AB - Spider silk threads are formed by the irreversible aggregation of silk proteins in a spinning duct with dimensions of only a few micrometers. Here, we present a microfluidic device in which engineered and recombinantly produced spider dragline silk proteins eADF3 (engineered Araneus diadematus fibroin) and eADF4 are assembled into fibers. Our approach allows the direct observation and identification of the essential parameters of dragline silk assembly. Changes in ionic conditions and pH result in aggregation of the two proteins. Assembly of eADF3 fibers was induced only in the presence of an elongational flow component. Strikingly, eADF4 formed fibers only in combination with eADF3. On the basis of these results, we propose a model for dragline silk aggregation and early steps of fiber assembly in the microscopic regime. PMID- 18445656 TI - Medullary thyroid cancer: targeting the RET kinase pathway with sorafenib/tipifarnib. AB - Medullary thyroid carcinoma (MTC) is an uncommon malignancy of hereditary and sporadic presentation. Mutations in the RET proto-oncogene are involved in the pathogenesis of familial MTC and >50% of the sporadic cases. Currently, there is no effective treatment for recurrent or metastatic MTC. We report here a rapid response to a sorafenib (RET and RAF kinase and vascular endothelial growth factor receptor inhibitor)--based regimen in a patient with sporadic MTC who had advanced, progressive disease and a novel RET kinase aberration at exon 11 shown in tumor tissue. PMID- 18445658 TI - Chemopreventive effects of oral gallic acid feeding on tumor growth and progression in TRAMP mice. AB - Our recent studies have identified gallic acid as one of the major constituents of grape seed extract showing strong in vitro anticancer efficacy against human prostate cancer cells. Herein, for the first time, we established the in vivo chemopreventive efficacy of gallic acid against prostate cancer by evaluating its activity against prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. At 4 weeks of age, male TRAMP mice were fed with drinking water supplemented with 0.3% and 1% (w/v) gallic acid until 24 weeks of age. Positive control group was fed with regular drinking water for the same period. Our results showed that gallic acid-fed groups had a higher incidence of differentiated lower-grade prostatic tumors at the expense of strong decrease ( approximately 60%; P < 0.01) in poorly differentiated tumors. Immunohistochemical analysis of prostate tissue showed a decrease in proliferative index by 36% to 41% (P < 0.05) in 0.3% to 1% gallic acid-fed groups, with an increase in the apoptotic cells by 3-fold (P < 0.05). Further, both doses of gallic acid completely diminished the expression of Cdc2 in the prostatic tissue together with strong decrease in the expression of Cdk2, Cdk4, and Cdk6. The protein levels of cyclin B1 and E were also decreased by gallic acid feeding. Together, for the first time, we identified that oral gallic acid feeding inhibits prostate cancer growth and progression to advanced-stage adenocarcinoma in TRAMP mice via a strong suppression of cell cycle progression and cell proliferation and an increase in apoptosis. PMID- 18445657 TI - Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL expressing leukemia cells. AB - Clinical studies of patients with chronic myeloid leukemia revealed that a common pattern of response is a dramatic fall in the circulating population of blast cells, with a minimal or delayed decrease in marrow blasts, suggesting a protective environment. These observations suggest that a greater understanding of the interaction of stromal cells with leukemic cells is essential. Here, we present an in vivo system for monitoring relative tumor accumulation in leukemic mice and residual disease in leukemic mice treated with a tyrosine kinase inhibitor and an in vitro system for identifying integral factors involved in stromal-mediated cytoprotection. Using the in vivo model, we observed high tumor burden/residual disease in tissues characterized as significant sources of hematopoiesis-promoting stroma, with bone marrow stroma most frequently showing the highest accumulation of leukemia in untreated and nilotinib-treated mice as well as partial protection of leukemic cells from the inhibitory effects of nilotinib. These studies, which showed a pattern of leukemia distribution consistent with what is observed in imatinib- and nilotinib-treated chronic myeloid leukemia patients, were followed by a more in-depth analysis of stroma leukemia cell interactions that lead to protection of leukemia cells from nilotinib-induced cytotoxicity. For the latter, we used the human BCR-ABL positive cell line, KU812F, and the human bone marrow stroma cell line, HS-5, to more closely approximate the bone marrow-associated cytoprotection observed in drug-treated leukemia patients. This in vitro system helped to elucidate stromal secreted viability factors that may play a role in stromal-mediated cytoprotection of tyrosine kinase inhibitor-treated leukemia cells. PMID- 18445659 TI - MRP7/ABCC10 expression is a predictive biomarker for the resistance to paclitaxel in non-small cell lung cancer. AB - We used the paclitaxel-resistant human small cell lung cancer subline PC-6/TAX1 1, selected from PC-6 cells by paclitaxel, to test whether MRP7/ABCC10 (ABCC10) confers paclitaxel resistance. We found that gene expression of both ABCB1/MDR1 (ABCB1) and ABCC10 was higher in PC-6/TAX1-1 cells than in PC-6 cells. The expression levels of ABCC10 showed a significant inverse correlation with paclitaxel sensitivity (r = 0.574; P < 0.05) in 17 non-small cell lung cancer (NSCLC) cells unlike the expression levels of ABCB1. Pretreatment with the ABCC10 inhibitor sulfinpyrazone altered the sensitivity to paclitaxel in ABCC10 expressing NSCLC cells, concomitant with increased intracellular paclitaxel accumulation. These findings suggest that expression of the ABCC10 gene is induced by paclitaxel and that ABCC10 confers paclitaxel resistance by enhancing the efflux for paclitaxel. To confirm this hypothesis, we tested the effect on paclitaxel cytotoxicity of decreasing the expression of ABCC10 by small interfering RNA and found that this enhanced paclitaxel cytotoxicity in NCI-H23 cells concomitant with increased intracellular paclitaxel accumulation. These data indicate that ABCC10 may be one of the biomarkers for paclitaxel resistance in NSCLC. PMID- 18445660 TI - Improved grading and survival prediction of human astrocytic brain tumors by artificial neural network analysis of gene expression microarray data. AB - Histopathologic grading of astrocytic tumors based on current WHO criteria offers a valuable but simplified representation of oncologic reality and is often insufficient to predict clinical outcome. In this study, we report a new astrocytic tumor microarray gene expression data set (n = 65). We have used a simple artificial neural network algorithm to address grading of human astrocytic tumors, derive specific transcriptional signatures from histopathologic subtypes of astrocytic tumors, and asses whether these molecular signatures define survival prognostic subclasses. Fifty-nine classifier genes were identified and found to fall within three distinct functional classes, that is, angiogenesis, cell differentiation, and lower-grade astrocytic tumor discrimination. These gene classes were found to characterize three molecular tumor subtypes denoted ANGIO, INTER, and LOWER. Grading of samples using these subtypes agreed with prior histopathologic grading for both our data set (96.15%) and an independent data set. Six tumors were particularly challenging to diagnose histopathologically. We present an artificial neural network grading for these samples and offer an evidence-based interpretation of grading results using clinical metadata to substantiate findings. The prognostic value of the three identified tumor subtypes was found to outperform histopathologic grading as well as tumor subtypes reported in other studies, indicating a high survival prognostic potential for the 59 gene classifiers. Finally, 11 gene classifiers that differentiate between primary and secondary glioblastomas were also identified. PMID- 18445661 TI - Association of CYP3A7*1C and serum dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome. AB - CONTEXT: Adrenal androgen excess is common in polycystic ovary syndrome (PCOS) and appears to be heritable. CYP3A7 metabolizes dehydroepiandrosterone and its sulfate (DHEAS). A promoter variant, CYP3A7*1C, which results in persistent expression in adults, was associated with reduced DHEAS levels in a previous study, which led us to consider CYP3A7*1C as a modulator of adrenal androgen excess in patients with PCOS. OBJECTIVE: The objective was to replicate the association between CYP3A7*1C and reduced DHEAS levels in PCOS patients and assess its possible role in modulating testosterone levels. DESIGN: Women with and without PCOS were genotyped for CYP3A7*1C, and this variant was tested for association with DHEAS and total and free testosterone. SETTING: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center (Los Angeles, CA). PARTICIPANTS: A total of 287 white women with PCOS and 187 controls were studied. MAIN MEASUREMENTS: CYP3A7*1C genotype, PCOS risk, and androgen levels were measured. RESULTS: PCOS subjects who carried the CYP3A7*1C variant had lower levels of serum DHEAS and total testosterone (P = 0.0006 and 0.046, respectively). The variant was not associated with PCOS risk. CONCLUSION: This study replicated prior work of the association of CYP3A7*1C and decreased DHEAS in a different population of young PCOS women, providing further genetic evidence that CYP3A7 plays a potential role in modulation of DHEAS levels. Adult expression of CYP3A7 may modify the PCOS phenotype by ameliorating adrenal androgen excess. PMID- 18445662 TI - Impact of treating acromegaly first with surgery or somatostatin analogs on cardiomyopathy. AB - OBJECTIVE: The objective of the study was to investigate whether first-line surgery or somatostatin analogs (SSA) have a different outcome on cardiomyopathy after 12 months. DESIGN: This was a retrospective, comparative, nonrandomized study. PATIENTS: Fifty-six patients treated with SSA and 33 operated on by transsphenoidal approach participated in the study. For the purposes of this study, only controlled patients were included. MEASUREMENTS: Primary outcome measures were changes in left ventricular mass index, diastolic (early to atrial mitral flow velocity), and systolic performance (left ventricular ejection fraction). Secondary outcome measures were reduction of total to high-density lipoprotein-cholesterol ratio as a cardiovascular risk parameter, and improvement of glucose profile and pituitary function as indirect causes of cardiovascular improvement. RESULTS: SSA and surgery groups were similar for gender, age, estimated disease duration, GH and IGF-I levels, and severity of cardiomyopathy lipid and glucose profile. Twelve months after treatment in both groups, left ventricular mass index, early to atrial mitral flow velocity, diastolic blood pressure, and heart rate decreased significantly, whereas only in SSA-treated patients, left ventricular ejection fraction increased significantly. The total to high-density lipoprotein-cholesterol ratio significantly reduced only in SSA treated patients, whereas fasting glucose levels significantly decreased only in surgery-treated patients. A normal pituitary function was found in 46.4% of SSA- and 36.4% of surgery-treated patients, with results unchanged in the former and slightly reduced in the latter. CONCLUSIONS: Twelve months after first-line treatment with SSA or surgery, we found a similar improvement in left ventricular hypertrophy and diastolic filling. In contrast, systolic function improved more evidently in SSA-treated patients. Both a direct effect of SSA and a more preserved pituitary function might explain these results. PMID- 18445663 TI - Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients. AB - CONTEXT: Body mass index (BMI) shows a direct correlation with plasma aldosterone concentration (PAC) and urinary aldosterone excretion in normotensive individuals; whether the same applies to hypertensive patients is unknown. OBJECTIVE: Our objective was to determine if BMI predicts PAC and the PAC/plasma renin activity ratio [aldosterone renin ratio (ARR)] in hypertensive patients, and if this affects the identification of primary aldosteronism (PA). DESIGN: This was a prospective evaluation of consecutive hypertensive patients referred nationwide to specialized hypertension centers. MAIN OUTCOME MEASURES: Sitting PAC, plasma renin activity, and the ARR, baseline and after 50 mg captopril orally with concomitant assessment of parameters, including BMI and daily sodium intake, were calculated. RESULTS: Complete biochemical data and a definite diagnosis were obtained in 1125 consecutive patients. Of them 999 had primary (essential) hypertension (PH) and 126 (11.2%) PA caused by an aldosterone producing adenoma in 54 (4.8%). BMI independently predicted PAC (beta = 0.153; P < 0.0001) in PH, particularly in the overweight-obese, but not in the PA group. Covariance analysis and formal comparison of the raw, and the BMI-, sex-, and sodium intake-adjusted ARR with receiver operator characteristic curves, showed no significant improvement for the discrimination of aldosterone-producing adenoma from PH patients with covariate-adjusted ARR. CONCLUSIONS: BMI correlated with PAC independent of age, sex, and sodium intake in PH, but not in PA patients. This association of BMI is particularly evident in overweight-obese PH patients, and suggests a pathophysiological link between visceral adiposity and aldosterone secretion. However, it does not impact on the diagnostic accuracy of the ARR for discriminating PA from PH patients. PMID- 18445665 TI - The exon 3-deleted/full-length growth hormone receptor polymorphism does not influence the effect of puberty or growth hormone therapy on glucose homeostasis in short non-growth hormone-deficient small-for-gestational-age children: results from a two-year controlled prospective study. AB - CONTEXT: The exon 3-deleted/full-length (d3/fl) GH receptor polymorphism (d3/fl GHR) has been associated with responsiveness to GH therapy in short small-for gestational-age (SGA) patients, although consensus is lacking. However, its influence on glucose homeostasis, at baseline or under GH therapy, has not been investigated. OBJECTIVE: Our objective was to evaluate whether the d3/fl-GHR genotypes influence insulin sensitivity in short SGA children before or after puberty onset or during GH therapy. DESIGN: We conducted a 2-yr prospective, controlled, randomized trial. SETTING: Thirty Spanish hospitals participated. Auxological, GH secretion, and glucose homeostasis evaluation was hospital based, whereas molecular analyses and data computation were centralized. PATIENTS: Patients included 219 short SGA children [body mass index sd score (SDS) < or = 2.0]; 159 were prepubertal (group 1), and 60 had entered puberty (group 2). INTERVENTION: Seventy-eight patients from group 1 were treated with GH (66 microg/kg.d) for 2 yr (group 3). MAIN OUTCOME MEASURES: Previous and 2-yr follow up auxological and biochemical data were recorded, d3/fl-GHR genotypes determined, and data analyzed. RESULTS: In groups 1 and 2, fasting glucose, insulin, homeostasis model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI) were similar in each d3/fl-GHR genotype. Group 2 glucose, insulin, and HOMA were significantly higher and QUICKI lower than in group 1. In group 3 GH-treated patients, height SDS, growth velocity SDS, fasting glucose, insulin, and HOMA significantly increased as did body mass index SDS at the end of the second year, and QUICKI decreased during the first and second years, with no differences among the d3/fl-GHR genotypes. CONCLUSION: In short SGA patients, the d3/fl-GHR genotypes do not seem to influence prepubertal or pubertal insulin sensitivity indexes or their changes over 2 yr of GH therapy (66 mug/kg.d). PMID- 18445664 TI - Growth hormone deficiency by growth hormone releasing hormone-arginine testing criteria predicts increased cardiovascular risk markers in normal young overweight and obese women. AB - CONTEXT: Little is known about the relationship between GH and cardiovascular risk markers in women without organic hypothalamic/pituitary disease. OBJECTIVE: The objective of the study was to determine whether healthy young overweight and obese women, who would be classified as having GH deficiency (GHD) based on standard criteria used in hypopituitarism (peak GH after stimulation with GHRH and arginine < 5 ng/ml), have increased cardiovascular risk markers. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at the General Clinical Research Center. STUDY PARTICIPANTS: Forty-five women of reproductive age, mean age 33.1 +/- 1.2 yr and mean body mass index (BMI) 30.9 +/- 1.0 kg/m(2). INTERVENTION: There was no intervention. MAIN OUTCOME MEASURES: Measures included carotid intima-medial thickness, high-sensitivity C-reactive protein (hsCRP), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, triglycerides, E-selectin, soluble intercellular adhesion molecule 1, TNF-alpha receptor I, TNF-alpha receptor II, fasting insulin levels, and oral glucose tolerance testing. RESULTS: Twenty-six percent of overweight or obese subjects and none with BMI less than 25 kg/m(2) met criteria for GHD. Subjects who met GHD criteria had a mean BMI of 37.0 +/- 1.7 kg/m(2) (range 28.6-43.6 kg/m(2)), and their mean waist circumference (110.1 +/- 3.5 cm) was higher than in overweight/obese women with GH sufficiency (P = 0.007). Mean carotid intima media thickness, hsCRP, soluble intercellular adhesion molecule-1, TNF-alpha receptor I, and TNF-alpha receptor II levels were higher, and HDL lower, in women meeting GHD criteria than in GH sufficiency. Differences in HDL, hsCRP, and TNF alpha receptor II remained after controlling for age plus BMI, waist circumference, or trunk fat. There were no differences in measures of insulin resistance. CONCLUSIONS: There may be a relative GHD syndrome in overweight and obese women without organic pituitary or hypothalamic disease that confers increased cardiovascular risk, independent of weight. PMID- 18445666 TI - Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels. AB - BACKGROUND: Younger age at the onset of menopause and lower circulating levels of estrogen are risk factors for cardiovascular disease. Several studies have detected associations between variations in genes encoding estrogen receptors alpha (ESR1) and beta (ESR2), and enzyme aromatase (CYP19A1), which regulates the estrogen to testosterone ratio, and cardiovascular phenotypes in the Framingham Heart Study. To explore potential mechanisms by which these gene variants may contribute to cardiovascular disease, we tested the hypothesis that the polymorphisms were associated with endogenous steroid hormone levels. METHODS: Multiple regression analysis was used to assess the relation between reported polymorphisms and total serum estradiol, testosterone, and dehydroepiandrosterone sulfate levels in 834 men and 687 women who attended the third and fourth Framingham Heart Study examination cycles. RESULTS: In men, significant associations were detected between CYP19A1 polymorphisms and estradiol and testosterone levels, and the estradiol to testosterone ratio (P ranges 0.0005 0.01). Specifically, carriers of common haplotype rs700518[G]-(TTTA)(n) [L] rs726547[C] had higher estradiol levels (5% per copy; P = 0.0004), lower testosterone levels (17% per copy; P = 0.036), and a higher estradiol to testosterone ratio (24% per copy; P < 0.0001) compared with the rs700518[A] (TTTA)(n) [S]-rs726547[C] carriers. In addition, postmenopausal carriers of the ESR2 (CA)(n) long allele and rs1256031 [C] allele had moderately higher estradiol levels (P < or = 0.03). No significant associations with the ESR1 variants were detected. CONCLUSIONS: Our findings suggest that variations in CYP19A1 correlate with steroid hormone levels in men. Knowledge that a specific carrier status may predispose to altered steroid hormone levels may lead to targeted intervention strategies to reduce health risks in genetically susceptible individuals. PMID- 18445667 TI - Leptin does not mediate short-term fasting-induced changes in growth hormone pulsatility but increases IGF-I in leptin deficiency states. AB - CONTEXT: States of acute and chronic energy deficit are characterized by increased GH secretion and decreased IGF-I levels. OBJECTIVE: The objective of the study was to determine whether changes in levels of leptin, a key mediator of the adaptation to starvation, regulate the GH-IGF system during energy deficit. DESIGN, SETTING, PATIENTS, AND INTERVENTION: We studied 14 healthy normal-weight men and women during three conditions: baseline fed and 72-h fasting (to induce hypoleptinemia) with administration of placebo or recombinant methionyl human leptin (r-metHuLeptin) (to reverse the fasting associated hypoleptinemia). We also studied eight normal-weight women with exercise-induced chronic energy deficit and hypothalamic amenorrhea at baseline and during 2-3 months of r metHuLeptin treatment. MAIN OUTCOME MEASURES: GH pulsatility, IGF levels, IGF and GH binding protein (GHBP) levels were measured. RESULTS: During short-term energy deficit, measures of GH pulsatility and disorderliness and levels of IGF binding protein (IGFBP)-1 increased, whereas leptin, insulin, IGF-I (total and free), IGFBP-4, IGFBP-6, and GHBP decreased; r-metHuLeptin administration blunted the starvation-associated decrease of IGF-I. In chronic energy deficit, total and free IGF-I, IGFBP-6, and GHBP levels were lower, compared with euleptinemic controls; r-metHuLeptin administration had no major effect on GH pulsatility after 2 wk but increased total IGF-I levels and tended to increase free IGF-I and IGFBP-3 after 1 month. CONCLUSIONS: The GH/IGF system changes associated with energy deficit are largely independent of leptin deficiency. During acute energy deficit, r-metHuLeptin administration in replacement doses blunts the starvation induced decrease of IGF-I, but during chronic energy deficit, r-metHuLeptin administration increases IGF-I and tends to increase free IGF-I and IGFBP-3. PMID- 18445668 TI - High molecular mass multimer complexes and vascular expression contribute to high adiponectin in the fetus. AB - CONTEXT: High plasma adiponectin concentrations in human fetuses and neonates are unique features of early developmental stages. Yet, the origins of the high adiponectin concentrations in the perinatal period remain elusive. OBJECTIVE: This study was undertaken to identify the sources and functional properties of adiponectin in utero. DESIGN AND METHODS: Tissue specimens were obtained at autopsy from 21- to 39-wk-old stillborn human fetuses. Adipose tissue and placenta were obtained at term elective cesarean section. Adiponectin complexes and expression were measured by immunodetection and real-time PCR. RESULTS: Adiponectin mRNA transcripts were detected in fetal sc and omental adipose depots at lower concentrations than in maternal adipose tissue. Immunoreactive adiponectin was also observed in vascular endothelial cells of fetal organs, including skeletal muscle, kidney, and brain. The absence of adiponectin in all placental cell types and lack of correlation between maternal and umbilical adiponectin indicate that umbilical adiponectin reflects its exclusive production by fetal tissues. The most prominent forms of adiponectin in fetal plasma were high and low molecular mass (HMW and LMW) multimers of 340 and 160 kDa, respectively. The proportion of the HMW complexes was 5-fold (P < 0.001) higher in umbilical plasma than in adult. The high HMW and total adiponectin levels were associated with lower insulin concentration and lower homeostasis model of assessment of insulin resistance indices in umbilical plasma, reflecting higher insulin sensitivity of the fetus compared with adult. CONCLUSIONS: The abundance of HMW adiponectin and its vascular expression are characteristics of human fetal adiponectin. Combined with high insulin sensitivity, fetal adiponectin may be a critical determinant of in utero growth. PMID- 18445669 TI - Lack of association of fatness-related FTO gene variants with energy expenditure or physical activity. AB - CONTEXT: A common variant in the first intron of FTO (rs9939609, T/A) is associated with fatness in Caucasians. OBJECTIVE: FTO may regulate energy homeostasis through the hypothalamus, and we hypothesized that AA-genotypes of rs9939609 FTO have lower energy expenditure and/or a lower level of physical activity. METHODS: The study population included all obese young men (body mass index > or = 31 kg/m(2)) at the mandatory draft board examinations in the Copenhagen area from 1943 to 1977 and a randomly selected control group from this population. Subgroups of 234 obese and 323 controls were examined in 1998-2000 (median age 48 yr). Fat mass (FM), lean body mass (LBM), leisure-time physical activity (LTPA), maximum oxygen uptake (VO(2)max), resting energy expenditure (REE), and glucose-induced thermogenesis (GIT) were measured. The FTO rs9939609 variant was genotyped. A recessive transmission mode fit the data best. Logistic regression was used to assess the odds ratios of the AA-genotype in relation to LTPA, VO(2)max, REE, and GIT. RESULTS: The AA-genotype of FTO rs9939609 had higher REE in the age-adjusted model, but the association was eliminated when adjusting for FM and LBM. The AA-genotype was not associated with LTPA, VO(2)max, or GIT. This was not influenced by adjustment for age, FM, or LBM. The AA genotype had increased FM, even with adjustment for age, LBM, REE, GIT, VO(2)max, and LTPA. Results were similar for FTO rs8050136 and rs7193144. CONCLUSIONS: Homozygous carriers of the A-allele of rs9939609 FTO do not have lower REE, GIT, VO(2)max, or LTPA but higher FM, irrespective of LBM, REE, GIT, VO(2)max, and LTPA. PMID- 18445670 TI - Serum levels of retinol-binding protein 4 and adiponectin in women with polycystic ovary syndrome: associations with visceral fat but no evidence for fat mass-independent effects on pathogenesis in this condition. AB - CONTEXT: Insulin resistance, which associates with levels of retinol-binding protein 4 (RBP4) and adiponectin, is implicated in the development of polycystic ovary syndrome (PCOS). OBJECTIVE: The objective of the study was to explore the potential contribution of RBP4 and adiponectin in the etiology of PCOS and their relationships with specific fat depot measurements. DESIGN: This was a cross sectional study. SETTING AND PARTICIPANTS: Serum RBP4 and adiponectin levels were compared between 50 PCOS cases and 28 female controls (including 22 body mass index/fat mass-matched pairs) and correlated with specific fat depot (including visceral) axial magnetic resonance imaging cross-sectional area measurements. All subjects were of U.K. British/Irish origin. MAIN OUTCOME MEASURE(S): Serum levels of RBP4 (automated immunonephelometric assay) and adiponectin [immunoassay: total and high molecular weight (HMW)]. Data are reported as geometric mean (sd, range) and optionally adjusted for fat mass and age. RESULTS: Between the 50 PCOS cases and 28 controls, serum RBP4 levels were indistinguishable [39.0 microg/ml (31.0, 49.0) vs. 41.6 microg/ml (32.7, 52.9), respectively, unadjusted P = 0.24; adjusted P = 0.55]. Total (and HMW) adiponectin levels were lower in PCOS cases [total adiponectin 19.9 microg/ml (14.2, 27.8) vs. 25.8 microg/ml (17.7, 37.7), respectively, unadjusted P = 2.4 x 10(-3); adjusted P = 0.10]. For the paired sample analyzes, there were no differences in RBP4 (P = 0.09), total adiponectin (P = 0.06), HMW adiponectin (P =0.19), or HMW to total adiponectin ratio (P = 0.98). In PCOS cases, L4-visceral fat area was associated positively with RBP4 (r(2) = 0.34, P = 0.01) and negatively with HMW to total adiponectin ratio (r(2) = -0.44, P = 1.3 x 10(-3)). Controls showed similar relationships. CONCLUSIONS: Although associated with visceral fat, serum RBP4 and adiponectin levels do not play important, fat-mass-independent primary roles in the development of PCOS. PMID- 18445671 TI - Functional and structural consequences of a novel point mutation in the CYP21A2 gene causing congenital adrenal hyperplasia: potential relevance of helix C for P450 oxidoreductase-21-hydroxylase interaction. AB - BACKGROUND: Congenital adrenal hyperplasia is caused by insufficient adrenal steroid biosynthesis due to impaired steroidogenic enzymes. The majority of patients suffer from deficiency of 21-hydroxylase (CYP21) coded by the CYP21A2 gene. OBJECTIVE: Our objective was to study the functional and structural consequences of the novel CYP21A2 missense mutation c.364A > C (K121Q) detected in a female patient with nonclassical 21-hydroxylase deficiency. The patient was compound heterozygous for the novel K121Q mutation and the mild P453S mutation. RESULTS: In vitro expression analysis of the mutant K121Q enzyme in transiently transfected COS-7 cells revealed reduced CYP21 activity of 14.0 +/- 5% for the conversion of 17-hydroxyprogesterone and 19.5 +/- 4% for the conversion of progesterone. K121 is located on helix C in the CYP21 protein, which is part of the heme coordinating system. In addition, helix C is involved in the interaction with the electron-providing enzyme P450 oxidoreductase. Protein modeling revealed that the substitution of glutamine for the basic amino acid lysine introduces an electrostatic change on the surface of CYP21 and may additionally change heme coordination. We hypothesize that the electron flux between P450 oxidoreductase and CYP21 is impaired and, moreover, that substrate affinity is altered due to heme dislocation with K121Q. CONCLUSION: Both the interaction of P450 oxidoreductase and CYP21 as well as heme coordination are likely to be disturbed due to the K121Q mutation. Our data exemplify how the combination of in vitro expression and structural protein analysis provide novel insights into molecular mechanisms of reduced CYP21 activity, eventually explaining the patient's phenotype. PMID- 18445672 TI - Longitudinal study of thyroid function in children with mild hyperthyrotropinemia at neonatal screening for congenital hypothyroidism. AB - OBJECTIVE: Long-term outcome of thyroid function in children with very short lasting neonatal hyperthyrotropinemia ("false positive" at neonatal screening) was studied in an observational, prospective study. Thyroid function and morphology were evaluated in 44 "false positive" children up to advanced childhood (8.0 +/- 0.7 yr of age). In these children a high prevalence (50%) of subclinical hypothyroidism in early childhood (2.8 +/- 0.5 yr) had already been described. RESULTS: At an average of 5.3 yr, subclinical hypothyroidism persisted in 19 of 44 (43.2%) children and, more specifically, in two of three of those who had increased TSH in early childhood. Euthyroidism was present in all cases that were euthyroid in early childhood, although they had TSH and free T(3) values significantly higher than control children with a normal TSH at birth (TSH = 2.6 +/- 0.7 vs. 1.5 +/- 0.6 mU/liter, P < 0.001; free T(3) = 4.9 +/- 0.8 vs. 3.9 +/- 0.9 pmol/liter, P < 0.01). Thyroid morphology alterations were frequent in the group of children with subclinical hypothyroidism. At an average of 8.0 yr, subclinical hypothyroidism persisted in 14 of 44 (31.8%) children. In all other children, TSH and thyroid hormones were confirmed within the normal range. CONCLUSIONS: This prospective longitudinal study confirms that newborns "false positive" at neonatal screening have a high risk to develop persistent subclinical hypothyroidism. The prevalence of hypothyroidism decreases with increasing age, but it is still high (>30%) in late childhood. Even those "false positive" children that maintain euthyroidism in late childhood have an average TSH value that, although within the normal range, is higher than in normal controls, a possible marker of minor congenital thyroid function abnormalities. PMID- 18445673 TI - The relative role of gonadal sex steroids and gonadotropin-releasing hormone pulse frequency in the regulation of follicle-stimulating hormone secretion in men. AB - OBJECTIVE: Our objective was to determine the importance of testosterone (T), estradiol (E(2)), and GnRH pulse frequency to FSH regulation in men. DESIGN: This was a prospective study with four arms. SETTING: The study was performed at the General Clinical Research Center. PATIENTS OR OTHER PARTICIPANTS: There were 20 normal (NL) men and 15 men with idiopathic hypogonadotropic hypogonadism (IHH) who completed the study. INTERVENTION: Medical castration and inhibition of aromatase were achieved using ketoconazole x 7 d with: 1) no sex steroid addback, 2) T addback starting on d 4, and 3) E(2) addback starting on d 4. IHH men in these arms received GnRH every 120 min. In a further six IHH men receiving ketoconazole with no addback, GnRH frequency was increased to 35 min for d 4-7. Blood was drawn every 10 min x 12 h at baseline, overnight on d 3-4 and 6-7. MAIN OUTCOME MEASURES: Mean FSH was calculated from the pool of each frequent sampling study. RESULTS: In NL men FSH levels increased from 5.1 +/- 0.7 to 8.7 +/- 1.3 and 9.7 +/- 1.5 IU/liter (P < 0.0001). T caused no suppression of FSH. E(2) reduced FSH from 12.4 +/- 1.8 to 9.3 +/- 1.3 IU/liter (P < 0.05). In IHH men on GnRH every 120 min, FSH levels went from 6.0 +/- 1.6 to 9.0 +/- 3.0 and 11.9 +/- 4.3 (P = 0.07). T caused no suppression of FSH. E(2) decreased FSH such that levels on d 6-7 were similar to baseline. Increasing GnRH frequency to 35 min had no impact on FSH. CONCLUSIONS: The sex steroid component of FSH negative feedback in men is mediated by E(2). Increasing GnRH frequency to castrate levels has no impact on FSH in the absence of sex steroids. When inhibin B levels are NL, sex steroids exert a modest effect on FSH. PMID- 18445674 TI - Short- and long-term safety of weekly high-dose vitamin D3 supplementation in school children. AB - BACKGROUND: Hypovitaminosis D is prevalent in youth worldwide, but the safety of vitamin D at doses exceeding 200 IU/d is unknown in this age group. We assessed the safety of high doses of vitamin D(3) administered to apparently healthy schoolchildren. METHODS: To assess short-term safety, 25 subjects randomly received placebo or vitamin D(3) at doses of 14,000 IU/wk for 8 wk. To assess long-term safety, 340 subjects randomly received placebo, vitamin D(3) as 1,400 IU/wk or 14,000 IU/wk for 1 yr. Biochemical variables were monitored at 0, 2, 4, 6, and 8 wk and 8 wk off therapy in the short-term study and at 0, 6, and 12 months in the long-term study. RESULTS: In both the short- and long-term studies, mean serum calcium and 1,25-hydroxyvitamin levels did not change in any group. In the short-term study, mean 25-hydroxyvitamin concentrations increased from 44 (+/ 11) to 54 (+/- 19) ng/ml in the treated groups (P = 0.033). In the long-term study, mean 25-hydroxyvitamin D levels increased from 15 +/- 8 to 19 +/- 7 ng/ml (P < 0.0001) in subjects receiving 1,400 IU/wk and from 15 +/- 7 to 36 +/- 22 ng/ml (P < 0.0001) in the group receiving 14,000 IU/wk. No subject developed vitamin D intoxication. CONCLUSION: Vitamin D(3) at doses equivalent to 2000 IU/d for 1 yr is safe in adolescents and results in desirable vitamin D levels. PMID- 18445675 TI - A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism. AB - CONTEXT: LHX4 is a LIM homeodomain transcription factor involved in pituitary ontogenesis. Only a few heterozygous LHX4 mutations have been reported to be responsible for congenital pituitary hormone deficiency. SUBJECTS AND METHODS: A total of 136 patients with congenital hypopituitarism associated with malformations of brain structures, pituitary stalk, or posterior pituitary gland was screened for LHX4 mutations. RESULTS: Three novel allelic variants that cause predicted changes in the protein sequence of LHX4 (2.3%) were found (p.Thr99fs, p.Thr90Met, and p.Gly370Ser). On the basis of functional studies, p.Thr99fs mutation was responsible for the patients' phenotype, whereas p.Thr90Met and p.Gly370Ser were likely polymorphisms. Patients bearing the heterozygous p.Thr99fs mutation had variable phenotypes: two brothers presented somato lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the mutation induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. We also identified prolactin and GH promoters as potential target genes of LHX4 and found that the p.Thr99fs mutant was also unable to transactivate these promoters. CONCLUSIONS: The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities. PMID- 18445676 TI - Long-term cardiovascular effects of levothyroxine therapy in young adults with congenital hypothyroidism. AB - CONTEXT: Congenital hypothyroidism (CH) is the most prevalent endocrine disorder in the newborn and is routinely treated with life-long levothyroxine replacement therapy. Although several studies have demonstrated that such therapy may impact on the cardiovascular system, little is known with regard to the effects of long term levothyroxine administration in patients with CH. OBJECTIVE: The aim of the current study was to evaluate whether long-term levothyroxine replacement therapy in young adults with CH is associated with cardiovascular abnormalities. PATIENTS AND METHODS: Thirty young adults with CH aged 18.1 +/- 0.2 yr and 30 age- and sex matched controls underwent cardiac and carotid Doppler ultrasound and symptom limited cardiopulmonary exercise testing. Hypothyroidism was diagnosed by neonatal screening, and levothyroxine treatment was initiated within the first month of life and carefully adjusted to maintain TSH levels in the normal range and free T(4) in the high-normal range. RESULTS: Compared with controls, hypothyroid patients exhibited left ventricular diastolic dysfunction, impaired exercise capacity, and increased intima-media thickness. At multiple regression analysis, the number of episodes of plasma TSH levels less than 0.5 mU/liter and greater than 4.0 mU/liter from the age of 1 yr onward, and mean TSH plasma levels during puberty were independent predictors of diastolic filling and cardiopulmonary performance indexes (multiple r values: 0.61-0.75). CONCLUSIONS: Long-term levothyroxine treatment in young adults with congenital hypothyroidism is associated with impaired diastolic function and exercise capacity and increased intima-media thickness. PMID- 18445677 TI - The lack of the C-terminal domain of adipose triglyceride lipase causes neutral lipid storage disease through impaired interactions with lipid droplets. AB - CONTEXT: The molecular mechanisms by which triglycerides in lipid droplets (LDs) are synthesized, stored, and degraded need to be elucidated. OBJECTIVE: The objectives were to report siblings with neutral lipid storage disease with myopathy (NLSDM) with a novel mutation of adipose triglyceride lipase (ATGL) and determine whether the C-terminal part of ATGL containing the hydrophobic region plays a role in the interaction with LDs. DESIGN AND PATIENTS: Skin fibroblasts and peripheral blood leukocytes were obtained from NLSDM patients. In vitro experiments were performed with fibroblasts and COS7 cells. MAIN OUTCOME MEASURES: Transfection studies were used to assess the effects of various recombinant ATGL proteins on lipase activities and lipid contents. Fluorescence microscopy were used for determination of intracellular distribution of ATGL proteins. RESULTS: The direct sequence of ATGL cDNA reveals that a patient is a homozygote for the 4-bp deletion, leading to a premature stop codon and causes the lack of the C terminus of the protein including the hydrophobic domain. Overexpressed control ATGL in NLSDM fibroblasts was found around the rims of LDs and caused significantly reduced cellular lipid accumulation. In contrast, NLSDM ATGL was homogeneously located in the cytoplasm despite the presence of LDs and had almost no effect on LD degradation despite its similar lipase activity. A series of C-terminal truncated ATGLs without the intact hydrophobic domain failed to localize around and degrade LDs. CONCLUSIONS: These findings indicate that the domain including the hydrophobic region of ATGL was essential for association with LDs. PMID- 18445678 TI - Dnm1p-dependent peroxisome fission requires Caf4p, Mdv1p and Fis1p. AB - Yeast peroxisomes multiply by fission. Fission requires two dynamin-related proteins, Dnm1p and Vps1p. Using an in vivo fission assay, we show that Dnm1p dependent peroxisome fission requires Fis1p, Caf4p and Mdv1p. Fluorescence microscopy of cells expressing GFP-tagged Caf4p and Mdv1p revealed that their association with peroxisomes relies on Fis1p. Vps1p-dependent peroxisome fission occurs independently of these factors. Vps1p contributes most to fission of peroxisomes when cells are grown on glucose. Overexpression of Dnm1p suppresses the fission defect as long as Fis1p and either Mdv1p or Caf4p are present. Conversely, overexpression of Dnm1p does not restore the vacuolar fusion defect of vps1 cells and Vps1p overexpression does not restore the mitochondrial fission defect of dnm1 cells. These data show that Vps1p and Dnm1p are part of independent fission machineries. Because the contribution of Dnm1p to peroxisome fission appears to be more pronounced in cells that proliferate peroxisomes in response to mitochondrial dysfunction, Dnm1p might be part of the mechanism that coordinates mitochondrial and peroxisomal biogenesis. PMID- 18445679 TI - Ubiquitin-independent binding of Hrs mediates endosomal sorting of the interleukin-2 receptor beta-chain. AB - Several lines of evidence have revealed that ubiquitylation of membrane proteins serves as a signal for endosomal sorting into lysosomes or lytic vacuoles. The hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) interacts with ubiquitylated cargoes through its ubiquitin-interacting-motif domain (UIM domain), and plays an essential early role in endosomal sorting. Here, we show that the C-terminal region of Hrs, which does not contain the UIM domain, can bind to interleukin-2 receptor beta (IL-2Rbeta). We found a direct interaction between bacterially expressed IL-2Rbeta and Hrs in GST pull-down assays, indicating that their binding is independent of ubiquitin. Trafficking and degradation assays revealed that, similarly to wild-type IL-2Rbeta, an IL-2Rbeta mutant lacking all the cytoplasmic lysine residues is sorted from Hrs-positive early endosomes to LAMP1-positive late endosomes, resulting in degradation of the receptor. By contrast, an IL-2Rbeta mutant lacking the Hrs-binding region passes through early endosomes and is mis-sorted to compartments positive for the transferrin receptor. The latter mutant exhibits attenuated degradation. Taken together, these results indicate that precise sorting of IL-2Rbeta from early to late endosomes is mediated by Hrs, a known sorting component of the ubiquitin dependent machinery, in a manner that is independent of UIM-ubiquitin binding. PMID- 18445680 TI - Isoform B of myosin II heavy chain mediates actomyosin contractility during TNFalpha-induced apoptosis. AB - Cells that are treated long-term with TNFalpha or short-term with TGFalpha together with cycloheximide (CHX) undergo apoptosis. Cell shrinkage and detachment during apoptosis is dependent on actomyosin contractility. Myosin II heavy chain (MHCII) isoforms have shared and distinct functions. Here, we investigated whether the involvement of MHCII isoforms A and B (MHCIIA and MHCIIB, respectively) in cell shrinkage and detachment differs during apoptosis. We show that TNFalpha induces caspase-dependent MHCIIA degradation, whereas MHCIIB levels and association with the cytoskeleton remained virtually unchanged in TtT/GF cells and NIH 3T3 fibroblasts. MHCIIA proteolysis also occurred in fibroblasts that lack MHCIIB when treated with TNFalpha and CHX together. The absence of MHCIIB did not affect cell death rate. However, MHCIIB-/- cells showed more resistance to TNFalpha-induced actin disassembly, cell shrinkage and detachment than wild-type fibroblasts, indicating the participation of MHCIIB in these events. Moreover, inhibition of atypical PKCzeta, which targets MHCIIB but not MHCIIA, blocked TNFalpha-induced shrinkage and detachment in TtT/GF cells and wild-type fibroblasts, but the inhibitory effect was significantly reduced in MHCIIB-/- fibroblasts. TNFalpha treatment increased cytoskeleton-associated myosin light chain (MLC) phosphorylation but did not induce actin cleavage. In conclusion, our results demonstrate that MHCIIB, together with MLC phosphorylation and actin, constitute the actomyosin cytoskeleton that mediates contractility during apoptosis. PMID- 18445681 TI - Haemocyte-derived SPARC is required for collagen-IV-dependent stability of basal laminae in Drosophila embryos. AB - SPARC is an evolutionarily conserved collagen-binding extracellular matrix (ECM) glycoprotein whose morphogenetic contribution(s) to embryonic development remain elusive despite decades of research. We have therefore used Drosophila genetics to gain insight into the role of SPARC during embryogenesis. In Drosophila embryos, high levels of SPARC and other basal lamina components (such as network forming collagen IV, laminin and perlecan) are synthesized and secreted by haemocytes, and assembled into basal laminae. A SPARC mutant was generated by P element mutagenesis that is embryonic lethal because of multiple developmental defects. Whereas no differences in collagen IV immunostaining were observed in haemocytes between wild-type and SPARC-mutant embryos, collagen IV was not visible in basal laminae of SPARC-mutant embryos. In addition, the laminin network of SPARC-mutant embryos appeared fragmented and discontinuous by late embryogenesis. Transgenic expression of SPARC protein by haemocytes in SPARC mutant embryos restored collagen IV and laminin continuity in basal laminae. However, transgenic expression of SPARC by neural cells failed to rescue collagen IV in basal laminae, indicating that the presence of collagen IV deposition requires SPARC expression by haemocytes. Our previous finding that haemocyte derived SPARC protein levels are reduced in collagen-IV-mutant embryos and the observation that collagen-IV-mutant embryos showed a striking phenotypic similarity to SPARC-mutant embryos suggests a mutual dependence between these major basal laminae components during embryogenesis. Patterning defects and impaired condensation of the ventral nerve cord also resulted from the loss SPARC expression prior to haemocyte migration. Hence, SPARC is required for basal lamina maturation and condensation of the ventral nerve cord during Drosophila embryogenesis. PMID- 18445682 TI - BNIP2 extra long inhibits RhoA and cellular transformation by Lbc RhoGEF via its BCH domain. AB - Increased expression of BCH-motif-containing molecule at the C-terminal region 1 (BMCC1) correlates with a favourable prognosis in neuroblastoma, but the underlying mechanism remains unknown. We here isolated BNIPXL (BNIP2 Extra Long) as a single contig of the extended, in-vitro-assembled BMCC1. Here, we show that in addition to homophilic interactions, the BNIP2 and Cdc42GAP homology (BCH) domain of BNIPXL interacts with specific conformers of RhoA and also mediates association with the catalytic DH-PH domains of Lbc, a RhoA-specific guanine nucleotide exchange factor (RhoGEF). BNIPXL does not recognize the constitutive active G14V and Q63L mutants of RhoA but targets the fast-cycling F30L and the dominant-negative T19N mutants. A second region at the N-terminus of BNIPXL also targets the proline-rich region of Lbc. Whereas overexpression of BNIPXL reduces active RhoA levels, knockdown of BNIPXL expression has the reverse effect. Consequently, BNIPXL inhibits Lbc-induced oncogenic transformation. Interestingly, BNIPXL can also interact with RhoC, but not with RhoB. Given the importance of RhoA and RhoGEF signaling in tumorigenesis, BNIPXL could suppress cellular transformation by preventing sustained Rho activation in concert with restricting RhoA and Lbc binding via its BCH domain. This could provide a general mechanism for regulating RhoGEFs and their target GTPases. PMID- 18445683 TI - Fos cooperation with PTEN loss elicits keratoacanthoma not carcinoma, owing to p53/p21 WAF-induced differentiation triggered by GSK3beta inactivation and reduced AKT activity. AB - To investigate gene synergism in multistage skin carcinogenesis, the RU486 inducible cre/lox system was employed to ablate Pten function (K14.cre/Delta5Pten flx) in mouse epidermis expressing activated Fos (HK1.Fos). RU486-treated HK1.Fos/Delta5Pten flx mice exhibited hyperplasia, hyperkeratosis and tumours that progressed to highly differentiated keratoacanthomas, rather than to carcinomas, owing to re-expression of high p53 and p21 WAF levels. Despite elevated MAP kinase activity, cyclin D1 and cyclin E2 overexpression, and increased AKT activity that produced areas of highly proliferative papillomatous keratinocytes, increasing levels of GSK3beta inactivation induced a novel p53/p21 WAF expression profile, which subsequently halted proliferation and accelerated differentiation to give the hallmark keratosis of keratoacanthomas. A pivotal facet to this GSK3beta-triggered mechanism centred on increasing p53 expression in basal layer keratinocytes. This increase in expression reduced activated AKT expression and released inhibition of p21 WAF, which accelerated keratinocyte differentiation, as indicated by unique basal layer expression of differentiation specific keratin K1 alongside premature filaggrin and loricrin expression. Thus, Fos synergism with Pten loss elicited a benign tumour context where GSK3beta induced p53/p21 WAF expression continually switched AKT-associated proliferation into differentiation, preventing further progression. This putative compensatory mechanism required the critical availability of normal p53 and/or p21 WAF, otherwise deregulated Fos, Akt and Gsk3beta associate with malignant progression. PMID- 18445685 TI - PAI1 stimulates assembly of the fibronectin matrix in osteosarcoma cells through crosstalk between the alphavbeta5 and alpha5beta1 integrins. AB - The plasminogen activation system regulates matrix remodeling through both proteolytic and non-proteolytic mechanisms. Studies were undertaken to determine the effects of the plasminogen activator inhibitor 1 (PAI1) on the assembly of the fibronectin matrix. The addition of PAI1 to MG-63 cells caused a 1.5- to threefold increase in the rate of fibronectin matrix assembly which was associated with an increase in beta integrin activation. PAI1 treatment led to a marked decrease in focal contacts and stress fibers, whereas tensin-containing matrix contacts remained unaffected. The effects of PAI1 on matrix assembly were independent of both urokinase-type plasminogen activator (uPA) and urokinase-type plasminogen activator receptor (uPAR), indicating that the stimulation of matrix assembly by PAI1 does not depend on its anti-proteolytic activity or on the association of uPAR with integrin receptors. Antagonists of the alphavbeta5 integrin mimicked the effect of PAI1 on cell morphology and fibronectin matrix deposition, indicating that stimulation of matrix assembly by PAI1 required disruption of the interaction between the alphavbeta5 integrin and vitronectin. Consistent with this conclusion, the Q123K PAI1 mutant which does not bind vitronectin had no effect on matrix assembly. Our data identify PAI1 as a novel regulator of fibronectin matrix assembly, and indicate that this regulation occurs through a previously undescribed crosstalk between the alphavbeta5 and alpha5beta1 integrins. PMID- 18445686 TI - EML3 is a nuclear microtubule-binding protein required for the correct alignment of chromosomes in metaphase. AB - Assembly of the mitotic spindle requires a global change in the activity and constitution of the microtubule-binding-protein array at mitotic onset. An important subset of mitotic microtubule-binding proteins localises to the nucleus in interphase and essentially contributes to spindle formation and function after nuclear envelope breakdown. Here, we used a proteomic approach to selectively identify proteins of this category and revealed 50 poorly characterised human gene products, among them the echinoderm microtubule-associated-protein-like gene product, EML3. Indirect immunofluorescence showed that EML3 colocalises with spindle microtubules throughout all mitotic stages. In interphase, EML3 colocalised with cytoplasmic microtubules and accumulated in interphase nuclei. Using YFP-fusion constructs of EML3, we located a nuclear localisation signal and confirmed the microtubule-binding domain of EML3. Functional analysis of EML3 using time-lapse fluorescence microscopy and detailed end-point analysis of phenotypes after siRNA knockdown demonstrates an important role for EML3 in correct metaphase chromosome alignment. Our proteomic identification screen combined with sensitive phenotypic analysis therefore provides a reliable platform for the identification and characterisation of proteins important for correct cell division. PMID- 18445684 TI - Integrin clustering enables anandamide-induced Ca2+ signaling in endothelial cells via GPR55 by protection against CB1-receptor-triggered repression. AB - Although the endocannabinoid anandamide is frequently described to act predominantly in the cardiovascular system, the molecular mechanisms of its signaling remained unclear. In human endothelial cells, two receptors for anandamide were found, which were characterized as cannabinoid 1 receptor (CB1R; CNR1) and G-protein-coupled receptor 55 (GPR55). Both receptors trigger distinct signaling pathways. It crucially depends on the activation status of integrins which signaling cascade becomes promoted upon anandamide stimulation. Under conditions of inactive integrins, anandamide initiates CB1R-derived signaling, including Gi-protein-mediated activation of spleen tyrosine kinase (Syk), resulting in NFkappaB translocation. Furthermore, Syk inhibits phosphoinositide 3 kinase (PI3K) that represents a key protein in the transduction of GPR55 originated signaling. However, once integrins are clustered, CB1R splits from integrins and, thus, Syk cannot further inhibit GPR55-triggered signaling resulting in intracellular Ca2+ mobilization from the endoplasmic reticulum (ER) via a PI3K-Bmx-phospholipase C (PLC) pathway and activation of nuclear factor of activated T-cells. Altogether, these data demonstrate that the physiological effects of anandamide on endothelial cells depend on the status of integrin clustering. PMID- 18445687 TI - Interaction between the Drosophila heterochromatin proteins SUUR and HP1. AB - SUUR (Suppressor of Under-Replication) protein is responsible for late replication and, as a consequence, for DNA underreplication of intercalary and pericentric heterochromatin in Drosophila melanogaster polytene chromosomes. However, the mechanism by which SUUR slows down the replication process is not clear. To identify possible partners for SUUR we performed a yeast two-hybrid screen using full-length SUUR as bait. This identified HP1, the well-studied heterochromatin protein, as a strong SUUR interactor. Furthermore, we have determined that the central region of SUUR is necessary and sufficient for interaction with the C-terminal part of HP1, which contains the hinge and chromoshadow domains. In addition, recruitment of SUUR to ectopic HP1 sites on chromosomes provides evidence for their association in vivo. Indeed, we found that the distributions of SUUR and HP1 on polytene chromosomes are interdependent: both absence and overexpression of HP1 prevent SUUR from chromosomal binding, whereas SUUR overexpression causes redistribution of HP1 to numerous sites occupied by SUUR. Finally, HP1 binds to intercalary heterochromatin when histone methyltransferase activity of SU(VAR)3-9 is increased. We propose that interaction with HP1 is crucial for the association of SUUR with chromatin. PMID- 18445688 TI - A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites. AB - Chloroquine resistance in the malaria parasite Plasmodium falciparum has made malaria increasingly difficult to control. Chloroquine-resistant parasites accumulate less chloroquine than their chloroquine-sensitive counterparts; however, the mechanism underlying this remains unclear. The primary site of accumulation and antimalarial action of chloroquine is the internal acidic digestive vacuole of the parasite, the acidity of which is maintained by inwardly directed H+ pumps, working against the (outward) leak of H+. In this study we have investigated the leak of H+ from the digestive vacuole of the parasite by monitoring the alkalinisation of the vacuole following inhibition of the H+ pumping V-type ATPase by concanamycin A. The rates of alkalinisation observed in three chloroquine-resistant strains were two- to fourfold higher than those measured in three chloroquine-sensitive strains. On addition of chloroquine there was a dramatic increase in the rate of alkalinisation in the chloroquine resistant strains, whereas chloroquine caused the rate of alkalinisation to decrease in the chloroquine-sensitive strains. The chloroquine-associated increase in the rate of alkalinisation seen in chloroquine-resistant parasites was inhibited by the chloroquine-resistance reversal agent verapamil. The data are consistent with the hypothesis that in chloroquine-resistant parasites chloroquine effluxes from the digestive vacuole, in association with H+, via a verapamil-sensitive pathway. PMID- 18445689 TI - Paraffin-based 6-gene model predicts outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. AB - Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by variable clinical outcomes. Outcome prediction at the time of diagnosis is of paramount importance. Previously, we constructed a 6-gene model for outcome prediction of DLBCL patients treated with anthracycline-based chemotherapies. However, the standard therapy has evolved into rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Herein, we evaluated the predictive power of a paraffin-based 6-gene model in R-CHOP-treated DLBCL patients. RNA was successfully extracted from 132 formalin-fixed paraffin embedded (FFPE) specimens. Expression of the 6 genes comprising the model was measured and the mortality predictor score was calculated for each patient. The mortality predictor score divided patients into low-risk (below median) and high risk (above median) subgroups with significantly different overall survival (OS; P = .002) and progression-free survival (PFS; P = .038). The model also predicted OS and PFS when the mortality predictor score was considered as a continuous variable (P = .002 and .010, respectively) and was independent of the IPI for prediction of OS (P = .008). These findings demonstrate that the prognostic value of the 6-gene model remains significant in the era of R-CHOP treatment and that the model can be applied to routine FFPE tissue from initial diagnostic biopsies. PMID- 18445690 TI - Role of ephrinB2 expression in endothelial cells during arteriogenesis: impact on smooth muscle cell migration and monocyte recruitment. AB - Expression of the arterial marker molecule ephrinB2 in endothelial cells is a prerequisite for adequate remodeling processes of the developing or angiogenic vasculature. Although its role in these processes has been extensively studied, the impact of ephrinB2 on the remodeling of adult arteries is largely unknown. To this end, we analyzed its expression during a biomechanically induced arteriolar remodeling process known as arteriogenesis and noted a significant increase in ephrinB2 expression under these conditions. By examining those biomechanical forces presumed to drive arteriogenesis, we identified cyclic stretch as a critical inducer of ephrinB2 expression in endothelial cells. Subsequent functional analyses in vitro revealed that endothelial cells expressing ephrinB2 limit the migration of smooth muscle cells, thereby enhancing segregation of both cell types. Moreover, MCP-1 induced transmigration of monocytes through a monolayer of endothelial cells overexpressing a truncated variant of ephrinB2 was clearly impeded. Taken together, these data suggest that expression of ephrinB2 in adult endothelial cells is up-regulated during arterial remodeling and controlled by cyclic stretch, a well-known inducer of such processes. This stretch-induced ephrinB2 expression may be pivotal for arteriogenesis as it limits smooth muscle cell migration within defined borders and controls monocyte extravasation. PMID- 18445691 TI - Mesenchymal stem cells exert differential effects on alloantigen and virus specific T-cell responses. AB - Mesenchymal stem cells (MSCs) suppress alloantigen-induced T-cell functions in vitro and infusion of third-party MSCs seems to be a promising therapy for graft versus-host disease (GVHD). Little is known about the specificity of immunosuppression by MSCs, in particular the effect on immunity to pathogens. We have studied how MSCs affect T-cell responses specific to Epstein-Barr virus (EBV) and cytomegalovirus (CMV). We found that EBV- and CMV-induced proliferation and interferon-gamma (IFN-gamma) production from peripheral blood mononuclear cells (PBMCs) was less affected by third-party MSCs than the response to alloantigen and that MSCs had no effect on expansion of EBV and CMV pentamer specific T cells. Established EBV-specific cytotoxic T cells (CTL) or CMV-CTL cultured with MSCs retained the ability to proliferate and produce IFN-gamma in response to their cognate antigen and to kill virally infected targets. Finally, PBMCs from 2 patients who received MSCs for acute GVHD showed persistence of CMV specific T cells and retained IFN-gamma response to CMV after MSC infusion. In summary, MSCs have little effect on T-cell responses to EBV and CMV, which contrasts to their strong immunosuppressive effects on alloreactive T cells. These data have major implications for immunotherapy of GVHD with MSCs and suggest that the effector functions of virus-specific T cells may be retained after MSC infusion. PMID- 18445692 TI - Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. AB - PURPOSE: Prostate cancer risk is increased for men carrying a pathogenic germline mutation in BRCA2, and perhaps BRCA1. Our primary aim was to test for loss of heterozygosity (LOH) at the locus of the mutation in prostate cancers from men who a carry pathogenic germline mutation in BRCA1 or BRCA2, and to assess clinical and pathologic features of these tumors. EXPERIMENTAL DESIGN: From 1,243 kConFab families: (a) 215 families carried a pathogenic BRCA1 mutation, whereas 188 families carried a pathogenic BRCA2 mutation; (b) of the 158 men diagnosed with prostate cancer (from 137 families), 8 were confirmed to carry the family specific BRCA1 mutation, whereas 20 were confirmed to carry the family-specific BRCA2 mutation; and (c) 10 cases were eliminated from analysis because no archival material was available. The final cohort comprised 4 and 14 men with a BRCA1 and BRCA2 mutation, respectively. We examined LOH at the BRCA1 and BRCA2 genes using multiplex ligation-dependent probe amplification of DNA from microdissected tumor. RESULTS: LOH at BRCA2 was observed in 10 of 14 tumors from BRCA2 mutation carriers (71%), whereas no LOH at BRCA1 was observed in four tumors from BRCA1 mutation carriers (P = 0.02). Under the assumption that LOH occurs only because the cancer was caused by the germline mutation, carriers of BRCA2 mutations are at 3.5-fold (95% confidence interval, 1.8-12) increased risk of prostate cancer. A high Gleason was the only distinct clinical feature. CONCLUSIONS: These observations are consistent with the idea that BRCA2, but not BRCA1, is a tumor suppressor of prostate cancer. PMID- 18445693 TI - Translocations involving the immunoglobulin heavy chain gene locus predict better survival in gastric diffuse large B-cell lymphoma. AB - PURPOSE: The pathogenesis and clinical heterogeneity of gastric diffuse large B cell lymphoma (DLBCL) are poorly understood. We have comprehensively investigated the incidence and clinical significance of lymphoma-associated chromosomal translocations, particularly those involving the immunoglobulin heavy chain (IGH) gene locus, in a large series of gastric DLBCL. EXPERIMENTAL DESIGN: One hundred forty-one cases of primary gastric DLBCL [58 with mucosa-associated lymphoid tissue (MALT) lymphoma and 83 without MALT lymphoma] were enrolled. Translocations involving BCL6, c-MYC, FOXP1, MALT1, and IGH were investigated using interphase fluorescence in situ hybridization. In positive cases, additional fluorescence in situ hybridization was done with appropriate probes for potential partner genes. Cases were classified into germinal center B-cell like (GCB) or non-GCB subgroups by immunophenotyping with CD10, BCL6, and MUM1. RESULTS: Translocations involving IGH were detected in 36 (32%) of 111 cases; their partner genes included BCL6 (n = 10), c-MYC (n = 5), and FOXP1 (n = 3) but remained unknown in the remaining 18 cases. t(14;18)/IGH-BCL2, t(14;18)/IGH MALT1, and t(1;14)/BCL10-IGH were not detected in any case. t(11;18)/API2-MALT1 was detected in none of the cases, except for one case of DLBCL with MALT lymphoma, which showed positive signals only in MALT lymphoma cells. IGH-involved translocation was associated with younger age but not with any other clinicopathologic factors including GCB or non-GCB immunophenotypes. Cox multivariate analysis revealed that IGH-involved translocation, in addition to younger age and early stage, was an independent prognostic factor for better overall and EFSs. CONCLUSION: IGH-involved translocations are frequent in gastric DLBCL and seem to identify cases with favorable prognosis. PMID- 18445694 TI - Imaging bone and soft tissue tumors with the proliferation marker [18F]fluorodeoxythymidine. AB - PURPOSE: We have determined the ability of positron emission tomography (PET) with the thymidine analogue 3'-deoxy-3'[18F]fluorothymidine (FLT) to detect manifestation sites of bone and soft tissue tumors, to assess tumor grading, and to differentiate malignant from benign tumors. MATERIALS AND METHODS: In this prospective bicenter trial, FLT-PET was done in 22 patients with established or suspected soft or bone tissue lesions. Routine diagnostic procedures included incisional biopsy, magnetic resonance imaging, and/or contrast-enhanced spiral computed tomography in all patients and [18F]fluorodeoxyglucose (FDG)-PET in 15 patients. Forty-five to 60 minutes after i.v. injection of 350 to 425 MBq FLT, emission and transmission scanning was done. Tracer uptake in the tumor was evaluated semiquantitatively by calculation of mean and maximum standardized uptake values (FLT-SUV) and compared with respective values of FDG. Results were correlated to histopathology and tumor grading. RESULTS: FLT-PET detected all malignant bone or soft tissue tumors (17 of 17). Mean FLT-SUV in benign lesions was 0.7 (range, 0.3-1.3), and 1.3 in low-grade sarcoma (grade 1; range, 1.0-1.6), 4.1 (range, 2.2-6.0; P = 0.002) and 6.1 (range, 2.5-8.3; P = 0.001) in grade 2 and grade 3 tumors, respectively. FLT but not FDG uptake correlated significantly with tumor grading (r = 0.71 versus r = 0.01), and a cutoff value of 2.0 for FLT SUV discriminated between low- and high-grade tumors. CONCLUSION: In this clinical study, the proliferation marker FLT was suitable for imaging malignant bone or soft tissue tumors. FLT but not FDG uptake correlated significantly with the tumor grade, suggesting FLT as superior PET tracer for noninvasive grading of sarcomas. PMID- 18445695 TI - The choice of sample size: a mixed Bayesian / frequentist approach. AB - Sample size computations are largely based on frequentist or classical methods. In the Bayesian approach the prior information on the unknown parameters is taken into account. In this work we consider a fully Bayesian approach to the sample size determination problem which was introduced by Grundy et al. and developed by Lindley. This approach treats the problem as a decision problem and employs a utility function to find the optimal sample size of a trial. Furthermore, we assume that a regulatory authority, which is deciding on whether or not to grant a licence to a new treatment, uses a frequentist approach. We then find the optimal sample size for the trial by maximising the expected net benefit, which is the expected benefit of subsequent use of the new treatment minus the cost of the trial. PMID- 18445696 TI - Recursive estimation method for predicting residual bladder urine volumes to improve accuracy of timed urine collections. AB - Clinical research studies often collect data via repeated measurements of collected urine. Unfortunately, the accuracy of timed urine collections is limited by the presence of a residual volume of urine remaining in the bladder following each timed void due to incomplete emptying of the bladder. This residual urine volume adds significant imprecision to the urine collection method, rendering an important and fundamental clinical research tool inaccurate. We present an unbiased method to estimate the residual bladder volumes via a mathematical model of the bladder process. Regardless of the substance of primary interest, the model leverages conservation of mass and conservation of concentration principles towards a substance of secondary interest in order to solve a system of recursive equations, resulting in our Recursive Residual Estimation method to predict the residual volumes at each time point. We verify the model on simulated patients and also investigate the sensitivity of the model to initial value specification. PMID- 18445697 TI - Reducing the effects of lead-time bias, length bias and over-detection in evaluating screening mammography: a censored bivariate data approach. AB - Measuring the benefit of screening mammography is difficult due to lead-time bias, length bias and over-detection. We evaluated the benefit of screening mammography in reducing breast cancer mortality using observational data from the SEER-Medicare linked database. The conceptual model divided the disease duration into two phases: preclinical (T(0)) and symptomatic (T(1)) breast cancer. Censored information for the bivariate response vector ( T(0), T(1)) was observed and used to generate a likelihood function. However, the contribution to the likelihood function for some observations could not be calculated analytically, thus, censoring boundaries for these observations were modified. Inferences about the impact of screening mammography on breast cancer mortality were made based on maximum likelihood estimates derived from this likelihood function. Hazard ratios (95% confidence intervals) of 0.54 (0.48-0.61) and 0.33 (0.26- 0.42) for single and regular users (vs. non-users), respectively, demonstrated a protective effect of screening mammography among women 69 years and older. This method reduced the impact of lead-time bias, length bias and over-detection, which biased the estimated hazard ratios derived from standard survival models in favour of screening. PMID- 18445698 TI - A piecewise-constant Markov model and the effects of study design on the estimation of life expectancies in health and ill health. AB - Multi-state models are frequently applied to describe transitions over time between three states: healthy, not healthy and death. The three-state model can be used to estimate life expectancies in health and ill health. In this article, continuous-time Markov models are specified for the transitions between the three states. Transition intensities are regressed on age as a time-dependent covariate. The covariate is handled in a piecewise-constant fashion where the time interval between two consecutive observations is divided into subintervals of fixed and equal lengths. Study design choices such as sample size, length of follow-up, and time intervals between observations are investigated in a simulation study. The effects on parameter estimation are discussed as well as the effects on the estimation of life expectancies. In addition, data taken from the UK Cognitive Functioning and Ageing Study are analysed. PMID- 18445699 TI - A comparison of various rate functions of a recurrent event process in the presence of a terminal event. AB - Several different rate functions of the recurrent event process have been proposed for analysing recurrent event data when the observation of a study subject can be terminated by a failure event, such as death. When the terminal event is correlated with the underlying recurrent event process, these rate functions have different interpretations; however, recognition of the differences has been lacking theoretically and practically. In this article, we study the relationship between these rate functions and demonstrate that models based on an inappropriate rate function may lead to misleading scientific conclusions in various scenarios. An analysis of data from an AIDS clinical trial is presented to emphasise the importance of cautious model selection. PMID- 18445700 TI - Mitochondrial Bax translocation partially mediates synergistic cytotoxicity between histone deacetylase inhibitors and proteasome inhibitors in glioma cells. AB - The effects of combining histone deacetylase (HDAC) inhibitors and proteasome inhibitors were evaluated in both established glioblastoma multiforme (GBM) cell lines and short-term cultures derived from the Mayo Clinic xenograft GBM panel. Coexposure of LBH589 and bortezomib at minimally toxic doses of either drug alone resulted in a striking induction of apoptosis in established U251, U87, and D37 GBM cell lines, as well as in GBM8, GBM10, GBM12, GBM14, and GBM56 short-term cultured cell lines. Synergism of apoptosis induction was also observed in U251 cells when coexposing cells to other HDAC inhibitors, including LAQ824 and trichostatin A, with the proteasome inhibitor MG132, thus demonstrating a class effect. In U251 cells, bortezomib alone or in combination with LBH589 decreased Raf-1 levels and suppressed Akt and Erk activation. LBH589 or bortezomib alone increased expression of the cell cycle regulators p21 and p27. Additionally, the combination, but not the individual agents, markedly enhanced JNK activation. Synergistic induction of apoptosis after exposure to LBH589 and bortezomib was partially mediated by Bax translocation from the cytosol to the mitochondria resulting from Bax conformational changes. Bax translocation precedes cytochrome c release and apoptosis, and selective down-regulation of Bax using siRNA significantly mitigates the cytotoxicity of LBH589 and bortezomib. This combination regimen warrants further preclinical and possible clinical study for glioma patients. PMID- 18445701 TI - Muscle unloading-induced metabolic remodeling is associated with acute alterations in PPARdelta and UCP-3 expression. AB - A number of physiological changes follow prolonged skeletal muscle unloading as occurs in spaceflight, bed rest, and hindlimb suspension (HLS) and also in aging. These include muscle atrophy, fiber type switching, and loss of the ability to switch between lipid and glucose usage, or metabolic inflexibility. The signaling and genomic events that precede these physiological manifestations have not been investigated in detail, particularly in regard to loss of metabolic flexibility. Here we used gene arrays to determine the effects of 24-h HLS on metabolic remodeling in mouse muscle. Acute unloading resulted in differential expression of a number of transcripts in soleus and gastrocnemius muscle, including many involved in lipid and glucose metabolism. These include the peroxisome proliferator-activated receptors (PPARs). In contrast to Ppar-alpha and Ppar gamma, which were downregulated by acute HLS, Ppar-delta was upregulated concomitant with increased expression of its downstream target, uncoupling protein-3 (Ucp-3). However, differential expression of Ppar-delta was both acute and transient in nature, suggesting that regulation of PPARdelta may represent an adaptive, compensatory response aimed at regulating fuel utilization and maintaining metabolic flexibility. PMID- 18445703 TI - Recommendations or mere prose? PMID- 18445704 TI - Relationship of in-hospital medication modifications of elderly patients to postdischarge medications, adherence, and mortality. AB - BACKGROUND: Medication regimens are constantly modified and updated during a patient's hospitalization. These modifications and those made after discharge might increase the risk for nonadherence, polypharmacy, and poor outcomes among elderly patients. OBJECTIVES: To investigate the extent of in-hospital modification of medication regimens of elderly patients and its relationship to medication adherence as well as one-month postdischarge drug regimen modifications and to examine the relationship of the modifications, adherence, and polypharmacy to mortality and readmissions 3 months postdischarge. METHODS: Clinical and demographic data, postdischarge medication modifications, and adherence were prospectively obtained in 212 elderly patients. Inhospital drug regimen modifications were retrospectively recorded. RESULTS: The average +/- SD in-hospital medication regimen modification rate was 49.8% +/- 28.4. No modifications were found in 9.7% of the patients. Using demographic and clinical parameters, we performed regression analysis and found that patients who were admitted with polypharmacy, discharged home, and cognitively normal experienced fewer medication modifications (p < 0.05). At one month postdischarge, the average medication regimen modification rate was 37.5% +/- 25.4. In- and posthospital modifications were directly correlated (p = 0.047). Three months postdischarge, 17 patients had died and 50 had been readmitted. The independent risk factors for mortality were in-hospital modification rate of 50% or greater (OR 6.4; 95% CI 1.3 to 29.7), impaired cognition (OR 4.2; 95% CI 1.4 to 12.3), and each chronic disease (OR 1.2; 95% CI 1 to 1.5). No relationships were found between in-hospital medication regimen modifications and readmissions or with postdischarge modifications, adherence, and polypharmacy to mortality and readmissions. CONCLUSIONS: Hospitalization of elderly patients is characterized by extensive medication regimen modifications, which are directly correlated with postdischarge modifications and may indicate an increased risk of mortality. PMID- 18445702 TI - The in vivo gene expression signature of oxidative stress. AB - How higher organisms respond to elevated oxidative stress in vivo is poorly understood. Therefore, we measured oxidative stress parameters and gene expression alterations (Affymetrix arrays) in the liver caused by elevated reactive oxygen species induced in vivo by diquat or by genetic ablation of the major antioxidant enzymes CuZn-superoxide dismutase (Sod1) and glutathione peroxidase-1 (Gpx1). Diquat (50 mg/kg) treatment resulted in a significant increase in oxidative damage within 3-6 h in wild-type mice without any lethality. In contrast, treatment of Sod1(-/-) or Gpx1(-/-) mice with a similar concentration of diquat resulted in a significant increase in oxidative damage within an hour of treatment and was lethal, i.e., these mice are extremely sensitive to the oxidative stress generated by diquat. The expression response to elevated oxidative stress in vivo does not involve an upregulation of classic antioxidant genes, although long-term oxidative stress in Sod1(-/-) mice leads to a significant upregulation of thiol antioxidants (e.g., Mt1, Srxn1, Gclc, Txnrd1), which appears to be mediated by the redox-sensitive transcription factor Nrf2. The main finding of our study is that the common response to elevated oxidative stress with diquat treatment in wild-type, Gpx1(-/-), and Sod1(-/-) mice and in untreated Sod1(-/-) mice is an upregulation of p53 target genes (p21, Gdf15, Plk3, Atf3, Trp53inp1, Ddit4, Gadd45a, Btg2, Ndrg1). A retrospective comparison with previous studies shows that induction of these p53 target genes is a conserved expression response to oxidative stress, in vivo and in vitro, in different species and different cells/organs. PMID- 18445705 TI - Etravirine has no effect on QT and corrected QT interval in HIV-negative volunteers. AB - BACKGROUND: Etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, has shown antiviral efficacy in 2 large Phase 3 trials. In vitro and in vivo studies have shown that etravirine is not associated with proarrhythmic potential. Electrocardiograms (ECGs) from healthy and HIV 1 infected volunteers showed no clinically relevant changes. OBJECTIVE: To evaluate the effect of 2 etravirine dosing regimens on QT/corrected QT interval (QTc) in HIV-negative volunteers and assess pharmacokinetic and additional safety parameters. METHODS: A double-blind, double-dummy, randomized, placebo- and active-controlled, 4-period crossover trial was conducted in 41 HIV-negative volunteers. Participants received 4 regimens: etravirine 200 mg twice daily, etravirine 400 mg once daily, moxifloxacin 400 mg once daily (positive control), and placebo in separate 8-day sessions, with each followed by a washout period of 14 or more days. On days -1, 1, and 8 of each session, ECGs were recorded at 11 time points over 12 hours. Pharmacokinetic profiles of etravirine regimens were evaluated and safety was assessed. RESULTS: Thirty-seven subjects completed the study. For etravirine, the upper limit of the 90% CIs of mean time-matched differences in QTc determined using Fridericia's formula (QTcF) was below 10 msec at all time points, the threshold for prolonged QT as defined by regulatory guidelines. The maximum mean (90% CI) difference of time-matched changes in QTcF versus placebo on day 1 was +0.1 msec (-2.6 to 2.9), -0.2 msec (-2.6 to 2.1), and +10.1 msec (7.3 to 12.8) for etravirine 200 mg twice daily, etravirine 400 mg once daily, and moxifloxacin, respectively. On day 8, these values were +0.6 msec (-2.1 to 3.3), -1.0 msec (-4.4 to 2.5), and +10.3 msec (6.8 to 13.9), respectively. Etravirine produced no clinically significant changes in other ECG parameters. No significant differences between males and females were observed. Both etravirine regimens had similar pharmacokinetic exposure and safety profiles. CONCLUSIONS: Etravirine does not prolong the QTc interval. No clinically relevant ECG changes were observed in HIV-negative volunteers. Short term dosing of etravirine in HIV-negative volunteers was generally safe and well tolerated. PMID- 18445706 TI - Heart failure worsening and exacerbation after venlafaxine and duloxetine therapy. AB - OBJECTIVE: To report 2 cases of worsened heart failure (HF) after the introduction of venlafaxine or duloxetine therapy in patients with previously stable disease. CASE SUMMARIES: Two patients, a 39-year-old female and a 68-year old male, both diagnosed with HF of left ventricular systolic dysfunction, had worsening symptoms in the presence of the serotonin and norepinephrine reuptake inhibitors (SNRIs) venlafaxine 75 mg twice daily and/or duloxetine 30-60 mg/day. Both patients developed tachycardia, which remitted after the discontinuation of these agents. The woman was rechallenged with duloxetine 60 mg daily after her HF worsened with venlafaxine, only to have the tachycardia and HF symptoms return. Other iatrogenic causes and metabolic disturbances (eg, anemia) were ruled out. DISCUSSION: Increased levels of norepinephrine secondary to reuptake inhibition may be potentially deleterious in patients with chronic HF of left ventricular dysfunction owing to the "progressive HF model" and neurohormonal compensatory responses. Use of the Naranjo probability scale showed a probable relationship between venlafaxine/duloxetine use and these adverse outcomes. Venlafaxine and duloxetine were discontinued. CONCLUSIONS: Use of drugs that increase serum norepinephrine levels, such as the SNRIs, may be potentially deleterious in individuals with unstable or advanced HF. These medications should be avoided or used with caution and monitored regularly in this patient population. PMID- 18445707 TI - Frequency of medication errors with intravenous acetylcysteine for acetaminophen overdose. AB - BACKGROUND: Acetadote, an intravenous preparation of acetylcysteine, became commercially available in the US in June 2004 for the treatment of acetaminophen poisoning. The dosing regimen is complex, consisting of a loading dose followed by 2 maintenance doses, each with different infusion rates. OBJECTIVE: To analyze the frequency of medication errors related to the complex dosing regimen for intravenous acetylcysteine. METHODS: A retrospective chart review of a regional poison center's records was performed for all patients treated with intravenous acetylcysteine from August 1, 2006, to August 31, 2007. Data collected included acetylcysteine dose, infusion rate, interruptions in therapy, unnecessary administration, and medical outcome. Records that revealed medication errors were further examined for the time and location of the errors. RESULTS: There were 221 acetaminophen overdose cases treated with intravenous acetylcysteine that met inclusion criteria. Of these, 84 medication errors occurred in 74 (33%) patients. The frequency and types of errors were 1.4% incorrect dose, 5% incorrect infusion rate, 18.6% more than 1 hour of interruption in therapy, and 13.1% unnecessary administration. The frequency and types of medication errors in pediatric patients were similar to those in the total patient population. Errors occurred most frequently in the emergency department compared with intensive care units or general medical floors. In addition, errors occurred most frequently on third shift, compared with first or second shift. Evaluation of medical outcomes in cases involving acetaminophen only found that medication errors did not have an impact on coded outcomes. CONCLUSIONS: Medication administration errors occur frequently with intravenous acetylcysteine. Awareness of this problem, coupled with increased vigilance in identifying factors associated with errors, should decrease medication errors with intravenous acetylcysteine therapy for acetaminophen poisoning. PMID- 18445708 TI - Novel interaction of the dopamine D2 receptor and the Ca2+ binding protein S100B: role in D2 receptor function. AB - S100B is a calcium-binding protein with both extracellular and intracellular regulatory activities in the mammalian brain. We have identified a novel interaction between S100B and the dopamine D(2) receptor. Our results also suggest that the binding of S100B to the dopamine D(2) receptor enhances receptor signaling. This conclusion is based on the following observations: 1) S100B and the third cytoplasmic loop of the dopamine D(2) receptor interact in a bacterial two-hybrid system and in a poly-histidine pull-down assay; 2) immunoprecipitation of the D(2) receptor also precipitates FLAG-S100B from human embryonic kidney 293 cell homogenates and endogenous S100B from rat neostriatal homogenates; 3) S100B immunoreactivity was detected in cultured neostriatal neurons expressing the D(2) receptor; 4) a putative S100B binding motif is located at residues 233 to 240 of the D(2) receptor, toward the amino terminus of the third cytoplasmic loop. D(3) IC3, which does not bind S100B, does not contain this motif; and 5) coexpression of S100B in D(2) receptor-expressing 293 cells selectively increased D(2) receptor stimulation of extracellular signal-regulated kinases and inhibition of adenylate cyclase. PMID- 18445710 TI - Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. AB - Nicotine can enhance working memory and attention. Activation of both alpha7 and beta2(*) nicotinic acetylcholine receptors (nAChRs) in the prefrontal cortex (PFC) has been implicated in these processes. The ability of presynaptic nAChRs to modulate neurotransmitter release, notably glutamate release, is postulated to contribute to nicotine's effects. We have examined the cellular mechanisms underlying alpha7 and beta2(*) nAChR-mediated [(3)H]d-aspartate release from the PFC in vitro. Using the alpha7 and beta2(*) nAChR-selective agonists (R)-N-(1 azabicyclo[2.2.2]-oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A) and 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380), respectively, in conjunction with inhibitors of voltage-operated Ca(2+) channels (VOCCs) and intracellular Ca(2+) stores, we show that [(3)H]d-aspartate release evoked by activation of beta2(*) nAChRs occurs via VOCCs. In contrast, alpha7 nAChR-evoked release was unaffected by VOCC blockers but was abolished by modulators of Ca(2+) stores, including ryanodine. The alpha7 nAChR ligand alpha-bungarotoxin and ryanodine receptors were colocalized to a subpopulation of PFC synaptosomes. Compound A-evoked [(3)H]d-aspartate release was also blocked by mitogen-activated protein kinase kinase 1 inhibitors, implicating extracellular signal-regulated kinase (ERK)1/2 in alpha7 nAChR-evoked exocytosis. Western blotting confirmed that compound A, but not 5-iodo-A-85380, application increased ERK2 phosphorylation in PFC synaptosomes, and this was dependent on ryanodine sensitive stores. Compound A also promoted synapsin-1 phosphorylation at ERK1/2 dependent sites, in a ryanodine-sensitive manner. Thus, beta2(*) and alpha7 nAChR subtypes in the PFC mediate [(3)H]d-aspartate release via distinct mechanisms as a result of their differential coupling to VOCCs and Ca(2+)-induced Ca(2+) release (CICR), respectively. The ability of alpha7 nAChRs to promote the phosphorylation of presynaptic ERK2 and synapsin-1, downstream of CICR, provides a potential mechanism for presynaptic facilitation in the PFC. PMID- 18445711 TI - Psoriatic exacerbation associated with insulin therapy. PMID- 18445709 TI - Postsynaptic density-95 (PSD-95) and calcineurin control the sensitivity of N methyl-D-aspartate receptors to calpain cleavage in cortical neurons. AB - The N-methyl-D-aspartate receptor (NMDAR) is a Ca(2+)-permeable glutamate receptor mediating many neuronal functions under normal and pathological conditions. Ca(2+) influx via NMDARs activates diverse intracellular targets, including Ca(2+)-dependent protease calpain. Biochemical studies suggest that NR2A and NR2B subunits of NMDARs are substrates of calpain. Our physiological data showed that calpain, activated by prolonged NMDA treatment (100 microM, 5 min) of cultured cortical neurons, irreversibly decreased the whole-cell currents mediated by extrasynaptic NMDARs. Animals exposed to transient forebrain ischemia, a condition that activates calpain, exhibited the reduced NMDAR current density and the lower full-length NR2A/B level in a calpain-dependent manner. Disruption of the association between NMDARs and the scaffolding protein postsynaptic density (PSD)-95 facilitated the calpain regulation of synaptic NMDAR responses and NR2 cleavage in cortical slices, whereas inhibition of calcineurin activity blocked the calpain effect on NMDAR currents and NR2 cleavage. Calpain-cleaved NR2B subunits were removed from the cell surface. Moreover, cell viability assays showed that calpain, by targeting NMDARs, provided a negative feedback to dampen neuronal excitability in excitotoxic conditions. These data suggest that calpain activation suppresses NMDAR function via proteolytic cleavage of NR2 subunits in vitro and in vivo, and the susceptibility of NMDARs to calpain cleavage is controlled by PSD-95 and calcineurin. PMID- 18445712 TI - Early subclinical atherosclerosis in women with previous gestational diabetes mellitus. PMID- 18445713 TI - Effect of fluoride-containing tubes on accuracy of glucometers. PMID- 18445714 TI - Cost-effectiveness of screening for pre-diabetes among overweight and obese U.S. adults: response to Hoerger et al. PMID- 18445716 TI - Mediterranean diet inversely associated with the incidence of metabolic syndrome: the SUN Prospective Cohort: response to Tortosa et al. PMID- 18445718 TI - Pancreatic fat content and beta-cell function in men with and without type 2 diabetes: response to Tushuizen et al. PMID- 18445720 TI - Impact of autonomic neuropathy on left ventricular function in normotensive type 1 diabetic patients: a tissue Doppler echocardiographic study: response to Karamitsos et al. PMID- 18445722 TI - Should nonalcoholic fatty liver disease be included in the definition of metabolic syndrome? A cross-sectional comparison with adult treatment panel III criteria in nonobese nondiabetic subjects: response to Musso et al. PMID- 18445724 TI - Standards of Medical Care in Diabetes--2008: response to Hirsch, Inzucchi, and Kirkman. PMID- 18445726 TI - Coffee consumption is associated with higher plasma adiponectin concentrations in women with or without type 2 diabetes: response to Williams et al. PMID- 18445728 TI - Where is the patient in diabetes performance measures? The case for including patient-centered and self-management measures. AB - OBJECTIVE: Health policies are important determinants of clinician and patient behavior, and an important policy issue is what items are included in healthcare quality and performance measures. There is consensus that patient-centered care and self-management support are essential evidence-based components of good diabetes care. However, most major diabetes performance measures such as the National Committee for Quality Assurance (NCQA)/American Diabetes Association (ADA) Provider Recognition Program indexes have not included self-management or psychosocial items. RESEARCH DESIGN AND METHODS AND RESULTS: We review the case for and propose a set of patient-centered, self-management indicators to be included as a standard part of diabetes quality indicators. The proposed indicators include: patient self-management goal(s), measures of health behaviors (e.g., healthy eating, medication taking, physical activity, and smoking status), quality of life, and patient-centered collaborative care. We discuss the evidence and the concerns about patient-report measures and summarize successful incorporation of such patient-centered measures in other countries and by the American Association of Diabetes Educators (AADE). CONCLUSIONS: The adage that "what gets measured, gets done" applies to diabetes management and many other areas of healthcare. Inclusion of the proposed indicators in national diabetes performance measures would be consistent with Institute of Medicine (IOM), ADA, Centers for Disease Control (CDC), Diabetes Attitudes, Wishes, and Needs (DAWN), AADE, and Society of Behavioral Medicine (SBM) recommendations. Such action would enhance both the priority and delivery of quality, patient-centered care, and diabetes self-management support. PMID- 18445729 TI - Cure, care, and commitment: what can we look forward to? PMID- 18445731 TI - Diabetic retinopathy. PMID- 18445733 TI - Associative learning of pictures and words by low-functioning children with autism. AB - This research investigates whether children with autism learn picture, word and object relations as associative pairs or whether they understand such relations as referential. In Experiment 1, children were taught a new word (e.g. ;whisk') repeatedly paired with a novel picture. When given the picture and a previously unseen real whisk and asked to indicate a whisk, children with autism, unlike typically developing peers matched on receptive language, associated the word with the picture rather than the object. Subsequent experiments respectively confirmed that neither a bias for selecting pictures nor perseverative responding accounted for these results. Taken together, these results suggest that children with autism with cognitive difficulties are learning picture-word and picture object relations via an associative mechanism and have difficulty understanding the symbolic nature of pictures. PMID- 18445732 TI - Screening for diabetes. PMID- 18445734 TI - Brief report: inhibition of return in young people with autism and Asperger's disorder. AB - The aim of this study was to investigate whether the superior search abilities observed in autism/Asperger's disorder may in part be a consequence of a more pronounced inhibition of return (IOR). Contrary to our prediction, IOR in individuals with autism was comparable to the matched comparison group. However, the autism group committed more false alarm responses than the matched comparison group; this may reflect a possible inhibitory deficit, or suggest that individuals with autism rely more on probabilities to determine their behavioural responses. There was a borderline-significant trend (p=0.052) to indicate that IOR may be more pronounced in individuals with Asperger's disorder. In contrast to the autism group, the Asperger's disorder group had a pattern of false alarm responses similar to that of the comparison group. The findings further inform Minshew's complex information processing theory which seeks to establish which areas of neuropsychological functioning are preserved and deficit in autism. PMID- 18445730 TI - Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. PMID- 18445735 TI - Recognition of biological motion in children with autistic spectrum disorders. AB - It is widely accepted that autistic children experience difficulties in processing and recognizing emotions. Most relevant studies have explored the perception of faces. However, context and bodily gestures are also sources from which we derive emotional meanings. We tested 23 autistic children and 23 typically developing control children on their ability to recognize point-light displays of a person's actions, subjective states and emotions. In a control task, children had to recognize point-light displays of everyday objects. The children with autism only differed from the control children in their ability to name the emotional point-light displays. This suggests that children with autism can extract complex meanings from bodily movements but may be less sensitive to higher-order emotional information conveyed by human movement. The results are discussed in the context of a specific deficit in emotion perception in children with autism. PMID- 18445736 TI - A comparison of contexts for assessing joint attention in toddlers on the autism spectrum. AB - Children on the autism spectrum often demonstrate atypical joint attention, leading some researchers to consider joint attention deficits a core feature of the autism spectrum. Structured measures, such as the Early Social Communication Scales (ESCS), are commonly used to provide a metric of joint attention. To explore the assessment of joint attention in multiple contexts, we implemented an alternative system for coding joint attention behaviors. We compared initiation of joint attention (IJA) and response to joint attention (RJA) behaviors coded from naturalistic examiner-child play samples with similar IJA and RJA behaviors elicited within the structured ESCS protocol. Participants were 20 toddlers on the autism spectrum. Levels of IJA and RJA within the two assessment contexts were significantly and positively correlated, providing support for the use of naturalistic sampling of joint attention skills as a viable alternative, or supplement, to structured measures. PMID- 18445737 TI - Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. AB - The present study was performed to determine whether acetaminophen (paracetamol) use after the measles-mumps-rubella vaccination could be associated with autistic disorder. This case-control study used the results of an online parental survey conducted from 16 July 2005 to 30 January 2006, consisting of 83 children with autistic disorder and 80 control children. Acetaminophen use after measles-mumps rubella vaccination was significantly associated with autistic disorder when considering children 5 years of age or less (OR 6.11, 95% CI 1.42-26.3), after limiting cases to children with regression in development (OR 3.97, 95% CI 1.11 14.3), and when considering only children who had post-vaccination sequelae (OR 8.23, 95% CI 1.56-43.3), adjusting for age, gender, mother's ethnicity, and the presence of illness concurrent with measles-mumps-rubella vaccination. Ibuprofen use after measles-mumps-rubella vaccination was not associated with autistic disorder. This preliminary study found that acetaminophen use after measles-mumps rubella vaccination was associated with autistic disorder. PMID- 18445738 TI - Parents' perceptions of communication with professionals during the diagnosis of autism. AB - In order to obtain the views of parents concerning their perceptions of the process of getting a diagnosis of an autistic spectrum disorder (ASD) for their child, 15 focus groups were conducted across a range of locations in England. These groups were split into parents of preschool-, primary- and secondary-aged children who had recently received an ASD diagnosis. At the time of diagnosis, most of the parents wished for a quicker and easier process. In particular, they would prefer the procedure to have a more coherent structure and content. They also requested greater professional training about ASD, in particular, regarding the information that professionals possess, and the interpersonal skills of some professionals. The idea of broad information sheets to be provided to parents at the time of diagnosis would be of value, especially to combat negative information provided from other sources. PMID- 18445740 TI - Imaging of mild cognitive impairment and early dementia. AB - The concept of mild cognitive impairment (MCI) has been introduced to describe older individuals who cognitively lie between normal ageing and dementia. Nowadays, there is a particular interest in MCI because this syndrome is thought to be a transitional stage to Alzheimer's disease (AD) that may define a window for effective therapeutic interventions. However, not all patients with MCI will go on to develop AD. Imaging offers an extraordinary opportunity to study MCI. We will review key findings of brain imaging studies in MCI, including structural brain changes studied with MRI, white matter changes with diffusion tensor imaging and altered brain activity and blood flow studied with various imaging modalities, such as positron emission tomography, single-photon emission computed tomography and arterial spin labelling MRI, a non-invasive approach to measure cerebral blood flow. The strength and limitations of each modality for diagnosis of MCI, prediction of MCI outcome and assessment of drug efficacy will be discussed. PMID- 18445739 TI - Exploring implementation and fidelity of evidence-based behavioral interventions for HIV prevention: lessons learned from the focus on kids diffusion case study. AB - Evidence-based interventions (EBIs) are used in public health to prevent HIV infection among youth and other groups. EBIs include core elements, features that are thought to be responsible for the efficacy of interventions. The authors evaluate experiences of organizations that adopted an HIV-prevention EBI, Focus on Kids (FOK), and their fidelity to the intervention's eight core elements. A cross-sectional telephone survey was administered to 34 staff members from organizations that had previously implemented FOK. Questions assessed how the organization adhered to, adapted, dropped, or altered the intervention. None of the organizations implemented all eight core elements. This study underscores the importance for HIV intervention researchers to clearly identify and describe core elements. More effort is needed to reflect the constraints practitioners face in nonresearch settings. To ensure intervention effectiveness, additional research and technical assistance are needed to help organizations implement HIV prevention EBIs with fidelity. PMID- 18445741 TI - White matter changes in dementia: does radiology matter? AB - White matter changes are frequently seen on MRI in elderly patients. The significance of these changes is still debated. The origin of white matter changes is heterogeneous but the majority are due to arteriosclerosis in brain vessels. The clinical consequence of the presence of white matter changes in relation to dementia is still unclear. Lately, however, many studies have found a relation between the presence and the degree of white matter changes and cognitive dysfunction. This is most obvious in vascular dementia, but has also been suggested to be of importance in Alzheimer's disease. In this review we discuss the background of these changes and the clinical consequences of them in relation to cognitive disorders. PMID- 18445742 TI - Cerebrovascular disease and dementia. AB - Cerebrovascular disease is a major contributor to later-life dementia, accounting for up to 20% of cases of dementia. Atherosclerotic and arteriolosclerotic mechanisms account for most of the burden of disease. Cerebrovascular disease may take several forms. Macrovascular disease in the form of large vessel and larger arteriole infarcts produce a wide spectrum of clinical syndromes. Single strategic infarctions, multiple bilateral infarctions and multiple lacunar infarctions can lead to cognitive dysfunction that spans a large range of both severity and type of cognitive deficits. Microvascular disease almost certainly plays a role in the pathogenesis of dementia. Small vessel disease, which is not evident radiographically, often coexists with macrovascular disease and also with Alzheimer's disease. Amyloid angiopathy is relevant in cognitive disorders in the elderly and causes microhaemorrhages and large haemorrhages. Other much less common aetiologies include vasculitides and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Neuroimaging plays a critical role in the diagnosis of vascular dementia. There is no framework for rating the extent of cerebrovascular pathology that is validated against increasing cognitive impairment. Although advances in imaging have increased our recognition of cerebrovascular disease in the elderly, vascular dementia is still inadequately recognized in clinical practice. PMID- 18445743 TI - Biomarkers of cerebrovascular disease in dementia. AB - There is increasing recognition that cerebrovascular disease contributes significantly to the development and progression of patients with dementia. The concepts of pure vascular and pure degenerative dementia have been replaced with a recognition that, in many patients, there is a spectrum of neurodegenerative and vascular processes. This is supported by preliminary studies showing response to vascular therapeutics and ventriculo-peritoneal shunting in patients with Alzheimer's disease. This article examines the imaging biomarkers that are available for the characterization of microvascular abnormality in the ageing brain, with particular reference to microvascular angiopathy, cerebral embolic disease, orthostatic hypotension and abnormalities of Monro-Kellie homeostasis. PMID- 18445744 TI - 1H magnetic resonance spectroscopy in dementia. AB - Present data support the concept that (1)H magnetic resonance spectroscopy ((1)H MRS) may become an adjunct to clinical evaluation for differential diagnosis of dementia in the future. The value of (1)H MRS in monitoring the disease progression in dementia is expected to be in areas where group effects are sought such as monitoring effectiveness of therapies in drug trials. Elevation of myoinositol to creatine (mI/Cr) and choline to creatine (Cho/Cr) and reduction in the neuronal integrity marker N-acetylaspartate to creatine (NAA/Cr) levels in individuals with mild cognitive impairment and pre-symptomatic Alzheimer's disease suggests that (1)H MRS may also be valuable in predicting future development of dementia and monitoring early disease progression for preventive therapies. Investigations of in vivo (1)H MRS as a marker for differential diagnosis and progression of dementia, however, has been limited to clinically confirmed cohorts and remains to be validated by histopathology at autopsy. Overall, MRS is a promising investigational technique in ageing and dementia at this time. The potential clinical application of MRS in ageing and dementia, however, is growing with technical advances in the field. PMID- 18445745 TI - SPECT imaging in dementia. AB - Single photon emission computed tomography (SPECT) is a non-invasive functional neuroimaging technique that can be used in the diagnosis of dementia. This review describes some of the SPECT radiotracers available for imaging dementia patients and discusses recommendations for the clinical use of this imaging technique. PMID- 18445746 TI - Positron emission tomography imaging in dementia. AB - Positron emission tomography (PET) is a well-established imaging modality. Measurement of regional cerebral glucose metabolism (rCMR(glc)) using PET and [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) has become a standard technique in both oncology and dementia research. When measuring rCMR(glc) in Alzheimer's disease (AD), characteristic reductions in rCMR(glc) are found in neocortical association areas including the posterior cingulate, precuneus, temporoparietal and frontal multimodal association regions; the primary visual cortex, sensorimotor cortex, basal ganglia and cerebellum are relatively unaffected. FDG-PET has been used in the study of mild cognitive impairment (MCI) to accurately predict the subsequent decline to AD. Impairment in rCMR(glc) may be seen in individuals at high genetic risk of AD, even before clinical symptoms are apparent. Characteristic patterns of regional hypometabolism are also seen in other degenerative dementias such as frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). The use of different radioisotopes and tracers increases the versatility of PET. Tracers adopted in dementia research include (11)C-PK-11195 and (11)C-PIB, which have been used to investigate neuroinflammation and amyloid deposition, respectively, in both AD and MCI populations. It is also possible to investigate neurotransmitter systems in dementia; targets have included the cholinergic, dopaminergic and serotonergic systems. Imaging the brains of dementia patients using PET provides important information about the brain function of these individuals that would otherwise be unavailable with other imaging modalities. PET will continue to be important in future dementia research as new tracers become available to help in the early and specific diagnosis of increasingly well defined clinical syndromes, and assist in the assessment of new therapeutic interventions. PMID- 18445747 TI - Role of imaging techniques in the diagnosis of dementia. AB - Dementia is a common and growing problem, affecting 5% of the over 65 s and 20% of the over 80s. The recent availability of new treatments for dementia, as well as the importance of subtype-specific management, has renewed interest in the use of brain imaging techniques that can assist in the accurate recognition of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia (VaD) and frontotemporal dementia (FTD). Structural imaging, historically used to exclude an intracerebral lesion as a cause for dementia, is increasingly playing a role in "ruling in" diagnoses, with atrophy of the hippocampus and entorhinal cortex an early and sensitive marker for AD, and cortical and subcortical infarcts and white matter lesions characteristic of VaD. Regionally distinct patterns of hypoperfusion on single-photon emission computed tomography (SPECT) or hypometabolism on positron emission tomography (PET) can help differentiate FTD, AD and VaD, and dopaminergic loss in the basal ganglia can differentiate DLB from AD. Newer techniques show great promise to detect specific neuroreceptor changes as well as pathological underpinnings of dementia, such as amyloid and tau pathology. PMID- 18445748 TI - Computational anatomical methods as applied to ageing and dementia. AB - The cellular hallmarks of Alzheimer's disease (AD) accumulate in the living brain up to 30 years before the characteristic symptoms of dementia can be identified. Brain changes in AD are difficult to distinguish from those in normal ageing, and this has led to the development of powerful computational methods to extract statistical information on the brain changes that are characteristic of AD, mild cognitive impairment (MCI) and different dementia subtypes. Time-lapse maps can be built to show how the disease spreads in the brain, and where treatment affects the disease trajectory. Here, we review three computational approaches to map brain deficits in AD: cortical thickness maps, tensor-based morphometry and hippocampal/ventricular surface modelling. Anatomical structures, modelled as three-dimensional geometrical surfaces, are mathematically combined across subjects for group or interval comparisons. Mathematical concepts from computational surface modelling, fluid mechanics and multivariate statistics are exploited to distinguish disease from normal variations in brain structure. These methods yield insight into the dynamics of AD and MCI, showing where brain changes correlate with cognitive or behavioural changes such as language dysfunction or apathy. We describe cortical and hippocampal changes that distinguish dementia subtypes (such as Lewy-body dementia, HIV-associated dementia and AD), and we describe brain changes that predict recovery or decline in those at risk. Finally, we indicate which computational methods are powerful enough to track dementia in clinical trials, on the basis of their efficiency and sensitivity to early change, and the detail in the measures they provide. PMID- 18445749 TI - Longitudinal imaging in dementia. AB - Dementia represents one of the major public health problems facing ageing populations, with 20% of those over 80 years of age suffering from this disorder. The advent of therapeutic agents has brought about an increasing demand for a more accurate and earlier diagnosis, and the value of neuroimaging in improving the diagnostic process is becoming widely accepted. Neuroimaging assessments may add weight to a diagnosis of neurodegeneration as opposed to healthy ageing, improve the differential diagnosis, aid in the prediction of conversion to dementia in individuals at a higher risk of developing the disorder, track disease progression and provide an outcome measure for assessment of drug efficacy. PMID- 18445750 TI - Neuroradiological characterization of normal adult ageing. AB - This paper provides a review of MRI and diffusion tensor imaging (DTI) findings in normal ageing as an essential context for evaluating imaging in dementia, and adding to the ever-growing number of such overviews. An additional extensive literature details the physics, MR acquisition, image reconstruction and mathematical computation approaches to both imaging modalities. The aim of this review is to illustrate how MR imaging modalities, spanning structural and diffusion tensor imaging, are suitable for visualizing and quantifying the macrostructural and microstructural disruptions sustained by the brain in normal ageing and to recognize the importance of normative data for identifying abnormalities characterizing neurodegenerative diseases and other conditions affecting brain tissue integrity. PMID- 18445752 TI - Molecular correlates for maximal oxygen uptake and type 1 fibers. AB - Maximal oxygen uptake (Vo(2max)) and the amount of type 1 fibers are interrelated, but the underlying unifying molecular mechanisms are poorly understood. To explore these mechanisms, we related gene expression profiles in skeletal muscle biopsies of 43 age-matched men from published datasets with Vo(2max) and the amount of type 1 fibers and replicated some of the findings in muscle biopsies from 154 young and elderly individuals using real-time PCR. We identified 66 probe sets (genes or expressed sequence tags) positively and 83 probe sets inversely correlated with Vo(2max) and 171 probe sets positively and 217 probe sets inversely correlated with percentage of type 1 fibers in human skeletal muscle. Genes involved in oxidative phosphorylation (OXPHOS) showed high expression in individuals with high Vo(2max), whereas the opposite was not the case in individuals with low Vo(2max). Instead, genes such as AHNAK and BCL6 were associated with low Vo(2max). Also, expression of the OXPHOS genes NDUFB5 and ATP5C1 increased with exercise training and decreased with aging. In contrast, expression of AHNAK in skeletal muscle decreased with exercise training and increased with aging. Eleven genes (NDUFB4, COX5A, UQCRB, ATP5C1, ATP5G3, ETHE1, FABP3, ISCA1, MYST4, C9orf3, and PKIA) were positively correlated with both Vo(2max) and the percentage of type 1 fibers. Vo(2max) closely reflects expression of OXPHOS genes, particularly that of NDUFB5 and ATP5C1, in skeletal muscle, suggesting good muscle fitness. In contrast, a high expression of AHNAK was associated with a low Vo(2max) and poor muscle fitness. PMID- 18445753 TI - Glucose transporter isoform-3-null heterozygous mutation causes sexually dimorphic adiposity with insulin resistance. AB - We examined male and female glucose transporter isoform-3 (GLUT3; placenta)-null heterozygous(+/-) mutation-carrying mice and compared them with age- and sex matched wild-type(+/+) littermates. No difference in postnatal (1-2 days, 6-7 days, 12-13 days, 20-21 days), postsuckling (1-2 mo), and adult (3-6 mo) growth pattern was seen except for an increase in body weight of 9- to 11-mo-old male but not female GLUT3(+/-) mice. This change in male mutant mice was associated with increased total body fat mass, perirenal and epididymal white adipose tissue weight, and hepatic lipid infiltration. These minimally glucose-intolerant male mutant mice demonstrated no change in caloric intake but a decline in basal metabolic rate and insulin resistance. No perturbation in basal circulating glucose concentrations but an increase in insulin concentrations, triglycerides, and total cholesterol was observed in GLUT3(+/-) male mice. Tissue analysis in males and females demonstrated diminished GLUT3 protein in GLUT3(+/-) brain and skeletal muscle with no change in brain and adipose tissue GLUT1 protein concentrations. Furthermore, the male GLUT3(+/-) mice expressed decreased insulin responsive GLUT4 in white adipose tissue and skeletal muscle sarcolemma. We conclude that the GLUT3(+/-) male mice develop adult-onset adiposity with insulin resistance. PMID- 18445751 TI - Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity. AB - O-linked beta-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that, analogous to phosphorylation, cycles on and off serine and/or threonine hydroxyl groups. Cycling of O-GlcNAc is regulated by the concerted actions of O-GlcNAc transferase and O-GlcNAcase. GlcNAcylation is a nutrient/stress-sensitive modification that regulates proteins involved in a wide array of biological processes, including transcription, signaling, and metabolism. GlcNAcylation is involved in the etiology of glucose toxicity and chronic hyperglycemia-induced insulin resistance, a major hallmark of type 2 diabetes. Several reports demonstrate a strong positive correlation between GlcNAcylation and the development of insulin resistance. However, recent studies suggest that inhibiting GlcNAcylation does not prevent hyperglycemia-induced insulin resistance, suggesting that other mechanisms must also be involved. To date, proteomic analyses have identified more than 600 GlcNAcylated proteins in diverse functional classes. However, O-GlcNAc sites have been mapped on only a small percentage (<15%) of these proteins, most of which were isolated from brain or spinal cord tissue and not from other metabolically relevant tissues. Mapping the sites of GlcNAcylation is not only necessary to elucidate the complex cross talk between GlcNAcylation and phosphorylation but is also key to the design of site-specific mutational studies and necessary for the generation of site specific antibodies, both of which will help further decipher O-GlcNAc's functional roles. Recent technical advances in O-GlcNAc site-mapping methods should now finally allow for a much-needed increase in site-specific analyses to address the functional significance of O-GlcNAc in insulin resistance and glucose toxicity as well as other major biological processes. PMID- 18445754 TI - Preserved protein synthesis in the heart in response to acute fasting and chronic food restriction despite reductions in liver and skeletal muscle. AB - Whole body protein synthesis is reduced during the fed-to-fasted transition and in cases of chronic dietary restriction; however, less is known about tissue specific alterations. We have assessed the extent to which protein synthesis in cardiac muscle responds to dietary perturbations compared with liver and skeletal muscle by applying a novel (2)H(2)O tracer method to quantify tissue-specific responses of protein synthesis in vivo. We hypothesized that protein synthesis in cardiac muscle would be unaffected by acute fasting or food restriction, whereas protein synthesis in the liver and gastrocnemius muscle would be reduced when there is a protein-energy deficit. We found that, although protein synthesis in liver and gastrocnemius muscle was significantly reduced by acute fasting, there were no changes in protein synthesis in the left ventricle of the heart for either the total protein pool or in isolated mitochondrial or cytosolic compartments. Likewise, a chronic reduction in calorie intake, induced by food restriction, did not affect protein synthesis in the heart, whereas protein synthesis in skeletal muscle and liver was decreased. The later observations are supported by changes in the phosphorylation state of two critical mediators of protein synthesis (4E-BP1 and eIF2alpha) in the respective tissues. We conclude that cardiac protein synthesis is maintained in cases of nutritional perturbations, in strong contrast to liver and gastrocnemius muscle, where protein synthesis is decreased by acute fasting or chronic food restriction. PMID- 18445756 TI - The effect of the binge drinking session on the activity of salivary, serum and urinary beta-hexosaminidase: preliminary data. AB - Our report is the first to show that an acute ingestion (6 h) of a relatively large, yet tolerable dose of alcohol (120-160 g), significantly increases activity of total serum beta-hexosaminidase (total beta-HEX), beta-HEX A and beta HEX B isoenzymes, as well as salivary total beta-HEX and urinary beta-HEX A, in eight infrequent binge drinkers. An increase in the activity of serum and urinary total HEX is mainly due to its secretory isoenzyme beta-HEX A. PMID- 18445755 TI - Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat. AB - Renin-angiotensin-aldosterone system (RAAS) activation mediates increases in reactive oxygen species (ROS) and impaired insulin signaling. The transgenic Ren2 rat manifests increased tissue renin-angiotensin system activity, elevated serum aldosterone, hypertension, and insulin resistance. To explore the role of aldosterone in the pathogenesis of insulin resistance, we investigated the impact of in vivo treatment with a mineralocorticoid receptor (MR) antagonist on insulin sensitivity in Ren2 and aged-matched Sprague-Dawley (SD) control rats. Both groups (age 6-8 wk) were implanted with subcutaneous time-release pellets containing spironolactone (0.24 mg/day) or placebo over 21 days. Systolic blood pressure (SBP) and intraperitoneal glucose tolerance test were determined. Soleus muscle insulin receptor substrate-1 (IRS-1), tyrosine phosphorylated IRS-1, protein kinase B (Akt) phosphorylation, GLUT4 levels, and insulin-stimulated 2 deoxyglucose uptake were evaluated in relation to NADPH subunit expression/oxidase activity and ROS production (chemiluminescence and 4-hydroxy-2 nonenal immunostaining). Along with increased soleus muscle NADPH oxidase activity and ROS, there was systemic insulin resistance and reduced muscle IRS-1 tyrosine phosphorylation, Akt phosphorylation/activation, and GLUT4 expression in the Ren2 group (each P < 0.05). Despite not decreasing blood pressure, low-dose spironolactone treatment improved soleus muscle insulin signaling parameters and systemic insulin sensitivity in concert with reductions in NADPH oxidase subunit expression/activity and ROS production (each P < 0.05). Our findings suggest that aldosterone contributes to insulin resistance in the transgenic Ren2, in part, by increasing NADPH oxidase activity in skeletal muscle tissue. PMID- 18445758 TI - Observational study of children with aerophagia. AB - Aerophagia is a rare disorder in children. The diagnosis is often delayed, especially when it occurs concomitantly with constipation. The aim of this report is to increase awareness about aerophagia. This study describes 2 girls and 7 boys, 2 to 10.4 years of age, with functional constipation and gaseous abdominal distention. The abdomen was visibly distended, nontender, and tympanitic in all. Documenting less distention on awakening helped to make the diagnosis. Air swallowing, belching, and flatulence were infrequently reported. The rectal examination often revealed a dilated rectal ampulla filled with gas or stool and gas. The abdominal X-ray showed gaseous distention of the colon in all and of the stomach and small bowel in 8 children. Treatment consisted of educating parents and children about air sucking and swallowing, encouraging the children to stop the excessive air swallowing, and suggesting to them not to use drinking straws and not to drink carbonated beverages. The aerophagia resolved in all in 2 to 20 months (mean=8 months). PMID- 18445757 TI - Red Wine, but not port wine, protects rat hippocampal dentate gyrus against ethanol-induced neuronal damage--relevance of the sugar content. AB - AIMS: Chronic ethanol consumption leads to oxidative damage in the central nervous system inducing neuronal degeneration and impairment of brain functions. Nevertheless, it has been reported that grape polyphenols might prevent the alluded ethanol effects. We have reported that prolonged red wine intake improves hippocampal formation oxidative status, a finding not replicated using Port wine. Thus, we thought of interest to compare the effects of chronic ingestion of these wines in the morphology of dentate gyrus (DG) neurons that are particularly vulnerable to alcohol effects. METHODS: Six-month-old Wistar rats were fed either with red wine or Port wine (both with 20% ethanol content, v/v), and the results were compared with 20% (v/v) ethanol-treated, ethanol/glucose and pair-fed control groups. After 6 months of treatment, the layer volumes of the DG and the total number of granule and hilar neurons were estimated. The dendritic trees of granule cells were also studied in Golgi-impregnated material. RESULTS: The number of granule cells and the DG layer volumes were similar among all groups. However, the number of hilar neurons was reduced in Port wine, ethanol-treated and ethanol/glucose animals. Furthermore, the granule cells from these groups showed a decrease in the total dendritic length. CONCLUSIONS: Although the Port wine and red wine have similar amounts of flavanols with identical ability to protect against oxidative stress, the differences observed are probably related to the very dissimilar processes of wine production, leading in Port wine to a high content of sugars, which are known to have potent pro-oxidant effects. PMID- 18445759 TI - African American adolescent perceptions of vulnerability and resilience to HIV. AB - HIV/AIDS is growing at a disproportional rate among African American adolescents. This trend has occurred despite the fact that 89% of schools have educational programs on HIV/AIDS. Barriers to effective HIV prevention may be related to a failure to develop educational programs based on the cultural competencies of vulnerable populations such as adolescents who are at risk for HIV. The purpose of this qualitative study was to explore African American adolescent perceptions of vulnerability and resilience to HIV/AIDS within a cultural competency paradigm. A group of 8 adolescents at an African American church participated in a focus group to discuss vulnerability and resilience to HIV. To facilitate discussion, the adolescents developed collages from pictures in African American magazines. Content analysis was used to identify themes. The themes revealed were confidence, safe social activities, innocence, image, music/drug culture, and peer pressure. PMID- 18445760 TI - Lesbians' disclosure of sexual orientation and satisfaction with care. AB - The overarching aim of this study was to explore demographic variables and their association with a woman's disclosure of sexual orientation to a health care provider (HCP). This descriptive correlation study used a convenience sample of 96 women recruited at gay and lesbian community events held in Delaware. A self report survey of 35 questions was used to obtain the data. None of the women identified themselves as exclusively heterosexual. The results indicate that a woman's self-identified sexual orientation is significant in predicting whether she has shared her orientation with her HCP. The more a woman's self-reported orientation moves toward the heterosexual end of the preference scale, the less likely she is to share her orientation with her HCP. Culturally competent care and a nondiscriminatory atmosphere will provide this population with the trust needed to enable open rapport with their HCPs. PMID- 18445761 TI - Measuring cultural awareness of nursing students: a first step toward cultural competency. AB - This pilot study was designed to measure nursing students' level of cultural awareness. It replicated phase II of Rew, Becker, Cookston, Khosropour, & Martinez's (2003) methodological study that developed and tested a Cultural Awareness Scale (CAS). Using a cross-sectional design, the CAS was distributed to nursing students in three nursing programs' (bachelor's, master's, doctoral) beginning and end courses. Cronbach's alpha for the CAS Total instrument was 0.869, with subscale scores ranging from 0.687 to 0.902, comparable to the findings of Rew et al. Given the limitations of this study, results must be viewed with a degree of caution. Recommendations include further educational research in the form of psychometric testing of the CAS among nursing students, including refinement of both the CAS instrument and the demographic tool. The authors also recommend that studies be conducted to determine the validity and reliability of the CAS with nurses in the health care arena. PMID- 18445762 TI - Health beliefs, practice, and priorities for health care of Arab Muslims in the United States. AB - The Arab Muslim population is one of the dramatically increasing minorities in the United States. In addition to other factors, religion and cultural background influence individuals' beliefs, behaviors, and attitudes toward health and illness. The author describes health beliefs and practices of the Arab Muslim population in the United States. That population is at an increased risk for several diseases and faces many barriers to accessing the American health care system. Some barriers, such as modesty, gender preference in healthcare providers, and illness causation misconceptions, arise out of their cultural beliefs and practices. Other barriers are related to the complexity of the health care system and the lack of culturally competent services within it. Nurses need to be aware of these religious and cultural factors to provide culturally competent health promotion services for this population. Nurses also need to integrate Islamic teachings into their interventions to provide appropriate care and to motivate healthy behaviors. PMID- 18445763 TI - Coronary heart disease in South Asian immigrants: synthesis of research and implications for health promotion and prevention in nursing practice. AB - Although the literature reflects that Asian Indians in the United States and globally have the highest rates of morbidity and mortality because of coronary heart disease (CHD) and diabetes, few studies have described the clinical implications in the United States. Traditional risk factors dictate practice, yet these risk factors do not fully explain the rates. Central obesity, lipoprotein (a), and insulin resistance may have a strong role. The literature suggests that proactive nursing using culturally specific clinical measures are necessary to reduce risk factors for CHD and diabetes in South Asians. Additional research and prevention strategies focused on immigrant South Asians in the United States are recommended. PMID- 18445764 TI - Partial hepatectomy-induced regeneration accelerates reversion of liver fibrosis involving participation of hepatic stellate cells. AB - Hepatic fibrosis underlies most types of chronic liver diseases and is characterized by excessive deposition of extracellular matrix (ECM), altered liver architecture, and impaired hepatocyte proliferation; however, the fibrotic liver can still regenerate after partial hepatectomy (PH). Therefore, the present study was aimed at addressing whether a PH-induced regeneration normalizes ECM turnover and the possible involvement of hepatic stellate cells (HSC) during resolution of a pre-established fibrosis. Male Wistar rats were rendered fibrotic by intraperitoneal administration of swine serum for 9 weeks and subjected afterwards to 70% PH or sham-operation. Histological and morphometric analyses were performed, and parameters indicative of cell proliferation, collagen synthesis and degradation, and activation of HSC were determined. Liver collagen content was reduced to 75% after PH in cirrhotic rats when compared with sham operated cirrhotic rats. The regenerating fibrotic liver oxidized actively free proline and had diminished transcripts for alpha-1 (I) collagen mRNA, resulting in decreased collagen synthesis. PH also increased collagenase activity, accounted for by higher amounts of pro-MMP-9, MMP-2, and MMP-13, which largely coincided with a lower expression of TIMP-1 and TIMP-2. Therefore, an early decreased collagen synthesis, mild ECM degradation, and active liver regeneration were followed by higher collagenolysis and limited deposition of ECM, probably associated with increased mitochondrial activity. Activated HSC readily increased during liver fibrosis and remained activated after liver regeneration, even during fibrosis resolution. In conclusion, stimulation of liver regeneration through PH restores the balance in ECM synthesis/degradation, leading to ECM remodeling and to an almost complete resolution of liver fibrosis. As a response to the regenerative stimulus, activated HSC seem to play a controlling role on ECM remodeling during experimental cirrhosis in rats. Therefore, pharmacological approaches for the resolution of liver fibrosis by blocking HSC activation should also evaluate possible effects on liver cell proliferation. PMID- 18445765 TI - Mercury in traditional medicines: is cinnabar toxicologically similar to common mercurials? AB - Mercury is a major toxic metal ranked top in the Toxic Substances List. Cinnabar, which contains mercury sulfide, has been used in Chinese traditional medicines for thousands of years as an ingredient in various remedies, and 40 cinnabar containing traditional medicines are still used today. Little is known about toxicology profiles or toxicokinetics of cinnabar and cinnabar-containing traditional medicines, and the high mercury content in these Chinese medicines raises justifiably escalations of public concern. This minireview, by searching the available database of cinnabar and by comparing cinnabar with common mercurials, discusses differences in their bioavailability, disposition, and toxicity. The analysis showed that cinnabar is insoluble and poorly absorbed from the gastrointestinal tract. Absorbed mercury from cinnabar is mainly accumulated in the kidneys, resembling the disposition pattern of inorganic mercury. Heating cinnabar results in release of mercury vapor, which in turn can produce toxicity similar to inhalation of these vapors. The doses of cinnabar required to produce neurotoxicity are 1000 times higher than methyl mercury. Following long-term use of cinnabar, renal dysfunction may occur. Dimercaprol and succimer are effective chelation therapies for general mercury intoxication including cinnabar. Pharmacological studies of cinnabar suggest sedative and hypnotic effects, but the therapeutic basis of cinnabar is still not clear. In summary, cinnabar is chemically inert with a relatively low toxic potential when taken orally. In risk assessment, cinnabar is less toxic than many other forms of mercury, but the rationale for its inclusion in traditional Chinese medicines remains to be fully justified. PMID- 18445767 TI - Multiple molecular pathways are involved in the neuroprotection of GDNF against proteasome inhibitor induced dopamine neuron degeneration in vivo. AB - The impairment of ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson's disease (PD). Glial cell line-derived neurotrophic factor (GDNF) is one of the most potent neurotrophic factors promoting the growth and survival of mesencephalic dopamine (DA) neurons. To investigate whether GDNF has neuroprotective effects in a PD model induced by UPS impairment we administered GDNF by osmotic pump in C57BL/6 mice after nigrostriatal lesions with stereotactic injection of proteasome inhibitor lactacystin in the middle forebrain bundle. We found that lactacystin injection severely injured the nigral DA neurons and reduced the striatal levels of DA and its metabolites, while prolonged administration of GDNF at a sustained moderate dose for two weeks can significantly attenuate the lactacystin-induced loss of nigral DA neurons and striatal DA levels by 31% and 40%, respectively. We also investigated the molecular mechanisms for the neuroprotective effects of GDNF showing that lactacystin administration can cause the phosphorylation of extracellular signal-regulated kinase (ERK), p38MAPK (p38), and the c-Jun N terminal kinase (JNK), whereas GDNF treatment can further enhance the phosphorylation of ERK and Akt but reduce the levels of JNK and p38. These results indicate that prolonged treatment with GDNF can protect the nigral DA neurons from the UPS impairment-induced degeneration. Several signaling path-ways including p38, JNK, Akt and ERK molecules seem to play an important role in this neuroprotection by GDNF. PMID- 18445766 TI - Measurement techniques for cellular biomechanics in vitro. AB - Living cells and tissues experience mechanical forces in their physiological environments that are known to affect many cellular processes. Also of importance are the mechanical properties of cells, as well as the microforces generated by cellular processes themselves in their microenvironments. The difficulty associated with studying these phenomena in vivo has led to alternatives such as using in vitro models. The need for experimental techniques for investigating cellular biomechanics and mechanobiology in vitro has fueled an evolution in the technology used in these studies. Particularly noteworthy are some of the new biomicroelectromechanical systems (Bio-MEMS) devices and techniques that have been introduced to the field. We describe some of the cellular micromechanical techniques and methods that have been developed for in vitro studies, and provide summaries of the ranges of measured values of various biomechanical quantities. We also briefly address some of our experiences in using these methods and include modifications we have introduced in order to improve them. PMID- 18445768 TI - Overexpression of transferrin receptor and ferritin related to clinical symptoms and destabilization of human carotid plaques. AB - Accumulation of tissue iron has been implicated in development of atherosclerotic lesions mainly because of increased iron-catalyzed oxidative injury. However, it remains unknown whether cellular iron import and storage in human atheroma are related to human atheroma development. We found that transferrin receptor 1 (TfR1), a major iron importer, is highly expressed in foamy macrophages and some smooth muscle cells in intimal lesions of human carotid atheroma, mainly in cytoplasmic accumulation patterns. In 52 human carotid atherosclerotic lesions, TfR1 expression was positively correlated with macrophage infiltration, ectopic lysosomal cathepsin L, and ferritin expression. Highly expressed TfR1 and ferritin in CD68-positive macrophages were significantly associated with development and severity of human carotid plaques, smoking, and patient's symptoms. The findings suggest that pathologic macrophage iron metabolism may contribute to vulnerability of human atheroma, established risk factors, and their clinical symptoms. The cytoplasmic overexpression of TfR1 may be the result of lysosomal dysfunction and ectopic accumulation of lysosomal cathepsin L caused by atheroma-relevant lipids in atherogenesis. PMID- 18445769 TI - Smooth muscle-specific gene delivery in the vasculature based on restriction of DNA nuclear import. AB - The two currently employed approaches restricting gene delivery and/or expression to desired cell types in vivo rely on cell surface targeting or cell-specific promoters. We have developed a third approach based on cell-specific nuclear transport of the delivered plasmid DNA. We have previously shown that plasmid nuclear import in non-dividing cells is sequence-specific and have identified a set of cell-specific DNA nuclear targeting sequences that can be used to limit DNA nuclear import to desired cell types. Specifically we have identified elements of the smooth muscle gamma actin (SMGA) promoter that direct plasmid nuclear import selectively in smooth muscle cells (SMCs) in vitro (Vacik et al, 1999, Gene Therapy 6:1006-1014). In the present study, we demonstrate that the SMC-specific DNA nuclear targeting sequence from the SMGA promoter drives nuclear accumulation of plasmids and subsequent gene expression exclusively in the smooth muscle cell layer of the vessel wall in the intact vasculature of rats using electroporation mediated delivery. These results demonstrate that certain DNA nuclear targeting sequences can be used to restrict DNA nuclear import to specific cell types providing a new, novel means of cell targeting for gene therapy. PMID- 18445770 TI - Homeostatic action of adenosine A3 and A1 receptor agonists on proliferation of hematopoietic precursor cells. AB - Two adenosine receptor agonists, N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) and N6-cyclopentyladenosine (CPA), which selectively activate adenosine A3 and A1 receptors, respectively, were tested for their ability to influence proliferation of granulocytic and erythroid cells in femoral bone marrow of mice using morphological criteria. Agonists were given intraperitoneally to mice in repeated isomolar doses of 200 nmol/kg. Three variants of experiments were performed to investigate the action of the agonists under normal resting state of mice and in phases of cell depletion and subsequent regeneration after treatment with the cytotoxic drug 5-fluorouracil. In the case of granulopoiesis, IB-MECA 1) increased by a moderate but significant level proliferation of cells under normal resting state; 2) strongly increased proliferation of cells in the cell depletion phase; but 3) did not influence cell proliferation in the regeneration phase. CPA did not influence cell proliferation under normal resting state and in the cell depletion phase, but strongly suppressed the overshooting cell proliferation in the regeneration phase. The stimulatory effect of IB-MECA on cell proliferation of erythroid cells was observed only when this agonist was administered during the cell depletion phase. CPA did not modulate erythroid proliferation in any of the functional states investigated, probably due to the lower demand for cell production as compared with granulopoiesis. The results indicate opposite effects of the two adenosine receptor agonists on proliferation of hematopoietic cells and suggest the plasticity and homeostatic role of the adenosine receptor expression. PMID- 18445771 TI - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) colonization and infection in intravenous and inhalational opiate drug abusers. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a significant pathogen in hospital-acquired and community-acquired infections. We hypothesized that drug abuse is a risk factor for community-acquired MRSA (CA-MRSA) infection, and we employed a rapid multiplex PCR technique for MRSA identification. The study was conducted on MRSA isolates from 60 opiate addicts (intravenous and inhalational drug users) to detect the rate and location of MRSA colonization and infection among them in comparison to 60 non-addict patients and 15 healthy volunteer controls. The proportion of addicts with MRSA colonization (and/or infection) was significantly higher than non-addict patients with MRSA colonization. MRSA colonization was associated with infection in 58% of MRSA-colonized addicts. The MRSA nasal carriage in the addicts was significantly higher than MRSA carriage elsewhere, whether in the addicts group or in the non-addict patients group. Moreover, the nasopharyngeal carriage rate of MRSA among addicts was significantly higher than among the non-addict patients. Increasing the duration of addiction resulted in a significant increase in CA-MRSA colonization in opiate addicts. Both inhalational and intravenous drug use led to significant MRSA colonization in the addict population. In conclusion, this study demonstrated how drug abusers, a high-risk group for infections with MRSA, could be a source or a reservoir of CA-MRSA infection in the non-addict population. PMID- 18445772 TI - Forced expression of MMP9 rescues the loss of angiogenesis and abrogates metastasis of pancreatic tumors triggered by the absence of host SPARC. AB - Pancreatic adenocarcinoma is characterized by desmoplasia, local invasion, and metastasis. These features are regulated in part by MMP9 and SPARC. To explore the interaction of SPARC and MMP9 in cancer, we first established orthotopic pancreatic tumors in SPARC-null and wild-type mice with the murine pancreatic adenocarcinoma cell line, PAN02. MMP9 expression was higher in tumors from wild type compared to SPARC-null mice. Coincident with lower MMP9 expression, tumors grown in SPARC-null mice were significantly larger, had decreased ECM deposition and reduced microvessel density compared to wild-type controls. In addition, metastasis was enhanced in the absence of host SPARC. Therefore, we next analyzed the orthotopic tumor growth of PAN02 cells transduced with MMP9 or a control empty vector. Forced expression of MMP9 by the PAN02 cells resulted in larger tumors in both wild-type and SPARC-null animals compared to empty vector controls and further diminished ECM deposition. Importantly, forced expression of MMP9 within the tumor reversed the decrease in angiogenesis and abrogated the metastatic potential displayed by control tumors grown in SPARC-null mice. Finally, contrary to the in vivo results, MMP9 increased cell migration in vitro, which was blocked by the addition of SPARC. These results suggest that SPARC and MMP9 interact to regulate many stages of tumor progression including ECM deposition, angiogenesis and metastasis. PMID- 18445773 TI - Direct interaction of tumor suppressor CEACAM1 with beta catenin: identification of key residues in the long cytoplasmic domain. AB - CEACAM1-4L (carcinoembryonic antigen cell adhesion molecule 1, with 4 extracellular Ig-like domains and a long, 71 amino acid cytoplasmic domain) is expressed in epithelial cells and activated T-cells, but is down-regulated in most epithelial cell cancers and T-cell leukemias. A highly conserved sequence within the cytoplasmic domain has ca 50% sequence homology with Tcf-3 and -4, transcription factors that bind beta-catenin, and to a lesser extent (32% homology), with E-cadherin that also binds beta-catenin. We show by quantitative yeast two-hybrid, BIAcore, GST-pull down, and confocal analyses that this domain directly interacts with beta-catenin, and that H-469 and K-470 are key residues that interact with the armadillo repeats of beta-catenin. Jurkat cells transfected with CEACAM1-4L have 2-fold less activity in the TOPFLASH reporter assay, and in MCF7 breast cancer cells that fail to express CEACAM1, transfection with CEACAM1 and growth in Ca2+ media causes redistribution of beta-catenin from the cytoplasm to the cell membrane, demonstrating a functional role for the long cytoplasmic domain of CEACAM1 in regulation of beta-catenin activity. PMID- 18445774 TI - An unexpected role for ion channels in brain tumor metastasis. AB - Over the past two decades it has become apparent that essentially all living cells express voltage-activated ion channels. While the role of ion channels for electrical signaling between excitable cells is well known, their function in non excitable cells is somewhat enigmatic. Research on cancer cells suggests that certain ion channels, K+ channels in particular, may be involved in aberrant tumor growth and channel inhibitors often lead to growth arrest. An unsuspected role for K+ and Cl(-) channels has now been documented for primary brain tumors, glioma, where the concerted activity of these channels promotes cell invasion and the formation of brain metastasis. Specifically, Ca2+-activated K+ (BK) channels colocalize with ClC-3 Cl(-) channels to the invading processes of these tumor cells. Upon a rise in intracellular Ca2+, these channels activate and release K+ and Cl(-) ions together with obligated water causing a rapid shrinkage of the leading process. This in turn facilitates the invasion of the cell into the narrow and tortuous extracellular brain spaces. The NKCC1 cotransporter accumulates intracellular Cl(-) to unusually high concentrations, thereby establishing an outward directed gradient for Cl(-) ions. This allows glioma cells to utilize Cl(-) as an osmotically active anion during invasion. Importantly, the inhibition of Cl(-) channels retards cell volume changes, and, in turn, compromises tumor cell invasion. These findings have led to the clinical evaluation of a Cl(-) channel blocking peptide, chlorotoxin, in patients with malignant glioma. Data from this clinical trial shows remarkable tumor selectivity for chlorotoxin. The experimental therapeutic was well tolerated and is now evaluated in a multi-center phase II clinical trial. A similar role for Cl(-) and K+ channels is suspected in other metastatic cancers, and lessons learned from studies of gliomas may pave the way towards the development of novel therapeutics targeting ion channels. PMID- 18445775 TI - Dissimilar differentiation of mesenchymal stem cells from bone marrow, umbilical cord blood, and adipose tissue. AB - Mesenchymal stem cells (MSCs) have been investigated as promising candidates for use in new cell-based therapeutic strategies such as mesenchyme-derived tissue repair. MSCs are easily isolated from adult tissues and are not ethically restricted. MSC-related literature, however, is conflicting in relation to MSC differentiation potential and molecular markers. Here we compared MSCs isolated from bone marrow (BM), umbilical cord blood (UCB), and adipose tissue (AT). The isolation efficiency for both BM and AT was 100%, but that from UCB was only 30%. MSCs from these tissues are morphologically and immunophenotypically similar although their differentiation diverges. Differentiation to osteoblasts and chondroblasts was similar among MSCs from all sources, as analyzed by cytochemistry. Adipogenic differentiation showed that UCB-derived MSCs produced few and small lipid vacuoles in contrast to those of BM-derived MSCs and AT derived stem cells (ADSCs) (arbitrary differentiation values of 245.57 +/- 943 and 243.89 +/- 145.52 mum(2) per nucleus, respectively). The mean area occupied by individual lipid droplets was 7.37 mum(2) for BM-derived MSCs and 2.36 mum(2) for ADSCs, a finding indicating more mature adipocytes in BM-derived MSCs than in treated cultures of ADSCs. We analyzed FAPB4, ALP, and type II collagen gene expression by quantitative polymerase chain reaction to confirm adipogenic, osteogenic, and chondrogenic differentiation, respectively. Results showed that all three sources presented a similar capacity for chondrogenic and osteogenic differentiation and they differed in their adipogenic potential. Therefore, it may be crucial to predetermine the most appropriate MSC source for future clinical applications. PMID- 18445776 TI - Amelioration of cisplatin-induced nephrotoxicity in rats by tetramethylpyrazine, a major constituent of the Chinese herb Ligusticum wallichi. AB - Nephrotoxicity of the anticancer drug, cisplatin (CP) involves enhanced renal generation of reactive oxygen metabolites and lipid peroxidation caused by decreased levels of antioxidants and antioxidant enzymes. Tetramethylpyrazine (TMP) is known to act as a strong antioxidant. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of TMP on CP nephrotoxicity in rats. TMP was given orally at a dose of 80 mg . kg(- 1) . day(- 1) for 7 days. Some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg on Day 6 of treatment. Animals were sacrificed 6 days after CP (or vehicle) treatment, and blood, urine, and kidneys were obtained. Nephrotoxicity was assessed biochemically by measuring creatinine and urea in serum, reduced glutathione (GSH) concentration in renal cortex, by urinalysis, and histopathologically by light microscopy. CP significantly increased the concentration of urea and creatinine (P < 0.05) by about 128% and 170%, respectively; increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity; and significantly decreased osmolality and protein concentrations. CP treatment reduced GSH by about 34% (P < 0.05) and superoxide dismutase (SOD) and total antioxidant activity (TOX) by about 28% and 21%, respectively (P < 0.05). TMP pretreatment significantly mitigated all of these effects. Sections from saline- and TMP-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly reduced when CP was given after pretreatment with TMP. CP cortical concentration was not significantly altered by TMP treatment. The results suggest that TMP ameliorated the histological, physiological, and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, TMP may potentially be useful as a nephroprotective agent. PMID- 18445778 TI - Bona fide genetic associations with bone mineral density. PMID- 18445777 TI - Multiple genetic loci for bone mineral density and fractures. AB - BACKGROUND: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture. METHODS: We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). RESULTS: Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11. CONCLUSIONS: We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis. PMID- 18445779 TI - Positive modulation of GABA(B) receptors decreased nicotine self-administration and counteracted nicotine-induced enhancement of brain reward function in rats. AB - Acute administration of gamma-aminobutyric acid (GABA)-B receptor agonists decreases nicotine, cocaine, ethanol, and heroin self-administration and also decreases food-maintained responding and suppresses locomotor activity at high doses. GABA(B) receptor-positive modulators may represent potentially improved therapeutic compounds because of their fewer side effects than receptor agonists. The present study investigated the effects of administration of the GABA(B) receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl) phenol (CGP7930) and N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4 (trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) and coadministration of the GABA(B) receptor-positive modulator N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro pyrimidine-4,6-diamine (GS39783) with the GABA(B) receptor agonist (3-amino-2[S] hydroxypropyl)-methylphosphinic acid (CGP44532) on nicotine- and food-maintained responding under fixed ratio (FR) 5 and progressive ratio schedules of reinforcement. Furthermore, the effects of BHF177 and CGP44532 on nicotine induced enhancement of brain reward function were evaluated. The results indicated that administration of CGP7930 decreased nicotine self-administration under an FR5 schedule. Administration of either GS39783 or CGP44532 selectively decreased nicotine self-administration, whereas coadministration of these compounds had additive effects. BHF177 administration selectively decreased nicotine- but not food-maintained responding under FR5 and progressive ratio schedules. The nicotine-induced enhancement of brain reward function was blocked by BHF177 or CGP44532, although the highest doses of both compounds, particularly CGP44532, decreased brain reward function when administered alone, suggesting an additive, rather than interactive, effect. Overall, the present results indicate that GABA(B) receptor-positive modulators, similarly to GABA(B) receptor agonists, attenuated the reinforcing and reward-enhancing effects of nicotine, perhaps with higher selectivity than GABA(B) receptor agonists. Thus, GABA(B) receptor-positive modulators may be useful antismoking medications. PMID- 18445781 TI - The function of the human interferon-beta 1a glycan determined in vivo. AB - Recombinant human interferon-beta (rhIFN-beta) is the leading therapeutic intervention shown to change the cause of relapsing-remitting multiple sclerosis, and both a nonglycosylated and a significantly more active glycosylated variant of rhIFN-beta are used in treatment. This study investigates the function of the rhIFN-beta1a glycan moiety and its individual carbohydrate residues, using the myxovirus resistance (Mx) mRNA as a biomarker in Mx-congenic mice. We showed that the Mx mRNA level in blood leukocytes peaked 3 h after s.c. administration of rhIFN-beta1a. In addition, a clear dose-response relationship was confirmed, and the Mx response was shown to be receptor-mediated. Using specific glycosidases, different glycosylation analogs of rhIFN-beta1a were obtained, and their activities were determined. The glycosylated rhIFN-beta1a showed significantly higher activity than its deglycosylated counterpart, due to a protein stabilization/solubilization effect of the glycan. It is interesting to note that the terminating sialic acids were essential for these effects. Conclusively, the structure/bioactivity relationship of rhIFN-beta1a was determined in vivo, and it provided a novel insight into the role of the rhIFN-beta1a glycan and its carbohydrate residues. The possibilities of improving the pharmacological properties of rhIFN-beta1a using glycoengineering are discussed. PMID- 18445780 TI - Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice. AB - Insulin is used to control pro-inflammatory hyperglycemia in critically ill patients. However, recent studies suggest that insulin-induced hypoglycemia may negate its beneficial effects in these patients. It is noteworthy that recent evidence indicates that insulin has anti-inflammatory effects that are independent of controlling hyperglycemia. To date, the mechanism by which insulin directly reduces inflammation has not been elucidated. It is well established that insulin activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling in many cell types. We and others have shown that this pathway negatively regulates LPS-induced signaling and pro-inflammatory cytokine production in monocytic cells. We hypothesized that insulin inhibits inflammation during endotoxemia by activation of the PI3K/Akt pathway. We used a nonhyperglycemic mouse model of endotoxemia to determine the effect of continuous administration of a low dose of human insulin on inflammation and survival. It is noteworthy that insulin treatment induced phosphorylation of Akt in muscle and adipose tissues but did not exacerbate lipopolysaccharide (LPS)-induced hypoglycemia. Insulin decreased plasma levels of interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein 1 (MCP1)/JE, and keratinocyte chemoattractant, and decreased mortality. The PI3K inhibitor wortmannin abolished the insulin-mediated activation of Akt and the reduction of chemokine and interleukin-6 levels. We conclude that insulin reduces LPS-induced inflammation in mice in a PI3K/Akt-dependent manner without affecting blood glucose levels. PMID- 18445782 TI - Signal transduction and transcriptional control of cardiac connexin43 up regulation after alpha 1-adrenoceptor stimulation. AB - Syncytial behavior of cardiac tissue is mainly controlled by the expression of cardiac gap junction proteins, and of these, connexin43 (Cx43) represents the predominant connexin in the working myocardium. Because the alpha(1)-adrenoceptor is involved in many cardiac diseases, the following experiments were performed to clarify the pathway whereby alpha(1)-adrenoceptor stimulation may control Cx43 expression. Cultured neonatal rat cardiomyocytes were stimulated with phenylephrine for 24 h, and Cx43 expression was investigated. Moreover, we investigated activation of p38 mitogenic-activated protein kinase (MAPK), p42/44 MAPK, and c-JUN NH(2)-terminal kinase (JNK) by phosphospecific enzyme-linked immunosorbent assay and nuclear translocation of the transcription factors c-fos and activator protein 1 (AP1). For verification of our results, a Cx43-promoter enhanced green fluorescent protein (EGFP) construct using the complete promoter [2771 base pairs (bp)] or fragments (0-2421 bp) with EGFP under control of the Cx43 promoter was transfected into cardiomyocytes, and fluorescence intensity was investigated. Phenylephrine exposure caused approximately 2-fold up-regulation of Cx43 protein with an EC(50) of approximately 5 nM, which was significantly inhibited by bisindolylmaleimide I [protein kinase C (PKC) inhibitor], 4-(4 fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580; p38 inhibitor), or 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059; p42/44 inhibitor). Similar findings were obtained for Cx43 mRNA. Furthermore, Cx43 up-regulation was accompanied by phosphorylation of p38, p42/44, and JNK. Moreover, we found translocation of c-fos and AP1 to the nucleus. Phenylephrine stimulation of Cx43-promoter EGFP-transfected cardiomyocytes significantly increased fluorescence, depending on the length of promoter fragments. A 91-bp fragment containing the first AP1 binding site produced approximately 50% of the fluorescence intensity of the complete promoter. Therefore, we conclude that alpha(1)-adrenoceptor stimulation up-regulates cardiac Cx43 expression via a PKC p38- and p42/44 MAPK-regulated pathway, possibly involving AP1. PMID- 18445783 TI - Age-dependent development of metabolic derangement and effects of intervention with pioglitazone in Zucker diabetic fatty rats. AB - Zucker diabetic fatty (ZDF) rats are a standard animal model for the study of type 2 diabetes and for pharmacological characterization of insulin-sensitizing drugs. To analyze the age-dependent development of their metabolic derangements and the associated changes in their responses to treatment with the insulin sensitizer pioglitazone, groups of 7, 10.5, or 15.5-week-old ZDF rats were treated orally with vehicle or pioglitazone (12 mg/kg/day). Metabolic parameters including circulating concentrations of glucose, insulin, lipids, and adiponectin as well as body weight, tissue glycogen content, and the activity of p70S6 kinase in skeletal muscle were determined. Blood glucose of ZDF rats rose steeply from 5.9 +/- 0.4 to 23.7 +/- 0.5 mM between 7 and 13 weeks of age and then reached a new steady state, which was associated with increased tissue glycogen content (in 15-week-old ZDF rats versus lean littermates: skeletal muscle, 18.0 +/- 0.9 versus 10.5 +/- 1.4 micromol/g; liver, 181 +/- 6 versus 109 +/- 14 micromol/g; both p < 0.001). Early intervention with pioglitazone at 7 weeks of age fully prevented the development of hyperglycemia (blood glucose, 6.4 +/- 0.4 versus 18.7 +/- 1.5 mM after 5.5 weeks of treatment), which was accompanied by a 40% (p = 0.01) reduction of the activity of p70S6 kinase in skeletal muscles. These beneficial effects of pioglitazone were progressively lost, if treatment was initiated at later stages of disease development. Thus, ZDF rats are suitable for preclinical characterization of insulin-sensitizing thiazolidinediones in many aspects, but several important differences versus human type 2 diabetes exist and are to be considered in the use of this animal model. PMID- 18445784 TI - Hydrolysis of cis- and trans-epoxyeicosatrienoic acids by rat red blood cells. AB - Erythrocytes serve as reservoirs for cis- and trans-epoxyeicosatrienoic acids (EETs). Incubation of rat red blood cells (RBCs) with cis- and trans-EETs produces threo- and erythro-dihydroxyeicosatrienoic acids, respectively. The V(max) of EET hydrolysis by rat intact RBCs (2.35 +/- 0.24 pmol/min/10(8) RBCs for 14,15-trans-EET) decreased by approximately 2 to 3-fold sequentially from 14,15-, 11,12- to 8,9-EETs for both cis- and trans-isomers. The V(max) of trans EET hydrolysis by RBCs is approximately 2 to 3 times that of the corresponding cis-EETs. Incubation of EETs with recombinant murine soluble epoxide hydrolase (sEH) yielded the same geometric and regio preferences of EET hydrolysis as with rat intact RBCs. The principal epoxide hydrolase activity for EET hydrolysis (approximately 90%) is present in the erythrocyte cytosol. Western blots of sEH suggested a concentration of sEH protein to be approximately 2 microg/mg protein or 0.4 microg/10(9) RBCs. The apparent K(m) values of EETs were between 1 and 2 microM, close to the K(m) for purified sEH as reported. Erythrocyte hydration of cis- and trans-EETs was blocked by sEH inhibitors, 1,3-dicyclohexylurea and 4-[4 (3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid. Erythrocyte sEH activity was inhibited more than 80% by 0.2% bovine serum albumin in the buffer. Preferred hydrolysis of 14,15-EETs and trans-epoxides characterizes sEH activity in RBCs that regulates the hydrolysis and release of cis- and trans-EETs in the circulation. Inhibition of sEH has produced antihypertensive and antiinflammatory effects. Because plasma trans-EETs would increase more than cis-EETs with sEH inhibition, the potential roles of trans-EETs and erythrocyte sEH in terms of circulatory regulation deserve attention. PMID- 18445786 TI - Masked heterogeneity in obesity between immigrant subgroups. PMID- 18445785 TI - The complex of TFII-I, PARP1, and SFPQ proteins regulates the DYX1C1 gene implicated in neuronal migration and dyslexia. AB - DYX1C1 was first identified as a candidate gene for dyslexia susceptibility, and its role in controlling neuronal migration during embryogenesis and effect on learning in rodents have been verified. In contrast, genetic association studies have been ambiguous in replicating its effects on dyslexia. To better understand the regulation of DYX1C1 and the possible functional role of genetic variation in the promoter of DYX1C1, we selected three single-nucleotide polymorphisms (SNPs) with predicted functional consequences or suggested associations to dyslexia for detailed study. Electrophoretic mobility shift assays suggested the allele specific binding of the transcription factors TFII-I (to rs3743205) and Sp1 (to rs16787 and rs12899331) that could be verified by competition assays. In addition, we purified a complex of protein factors binding to the previously suggested dyslexia-related SNP, -3G/A (rs3743205). Three proteins, TFII-I, PARP1, and SFPQ, were unambiguously identified by mass spectrometry and protein sequencing. Two SNPs, rs16787 and rs3743205, showed significant allelic differences in luciferase assays. Our results show that TFII-I, PARP1, and SFPQ proteins, each previously implicated in gene regulation, form a complex controlling transcription of DYX1C1. Furthermore, allelic differences in the promoter or 5' untranslated region of DYX1C1 may affect factor binding and thus regulation of the gene. PMID- 18445787 TI - Assessment of the effects of social support on adolescents with parents with HIV/AIDS. PMID- 18445788 TI - Lost luggage, recovered lives. PMID- 18445789 TI - Sexual and gender minority health: what we know and what needs to be done. AB - We describe the emergence of lesbian, gay, bisexual, and transgender (LGBT) health as a key area of study and practice for clinicians and public health professionals. We discuss the specific needs of LGBT populations on the basis of the most recent epidemiological and clinical investigations, methods for defining and measuring LGBT populations, and the barriers they face in obtaining appropriate care and services. We then discuss how clinicians and public health professionals can improve research methods, clinical outcomes, and service delivery for lesbian, gay, bisexual, and transgender people. PMID- 18445790 TI - Receipt of prevention services among HIV-infected men who have sex with men. AB - Unprotected sexual intercourse remains a primary mode of HIV transmission in the United States. We found that receipt of services to reduce HIV transmission-risk behaviors was low among 3787 HIV-infected individuals and that men who have sex with men were especially unlikely to receive these services even though they were more likely to report unprotected sexual intercourse with seronegative and unknown serostatus casual partners. Greater efforts should be made to ensure that prevention counseling is delivered to all HIV-infected persons, especially men who have sex with men. PMID- 18445791 TI - Turning loss into legislation. AB - Same-sex partnerships encounter tremendous challenges in the context of healthcare, including empowerment to act on behalf of loved ones. We share challenges faced by two women who confronted this issue head-on when their same sex partners were critically, and, in one case, fatally, injured. In both cases, hospitals initially refused to recognize these women as next of kin; one woman endured years of legal battles in her struggle to win the right to care for her partner. The other testified about her heartrending experience before the Washington State Judiciary Committee, helping to inspire legislation regarding rights for visitation and end-of-life decisions on behalf of same-sex partners. We seek to remind health care providers of the limitations of current laws and to inspire them to support change. PMID- 18445792 TI - Beyond abuse and exposure: framing the impact of prescription-medication sharing. AB - OBJECTIVES: We sought to document the frequency, circumstances, and consequences of prescription medication-sharing behaviors and to use a medication-sharing impact framework to organize the resulting data regarding medication-loaning and borrowing practices. METHODS: One-on-one interviews were conducted in 2006, and participants indicated (1) prescription medicine taken in the past year, (2) whether they had previously loaned or borrowed prescription medicine, (3) scenarios in which they would consider loaning or borrowing prescription medicine, and (4) the types of prescription medicines they had loaned or borrowed. RESULTS: Of the 700 participants, 22.9% reported having loaned their medications to someone else and 26.9% reported having borrowed someone else's prescription. An even greater proportion of participants reported situations in which medication sharing was acceptable to them. CONCLUSIONS: Sharing prescription medication places individuals at risk for diverse consequences, and further research regarding medication loaning and borrowing behaviors and their associated consequences is merited. PMID- 18445793 TI - Incidence of and risk factors for sexual orientation-related physical assault among young men who have sex with men. AB - OBJECTIVES: We sought to determine incidence of, prevalence of, and risk factors for sexual orientation-related physical assault in young men who have sex with men (MSM). METHODS: We completed a prospective open cohort study of young MSM in Vancouver, British Columbia, surveyed annually between 1995 and 2004. Correlates of sexual orientation-related physical assault before enrollment were identified with logistic regression. Risk factors for incident assaults were determined with Cox regression. RESULTS: At enrollment, 84 (16%) of 521 MSM reported ever experiencing assault related to actual or perceived sexual orientation. Incidence was 2.3 per 100 person-years; cumulative incidence at 6-year follow-up was 10.8 per 100 person-years. Increased risk of incident sexual orientation-related physical assault was observed among MSM 23 years or younger (relative hazard=3.1; 95% confidence interval [CI] = 1.6, 5.8), Canadian Aboriginal people (relative hazard = 3.0; 95% CI=1.4, 6.2), and those who previously experienced such assault (relative hazard=2.5; 95% CI=1.3, 4.8). CONCLUSIONS: These data underscore the need for increased public awareness, surveillance, and support to reduce assault against young MSM. Such efforts should be coordinated at the community level to ensure that social norms dictate that such acts are unacceptable. PMID- 18445794 TI - Moving upstream: ecosocial and psychosocial correlates of sexually transmitted infections among young adults in the United States. AB - OBJECTIVES: We determined the associations of ecosocial factors and psychosocial factors with having a prevalent sexually transmitted infection (STI), recent STI diagnoses, and sexual risk behaviors. METHODS: Young adults aged 18 to 27 years in the National Longitudinal Study of Adolescent Health (n=14322) provided ecosocial, psychosocial, behavioral, and STI-history data. Urine was tested for Chlamydia trachomatis and Neisseria gonorrhoeae by ligase chain reaction and for Trichomonas vaginalis, human papillomavirus, and Mycoplasma genitalium by polymerase chain reaction. RESULTS: Prevalent STI was associated with housing insecurity (adjusted odds ratio [AOR] = 1.3; 95% confidence interval [CI] = 1.00, 1.72), exposure to crime (AOR=1.4; 95% CI=1.02, 1.80), and having been arrested (AOR=1.4; 95% CI=1.07, 1.84). STI prevalence increased linearly from 4.9% for 0 factors to 14.6% for 4 or more (P < .001, for trend). Nearly all contextual conditions predicted more lifetime partners and earlier sexual debut. Recent STI diagnosis was associated with childhood sexual abuse, gang participation, frequent alcohol use, and depression, adjusted for sexual risk behaviors. CONCLUSIONS: Often present before sexual debut, contextual conditions enhance STI risk by increasing sexual risk behaviors and likelihood of exposure to infection. These findings suggest that upstream conditions such as housing and safety contribute to the burden of STIs and are appropriate targets for future intervention. PMID- 18445795 TI - Evaluation of an HIV prevention intervention adapted for Black men who have sex with men. AB - OBJECTIVES: We assessed the efficacy of an HIV behavioral intervention adapted for Black men who have sex with men (MSM). METHODS: We conducted serial cross sectional surveys, 1 baseline measurement followed by initiation of an intervention and 3 follow-up measurements, among Black MSM in 3 North Carolina cities over 1 year. RESULTS: We observed significant decreases in unprotected receptive anal intercourse at 4 months (by 23.8%, n=287) and 8 months (by 24.7%, n=299), and in unprotected insertive anal intercourse (by 35.2%), unprotected receptive anal intercourse (by 44.1%), and any unprotected anal intercourse (by 31.8%) at 12 months (n=268). Additionally, at 12 months, the mean number of partners for unprotected receptive anal intercourse decreased by 40.5%. The mean number of episodes decreased by 53.0% for unprotected insertive anal intercourse, and by 56.8% for unprotected receptive anal intercourse. The percentage of respondents reporting always using condoms for insertive and receptive anal intercourse increased by 23.0% and 30.3%, respectively. CONCLUSIONS: Adapting previously proven interventions designed for other MSM can significantly reduce HIV risk behaviors of Black MSM. PMID- 18445796 TI - The prevalence of metabolic syndrome among US women of childbearing age. AB - OBJECTIVES: We sought to determine whether the prevalence of metabolic syndrome among US women of childbearing age (18-44 years) has increased since 1988 and to estimate its current prevalence by race/ethnicity and risk that a maternal history of select metabolic syndrome characteristics imposes on offspring. METHODS: We used survey-specific data analysis methods to examine data from the National Health and Nutrition Examination Surveys conducted from 1988 to 2004. RESULTS: The prevalence of the metabolic syndrome phenotype and 2 of its clinical correlates significantly increased between 1988 and 2004 (increase for metabolic syndrome phenotype=7.6%, for obesity=13.3%, and for elevated C-reactive protein=10.6%; P < .001 for all 3). Hispanic women were more likely than were White women to possess the phenotype (P = .004). Women who reported that their mothers had been diagnosed with diabetes were more likely to possess the phenotype than those whose mothers had not been so diagnosed (odds ratio=1.9; 95% confidence interval=1.3, 2.8). CONCLUSIONS: The current trends of metabolic syndrome among women of childbearing age demonstrate the need for additional rigorous investigations regarding its long-term effects in these women and their offspring. PMID- 18445797 TI - Health-related quality of life among adults who experienced maltreatment during childhood. AB - OBJECTIVES: We sought to assess the difference in a preference-based measure of health among adults reporting maltreatment as a child versus those reporting no maltreatment. METHODS: Using data from a study of adults who reported adverse childhood experiences and current health status, we matched adults who reported childhood maltreatment (n = 2812) to those who reported no childhood maltreatment (n = 3356). Propensity score methods were used to compare the 2 groups. Health related quality-of-life data (or "utilities") were imputed from the Medical Outcomes Study 36-Item Short Form Health Survey using the Short Form-6D preference-based scoring algorithm. RESULTS: The combined strata-level effects of maltreatment on Short Form-6D utility was a reduction of 0.028 per year (95% confidence interval=0.022, 0.034; P<.001). All utility losses for the childhood maltreatment versus no-childhood-maltreatment groups by age group were significantly different: 18-39 years, 0.042; 40-49 years, 0.038; 50-59 years, 0.023; 60-69 years, 0.016; 70 or more years, 0.025. CONCLUSIONS: Persons who experienced childhood maltreatment had significant and sustained losses in health related quality of life in adulthood relative to persons who did not experience maltreatment. These data are useful for assessing the cost-effectiveness of interventions designed to prevent child maltreatment in terms of cost per quality adjusted life years saved. PMID- 18445798 TI - Resilience to urban poverty: theoretical and empirical considerations for population health. AB - OBJECTIVES: To better understand the trajectory that propels people from poverty to poor health, we investigated health resilience longitudinally among African American families with incomes below 250% of the federal poverty level. METHODS: Health resilience is the capacity to maintain good health in the face of significant adversity. With higher levels of tooth retention as a marker of health resilience, we used a social-epidemiological framework to define capacity for health resilience through a chain of determinants starting in the built environment (housing quality) and community context (social support) to familial influences (religiosity) and individual mental health and health behavior. RESULTS: Odds of retaining 20 or more teeth were 3 times as likely among adults with resilience versus more-vulnerable adults (odds ratio=3.1; 95% confidence interval [CI]=1.3, 7.4). Children of caregivers with resilience had a lower incident rate of noncavitated tooth decay at 18- to 24-month follow-up (incidence risk ratio=0.8; 95% CI=0.7, 0.9) compared with other children. CONCLUSIONS: Health resilience to poverty was supported by protective factors in the built and social environments. When poverty itself cannot be eliminated, improving the quality of the built and social environments will foster resilience to its harmful health effects. PMID- 18445799 TI - Condom use and hip hop culture: the case of urban young men in New York City. AB - OBJECTIVES: We explored how young men's perceptions of and participation in hip hop culture--urban social and artistic expressions, such as clothing style, breakdancing, graffiti, and rap music--and how contextual factors of the hip hop scene may be associated with their condom use, condom-use self-efficacy, and sense of community. METHODS: We conducted a cross-sectional survey of 95 African American and Latino men aged 15 to 25 years as part of a 4-year ethnographic study in New York City. RESULTS: Differences in young men's perceptions of and levels of affiliation with hip hop culture were not statistically associated with differences in their sense of community or condom-use self-efficacy. Frequency of participation in the hip hop nightclub scene was the strongest factor negatively associated with condom use. CONCLUSIONS: Popular discourses on young men's health risks often blame youths' cultures such as the hip hop culture for increased risk practices but do not critically examine how risk emerges in urban young men's lives and what aspects of youths' culture can be protective. Further research needs to focus on contextual factors of risk such as the role of hip hop nightlife on increased HIV risk. PMID- 18445800 TI - "If you know you exist, it's just marketing poison": meanings of tobacco industry targeting in the lesbian, gay, bisexual, and transgender community. AB - In the public health literature, it is generally assumed that the perception of "targeting" as positive or negative by the targeted audience depends on the product or message being promoted. Smoking prevalence rates are high among lesbian, gay, bisexual, and transgender (LGBT) individuals, but little is known about how they perceive tobacco industry targeting. We conducted focus groups with LGBT individuals in 4 US cities to explore their perceptions. Our findings indicated that focus group participants often responded positively to tobacco company targeting. Targeting connoted community visibility, legitimacy, and economic viability. Participants did not view tobacco as a gay health issue. Targeting is a key aspect of corporate-community interaction. A better understanding of targeting may aid public health efforts to counter corporate disease promotion. PMID- 18445801 TI - Risk for reassault in abusive female same-sex relationships. AB - OBJECTIVES: We revised the Danger Assessment to predict reassault in abusive female same-sex relationships. METHODS: We used focus groups and interviews to evaluate the assessment tool and identify new risk factors and telephone interviews at baseline and at 1-month follow-up to evaluate the revised assessment. RESULTS: The new assessment tool comprised 8 original and 10 new items. Predictors included increase in physical violence (relative risk ratio [RRR]=1.95; 95% confidence interval [CI]=0.84, 4.54), constant jealousy or possessiveness of abuser (RRR = 4.07; 95% CI = 0.61, 27.00), cohabitation (RRR = 1.96; 95% CI = 0.54, 7.12), threats or use of gun by abuser (RRR=1.93; 95% CI=0.79, 4.75), alcoholism or problem drinking of abuser (RRR=1.47; 95% CI=0.79, 2.71), illegal drug use or abuse of prescription medications by abuser (RRR = 1.33; 95% CI = 0.72, 2.46), stalking by abuser (RRR=1.39; 95% CI=0.70, 2.76), failure of individuals to take victim seriously when she sought help (RRR=1.66; 95% CI=0.90, 3.05), victim's fear of reinforcing negative stereotypes (RRR=1.42; 95% CI=0.73, 2.77), and secrecy of abuse (RRR=1.72; 95% CI=0.74, 3.99). Both unweighted (P < .005) and weighted (P < .004) versions of the revised assessment were significant predictors of reassault. CONCLUSIONS: The revised Danger Assessment accurately assesses risk of re-assault in abusive female relationships. PMID- 18445802 TI - Paternal race/ethnicity and birth outcomes. AB - OBJECTIVES: I sought to identify whether there were associations between paternal race/ethnicity and birth outcomes among infants with parents of same- and mixed races/ethnicities. METHODS: Using the National Center for Health Statistics 2001 linked birth and infant death file, I compared birth outcomes of infants of White mothers and fathers of different races/ethnicities by matching and weighting racial/ethnic groups following a propensity scoring approach so other characteristics were distributed identically. I applied the same analysis to infants of Black parents and infants with a Black mother and White father. RESULTS: Variation in risk factors and outcomes was found in infants of White mothers by paternal race/ethnicity. After propensity score weighting, the disparities in outcomes by paternal or parental race/ethnicity could be largely attributed to nonracial parental characteristics. Infants whose paternal race/ethnicity was unreported on their birth certificates had the worst outcomes. CONCLUSIONS: The use of maternal race/ethnicity to refer to infant race/ethnicity in research is problematic. The effects of maternal race/ethnicity on birth outcomes are estimated to be much larger than that of paternal race/ethnicity after I controlled for all covariates. Not listing a father on the birth certificate had a strong association with outcomes, which might be a source of bias in existing data and a marker for identifying infants at risk. PMID- 18445803 TI - Sexual orientation and related viral sexually transmitted disease rates among US women aged 15 to 44 years. AB - I used data from the 2002 National Survey of Family Growth to measure sexual orientation and viral sexually transmitted disease (STD) rates among US women aged 15 to 44 years. Sexual behavior and sexual identity data indicated that 1.3% to 1.9% of the women were lesbians and 3.1% to 4.8% were bisexual. Self-reported viral STD rates were significantly higher among bisexual women (15.0% to 17.2%) than among lesbians (2.3% to 6.7%). These findings support the need for STD prevention interventions that consider lesbians and bisexual women separately. PMID- 18445805 TI - America's first amphetamine epidemic 1929-1971: a quantitative and qualitative retrospective with implications for the present. AB - Using historical research that draws on new primary sources, I review the causes and course of the first, mainly iatrogenic amphetamine epidemic in the United States from the 1940s through the 1960s. Retrospective epidemiology indicates that the absolute prevalence of both nonmedical stimulant use and stimulant dependence or abuse have reached nearly the same levels today as at the epidemic's peak around 1969. Further parallels between epidemics past and present, including evidence that consumption of prescribed amphetamines has also reached the same absolute levels today as at the original epidemic's peak, suggest that stricter limits on pharmaceutical stimulants must be considered in any efforts to reduce amphetamine abuse today. PMID- 18445804 TI - Sexual risk taking among young internet-using men who have sex with men. AB - OBJECTIVES: We examined the characteristics of young Internet-using men who have sex with men (MSM) and risks associated with seeking sex online, offline, or through both strategies. METHODS: Data were obtained from MSM aged 18 to 24 years who completed a 45-minute online survey regarding sex and Internet use in the preceding 3 months. RESULTS: Significantly more Internet-using MSM who had met sexual partners both online and offline (43%) reported unprotected anal intercourse than did those who had met sexual partners exclusively online (29%) or offline (34%). MSM who met sexual partners exclusively offline reported the fewest partners but the greatest proportion of partnerships involving unprotected anal intercourse (49%). Meeting sexual partners both online and offline (odds ratio [OR]=3.38-58.42) and being drunk (OR=1.57) or high (OR=2.24) increased the odds of having more sexual partners. The same factors increased the odds of having unprotected anal intercourse (online and offline sexual partners, OR=1.60; being drunk, OR=1.43; being high, OR=1.61). CONCLUSIONS: Risky sexual behavior was prevalent among all of the study subgroups. Our findings suggest that online sex seeking is associated with greater numbers of sexual partners but neither promotes nor discourages unprotected anal intercourse. Regardless of where sexual partners met, being drunk and high were significant risks for unprotected anal intercourse. PMID- 18445806 TI - HIV prevalence and associated risk behaviors in New York City's house ball community. AB - OBJECTIVES: We measured HIV seroprevalence and associated risk factors among persons in New York City's house ball community. METHODS: In 2004 we conducted a venue-based risk-behavior survey and HIV testing in the house ball community. RESULTS: Of the 504 study participants, 67% were male, 14% female, and 18% transgender. Mean age was 24 years (range=15-52 years); 55% were Black, and 40% were Latino. More than 85% of participants had previously been tested for HIV, although only 60% had been tested in the previous 12 months. Of the 84 (17%) persons who tested positive for HIV in our study, 61 (73%) were unaware of their HIV status. A logistic regression analysis on data from 371 participants who had had a male sexual partner in the previous 12 months showed that HIV-infected participants were more likely than were HIV-negative participants to be Black, to be older than 29 years, and not to have been tested for HIV in the previous 12 months. CONCLUSIONS: Culturally specific community-level prevention efforts are warranted to reduce risk behaviors and increase the frequency of HIV testing in New York City's house ball community. PMID- 18445807 TI - HIV infection, sexual risk behavior, and substance use among Latino gay and bisexual men and transgender persons. AB - OBJECTIVES: We examined HIV prevalence and the socioeconomic correlates of HIV infection, sexual risk behaviors, and substance use among Latino gay and bisexual men and transgender persons in Chicago and San Francisco. METHODS: Data were collected from a sample of 643 individuals (Chicago: n=320; San Francisco: n=323) through respondent-driven sampling and computer-assisted self-administered interviews. RESULTS: HIV prevalence in San Francisco (0.325; 95% confidence interval [CI]=0.260, 0.393) was higher than in Chicago (0.112; 95% CI=0.079, 0.163). In San Francisco, HIV prevalence was higher among US-born residents than among those born outside the country; in Chicago, the opposite was true. Heavy use of alcohol was prevalent, especially in Chicago (0.368; 95% CI=0.309, 0.432; San Francisco: 0.154; 95% CI=0.116, 0.192). Drug use and more education were positively correlated and greater age was negatively correlated with unprotected anal intercourse. CONCLUSIONS: Heavy alcohol drinking and use of drugs remain a significant public health problem in this population. Drug use was more closely linked to HIV sexual risk behaviors than was heavy drinking. PMID- 18445808 TI - Determinants of recent HIV infection among Seattle-area men who have sex with men. AB - OBJECTIVES: We sought to identify HIV-infection risk factors related to partner selection and sexual behaviors with those partners among men who have sex with men (MSM) in King County, Washington. METHODS: Participants were recruited from HIV testing sites in the Seattle area. Recent HIV infection status was determined by the Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS) or a self-reported previous HIV-negative test. Data on behaviors with 3 male partners were collected via computer-based self-interviews. Generalized estimating equation models identified partnership factors associated with recent infection. RESULTS: We analyzed data from 32 HIV-positive MSM (58 partners) and 110 HIV negative MSM (213 partners). In multivariate analysis, recent HIV infection was associated with meeting partners at bathhouses or sex clubs, bars or dance clubs, or online; methamphetamine use during unprotected anal intercourse; and unprotected anal intercourse, except with HIV-negative primary partners. CONCLUSIONS: There is a need to improve efforts to promote condom use with casual partners, regardless of their partner's HIV status. New strategies to control methamphetamine use in MSM and to reduce risk behaviors related to meeting partners at high-risk venues are needed. PMID- 18445810 TI - Busting cancer clusters: realities often differ from perceptions. PMID- 18445809 TI - Dimensions of sexual orientation and HIV-related risk among adolescent females: evidence from a statewide survey. AB - OBJECTIVES: We examined the relationship of 2 dimensions of sexual orientation- sexual identity and sex of partners--with self-reported behaviors and experiences to identify factors that may place adolescent females at risk of HIV/AIDS. METHODS: We gathered data on sexually experienced female high school students from 4 waves of a population-based survey. We used logistic regression analyses to investigate the association between their sexual identity (3666 heterosexual; 184 lesbian, gay, or bisexual; 113 not sure) and sex of partners (3714 male only, 79 female only, and 180 both males and females) with HIV-related risk behaviors. RESULTS: Self-defined sexual identity was often inconsistent with sex of sexual partners. Sexual identities other than heterosexual and having same-sex partners (either exclusively or in addition to male partners) were associated with high rates of several HIV-related risk behaviors. Coerced sexual contact was significantly associated with every risk outcome. AIDS education in school predicted lower HIV risk on 4 of 6 indicators. CONCLUSIONS: Programs to prevent HIV infection among adolescent females should take into account the complexity of sexual orientation and should address the needs and behaviors of sexual-minority youths. PMID- 18445811 TI - End of high-dose chemotherapy for high-risk breast cancer patients? PMID- 18445812 TI - Understanding pathways of calorie restriction: a way to prevent cancer? PMID- 18445813 TI - Curry compound fights cancer in the clinic. PMID- 18445814 TI - StatBite: Percentage of current childhood smokers worldwide. PMID- 18445816 TI - Estimating the cost of cancer care in the United States: a work very much in progress. PMID- 18445817 TI - Routine audit of large-scale cervical cancer screening programs. PMID- 18445818 TI - A model citizen? Is tamoxifen more effective than aromatase inhibitors if we pick the right patients? PMID- 18445819 TI - Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. AB - BACKGROUND: Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44(>)/CD24(>/low)) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44(>) and CD24(>/low) cell population. METHODS: Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2 positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided. RESULTS: Chemotherapy treatment increased the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P < .001) and increased mammosphere formation efficiency (MSFE) (mean at baseline vs 12 weeks, 13.3%, 95% CI = 6.0% to 20.6%, vs 53.2%, 95% CI = 42.4% to 64.0%; P < .001). Conversely, lapatinib treatment of patients with HER2-positive tumors led to a non-statistically significant decrease in the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a statistically non-significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%). CONCLUSION: These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival. PMID- 18445821 TI - Re: Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. PMID- 18445820 TI - Treating metastatic solid tumors with bortezomib and a tumor necrosis factor related apoptosis-inducing ligand receptor agonist antibody. AB - BACKGROUND: Resistance of tumors to cell death signals poses a complex clinical problem. We explored the therapeutic potential and in vivo toxicity of a combination of bortezomib, a proteasome inhibitor, and MD5-1, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor (DR5) agonist monoclonal antibody, in mouse carcinomas. METHODS; Mice bearing Renca-FLAG (renal) or 4T1 (mammary) tumors were treated with bortezomib and/or MD5-1 and examined for lung metastases (Renca-FLAG: n = 93; 4T1: n = 40) or monitored for survival (Renca-FLAG: n = 143). Toxicity was assessed by histopathology and hematology. Viability and apoptotic signaling in Renca-FLAG and 4T1 cells treated with bortezomib alone or in combination with TRAIL were analyzed using 3-[4,5 dimethyiazol-2-yl-5]-[3-carboxymethyloxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium assay and by measuring mitochondrial membrane depolarization and caspase-8 and caspase-3 activation. All statistical tests were two-sided. RESULTS: Bortezomib (20 nM) sensitized Renca-FLAG and 4T1 cells to TRAIL-mediated apoptosis (mean percent decrease in numbers of viable cells, bortezomib + TRAIL vs TRAIL: Renca FLAG, 95% vs 34%, difference = 61%, 95% confidence interval [CI] = 52% to 69%, P < .001; 4T1, 85% vs 20%, difference = 65%, 95% CI = 62% to 69%, P < .001). Sensitization involved activation of caspase-8 and caspase-3 but not mitochondrial membrane depolarization, suggesting an amplified signaling of the extrinsic cell death pathway. Treatment with bortezomib and MD5-1 reduced lung metastases in mice carrying Renca and 4T1 tumors (mean number of metastases, bortezomib + MD5-1 vs MD5-1: Renca-FLAG, 1 vs 8, difference = 7, 95% CI = 5 to 9, P < .001; 4T1, 1 vs 12, difference = 11, 95% CI = 9 to 12, P < .001) and increased median survival of mice bearing Renca-FLAG tumors (bortezomib + MD5-1 vs bortezomib + control isotype antibody: 22 of 30 [73%] were still alive at day 180 vs median survival of 42 days [95% CI = 41 to 44 days, P < .001]) in the absence of obvious toxicity. CONCLUSION: Bortezomib combined with DR5 agonist monoclonal antibody may be a useful treatment for metastatic solid tumors. PMID- 18445822 TI - Re: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. PMID- 18445823 TI - Re: Projecting individualized absolute invasive breast cancer risk in African American women. PMID- 18445824 TI - Re: Adaptive therapy for androgen-independent prostate cancer: a randomized selection trial of four regimens. PMID- 18445825 TI - Cost of care for elderly cancer patients in the United States. AB - BACKGROUND: Timely estimates of the costs of care for cancer patients are an important element in the formulation of national cancer programs and policies. We estimated net costs of care for elderly cancer patients in the United States for the 18 most prevalent cancers and for all other tumor sites combined. METHODS: We used Surveillance, Epidemiology, and End Results-Medicare files to identify 718,907 cancer patients and 1,623,651 noncancer control subjects. Within each tumor site, noncancer control subjects were matched to patients by sex, age group, geographic location, and phase of care (ie, initial, continuing, and last year of life). Costs of care were estimated for each phase by use of Medicare claims data from January 1, 1999, through December 31, 2003. Per-patient net costs of care were applied to the 5-year survival of cancer patients by phase of care to estimate 5-year costs of care and extrapolated to the elderly US Medicare population diagnosed with cancer in 2004. RESULTS: Across tumor sites, mean net costs of care were highest in the initial and last year of life phases of care and lowest in the continuing phase. Mean 5-year net costs varied widely, from less than $20,000 for patients with breast cancer or melanoma of the skin to more than $40,000 for patients with brain or other nervous system, esophageal, gastric, or ovarian cancers or lymphoma. For elderly cancer patients diagnosed in 2004, aggregate 5-year net costs of care to Medicare were estimated to be approximately $21.1 billion. Costs to Medicare were highest for lung, colorectal, and prostate cancers, reflecting underlying incidence, stage distribution at diagnosis, survival, and phase-specific costs for these tumor sites. CONCLUSIONS: The costs of cancer care to Medicare are substantial and vary by tumor site, phase of care, stage at diagnosis, and survival. PMID- 18445826 TI - Persistent organochlorine pesticides and risk of testicular germ cell tumors. AB - BACKGROUND: Exposure to endocrine-disrupting chemicals, such as persistent organochlorine pesticides, has been suggested to increase the risk of testicular germ cell tumors (TGCTs). METHODS: To study the relationship of POP exposure to TGCT risk, prediagnostic serum samples from 754 case subjects and 928 control subjects enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study were analyzed for cis-nonachlor, trans-nonachlor, oxychlordane, total chlordanes, beta-hexachlorocyclohexane, mirex, p,p' dichlorodiphenyldichloroethylene (p,p'-DDE), and p,p' dichlorodiphenyltrichloroethane. Adjusted odds ratios (ORs) and their associated 95% confidence intervals (CIs) for the risk of TGCT overall and for the histological subgroups, seminoma and nonseminoma, were estimated using multivariable logistic regression. All statistical tests were two-sided. RESULTS: TGCT risk was statistically significantly associated with higher plasma levels of p,p'-DDE (for highest quartile [Q4] vs lowest quartile [Q1], OR = 1.71, 95% CI = 1.23 to 2.38, P(trend) = .0002) and of two chlordane components, cis-nonachlor (Q4 vs Q1, OR = 1.56, 95% CI = 1.11 to 2.18, P(trend) = .009) and trans-nonachlor (Q4 vs Q1, OR = 1.46, 95% CI = 1.07 to 2.00, P(trend) = .026). Seminoma risk was statistically significantly associated with p,p'-DDE (Q4 vs Q1, OR = 1.91, 95% CI = 1.22 to 2.99, P(trend) = .0008), cis-nonachlor (Q4 vs Q1, OR = 1.93, 95% CI = 1.27 to 2.93, P(trend) = .0045), trans-nonachlor (Q4 vs Q1, OR = 1.72, 95% CI = 1.11 to 2.67, P(trend) = .033), and a chlordane metabolite, oxychlordane (Q4 vs Q1, OR = 1.64, 95% CI = 1.04 to 2.60, P(trend) = .048), whereas nonseminoma risk showed a statistically significant association with p,p'-DDE only (Q4 vs Q1, OR = 1.63, 95% CI = 1.10 to 2.42, P(trend) = .0044). CONCLUSIONS: Increased exposure to p,p'-DDE may be associated with the risk of both seminomatous and nonseminomatous TGCTs, whereas exposure to chlordane compounds and metabolites may be associated with the risk of seminoma. Because evidence suggests that TGCT is initiated in very early life, it is possible that exposure to these persistent organic pesticides during fetal life or via breast feeding may increase the risk of TGCT in young men. PMID- 18445828 TI - Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. AB - BACKGROUND: The effectiveness of cervical cancer screening programs differs widely in different populations. The reasons for these differences are unclear. Routine and comprehensive audits have been proposed as an ethically required component of screening. We performed a nationwide audit of the effectiveness of the Swedish cervical cancer screening program. METHODS: We identified all invasive cervical cancer cases that were diagnosed in Sweden from January 1, 1999, through December 31, 2001, and had been reported to the Swedish Cancer Registry (n = 1230 cases). We verified the diagnoses by histopathologic rereview and matched each case subject to five (population-based) age-matched control subjects who were identified from the National Population Register. The Pap smear screening histories for case and control subjects were reviewed for a 6-year period using the National Cervical Cancer Screening Register, which contains data on essentially all relevant cytological and histological diagnoses in Sweden. Odds ratios (ORs), and their 95% confidence intervals (CIs), of cervical cancer according to screening history were calculated in conditional logistic regression models. All statistical tests were two-sided. RESULTS: Women who had not had a Pap smear within the recommended screening interval had higher risk of cervical cancer than women who had been screened (OR = 2.52, 95% CI = 2.19 to 2.91). This risk was similarly increased for all age groups (P(homogeneity) = .96). The risk for non-squamous cell cervical cancers (OR = 1.59, 95% CI = 1.20 to 2.11) was also increased. Women who had not had a Pap smear within the recommended screening interval had a particularly high risk of advanced cancers (OR = 4.82, 95% CI = 3.61 to 6.44). Among women who had been screened within the recommended interval, those with abnormal Pap smears had a higher risk of cervical cancer than those with normal smears (OR = 7.55, 95% CI = 5.88 to 9.69) and constituted 11.5% of all women with cervical cancer. CONCLUSIONS: Nonadherence to screening intervals was the major reason for cervical cancer morbidity. The screening program was equally effective for women of all ages and was also effective against non-squamous cancers. PMID- 18445827 TI - Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. AB - BACKGROUND: Adjuvant endocrine treatment with aromatase inhibitors improves disease-free survival compared with tamoxifen in postmenopausal women with estrogen receptor-positive breast cancer. This difference could be due to differences in tamoxifen metabolism because levels of endoxifen, the active tamoxifen metabolite, vary with the number of mutant alleles, including the *4 allele, of the gene encoding cytochrome P450 2D6 (CYP2D6). METHODS: We created a Markov model to determine whether tamoxifen or aromatase inhibitor monotherapy maximized 5-year disease-free survival for patients with the wild-type CYP2D6 genotype (wt/wt). Annual risks of recurrence with aromatase inhibitors and tamoxifen in breast cancer patients who were not selected by CYP2D6 genotype were derived from the Breast International Group 1-98 trial. Genotype frequencies and the hazard ratio for cancer recurrence on tamoxifen among patients with the *4/*4 genotype relative to the wt/wt or wt/*4 genotypes (HR(*4/*4) = 1.86) were based on data from an analysis of the North Central Cancer Treatment Group trial of adjuvant tamoxifen. We explored the impact of CYP2D6(*4) heterozygosity on disease-free survival for wt/wt patients by studying a range of effect (ie, recurrence on tamoxifen) estimates, from no effect of the single mutation (Eff(wt/*4) = 0, recurrence rate in wt/*4 patients same as that in wt/wt patients) to complete effect (Eff(wt/*4) = 1 recurrence rate in wt/*4 patients same as that in *4/*4 patients). RESULTS: With HR(*4/*4) = 1.86 and Eff(wt/*4) = 0.5, the 5-year disease-free survival of tamoxifen-treated patients with no mutations (wt/wt) was 83.9%, that is, essentially the same as that (84.0%) for genotypically unselected patients who were treated with aromatase inhibitors. With greater HR(*4/*4) estimates, disease-free survival with tamoxifen exceed that with aromatase inhibitors in wt/wt patients, even at lower assumed Eff(wt/*4) ratios. CONCLUSIONS: Modeling suggests that among patients who are wild type for CYP2D6, 5-year disease-free survival outcomes are similar to or perhaps even superior with tamoxifen than with aromatase inhibitors. Endocrine therapy tailored to CYP2D6 genotype could be considered for women who are newly diagnosed with breast cancer, particularly those who have with concerns about either the relative toxicity or the increased cost of aromatase inhibitors. PMID- 18445829 TI - Development and preliminary psychometric evaluation of the domestic violence- related financial issues scale (DV-FI). AB - Intimate partner violence (IPV) occurs at disproportionate rates within impoverished groups of women and can include economic abuse as a form of psychological maltreatment. The current study developed a comprehensive assessment of the unique financial issues facing female victims of IPV using a sheltered sample (N = 113). An exploratory factor analysis (principal-axis factoring with varimax rotation) was conducted on 24 items of the newly developed Domestic Violence-Related Financial Issues Scale. Preliminary results supported five extracted factors, which accounted for approximately 53% of the total common variance in the women's responses. Psychometric properties of the instrument are presented. PMID- 18445830 TI - The function of aggression in personality disordered patients. AB - It has been suggested that psychological interventions for personality disorders should focus on improving adaptive expression of the functional needs expressed through problematic behaviors such as aggression. The measurement of function is a necessary condition for devising a function-based treatment approach. Two studies that employ a method for assessing the functions of aggressive behavior in personality disordered patients are described by: (a) a retrospective analysis, through file review of inpatient aggressive behaviors and of the index offenses of patients admitted for treatment, and (b) an analysis of inpatient aggressive incidents where staff and patients were interviewed to elicit functions. Results showed that most aggression had the function of expressing anger, although other functions were also evident. The profile of functions observed in the inpatient studies was somewhat dissimilar to that observed in the studies of predominantly psychotic patients. Therapeutic implications of these findings are discussed. PMID- 18445831 TI - Psychiatric diagnosis as a risk marker for victimization in a national sample of children. AB - Research examining childhood abuse has shown an association between victimization and psychiatric diagnoses (e.g., posttraumatic stress disorder, depression). Historically, psychiatric diagnoses have been emphasized as a consequence of victimization, with less research examining if it also functions as a risk factor for further victimization, perhaps making diagnoses a general victimization risk marker. In addition, much of this research has emphasized particular types of victimization such as childhood physical or sexual abuse. Researchers have given less attention to other forms of victimization (e.g., peer victimization, witnessed violence) or a diverse victimization history. Using the Juvenile Victimization Questionnaire (JVQ) we surveyed parents and children between the ages of 2 and 17 using a random digit dial (RDD) methodology. We examined the relationship between a number of different forms of victimization (termed poly victimization ) in the preceding year and parent-reported lifetime psychiatric diagnosis. Results show that children with a psychiatric diagnosis have significantly higher rates of victimization than children without a psychiatric diagnosis. In addition, using logistic regression models, we find that psychiatric diagnosis was associated with increased risk for poly-victimization, conventional crime victimization, maltreatment, peer or sibling victimization, and witnessing violence, but not sexual abuse. The results highlight the need to consider psychiatric diagnoses as a risk marker for past and possible future victimization. In addition, the importance of obtaining a comprehensive and more diverse victimization history when working with children is highlighted. PMID- 18445832 TI - Interparental conflict and adolescent dating relationships: the role of perceived threat and self-blame appraisals. AB - In line with the cognitive-contextual framework proposed by Grych and Fincham (1990), evidence suggests that children exposed to interparental conflict (IPC) are at risk for experiencing conflict within their own intimate relationships. The mediating role of adolescent appraisal in the relation between IPC and adolescent dating behavior was examined in the current study. Specifically, it was hypothesized that self-blame and threat appraisals would mediate the relation between IPC and adolescent maladaptive dating behaviors. To examine the potential mediating role of appraisal, 169 high school students completed the Children's Perception of Interparental Conflict (Grych, Seid, & Fincham, 1992) and Child and Adolescent Dating Relationships Inventory (Wolfe, Scott, Reitzel-Jaffe, Wekerle, Grasley, & Straatman, 2004). Findings suggest that self-blame appraisal partially mediated the relation between IPC and adolescent sexual aggression, and between IPC and adolescent threatening behavior. In addition, perceived threat appraisal partially mediated the relation between IPC and adolescent sexual aggression. Implications for the current findings are discussed. PMID- 18445833 TI - Notch signaling in osteoblasts. AB - Bone remodeling is the result of the coordinated activity of osteoblasts, which form new matrix, and osteoclasts, which resorb bone. Notch proteins are single pass transmembrane receptors that determine cell fate. Recent gain-of-function and loss-of-function experiments reveal a suppressive effect of Notch in osteoblast and osteoclast differentiation in development and in the postnatal bone, which establishes a role for Notch signaling in bone remodeling. PMID- 18445834 TI - Back from the dormant stage: second messenger cyclic ADP-ribose essential for Toxoplasma gondii pathogenicity. AB - Cyclic adenosine diphosphoribose (cADPR) is an endogenous Ca2+-mobilizing second messenger found in cells of animals, plants, and protozoans. It is formed by a specific class of enzymes, the ADP-ribosyl cyclases. cADPR stimulates Ca2+ release by means of ryanodine receptors located in the sarcoplasmic and endoplasmic reticulum. Recently, a role for cADPR has been demonstrated in the obligate intracellular protozoan pathogen Toxoplasma gondii. In T. gondii, stress conditions evoked synthesis of the plant hormone abscisic acid by the apicoplast, a remnant organelle of an algal endosymbiont of T. gondii. Abscisic acid in turn activated formation of cADPR within T. gondii, resulting in Ca2+ release and secretion of proteins involved in egress of T. gondii from its host cell. Evidence for a synthetic pathway of plant origin was obtained with the ABA synthesis inhibitor fluridone, which antagonized cellular egress and induced differentiation of long-lived semidormant cystic forms of T. gondii. Moreover, fluridone protected mice from toxoplasmosis. PMID- 18445835 TI - Evolution of knowledge related to breast cancer heterogeneity: a 25-year retrospective. PMID- 18445836 TI - One to three versus four or more positive nodes and postmastectomy radiotherapy: time to end the debate. PMID- 18445837 TI - Will we ever be ready for blood level-guided therapy? PMID- 18445838 TI - Nomogram for the prediction of having four or more involved nodes for sentinel lymph node-positive breast cancer. AB - PURPOSE: The standard of care for patients with a positive (+) sentinel lymph node (SLN) is axillary dissection; however, for various reasons, some SLN+ patients do not undergo dissection. The purpose of this study was to define possible predictors of having four or more involved nodes to provide information for clinicians and patients making decisions about adjuvant chemotherapy and radiation. PATIENTS AND METHODS: We reviewed the records of 402 patients with invasive breast cancer and one to three involved SLNs who underwent completion axillary dissection at two academic cancer centers. None of these patients received neoadjuvant chemotherapy. Factors associated with having four or more involved axillary nodes (SLNs and non-SLNs) were evaluated by univariate and multivariate logistic regression analysis. RESULTS: Eighty-seven patients had four or more positive nodes. On multivariate analysis, having four or more SLNs was associated with tumor histology, primary tumor size, lymphovascular space invasion, extranodal extension, the number of involved SLNs, the number of uninvolved SLNs, and the size of the largest SLN metastasis. A nomogram to predict the probability of having four or more nodes based on patients' pathologic data was developed from the multivariate logistic regression model. A separate previously published data set of 206 SLN+ patients treated at a community hospital in another city was used to validate this model. CONCLUSION: Patients with a low probability of having four or more nodes can be identified from known pathologic features. The nomogram developed will be helpful to clinicians making adjuvant treatment recommendations. PMID- 18445839 TI - Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. AB - PURPOSE: A phase III, multicenter, randomized study compared conventional dosing of fluorouracil (FU) plus folinic acid with pharmacokinetically guided FU dose adjustment in terms of response, tolerability, and survival. PATIENTS AND METHODS: Two hundred eight patients with measurable metastatic colorectal cancer were randomly assigned to one of two arms: arm A (104 patients; 96 assessable), in which the FU dose was calculated based on body-surface area; and arm B (104 patients; 90 assessable), in which the FU dose was individually determined using pharmacokinetically guided adjustments. The initial regimen was 1,500 mg/m(2) FU plus 200 mg/m(2) folinic acid infusion during a continuous 8-hour period administered once weekly. FU doses were adjusted weekly in arm B based on a single-point measurement of FU plasma concentrations at steady state until the therapeutic range (targeted area under the curve 20-25 mg x h x L(-1)) previously established in other studies was reached. RESULTS: An intent-to-treat analysis of the 208 patients showed the objective response rate was 18.3% in arm A and 33.7% in arm B (P = .004). Median overall survival was 16 months in arm A and 22 months in arm B (P = .08). The mean FU dose throughout treatment was 1,500 mg/m(2)/wk in arm A and 1,790 +/- 386 mg/m(2)/wk (range, 900 to 3,300 mg/m(2)/wk) in arm B. Toxic adverse effects were significantly more frequent and severe in arm A compared with arm B (P = .003). CONCLUSION: Individual FU dose adjustment based on pharmacokinetic monitoring resulted in significantly improved objective response rate, a trend to higher survival rate, and fewer grade 3/4 toxicities. These results support the value of pharmacokinetically guided management of FU dose in the treatment of metastatic colorectal patients. PMID- 18445840 TI - Potential regional differences for the tolerability profiles of fluoropyrimidines. AB - PURPOSE: We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability. METHODS: Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study). RESULTS: In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR. CONCLUSION: Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR. PMID- 18445841 TI - Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. AB - PURPOSE: Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slow-growing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [(177)Lu DOTA(0),Tyr(3)]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients. PATIENTS AND METHODS: Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients. RESULTS: Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis. CONCLUSION: Treatment with [(177)Lu DOTA(0),Tyr(3)]octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years. PMID- 18445842 TI - Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group. AB - PURPOSE: This phase II study evaluated the efficacy and safety of sorafenib plus dacarbazine in patients with advanced melanoma. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled, multicenter study enrolled chemotherapy-naive patients with stage III (unresectable) or IV melanoma. A total of 101 patients received placebo plus dacarbazine (n = 50) or sorafenib plus dacarbazine (n = 51). On day 1 of a 21-day cycle, patients received intravenous dacarbazine 1,000 mg/m(2) for a maximum of 16 cycles. Oral sorafenib 400 mg or placebo was administered twice a day continuously. The primary end point was progression-free survival (PFS) by independent assessment. Secondary and tertiary end points included time to progression (TTP), response rate, and overall survival (OS). RESULTS: Median PFS in the sorafenib plus dacarbazine arm was 21.1 weeks versus 11.7 weeks in the placebo plus dacarbazine arm (hazard ratio [HR], 0.665; P = .068). There were statistically significant improvements in PFS rates at 6 and 9 months, and in TTP (median, 21.1 v 11.7 weeks; HR, 0.619) in favor of the sorafenib plus dacarbazine arm. No difference in OS was observed (median, 51.3 v 45.6 weeks in the placebo plus dacarbazine and sorafenib plus dacarbazine arms, respectively; HR, 1.022). The regimen was well tolerated and had a manageable toxicity profile. CONCLUSION: Sorafenib plus dacarbazine was well tolerated in patients with advanced melanoma and yielded an encouraging improvement in PFS. Based on these findings, additional studies with the combination are warranted in this patient population. PMID- 18445843 TI - Prospective analysis of TEL gene rearrangements in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. AB - PURPOSE: To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years. RESULTS: Rearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate (+/- SE) for patients with TEL rearrangements was 86% +/- 2%, compared with 72% +/- 2% for those with germline TEL (P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (P = .0002). CONCLUSION: We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects. PMID- 18445844 TI - MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. AB - PURPOSE: Standard therapy for glioblastoma (GBM) is temozolomide (TMZ) administration, initially concurrent with radiotherapy (RT), and subsequently as maintenance therapy. The radiologic images obtained in this setting can be difficult to interpret since they may show radiation-induced pseudoprogression (psPD) rather than disease progression. METHODS: Patients with histologically confirmed GBM underwent radiotherapy plus continuous daily temozolomide (75 mg/m(2)/d), followed by 12 maintenance temozolomide cycles (150 to 200 mg/m(2) for 5 days every 28 days) if magnetic resonance imaging (MRI) showed no enhancement suggesting a tumor; otherwise, chemotherapy was delivered until complete response or unequivocal progression. The first MRI scan was performed 1 month after completing combined chemoradiotherapy. RESULTS: In 103 patients (mean age, 52 years [range 20 to 73 years]), total resection, subtotal resection, and biopsy were obtained in 51, 51, and 1 cases, respectively. MGMT promoter was methylated in 36 patients (35%) and unmethylated in 67 patients (65%). Lesion enlargement, evidenced at the first MRI scan in 50 of 103 patients, was subsequently classified as psPD in 32 patients and early disease progression in 18 patients. PsPD was recorded in 21 (91%) of 23 methylated MGMT promoter and 11 (41%) of 27 unmethylated MGMT promoter (P = .0002) patients. MGMT status (P = .001) and psPD detection (P = .045) significantly influenced survival. CONCLUSION: PsPD has a clinical impact on chemotherapy-treated GBM, as it may express the glioma killing effects of treatment and is significantly correlated with MGMT status. Improvement in the early recognition of psPD patterns and knowledge of mechanisms underlying this phenomenon are crucial to eliminating biases in evaluating the results of clinical trials and guaranteeing effective treatment. PMID- 18445845 TI - Cancer survivors' adherence to lifestyle behavior recommendations and associations with health-related quality of life: results from the American Cancer Society's SCS-II. AB - PURPOSE: To examine the prevalence and clustering of physical activity (PA), fruit and vegetable consumption (5-A-Day), and smoking across six major cancer survivor groups and to identify any associations with health-related quality of life (HRQoL). METHODS: A total of 9,105 survivors of six different cancers completed a national cross-sectional survey that included the lifestyle behavior questions and the RAND-36 Health Status Inventory. RESULTS: Only a minority of cancer survivors were meeting the 5-A-Day (14.8% to 19.1%) or PA (29.6% to 47.3%) recommendations, whereas most were meeting the smoking recommendation (82.6% to 91.6%). In terms of the lifestyle behavior clusters, only 5% of cancer survivors were meeting all three recommendations. Analyses of covariance generally showed higher HRQoL in survivors who were meeting versus not meeting each lifestyle behavior recommendation with the strongest associations emerging for PA. Trend analyses showed a steep positive association between the number of lifestyle behavior recommendations being met and HRQoL for breast (P < .001), prostate (P < .001), colorectal (P < .001), bladder (P < .001), uterine (P < .001), and skin melanoma (P < .001) cancer survivors. CONCLUSION: Few cancer survivors are meeting the PA or 5-A-Day recommendations, and even fewer are meeting all three lifestyle recommendations. The association between the current lifestyle recommendations and HRQoL in cancer survivors appears to be cumulative. Interventions to increase PA and fruit and vegetable consumption and reduce smoking are warranted and may have additive effects on the HRQoL of cancer survivors. PMID- 18445846 TI - Consistency of phase III clinical trial abstracts presented at an annual meeting of the American Society of Clinical Oncology compared with their subsequent full text publications. AB - PURPOSE: This study aimed to determine the consistency of phase III clinical trial abstracts presented at American Society of Clinical Oncology (ASCO) Annual Meetings compared with their subsequent full-text publications. METHODS: We identified abstracts describing phase III clinical trials of chemotherapy, chemoradiotherapy, immunotherapy, and hormone therapy presented at the 36th ASCO Annual Meeting in May 2000. We searched MEDLINE and PubMed for all corresponding publications. Data were extracted from the abstracts and publications that met our inclusion criteria. RESULTS: A total of 192 abstracts were identified. Seventy-four abstracts met our inclusion criteria. Six years after the 2000 ASCO Meeting, 74% of abstracts had corresponding publications. The primary end point was stated in 34% of abstracts and 100% of published papers. The primary end point result differed by more than 5% between the abstract and publication in 42% of comparisons. The statistical significance of the primary end point and study conclusions were consistent between abstracts and subsequent publications in 89% and 91% of the comparisons, respectively. Abstracts selected as plenary or oral presentations were significantly more likely to be published. No factors predicted consistency for primary end point significance and overall conclusion between ASCO abstracts and their journal publications. CONCLUSION: When carefully selected, ASCO Annual Meeting abstracts of phase III trials consistently reflect final published results, but some differences were observed that warrant caution in using abstract results to shape treatment decisions before full publication. PMID- 18445847 TI - Burkitt's leukemia after treatment of primary mediastinal nonseminomatous germ cell tumor. PMID- 18445848 TI - Invasive pulmonary aspergillosis associated with marijuana use in a man with colorectal cancer. PMID- 18445849 TI - Intrathoracic malignant peripheral nerve sheath tumor in neurofibromatosis 1. PMID- 18445850 TI - Horns of a dilemma. PMID- 18445852 TI - Randomized clinical trials, clinical use, and hope: what relationship? PMID- 18445853 TI - Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. PMID- 18445854 TI - Pharmacoeconomic benefits of capecitabine-based chemotherapy in metastatic colorectal cancer. PMID- 18445855 TI - Re: Should capecitabine replace infusional fluorouracil and leucovorin when combined with oxaliplatin in metastatic colorectal cancer? PMID- 18445856 TI - KRAS mutation signature in colorectal tumors significantly overlaps with the cetuximab response signature. PMID- 18445857 TI - Hepatic arterial infusion: the beginning of the combination era. PMID- 18445858 TI - Germline PTEN mutations as a cause of early-onset endometrial cancer. PMID- 18445859 TI - Is there a definitive answer to the question of involved-field radiotherapy for inoperable non-small-cell lung cancer? PMID- 18445860 TI - Area between curves: what you see is not what you get. PMID- 18445861 TI - Pediatric palliative care: an assessment of physicians' confidence in skills, desire for training, and willingness to refer for end-of-life care. AB - This study determines the confidence levels of physicians in providing components of pediatric palliative care and identifies their willingness to obtain training and to make palliative care referrals. Surveys were mailed to all physicians at Primary Children's Medical Center. The survey instrument includes 3 demographic items, 9 items designed to assess physician confidence in core palliative care skills, and 4 items designed to assess what steps physicians would be likely to take to assure that patients receive palliative care. Physicians were asked to rate their confidence levels to provide palliative care components on a 4-point scale for each of the items. Five hundred ninety-seven surveys were mailed, with 323 usable surveys returned. The proportion of physicians who rate their ability to provide palliative care as "confident" or "very confident" ranges from 74% for giving difficult news to families to 23% for managing end-of-life symptoms. Thirty-six percent of the physicians say they would be "likely" or "very likely" to attend training to improve their ability to provide palliative care to children. Eighty-six percent would be "likely" or "very likely" to refer for a palliative care consult and 91% to a home health agency or hospice. There is wide variation in the confidence levels of physicians to provide the core components of palliative care. Few are interested in obtaining additional training, but most are willing to obtain consultation or to refer to a palliative care service. These results argue in favor of hospital-based palliative care teams and for specialty training and certification in pediatric palliative care. PMID- 18445862 TI - Some common problems faced by hospice palliative care volunteers. AB - This paper examines 4 common problems that many hospice palliative care volunteers in Canada (and the United States) encounter, namely, being underutilized, being placed with a patient too late in the patient's illness, feeling undervalued by some members of the medical staff, and not being able to do more to help patients and their families. The implications of each of these problems are discussed along with suggestions for overcoming them. Finally, some ideas for future research are proposed. PMID- 18445863 TI - Prediction of patient survival by healthcare professionals in a specialist palliative care inpatient unit: a prospective study. AB - Accurate prognostication is an enormous challenge for professionals caring for patients with advanced disease. Few studies have compared the prognostic accuracy of different professional groups within a hospice setting. The aim of this study was to compare the ability of 5 professional groups to estimate the survival of patients admitted to a specialist palliative care unit. No group accurately predicted the length of patient survival more than 50% of the time. Nursing and junior medical staff were most accurate while care assistants were least accurate. When in error, senior clinical staff tended to under-estimate survival. Independent mobility on admission was the only variable predictive of length of survival. Thus, professional groups differ in their prognostic accuracy. An awareness of a group's propensity to over- or under-estimate prognosis should be incorporated into future work on prognostication models. PMID- 18445865 TI - Locked-in syndrome. PMID- 18445864 TI - Methadone. AB - Methadone hydrochloride is an old drug that has been in vogue off and on. It has complex pharmacodynamics and can be potentially fatal in inexperienced settings. Drug switching from an opioid to methadone or vice versa requires knowledge of equianalgesic dosing. It is critical when using the drug to monitor for signs and symptoms of toxicity so that overdosing or toxicity can be identified in a timely manner. This review discusses these important topics so that methadone can be used safely and effectively. PMID- 18445866 TI - Why opioids and sedatives may prolong life rather than hasten death after ventilator withdrawal in critically ill patients. AB - The process of death in patients in whom cardiorespiratory support is withdrawn is related to the occurrence of tissue hypoxia that results from an imbalance between the demand for oxygen and the delivery of oxygen to the organs. Limiting the demand for oxygen may thus delay the occurrence of tissue hypoxia. Because the demand for oxygen increases significantly after ventilator withdrawal and because sedatives and opioids are known to decrease the demand for oxygen in patients with cardiorespiratory distress, these agents might thus actually prolong life rather than hasten death. PMID- 18445868 TI - [Review of symptoms and therapy of paraphylias]. AB - The authors review the historical main milestones in the legislative aspects of sexual deviances, from ancient times through age of enlightenment to present times, including the factors affecting the Hungarian public attitudes towards it. The evolution of nomenclature of sexual orientation disorders is also evaluated thoroughly, detailing the DSM-IV-TR classification and the attempts and difficulties to further develop the present classification system. The authors also review the difficulties of epidemiological studies and sum up the pioneer work of Alfred Kinsey. The etiology of paraphylias is summed up based on biological, psychodynamic and learning theory approaches. Finally, the pharmacological and psychotherapeutic interventions are evaluated considering also comorbidity, outer control and forensic psychiatric aspects. PMID- 18445867 TI - Palliative care in overdrive: patients in danger. PMID- 18445869 TI - [Mirror neurons--novel data on the neurobiology of intersubjectivity]. AB - Social experiences are largely intersubjective in nature, offering an abundance of pre-reflective, simulative knowledge of others' subjective experiences. In the last decades, special mirror neurons have been found in the premotor area and in the posterior parietal cortex. They directly link perception to action: the perception of actions activates the relevant parts of the observer's motor system. Emotional expressions evoke resonance states inside the observer in a similar way. Besides underscoring the prereflective and implicit nature of intersubjectivity, this can provide an access to the neuronal basis of empathy and intuition. Moreover, a new integration of psychoanalysis and neuroscience seems to be possible, which shifts the psychoanalytic technique toward non-verbal and non-interpretative methods, and can explain psychoanalytic phenomena, such as introjection, projection, transference, counter-transference, and the very complex enactments. PMID- 18445870 TI - [Relationship between suicide and antidepressant consumption (N06A) in an elderly population (over 60 years) from Bacs-Kiskun county and the Kiskunhalas region in Hungary between 1999 and 2005]. AB - INTRODUCTION: Although the number of suicides has been decreasing significantly in Hungary since 1983, it is still at a very high level. In spite of the general decrease in statistical figures, between 2004 and 2005 the number of male suicide victims increased in 8 counties and in 3 regions, while the number of female suicide victims increased in 4 counties. There are several new hypotheses to explain the decrease, among which, the most controversial is the one looking for connections between the decreasing number of suicide victims and the increasing consumption of antidepressants (N06A). METHODOLOGY: Between 1999 and 2005, the relationship between suicides and antidepressant consumption was examined and analyzed in the 60+ population, coming from the Kiskunhalas, Kiskunmajsa and Janoshalma small regions, the service area of the psychiatric ward of Kiskunhalas Hospital, from Bacs-Kiskun County and from Hungary. These data were compared with those of the small region of Kiskunfelegyhaza, which was the control area of the Kiskunhalas suicide prevention programme. Four indicators were used in the analysis of antidepressant consumption and suicides: 1. The number of patients using antidepressants. 2. The days of treatment; DOT. 3. The amount of the antidepressant used. 4. DHD: DDD/1000 inhabitant/day. (DDD: Defined daily dose by the WHO). Considering the fact that depressive states mixed with anxiety increase the risk of suicide, the connections between the number of suicides and the use of anxiety drugs were also analyzed. The connections were identified with correlation coefficients. RESULTS: The results of the analysis supported the hypothesis that despite some contradictions, there is a connection between the increase in antidepressant use and the decrease in the number of suicides. CONCLUSIONS: First, the complex diagnostics and treatment of depression has led to the decrease in suicidal risk in depressed patients. Second: more attention must be paid to anxiety disorders. Third: in the forthcoming suicide prevention programmes, greater attention must be paid to the 60+ population. Fourth: there is an underlying question which remains to be explained by future research: considering the fact that depressive disorders can be treated, why cannot this lead to a sharper decrease in the number of suicides? PMID- 18445871 TI - [Individual aspirations and depression]. AB - The aim of our survey was to reveal the individual aspirations and personal strivings among college students which may play an important role as protective factors in the preservation of mental health, particularly regarding sub-clinical depressive syndromes. 712 college students were involved in the study (545 females and 167 males). The abridged version of Beck's Depression Inventory was used for measuring the severity of depression, while the Aspiration Questionnaire was used to assess the rate of individual aspirations. RESULTS: When estimating the importance of individual aspirations, we found intrinsic aspirations to be predominant for both genders of college students, with a minor shift in individual parameters. While in the case of women, health, social relationships and personal advancement were listed in this order of importance; in the case of men, personal advancement was ranked first, followed by the categories of health and social relationships. Out of the symptoms of depression, social reservation showed the closest correlation with the importance of certain personal strivings, and, within these, with the lack of intrinsic aspirations. Certain symptoms of depression - irrespective of sex - were found to have a very close correlation with the probability of nearly every personal aspiration, as well as with their realisation, and, within these, they were in a stronger correlation with the intrinsic aspirations than with the extrinsic ones (in the case of men, stronger correlation between the probability of every aspiration for depressive syndromes and the realisation thereof were also found to be stronger than in the case of women). When examining the overall correlation between all the three categories of individual aspirations (importance, probability, realisation) in depression, we found that depression showed a close negative correlation with the probability of personal growth and social relationships and the realisation of health; while a positive correlation was detected with the importance attributed to intrinsic aspirations, which explained almost one-fourth of the variances of depression altogether. The depressive syndromes found to be typical of college students (worthlessness, fatigue, hesitation, hopelessness, dissatisfaction) showed a much closer correlation with the importance, probability and realisation of individual aspirations in the case of men than in the case of women. Out of the aforementioned symptoms of depression, individual aspirations had the closest correlation with hopelessness in both genders. While in the case of men, the importance of intrinsic aspirations and the current dissatisfaction with these may lead mainly to the development of hopelessness; for women, the development of the feeling of hopelessness is primarily correlated with an extrinsic aspiration, the importance of wealth and the current lack thereof. As for the rest of the depressive syndromes, the explanatory power of the correlation with individual aspirations was different for women and men. PMID- 18445872 TI - [Structural MRI investigation in schizophrenia with optimised voxel-based morphometry--a pilot study]. AB - The quantitative and structural MRI methods have an emergent role in the fields of psychiatric disorders. In our paper we present voxel-based morphometry, which is the most frequently used structural MRI method. We compared eight patients with schizophrenia and eight, age-matched healthy subjects to detect focal tissue differences in gray and white matter, and cerebrospinal fluids between the two groups. As with earlier studies, patients with schizophrenia showed decreased gray matter tissue density in frontotemporal and insular regions bilaterally. Moreover, the left-sided parietal operculum and the calcarina showed focal decrease in tissue density. Density decrease in the frontotemporal and insular white matter was detected bilaterally, which was similar to gray matter changes. The left sided precuneus and lingual gyrus were also involved in reduced white matter density. Increased cerebrospinal fluid spaces were detected in the frontal regions and the ventricles. Our results with the optimised voxel-based morphometry are in line with earlier imaging studies and correspond with neuropsychological detectable frontotemporal deficits in schizophrenia. PMID- 18445873 TI - Time-domain finite-difference/finite-element hybrid simulations of radio frequency coils in magnetic resonance imaging. AB - A hybrid method that combines the finite-difference time-domain (FDTD) method and the finite-element time-domain (FETD) method is presented for simulating radio frequency (RF) coils in magnetic resonance imaging. This method applies a high fidelity FETD method to RF coils, while the human body is modeled with a low-cost FDTD method. Since the FDTD and the FETD methods are applied simultaneously, the dynamic interaction between RF coils and the human body is fully accounted for. In order to simplify the treatment of the highly irregular FDTD/FETD interface, composite elements are proposed. Two examples are provided to demonstrate the validity and effectiveness of the hybrid method in high-field receive-and transmit coil design. This approach is also applicable to general bio electromagnetic simulations. PMID- 18445874 TI - In vivo prompt gamma neutron activation analysis for the screening of boron-10 distribution in a rabbit knee: a simulation study. AB - Boron neutron capture synovectomy (BNCS) is under development as a potential treatment modality for rheumatoid arthritis (RA). RA is characterized by the inflammation of the synovium (the membrane lining articular joints), which leads to pain and a restricted range of motion. BNCS is a two-part procedure involving the injection of a boronated compound directly into the diseased joint followed by irradiation with a low-energy neutron beam. The neutron capture reactions taking place in the synovium deliver a local, high-linear energy transfer (LET) dose aimed at destroying the inflamed synovial membrane. For successful treatment via BNCS, a boron-labeled compound exhibiting both high synovial uptake and long retention time is necessary. Currently, the in vivo uptake behavior of potentially useful boronated compounds is evaluated in the knee joints of rabbits in which arthritis has been induced. This strategy involves the sacrifice and dissection of a large number of animals. An in vivo (10)B screening approach is therefore under investigation with the goal of significantly reducing the number of animals needed for compound evaluation via dissection studies. The 'in vivo prompt gamma neutron activation analysis' (IVPGNAA) approach uses a narrow neutron beam to irradiate the knee from several angular positions following the intra-articular injection of a boronated compound whose uptake characteristics are unknown. A high-purity germanium detector collects the 478 keV gamma photons produced by the (10)B capture reactions. The (10)B distribution in the knee is then reconstructed by solving a system of simultaneous equations using a weighted least squares algorithm. To study the practical feasibility of IVPGNAA, simulation data were generated with the Monte Carlo N-particle transport code. The boron-containing region of a rabbit knee was partitioned into 8 compartments, and the (10)B prompt gamma signals were tallied from 16 angular positions. Results demonstrate that for this level of spatial resolution, an estimate of (10)B distribution inside the joint can be obtained to within 10% uncertainty, under ideal conditions. Variations of the anatomic dimensions among individual rabbit knees and potential knee positioning errors will result in an uncertainty of over 20%. IVPGNAA thus provides sufficient resolution and quantification regarding the in vivo uptake characteristics of boronated pharmaceuticals to serve as a useful means of screening new compounds of potential use in BNCS. PMID- 18445875 TI - Interactively variable isotropic resolution in computed tomography. AB - An individual balancing between spatial resolution and image noise is necessary to fulfil the diagnostic requirements in medical CT imaging. In order to change influencing parameters, such as reconstruction kernel or effective slice thickness, additional raw-data-dependent image reconstructions have to be performed. Therefore, the noise versus resolution trade-off is time consuming and not interactively applicable. Furthermore, isotropic resolution, expressed by an equivalent point spread function (PSF) in every spatial direction, is important for the undistorted visualization and quantitative evaluation of small structures independent of the viewing plane. Theoretically, isotropic resolution can be obtained by matching the in-plane and through-plane resolution with the aforementioned parameters. Practically, however, the user is not assisted in doing so by current reconstruction systems and therefore isotropic resolution is not commonly achieved, in particular not at the desired resolution level. In this paper, an integrated approach is presented for equalizing the in-plane and through-plane spatial resolution by image filtering. The required filter kernels are calculated from previously measured PSFs in x/y- and z-direction. The concepts derived are combined with a variable resolution filtering technique. Both approaches are independent of CT raw data and operate only on reconstructed images which allows for their application in real time. Thereby, the aim of interactively variable, isotropic resolution is achieved. Results were evaluated quantitatively by measuring PSFs and image noise, and qualitatively by comparing the images to direct reconstructions regarded as the gold standard. Filtered images matched direct reconstructions with arbitrary reconstruction kernels with standard deviations in difference images of typically between 1 and 17 HU. Isotropic resolution was achieved within 5% of the selected resolution level. Processing times of 20-100 ms per frame allow for interactive use. PMID- 18445876 TI - [Osteoporosis in diabetes]. AB - The diabetes is at great risk of the osteoporosis, and the bone fragility unrelated to bone density forms the pathological conditions peculiar to diabetes. The factor participating in diabetic osteoporosis has a state of insulin action deficiency, a hyperglycemic state, diabetic complications, and so on. An osteoblastic cell function is deteriorated and the number of that is decreased by the absolute and relative insulin deficiency, and sustained hyperglycemia also decreases an osteoblastic cell function still more. Furthermore, the osteoclast related bone resorption is also promoted through sorbitol accumulation in the cell by the hyperglycemia state. The expression of transcription factors regulating osteoblastic cell differentiation is restrained, and the apoptosis of those cells is promoted. As a result, osteoplasty is obstructed. In the bone, AGEs (advanced glycation endproducts) is produced in excess, and bone fragility is promoted by the ratio of the AGEs bridging with the collagen rising. The complications of diabetes, such as visual disorder and the neuropathy, raise the risk of the fall in the diabetic osteoporosis patient, therefore, they will have more chance of fractures. PMID- 18445877 TI - [Bone quality changes in diabetes]. AB - Diabetes-related bone fragility has recently drawn many researchers' attention. Diabetes would affect bone remodeling by various mechanisms, including deficiency of insulin actions, increased accumulation of advanced glycation end products and microangiopathy. The combination of poor bone quality of microstructure and nanoarchitecture (type I collagen and non-collageous proteins) would reduce bone strength. Bone mineral density is the best predictor for fractures of primary osteoporosis, but presumably not for type 2 diabetes. Quality changes of diabetic bone, therefore, should be more thoroughly studied. PMID- 18445878 TI - [Osteoporosis associated with the metabolic syndrome]. AB - The metabolic syndrome is featured by the combination of obesity, dyslipidemia, hyperglycemia, and hypertension. It is well documented that obesity is positively linked to increased bone mineral density (BMD) and reduced fracture risk through body weight increase. Hyper-triglycemia and hypo-HDL-cholesterolemia, which are frequently accompanied with obesity, might also protect against fracture. On the other hand, clinical observations on diabetic patients suggest that hyperglycemia per se tends to reduce BMD and to increase fracture risk in contrast to the above factors. Thus, BMD and fracture risk in patients with the metabolic syndrome may be determined by the balance between beneficial effects of obesity and dyslipidemia versus detrimental ones of hyperglycemia on bone. PMID- 18445879 TI - [Involvement of insulin and IGF-1 signaling molecules in bone metabolism]. AB - Insulin and IGF-1 signaling is the most important factors in diabetes, but is also important regulators in bone metabolism. Insulin and IGF-1 have anabolic effects on osteoblasts in vitro and an association of diabetes with abnormal bone metabolism has been reported. Insulin receptor substrates (IRS), which is a main target molecule of insulin/IGF-1 receptor signaling, have been shown to play important roles in maintaining normal bone turn-over by skeletal analysis of IRS 1 and -2 knock-out mice. Skeletal analysis of disruptive AKT, a downstream molecule of IRS, in mice also revealed that AKT was established as a crucial regulator of osteoblasts and osteoclasts by promoting their differentiation and survival to maintain bone mass and turnover. Further analysis of molecular network in diabetes and bone metabolism will provide a basis for rational therapeutic targets for bone disorders. PMID- 18445880 TI - [Role of adipocytokine in bone metabolism]. AB - Growing evidence suggests that positive association between fat mass and bone mineral density (BMD) is mediated not only biomechanical but also biochemical factors. Recent studies on adipocyte function have revealed that adipose tissue is not merely an energy-storing organ but it secretes a variety of biological active molecules, conceptualized as "adipocytokines", including leptin and adiponectin. Adipocyte also exist in bone marrow, and experimental finding indicate the dynamic involvement of adipocytokines in bone metabolism. This report aims to review some of the effects of adipocytokines in bone metabolism, in relation to visceral fat accumulation. PMID- 18445881 TI - [Effect of obesity on bone metabolism]. AB - Obesity regulates bone metabolism not only by increasing weight loading but by modulating cytokines or hormones which are known to affect bone remodeling. As a result, it has been generally believed that obesity leads to an increase in bone mass. However, recent observations revealed that excessive fat mass may not protect against osteoporotic fractures. PMID- 18445882 TI - [Links between osteoporosis and atherosclerosis; beyond insulin resistance]. AB - Both osteoporosis and atherosclerosis progress with aging. For the progression of atherosclerosis, insulin resistance, often resulted from obesity, is one of the established contributing factors. However, obesity, hence insulin resistance, act protectively for bone. Recently, chronic inflammation, associated with oxidative stress, has been proposed to be one of the missing links between atherosclerosis and osteoporosis. PMID- 18445883 TI - [Regulation of energy metabolism by bone]. AB - In terms of feedback regulation in Endocrinology, one question was arisen from the evidences that energy metabolism regulates bone metabolism. "Does bone metabolism regulates energy metabolism?" To address this question, Dr. Gerard Karsenty and his colleagues studied energy metabolism in the mice lacking Osteocalcin, an osteoblast-specific gene. The mutant mice exhibited abnormal energy metabolism phenotypes, diabetes and obesity. Here I would like to remind you his previous and recent works so that we can discuss how to apply bone metabolism information to therapeutic strategy for metabolic syndrome. PMID- 18445884 TI - [Do thiazolidinediones harm skeletal integrity?]. AB - Thiazolidinediones (TZDs) , a class of drugs that potentiate insulin actions, are widely prescribed to patients with type 2 diabetes mellitus. TZDs are able to bind to and activate PPAR-gamma, a member of nuclear transcription factors, and have been found to be involved in differentiation of many types of cells in addition to improve glucose metabolism. In particular, TZDs possibly reduce bone formation in vivo , since they have been reported to stimulate adipogenesis but inhibit osteoblastogenesis of bone marrow stromal cells. Recently, it has been reported that female patients with type 2 diabetes who were treated with rosiglitazone, a member of TZDs, had higher fracture incident than those with metformin. These observations make us seriously consider if it is good or not to prescribe TZDs to patients with type 2 diabetes, especially older women who have multiple fracture risks. PMID- 18445885 TI - [Molecular mechanism of switching adipocyte / osteoblast differentiation through regulation of PPAR-gamma function]. AB - Adipocytes and osteoblasts are derived from mesenchymal stem cells, and some adipocyte differentiation regulators suppress osteoblast differentiation. PPAR gammaplays a pivotal role for adipocyte differentiation and glucose tolerance. PPAR-gammais a member of nuclear receptor super family and regulates mRNA expression level of target genes by binding to fatty acid derivatives and thiazolidinediones. Recently, it was found that PPAR-gammainhibits osteoblast differentiation and regulates bone metabolism. In this report, we show recent studies about the extracellular signals regulating the transactivation function of PPAR-gamma. PMID- 18445886 TI - [Diet therapy for diabetes and obesity, considering osteoporosis]. AB - The main concept of diet therapy for diabetes and obesity is restricting calorie intake. However, the risk of osteoporosis increases when losing weight. Therefore, when using this diet, one must consider the prevention of osteoporosis. That means taking more calcium while also restricting the total amount of calories and cutting down on fat and carbohydrates. Even if the total energy is the same, calcium intake will vary when only consulting a food exchange list. Table 3, 4, and 6 display foods containing a lot of calcium, but even between table 3 and 6 there are foods with high calcium and foods with low calcium. A specially designed menu makes calorie reduction possible while taking enough calcium. The Japanese average daily calcium intake is 545 for men and 521 mg for women, which is still short of the recommended level of 600 to 700 mg, so taking a supplement while on the diet might be considered. PMID- 18445887 TI - [Relationship between lipid and glucose metabolism and bone mineral metabolism : pleiotropic effects of therapeutic agents for diabetes and hyperlipidemia]. AB - Bone mineral metabolism and bone remodeling involve a variety of molecules, for instance, bone morphogenetic proteins (BMPs) , fibroblast growth factors (FGFs) , insulin growth factors (IGFs) , interleukin-1 (IL-1) , prostagrandin E(2) (PGE(2)) , and tumor necrosis factor-alpha (TNF-alpha) . Most of them are also involved in lipid and glucose metabolism. Recent in vitro and in vivo studies have reported that therapeutic agents for diabetes and hyperlipidemia, such as insulin, thiazolidinediones, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have pleiotropic effects on bone mineral metabolism. These agents may be useful tools for treatment of bone and mineral disorders. PMID- 18445889 TI - [Pyogenic vertebral osteomyelitis]. AB - Historically, pyogenic vertebral osteomyelitis was disease with high morbidity and mortality rate. In recent years, with advance of new diagnostic techniques, antimicrobial chemotherapy, and improvement in surgical techniques, the prognosis has improved dramatically. However, as a recent tendency, the number of patients tends to increase by aging of the patient, increase of immuno-compromised host and resistant bacteria. There is a case the spine infection with immuno compromised host sometimes accompanies sepsis and to die. Therefore, the management of this disease has still many pitfalls and problems. An early diagnosis is necessary, and identification of causative organism and appropriate antimicrobial chemotherapy are basics of treatment. But when indicated, we should cooperate with a spinal surgeon closely, and choose surgical intervention. PMID- 18445888 TI - [Effects of antiosteoporotic agents on glucose and lipid metabolism and cardiovascular system]. AB - Cardiovascular disease is the main contributor of mortality among postmenopausal women. Hormone Replacement Therapy (HRT) has been reported to have a beneficial effect on metabolic and vascular factors. Although, randomized clinical trials have questioned the efficacy of HRT in primary and secondary coronary artery disease (CAD) prevention despite confirming the lipid-lowering effect of HRT. As for selective estrogen receptor modulators (SERMs) , the available information suggests a neutral balance on CAD and stroke, and an increase in risk similar to estrogens for venous thromboembolic diseases. Evidence from both basic science and clinical studies supports the protective role of vitamin D beyond its effect on mineral metabolism. Recent studies suggest that Vitamin D improves vascular compliance, and reduces pro-inflammatory cytokines which may contribute to the improved survival observed in retrospective studies examining the outcome of patients treated with activated Vitamin D compared to those who were not. PMID- 18445890 TI - [Mechanism of bone and cartilage growth during childhood and growth disorders]. AB - Longitudinal growth of bone depends on the proliferation and differentiation of chondrocytes located in growth plate. Recent advances in understanding the process of chondrocyte proliferation and differentiation reveal the local and systemic factors responsible for the process. SOX9, Ihh and FGFR3 are the former, growth hormone and thyroid hormone the latter. Achondroplasia, a representative entity of skeletal dysplasia is caused by the abnormality of FGFR3 and exhibits short stature. Hypofunction of growth hormone and thyroid hormone are associated with short stature as well. PMID- 18445891 TI - Contribution of inflammation to vascular disease in chronic kidney disease patients. AB - Chronic kidney disease (CKD) is characterized by an exceptionally high mortality rate, much of which results from cardiovascular disease (CVD). Chronic low-grade inflammation, as evidenced by increased levels of pro-inflammatory cytokines and C-reactive protein (CRP), is a common feature of CKD and may cause atherosclerotic CVD through various pathogenetic mechanisms. Evidence suggests that persistent inflammation may also be a risk factor for progression of CKD, which may result in a vicious inflammation-driven circle. The causes of inflammation in CKD are multifactorial. The influence of various comorbidities may contribute to inflammation in the setting of progressive loss of renal function. Available data suggest that pro-inflammatory cytokines also play a central role in the genesis of the metabolic syndrome. There is a lack of epidemiological data on the prevalence and consequences of inflammation in relation to protein-energy wasting (PEW) and CVD in CKD patients from developing countries. The 'westernization' of nutritional intakes and changes of life style besides the high prevalence of chronic infections in developing countries are possible additive contributors to a high prevalence of inflammation, PEW and CVD among CKD patients. Also, genetic differences may affect inflammatory responses and nutritional status and, thus, the susceptibility to CVD in different regions. PMID- 18445892 TI - Need for renal biopsy registry in Saudi Arabia. AB - Many renal lesions may result in chronic kidney disease if not detected early or treated properly. Glomerulonephritis is considered one of the leading causes of end-stage renal disease. The prevalence of different renal lesions were identified by inconsistent studies. The causes of inconsistencies include lack of unified methods in diagnosing and processing renal biopsies by different pathologists, patients selection's bias for renal biopsy, and the variable policies and protocols adopted by different nephrologists. Establishment of renal biopsy registry may help to surmount these differences. In addition, combined data obtained from renal biopsy renal and replacement therapy registries can help study the long-term outcome of patients with renal diseases. PMID- 18445893 TI - Candiduria: a review of clinical significance and management. AB - Candiduria is a common nosocomial infection afflicting the urinary tract. This review is aimed at providing an updated summary of the problem in hospitalized adult patients. A review of English Medline literature published between Jan 1970 until June 2007 was performed. Reviews, clinical trials and case-controlled studies in adult patients were included. Risk factors for candiduria included urinary indwelling catheters, use of antibiotics, elderly age, underlying genitourinary tract abnormality, previous surgery and presence of diabetes mellitus. Presence of candiduria may represent only colonization and there are no consistent diagnostic criteria to define significant infection. Candiduria may not be associated with candidemia and most cases are asymptomatic. Asymptomatic candiduria is usually benign, and does not require local or systemic antifungal therapy. Physicians need to confirm the infection by a second sterile urine sample, adopt non-pharmacologic interventions and modify risk factors. Mortality rate can be high particularly in debilitated patients and awareness to validate candiduria is necessary to stratify treatment according to patient status. Appropriate use of anti fungal drugs, when indicated, should not replace correction of the underlying risk factors. Treatment of symptomatic candiduria is less controversial and easier. PMID- 18445895 TI - Factors predisposing to post-renal transplant erythrocytosis: a retrospective study. AB - A retrospective study was conducted on 143 consecutive renal transplant recipients who had a functioning graft for three months or longer, to evaluate the prevalence of post-transplant erythrocytosis (PTE) and its potential risk factors. True PTE was defined as hematocrit (Ht) above 52% and hemoglobin (Hb) above 18 g/dl in males, and Ht above 50% and Hb above 17 g /dl in females. A total of 31 patients (21.6%) developed PTE; none had any evidence of polycythemia vera (PV), or secondary polycythemia due to reduced arterial oxygen, kidney or hepatic tumors, or relative erythrocytosis due to a decrease in plasma volume by overuse of diuretics. Thirty-one non-polycythemic patients (Hb 12.9 +-1.6 g/dl) matched for sex, age and renal function were used as case controls. PTE was more common in males (p= 0.043). The majority of our patients developed PTE within the first year post-transplantation and all had excellent renal function at the time of diagnosis. Also, PTE was found to be related to duration on dialysis prior to transplantation (p= 0.0013) and acute rejection (p= 0.0031). PMID- 18445894 TI - Normal reference levels of serum cystatin C in Saudi adults. AB - This is the first report from Saudi Arabia studying the normal reference intervals in adult Saudi subjects and evaluating serum cystatin C as a prospective marker for the assessment of the glomerular filtration rate (GFR). Three hundred healthy adult Saudi subjects including 156 males (52%) and 144 females (48%), with a mean age of 31.21 +/- 9.82 years were prospectively studied to establish normal reference ranges for cystatin C. A total of 68.34% of the study patients were in the age-group of 21-40 years. The mean serum cystatin C in the 300 healthy subjects was 0.751 +/- 0.11 mg/L (0.50 - 1.09), increasing gradually with age: it was 0.738 +/- 0.11 mg/L (0.51 - 1.09) in the age-group 21 30 years and 0.807 +/- 0.12 (0.51 - 1.09) among subjects who were > 50 years of age. The mean serum cystatin C in females (0.778 +/- 0.118 mg/L) was significantly hig-her than in males (0.726 +/- 0.095 mg/L) (p < 0.0001). The serum cystatin C level was within the defined reference range of 0.53 - 0.95 mg/L in 95% of the subjects with a mean value of 0.74 +/- 0.097 mg/L, and was falling within the 95% confidence interval of 0.73865 - 0.7637 mg/L, and with 98.84% area under the curve (AUC). All the other renal function markers (urea, serum creatinine, calculated GFR, BMI) among the studied subjects were within the normal reference ranges for adult Saudi population. The serum cystatin C level had a significant correlation with the body mass index (BMI) (r = 0.155; p = 0.007) and a correlation with serum creatinine as well (r = 0.009; p = 0.873). It showed a negative correlation with calculated GFR as per Cockroft-Gault equation (r = - 0.101; p = 0.083). PMID- 18445896 TI - Stabilizing effects of cool dialysate temperature on hemodynamic parameters in diabetic patients undergoing hemodialysis. AB - To investigate the effect of cool dialysis on hemodynamic parameters and serum nitric oxide levels in diabetic patients, we studied 20 old (mean age 63.3 +/- 7.5) chronic hemodialysis diabetics who were dialyzed twice, once using cool and once using standard (37 degrees C) temperature dialysate solution. During the study, all the dialysis conditions were maintained the same except cooling the dialysate from 37 degrees C to 35 degrees C. Hemodynamic parameters including SBP, DBP, and HR were measured hourly. Oral temperature was measured before and after dialysis. Serum urea and nitric oxide metabolites were determined before and after hemodialysis. Systolic, diastolic, and mean arterial pressure decreased significantly during standard temperature compared to cool dialysis. Maximum decrease of systolic, diastolic, and mean arterial pressure was observed during the third hour of dia-lysis and the magnitude of decrease was 18, 17, and 14 percent for standard temperature and 6, 1, and 4 percent for cool dialysis, respectively. Heart rate did not differ significantly between the two study groups. Compared to the pre dialysis levels of serum nitric oxide metabolites, the post dialysis levels decreased significantly with cool and standard temperature dialysate (59 +/- 5 vs. 37 +/- 4, and 63 +/- 7 vs. 41 +/- 5, micromol/L respectively, P< 0.01). Cool dialysis could decrease episodes of hypotension and stabilized hemodynamic parameters in diabetic patients. Probably other mechanisms than increased serum nitric oxide levels may be involved in hemodialysis hypotension in this group of patients. PMID- 18445897 TI - High failure rate of first arterio-venous fistula in patients starting hemodialysis treatment: a report from the Ivory Coast. AB - This study was conducted in order to identify the failure rate of the first arterio-venous fistula (AVF) in patients starting hemodialysis (HD) with a central venous catheter (CVC) and to search for factors responsible for this failure. A retrospective study was conducted on 85 patients on chronic HD in Abidjan, from March 15 th to April 15 th , 2007. Factors that could potentially influence the failure of the first AVF were collected. Statistical analysis was used for comparison between groups. Among the study subjects, 7.14% had AVF at the start of their dialysis as against 92.86% who had CVC. About 50% of the patients starting dialysis with CVC failed to have an AVF created within 90 days of commencing dialysis. The number of catheters inserted was significantly higher in patients with failed first AVF as compared to their counterparts (49.29 % versus 30.77%) (p< 0.001). Similarly, the number of attempts at AVF creation, within 90 days of starting HD, was significantly higher in patients with failed first AVF (81.48% versus 18.52%) (p< 0.001). Multivariate analysis did not reveal any specific factor(s) that influenced the failure rate of the first AVF. Our study suggests that a very small number of patients in Ivory Coast started dialysis with an AVF. The failure rate of the first AVF in patients starting dialysis on CVC is about 50%. PMID- 18445898 TI - The role of early identification of superior mesenteric artery in a modified technique for retrieval of abdominal organs for transplantation. AB - Abdominal organ recovery has undergone important changes in concepts and practice in recent years, most importantly in the combined approach to retrieve the liver and pancreas by one surgical team. We studied retrospectively 81 organ donors and their respective recipients that were performed from 1996-1997. We compared the results of organ function, morbidity, mortality, and operative time of two different surgical techniques. Besides the standard technique (group 1), we used a new technique (group 2) that involves pre cross-clamp identification of the superior mesenteric artery (SMA). There was no significant difference in organ function parameters between the two groups supporting the safety of the new technique. However, there was a 50% reduction in the time needed to achieve aortic cross clamping with the new technique. We conclude that this new technique is safe to apply, distinct in reducing organ retrieval time, and easy to learn. PMID- 18445899 TI - Effect of diuretics on ureteral stone therapy with extracorporeal shock wave lithotripsy. AB - To evaluate the effect of diuretics on ureteral stone fragmentation and clearance during therapy with extra corporeal shock wave lithotripsy (ESWL), we studied 87 patients with ureteral stone at different levels and treated with ESWL. The patients were randomized into two groups treated by standard ESWL; the treatment protocol included 3500 shock wave per patient in each session, energy of the shock in two groups was 13 to 9 kv per patient, and the number of sessions was 3 per patient. The first group included 43 patients who received only ESWL, while the second group of 44 patients received as well 40 mg of furosemide. Stone fragmentation rate was 81% and 93.1% and stone clearance rate was 68.2% and 88.4% for the first and the second groups, respectively. With diuretics, fragmentation was 18.8% more in the middle ureteral stones, 16.9% more in the upper tract stones, and 5.4% more in the distal stones. Moreover, clearance of fragmented stones was 38%, 28%, 15.4% more at middle and upper and distal ureteral stone, respectively. We conclude that the stone fragmentation and clearance were higher with ESWL and diuretics than without diuresis. Diuresis is safe and has some advantage at increasing the effect of ESWL on ureteral stones especially the middle ureteral calculi. PMID- 18445900 TI - Predictors of hyperparathyroidism in renal transplant recipients. AB - The changes in parathyroid hormone secretion after successful renal transplantation remain to be clearly elucidated. Our study was aimed at identifying the predictors of hyperparathyroidism in renal transplant recipients. A retrospective single center study involving 37 renal transplant recipients, with a follow-up of at least one year, was performed. All transplants were performed using kidneys from living related donors. The average age of the study patients was 30 +/- 10 years, with a male-female ratio of 1.31. The mean duration on hemodialysis (HD) prior to transplantation was 25 +/- 18 months. All the grafts but one, were functional after a mean follow-up of 41 +/- 21 months. We noted a rapid reduction of the mean parathyroid hormone (iPTH) level from 383 +/- 265 pg/ml before transplantation to 125 +/- 67 pg/ml at one year and 108 +/- 66 pg/ml at two years after transplantation (p = 0.01). Bivariate analysis revealed that the level of iPTH obtained during follow-up correlated with the duration on HD (p = 0.03), the serum creatinine at 24-months (p = 0.013), and to the level of iPTH in the first year post-transplantation (p = < 0.001). Other clinical or laboratory parameters were not predictive of hyperparathyroidism after kidney transplantation. Linear regression showed that only the serum creatinine at 24 months independently correlated with the level of iPTH at last follow-up (p = 0.02). Our study suggests that short duration on HD and a functional graft are the main predictors of correction of hyperparathyroidism after renal transplantation. PMID- 18445901 TI - Acute renal failure in snake envenomation: a large prospective study. AB - Venomous snakebite is a common problem in India. The aim of this study is to assess the prevalence, risk factors and prognostic factors in snakebite induced acute renal failure and to determine their outcome from a tertiary care center in India. A total of 1548 cases of snakebite admitted to adult medical wards of Government Rajaji hospital from January 2003 to December 2004, were studied from hospitalization to discharge or death. There were 1180 poisonous and 368 nonpoisonous snakebites. Among the poisonous, there were 1121 viperidae and 59 elapidae bites. A total of 159 (13.5%) patients (M = 98, F = 61) developed acute renal failure; of them 72 (45.3%) required dialysis and 36 (22.6%) expired (of them, 23 required dialysis). ARF patients were older than non ARF (39.1 vs. 35.4 years, p = 0.03). Cellulites (OR 9.20, p = 0.032), regional lymphadenopathy (OR 22.0, p= 0.001), intravascular hemolysis (OR 3.70, p = 0.004) and bite to needle time more than 2 hours (OR 2.10, p = 0.001) were identified as independent risk factors for the development of acute renal failure. Bite to needle time more than 2 hours (OR 2.10, p = 0.01), presence of intravascular hemolysis (OR 13.0, p = 0.004) and hypotension (OR 22.2, p = 0.04) and the presence of bleeding manifestations (OR 7.91, p = 0.032) were identified as independent predictors of poor outcome in snakebite victims. We conclude that our study demonstrates several risk factors and predictors for the development and outcome of ARF in patients with snakebites. PMID- 18445903 TI - Association of serum lipoprotein (a) with hypertension in diabetic patients. AB - To evaluate the influence of serum Lp(a) concentration on hypertension in patients with diabetes mellitus (DM) and under treatment with oral hypoglycemic agents or insulin injections, we studied 122 patients, 82 females and 40 males with a mean age of 63 +/- 10 years and duration of DM and HTN of 7.4 +/- 5.8 and 3.2 +/- 4.6 years, respectively. The mean systolic and diastolic blood pressure (BP) were 138 +/-23 mmHg and 83 +/- 12 mmHg, respectively. In this cross sectional study, we measured serum lipoprotein(a) (Lp(a), glycosilated hemoglobine (HbA1c) and other lipids while the patients were receiving either oral hypogycemic agents or insulin. In addition, body mass index (BMI) and creatinine clearance (CrCL) were asessed. The mean serum Lp(a) was 22.2 +/- 24.7 mg/dl (median: 18.3 mg/dl), and serum Lp(a) levels > 30 mg/dl was found in 29 (23.8%) patients. There were significant positive correlations of duration of DM and duration of hypertension, and serum Lp(a) levels with of systoli and diastolic levels of BP. However, a significant inverse correlation of serum Lp(a) with CrCL were observed. This study suggests that kidney function is an independent determinant of Lp(a) and HTN in diabetic patients. Furthermore, Lp(a) in diabetic patients may have important implications for the increased susceptibility to vascular disease in these patients. PMID- 18445902 TI - Microalbuminuria in patients with essential hypertension and its relationship to target organ damage: an Indian experience. AB - Persistent microalbuminuria (MA) is the earliest indicator of chronic kidney disease (CKD) in patients with diabetes mellitus and hypertension. Patients with MA have high risk for target organ damage (TOD) resulting in stroke, retinopathy and adverse cardiovascular events. Though the prevalence of hypertension is high in India, the relationship between MA and TOD in hypertension is not well studied. To address this issue, this study was conducted at the Kottayam Medical College, Kerala, South India, between May 2005 and October 2006. The principal aim was to find out the prevalence of MA and its relationship to TOD in patients with essential hypertension. A total of 150 hypertensives without diabetes mellitus and/or other conditions causing MA were studied. Urine albumin creatinine ratio (ACR) was assessed and MA was defined as albumin excretion between 30-300 mg/day. The relationship of MA with the duration, severity and previous treatment of hypertension, body mass index (BMI), lipid profile and TOD's like left ventricular hypertrophy (LVH), hypertensive retinopathy and stroke was assessed by univariate analysis. Forty patients (26.67%) were found to have MA of whom 24 were males and 16 were females. MA was significantly higher in those with longer duration and greater severity of hypertension (p < 0.001 in each). Older age (p < 0.001), adverse lipid profile (p < 0.01) and higher BMI (p < 0.04) were the other identifiable risk factors for MA. Gender and history of smoking did not pose higher risk for MA. Stroke (OR=3.8), echocardiography-proven LVH (OR=9.42) and hypertensive retinopathy (OR=9.7) were significantly higher in those with MA. In conclusion, the prevalence of MA in essential hypertension is high and patients with MA have high odds for developing TOD like stroke, LVH and hypertensive retinopathy. Early screening of hypertensives for MA and prompt treatment of positive cases might reduce the burden of CKD and cardiovascular disease in the community. PMID- 18445904 TI - Brucella peritonitis in a patient on peritoneal dialysis. AB - Brucellosis is endemic in Saudi Arabia. Brucella peritonitis is an uncommon clinical condition. We herewith report a 67-year-old man with chronic renal failure on continuous ambulatory peritoneal dialysis (CAPD) for four months, who developed chronic brucella peritonitis. Peritoneal fluid grew brucella species with positive brucella serology. PMID- 18445905 TI - Giant megaureters presenting as a multicystic abdominal mass. AB - Megaureter is a developmental anomaly of the ureter, which is associated with significant morbidity in children and frequently requires surgical intervention. I am presenting here a case of massively dilated ureters in a child that occupied almost the entire abdomen and was wrongly misinterpreted as a cystic lymphangioma due to its unusual presentation. PMID- 18445906 TI - Aphallia associated with urethro-rectal fistula and stones in the bladder and urethra. AB - Aphallia is a rare urogenital anomaly. It usually coexists with other serious anomalies, which are incompatible with normal life. We present herewith a 18 month-old child who presented with aphallia and urethro-scrotal fistula along with stones in the bladder and urethra. The stones were removed and the fistula was surgically corrected. PMID- 18445908 TI - Senior-Loken syndrome in a Saudi child. AB - Senior-Loken syndrome is a rare syndrome of retinopathy and nephronophthisis. The clinical features of this syndrome include renal involvement, ocular involvement, retinitis pigmentosa and other systemic involvement. We describe an 11-year-old Saudi girl who was diagnosed to have this syndrome. To the best of our knowledge, this is the first report of this syndrome from the Arabian Peninsula. PMID- 18445907 TI - Cyclosporin-A induced posterior reversible encephalopathy syndrome. AB - Posterior reversible encephalopathy syndrome (PRES) is a recently proposed clinico-neuroradiological entity observed in a variety of clinical settings such as cyclosporin A (CsA) neurotoxicity. We report a 3.5-year-old Syrian boy in whom steroid-resistant focal segmental glomerulosclerosis (FSGS) was recently diagnosed. The patient remitted his nephrotic syndrome after 10 days of CsA administration. However, he shortly developed altered mental status, visual impairment, focal neurological deficits and seizures. We discontinued CsA that resulted in complete reversal of the patient's encephalopathical condition over a period of 4 months. We conclude that PRES should be suspected in immunosuppresed patients with kidney disease if they have a sudden episode of neurological symptoms. PMID- 18445909 TI - Confusion and agitation after a recent kidney transplantation. AB - A 51-year-old man, who received a living related transplant from his wife and anti-thymocyte globulin (ATG) as induction therapy, developed delayed graft function after transplantation. One day after he received an i.v. dose of ganciclovir, the patient developed hallucinations, confusion and agitation, which worsened the following day. CT-scan of the brain and cerebrospinal fluid were unremarkable. Ganciclovir-induced encephalopathy was considered the most likely reason for the patient's neurological condition, since he recovered completely a few days after discontinuation of this drug. Since anti-CMV prophylactic treatment is now widely used after transplantation, a high index of suspicion is required to diagnose ganciclovir (or acyclovir) induced neurotoxicity. PMID- 18445910 TI - Acute interstitial nephritis induced by intermittent use of rifampicin in patient with brucellosis. AB - Acute oliguric renal failure (ARF) developed in a patient 2 days after she was started on intermittent anti-Brucella therapy including rifampicin. The clinical picture was compatible with acute allergic interstitial nephritis. Renal histology revealed mainly acute tubular necrosis with mild tubulo-interstitial mononuclear cellular infiltrate. Intermittent therapy, as in our patient, has been the major factor in the development of rifampicin induced ARF in cases reviewed in literature. PMID- 18445911 TI - Focal and segmental glomerulosclerosis and von Recklinghausen's neurofibromatosis: coincidental or associated? PMID- 18445912 TI - Poor mineral metabolism as a risk for early graft dysfunction. PMID- 18445913 TI - Pediatric nephrology consultations in a tertiary academic center in Jordan. AB - To determine the conditions that result in pediatric nephrology consultations in an academic hospital setting, we studied 178 prospective consecutive consultations for 125 inpatients (69 boys and 56 girls) at the Jordan University Hospital, Amman, Jordan from January 2006 to December 2006. The mean age at the time of consultation was 3.1 years (median of 1 year, and range from 1 day to 16 years). Of the 125 patients, 87 (69.6%) patients had a single consultation, while 38 (30.4%) patients had multiple encounters (range from 1-4 consultations). The reasons for consultations included fluids and electrolytes imbalances (29.0%), hydronephrosis (15.7%), urinary tract infections (14.2%), acute renal failure (ARF) (14.2%), hypertension (8.40%), and miscellaneous conditions (18.5%). The most frequent fluids and electrolyte disorders were polyuria, hypocalcemia, and hyponatremia. Routine administration of hypotonic intravenous fluids was a major contributory factor to hyponatremia. The most frequent cause of ARF was acute tubular necrosis in association with multiple organ dysfunction and antibiotic nephrotoxicity. Hypertension was mostly neurogenic in origin. PMID- 18445914 TI - Hepatitis C virus genotypes in patients with end-stage renal disease in East Azerbaijan, Iran. AB - Information about the genotypes and associated risk factors in hepatitis C virus (HCV) infected patients in Iran is limited. The aim of this study was to identify the HCV genotypes and associated risk factors in a group of HCV infected patients on dialysis therapy in Iran. The sera of 753 patients with chronic renal failure from fifteen dialysis units in East Azerbaijan Province were screened for anti HCV antibodies as well as HCV RNA; viral RNA was extracted for the genotype specific primer approach. Patients were questioned concerning documented risk factors. Genotyping analysis was performed in 55 patients with positive anti-HCV and HCV-RNA. Genotypes 1 and 3 were found in 46 (83.7%) and three (5.5%) patients, respectively. The most frequent HCV subtype was 1a (76.4%), followed by 3a and 1b and 1b (5.5% each) while one patient was infected with both 1a and 1b. There was no statistically significant difference between the risk factors analyzed and the acquisition of HCV infection. This study gives added evidence of the predominant HCV genotypes in Iran, which is different than reports from other Arab countries and similar with the pattern of genotype in both Europe and United States. PMID- 18445915 TI - Survey of hepatitis B status in hemodialysis patients in a training hospital in Urmia, Iran. AB - To evaluate the prevalence of HBV infection in chronic hemodialysis patients at our dialysis center of Urmia's Taleqni Hospital, Urmia, Iran, we studied cross sectionally the hepatitis surface antigen (HbsAg) status in blood samples of 167 active chronic hemodialysis patients at our center with enzyme linked immunosorbant assay (ELISA). The mean frequency of HbsAg+ was 6.58%, which was higher in patients less than 50 years old than in those above 50 years (9.3% vs. 5.3%, respectively), in males than females (10.5% vs. 2.5%, respectively), and in those on three times dialysis than twice per week (7.1% vs. 0.0%, respectively). We did not find a significant relationship between the factors of: age, sex, being resident in city or village, duration of the therapy, history of blood transfusion, marital status, job status, history of kidney transplantation, and prevalence of HbsAg+. PMID- 18445916 TI - Lupus nephritis in Senegal: a study of 42 cases. AB - Renal involvement determines the prognosis of systemic lupus erythematosus (SLE). The aims of this study were to assess the clinical, laboratory and therapeutic aspects of lupus nephritis (LN) in Senegal in order to improve its management. We included all patients presenting with SLE followed-up in the Internal Medicine and Dermatology Clinics of the Aristide Le Dantec University Teaching Hospital of Dakar, from January 1993 to December 2002. Patients with SLE without evidence of LN (defined by proteinuria more than 0.5 g/24 hours and/or hematuria) were excluded. A total of 74 patients with a diagnosis of SLE were studied, 42 of whom (56.75%) had features of LN. Their mean age was 29.6 years and male-female ratio was 0.13. The nephrotic syndrome was seen in 45.23% of the cases and renal insufficiency in 37.71%. Renal biopsy was performed in 52.38% of the cases, which showed predominantly WHO classes IV and V lesions. The main treatment modality employed was corticosteroids, while immunosuppressive drugs in addition were used in 35.71% of the patients. The short-term prognosis was favorable but in the middle-term, many patients were lost to follow-up. We conclude that early diagnosis by systematic urine screening, good patient information, percutaneous renal biopsy and use of appropriate immunosuppressive therapy will help improving the prognosis of LN in Senegal. PMID- 18445917 TI - Prevalence of hepatitis C virus infection in hemodialysis patients. AB - The prevalence of hepatitis C virus (HCV) infection in hemodialysis patients (HD) has decreased significantly during the past decade in most HD units. To evaluate the cause(s) of this reduction, we studied the HCV antibodies measurements in 1006 HD patients in the Province of Mazandaran, Iran, from January 2001 to December 2006. In December 2001, the prevalence of antibody to HCV was 18%, whereas by December 2006, it decreased to 12%. Causes implicated in the reduction of prevalence of HCV infection in HD patients include a low percentage of new anti-HCV+ patients, a decrease in the conversion rate in HD patients, and more strict infection control measures in the dialysis units. PMID- 18445919 TI - Careers in medicine or what do you want when you grow up? AB - This paper is in the form of a letter to a medical student advising her/him on how to choose his/her future specialty. PMID- 18445918 TI - Single pass albumin dialysis in hepatorenal syndrome. AB - Hepatorenal syndrome (HRS) is the most appalling complication of acute or chronic liver disease with 90% mortality rate. Single pass albumin dialysis (SPAD) can be considered as a noble liver support technique in HRS. Here, we present a case of a young healthy patient who developed hyperacute fulminant liver failure that progressed to HRS. The patient was offered SPAD as a bridge to liver transplantation, however, it resulted in an excellent recovery. PMID- 18445920 TI - Scientific writing: the Indian scenario. PMID- 18445921 TI - Estimation of nicotine content in popular Indian brands of smoking and chewing tobacco products. AB - OBJECTIVES: To estimate the nicotine content of some popular Indian brands of smoking tobacco (cigarettes and bidis) and pan masalas (chewable tobacco). MATERIALS AND METHODS: Commercially available cigarettes, bidis, and pan masalas (chewable tobacco) were obtained from local retail outlets for the study. Nicotine was estimated using gas-liquid chromatography. RESULTS: The analyses showed relatively higher levels of nicotine in tobacco from bidis (26.9 mg gm) as compared to cigarettes(15 mg/gm); the difference is statistically significant ( P P > 0.01). Nicotine concentration in chewing tobacco was 3.4 mg/gm. CONCLUSION: The study concludes that the nicotine content of Indian brands of smoking tobacco was slightly high compared to other international brands. Higher concentration of nicotine was found in bidis compared to cigarettes. The nicotine content in commercially available chewing tobacco products was found to be much lower than in the smoking form of tobacco, but the average daily consumption made it comparable to the smoking form. PMID- 18445922 TI - Evaluation of the pulp chamber size of human maxillary first molars: an institution based in vitro study. AB - The aim of this in vitro study was to determine the morphological measurements of the pulp chamber and also to establish the relationship of the cemento-enamel junction (CEJ) to the roof of the pulp chamber of the maxillary first molars in an Indian population. One hundred extracted human maxillary first molars were used. Each molar tooth was radiographed by radio visiography (RVG). Measurements were made by using the grid option in RVG. The results (mean +/- SD; in mm) were as follows: distance from floor of the pulp chamber to the furcation = 2.7 +/- 0.63; distance from roof of the pulp chamber to the furcation = 5.34 +/- 0.9; distance from tip of the palatal cusp to the furcation = 11.58 +/- 1.01; distance from the tip of the palatal cusp to the floor of the pulp chamber = 8.86 +/- 0.68; distance from the tip of the palatal cusp to the roof of the pulp chamber = 6.2 +/- 0.66; height of the pulp chamber = 2.62 +/- 0.61. The results of these measurements revealed that the morphological measurements of the maxillary first molars in the Indian population were similar to that reported by previous studies; the roof of the pulp chamber was found at the CEJ in 96% of the specimens. PMID- 18445923 TI - Prevalence of dental caries among adults and elderly in an urban resettlement colony of New Delhi. AB - BACKGROUND: Dental caries remains the most important dental health problem in developing countries. In India the prevalence of dental caries is reported to be about 50-60%. Most of the Indian studies have been carried out in school children and very few in adults. This study aimed to estimate the prevalence of dental caries in the adult population (aged 35-44 years) and in the elderly (60 years and above) in an urban resettlement colony in New Delhi. METHODOLOGY: A community based cross-sectional study was carried out in Dakshinpuri, New Delhi, from January to February 2007. A local adaptation of the WHO questionnaire was used. Oral examination was done and dentition status was recorded by trained investigators and according to the standard procedures. RESULTS: A total of 452 participants were enrolled in the study. The prevalence of dental caries in the 35-44 years age-group was 82.4% and it was 91.9% in those > or =60 years. The DMF index was 5.7 +/- 4.7 in the 35-44 years age-group and 13.8 +/- 9.6 in the > or =60 years age-group. Of the participants, 27.9% were currently using tobacco. A statistically significant association was found between tobacco consumption and dental caries ( P = 0.026). The awareness about good and bad dental practices was found to be low among the study participants. One-fifth of the individuals with dental problems relied on home remedies. CONCLUSION: The prevalence of dental caries among adults is high in this population. There is a need to generate awareness about oral health and the prevention of dental caries and to institute measures for the provision of dental care services at the primary level. PMID- 18445924 TI - The prevalence of oral mucosal lesions in patients visiting a dental school in Southern India. AB - The purpose of the present study was to evaluate the prevalence of oral mucosal lesions in Manipal, Karnataka State, India. A total of 1190 subjects who visited the department of oral medicine and radiology for diagnosis of various oral complaints over a period of 3 months were interviewed and clinically examined for oral mucosal lesions. The result showed the presence of one or more mucosal lesions in (41.2%) of the population. Fordyce's condition was observed most frequently (6.55%) followed by frictional keratosis (5.79%), fissured tongue (5.71%), leukoedema (3.78%), smoker's palate (2.77%), recurrent aphthae, oral submucous fibrosis (2.01%), oral malignancies (1.76%), leukoplakia (1.59%), median rhomboid glossitis (1.50%), candidiasis (1.3%), lichen planus (1.20%), varices (1.17%), traumatic ulcer and oral hairy leukoplakia (1.008%), denture stomatitis, geographic tongue, betel chewer's mucosa and irritational fibroma (0.84%), herpes labialis, angular cheilitis (0.58%), and mucocele (0.16%). Mucosal lesions like tobacco-related lesions (leukoplakia, smoker's palate, oral submucous fibrosis, and oral malignancies) were more prevalent among men than among women. Denture stomatitis, herpes labialis, and angular cheilitis occurred more frequently in the female population. PMID- 18445925 TI - Knowledge and attitudes of pharmacists regarding oral health care and oral hygiene products in Chennai city. AB - OBJECTIVES: This study was done to find out the knowledge and attitudes of pharmacists regarding oral health care and oral hygiene products in Chennai city. MATERIALS AND METHODS: A cross-sectional survey among a sample of the pharmacists in Chennai city was done and data regarding their knowledge and attitudes towards oral health care and oral hygiene products were obtained using a closed-ended questionnaire. RESULTS: Among the 60 pharmacies approached, 50 pharmacists participated in the study and completed the questionnaire. Though 48% of the participants gave a positive answer when asked whether they had met the dentist practicing close to their pharmacies, the frequency with which they met the dentist ranged from once a week (24%) to once a month (28%). Most of the pharmacists stocked oral health-related products, which comprised 15-25% of their total stock. Of these products toothpaste was the most common (62%), followed by mouth rinses (12%). Toothache or painful teeth was the most common dental problem (78%) for which patients approached the pharmacists for advice. With regard to the advice given, 38.5% of the pharmacists asked the patient to consult a nearby dentist after dispensing medications, while 22.4% of the pharmacists dispensed antibiotics and painkillers without any referral. Seventy percent of the pharmacists expressed interest in giving oral health care advice to patients. However, many of them (38%) felt that lack of proper knowledge is a barrier to providing oral health care advice. CONCLUSION: It is clear from the present study that pharmacists are presently an underutilized resource, and there is a definitive need to improve their training and access to information on available dental services. PMID- 18445926 TI - Maxillofacial intervention in trauma patients aged 60 years and older. AB - The purpose of this study was to evaluate the incidence of trauma victims of age 60 years and older who required maxillofacial intervention. The study analyses the pattern of injuries and the various factors that predict the treatment plan of these patients. A retrospective study was carried out in 1820 trauma patients who reported to the Sri. Ramachandra Dental College and Hospital and required maxillofacial intervention, over a period of 5 years (October 2000 and September 2005). Of the total trauma victims, 185 patients were found to be aged 60 years more. In the majority of the patients, the injury was due to road traffic accidents (79.4%). Males (72.4%) sustained more injuries than females (27.6%). Soft tissue injuries were seen in 49.1% of the patients, while 14% had mandibular fractures. People in their early 60s were injured more often than their older counterparts. The findings of this study highlight the present situation with regard to maxillofacial trauma in patients aged 60 years and older and its management in this part of the country. PMID- 18445927 TI - The antimicrobial and antifungal efficacy of tetracycline-integrated gutta percha. AB - The purpose of this study was in vitro evaluation of the antimicrobial and antifungal efficacy of commercially available gutta-percha containing tetracycline on some potential endodontic pathogens. The test microorganisms were Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, Porphyromonas endodontalis, and Candida albicans . Tetracycline-integrated gutta percha (TGP) cones, tetracycline disc, and conventional gutta-percha cones of the same size were placed on the inoculated plates. The plates were incubated at 37 degrees C aerobically or anaerobically. Growth inhibition zones on each plate were inspected at 24, 48, and 72 h. Tetracycline disc and TGP cones inhibited all the tested bacterial strains, however the greatest antimicrobial effect was seen on S. aureus. Tetracycline disc and TGP seemed less effective on E. faecalis and P. aeruginosa. However, all tested treatments were unable to affect C. albicans . Based on the results of this study, it seems that TGP offers an antimicrobial advantage over conventional gutta-percha. PMID- 18445929 TI - Study of the patterns of periodontal destruction in smokers with chronic periodontitis. AB - Cigarette smoking is a well-established risk factor for periodontitis and carries an increased risk for loss of periodontal attachment as well as for bone loss. AIMS: The purpose of the study was to investigate the pattern of the intraoral distribution of periodontal destruction among cigarette smokers with periodontitis by assessing the periodontal probing depth (PPD) and clinical attachment level (CAL). MATERIALS AND METHODS: Thirty smokers with chronic periodontitis were enrolled in the study. PPD, CAL, plaque index (PI), and bleeding on probing (BOP) were measured. The data was pooled for the anterior sextant and the posterior sextant as well as for the facial and lingual surfaces. The degree of periodontal destruction was compared in these sextants. STATISTICAL ANALYSIS: Comparisons were made between maxillary anterior, maxillary posterior, mandibular anterior, and mandibular posterior using the one-way analysis of variance (ANOVA) test. When the overall ANOVA showed statistical significance, post hoc testing (Tukey-Kramer multiple comparisons test) was performed to explore the differences between any two groups. P -values < 0.05 were considered significant. RESULTS: The maxillary anterior sextant showed significantly higher PPD and CAL loss than the other sextants. Similarly, the maxillary palatal area showed higher probing depth and clinical attachment loss than the facial sites and the mandibular regions. CONCLUSIONS: From the results it can be concluded that there is variation in the periodontal tissue destruction in different areas of the oral cavity, with the maximum periodontal destruction in the maxillary palatal region. These observations emphasize the deleterious effects of smoking on the periodontal tissues. PMID- 18445928 TI - Evaluation of the regenerative potential of 25% doxycycline-loaded biodegradable membrane vs biodegradable membrane alone in the treatment of human periodontal infrabony defects: a clinical and radiological study. AB - BACKGROUND: Microbial colonization of the barrier membranes used for guided tissue regeneration is inevitable and can lead to delayed healing. AIMS: Antimicrobial coating of the membrane with 25% doxycycline paste has been attempted to prevent infection and achieve enhanced regeneration in periodontal infrabony defects. MATERIALS AND METHODS: Twenty-four patients with 2-walled or 3 walled infrabony defects were selected and randomly divided into two equal groups. Infrabony defects of group A were treated with a biodegradable membrane coated with 25% doxycycline while those of group B were treated with membrane alone. Clinical assessment of probing depth and attachment level and radiographic evaluation of the defect depth was done preoperatively and at 12 and 24 weeks postoperatively. STATISTICAL ANALYSIS: The relative efficacy of the two treatment modalities were evaluated using the paired Student's t- test and the comparative evaluation between the two groups was done using the independent Student's t test. RESULTS: Both the groups exhibited a highly significant reduction in probing depth and gain in clinical attachment level and linear bone fill at the end of 24 weeks. Comparative evaluation between the two study groups revealed a significant reduction in probing depth ( P = 0.016 FNx01 ) and linear bone fill ( P = 0.02 FNx01 ) in group A as compared to group B. Mean gain in attachment level was greater for group A than for group B but the difference was statistically nonsignificant ( P = 0.065 NS ). CONCLUSIONS: The results suggest that doxycycline is beneficial in reducing membrane-associated infection and can potentiate regeneration through host modulation. PMID- 18445930 TI - Evaluation of microtensile bond strength of total-etch, self-etch, and glass ionomer adhesive to human dentin: an in vitro study. AB - AIM: To evaluate the microtensile bond strength of Single Bond, AdheSE, and Fuji Bond LC to human dentin. Fifteen non-carious third molars were selected for the study. The teeth were randomly divided into three groups of five teeth each. Each group was given a different bonding treatment. Group I was treated with Single Bond (3M, ESPE), group II with AdheSE (Ivoclar, Vivadent), and group III was treated with Fuji Bond LC (GC America). A T-band metal matrix was placed and composite resin bonded on to the tooth surface using appropriate bonding agents. The composite resin was packed in increments and light cured. Each tooth was sectioned to obtain 1 mm x 1 mm beams of dentin-resin samples. Tensile bond testing was done using a universal testing machine (Instron) at a cross-head speed of 0.5 mm/min. RESULTS: The mean bond strength of Single Bond (35.5 MPa) was significantly higher than that of AdheSE (32.8 MPa) and Fuji Bond LC (32.6 MPa). The difference between the microtensile bond strength values of AdheSE and Fuji Bond LC was statistically insignificant. INFERENCE: Though the bond strength of AdheSE and Fuji Bond LC was above 30 MPa, it was less than that of Single Bond as evaluated by testing of microtensile bond strength. PMID- 18445931 TI - Subepithelial connective tissue grafts for the coverage of denuded root surfaces: a clinical report. AB - AIMS AND OBJECTIVES: The aim of this study is to determine the effectiveness of subepithelial connective tissue grafts (SCTG) in the coverage of denuded roots. MATERIALS AND METHODS: A total of 16 sites with > or =2 mm of recession height were included in the study for treatment with SCTG. The clinical parameters, such as recession height, recession width, width of keratinized gingiva, probing pocket depth, and clinical attachment level were measured at the baseline, third month, and at the end of the study [sixth month]. The defects were treated with a coronally positioned pedicle graft combined with connective tissue graft. RESULTS: Out of 16 sites treated with SCTG, 11 sites showed complete (100%) root coverage; the mean root coverage obtained was 87.5%. There was a statistically significant reduction in recession height, recession width, and probing pocket depth. There was also a statistically significant increase in the width of keratinized gingiva and also a gain in clinical attachment level. The postoperative results were both clinically and statistically significant ( P 0.05). CONCLUSION: From this study, it may be concluded that SCTG is a safe and effective method for the coverage of denuded roots. PMID- 18445932 TI - Argyrophilic nucleolar organizer regions in inflammatory, premalignant, and malignant oral lesions: a quantitative and qualitative assessment. AB - BACKGROUND AND OBJECTIVE: Argyrophilic nucleolar organizer regions (AgNORs) have found widespread application in the past, especially in tumor histopathology. This study was undertaken to evaluate the significance of various AgNOR parameters and to assess their role in differentiating hyperplastic, premalignant, and malignant lesions. MATERIALS AND METHODS: The study sample consisted of archival biopsy specimens of ten squamous cell carcinomas, ten premalignant lesions, and five inflammatory lesions. Two biopsies from normal mucosa acted as control. AgNORs were assessed both quantitatively and qualitatively. The data were analyzed using Student's independent t-test, one-way analysis of variance (ANOVA), and multiple range test (Tukey-HSD). RESULTS: Quantitatively significant difference existed in the number of AgNORs between the normal mucosa, inflammatory lesions, and carcinomas, but the premalignant lesions failed to differ significantly from the normal mucosa. The number of AgNORs was found to be related to epithelial proliferation. Qualitatively, in terms of size, shape, and pattern of distribution, the normal mucosa and inflammatory lesion were alike, but the premalignant and malignant lesions differed significantly from the normal, with a marked degree of AgNOR pleomorphism being observed in carcinomas. CONCLUSIONS: AgNOR quantity is strictly proportional to the proliferative activity of the cell and does not necessarily indicate malignancy. It is the qualitative characteristics of AgNOR that help to differentiate hyperplastic, premalignant, and malignant lesions. PMID- 18445933 TI - Heat radiation vs air drying to remove interfacial water from self-etch adhesives. AB - The clinician's quest for time-saving and technique-insensitive technology has led to the development of simplified self-etch adhesives that are predominantly water or solvent based. Several studies have shown that conventional air-drying procedures are incapable of eliminating all the residual water in the adhesive and that it may even cause collapse of the underlying collagen matrix. We hypothesized that heat from a light source may be effective in removing water from these adhesives. The aim of this study was, therefore, to evaluate the effectiveness of heat vs conventional air drying in eliminating water droplets from self-etch adhesive. A self-etch adhesive was applied to bur-cut dentin surfaces, which were then allotted to one of two treatment procedures for eliminating residual water from the adhesive: conventional air drying or the experimental heat application. Specimens were then prepared and analyzed using SEM. Specimens in the experimental group showed no evidence of water treeing within the adhesive layer. Thus, it was concluded that heat radiation was an effective method to remove residual water from simplified adhesives. PMID- 18445934 TI - Stature estimation using odontometry and skull anthropometry. AB - OBJECTIVE: To investigate the possibility of estimating height from odontometry and anthropometric data of the skull for the positive identification of height in forensic investigations concerned with fragmentary human remains. MATERIALS AND METHODS: The study was carried out on 100 Mysorean patients, 50 males, and 50 females. Measurements of mesiodistal widths of the six maxillary anterior teeth, circumference of the skull, and height were made directly on each patient. Anteroposterior diameter of the skull was obtained on the lateral cephalograph. The data collected were subjected to statistical methods. The known heights of the combined data, data for males, and females were regressed against the odontometric and anthropometric variables using linear regression analysis. RESULTS: Significant sexual dimorphism was observed for the parameters studied ( P 0.05). Highly significant correlation was found between height and other parameters when combined data and data for males were regressed. The equation relating height to the combined mesiodistal width of maxillary anterior teeth was derived as height = 982.421 + 13.65 x combined mesiodistal width of maxillary anterior teeth ( P 0.0001). Similarly equations were obtained by regressing height to head circumference and skull diameter ( P 0.0001 for both). The above findings may hence provide reliable method of estimation of height from skeletal remains in the forensic setup. PMID- 18445935 TI - Molluscum contagiosum in human immunodeficiency virus infected patients. AB - Molluscum contagiosum (MC) is a cutaneous lesion caused by a DNA virus from the poxvirus family. Worldwide in distribution, MC is most frequently encountered as an easily treated disease of childhood and has rarely been a cause of serious morbidity. With the advent of new populations of immunocompromised individuals, especially those infected with the human immunodeficiency virus (HIV), MC has emerged as a difficult clinical challenge and the focus of renewed interest for dental professionals. This article presents four cases of HIV positive patients afflicted by MC along with a review of the literature on this dermatopathological lesion. PMID- 18445936 TI - Glass embedded in labial mucosa for 20 years. AB - Foreign bodies may be deposited in the oral cavity either by traumatic injury or iatrogenically. Among the commonly encountered iatrogenic foreign bodies are restorative materials like amalgam, obturation materials, broken instruments, needles, etc. Few reports of glass pieces embedded in the soft tissues of the mouth have been published. We report a case where glass pieces had been lodged in the lower labial mucosa for 20 years, with consequent peripheral reactive bone formation. PMID- 18445937 TI - A massive ameloblastic fibro-odontoma of the maxilla. AB - Ameloblastic fibro-odontoma is a rare, benign mixed odontogenic tumor. It occurs exclusively as an intraosseous lesion. It usually has a slow growth and is seen in children and young adults. A painless swelling is the most common clinical sign. Radiographically, ameloblastic fibro-odontoma appears as a circumscribed radiolucency which may contain radiopaque foci. Most cases of ameloblastic fibro odontoma exhibit benign behavior, but cases of malignant transformation have been reported. The treatment modality in most cases involves conservative surgery, but cases with malignant transformation will require more radical treatment. A massive ameloblastic fibro-odontoma involving the maxilla has been described here with its clinical, radiological, and histopathological features. PMID- 18445938 TI - Dynamic commissural splint. AB - Microstomia, an abnormally small oral orifice, can manifest as a sequela of burns involving the oral and perioral tissues due to contraction of the tissues and hypotonia of the circumoral musculature. Regardless of the etiology, scar contracture results in deformities that produce esthetic and functional impairment. Changes in the circumoral anatomy prevent optimal dental care and maintenance of good oral hygiene. The anatomic changes may detrimentally alter eating, speech, and mandibular motion. Prosthetic treatment involves providing physical resistance to scar contracture by maintaining the oral commissures in their normal relationship by means of a splint. This article describes a method to fabricate a dynamic commissural splint and describes its use in two cases. PMID- 18445939 TI - Oil pulling therapy. PMID- 18445940 TI - Research as a career choice for Indian dentists. PMID- 18445941 TI - Dental age estimation using amino acid racemization. PMID- 18445942 TI - Geriatric dentistry: is rethinking still required to begin undergraduate education? PMID- 18445943 TI - Need for national/regional guidelines and policies in India to combat antibiotic resistance. PMID- 18445944 TI - Onychomycosis--epidemiology, diagnosis and management. AB - Onychomycosis is a fungal infection of nails caused by dermatophytes, yeasts or nondermatophyte molds and represents about 30% of mycotic cutaneous infections. Increasingly onychomycosis is being viewed as more than a mere cosmetic problem. In spite of improved personal hygiene and living environment, onychomycosis continues to spread and persist. The prevalence rate of onychomycosis is determined by age, predisposing factor, social class, occupation, climate, living environment and frequency of travel. Onychomycosis in immunocompromised patients can pose a more serious health problem. Dermatophytes are the most frequently implicated causative agents in onychomycosis. Previously regarded as contaminants, yeasts are now increasingly recognised as pathogens in fingernail infections, as are some moulds. Clinical diagnosis of onychomycosis is based on the patients' history; a physical examination, microscopy and culture of nail specimens. The treatment of onychomycosis has been attempted throughout the ages, but only in the last two decades have safe, effective systemic treatments been available for this chronic superficial fungal disease. Oral Griseofulvin and Ketoconazole; once the agents of choice for the treatment of onychomycosis, have been superseded by newer systemic compounds that have a higher cure and lower relapse rates, cause fewer side effects and are suitable for short-term dosing. PMID- 18445945 TI - Evaluation of the effectiveness of peracetic acid in the sterilization of dental equipment. AB - PURPOSE: To evaluate the effectiveness of peracetic acid in the microbiological sterilisation of dental materials. METHODS: Peracetic acid solution was evaluated at concentrations of 800, 1500 and 2500 ppm. At these concentrations, it was determined whether peracetic acid caused corrosion to dental instruments and induced cellular mutagenicity and cytotoxicity. In addition, the minimum inhibitory concentration (MIC), the minimum bactericidal concentration (MBC), agar diffusion and diffusion by well method, were also verified. RESULTS: The corrosion rate, calculated from potentiodynamic assays was 10(-6) cm/year, indicating that the product does not damage equipment. The sterilisation capacity of peracetic acid at 2500 ppm was the best. The comet assay indicated genotoxic activity at 2500 ppm. CONCLUSIONS: This study demonstrated the effectiveness of peracetic acid for sterilizing dental equipment, providing another alternative for the prevention of infections in clinics. PMID- 18445946 TI - The highest prevalence of human metapneumovirus in Ahwaz children accompanied by acute respiratory infections. AB - PURPOSE: The newly described human metapneumovirus (hMPV) has been recently discovered as an etiological agent of acute respiratory infections (ARTI) in infants and children. The aim of this study was to determine the prevalence of hMPV and its potential role as causative agent of ARTI in Ahwaz children. METHODS: In the present study, we examined 124 nasal swabs from infants affected by ARTI for the presence of hMPV by RT-PCR technique. RESULTS: Sixty-eight out of 124 (54.4%) cases were positive for hMPV which is the highest incidence of hMPV ever reported in the world, 94.1% of positive cases belonged to genotype A; whereas no B genotype was detected. Our positive hMPV children were affected by upper (URTI) as well as lower respiratory tract infection (LRTI); however, LARTIs had higher prevalence. CONCLUSIONS: We suggest a probable role of F protein alteration as the causative agent for the highest prevalence of hMPV infection among Ahvaz children. PMID- 18445947 TI - Advantage of using a home-made ELISA kit for detection of Helicobacter pylori infection over commercially imported kits. AB - PURPOSE: To evaluate a home-made ELISA kit for detection of Helicobacter pylori (Hp) infection and comparison of its immunologic criteria with those of foreign commercial kits. METHODS: A home-made IgG ELISA kit was developed using soluble antigenic fractions of Hp proteins. Confirmed sera were tested and serological criteria were evaluated through assessment of 199 serum samples. RESULTS: The accuracy, sensitivity and specificity values of home-made kit were 92, 92 and 90.4%, respectively. These immunologic criteria for Trinity kit were 95.2, 95.2 and 95% in comparison with IBL kit (91.3, 92.2 and 88.5%), BIOHIT kit (72.4, 41.6 and 94.1%) and HelicoBlot2.1 (94.2, 93.4 and 100%). Kappa agreement assessment demonstrated that two of the imported ELISA kits had fair to moderate agreement with the home-made kit while the other one had a poor agreement value. CONCLUSIONS: Apart from comparable values between the home-made kit and the most efficient imported kit (Trinity) there was significant cost benefit. Therefore, we recommend the home-made kit as a suitable substitution for detection of Hp infection in the Iranian population. PMID- 18445948 TI - Prevalence and correlates of bacterial vaginosis among young women of reproductive age in Mysore, India. AB - PURPOSE: Bacterial vaginosis (BV) is the most common cause of abnormal vaginal discharge among women of childbearing age and is associated with STI/HIV and adverse birth outcomes. The objective of this study was to determine the prevalence and correlates of BV among young women of reproductive age in Mysore, India. METHODS: Between October 2005 and December 2006, 898 sexually active women of 15-30 years of age were enrolled from two reproductive health clinics in Mysore. The women underwent an interview followed by physical examination, HSV-2 serologic testing, endocervical culture for Neisseria gonorrhoeae , and vaginal swabs for diagnosis of BV, Trichomonas vaginalis infection and candidiasis. Statistical analyses included conventional descriptive statistics and multivariable analysis using logistic regression. RESULTS: Of the 898 women, 391 (43.5%) were diagnosed with >or=1 endogenous reproductive tract infection and 157 (17.4%) with >or=1 sexually transmitted infection. Only 863 women had Gram stained vaginal smears available, out of which 165 (19.1, 95% confidence interval [CI]: 16.3%-22.2%) were found to have BV and 133 (15.4, 95% CI: 12.9%-18.3%) were in the 'intermediate' stage. BV was related to concurrent infections with T. vaginalis (odds ratio [OR]=4.07, 95% CI: 2.45-6.72) and HSV-2 seropositivity (OR=2.22, 95% CI: 1.39-3.53). CONCLUSIONS: In this population, the prevalence of BV at 19% was relatively low. Coinfection with T. vaginalis , however, was common. BV was independently associated with concurrent T. vaginalis infection and partner's alcohol use. Muslim women had reduced odds of BV as compared to non Muslim women. Further research is needed to understand the role of T. vaginalis infection in the pathogenesis of BV and the sociocultural context surrounding the condition in India. PMID- 18445949 TI - Diagnosing different stages of hepatitis B infection using a competitive polymerase chain reaction assay. AB - PURPOSE: Different stages of hepatitis B virus (HBV) infection can be defined by serum HBV DNA levels. This study attempts to (1) investigate serum HBV DNA levels in inactive carriers and patients with chronic HBV (CHB) infection and (2) define cut-off value between inactive carriers and HBeAg (precore antigen of HBV) negative CHB patients in Indian population. METHODS: One hundred and forty samples encompassing 42 inactive HBsAg carriers and 98 CHB patients (53 HBeAg positive and 45 HBeAg-negative) were analysed. Serum HBV DNA levels were determined employing an in-house competitive polymerase chain reaction (cPCR) assay. RESULTS: The HBeAg-positive patients were found to have the maximum median HBV DNA load, which was significantly higher than the HBeAg-negative ones (median; 1.25 x 10(8) vs. 2.30 x 10(5) copies/mL ; P<0.05). Interestingly, the latter group has significantly higher HBV DNA levels than the inactive carriers (median; 2.30 x 10(5) vs. 4.28 x 10(3) copies/mL; P<0.05). The 2.5 x 10(4) copies/ml HBV DNA levels were optimal for discriminating CHB patients (HBeAg negative) from inactive carriers with 75.6 and 78.6% sensitivity and specificity, respectively. CONCLUSIONS: Despite the extensive overlapping of HBV DNA levels in inactive carriers and HBeAg negative CHB patients, 2.5 x 10(4) copies/mL is the most favourable cut-off value to classify these individuals and would be imperative in the better management of this dreadful disease. PMID- 18445950 TI - Detection of mutation in isoniazid-resistant Mycobacterium tuberculosis isolates from tuberculosis patients in Belarus. AB - The aim of this study was to investigate the frequency, location and type of katG mutations in Mycobacterium tuberculosis strains isolated from patients in Belarus. Forty two isoniazid-resistant isolates were identified from sputum of 163 patients with active pulmonary tuberculosis. Drug susceptibility testing was determined by using CDC standard conventional proportional method and BACTEC system. Standard PCR method for detection of isoniazid resistance associated mutations was performed by katG gene amplification and DNA sequencing. Most mutations were found in katG gene codons 315, 316 and 309. Four types of mutations were identified in codon 315: AGC-->ACC (n=36) 85%, AGC-->AGG (n=1) 2.3%, AGC-->AAC (n=2) 4.7%, AGC-->GGC (n=1) 2.3%. One type of mutation was found in codon 316: GGC-->AGC (n=18) 41.4%, four types of mutations were detected in codon 309: GGT-->GGT (n=7) 16.1%, GGT-->GCT (n=4) 9.2%, GGT-->GTC (n=3)6.9%, GGT- >GGG (n=1) 2.7%. The highest frequency of mutations sharing between primary and secondary infections was found in codon 315. PMID- 18445951 TI - Molecular characterization of genes encoding the quinolone resistance determining regions of Malaysian Streptococcus pneumoniae strains. AB - Genes encoding the quinolones resistance determining regions (QRDRs) in Streptococcus pneumoniae were detected by PCR and the sequence analysis was carried out to identify point mutations within these regions. The study was carried out to observe mutation patterns among S. pneumoniae strains in Malaysia. Antimicrobial susceptibility testing of 100 isolates was determined against various antibiotics, out of which 56 strains were categorised to have reduced susceptibility to ciprofloxacin (>or=2 microg/mL). These strains were subjected to PCR amplification for presence of the gyrA, parC , gyrB and parE genes. Eight representative strains with various susceptibilities to fluoroquinolones were sequenced. Two out of the eight isolates that were sequenced were shown to have a point mutation in the gyrA gene at position Ser81. The detection of mutation at codon Ser81 of the gyrA gene suggested the potential of developing fluoroquinolone resistance among S. pneumoniae isolates in Malaysia. However, further experimental work is required to confirm the involvement of this mutation in the development of fluoroquinolone resistance in Malaysia. PMID- 18445952 TI - Genotypic resistance profile of HIV-1 protease gene: a preliminary report from Vellore, south India. AB - HIV-1 subtypes other than B are responsible for most new HIV infections worldwide; virus sequence data for drug resistance is described only from a limited number of non-B subtype HIV-1. This study is on mutations and polymorphisms of HIV-1 protease gene that can predict drug resistance in subtype C. The genotypic resistance assay was carried out on 38 HIV-1 strains with their plasma RNA and in nine, the proviral protease gene was sequenced. The treatment naive strains showed minor resistance mutations, there were no major resistance mutations in the protease gene. We suggest the use of resistance testing to monitor individuals on therapy and also before initiation of therapy, gathering more sequence information for a data bank of Indian strains. PMID- 18445953 TI - Antibiotic resistance of Gardnerella vaginalis in recurrent bacterial vaginosis. AB - Fifty strains of Gardnerella vaginalis isolated from 321 high vaginal swabs over a period of five months were tested for their antibiotic sensitivity. Sixty eight per cent of all isolates were resistant to metronidazole while 76% were sensitive to clindamycin. All the strains isolated from cases with recurrence of infection were resistant to metronidazole. Clindamycin therapy has a better clinical efficacy than metronidazole in cases of recurrent bacterial vaginosis. PMID- 18445954 TI - Identification of weak points prone for mutation in ferredoxin of Trichomonas vaginalis. AB - Trichomonas vaginalis, the causative agent for human trichomoniasis, is a problematic sexually transmitted disease mainly in women. At present, metronidazole-resistant trichomoniasis is an infrequent but challenging problem with no universally successful treatment. Genetic mutation is believed to be an important factor leading to increasing drug resistance. Understanding the mutation status will help to design accurate strategies of therapy against mutant strains of T. vaginalis. The author performed a bioinformatic analysis to determine positions that tend to comply peptide motifs in the amino acid sequence of ferredoxin of T. vaginalis. Based on this study, the weak linkages in the studied protein can be identified and can be useful information for prediction of possible new mutations that can lead to drug resistance. In addition, the results from this study can be good information for further research on the diagnosis for mutants and new effective drug development. PMID- 18445955 TI - Comparison of efficacy of three commercially available antibiotic discs. AB - A study was undertaken to evaluate the efficacy of commercially available antimicrobial discs manufactured by Oxoid, UK, HiMedia Laboratories, Mumbai and Span Diagnostics, Surat. The discs were evaluated for their performance on the basis of percentage of coefficient of variation (%CV) which is a measure of reproducibility, mean zone diameters which is a measure of accuracy and range of zone diameter using both standard ATCC strains and clinical isolates. The data showed variation for all three manufacturers and therefore routine and regular quality control of discs as well as meticulous following of good laboratory practices is strongly advocated in clinical laboratories. PMID- 18445956 TI - Detection of Enterobacteriaceae producing CTX-M extended spectrum beta-lactamases from a tertiary care hospital in south India. AB - A total of 23 clinical isolates (15 Escherichia coli and 8 Klebsiella pneumoniae), resistant to cefotaxime and ceftazidime recovered during 2002 and 2003, were investigated for production of CTX-M extended spectrum beta-lactamase (ESBL) by phenotypic and molecular methods. The presence of ESBL was tested by NCCLS phenotypic confirmatory test using cephalosporin/clavulanate combination discs and E-test ESBL strips. Determination of MIC of cefotaxime and ceftazidime was done with and without the presence of clavulanic acid by agar dilution technique. Polymerase chain reaction revealed the presence of CTX-M type ESBLs in 19 isolates. Further sequencing resulted in identification of CTX-M-15 ESBLs. This is the first report identifying CTX-M type ESBL from clinical isolates of E. coli and K. pneumoniae from a tertiary care hospital in south India. PMID- 18445957 TI - Emergency department based HIV screening: an opportunity for early diagnosis in high prevalent areas. AB - The Emergency Medicine Department (EMD) is an ideal place for public health interventions and provides ready access to the health care system, offering a great opportunity for HIV testing and counselling. Between 2003 and 2005, rapid test was requested for 59.39% of 10,752 cases from EMD, where as ELISA was requested for 40.61%. Of the 317 HIV reactive cases, available medical records of 249 were reviewed for epidemiological and clinical information. Nearly 42% of total reactive cases detected in our Institute were from EMD. Three percent (317/10,752) were diagnosed as HIV reactive, 1.52% of the total samples were reactive by rapid test and the other 1.43% by ELISA. Two and half percent (163/6386) of those who had rapid testing and 3.53% (154/4366) who had ELISA testing, were identified as HIV reactive. All these cases were diagnosed within a mean EMD stay of 2.5 days. Eighty-five percent of HIV reactive individuals were unaware of their reactive status. Additional 53 cases of asymptomatic spouses were diagnosed as HIV reactive, thus making it possible to seek early treatment for HIV infection. The study emphasizes the importance of offering HIV testing to all patients who present to emergency department. PMID- 18445958 TI - Chronic diarrhoea in HIV patients: prevalence of coccidian parasites. AB - The purpose of this study was to determine the prevalence of intestinal parasites in HIV patients with or without diarrhoea and to see an association between diarrhoea and the coccidian parasites in our setting. Stool samples from 113 HIV patients, 34 chronic diarrhoea and 79 without any history of diarrhoea were collected and examined for enteric parasites by microscopy. One hundred and thirteen control samples from HIV negative patients complaining of prolonged diarrhoea were also collected and analysed. Prevalence of coccidian parasites in HIV and non-HIV patients; with and without diarrhoea was compared using chi square tests. Enteric parasites were detected in 55.8% HIV patients with diarrhoea compared to 16.4% in patients without diarrhoea (P<0.001). Isospora belli was found in 41.1% (14/34) of chronic diarrhoea and 6.3% (5/79) in non diarrhoeal cases (P<0.001). Cryptosporidium was detected in 20.6% (7/34) of chronic diarrhoea and 2.5% (2/79) in non-diarrhoeal cases (P<0.001). Cyclospora cayetanensis associated diarrhoea was detected in only one case of chronic diarrhoea (2.9%). CD4+ T-cell count was lower (180 cells/microL) in diarrhoeal HIV patients as compared to non-diarrhoeal patients. Coccidian parasites were seen at a mean CD4+ T-cell count of 186.3 cells/microL. This study concluded that Isospora belli was the predominant parasite followed by Cryptosporidium spp. and both were strongly associated with diarrhoea among HIV patients. PMID- 18445959 TI - Modified PAP method to detect heteroresistance to vancomycin among methicillin resistant Staphylococcus aureus isolates at a tertiary care hospital. AB - This study was an attempt at developing, establishing, validating and comparing the modified PAP method for detection of hetero-vancomycin resistant Staphylococcus aureus (h-VRSA) with the routine antimicrobial susceptibility testing (using the BSAC standardized disc diffusion method), minimum inhibitory concentrations of vancomycin using standard E-test methodology and the Hiramatsu's screening method. A total of 50 methicillin resistant Staphylococcus aureus obtained from various clinical specimens, along with the Mu 3 and Mu 50 strains as controls, were studied. No VRSA isolates were obtained. However, four of the test strains were positive by the Hiramatsu's screening method, of which only one isolate could be confirmed by the modified PAP analysis method. This isolate was a coloniser from the drain fluid of a liver transplant recipient. The sensitivity, specificity, positive predictive value and the overall efficiency of the Hiramatsu's screening method with the modified PAP analysis as the gold standard were found to be 100, 93.8, 25 and 94%, respectively. It is very essential for clinical laboratories to screen for h-VRSA, given the increasing use of glycopeptide antibiotics in therapy and the potential for failed therapy in patients infected with these strains. PMID- 18445960 TI - Acute abdomen: an unusual presentation of disseminated Penicillium marneffei infection. AB - Varied clinical presentations of Penicillium marneffei, an opportunistic pathogen in HIV disease has been rarely described in literature. We report a patient with advanced AIDS who presented to us with prolonged fever and had features of an acute abdomen. On radiologic imaging he had features of intestinal obstruction and mesenteric lymphadenitis. A diagnosis was made possible by endoscopic biopsies of the small bowel and bone marrow culture which grew P. Marneffei. He was treated with intravenous amphotericin for 2 weeks followed by oral itraconazole. This case is reported for its rarity and unusual presentation and to sensitise clinicians and microbiologists to consider this as an aetiology in patients with advanced HIV/AIDS who present with acute abdomen, more so in patients from a distinct geographic region--South-East Asia. PMID- 18445961 TI - Acanthamoeba encephalitis. AB - Central nervous system infection with free-living amoebae is rare. We present a fatal case of Acanthamoeba encephalitis in a 63-year-old female from India where acanthamoebae were demonstrated and cultured from CSF. In spite of treatment with amphotericin B, fluconazole and rifampicin the patient did not survive. Amoebic infection should be suspected in a patient of encephalitis of unexplained aetiology as timely diagnosis can lead to a favourable outcome. PMID- 18445962 TI - Primary cutaneous actinomycosis: a rare soft tissue infection. AB - Actinomycosis caused by Actinomyces spp. is a chronic and suppurative infection caused by an endogenous gram positive bacterium. The unusual sites of infection are the head and neck, thorax and abdomen and are almost always endogenous in origin. Primary cutaneous actinomycosis is very rare and is usually associated with external trauma and local ischemia. We report a case of a primary cutaneous actinomycosis of the thigh in a 30-year-old man. The patient acquired the infection through an injection wound which progressed to multiple discharging sinuses. Clinical material from the wound demonstrated the presence of Actinomyces in smears and cultures. The patient was diagnosed and successfully treated with surgical resection and combined antibiotic therapy. PMID- 18445963 TI - Gastrointestinal histoplasmosis presenting as colonic pseudotumour. AB - We report a case of gastrointestinal histoplasmosis in a 45-year-old HIV positive man who was misdiagnosed as a case of colonic cancer. The patient presented with low-grade fever, pain in lower abdomen, anorexia and weight loss of six months duration. On examination a lump in the left iliac fossa was detected. Colonoscopy revealed stricture and ulcerated growth in the sigmoid colon. Radiological investigations suggested malignant/inflammatory mass in the sigmoid colon with luminal compromise. Patient was operated and ulcerated tissue was sent for histopathological examination, which revealed numerous intracellular, 2-4 microm, oval, narrow-based budding yeast cells suggestive of Histoplasma capsulatum. Subsequently, the patient developed fluffy opacities on X-ray chest. Examination of sputum revealed presence of acid-fast bacilli and yeast forms of H. capsulatum. Patient was started on amphotericin B but died on the seventeenth postoperative day. The diagnosis of histoplasmosis was made retrospectively. Atypical presentation and rarity of the disease led to this diagnostic pitfall. To the best of our knowledge this is the first report of gastrointestinal histoplasmosis presenting as colonic pseudotumour from India. PMID- 18445964 TI - Myiasis in different types of carcinoma cases in southern India. AB - Myiasis maggots were isolated from the cancerous wounds, when the patients reported to the Department of ENT-OPD, JIPMER, Pondicherry. Maggots were identified to Chrysomyia bezziana based on characteristic patterns of posterior and anterior spiracles. Although the categories of cancer wounds were different, invasions were due to C. bezziana, which is very common in suburban areas of Tamil Nadu and Pondicherry in southern parts of India. This observation showed the importance of hygiene and sanitation in tropical countries with high fly population and emphasised the need for correct diagnosis of this obligatory myiasis, which was destructive. Through proper health care, further destabilization due to myiasis was avoided. PMID- 18445965 TI - Soft tissue infections with Arcanobacterium haemolyticum: report of three cases. AB - We report here three polymicrobial wound infections associated with Arcanobacterium haemolyticum in rural patients aged between 60-65 years. In two patients, one with cellulitis and the other with postoperative wound infection following amputation of the limb, Arcanobacterium haemolyticum was isolated repeatedly along with beta haemolytic streptococci (BHS). The BHS belonged to Lancefield's group G and group C respectively. In another patient, who was a diabetic with chronic osteomyelitis, Arcanobacterium haemolyticum was isolated along with Proteus vulgaris . All the three isolates of Arcanobacterium haemolyticum isolated by us were uniformly resistant to cotrimoxazole and sensitive to penicillin, erythromycin, clindamycin, ciprofloxacin and gentamicin. Erythromycin alone or combined therapy of penicillin with erythromycin or penicillin with ciprofloxacin was effective in treating these infections. PMID- 18445967 TI - Bacteriological and molecular studies of group A streptococcal pharyngitis in a south Indian hospital. PMID- 18445966 TI - Prevalence of tuberculosis, hepatitis B, hepatitis C and syphilis co-infections among HIV/AIDS patients. PMID- 18445968 TI - Preservation of Vibrio cholerae by suspension in normal saline. PMID- 18445969 TI - Prevalence of syphilis and biological false positive reactions in VDRL test among injecting drug users: a preliminary study. PMID- 18445970 TI - Experience with a fourth generation human immunodeficiency virus serological assay at a tertiary care centre in south India. PMID- 18445971 TI - An explanation in nanostructure level based on the view of energy change for G333d mutation relating to drug resistance in HIV-1 reverse transcriptase. PMID- 18445972 TI - Microscopy for cryptosporidiosis screening in remote areas. PMID- 18445973 TI - Occurrence of cytomegalo virus and herpes simplex virus infections in pregnancy. PMID- 18445974 TI - Seroprevalence of HIV, hepatitis C and hepatitis B in multitransfused thalassemics. PMID- 18445975 TI - Leptospirosis laboratory, Madras Medical College: review of our experience (2004 2006). PMID- 18445976 TI - Reporting ethical processes in journals. PMID- 18445977 TI - Reporting ethical processes in Indian journals. PMID- 18445978 TI - Statement on publishing clinical trials in Indian biomedical journals. PMID- 18445979 TI - Reporting ethical processes in two Indian journals. AB - BACKGROUND: In biomedical journals, authors are expected to report if the study was carried out in accordance with international and national ethical guidelines and inform readers if approval from ethics committee was obtained and if written informed consent was taken from the participant or legal guardian. AIMS: To determine the proportion of research manuscripts in two pediatric journals published from India reporting on ethical clearance, obtaining of informed consent and/or assent. SETTINGS AND DESIGN: Retrospective study for analysis of research articles published. MATERIALS AND METHODS: Research articles published in the issues of Indian Pediatrics and Indian Journal of Pediatrics in 2006 were reviewed for reporting regarding ethical clearance, obtaining written informed consent from guardians or parents, and obtaining assent from research participants. STATISTICAL ANALYSIS USED: Descriptive statistics was used. The number of articles according to their types; the number of research designs employed according to their types; and the number of research studies mentioning ethical clearance, consent, and assent were expressed as percentages mentioning ethical clearance, consent and assent were expressed as percentages. RESULTS: Of the 132 manuscripts reporting biomedical research, 39 (29.53%) reported having obtained approval from the ethics committee. Forty-six of the 98 (46.94%) manuscripts reporting on prospective studies indicated that informed consent was obtained from parents or lawful guardians. Neither ethical approval nor informed consent was mentioned in 45 (34.10%) published articles reporting prospective studies. A total of 54/98 (55.1%) studies enrolled children aged 7 years or more and hence were assessed for reporting of assent; eight (14.81%) reported that children's assent was obtained. Only four (7.41%) eligible studies reported ethics committee's approval, informed consent, as well as assent. CONCLUSIONS: A significant proportion of research articles published in the two pediatric journals did not provide information regarding ethical approval, written informed consent, and obtaining of assent. PMID- 18445980 TI - Effect of alpha-tocopherol on pro-oxidant and antioxidant enzyme status in radiation-treated oral squamous cell carcinoma. AB - OBJECTIVES: The relationships between alpha-tocopherol, pro-oxidant and antioxidant enzyme status, and radiation toxicity were studied in stage II, III, and IVA oral squamous cell carcinoma patients. The low levels of malondialdehyde and increased activities of antioxidant enzymes were correlated with decreased oxidative stress by alpha-tocopherol in oral cancer patients treated with radiotherapy. The objective of the present study was to evaluate the effect of alpha-tocopherol on oxidant-antioxidant enzyme status in oral squamous cell carcinoma patients treated with radiotherapy. MATERIALS AND METHODS: The study included three groups with histologically confirmed oral squamous cell carcinoma patients (untreated), and they were further divided into two groups, viz., one consisting of patients who underwent radiotherapy alone (radiotherapy was given at the dosage of 6000 cGy in five fractions per week for a period of 6 weeks); and the other group treated with radiotherapy plus alpha-tocopherol supplementation (alpha-tocopherol was supplemented at a dosage of 400 IU/day) for the entire period of radiotherapy. RESULTS: A significant decrease ( P < 0.001) in malondialdehyde levels and increase in activities of antioxidant enzymes ( P < 0.001) in hemolysate were noticed in patients treated with radiotherapy and simultaneously supplemented with alpha-tocopherol when compared to radiation treated patients. CONCLUSION: It was seen that alpha-tocopherol played a role in protecting against the damage caused by irradiation in oral squamous cell carcinoma patients treated with radiotherapy, by enhancing the antioxidant enzyme status and reducing the pro-oxidant status. PMID- 18445981 TI - Growth hormone deficiency short stature in a third world adult endocrine clinic: usefulness of clonidine test in its diagnosis. AB - BACKGROUND: Short stature (SS) can be treatable; yet the diagnostic value of a simple test in correctly identifying the two common etiologies in developing countries, viz., growth hormone deficiency (GHD) and normal variant short stature (NVSS), has not been reported in a typical third world population. OBJECTIVES: The aim of the study was to evaluate the reliability of clonidine test in differentiating short stature caused by GHD from NVSS. SETTINGS AND DESIGN: Data of subjects evaluated for growth hormone deficiency SS at a Saudi Arabian university hospital were retrospectively reviewed. MATERIALS AND METHODS: Clonidine and insulin tolerance tests (ITT) were conducted on 60 subjects aged 12 years and above with SS, while peak stimulated growth hormone cut off value of < 10 microg/l was used to diagnose GHD. STATISTICAL ANALYSIS: Sensitivity and specificity for clonidine test and ITT were computed, while receiver operator characteristic (ROC) curves were constructed from the results in order to assess the diagnostic usefulness of the two tests. Mann-Whitney test was used to determine level of significance. RESULTS: Clonidine test showed superior sensitivity and specificity, viz., 81% and 82%, as against 65% and 59% for ITT respectively. Overall, the efficiency of clonidine test in correctly differentiating short stature caused by GHD from NVSS was higher, viz., 90%, compared to ITT's 77%. CONCLUSIONS: Clonidine test proved to be an excellent test for initial assessment of GHD and may be used as a screening test for short stature in third world countries. PMID- 18445983 TI - Abnormal radial artery in Down syndrome: a rare but clinically important association. PMID- 18445982 TI - Chronic urticaria and Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori (HP) have recently emerged as a novel eliciting factor for chronic urticaria (CU). The possible association between HP and CU has enormous potential, as eradicating HP could cure CU. AIMS AND OBJECTIVES: We conducted a study to assess the prevalence of HP infection and effect of bacterium eradication on skin lesions in patients of chronic idiopathic urticaria (CIU). SETTINGS AND DESIGN: Four hundred sixty patients of CU attending the allergy clinic, SMS hospital, Jaipur during the period February 6, 2004, to February 6, 2006, were screened for possible eliciting factors. Patients with CIU were enrolled and others were excluded. MATERIALS AND METHODS: Sixty-eight patients of CIU and similar number of age and sex matched controls, attending the allergy clinic, SMS Hospital, Jaipur were enrolled in the study. All patients underwent endoscopy with antral biopsy for urease and histopathology to identify HP-associated gastritis. Infected patients were given HP eradication therapy. Eradication of bacterium was confirmed by fecal antigen assay. Subjective response to treatment was judged using chronic urticaria quality-of-life questionnaire (CU-Q 2 oL) while objective response to treatment was judged by need for 'rescue medication' (antihistaminics). STATISTICAL ANALYSIS: Data were analyzed using Chi square and paired 't' test for their level of significance. RESULTS: HP associated gastritis was present in 48 (70.58%) patients, out of which 39 (81.25%) patients responded to eradication therapy. Ten (50.00%) patients without HP associated gastritis showed response to symptomatic therapy. Overall 49 (72.05%) patients responded and 19 (27.94%) showed no response. The value of chi2 was 28.571 (P = 0.003), which showed significant association between presence of HP and response to eradication regimen. CONCLUSION: The response of HP eradication therapy in infected patients of CIU is significant. HP should be included in diagnostic workup of patients with CIU. PMID- 18445984 TI - Aural myiasis in a 1-day-old neonate. PMID- 18445985 TI - Current status of 5alpha-reductase inhibitors in the treatment of benign hyperplasia of prostate. AB - Benign prostatic hyperplasia (BPH) is a common problem in aging men, which is associated with lower urinary tract symptoms. This condition is dependent on the presence of androgens for its progression, and medical therapy is the first-line treatment for BPH patients with moderate-to-severe symptoms and includes the use of either alpha 1-adrenergic blockers or 5alpha-reductase inhibitors. Adrenergic blocking drugs reduce the dynamic component while the 5alpha-reductase inhibitors reduce the static component of bladder outlet obstruction in BPH. By inhibiting the generation of active form of testosterone, viz., dihydrotestosterone, the 5alpha-reductase inhibitors not only reduce the symptoms of BPH but also decrease the need for surgery and further progression of BPH. Besides, prolonged use of combination of 5alpha-reductase inhibitors and alpha 1-adrenergic blockers has been found to be more beneficial than either of the two drugs given alone. This review gives a brief account of rationale and efficacy of treatment by 5alpha reductase inhibitors in the management of BPH. PMID- 18445986 TI - Pharmacokinetics and pharmacodynamics: where are they going? PMID- 18445987 TI - Intestinal first-pass metabolism of CYP3A4 substrates. AB - Cytochrome P450 3A4 (CYP3A4) is present not only in the liver but also in the small intestine, where it functions as a barrier against xenobiotics. Some CYP3A4 substrates exhibit low bioavailability due to intestinal first pass metabolism. The AUCs of such CYP3A4 substrates are remarkably changed by the inhibition, induction, and saturation of CYP3A4 and so prediction of intestinal first-pass metabolism is important. In this article, factors affecting intestinal first-pass metabolism of drugs are reviewed, focusing on the intestinal metabolism by CYP3A. The methods to predict intestinal first-pass metabolism are also reviewed. PMID- 18445988 TI - No effect of imidafenacin, a novel antimuscarinic drug, on digoxin pharmacokinetics in healthy subjects. AB - Plasma digoxin concentrations are increased by the coadministration of anticholinergic drugs, such as propantheline, which decrease gastrointestinal motility. The present study evaluated the effect of imidafenacin, a novel anticholinergic drug, on the pharmacokinetics of digoxin. The effect of imidafenacin on the pharmacokinetics of digoxin was examined in 14 healthy Japanese male subjects in a single-centre, open-label, randomized, two-way crossover study. Subjects received a daily oral dose of digoxin 0.25 mg on days 1 and 2 and digoxin 0.125 mg on days 3 to 8 (period 1). Following a 2-week washout period, digoxin was administered orally for 8 days in a similar manner (period 2). A twice daily dose of imidafenacin 0.1 mg was concomitantly administered with digoxin for 8 days either in period 1 or 2. The geometric mean ratios [GMR] (90% confidence intervals [CIs]) for digoxin C(max) and AUC(0-24) (with/without imidafenacin) at steady state were 0.88 (0.74, 1.04) and 1.00 (0.90, 1.10), respectively. The 90% CIs of GMR for digoxin trough concentration, urinary excretion amount and renal clearance at steady state fell within the range of 0.8 to 1.25. The steady-state pharmacokinetics of digoxin is not affected by concomitant administration of imidafenacin in healthy subjects. PMID- 18445989 TI - CYP2D6 is primarily responsible for the metabolism of clomiphene. AB - Clomiphene is a first line treatment for anovulation, a common cause of infertility. Response to clomiphene is variable and unpredictable. Tamoxifen is structurally related to clomiphene, and also shows considerable variation in response. CYP2D6 and CYP3A4 are major contributors to the metabolism of tamoxifen. The aim of the present work was to define the role of CYP2D6 and CYP3A4 in the in vitro metabolism of enclomiphene, regarded by some as the more active isomer of clomiphene. Enclomiphene (25 microM) was incubated with human liver microsomes (from 4 extensive (EM) and 1 poor metaboliser with respect to CYP2D6) and with microsomes from lymphoblastoid cells expressing CYP2D6. Microsomes from all the EM livers and recombinant CYP2D6 metabolised enclomiphene (the disappearance of drug ranged from 40-60%). No metabolism was detected in microsomes from the PM liver. Quinidine (1 microM) completely inhibited the metabolism of enclomiphene by all the EM livers and by recombinant CYP2D6 (p<0.001, one way ANOVA). Ketoconazole (2 microM) had no significant effect on enclomiphene metabolism in 3 out of the 4 EM livers. The extent of enclomiphene metabolism was correlated with the amount of CYP2D6 present (p<0.001, Pearson correlation test). The findings indicate that CYP2D6 is primarily responsible for the metabolism of enclomiphene. PMID- 18445990 TI - P-glycoprotein limits the brain penetration of olopatadine hydrochloride, H1 receptor antagonist. AB - Olopatadine, a new second-generation antihistamine, is widely used in the treatment of allergic disorders. The low levels of histamine H1 receptor occupancy in human brain by olopatadine, which is related to its minimal sedation, suggest its low penetration into the brain. The present study evaluates the impact of P-glycoprotein (P-gp) on brain penetration and plasma concentration of olopatadine. The uptake amount of olopatadine in human P-gp transfected LLC PK1 cells (LLC-GA5-COL150) was lower than that in LLC-PK1. The uptake of olopatadine in LLC-GA5-COL150 was increased in the same level as that in LLC-PK1 in the presence of cyclosporine A, a P-gp inhibitor. After intravenous or oral administration of olopatadine to wild type (WT) and mdr1a/1b knockout (KO) mice at a dose of 1 mg/kg, the brain concentration in KO mice was higher than that in WT mice. On the other hand, the plasma concentration of olopatadine after either route of administration was not different between WT and KO mice. These results suggest that olopatadine is a substrate of P-gp, and that P-gp limits the brain penetration but dose not affect the plasma concentration of olopatadine. PMID- 18445992 TI - Rapid characterization of drug-drug interaction in plasma protein binding using a surface plasmon resonance biosensor. AB - High-throughput characterization of drug-drug interactions in plasma protein binding was demonstrated by using a surface plasmon resonance (SPR) biosensor. The method used in this study enabled the discrimination between the two modes of binding inhibition, direct competition and negative allosteric effect, which was difficult in conventional SPR approaches. Two theoretical equations were used representing SPR binding response for directly competitive binding or for independent binding. The experimental binding data for human serum albumin was processed by non-linear least squared regression of the equations. By this approach, drug-drug interactions were classified into three modes, direct competition, independent binding, and allosteric interaction, which were almost consistent with previous reports. In addition, dissociation constants were also estimated roughly for direct competition and for independent binding. The analytical throughput was almost as high as in the previous reports; three minutes per injection. This method is a powerful tool for the characterization of drug-drug interaction at an early stage of new drug development. PMID- 18445991 TI - The effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan. AB - Losartan, a selective angiotensin receptor antagonist, is mainly metabolized by CYP2C9 to an active carboxylic acid, E3174, which is pharmacologically more potent inhibitor than the parent compound. We evaluated the effect of bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan and E3174, which were measured by high performance liquid chromatography in human volunteers and rats. A randomized crossover design study with two phases was done in the volunteer study. In the first phase, the volunteers received losartan 25 mg alone orally (LOS group), and, in the second phase, losartan 25 mg was given after repeated oral administration of 300 mg bucolome for 7 days (LOS+BUC group). In the LOS group, the maximum concentration (C(max)) and area under the concentration curve (AUC) of losartan were significantly higher than in the LOS+BUC group. On the other hand, in the LOS+BUC group, the C(max) and AUC of E3174 were significantly lower than in the LOS group. In the rat study, male Wistar ST rats were used. In the first phase, the rats orally received losartan 10 mg/kg alone or after bucolome was given repeatedly at a dose of 20, 50, or 200 mg/kg for 7 days. In the second phase for steady state, the rats were given losartan 10 mg/kg for 14 days (group A) or losartan 10 mg/kg and bucolome 50 mg/kg for 14 days (Group B). Bucolome at doses 50 and 200 mg/kg significantly increased the AUC losartan and significantly decreased the AUC of 3174. At the steady state, there were no significant differences in AUC of losartan between Group A and B, but the C(max) and AUC of E3174 were significantly lower in Group B than Group A. PMID- 18445993 TI - Additional notes on clinical repeated-dose pharmacokinetic trials applying a peak and-trough sampling design to estimate oral clearance. AB - In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral administration at the dose, D, and dosing interval, tau. The approximate oral clearance (CL/F(approx)), estimated as 2 x D/(C(peak) x tau+C(trough) x tau), is accurate for drugs with an elimination half-life comparative to or longer than tau; however, it was suggested that we might not use CL/F(approx) for drugs with a considerably short elimination half-life relative to tau. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F(exp)) estimated by the simple monoexponential model. In contrast to CL/F(approx), CL/F(exp) was accurate for drugs with a short elimination half-life relative to tau. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F(approx) and CL/F(exp)) for a target drug should be evaluated carefully before and after a real clinical trial. PMID- 18445994 TI - Interaction between tacrolimus and lansoprazole, but not rabeprazole in living donor liver transplant patients with defects of CYP2C19 and CYP3A5. AB - We report different effects of administration of proton pump inhibitors on tacrolimus blood concentration in two living-donor liver transplant patients. In case 1, a 51-year-old man with liver cirrhosis due to hepatitis C virus underwent living-donor liver transplantation, and tacrolimus was orally administered. Omeprazole (40 mg/day) was introduced intravenously between postoperative days 5 and 6, and oral lansoprazole (30 mg/day) was introduced from day 6, leading to an increase in the concentration/dose ratio of tacrolimus from day 10. In case 2, a 41-year-old living-donor liver transplant woman received tacrolimus, and co administered with omeprazole (40 mg/day) intravenously during 7 days immediately after surgery. During this period, trough concentration of tacrolimus was high, but the concentration/dose ratio of tacrolimus was gradually decreasing with time. Switched to rabeprazole (10 mg/day) orally on the postoperative 8th day, the concentration/dose ratio of tacrolimus remained low, indicating little drug drug interaction between tacrolimus and rabeprazole. In both cases, the genotypes of CYP2C19 and CYP3A5 were defective both in the graft liver and in the native intestine. A drug-drug interaction between rabeprazole and tacrolimus was not observed in this case study presented, suggesting that this combination could be safely used in tacrolimus therapy after liver transplantation. PMID- 18445995 TI - Genetic variations and haplotypes of ABCC2 encoding MRP2 in a Japanese population. AB - The multidrug resistance-associated protein 2 (MRP2) encoded by the ABCC2 gene is expressed in the liver, intestine and kidneys and preferentially exports organic anions or conjugates with glucuronide or glutathione. In this study, all 32 exons and the 5'-flanking region of ABCC2 in 236 Japanese were resequenced, and 61 genetic variations including 5 novel nonsynonymous ones were detected. A total of 64 haplotypes were determined/inferred and classified into five *1 haplotype groups (*1A, *1B, *1C, *1G, and *1H) without nonsynonymous substitutions and *2 to *9 groups with nonsynonymous variations. Frequencies of the major 4 haplotype groups *1A (-1774delG), *1B (no common SNP), *1C (-24C>T and 3972C>T), and *2 [1249G>A (Val417Ile)] were 0.331, 0.292, 0.172, and 0.093, respectively. This study revealed that haplotype *1A, which has lowered activity, is quite common in Japanese, and that the frequency of *1C, another functional haplotype, was comparable to frequencies in Asians and Caucasians. In contrast, the haplotypes harboring 3972C>T but not -24C>T (*1G group), which are reportedly common in Caucasians, were minor in Japanese. Moreover, the allele 1446C>T (Thr482Thr), which has increased activity, was not detected in our Japanese population. These findings imply possible differences in MRP2-mediated drug responses between Asians and Caucasians. PMID- 18445996 TI - Hepatic failure and enhanced oxidative stress in mitochondrial diabetes. AB - Mitochondrial diabetes is characterized by diabetes and hearing loss in maternal transmission with a heteroplasmic A3243G mutation in the mitochondrial gene. In patients with the mutation, it has been reported that hepatic involvement is rarely observed. We demonstrated a case of hypertrophic cardiomyopathy and hepatic failure with mitochondrial diabetes. To clarify the pathogenesis we analyzed the mitochondrial ultrastructure in the myocytes, the reactive oxygen species (ROS) production in the liver and the status of heteroplasmy of the mitochondrial A3243G mutation in the organs involved. In cardiomyocytes and skeletal muscle, electron microscopic analysis demonstrated typical morphological mitochondrial abnormalities. Immunohistochemical analysis demonstrated enhanced ROS production associated with marked steatosis in the liver, which is often associated with mitochondrial dysfunction. Analysis of the A3243G mutation revealed a substantial ratio of heteroplasmy in these organs including the liver. The presence of steatosis and enhanced oxidative stress in the liver suggested that hepatic failure was associated with mitochondrial dysfunction. PMID- 18445997 TI - Glycated albumin is a better indicator for glucose excursion than glycated hemoglobin in type 1 and type 2 diabetes. AB - To determine the impact of blood glucose profile, involving fluctuation and excursion of blood glucose levels, on glycated proteins, we evaluated the association among the daily profile of blood glucose, and glycated albumin (GA) and HbA1c levels in patients with type 1 diabetes (n = 93) and type 2 diabetes (n = 75). GA levels were strongly correlated with HbA1c levels in type 1 (r = 0.85, P<0.0001) and type 2 diabetes (r = 0.61, P<0.0001), respectively. HbA1c levels were similar between patients with type 1 and type 2 diabetes, while GA levels were significantly higher in type 1 diabetes. Thus the ratio of GA levels to HbA1c levels was significantly higher in type 1 diabetes than that in type 2 diabetes (3.32 0.36 vs. 2.89 0.44, p<0.001). The degrees of GA levels and HbA1c levels correlated with maximum and mean blood glucose levels in patients with type 1 and type 2 diabetes. Stepwise multivariate analysis revealed that GA levels independently correlated with maximum blood glucose levels in type 1 diabetes (F = 43.34, P<0.001) and type 2 diabetes (F = 41.57, P<0.001). HbA1c levels also independently correlated with maximum blood glucose levels in type 1 diabetes (F = 34.78, P<0.001), as well as being correlated with mean blood glucose levels in type 2 diabetes (F = 11.28, P<0.001). In summary, GA could be a better marker for glycemic control than glycated hemoglobin in diabetic patients, especially for evaluating glycemic excursion, which is considered to be a major cause of diabetic angiopathy. PMID- 18445998 TI - The association of thyroid function and heart valve sclerosis. Results from a population-based study. AB - OBJECTIVES: Thyroid dysfunction is associated with detrimental cardiovascular effects. We analyzed whether thyroid status is associated with aortic valve sclerosis (AVS) and mitral annular calcification (MAC) as markers of generalized atherosclerosis. DESIGN: Data of 2065 subjects (923 women and 1142 men) aged > or =45 years from the Study of Health in Pomerania (SHIP) were analyzed with respect to low, medium and high TSH levels. Logistic regression models were adjusted for major confounders of atherosclerosis. MAIN OUTCOME: In women, the prevalence of AVS was the highest in those with low TSH (35.1% vs. 26.7% in medium TSH; p<0.05), while there was a higher prevalence of MAC in men with high TSH levels (9.2% vs. 5.2% in medium TSH; p<0.05). Compared with euthyroid men there was an increased adjusted odds ratio for MAC (OR 2.07; 95% CI 1.12-3.89, p<0.05), for the combination of AVS and MAC (OR 2.13; 95% CI 1.08-4.21, p<0.05) or for one of both (OR 1.47; 95% CI 1.02-2.13, p<0.05) among men with high TSH. No such association was found in women. CONCLUSIONS: There was an association between thyroid function and valvular sclerosis. Men with high TSH values had increased odds for AVS or MAC, and the combination of both. These findings may reflect an increased atherosclerotic state in affected subjects. PMID- 18445999 TI - Case study of a 15-year-old boy with McCune-Albright syndrome combined with pituitary gigantism: effect of octreotide-long acting release (LAR) and cabergoline therapy. AB - The use of octreotide-LAR and cabergoline therapy has shown great promise in adults with acromegaly; however, the experience in pediatric patients has rarely been reported. We described a clinical course of a 15-year-old boy of McCune Albright syndrome (MAS) with pituitary gigantism. At the age of 8 years, a growth hormone (GH) and prolactin (PRL) producing pituitary adenoma was diagnosed at our hospital. He also had multiple fibrous dysplasia, so that he was diagnosed as having MAS. The tumor was partially resected, and GNAS1 gene mutation (R201C) was identified in affected tissues. We introduced octreotide to suppress GH secretion (100 mug 2/day s.c). During therapy with octreotide, IGF-1 and GH levels could not be suppressed and the patient frequently complained of nausea from octreotide treatment. Therefore, the therapy was changed to monthly injections of octreotide LAR at the age of 12.3 years and was partially effective. However, as defect of left visual field worsened due to progressive left optic canal stenosis, he underwent second neurological decompression of the left optic nerve at 13.4 years of age. After surgery, in addition to octreotide-LAR, cabergoline (0.25 mg twice a month) was started. This regimen normalized serum levels of GH and IGF-1; however, he showed impaired glucose tolerance and gallstones at 15.7 years of age. Therefore, the dose of octreotide-LAR was reduced to 10 mg and the dose of cabergoline increased. This case demonstrated the difficulty of treating pituitary gigantism due to MAS. The use of octreotide-LAR and cabergoline should be considered even in pediatric patients; however, adverse events due to octreotide-LAR must be carefully examined. PMID- 18446000 TI - A case of hypothyroidism with brugada electrocardiographic waveforms. AB - A 77-year-old man was diagnosed as having hypothyroidism. An electrocardiogram obtained at the time of the first examination revealed Brugada electrocardiographic waveforms in leads V1 to V3. When pilsicainide hydrochloride loading changed the waveforms of the electrocardiographic ST segment, this result suggested an abnormality of the cardiac muscle sodium channels. The Brugada electrocardiographic waveforms disappeared with the normalization of thyroid function. This case is the first report ever of hypothyroidism that presented Brugada electrocardiographic waveforms. The results obtained in this case suggested that thyroid functions changed the waveforms of the electrocardiogram because of its effect on myocardial ion channels. PMID- 18446002 TI - A C/T polymorphism in CD40 gene is not associated with susceptibility and phenotype of Graves' disease in Taiwanese. AB - A single nucleotide polymorphism (SNP) located at position-1 in the Kozak sequence of the CD40 gene has been associated with the development of GD in Caucasian and Koreans. This study investigated possible associated between CD40 SNP and the development of GD in a Taiwanese population. To do this, we enrolled 215 Taiwanese patients with GD and 141 controls from the Endocrine Clinic of Kaohsiung Medical University Hospital. This study investigated the association between gene polymorphism and relapse of hyperthyroidism after the discontinuation of medication in three GD patient groups based on time to relapse and a control group, and compared clinical and laboratory data of patients regrouped in three CD40 SNP genotypes. No significant difference in allele or CD40 SNP genotype frequency was observed between patients with GD and control subjects (P = 0.859 and P = 0.959, respectively). Furthermore, we analyzed the distribution of CD40 genotypes and three groups based on time to relapse after drug withdrawal. The cutoff points were 9 months, 9 months to 3 years, and more than 3 yr in subgroups of patients with GD divided by clinical and laboratory variables. Although no significant genotype-phenotype associations were found, the T allele and TT genotype frequency was significantly smaller in GD patients who had developed the disease before 35 years old than those who developed it after 35 years old (x (2) = 6.272, P = 0.043) (TT + CT v.s. CC, x (2) = 4.951, P = 0.030). These findings suggest that this CD40 gene polymorphism is not associated with GD in Taiwan and is, therefore, not contributing to susceptibility to the disease there. PMID- 18446001 TI - Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice. AB - Adiponectin has been proposed to act as an antidiabetic adipokine, suppressing gluconeogenesis and stimulating fatty acid oxidation in the liver and skeletal muscle. Although adiponectin-knockout (adipo(-/-)) mice are known to exhibit insulin resistance, the degrees of insulin resistance and glucose intolerance are unexpectedly only moderate. In this study, the adipo(-/-) mice showed hepatic, but not muscle, insulin resistance. insulin-stimulated phosphorylation of IRS-1 and IRS-2 was impaired, the IRS-2 protein level was decreased, and insulin stimulated phosphorylation of Akt was decreased in the liver of the adipo(-/-) mice. However, the triglyceride content in the liver was not increased in these mice, despite the decrease in the PPARalpha expression involved in lipid combustion, since the expressions of lipogenic genes such as SREBP-1 and SCD-1 were decreased in association with the increased leptin sensitivity. Consistent with this, the down-regulation SREBP-1 and SCD-1 observed in the adipo(-/-) mice was no longer observed, and the hepatic triglyceride content was significantly increased in the adiponectin leptin double-knockout (adipo(-/-)ob/ob) mice. On the other hand, the triglyceride content in the skeletal muscle was significantly decreased in the adipo(-/-) mice, probably due to up-regulated AMPK activity associated with the increased leptin sensitivity. In fact, these phenotypes in the skeletal muscle of these mice were no longer observed in the adipo(-/-)ob/ob mice. In conclusion, adipo(-/-) mice showed impaired insulin signaling in the liver to cause hepatic insulin resistance, however, no increase in the triglyceride content was observed in either the liver or the skeletal muscle, presumably on account of the increased leptin sensitivity. PMID- 18446003 TI - Markedly reduced white adipose tissue and increased insulin sensitivity in adcyap1-deficient mice. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide implicated in several metabolic functions, including insulin secretion and sympathoadrenal activation. To clarify the roles of PACAP in maintenance of whole body glucose and lipid homeostasis, the impact of the deletion of PACAP on glucose homeostasis, body weight, and adipose tissue mass was examined by comparing mice lacking the Adcyap1 gene encoding PACAP (Adcyap1(-/-)) with wild type littermate controls. Adcyap1(-/-) mice showed significant hypoinsulinemia, although being normoglycemic, and lower body weight as well as reduced food intake. They also showed greatly reduced white adipose tissue mass, in which the mRNA expression of adipocyte fatty acid-binding protein (aP2), a marker of adipocyte differentiation, was decreased. Glucose and insulin tolerance tests revealed increased insulin sensitivity in Adcyap1(-/-) mice. In accordance with these observations, plasma levels of resistin, an adipocytokine implicated in insulin resistance, were decreased in Adcyap1(-/-) mice. After a high-fat dietary challenge for six weeks, Adcyap1(-/-) mice still showed lower body weights and increased insulin sensitivity. These results indicate the crucial roles of PACAP in energy metabolism, including lipid metabolism, and in the regulation of body weight, raising the possibility that the PACAP-signaling pathway that favors energy storage could be a therapeutic target for obesity. PMID- 18446004 TI - Effect of decreased levels of intrinsic tetrahydrobiopterin on endothelial function in anesthetized rats. AB - Tetrahydrobiopterin (BH4) deficiency has been suggested to be an important factor in vascular endothelial dysfunction. In this study, we investigated the influence of decreased BH4 level produced by administration of 2,4-diamino-6 hydroxypyrimidine (DAHP), a specific inhibitor of the rate-limiting enzyme of BH4 synthesis, on vascular endothelial function in anesthetized rats. Wistar rats were given DAHP (0.1 - 1.0 g/kg, i.p.) or the vehicle 5 h before the experiment. Depressor responses to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside were tested. After the experiment, blood and thoracic aorta were taken for estimating their BH4 levels and plasma concentrations of nitrite plus nitrate. DAHP produced marked decreases in BH4 levels in plasma and aorta in a dose-related manner. Baseline values for hemodynamics were not affected by DAHP. Depressor responses to acetylcholine were attenuated with the highest dose of DAHP (1.0 g/kg) but not with DAHP (0.3 g/kg), although similar decreases in BH4 levels were seen with these two doses of DAHP. Treatment with DAHP at each dose did not decrease plasma concentrations of nitrite plus nitrate. These findings suggest that a decrease in BH4 levels by acute inhibition of de novo BH4 synthesis does not necessarily cause endothelial dysfunction. PMID- 18446005 TI - Intact cell binding for in vitro prediction of sedative and non-sedative histamine H1-receptor antagonists based on receptor internalization. AB - We evaluated changes in the binding properties of sedative and non-sedative histamine H1-receptor antagonists induced by internalization of H1 receptors in intact human U373 MG astrocytoma cells. Internalization of H1 receptors was induced without their degradation by treatment with 0.1 mM histamine for 30 min at 37 degrees C, and then the intact cell binding assay was performed at 4 degrees C. The binding properties of [3H]mepyramine, a cell-penetrating radioligand for H1 receptors, were not changed by histamine pretreatment. Displacement curves for sedative H1-receptor antagonists (diphenhydramine, chlorpheniramine, promethazine, ketotifen, azelastine and oxatomide) against [3H]mepyramine binding were not changed by histamine pretreatment. In contrast, the displacement curves for non-sedative H1-receptor antagonists (mequitazine, bepotastine, olopatadine, epinastine, carebastine, desloratadine and fexofenadine) were changed by histamine pretreatment: two types of changes, i.e. a rightward shift in the monophasic curve or an increase in the proportion of the low affinity component of the biphasic curve, were prevented under hypertonic conditions, in which clathrin-mediated receptor internalization is known to be inhibited. Thus, internalization-mediated changes in the binding properties of H1 receptor antagonists were well correlated with their sedative and non-sedative behaviors, which might confirm their permeability through the biomembrane and possibly the blood brain barrier. PMID- 18446007 TI - Technical development for production of gene-modified laboratory rats. AB - Transgenic rats have been used as model animals for human diseases and organ transplantation and as animal bioreactors for protein production. In general, transgenic rats are produced by pronuclear microinjection of exogenous DNA. Improvement of post-injection survival has been achieved by micro-vibration of the injection pipette. The promoter region, structural gene, chain length and strand ends of the exogenous DNA are not involved in the production efficiency of transgenic rats. Exogenous DNA prepared at 5 microg/ml seemed to be better integrated than lower and higher concentrations. Intracytoplasmic sperm injection (ICSI) has been successfully achieved in rats using a piezo-driven injection pipette. The ICSI technique has not only been applied to rescue infertile male strains but also to produce transgenic rats. The optimal DNA concentration for the ICSI-tg method (0.1 to 0.5 microg/ml) is lower than that for the conventional pronuclear microinjection. Production efficiency was improved when the membrane structure of the sperm head was partially disrupted by detergent or ultrasonic treatment before exposure to the exogenous DNA solution. For successful production of transgenic rats with a modified endogenous gene, establishment of embryonic stem cell lines or alternatively male germline stem cell lines and technical development of somatic cell nuclear transfer are still necessary for this species. PMID- 18446006 TI - Ginsenoside Rb1 reduces neurodegeneration in the peri-infarct area of a thromboembolic stroke model in non-human primates. AB - Ginsenoside Rb1 (GRb1), a major component of the traditional herb ginseng, has been reported to show a neuroprotective effect in a rodent ischemic model. The purpose of this study was to investigate effects of GRb1 on early and delayed brain injuries in a non-human primate thromboembolic stroke model. Thromboembolic stroke was induced by occlusion of the middle cerebral artery by injection of an autologous blood clot into the left internal carotid artery. GRb1 (300 microg/kg per day, i.v.) and vehicle were administered from 7 days before embolization to the day following embolization (total: 8 times). Neurological deficits were observed at 1, 6, and 24 h and at 2, 4, and 7 days after embolization. At 7 days after embolization, neuron damage in the peri-infarct area and core region were assessed by NeuN, TUNEL, and GFAP staining. GRb1 improved the skeletal muscle coordination score of the neurologic deficits (median: GRb1 vs vehicle = 10 vs 12, P<0.05). In the GRb1 group, positive neurons expressed by NeuN staining were noted in the ischemic peri-infarct area, and TUNEL- and GFAP-positive cells significantly decreased, when compared with vehicle. These results demonstrated that GRb1 ameliorated both early and delayed injuries in the thromboembolic stroke model in non-human primates. PMID- 18446008 TI - [Terminology beyond the realm of clinical practice--IL-6 as an example]. PMID- 18446009 TI - [Role of IL-6 in the development and pathogenesis of CIA and EAE]. AB - Interleukin (IL)-6 is a pleiotropic cytokine that has crucial roles in the regulation of immune response, inflammation and hematopoiesis. Recently, a new inflammatory helper T cell subset which produces IL-17A (IL-17), termed Th17 cells was identified and has been reported to be involved in the development and pathogenesis of collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE), which are known as the mouse model of rheumatoid arthritis and multiple sclerosis, respectively. It has been demonstrated that IL 6 together with TGF-beta induces the differentiation of Th17 cells from naive helper T cells in vitro. However, IL-6 independent pathway of Th17 differentiation has also been reported, suggesting that the role of IL-6 in vivo in these diseases remains unclear. With the treatment of anti-IL-6R antibody in CIA and EAE, we could suppress the differentiation of antigen specific Th17 cells and the onset of diseases. These results indicate that IL-6 is involved in the induction of Th17 cells in vivo, and anti-IL-6R antibody might be a promising therapy of Th17-mediated autoimmune diseases. PMID- 18446010 TI - [Recent research developments in polymyositis/dermatomyositis]. AB - The idiopathic inflammatory myopathies, polymyositis (PM) and dermatomyositis (DM), are evaluated as systemic autoimmune diseases without the pathology determined. Past immunohistochemical findings suggested that the effector response is driven predominantly by CD4 T cells and by humoral immunity in DM, and by cytotoxic T cells in PM. However, histological observations of muscle tissue do not necessarily distinguish DM and PM. Thus, the two diseases including amyopathic DM might represent a spectrum of illness in which some patients suffer only from a muscle disease or from a skin disease. In comparison with research studies on other rheumatic diseases, there are much fewer research studies conducted on PM/DM. The relationship between PM and DM is not clear yet. We reviewed past clinical and basic research on the pathology of PM/DM, including research on relevant T cells, B cells and cytokines. PMID- 18446011 TI - [Role of IL-6 in regulation of inflammation and stem cell differentiation in CNS trauma]. AB - Interleukin-6 (IL-6) has been demonstrated to play a pivotal role in CNS trauma as a proinflammatory cytokine which regulates inflammatory response. Not only being a mediator of inflammation, but IL-6 induces neural stem/progenitor cells to undergo astrocytic differentiation selectively in the injured CNS. These effects are considered to coordinate to prevent the CNS repair after traumatic injury. Consistently, we previously reported that the administration of anti-IL-6 receptor antibody (MR16-1) immediately after spinal cord injury in mice decreased the number of invading inflammatory cells and the severity of connective tissue scar formation, and led to improved functional recovery. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI will be beneficial for CNS repair. A critical merit of this anti-IL-6 receptor antibody is that humanized antibody to human IL-6 receptor (MRA; Atlizumab) has already been reshaped. However, there are several studies which show beneficial aspects of IL-6 signaling in the pathology of CNS trauma. Further investigation of the mechanisms how MR16-1 reduces tissue damage should be required for clinical application. PMID- 18446012 TI - [Interleukin-6 as a pathogenic factor of systemic-onset juvenile idiopathic arthritis]. AB - Systemic-onset juvenile idiopathic arthritis (JIA) is a subtype of chronic childhood arthritis of unknown cause, manifested by spiking fever, erythematous rash, arthritis, pericarditis, and hepatosplenomegaly. It has been believed a disease developed due to an excessive production of pro-inflammatory cytokines, especially interleukin (IL)-6. We organized trials of a new biologic response modifier, Toclizimuab, anti-IL-6 receptor monoclonal antibody, to patients with systemic-onset JIA. Tocilizumab directs to solely IL-6 receptor, and is called as a one-point hit drug. We successfully administered Tocilizumab to stabilize the inflammation, and inflammatory symptoms and signs of the patients were abruptly gone. Previously, corticosteroids were the only life-saving drugs, but we proved Tocilizumab will be the possible alternative for treating these children. Basic science will help us to save the children, and clinical science also will promote the basic science in turn. PMID- 18446013 TI - [Pathogenic analysis of chronic inflammatory disease based on the clinical results by IL-6 blocking therapy]. AB - Every clinician knows the elevation of acute phase proteins at the inflammatory status, but nobody knows the CRP or SAA induction mechanism on inflammation, in which a lot of cytokines or chemokines are activated. Induction mechanism of CRP and SAA is analyzed based on the result of the normalization of serum CRP or SAA in rheumatoid arthritis by the IL-6 blocking therapy with a humanized anti IL-6 receptor antibody. Ultimately, IL-6 is a pivotal cytokine among IL-6, IL-1 and TNF-a in induction of CRP and SAA in hepatocyte. Furthermore, activation of STAT3, a transcriptional factor under IL-6 signal transduction pathway, is critical on the expression of these mRNAs. Based on this mechanism, the depression of CRP and SAA induction could be explained by the IL-6 blockage both in vitro and in vivo. Therefore, IL-6 blocking therapy may elucidate the pathogenic significance of IL-6 in chronic inflammatory disease. PMID- 18446014 TI - [A case of Achilles tendon rupture in a patient of refractory Reiter's syndrome]. AB - We herein report a case of spontaneous rupture of Achilles tendon in a 51-year old man with refractory Reiter's syndrome. On the diagnosis in November, 2006, physical examinations and MR images showed a remarkable inflammation at the calcaneal insertion area of Achilles tendon. He required aggressive treatments with nonsteroidal anti-inflammatory drug (NSAID), oral prednisolone 30 mg daily and methotrexate (8 mg weekly) to control the disease. Two months later, the Achilles tendon ruptured at its insertion point. This ruptured lesion of Achilles tendon was an unusual site compared to previous reports. Histological findings in the ruptured lesion of Achilles tendon revealed the existence of granulomatous lesion consisted of severe infiltration of fibroblasts and vessels proliferation beside tendon. These findings suggest a prolonged inflammation. Although it is widely accepted that Reiter's syndrome is associated with enthesis, especially at the attachment of Achilles tendon to calcaneum, there have been only two reports of Achilles tendon rupture associated with Reiter's syndrome. The possible cause of the Achilles tendon rupture in this patient might be due to the weakened strength of the Achilles tendon by the prolonged and severe enthesis of Achilles tendon near the insertion lesion. PMID- 18446015 TI - [A case of polyarteritis nodosa successfully treated by rituximab]. AB - A 47-year-old man was admitted to our hospital in January, 2006 because of a huge cutaneous ulcer in his lower limb. He was diagnosed with polyarteritis nodosa due to the cutaneous ulcer, mononeuritis multiplex, muscular pain, elevated serum CRP level and from histological findings of a skin biopsy. He was initially treated with 60 mg/day of prednisolone, followed by 1000 mg/day of intravenous cyclophosphamide (IVCY) therapy. In June, skin grafting to the cutaneous ulcer was carried out, although the graft did not survive. He revealed therapy resistance to high dose corticosteroid and IVCY therapy, and so was treated with intravenous high dose immunoglobulin therapy. Serum CRP level then decreased and in October skin grafting was once again undertaken, this time the graft successfully survived. In December, serum CRP level increased again and cutaneous ulcer relapsed, thus he was treated with leukocyte apheresis therapy, although it was ineffective. In February 2007, he subsequently received rituximab (375 mg/m(2)/week x 3). Then, serum CRP level decreased rapidly, and cutaneous ulcer also improved. Recently the efficacy of rituximab against rheumatoid arthritis, systemic lupus erythematosus, polymyositis/dermatomyositis and ANCA-associated vasculitis has been recognized. This case suggests that rituximab is also effective against corticosteroid-resistant polyarteritis nodosa. PMID- 18446017 TI - Retinoblastoma: from disease to discovery. AB - Retinoblastoma has contributed much to the understanding of cancer. It provided the classic 'two-hit model' for oncogenesis and helped to identify the first tumor suppressor gene RB1. Thirty years since then, the search for additional events underlying disease progression continues. Phenotypic variations in retinoblastoma offer numerous clues to disease pathogenesis. Understanding their molecular biological basis will provide insight into mechanisms underlying tumor progression. These not fully understood genetic and stochastic events play a major role in uncontrolled retinal precursor cell proliferation. Comparative genomic hybridization and gene expression studies have facilitated probing of genes controlling basic events in cellular development, i.e. proliferation, differentiation and apoptosis. Research to determine the cell of origin that underlies the evolution of retinoblastoma can lead to understanding of the stochastic events underlying the genesis of this cancer, which currently remains unclear. In this review, we discuss the recent developments in retinoblastoma and describe how they are beginning to shape a new and revised picture of retinoblastoma pathogenesis and progression. PMID- 18446018 TI - Dose and time effects of estrogen on expression of neuron-specific protein and cyclic AMP response element-binding protein and brain region volume in the medial amygdala of ovariectomized rats. AB - Although estrogen has been shown to be neuroprotective, studies concerning its effect on some behaviors are contradictory, reporting both ameliorative and detrimental effects. A factor involved in hormone efficacy is the estrogen regimen. We reported an effect of 10 microg estrogen for 14 days on the cyclic AMP response element-binding protein (CREB) pathway, including brain-derived neurotrophic factor, in rat medial amygdala (MeA). To determine the effects of estrogen on neuronal numbers and brain region volume in MeA and central nucleus of the amygdala (CeA), we used stereology to test the effect of various estrogen regimens on the number of neuron-specific protein (NeuN)-labeled neurons and brain region volume of MeA and CeA. Ovariectomized rats were injected with vehicle for 14 days, 2.5 microg estradiol benzoate (E2) for 4 or 14 days, or 10 microg estrogen for 14 days. Because NeuN-labeled neuronal number may be related to neuronal survival and upregulation of CREB signaling, we tested the effect of these regimens on levels of phosphorylated CREB (pCREB) labeling in the MeA and CeA. The 2.5 microg estrogen for 14 days regimen increased the mean number of NeuN-labeled neurons and pCREB-labeled cells in the MeA compared to vehicle or 2.5 microg for 4 days. There was an increase in volume of the MeA with 2.5 microg estrogen for 14 days compared to vehicle or 2.5 microg for 4 days. No differences in these parameters were seen in CeA. These data indicate a neuroanatomical heterogeneity of a time effect of estrogen on cells expressing NeuN and pCREB in the MeA versus CeA. PMID- 18446019 TI - The effect of zinc supplements in cystic fibrosis patients. AB - AIM: To study the effect of Zn supplements in cystic fibrosis (CF) on disease evolution. METHODS: A retrospective study of all CF patients treated with Zn supplements (January 2002 to December 2004). Data from patient files for the year before and the first year of supplementation were compared. The controls were CF patients with normal serum Zn and without Zn supplementation. RESULTS: 21 patients (7 females), median age 8.9 (interquartile range 13.1) years, received 5 mg/kg Zn sulfate/day (maximum 150 mg). The number of infections decreased from 3 (1.25) to 2 (2.0) (tied p < 0.02) and the forced expiratory volume in 1 s (FEV(1)) increased from 72.0 (38.4) to 76.5 (52)% (p < 0.02). Energy intake improved (92.3 (14.5) to 117.0 (28.5)%; tied p < 0.02), as did weight for height (W/H; 90 (9.4) to 94 (8.5)%; tied p = 0.043). In the CF control patients the number of infections (2.0 (2.0)), energy intake (116 (43.3)%) and nutritional status remained stable (W/H 99 (17.2)%), but pulmonary function decreased significantly (DeltaFEV(1) loss of 2.0 (8.0)%). There was a significantly different evolution for the change in forced vital capacity (p < 0.004) and DeltaFEV(1) (p < 0.001) between supplemented and control patients. CONCLUSIONS: Analysis of the clinical data on Zn supplementation in CF showed beneficial effects in Zn-deficient CF patients. These results must be confirmed in a prospective double-blind randomized control trial. PMID- 18446020 TI - Supplementation with 200 mg/day docosahexaenoic acid from mid-pregnancy through lactation improves the docosahexaenoic acid status of mothers with a habitually low fish intake and of their infants. AB - BACKGROUND/AIMS: The supply of docosahexaenoic acid (DHA, 22:6omega-3), important for fetal/infant neurodevelopment, depends on the maternal fatty acid (FA) status, which may be marginal in central Europe. Therefore, we investigated the effect of a daily vitamin/mineral supplement with and without 200 mg DHA from mid pregnancy through lactation on the DHA concentrations in maternal and infant red blood cell phospholipids (RBC%), and in breast milk FA (%). METHODS: At 21 weeks' gestation, 144 women were enrolled into a randomised, double-blind clinical trial receiving daily: (1) a basic vitamin-mineral supplement (Vit/Min group), (2) Vit/Min plus 4.5 g fructo-oligosaccharide (FOS group), or (3) Vit/Min plus 4.5 g FOS plus 200 mg fish oil-derived DHA (DHA-FOS group). FAs were determined by capillary gas-liquid chromatography. RESULTS: While maternal RBC-DHA% at enrolment was not different, at 37 weeks gestation, and 3 months after delivery RBC-DHA% were significantly higher in the DHA-FOS group. The breast milk DHA% was twice as high in the DHA-FOS group (0.50%) than in the two others (0.25 %) (p < 0.001), and the ratio ARA/DHA in the DHA-FOS group was 1.0 +/- 0.43, in the others 2.1 +/- 0.43 (p < 0.001). The RBC-DHA% of the infants in the DHA-FOS group was also significantly higher, and correlated significantly with maternal RBC DHA% before and 3 months after delivery. CONCLUSIONS: In central Europe, a dose of 200 mg/day DHA from mid-pregnancy through lactation seems appropriate to improve the DHA status of mothers and infants. PMID- 18446021 TI - High dosage of ascorbic acid and alpha-tocopherol is not useful for diminishing oxidative stress and DNA damage in healthy elderly adults. AB - AIM: To determine the useful dosage of ascorbic acid and alpha-tocopherol against oxidative stress and DNA damage in the elderly. METHODS: A double-blind controlled clinical assay carried out in a sample of 66 healthy subjects divided into three age-paired random groups with 22 subjects in each group. Group A received placebo and group B was administered 500 mg of ascorbic acid and 400 IU of alpha-tocopherol, whereas group C received 1,000 mg of ascorbic acid and 400 IU of alpha-tocopherol for a 6-month period. The following measurements were performed before and after the 6-month treatment period: thiobarbituric acid reactive substances (TBARS); total antioxidant status (TAS); superoxide dismutase (SOD), and glutation peroxidase (GPx) and DNA damage by comet assay. RESULTS: After 6 months, group B subjects exhibited an increase in SOD and GPx enzyme levels; however, this was not statistically significant (p > 0.05). Likewise, TBARS and TAS concentrations remained unchanged (p > 0.05). In addition, in group C the decrease in TBARS and increase in SOD, GPx, and TAS were not statistically significant (p > 0.05). Similarly, average DNA migration showed no significant differences with high-dosage ascorbic acid and alpha-tocopherol. CONCLUSION: These findings suggest that administration of 1,000 mg of ascorbic acid plus 400 IU of alpha-tocopherol for 6 months is not useful for diminishing oxidative stress and DNA damage in healthy elderly adults. PMID- 18446022 TI - Evolutionary changes of astroglia in Elasmobranchii comparing to amniotes: a study based on three immunohistochemical markers (GFAP, S-100, and glutamine synthetase). AB - This paper supplements former studies on elasmobranch species with an immunohistochemical investigation into glutamine synthetase and S-100 protein, in addition to GFAP, and extends its scope to the representatives of almost every group of Elasmobranchii: squalomorph sharks, galeomorph sharks, skates (Rajiformes) and rays (Torpediniformes and Myliobatifomes). More glial elements were labeled by S-100 protein, and even more so by using glutamine synthetase immunostaining than by GFAP: more astrocytes (mainly non-perivascular ones) were detected in the telencephalon of sharks, skates and rays. Only the markers S-100 and glutamine synthetase, but not GFAP, characterized the Bergmann-glia of skates and rays and astrocyte-like non-ependymal cells in Squalus acanthias. Another squalomorph shark species, Pristiophorus cirratus, however, had GFAP immunopositive astrocytes. Of all the species studied, the greatest number of GFAP positive astrocytes could be observed in Mobula japanica (order Myliobatiformes), in each major brain part. According to anatomical location, perivascular glia comprised varied types, including even a location in Mobula, which can also be found in mammals. Remnants of radial glia were found in confined areas of skates, less so in rays. In the rhombencephalon and in the spinal cord modified ependymoglia predominated in every group. In conclusion, there was no meaningful difference between the astroglial architectures of squalomorph and galeomorph sharks. The difference in the astroglial structure between sharks and batoids, however, was confined to the telencephalon and mesencephalon, and did not take place in the rhombencephalon, the latter structure being quite similar in all the species studied. The appearance of astrocytes in the relatively thin-walled shark telencephalon, however, indicates that the brain thickening promoted the preponderance of astrocytes rather than their appearance itself. Although the evolutionary changes of astroglia had some similarities in Elasmobranchii and Amniota, there was one meaningful difference: in Elasmobranchii astrocytes did not prevail in conservative brain regions as they did in the progressive brain regions. PMID- 18446023 TI - Relationship between nanohardness and mineral content of artificial carious enamel lesions. AB - The aim of this study was to compare cross-sectional nanohardness, measured using an ultra-microindentation system, with mineral content, from transversal microradiography, of artificial enamel caries lesions. Sections (85 +/- 10 microm) from 16 bovine enamel samples with artificial caries were prepared. The mineral content and cross-sectional nanohardness at known depths from the surface were compared. Both methods showed lesion profiles with a surface layer. The determination of nanohardness seems limited to lesions with a mineral content >45 vol%. There was a moderate linear relationship between mineral content and the square root of nanohardness (R2 = 0.81). It was concluded that the conversion of cross-sectional hardness into mineral content remains questionable and cannot be recommended. PMID- 18446024 TI - Unrestored dentin caries and deep dentin restorations in Swedish adolescents. AB - The objectives of this longitudinal study were to assess: (a) the prevalence of unrestored dentin caries among 15-year-olds, (b) the proportion of these lesions that had progressed to deep dentin lesions (inner half of dentin) since the immediately preceding examination at the age of 14 and (c) the frequency of deep restorations (extending into the inner half of the dentin). The sample consisted of all 15-year-olds (n = 2,487) born in 1990 and included in the Public Dental Service in Malmo, Sweden. Bitewing radiographs taken during 2005-2007 and the immediately preceding radiographs were analysed and scored by two examiners. The main radiographic scores were: sound; radiolucency in the outer or inner half of dentin; restored surface. The results showed that 22% of the individuals had 1 or more dentin lesions left unrestored from the time of the examination at the age of 14 until the next recall examination at the age of 15. During the observation period (median time 1.2 years), 9% of the unrestored outer dentin lesions progressed to deep dentin lesions. The majority of these (93%) were in molars. One or more deep restorations were found in 22% of the 15-year-olds; the majority involved occlusal surfaces of first molars. In conclusion, unrestored dentin lesions were common in 15-year-olds. Progression to deep dentin lesions occurred in 9% of these lesions and was most common in first molars. Occlusal surfaces of first molars had the highest frequency of deep restorations. PMID- 18446025 TI - The anticariogenic effect of sugar-free gum containing CPP-ACP nanocomplexes on approximal caries determined using digital bitewing radiography. AB - This study investigated, using digital bitewing radiography, the progression and regression of approximal caries in adolescent subjects chewing a sugar-free gum containing 54 mg CPP-ACP relative to the identical gum without CPP-ACP. 2,720 subjects from 29 schools were randomly assigned to one of the two gums and were instructed to chew their assigned gum for 3 x 10 min/day, with one session supervised on school days, over the 24-month study period. Standardized digital bitewing radiographs were taken at the baseline and 24-month clinical examinations for each subject. The radiographs, scored by a single examiner, were assessed for approximal surface dental caries at both the enamel and dentine level. Surface level transitions were scored using a transition matrix. Caries progression or regression was analysed using proportional-odds ordered logistic regression modelling of the transition scores at the tooth surface level. There was a statistically significant difference in the frequency distributions of the transition scores between the two gum groups (OR = 0.82, p = 0.03). For subjects chewing the CPP-ACP gum the odds of a surface experiencing caries progression were 18% less than those of a surface experiencing caries progression for subjects chewing the control gum. In conclusion, the 54 mg CPP-ACP sugar-free gum significantly slowed progression and enhanced regression of approximal caries relative to a control sugar-free gum in a 24-month clinical trial. PMID- 18446027 TI - Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years. AB - BACKGROUND: Few prospective community-based cohort studies have so far concentrated specifically on the risk factors for Alzheimer dementia (AD) with onset after the age of 75 years. METHODS: We prospectively investigated a birth cohort of 585 nondemented inhabitants in the area on the East bank of the river Danube who were born between 1925 and 1926. They were investigated at the age of 75 years and followed up after 30 months. The follow-up was possible with 488 probands; 36 died, and 61 refused to participate. RESULTS: In multivariate analysis an elevated risk for late-onset AD could be found for (1) history of depressive episodes (OR = 2.09; 95% CI = 1.25-3.48); (2) the epsilon 4 allele of the APOE gene (OR = 1.86; 95% CI = 1.08-3.23); (3) lower serum level of folate (OR = 0.92; 95% CI = 0.87-0.98); (4) no chronic use of nonsteroidal anti inflammatory drugs (OR = 0.40; 95% CI = 0.20-0.81), and (5) lower education (OR = 1.43; 95% CI = 1.03-2.00). CONCLUSIONS: Five risk factors for late-onset AD could be confirmed, which might be targets for preventive strategies. PMID- 18446028 TI - Strongyloides stercoralis: a rare cause of obstructive duodenal stenosis. AB - BACKGROUND: Strongyloidiasis is a rare helminthic infection in Europe, and it may cause duodenal obstruction. METHODS: We report a patient who was admitted to our Medical Department with nausea and repeated vomiting since 10 years until food intake became impossible. Subsequent investigations revealed a duodenal obstruction at the upper third of the duodenum, as well as enterocolitis of the terminal ileum with eosinophils dispersed throughout the mucosa. Since food intake was still not possible after treatment with a course of i.v. PPI and prokinetic applications, we decided to perform a resection of the upper duodenum with Y-Roux reconstruction. RESULTS: The histopathological examination of the resected specimen revealed strongyloidiasis. CONCLUSION: Parasite infections such as strongyloidiasis represent a rare differential diagnosis of duodenal obstruction especially if patients originate from endemic regions. PMID- 18446029 TI - Facial cosmetic filler injections as possible target for systemic sarcoidosis in patients treated with interferon for chronic hepatitis C: two cases. AB - BACKGROUND: Cosmetic filler injections are now a very common procedure for aesthetic purposes. Today no contra-indication is given anymore to any patient for an intradermal filling. OBJECTIVES: We draw attention to a possible side effect of facial fillers in a population at risk. RESULTS: We report 2 similar cases of systemic sarcoidosis in patients who both developed a sarcoidal granuloma at the location of a cosmetic filler injection during combined interferon and ribavirin treatment for chronic hepatitis C infection. Cosmetic fillers were hyaluronic acid for one patient and probably silicone for the other. CONCLUSION: Patients with chronic hepatitis C have a higher risk of interferon induced sarcoidosis. Physicians must be aware of the risk that a granuloma can develop after a dermal filler injection especially in patients treated with interferon for chronic hepatitis C. These reactions may reveal a systemic sarcoidosis. We propose to perform a test for a hepatitis C virus infection before injecting a dermal filler and to inform the patient of this risk in case of a hepatitis C infection that could necessitate an interferon treatment. PMID- 18446030 TI - Disseminated eruptive giant mollusca contagiosa in an adult psoriasis patient during efalizumab therapy. AB - Molluscum contagiosum is a common viral skin infection in children with atopic diathesis and not rare in HIV patients. We report a 45-year-old psoriasis patient who developed eruptive mollusca contagiosa during an antipsoriatic treatment with efalizumab. PMID- 18446031 TI - Mycosis fungoides in a lung transplant recipient with advanced ciclosporin nephropathy: management with mechlorethamine and subsequent renal transplantation. AB - Posttransplant cutaneous T cell lymphomas are rare and have been reported to have a poor prognosis. We report the case of a follicular mycosis fungoides in a lung transplant recipient who was successfully treated with topical mechlorethamine, prior to subsequent renal transplantation. PMID- 18446032 TI - Clinical and epidemiological study of cutaneous tuberculosis in Northern Ethiopia. AB - BACKGROUND: Tuberculosis is a major public health problem in Ethiopia but cutaneous tuberculosis (CT) has not been documented. OBJECTIVE: This study was conducted to determine its existence and its clinical pattern in Tigray, a northern region of Ethiopia. METHODS: We report 202 cases of CT who attended the Italian Dermatological Centre in the 34-month period between January 2005 and October 2007. The diagnosis was made on a clinical, cytological and histological basis. RESULTS: Clinically, 143 cases of scrofuloderma, 22 of lupus vulgaris, 18 of gumma, 11 of lichen scrofulosorum, 6 of tuberculosis verrucosa cutis and 2 of erythema induratum of Bazin were observed in our department. All patients were aged between 18 months and 69 years, and 49 were paediatric cases. Forty-five were HIV positive. CONCLUSION: The number of CT cases observed in the period of 34 months indicates a high incidence of the disease in the region also in the paediatric age. CT is still underdiagnosed due to the low number of dermatologists as well as the poor life conditions of the population and the traditional belief in magic medicine. The current study may therefore provide some indication about the epidemiology of CT in Ethiopia. PMID- 18446033 TI - Cutaneous tuberculosis and the control of infection in resource-poor environments. PMID- 18446034 TI - Cholangiocarcinoma complicating primary sclerosing cholangitis: a 24-year experience. AB - AIM: To report the prevalence and outcome of cholangiocarcinoma arising in primary sclerosing cholangitis for a British tertiary referral centre. METHODS: All patients diagnosed with primary sclerosing cholangitis and concurrent cholangiocarcinoma were identified from a prospectively maintained departmental database, and the mode of presentation, management and outcome were determined. RESULTS: Of 370 patients with primary sclerosing cholangitis, 48 patients (13%) were diagnosed with a cholangiocarcinoma within a median time of 0.51 months (range: 0-73.12) from presentation to the unit. Mode of presentation included: inoperable tumours (n = 14); incidental findings in transplant hepatectomy specimens (n = 13); primary sclerosing cholangitis follow-up (n = 9); transplant work-up (n = 5); transplant waiting list (n = 5); suspected tumour confirmed at transplant (n = 1), and incidental finding at cholecystectomy (n = 1). The diagnosis was confirmed by: radiology-guided biopsy (n = 27); MRI (n = 3); CT (n = 2); laparoscopy or laparotomy (n = 2), and frozen section at transplant (n = 1). Management consisted of: transplantation (n = 14, including 1 abandoned); hepatic resection (n = 8), and palliation through stenting (n = 26). The overall median survival of the cohort was 4.9 months (range: 0.09-104.5). Median survival ranged from 2.6 months (range: 0.09-35.3) for palliation to 7.6 months (range: 0.6-99.6) for transplantation and 52.8 months (range: 3.7-104.5) for resection. There was no difference in survival between the transplant and resection groups (p = 0.14). CONCLUSIONS: Cholangiocarcinoma is a common finding in primary sclerosing cholangitis and regular screening of this cohort of patients at referring centres is advocated to detect early tumours, as surgical treatment at an early stage offers significantly better outcomes for this cohort of patients. PMID- 18446035 TI - Emergency surgery for complicated colorectal cancer. A two-decade trend analysis. AB - BACKGROUND/AIMS: Emergency procedures for colorectal cancer have worse outcomes than elective resections. Temporal trends in emergency surgery are analyzed by comparing two decade-related series of colorectal cancer patients. METHODS: The clinical data of 985 patients undergoing colorectal cancer surgery were collected during two decades (1975-1984 and 1995-2004). Rates of emergency surgery, operative mortality, 5-year cancer-related and overall survival were compared retrospectively. RESULTS: The rate of emergency surgery decreased from 81 out of 513 cases (16%) during 1975-1984 to 41 out of 471 cases (9%) during 1995-2004 (p = 0.005). Over the same time, the rate of curative resections in emergency increased from 46% (37/81 cases) to 76% (31/41 cases) (p < 0.001), while patient and tumor characteristics remained similar. Operative mortality after emergency procedures decreased from 14% (11 deaths) to 5% (2 deaths) and cancer-related survival increased from 21 to 42% (p = 0.03). However, when excluding palliative procedures, survival after emergency surgery increased from 52 to 58%, while after elective treatment it increased from 56 to 78% (p < 0.001). CONCLUSIONS: Frequency and operative mortality of emergency colorectal cancer surgery decreased substantially from 1975-1984 to 1995-2004. No significant improvement in long-term survival was observed when curative emergency resections only were considered. Further efforts are needed to reverse the diverging trend of long term outcomes between emergency and elective curative procedures. PMID- 18446036 TI - Immunological consequences of laparoscopic versus open transhiatal resection for malignancies of the distal esophagus and gastroesophageal junction. AB - BACKGROUND/AIM: Surgery remains the only curative therapy for esophageal cancer. The objective of the current study was to evaluate the impact of laparoscopic transhiatal esophagectomy versus open transhiatal esophagectomy on both inflammatory and immunological responses. METHODS: Seventeen patients undergoing laparoscopic or open surgery were included in the study. The postoperative inflammatory response was assessed by measuring WBC count and CRP, IL-6, IL-8, soluble TNF I and II receptor, and elastase levels. The postoperative immune function was assessed by measuring the monocyte HLA-DR expression. LPS-binding protein (LBP) and bactericidal/permeability-increasing protein (BPI) were measured to evaluate bacterial translocation. RESULTS: The IL-6 level increased significantly more in the patients who received open surgery as compared with the laparoscopic group. Both LBP and BPI increased predominantly in the laparoscopic group as compared with the group who received open surgery. No difference was found in HLA-DR expression between the two groups. CONCLUSION: Although both laparoscopic and conventional esophageal resections result in an activation of the inflammatory response, this study suggests that this response could be less pronounced after the laparoscopic approach. However, in the laparoscopic group higher LBP and BPI levels were seen, suggesting an increased endotoxemia. We postulate that the persistently elevated abdominal pressure results in a loss of mucosal barrier function, resulting in bacterial translocation. The cellular acidification of the cells of the peritoneum induced by CO(2) insufflation, however, blunts the expected inflammatory response. PMID- 18446037 TI - High tie of the inferior mesenteric artery in curative surgery for left colonic and rectal cancers: a systematic review. AB - BACKGROUND: During surgery for left colonic and rectal cancers, the inferior mesenteric artery (IMA) can be ligated either at its aortic origin (high tie) or below the origin of the left colic artery (low tie). There is no consensus as to which method should be employed. METHODS: We searched Medline, EMBASE, Cochrane collaboration, and National Guidelines Clearinghouse databases and undertook a systematic review on the use of IMA high tie during curative resections for left colonic and rectal cancers and its impact on patient survival, peri-operative morbidity and mortality, and lymph node retrieval rates. RESULTS: Sixteen studies were eligible for systematic review, including one randomized controlled study, 7 quasi-experimental studies, and 8 retrospective cohort studies. Data on 7,649 patients were analyzed, of whom 4,847 underwent high ligation of the IMA. Despite a trend for improved survival in patients in whom high tie was employed, there is no conclusive evidence to support this. Mortality and morbidity, including anastomotic leak and autonomic nerve injury rates, are similar, while lymph node retrieval is improved. CONCLUSIONS: Although there is no undisputable evidence of improved survival, the use of IMA high tie contributes to improved lymph node retrieval rates and accuracy of tumour staging. PMID- 18446038 TI - Hearing aid low frequency cut: effect on Mandarin tone and vowel perception in normal-hearing listeners. AB - OBJECTIVE: To investigate the impact of low frequency cuts (LCs) in hearing aid frequency response on Mandarin tone and vowel perception at varying signal-to noise ratios (S/N ratios). PATIENTS AND METHODS: Four LC conditions were reviewed, using a programmable, behind-the-ear hearing aid: no LC (NoLC), a 6 dB/octave LC (LC6), a 12-dB/octave LC (LC12), and an 18-dB/octave LC (LC18). Five S/N ratios for speech to white noise were selected: +10 dB, +5 dB, 0 dB, -5 dB and -10 dB. Speech and noise stimuli were presented to 25 normal-hearing, native Mandarin-speaking listeners monaurally. RESULTS: Tone and vowel recognition scores were high for subjects in all experimental conditions except for LC18 and S/N -10 dB. The LCs had minimal impact on tone perception in the positive S/N and S/N 0 conditions. Significant differences for tone recognition were found between the NoLC and LC6, and the LC6 and LC18 conditions with negative S/N ratios. Significant differences in vowel recognition were observed between the LC12 and LC18 settings, at all S/N conditions. CONCLUSION: LC hearing aid settings may negatively impact on vowel recognition, and may adversely affect Mandarin tone recognition in adverse noise conditions, in normal-hearing listeners. PMID- 18446039 TI - Rapid prenatal diagnosis of common aneuploidies in amniotic fluid using quantitative fluorescent polymerase chain reaction. AB - BACKGROUND/AIMS: Quantitative fluorescent polymerase chain reaction (QF-PCR) is a successful prenatal diagnostic method which has been regularly used for the diagnosis of common chromosomal abnormalities in recent years. This method provides diagnosis of common aneuploidies in a few hours after sampling with a high throughput, very low error rates and low cost. METHODS: In this study, 576 amniotic fluid samples were analyzed for trisomies 13, 18, and 21 and sex chromosome aneuploidies using different commercial QF-PCR kits (ChromoQuant version 1, Aneufast, ChromoQuant version 2). Test results were compared with those obtained by conventional cytogenetic analyses. RESULTS: Nine cases of trisomy 21 (1.6%), 1 case of trisomy 13 (0.17%), 3 cases of trisomy 18 (0.52%), 1 case of Turner syndrome (0.17%), 2 cases of Klinefelter's syndrome (0.34%), 2 cases of triploidy (0.34%) and 1 case of XXX (0.17%) were detected by QF-PCR. The results obtained by QF-PCR were consistent with the results of cytogenetic studies (except for 2 samples which had structural chromosomal abnormalities which could not be detected by QF-PCR). CONCLUSION: The QF-PCR method is an appropriate choice for rapid aneuploidy testing in our as well as in other populations. PMID- 18446041 TI - Hysterosalpingographic tubal abnormalities and HIV infection among black women with tubal infertility in sub-Saharan Africa. AB - BACKGROUND: Tubal factor remains a common cause of infertility. The association of HIV infection and tubal infertility is a cause for concern. OBJECTIVE: To determine hysterosalpingographic tubal abnormalities and HIV infection among patients with tubal infertility. RESULTS: Over a 4-year period, 207 patients were analyzed. Of these, 174 (84.1%) presented with secondary infertility and 33 (15.9%) with primary infertility. The patients' age range was 21-48 years and mean age was 36.2 years. One hundred and two (49.3%) patients had a history of induced abortion. Concordant bilateral tubal occlusion was found in 139 (67.2%) patients while 68 (32.8%) had discordant bilateral tubal occlusion. Of the 414 fallopian tubes studied, proximal tubal occlusion was found in 66 (15.9%) cases and distal tubal occlusive pathology occurred in 348 (84.1%). An HIV positivity rate of 13.5% was recorded. Distal tubal occlusion with hydrosalpinx was more associated with HIV infection in this series. CONCLUSION: A high HIV positivity rate was recorded among the patients with tubal infertility compared to the general population. There is prepondence of distal tubal occlusion in infertile women with tubal factor. PMID- 18446040 TI - Pilot study: absorption and efficacy of multiple hormones delivered in a single cream applied to the mucous membranes of the labia and vagina. AB - BACKGROUND/AIMS: There is a lack of evidence in the literature supporting vaginal application of a combination hormone-containing cream for local and systemic symptom relief. This pilot study examined the extent of absorption of a single cream containing estriol, estradiol, progesterone, DHEA, and testosterone. METHODS: A combination cream was administered to 12 postmenopausal women in two differing doses over two independent time periods. Following 28 days (arm 1) and an additional 14 days (arm 2), measurement of hormones in saliva and blood and measurements of symptom relief, patient tolerability, and health-related quality of life (HRQoL) were obtained. RESULTS: The dosage and time of evaluation for study arm 1 was not ideal for providing documented increases in hormone levels. HRQoL measurements supported measured improvement in this arm. The second arm did document absorption of the various hormones when given vaginally. CONCLUSION: This study is the first documenting systemic absorption of multiple hormones by both saliva and blood as well as improvement of HRQoL. This therapy was generally well-tolerated with only 2 patients experiencing minor irritation, not necessitating discontinuation. Additional studies in larger numbers of patients will provide better knowledge for clinicians wanting to provide similar therapy at the lowest effective dose. PMID- 18446042 TI - Successful use of balloon ablation to treat menorrhagia complicating aplastic anemia. AB - BACKGROUND: Aplastic anemia (AA) complicated by menorrhagia is treated with transfusion and hormonal therapy. When bleeding is life-threatening, balloon endometrial ablation can safely be used to treat menorrhagia in selected patients. CASE: A 56-year-old postmenopausal woman was diagnosed with AA after several weeks of menorrhagia and pancytopenia. She became heavily alloimmunized after extensive platelet transfusion. During treatment with antithymocyte globulin, vaginal bleeding increased and the platelet count fell to 1,000/microl on supportive measures. After bleeding stopped with use of intravenous Premarin, she was examined in the operating room. There, a clot was removed and appeared to be a uterine caste; hemostasis continued. Transvaginal ultrasound revealed a normal endometrial contour and thin endometrium; endometrial histology was benign. After she completed antithymocyte globulin and her platelet count could be maintained over 30,000/microl with matched platelets, endometrial ablation was performed without any complications. CONCLUSION: Thermal balloon endometrial ablation is an effective alternative to hysterectomy for women with persistent menorrhagia and AA when supportive measures fail. Prior to endometrial ablation, evaluation should ensure normal endometrial contour and histology, and that sufficient blood products are available to maintain platelet counts above 30,000/microl during the healing process. PMID- 18446043 TI - Ischemic stroke and intracerebral hemorrhage: the latest evidence on mortality, readmissions and hospital costs from Scotland. AB - BACKGROUND AND PURPOSE: Stroke is the third leading cause of death in the UK, yet little information exists on current treatment patterns, outcomes and costs. This study assessed survival, readmissions and total hospital costs over 12 months in patients with first-ever intracerebral hemorrhage (ICH) or ischemic stroke (IS) in Scotland. METHODS: Hospital-based retrospective inception cohort design using data from the Hospital Record Linkage System in the National Health Service in Scotland. Survival, readmissions and total hospital costs were evaluated in all patients admitted to hospital for ICH or IS from April 1, 2004, to March 31, 2005. RESULTS: A total of 1,016 patients with ICH and 4,295 with IS were identified. The average age was 67.6 years (SD 14.5) for ICH and 70.4 years (SD 12.7) for IS at stroke onset. In-hospital mortality was 45.2% (95% confidence interval, CI, 41.0-49.3) for ICH and 15.6% (95% CI, 14.4-16.7) for IS, while 52.5% (95% CI, 48.0-56.9) and 27.2% (95% CI, 25.7-28.8), respectively, were dead at 1 year after stroke onset. The cumulative 1-year risk of rehospitalization for stroke and severe cardiac events was 15.0 and 1.0% in the ICH cohort, respectively, and 10.8 and 1.5% in the IS cohort. The average length of initial hospital stay was 38.4 days for ICH and 39.3 days for IS. The average total hospital costs over 12 months were GBP 13,960 (SD 21,487) for ICH and GBP 14,051 (SD 17,850) for IS. CONCLUSION: Individuals experiencing an ICH continue to exhibit a much worse prognosis than IS, and both forms of stroke continue to imply significant hospital costs to the National Health Service in Scotland. PMID- 18446044 TI - Complete dermatological examination in the elderly: an exploratory study from an outpatient clinic in Turkey. AB - BACKGROUND: The geriatric population is growing continuously, therefore more aged patients are being admitted to dermatology clinics. Successful management of these patients requires a thorough understanding of the features of geriatric patients and prevalence of skin diseases in this group. MATERIALS AND METHODS: Patients aged 65 years and older admitted to the dermatology outpatient clinic over a 3-month period were included. Patients aged between 65 and 74 years were included in group I, and patients older than 74 years were included in group II. Demographic features of the patients were noted. Total dermatological examination was performed in each patient. Fifteen days after the first visit, the patients were phoned up to obtain information about their level of satisfaction regarding the treatments and were invited to the clinic for reexamination where their improvement levels were scored. RESULTS: A total of 209 patients were included in this study. The most common complaints were in the chronic eczema-dermatitis group. However, the most commonly detected disorders were in the chronic sun exposure group. Some severe cutaneous and noncutaneous diseases were detected incidentally at total dermatological examination. Treatment satisfaction scores of patients and improvement scores of doctor had a significantly good correlation. DISCUSSION: The study results indicated that in the management of elderly patients, social and physical evaluation should be carried out and treatment must be recommended accordingly. In all elderly patients, total dermatological examination must be performed because it may reveal some severe cutaneous or underlying noncutaneous diseases. PMID- 18446045 TI - Polymyalgia rheumatica relapse presenting with peripheral pitting edema. PMID- 18446046 TI - The at-risk foot concerns not only patients with diabetes mellitus. AB - BACKGROUND: The prevalence of the at-risk foot in patients with diabetes is high and is increasing with age. The screening of the at-risk foot should be performed in all geriatric patients and on a regular basis. OBJECTIVE: To estimate the prevalence of at-risk foot in a geriatric population of patients and to identify associated principal risk factors in patients with diabetes, nondiabetic patients with neurological disorders and subjects without any known cause of sensory loss at the lower limb. METHODS: A longitudinal prospective study has been conducted in a university long-term care facility with mostly geriatric patients.Four hundred and twenty-six consecutive hospital admissions were recruited between October 2005 and September 2006.Lower limb neuropathy (LLN) was evaluated by the vibration perception threshold using a 128-Hz Rydel-Seiffer tuning fork. Peripheral vascular disease (PVD) was evaluated by the Doppler technique. Patients with LLN and/or PVD were considered to have at-risk foot. RESULTS: Of the 426 participants (median age 80 years, range 26-97), 110 (25.8%) had LLN, 82 (19.2%) had PVD and 92 (21.6%) had both LLN and PVD. Diagnosed diabetes mellitus was present in 96 (22.5%) patients and different neurological disorders having impact on foot sensitivity in 100 (23.5%) patients. The prevalence of the at-risk foot was similar in patients with diabetes (68.7%), in nondiabetic patients with chronic neurological medical conditions (66.0%), or in those without any evidence of diabetes or neurological disease (66.1%). Age was shown to be a predictive factor for the presence of LLN (OR 1.02, 95% CI 1.01-1.04, p = 0.002). CONCLUSION: The prevalence of the at-risk foot in geriatric patients is high, independently of the presence of diabetes. The results suggest that both nondiabetic patients and patients with chronic neurological disorders should be screened for the presence of LLN and PVD as diabetic patients. This screening should be mandatory both in institutions and at home by the general practitioner(s). PMID- 18446047 TI - Eosinophilic bronchitis without asthma. AB - BACKGROUND: Eosinophilic bronchitis without asthma causes chronic coughs without the physiologic features of asthma. The aim of this study was to review the clinical features, pathogenesis, diagnosis, treatment and prognosis of this condition. METHODS: The current literature was reviewed using Pubmed for all studies published in the English language using the search term 'eosinophilic bronchitis'. RESULTS: Eosinophilic bronchitis presents as normal spirometry, without evidence of airway hyperresponsiveness, and normal peak expiratory flow variability. When compared with asthma, mast cell recruitment to the superficial airways and mast cell activation appear to be a feature of eosinophilic bronchitis. In contrast, mast cell infiltration in the smooth muscle is significantly higher in asthma patients than in either eosinophilic bronchitis patients or healthy control subjects. In this condition, the absence of high IL 13 expression can contribute to the normal airway reactivity. The cough usually responds well to inhaled corticosteroids but dose and duration of treatment remain unclear. The condition can be transient, episodic or persistent unless treated, and occasionally, patients may require long-term treatment with oral corticosteroids. CONCLUSIONS: The condition is an important cause of chronic coughs which are corticosteroid responsive. The study of eosinophilic bronchitis suggests that eosinophil-dependent mechanisms are generally not important in the pathogenesis of asthma. PMID- 18446048 TI - Immunomodulatory effects of CpG oligodeoxynucleotides on house dust mite-induced airway inflammation in mice. AB - BACKGROUND: CpG oligodeoxynucleotides (CpG ODNs) are reported to protect against airway eosinophilia and hyperresponsiveness in animal models of asthma. However, little is known about the effects of CpG ODNs on house dust mites, one of the most common environmental allergens, causing allergic asthma. In the present study, we evaluated the immunomodulatory effects of CpG ODNs on the development of house dust mite-induced airway inflammation and remodeling in mice. METHODS: Mice were instilled with Dermatophagoides farinae (Der f) into the trachea 8 times without any additional adjuvants. 48 h after the final allergen instillation, the airway responsiveness to acetylcholine (Ach) was measured, and bronchoalveolar lavage (BAL) and histopathological examination were carried out. CpG ODNs were instilled into the trachea mixed with Der f at the first allergen instillation. RESULTS: Repeated instillation of Der f induced increases in airway responsiveness to Ach, the numbers of inflammatory cells, the levels of T-helper type 2 cytokines and transforming growth factor-beta(1) in the BAL fluid. Furthermore, goblet cell hyperplasia, the thickness of the epithelium and subepithelial fibrosis were observed. The simultaneous instillation of CpG ODNs with Der f at the first allergen instillation showed significant inhibition of these parameters dose dependently. CONCLUSIONS: Our results demonstrate that CpG ODNs have inhibitory effects on Der f-induced airway hyperresponsiveness and eosinophilia, as well as airway remodeling, and that CpG ODNs can be a therapeutic approach for the treatment of house dust mite-induced asthma. PMID- 18446049 TI - Differential mRNA expression of antimicrobial peptides and proteins in atopic dermatitis as compared to psoriasis vulgaris and healthy skin. AB - BACKGROUND: Patients with atopic dermatitis (AD) are prone to have skin infections. We aimed to investigate mRNA expression levels of various antimicrobial peptides and proteins (AMPs) in AD patients, and compare it with psoriasis vulgaris (PV) patients and healthy subjects. METHODS: Skin biopsies were obtained from healthy subjects and patients with AD and PV. Quantitative real-time RT-PCR was used to determine the mRNA levels of human beta-defensin (hBD)-1, hBD-2, hBD-3, LL-37, psoriasin, RNase 7, interferon-gamma, and interleukin-10 (IL-10). RESULTS: Except for LL-37, mRNA of hBDs, psoriasin, and RNase 7 was significantly higher expressed in AD (n = 42) and/or PV (n = 35) patients when compared to controls (n = 18). While PV lesions showed significantly higher mRNA hBD-2 levels than lesions of AD, the latter was associated with significantly higher mRNA levels of RNase 7 when compared to PV. A significant positive correlation of hBD expression was observed both in AD patients and PV patients. hBD mRNA levels of AD skin correlated with psoriasin and RNase 7 levels. hBD-1 mRNA expression correlated with AD activity and IL-10 mRNA expression. CONCLUSIONS: Most AMPs investigated in this study proved to be overexpressed in AD as well as PV when compared to controls. However, a statistically significant difference in AMP mRNA expression between AD and PV was only found for hBD-2 and RNase 7. A moderate-to-strong linear relationship between the mRNA expression of particular AMPs appears to exist in AD, and to a lesser extent in PV as well. PMID- 18446050 TI - Lipopolysaccharides modulate allergen-specific immune regulation in a murine model of mucosal tolerance induction. AB - BACKGROUND: Farming has been widely reported to be associated with decreased risk of developing atopic disorders, but underlying immunomodulatory mechanisms are still not fully defined. We delineated T-cell functions after induction of mucosal tolerance in the context of intranasally delivered organic dust compounds, lipopolysaccharides (LPS). METHODS: BALB/c mice were pretreated intranasally with ovalbumin (OVA) with or without LPS (Escherichia coli) three times (days -21, -14, -7) prior to systemic OVA sensitization (days 1 and 14) and airway allergen challenges (days 28-30). CD4+ spleen T cells from pretreated and sensitized donors were characterized for cytokine function, and transferred into naive recipients prior to subsequent OVA sensitization and challenges. RESULTS: Intranasal OVA pretreatment suppressed Th2-mediated immune and inflammatory responses and enhanced frequency of regulatory T cells in OVA-sensitized and challenged mice. Addition of LPS to OVA, but not LPS alone, inhibited development of allergen-induced sensitization and eosinophilic airway infiltration, and markedly enhanced allergen-specific IgG1 serum levels and frequencies of IL-10- and IFN-gamma-producing CD4+ T cells. Transfer of CD4+ spleen T cells from OVA pretreated animals protected naive recipients against subsequent allergen sensitization and airway disease, whereas transfer from LPS/OVA-pretreated animals only protected against allergen sensitization. CONCLUSION: Microbial LPS modulated mucosal tolerance by inducing allergen-specific IgG1 production and distinct effector CD4+ T cells with a mixed regulatory/Th1 phenotype. Organic dust components such as LPS might therefore be important immune modulators in naturally occurring or preventive allergen-specific tolerance induction. PMID- 18446051 TI - High serum tryptophan concentration in pollinosis patients is associated with unresponsiveness to pollen extract therapy. AB - BACKGROUND/AIMS: The immunologic background of allergic asthma and rhinitis includes a preponderance of Th2-type immunity. In parallel, Th1-type immune response is suppressed by Th2-type cytokines. As a consequence, biochemical pathways triggered by Th1-type cytokine interferon-gamma, such as tryptophan degradation by indoleamine 2,3-dioxygenase and neopterin production, might be altered. We examined whether they are related to the outcome of hyposensitization therapy in atopic patients. METHODS: In serum specimens of 44 atopic patients (18 women, 26 men) before any specific immunotherapy, tryptophan and kynurenine concentrations were measured by HPLC, and the kynurenine to tryptophan ratio (kyn/trp) was calculated. Neopterin concentrations were measured by ELISA. Results were compared with concentrations in 38 serum specimens from healthy blood donors and with the outcome of specific subcutaneous immunotherapy in atopics: on clinical grounds, 27 patients were classified as responders, and 17 patients as non-responders. RESULTS: Serum tryptophan concentrations were higher in atopics (84.3 +/- 24.4 microM) than in blood donors (57.9 +/- 7.46 microM; p < 0.001), kynurenine and kyn/trp were not different between the 2 groups. All of the neopterin concentrations measured in patients were <8.7 nM, the upper limit of the normal. Non-responders to subcutaneous immunotherapy had significantly higher tryptophan concentrations (95.7 +/- 27.0 microM) than responders (77.1 +/- 19.9 microM; p = 0.01). No other marker concentrations differed between the groups. CONCLUSIONS: The measurement of serum tryptophan may present an option to predict the outcome of pollen extract therapy. Higher tryptophan levels may result from lower indoleamine 2,3-dioxygenase activity in atopics. However, this possible relationship needs to be confirmed in further studies. PMID- 18446052 TI - Immunostimulatory sequence CpG elicits Th1-type immune responses in inflammatory skin lesions in an atopic dermatitis murine model. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease, for which no fundamental therapy exists. Immunostimulatory sequence CpG (ISS CpG) has potential in reducing susceptibility to allergic diseases and reversing established allergic reactions. OBJECTIVE: To investigate the effects of ISS CpG in the prevention and treatment of AD in an AD murine model. METHODS: BALB/c mice were epicutaneously exposed to ovalbumin (OVA) for 3 or 4 weeks with a 2-week resting period between each exposure week. ISS i.d. injection was given either on the 1st day of each exposure week (in the prevention experiment) or 3 days before and on the 1st, 4th and 7th day of the last exposure week (in the treatment experiment). Skin biopsy and blood were obtained at the end of the experiments. RESULTS: ISS CpG treatment increased drastically mRNA expression of proinflammatory and Th1-type cytokines and chemokines in OVA-treated skin both in the prevention and treatment experiments. The suppressing effect of ISS CpG on Th2-type cytokines and chemokines was weak and limited to IL-13 and CCL24 in the treatment experiment. No significant reduction in OVA-elicited infiltration of eosinophils and T cells in the skin was seen after ISS administration but infiltration of plasmacytoid dendritic cells was absent in ISS CpG-treated skin. In contrast, ISS injection elicited dramatic infiltration of F4/80+ and CCR5+ cells into the dermis and subcutaneous tissue. CONCLUSION: Due to unwanted side effects and minor beneficial effects in our model, administration of ISS CpG may not be suitable for the treatment of AD in humans. PMID- 18446054 TI - Polymorphisms in two genes, IL-1B and ACE, are associated with erythropoietin resistance in Korean patients on maintenance hemodialysis. AB - Genetic polymorphisms may be linked to inter-individual differences in erythropoietin (EPO) resistance. We investigated the -511C/T polymorphism of the IL-1B gene and the I/D polymorphism of the ACE gene for any association with EPO resistance index (ERI) in maintenance hemodialysis patients (n=167). Because EPO responsiveness is multi-factorial, we also included other possible influences (age, sex, time on dialysis, ACE inhibitor or angiotensin receptor blocker use, ferritin, transferrin saturation, intact PTH, high sensitivity C-reactive protein, albumin, Kt/V, and presence of diabetes mellitus) on ERI in our analyses. Multiple regression analysis showed significant association of the IL 1B-511CC and ACE DD polymorphisms with ERI (P=0.038 and P=0.004 in the recessive model, respectively). The combination (C) of alleles of two loci showed that C1 (I-T) was significantly associated with ERI in the co-dominant and recessive models (P=0.005 and P=0.0001, respectively). Subjects who did not carry C1 showed significantly decreased ERI (10.10+/-5.15 IU/kg weight/g hemoglobin) compared to other study subjects (C1/C1 and C1/-; 12.97+/-4.90 and 15.12+/-7.43 IU/kg weight/g hemoglobin, respectively). Our study indicates that the IL-1B-511C/T and ACE I/D polymorphisms may be useful genetic markers of EPO requirement in hemodialysis patients. These findings might also provide a new perspective on therapeutic approaches to the treatment of end stage renal disease patients with anemia. PMID- 18446053 TI - Membrane transducing activity of recombinant Hoxc8 protein and its possible application as a gene delivery vector. AB - In order to examine whether the Hoxc8 protein can deliver nucleic acid into mammalian cells, we designed several Hoxc8-derived recombinant proteins to be synthesized as glutathione S-transferase (GST) fused forms in E. coli (GST Hoxc8(1-242), containing a full length of Hoxc8; GST-Hoxc8(152-242), possessing a deletion of the acidic N-terminus of Hoxc8; GST-Hoxc8(149-208), which contained the homeodomain only). After labeling these proteins with Oregon 488, we examined their membrane transduction ability under the fluorescence microscope and verified that all three proteins showed similar transduction efficiency. The ability of the proteins to form in vitro protein-DNA complexes was analyzed on agarose gel; both GST-Hoxc8(1-242) and GST-Hoxc8(149-208) formed complexes. In contrast, the GST-Hoxc8(152-242) protein did not form a complex. The GST Hoxc8(149-208) protein formed a complex with DNA at a mass ratio of 1u1 (DNAuprotein), and GST-Hoxc8(1-242) formed a complex at a mass ratio of 1u5. When the DNA (pDsRed1-C1) and protein complexes were added to culture media containing mammalian cells, the cells uptook the complexes, which was indicated by red fluorescence expression under the fluorescent microscope. These results indicate that recombinant Hoxc8 derivatives that harbor a homeodomain are able to traverse the mammalian cellular membrane. DNA that is bound to the recombinant derivatives can be carried across the membrane as well. This process could be applied in the development of a useful delivery vector for gene therapy in the future. PMID- 18446055 TI - TNF-alpha-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells. AB - Up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the lung airway epithelium is associated with the epithelium-leukocyte interaction, critical for the pathogenesis of various lung airway inflammatory diseases such as asthma. However, little is known about how ICAM-1 is up-regulated in human airway epithelial cells. In this study, we show that tumor TNF-alpha induces monocyte adhesion to A549 human lung airway epithelium and also up-regulation of ICAM-1 expression. These effects were significantly diminished by pre-treatment with diphenyliodonium (DPI), an inhibitor of NADPH oxidase-like flavoenzyme. In addition, the level of reactive oxygen species (ROS) was increased in response to TNF-alpha in A549 cells, suggesting a potential role of ROS in the TNF-alpha induced signaling to ICAM-1 expression and monocyte adhesion to airway epithelium. Further, we found out that expression of RacN17, a dominant negative mutant of Rac1, suppressed TNF-alpha-induced ROS generation, ICAM-1 expression, and monocyte adhesion to airway epithelium. These findings suggest that Rac1 lies upstream of ROS generation in the TNF-alpha-induced signaling to ICAM-1 expression in airway epithelium. Finally, pretreatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB, reduced TNF-alpha-induced ICAM 1 expression and both DPI and RacN17 significantly diminished NF-kappaB activation in response to TNF-alpha. Together, we propose that Rac1-ROS-linked cascade mediate TNF-alpha-induced ICAM-1 up-regulation in the airway epithelium via NF-kappaB-dependent manner. PMID- 18446056 TI - Gene network and canonical pathway analysis in prostate cancer: a microarray study. AB - The molecular mechanism playing a role in the development of prostate cancer (PCA) is not well defined. We decided to determine the changes in gene expression in PCA tissues and to compare them to those in non-cancerous samples. Prostate tissue samples were collected by needle biopsy from 21 PCA and 10 benign prostate hyperplasic (BPH) patients. Total RNA was isolated, cDNA was synthesized, and gene expression levels were determined by microarray method. In the progression to PCA, 738 up-regulated and 515 down-regulated genes were detected in samples. Analysis using Ingenuity Pathway Analysis (IPA) software revealed that 466 network and 423 functions-pathways eligible genes were up-regulated, and 363 network and 342 functions-pathways eligible genes were down-regulated. Up regulated networks were identified around IL-1beta and insulin-like growth factor 1 (IGF-1) genes. The NFKB gene was centered around two up- and down-regulated networks. Up-regulated canonical pathways were assigned and four of them were evaluated in detail: acute phase response, hepatic fibrosis, actin cytoskeleton, and coagulation pathways. Axonal guidance signaling was the most significant down regulated canonical pathway. Our data provide not only networks between the genes for understanding the biologic properties of PCA but also useful pathway maps for future understanding of disease and the construction of new therapeutic targets. PMID- 18446057 TI - Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase. AB - Previous studies have demonstrated that rottlerin, a specific PKCdelta inhibitor, potentiates death receptor- mediated apoptosis through a cytochrome c-dependent or -independent pathway. However, its ability to regulate necrotic cell death, as well as the underlying mechanism, remains unknown. We found that in murine fibrosarcoma L929 cells, treatment with rottlerin protected the cells against TNF induced necrosis, whereas it sensitized the cells to apoptosis induced by co treatment with Hsp90 inhibitor geldanamycin and TNF, in a manner independent of its ability to inhibit PKC-delta. TNF treatment induced rapid accumulation of mitochondrial superoxide (O2-) through the Nox1 NADPH oxidase when cells undergo necrosis. Moreover, pretreatment with rottlerin failed to induce the GTP-bound form of small GTPase Rac1 by TNF treatment, and subsequently suppressed mitochondrial O2- production and poly(ADP-ribose) polymerase activation, thus inhibiting necrotic cell death. Therefore, our study suggests that Nox1 NADPH oxidase is a new molecular target for anti-necrotic activity of rottlerin upon death-receptor ligation. PMID- 18446058 TI - T-CAM, a fastatin-FIII 9-10 fusion protein, potently enhances anti-angiogenic and anti-tumor activity via alphavbeta3 and alpha5beta1 integrins. AB - We made fusion protein of fastatin and FIII 9-10, termed tetra-cell adhesion molecule (T-CAM) that can interact simultaneously with alphavbeta3 and alpha5beta1 integrins, both playing important roles in tumor angiogenesis. T-CAM can serve as a cell adhesion substrate mediating adhesion and migration of endothelial cells in alphavbeta3 and alpha5beta1 integrin-dependent manner. T-CAM showed pronounced anti-angiogenic activities such as inhibition of endothelial cell tube formation, endothelial cell proliferation, and induction of endothelial cell apoptosis. T-CAM also inhibited angiogenesis and tumor growth in mouse xenograft model. The anti-angiogenic and anti-tumoral activity of molecule like fastatin could be improved by fusing it with integrin-recognizing cell adhesion domain from other distinct proteins. The strategy of combining two distinct anti angiogenic molecules or cell adhesion domains could facilitate designing improved anticancer agent of therapeutic value. PMID- 18446059 TI - Transcriptional profiling in human HaCaT keratinocytes in response to kaempferol and identification of potential transcription factors for regulating differential gene expression. AB - Kaempferol is the major flavonol in green tea and exhibits many biomedically useful properties such as antioxidative, cytoprotective and anti-apoptotic activities. To elucidate its effects on the skin, we investigated the transcriptional profiles of kaempferol-treated HaCaT cells using cDNA microarray analysis and identified 147 transcripts that exhibited significant changes in expression. Of these, 18 were up-regulated and 129 were down-regulated. These transcripts were then classified into 12 categories according to their functional roles: cell adhesion/cytoskeleton, cell cycle, redox homeostasis, immune/defense responses, metabolism, protein biosynthesis/modification, intracellular transport, RNA processing, DNA modification/ replication, regulation of transcription, signal transduction and transport. We then analyzed the promoter sequences of differentially-regulated genes and identified over-represented regulatory sites and candidate transcription factors (TFs) for gene regulation by kaempferol. These included c-REL, SAP-1, Ahr-ARNT, Nrf-2, Elk-1, SPI-B, NF-kappaB and p65. In addition, we validated the microarray results and promoter analyses using conventional methods such as real-time PCR and ELISA-based transcription factor assay. Our microarray analysis has provided useful information for determining the genetic regulatory network affected by kaempferol, and this approach will be useful for elucidating gene-phytochemical interactions. PMID- 18446060 TI - Secretion of adenylate kinase 1 is required for extracellular ATP synthesis in C2C12 myotubes. AB - Extracellular ATP (exATP) has been known to be a critical ligand regulating skeletal muscle differentiation and contractibility. ExATP synthesis was greatly increased with the high level of adenylate kinase 1 (AK1) and ATP synthase beta during C2C12 myogenesis. The exATP synthesis was abolished by the knock-down of AK1 but not by that of ATP synthase beta in C2C12 myotubes, suggesting that AK1 is required for exATP synthesis in myotubes. However, membrane-bound AK1beta was not involved in exATP synthesis because its expression level was decreased during myogenesis in spite of its localization in the lipid rafts that contain various kinds of receptors and mediate cell signal transduction, cell migration, and differentiation. Interestingly, cytoplasmic AK1 was secreted from C2C12 myotubes but not from C2C12 myoblasts. Taken together all these data, we can conclude that AK1 secretion is required for the exATP generation in myotubes. PMID- 18446061 TI - Implication of leucyl-tRNA synthetase 1 (LARS1) over-expression in growth and migration of lung cancer cells detected by siRNA targeted knock-down analysis. AB - Molecular mechanism of lung carcinogenesis and its aggressive nature is still largely elusive. To uncover the biomarkers related with tumorigenesis and behavior of lung cancer, we screened novel differentially expressed genes (DEG) in A549 lung cancer cell line by comparison with CCD-25Lu, normal pulmonary epithelial cell line, using annealing control primer(ACP)-based GeneFishing system. Of the DEGs, over-expression of leucyl-tRNA synthetase 1 (LARS1) was prominent and this up-regulation was confirmed by immunoblotting and real-time quantitative RT-PCR analysis. In addition to A549 cell line, primary lung cancer tissues also expressed higher level of LARS1 mRNA than their normal counter tissues. To explore the oncogenic potential of LARS1 over-expression in lung cancer, we knocked-down LARS1 by treating siRNA and observed the tumor behavior. LARS1 knock-down cells showed reduced ability to migrate through transwell membrane and to form colonies in both soft agar and culture plate. Taken together, these findings suggest that LARS1 may play roles in migration and growth of lung cancer cells, which suggest its potential implication in lung tumorigenesis. PMID- 18446062 TI - IL-17 induces the production of IL-16 in rheumatoid arthritis. AB - The purpose of this study was to investigate the expression of IL-16 in the rheumatoid synovium and the role of inflammatory cytokines and Toll-like receptor (TLR) ligands in IL-16 production by fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) patients. Immunohistochemical staining was performed with a monoclonal antibody to IL-16 in synovial tissues from patients with RA and likewise in patients with osteoarthritis (OA). FLS were isolated from RA synovial tissues and stimulated with IL-15, IL-1beta, IFN-gamma, and IL-17. The IL-16 mRNA level was assessed by semiquantitative RT-PCR and real time (RT) PCR and a comparison was made between IL-16 mRNA levels produced by RA-FLS and OA-FLS. Production of IL-16 was identified by a western blot assay, and IL-16 production after stimulation by specific ligands of TLR2 and TLR4 was assessed by RT-PCR. While immunohistochemical staining demonstrated strong expression of IL-16 mRNA in synovial tissues from patients with RA, similar findings were not present in the OA group. Moreover, mRNA expression of IL-16 by RA-FLS increased after treatment with IL-17 but not with IL-15, IL-1beta, and IFN-gamma. Specifically, IL-17 increased IL-16 mRNA level by RA-FLS and peripheral blood mononuclear cells in a dose-dependent manner. However, IL-17 did not stimulate IL-16 production in OA-FLS. Peptidoglycan, a selective TLR2 ligand, also increased production of IL 16 by RA-FLS dose- dependently, whereas LPS, a selective TLR4 ligand, had no such stimulatory effect. The results from our data demonstrate that IL-17 and TLR2 ligands stimulate the production of IL-16 by RA-FLS. PMID- 18446063 TI - Transient downregulation of protein O-N-acetylglucosaminylation by treatment of high-dose nicotinamide in human cells. AB - Nicotinamide at millimolar concentrations affects cell survival in various conditions, and is being utilized therapeutically in many human diseases. However, the effect of an acute treatment of nicotinamide at such high dose on gene expression and cellular metabolism has rarely been determined previously. In this study, we found that levels of O-N-acetylglucosamin(O-GlcNAc)ylated proteins including Sp1 acutely decreased upon treatment of 10 mM nicotinamide. Concomitantly, Sp1 protein level decreased rapidly through accelerated proteasome mediated proteolysis. Cotreatment of glucosamine or 2-deoxyglucose, which inhibits protein deGlcNAcylation, effectively blocked the decrease induced by nicotinamide. Interestingly, the decline in the levels of Sp1 and protein O- GlcNAcylation was only transient lasting for two days post treatment, and this pattern matched closely the rapid fluctuation of the cellular [NAD+]. Our results suggest a possible link between cellular nicotinamide metabolism and protein O GlcNAcylation, and an existence of cellular [NAD+] homeostasis. PMID- 18446064 TI - An NH2-terminal truncated cytochrome P450 CYP3A4 showing catalytic activity is present in the cytoplasm of human liver cells. AB - Cytochrome P450 3A4 (CYP3A4), is the dominant human liver hemoprotein enzyme localized in the endoplasmic reticulum (ER), and is responsible for the metabolism of more than 50% of clinically relevant drugs. While we were studying CYP3A4 expression and activity in human liver, we found that anti-CYP3A4 antibody cross-reacted with a lower band in liver cytoplasmic fraction. We assessed the activities of CYP3A4 and its truncated form in the microsomal and cytoplasmic fraction, respectively. In the cytoplasmic fraction, truncated CYP3A4 showed catalytic activity when reconstituted with NADPH-cytochrome P-450 reductase and cytochrome b5. In order to determine which site was deleted in the truncated form in vitro, we transfected cells with N-terminal tagged or C-terminal tagged human CYP3A4 cDNA. The truncated CYP3A4 is the N-terminal deleted form and was present in the soluble cytoplasmic fraction. Our result shows, for the first time, that N terminal truncated, catalytically active CYP3A4 is present principally in the cytoplasm of human liver cells. PMID- 18446065 TI - Limb fractures and nonaccidental injury in children less than 24 months of age. AB - AIM: The pattern of limb fractures in children aged 24 months or younger is poorly understood. This age group is particularly vulnerable to nonaccidental injury, which can be difficult for inexperienced clinicians to detect. The aim of this study is to identify fracture patterns in children below the age of 24 months. METHODS: Data was collected prospectively. For all fractures, the mechanism of injury including height of fall (cm), severity of injury, outcome and deprivation scores were collected. Information on children referred for child protection review was also noted. RESULTS: During the 12 months of the year 2003, 122 new patients aged less than 24 months presented with limb fractures directly to the Emergency Department of the Royal Hospital for Sick Children, giving an incidence of 4.55 per 1000 in the 0-12-month group and 17 per 1000 in the 13-24 month group. Sixty-three (52%) children sustained the injury during a fall and only 7% of children were admitted, the rest being followed up as outpatients. Thirty-eight (31%) had simple distal radius/ulna fractures. Five children with unclear histories or mechanisms of injury underwent formal child-protection procedures. All were less than 14 months of age. CONCLUSIONS: Fractures are relatively rare in the first 2 years of life. Child protection needs to be considered in all children, but specifically in those patients with atypical fractures presenting with an unclear mechanism of injury. PMID- 18446066 TI - Emergency department at the cutting edge. AB - OBJECTIVE: This paper reviews the experience of penetrating chest trauma over a 3 year period in one UK emergency department. METHODS: A retrospective review was performed of patients assessed in the emergency department resuscitation room between 1 January 2002 and 31 December 2005. Patients with penetrating chest trauma, either isolated or in combination with other injuries, were included. A Medline search was performed using the terms 'chest', 'trauma' and 'penetrating'. RESULTS: A total of 120 patients presented with penetrating chest trauma. Ninety two percent were male. Ninety-six percent (115) of the patients survived to hospital discharge. Seventy-eight percent of the patients presented at night (20.00 and 8.00 h). A single wound accounted for 52% (63) of patients, multiple wounds 43% (52) with 2% (two) gun-shot wounds and 3% (three) impalings. The mean prehospital time of patients in cardiac arrest was 42 min with a mean on-scene time of 24 min. The mean prehospital time for patients undergoing formal emergency surgery was 39 min with a mean on-scene time of 16 min. Twenty-three patients required one or more tube thoracostomies to be performed in the emergency department and six underwent emergency department thoracotomy. Sixteen patients required immediate formal emergency surgery for haemorrhage control. CONCLUSION: Penetrating chest trauma contributes significantly to our trauma workload with a high proportion of patients sustaining life-threatening injuries requiring immediate intervention. Significant prehospital delays occur. Overall mortality of 4.2% is comparable with that of a major American case series. Further education and protocol development is required to ensure that prehospital and emergency department management of these patients reflects the latest evidence-based guidelines. PMID- 18446067 TI - Stroke thrombolysis in the emergency department as an alternative service for community hospitals lacking a stroke unit. AB - OBJECTIVE: A significant advancement in the management of acute ischemic stroke has been the use of the recombinant tissue plasminogen activator (rtPA). French guidelines recommend that stroke patients should be treated in stroke units (SU); however, community hospitals experience practical difficulties in treating their patients because SUs are not sufficient in number. Only one SU is available in the Aquitaine area (southwest of France) and it is located in Bordeaux. To improve quality of care and to provide modern stroke therapy, we decided to assess whether thrombolysis was feasible in our community hospital located in Pau, 200 km from Bordeaux. METHODS: Selected patients were treated with rtPA and observed for 24 h in the emergency department. According to French legislation, rtPA therapy was defined as 'off-label use'. National Institutes of Health stroke scale (NIHSS) was obtained on admission, immediately after treatment and 24 h after treatment. RESULTS: Results from the first 40 patients are reported in this study. They were treated between September 2004 and June 2006. In total, 1169 patients were admitted for stroke during this period. Outcomes and mortality rates were consistent with experience elsewhere. CONCLUSIONS: According to the local infrastructural criteria and prerequisites described in this study, thrombolysis is a viable and feasible treatment option for stroke patients in emergency departments of French community hospitals. In the absence of an SU, this type of emergency treatment can be used as an alternative until SUs become more numerous throughout the country. PMID- 18446068 TI - Evaluation of an international emergency medicine intervention in Tuscany. AB - OBJECTIVE: To measure the effectiveness of a 9-month emergency medicine 'train the trainers' program in Tuscany, Italy. METHODS: A total of 81 physicians with emergency department experience completed a training course in Italy. The course included 120 h of didactic lectures, 700 h of clinical rotations and 30 h of practical workshops. The effect of the training course was measured by written multiple-choice and oral case-simulation examinations, and a precourse and postcourse self-assessment instrument using a four-point Likert scale, to describe the ability to care for different types of emergency medicine patients. RESULTS: Twenty-four physicians completed the course in 2003-2004 and 57 physicians completed the course in 2004-2005. A comparison of an identical examination given as a posttest to the first group and a pretest to the second group demonstrated significant improvement on a 75-question multiple-choice examination (38.7 vs. 46.2 points, P<0.001). Improvement was also seen in oral case examinations, in pediatrics (17.8 vs. 37.3 points, P<0.001) and neurology (24.8 vs. 34.5, P<0.001). In the self-assessment survey, when asked to describe the ability to diagnose and provide initial treatment for several types of patients before and after the course, significant improvement was reported by 13 of 20 participants (65%). When asked to describe the ability to perform a variety of procedures, significant improvement was seen in seven of sixteen (44%). CONCLUSIONS: When measured by written examinations, oral examinations and physician self-assessment, a train the trainers program, designed as part of an international emergency medicine collaboration, was efficacious. PMID- 18446069 TI - Prospective evaluation of emergency physician performed bedside ultrasound to detect acute appendicitis. AB - OBJECTIVES: To evaluate the accuracy of emergency physicians using bedside ultrasound to detect appendicitis (BUSA). METHODS: Patients presenting to the emergency department with a clinical suspicion of appendicitis were prospectively enrolled and received a 5-min BUSA. Patients received routine work-up for acute appendicitis as deemed appropriate by the attending physician. Radiologists and consulting surgeons were blinded to BUSA results. The criterion standard for the presence or absence of acute appendicitis was the pathology report for patients who received appendectomies, and telephone follow-up for patients discharged home without surgical intervention. RESULTS: A total of 132 patients were enrolled. In 44 cases BUSA was positive. Of these, 37 had surgical pathology reports consistent with acute appendicitis, whereas seven did not have appendicitis. In 82 cases, BUSA was negative. Of these, 62 were determined not to have appendicitis, whereas 20 had appendicitis by pathology. Sensitivity for BUSA was 65% [95% confidence interval (CI) 52-76], specificity was 90% (95% CI 81-95), positive predictive value was 84% (95% CI 71-92), and negative predictive value was 76% (95% CI 65-84). The likelihood ratio of a positive BUSA was 6.4 (95% CI 3.1-13.2). Five patients discharged home with a diagnosis other than appendicitis were unable to be reached by telephone, and were excluded from data analysis. CONCLUSION: Our study gives insufficient evidence to support the use of bedside ultrasound by emergency physicians to rule out appendicitis. The high specificity in our study, however, suggests that with further training, BUSA may be useful to rule-in appendicitis in some patients. PMID- 18446070 TI - Correlation between acid-base parameters measured in arterial blood and venous blood sampled peripherally, from vena cavae superior, and from the pulmonary artery. AB - OBJECTIVE: In intensive care units arterial blood sampling is routine for analysing acid-base and oxygenation status. In nonintensive departments arterial blood sampling is seldom performed. Venous blood sampling is routine but not usually analysed for acid-base and oxygenation status. This study describes the correlation between arterial and peripheral, central and mixed venous pH, PCO2 and PO2 in a wide range of adult patients. METHODS: Arterial and venous blood samples were taken anaerobically and simultaneously. The values of pH, PCO2 and PO2 were compared using Bland-Altman plots. RESULTS: A total of 103 patients were included. The arteriovenous difference (bias+/-SD) for pH was 0.026+/-0.023 and for PCO2 -0.60+/-0.57 kPa (peripheral venous blood), 0.036+/-0.014 and -0.79+/ 0.26 kPa (central venous blood) and 0.026+/-0.010 and -0.67+/-0.22 kPa (mixed venous blood). The arteriovenous difference for PO2 for peripheral, central and mixed venous blood was 6.27+/-4.36, 8.33+/-3.94 and 11.00+/-4.87 kPa, respectively. CONCLUSION: The venous values of pH, corrected for bias, can give arterial values which are within reasonable laboratory and clinical acceptance criteria. For PCO2 this is also true, except for peripheral blood, where the standard deviation is outside laboratory acceptance criteria but within clinical acceptance criteria. For PO2 the arteriovenous differences are not randomly distributed and even for PO2 or =1:16. Five of 6 patients with early syphilis and asymptomatic neurosyphilis, presented serum VDRL > or =1:16. Symptomatic patients showed lower CD4 T cell counts (59 cell/muL vs. 208 cell/muL, P = 0.03) and higher protein concentration on CSF (118 mg/dL vs. 39 mg/dL, P <0.001) than asymptomatic patients. CONCLUSIONS: Most patients had early and asymptomatic neurosyphilis, and more than one third had early syphilis. Patients with symptomatic neurosyphilis showed lower CD4 T cell counts and higher protein concentration on CSF than those asymptomatic. Most patients had serum VDRL titers > or =1:16, regardless of syphilis stage. PMID- 18446083 TI - A consequence of the syphilis epidemic among men who have sex with men (MSM): neurosyphilis in Los Angeles, 2001-2004. AB - OBJECTIVES: To describe the epidemiology and clinical findings of neurosyphilis (NS) cases diagnosed during the current syphilis epidemic occurring predominantly among men who have sex with men. METHODS: Syphilis cases reported to the health department were reviewed for diagnosis of NS, cerebrospinal fluid venereal disease research laboratory results, and/or treatment for NS. RESULTS: During 2001-2004, 7083 cases of syphilis were diagnosed in Los Angeles. One hundred nine cases of confirmed or probable NS occurring among persons aged 19 to 65 years were identified during this period (1.5%). Symptomatic NS was present in 1.2% of reported syphilis cases (86 of 7083). NS cases were inclusive of 71 (65%) men who have sex with men. Forty-two (49%) of the symptomatic NS cases occurred during secondary (N = 28) or early latent (N = 14) syphilis. Sixty-eight percent (N = 74) of the NS cases were human immunodeficiency virus (HIV)-positive. The estimated incidence of symptomatic NS among HIV-infected persons with early syphilis was 2.1% as compared with 0.6% among HIV-negative persons. CONCLUSION: Providers should maintain a high index of suspicion for NS among patients with syphilis, particularly those with HIV infection. PMID- 18446084 TI - Mind the gap: the role of time between sex with two consecutive partners on the transmission dynamics of gonorrhea. AB - OBJECTIVE: Both the duration of sexual partnerships and the time between two consecutive partnerships (gap length) varies between populations. We use a mathematical model with multiple partnership durations and gap lengths to identify the types of relationship cycles that sustain gonorrhea transmission in the United Kingdom. STUDY DESIGN: A mathematical model for gonorrhea transmission was constructed which tracks the duration of partnerships and their preceding gap lengths. The National Survey of Sexual Attitudes and Lifestyles was used to parameterize the model population into 5 different partnership lengths (mean of 1 day, 2 weeks, 8 weeks, 30 weeks, and 10 years) and 3 preceding gap lengths (14 days, 8 weeks, and 1.5 years). RESULTS: The model was able to reproduce patterns of gonococcal infection in the United Kingdom. Assortative (like-with-like) mixing of individuals with short gaps between partnerships was required for gonorrhea infection to persist. Prevalence was highest in individuals with short (>1 day-<1 month) and midterm partnership durations (>1 month-<3 months). Interventions (such as increased condom use) targeted at those with medium-term partnerships were most effective at reducing prevalence; in contrast targeting interventions at those with short partnerships but longer gap lengths (i.e., the group with the highest number of sexual partners) had relatively less impact. CONCLUSION: Our model suggests that gonorrhea is sustained by the presence of a small group of individuals with short gap lengths and medium length partnerships. Interventions targeted at this group are more effective than those targeted at individuals with high numbers of sexual partners but longer gap lengths. PMID- 18446085 TI - Partner age difference and prevalence of chlamydial infection among young adult women. AB - OBJECTIVES: Sexual partner mixing by age is common among adolescents and adults. Although adolescent girls with older male partners are at increased risk of sexually transmitted infection, the importance of this association in young adults is unclear. GOAL: To assess the association between partner age difference and prevalence of chlamydial infection among young women. STUDY DESIGN: Using Wave III of the National Longitudinal Study of Adolescent Health (April 2, 2001 May 9, 2002), the authors examined the relation between the prevalence of chlamydial infection and the partner age among women aged 18 to 26 years. RESULTS: Among women with most recent partners 2 to 8 years younger, the odds of chlamydial infection were approximately 2 times greater [adjusted odds ratio (OR), 1.8; 95% confidence interval (CI), 0.9, 3.5] than among women with partners within 1-year age difference, adjusting for number of partners in the past year. Prevalence of chlamydial infection was only slightly greater for women with partners 2 to 5 years older (adjusted OR, 1.4; 95% CI, 0.9, 2.3) and partners 6 or more years older (adjusted OR, 1.6; 95% CI, 0.9, 2.8), when compared with women with partners within 1-year age difference. The relation between most discordant partner age difference and chlamydial infection seems to vary by women's race/ethnicity, although these stratified estimates are imprecise. CONCLUSIONS: These findings suggest that among young adult women, in contrast to adolescents, older male partners are only moderately associated with the prevalence of chlamydial infection. Young adult women have the lowest odds of infection with partners within 1 year of age difference. PMID- 18446087 TI - Peripheral arterial disease: an underestimated aetiology of exercise intolerance in chronic obstructive pulmonary disease patients. AB - OBJECTIVE: To assess the prevalence of peripheral arterial disease and its implications for exercise limitation in chronic obstructive pulmonary disease (COPD) patients. METHOD: One hundred and fifty-one moderate-to-severe COPD patients (forced expiratory volume in 1 s: 37+/-6 SD% predicted) and 73 healthy age-matched control individuals (divided into 31 smokers and 42 nonsmokers) participated in this study. All COPD patients were either exsmokers or current smokers and their tobacco-smoking history was similar to that of healthy smokers. To evaluate the existence of arterial disease, lower limb perfusion pressure impairment was assessed using the ankle brachial index, whereas arterial stiffness was assessed by the pulse wave velocity (PWV). The definition of peripheral arterial disease required an ankle brachial index value of 0.90 or less, whereas the PWV increment was considered to be a direct witness of arterial stiffness increase. A 6-min walk test was performed to assess physical exercise capacity. RESULTS: Prevalence of peripheral arterial disease was higher in COPD patients than in healthy participants (81+/-3 SD; 49+/-5 SD and 9+/-2 SD%, respectively, in COPD, healthy smokers and nonsmokers). PWV mean values were significantly higher in COPD patients compared with healthy smokers and nonsmokers (10.3+/-2.1 SD m/s; 9.2+/-1.3 SD m/s and 8.7+/-2.2 SD m/s, respectively). The distance covered during the 6-min-walk test was associated positively with the degree of peripheral arterial disease (r=0.78; P=0.05) and negatively with the PWV values (r=-0.74; P=0.05). Not only tobacco-smoking history but also COPD severity was shown to influence these associations. CONCLUSION: The effect of peripheral arterial disease on exercise intolerance in COPD seems to be considerable. Therefore, COPD patients participating in a pulmonary rehabilitation programme should profit from a systematic search for arterial disease. Arterial dysfunction has to be taken into account in the multidisciplinary treatment of these patients. PMID- 18446088 TI - Methylphenidate in the treatment of female adolescents with cooccurrence of attention deficit/hyperactivity disorder and borderline personality disorder: a preliminary open-label trial. AB - Recent studies reported symptomatic overlap between attention deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD). Methylphenidate (MPH) is the most efficient treatment for ADHD. We assessed the efficacy and tolerability of MPH treatment in adolescent females who met the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for both disorders. Fourteen BPD/ADHD female adolescents aged 14-19 years were treated with MPH for 12 weeks, targeting ADHD, BPD symptoms, and aggressive behavior, as rated by ADHD-rating scale (ADHD-RS) and Clinical Global Impression-Severity (CGI S) scale for BPD and aggressive behavior severity. A significant improvement was detected in both ADHD and BPD severity (baseline vs. end point, ADHD-RS: 33.1+/ 4.8 vs. 17.6+/-5.2, P<0.001; BPD CGI-S: 4.6+/-0.8 vs. 3.4+/-0.8, P<0.0005, respectively) as well as in aggressive behavior (Aggression CGI-S: 3.5+/-1.3 vs. 1.8+/-0.5, P<0.001). MPH was well tolerated. MPH may be useful and well tolerated in treating some shared symptoms of ADHD and BPD among female adolescents. Controlled studies are needed to substantiate these findings. PMID- 18446086 TI - Epidemiology of genital Chlamydia trachomatis infection among young women in Costa Rica. AB - OBJECTIVE: To investigate Chlamydia trachomatis (Ct) epidemiology among 5829 women 18 to 25 years old, in Costa Rica. METHODS: Data are from a community-based human papillomavirus 16/18 vaccine trial. Before randomization, eligible women who reported previous sexual activity were interviewed and tested for Ct DNA by Hybrid Capture 2 and polymerase chain reaction-based genotyping. Multivariate models were developed. RESULTS: Overall prevalence was 14.2% (95% confidence interval, 13.3-15.1). Among Ct genotypes, serovar E was the most common (4.3%), followed by serovar F (3.0%), serovar D/Da (2.9%), and serovar I/Ia (2.1%).Ct increased with lifetime sexual partners of the women, and among women with 1 lifetime partner, with sexual partners of the partner. Current intrauterine device users had an increase in Ct detection [odds ratio (OR) 1.6, 1.1-2.5] but hormonal contraceptives or condom users did not. Miscarriages were associated with a reduction in Ct detection (OR 0.7, 0.5-1.0) while current regular smoking increased it (OR 1.7, 1.2-2.5). Vaginal discharge, reactive changes, ASCUS or LSIL and moderate to severe inflammation in the cytology were significantly more common among Ct positive women (P <0.001). Gonorrhea prevalence was 0.8%, and it was, as other STIs, highly correlated with Ct detection. CONCLUSIONS: This is a high-prevalence population where we confirmed the strong link between Ct and sexual behavior of women and their partners. The establishment of a screening program in the age group included in this study should be considered. More studies are needed in developing countries to further investigate the role of intrauterine devices and the lack of protection by condoms, in addition to the interplay between Ct and other STIs, ectopy, inflammation, and epithelial abnormalities. PMID- 18446089 TI - Assessment of visuospatial neglect in stroke patients using virtual reality: a pilot study. AB - One of the neuropsychological deficits that can result from a stroke is the neglect phenomenon. Neglect has traditionally been assessed with paper-and-pencil tasks, which are administered within the reaching space of a person. The purpose of this explorative study is to investigate whether it is possible to assess neglect in the extrapersonal space based on the performance of acute stroke patients, chronic stroke patients and healthy elderly in orientation and exploration tasks when immersed in a three-dimensional (3D)-virtual environment. Six able-bodied healthy elderly and 12 stroke patients (six subacute and six chronic) participated in this explorative cross-sectional study. Neglect was assessed by means of the 3D neglect test. Different parameters were measured at two challenge levels with increasing difficulty. In the easiest level significant differences between the groups were found for total time spent in the test, mean response time left field of vision, and mean response time in the left field of vision of the left virtual reality environment. Differences in search patterns showed that subacute stroke patients had a much more fuzzy search pattern in scanning the environment than healthy elderly and chronic stroke patients. With respect to the more difficult level results showed significant differences between healthy elderly and the total group of stroke patients. The results of this study suggest that a 3D neglect test by means of virtual reality has the potential to detect and measure unilateral neglect. PMID- 18446091 TI - The North American Menopause Society: from abstract to publication. AB - OBJECTIVE: The North American Menopause Society (NAMS) provides a forum through which researchers can present scientific abstracts. After presenting an abstract, the goal is to publish the research as a full-length article. The objective for this study was to determine the publication rate of abstracts presented at NAMS meetings. DESIGN: The PubMed database was searched for full-length, peer-reviewed publications, corresponding to the abstracts presented at the 1999 to 2003 NAMS meetings. When a full-length article was found, the title, authors, date of publication, and the journal were collected. RESULTS: Of the 661 abstracts presented at the five consecutive annual meetings, 253 (38.3%) have been published in peer-reviewed journals. The average time to publication was 2.0 +/- 1.5 years. The average time to publication for oral presentations was 1.7 +/- 1.3 years, and that for poster presentations was 2.0 +/- 1.5 years (P = 0.241). The publication rate of oral presentations was significantly greater than that of poster presentations (57.7% vs 36.5%; P < 0.003). Manuscripts were published in a total of 97 journals, with four (Menopause, Journal of Clinical Endocrinology and Metabolism, Climacteric, and Maturitas) accounting for 38.3% of the publications. CONCLUSIONS: The percentage of abstracts published by NAMS is within the range and within a similar time frame compared with other scientific meetings. Oral presentations are more likely to be rapidly published and may therefore be of higher interest and clinical relevance along with sound methodology and results. Menopause contained the most manuscripts, demonstrating a possible preference of submission to the Society's journal. PMID- 18446092 TI - Induction of cell migration of neural progenitor cells in vitro by alpha-1 adrenergic receptor and dopamine D1 receptor stimulation. AB - The radial migration is an important process in the development of the cerebral cortex. Earlier studies have reported that classical neurotransmitters such as L dopamine and L-adrenaline regulate the proliferation of neural progenitor cells. We examined whether L-dopamine and L-adrenaline regulate cell migration, using embryonic neural progenitor cells from mouse embryonic telencephalon in vitro. In this study, we showed that dopamine D1 agonist induces cell migration of embryonic neural progenitor cells. In addition, we have demonstrated that L adrenaline induces cell migration of embryonic neural progenitor cells, mediated through the activation of alpha-1 adrenergic receptors. Our results suggest that alpha-1 adrenergic receptor and dopamine D1 receptor stimulations in neural progenitor cells are the important process for embryonic brain development, respectively. PMID- 18446090 TI - Effects of a high daily dose of soy isoflavones on DNA damage, apoptosis, and estrogenic outcomes in healthy postmenopausal women: a phase I clinical trial. AB - OBJECTIVE: A phase I double-blind clinical trial was conducted to evaluate the effects of a high oral dose of soy isoflavones administered daily for 84 days to healthy postmenopausal women. Principal outcome measures included DNA damage, apoptosis, and changes indicative of estrogenic stimulation. DESIGN: After eligibility and equol-producer status were determined, stratified randomization was used to assign women to the isoflavone (active) or placebo group. Of the 30 women who completed the study, 18 were in the active group. DNA damage was assessed via COMET and apurinic/apyrimidinic site assays in lymphocytes. Apoptosis was evaluated via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and activated caspase-3 assays in lymphocytes. Estrogenic/antiestrogenic effects were assessed using a self-report questionnaire and by assaying for estrogen, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin in blood. RESULTS: In treated postmenopausal women, there was no indication that high doses of soy isoflavones caused DNA strand breakage, increased apurinic/apyrimidinic sites, or increased apoptosis in peripheral lymphocytes. There were no significant changes in mean values for estrogenic effects or other laboratory measurements. Very few adverse events occurred, and the only drug-related adverse events were mild or grade 1 in severity. CONCLUSIONS: Unconjugated soy isoflavones appear to be safe and well tolerated in healthy postmenopausal women at doses of 900 mg/day. PMID- 18446093 TI - Radiosynovectomy: current status in the management of arthritic conditions. PMID- 18446094 TI - Transpulmonary thermodilution: finally, a gold standard for pediatric cardiac output measurement. PMID- 18446095 TI - Pediatric oncology and hematopoietic stem cell transplant patients requiring invasive mechanical ventilation: do we do a better job? PMID- 18446096 TI - Cardiac output measurement in children: what is lacking? PMID- 18446097 TI - To be or not to be--a biomarker of brain damage in sepsis. PMID- 18446098 TI - Pediatric cardiorenal syndrome: a new name for an old problem? PMID- 18446099 TI - Ask, and they will tell. PMID- 18446100 TI - Nurses' attitudes toward donation after cardiac death: implications for nurses' roles and moral distress. PMID- 18446101 TI - A prospective review of adverse events during interhospital transfers of neonates by a dedicated neonatal transfer service. AB - OBJECTIVES: To categorize and quantify adverse events occurring during emergency interhospital transfers performed by a specialized neonatal retrieval team and to assign levels of associated risk. DESIGN: Prospective review of adverse events during emergency interhospital transfers of neonates by the London Neonatal Transfer Service over a 6-month period. The events were categorized based on an adapted retrieval team model from the Paediatric & Neonatal Safe Transfer and Retrieval Course (PANSTAR). Risk levels were measured using a modified risk assessment score. SETTING: Emergency interhospital transfers by a specialized neonatal retrieval team. PATIENTS: Patients were 346 emergency neonatal transfers over 6 months. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We found that 125 transfers (36.1%) had at least one adverse event. There were 205 adverse events in total; 139 events (67%) were perceived as being due to avoidable human errors. Almost a third of events (30%) occurred even before the retrieval team arrived at the referring hospital and made contact with the patient. The largest group of events occurred due to problems in preparation (n = 69) and communication (n = 49). Most events (n = 143) had insignificant impacts on patients, but six events could have potentially caused major harm. CONCLUSIONS: Adverse events commonly occur during neonatal transfers, even if performed by a dedicated transfer service. Early identification of potentially harmful episodes is important. Human error is likely to be a factor in the majority of adverse events; hence, opportunities should be taken to reduce the number of these through education, training, and risk management. PMID- 18446102 TI - Intensive care experience with sclerotherapy for cervicofacial lymphatic malformations. AB - OBJECTIVE: To describe a cohort of patients needing intensive care support after sclerotherapy for cervicofacial lymphatic malformations. DESIGN: Retrospective review of case records of patients undergoing sclerotherapy between January 2004 and November 2006. SETTING: A tertiary, university-affiliated, pediatric teaching hospital. PATIENTS: Five patients needing admission to a pediatric intensive care unit (PICU) following sclerotherapy with OK432. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five patients needed a total of 13 PICU admissions. Ages ranged from 4 months to 19 months. All patients had extensive lesions that involved the airways, mediastinum, or floor of the mouth, documented by magnetic resonance imaging. Nine admissions involved elective intubation and ventilation following sclerotherapy due to the extent of lesions. There were four urgent admissions to the PICU with respiratory distress ranging from 3 to 18 days after sclerotherapy. The mean duration of admission was 7 days (total 93 days, range 2-22 days). Total ventilated hours were 1656 hrs with a range of 16.5-370 hrs per admission. Multiple procedures, such as drainage of cysts and further sclerotherapy procedures, were performed before extubation on the PICU. CONCLUSIONS: Children with extensive disease and airway involvement need multiple PICU admissions. The potential for life-threatening respiratory embarrassment is unpredictable following sclerotherapy. Consideration should be given to performing further sclerotherapy while the patients are intubated in the PICU. The PICU provides a safe and secure environment for such procedures. PMID- 18446103 TI - Use of methylene blue spectrophotometry to detect subclinical aspiration in enterally fed intubated pediatric patients. AB - OBJECTIVE: Enteral feeding is widely used in ventilated patients admitted to pediatric intensive care units. Although studies in adult patients have shown that the site of feeding (stomach vs. small intestine) may be associated with aspiration pneumonia, there are no such reports in critically ill pediatric patients. We hypothesized that in intubated pediatric patients, there was no difference in the frequency of aspiration between nasogastric and postpyloric enteral feeding. DESIGN: Randomized, prospective clinical study. SETTING: Single pediatric intensive care unit of a tertiary care children's hospital. PATIENTS: Forty-four intubated patients (< or = 18 yrs old). INTERVENTIONS: Intubated patients were randomized to receive either nasogastric (n = 27) or postpyloric (n = 17) enteral feeding. Feeding tube placement by the bedside nurse was confirmed by abdominal radiograph. Methylene blue was added at a standard dilution to an age-appropriate formula. Tracheal secretions were suctioned every 8 hrs, tested for blue color by observation, and analyzed via spectrophotometry. Patients were followed until feeds were stopped for anticipated extubation. Aspiration pneumonia was defined using criteria of the Centers of Disease Control and Prevention (CDC). MEASUREMENTS AND MAIN RESULTS: Methylene blue was detected in two patients in the postpyloric group by spectrophotometry. None of the patients met the CDC criteria for aspiration. There was no difference in the frequency of aspiration between the two groups (p < .07). The time until beginning feedings in the postpyloric group was greater than that for the nasogastric group (18-24 hrs vs. 6 hrs, p < .05). The postpyloric group required more abdominal radiographs compared with the nasogastric group (three radiographs vs. one, p < .05). CONCLUSIONS: Use of nasogastric feeding shortens the time needed to reach nutritional goals and reduces the number of radiographic studies. Nasogastric feeding demonstrates no increase in aspiration compared with postpyloric feeding in intubated pediatric patients. PMID- 18446104 TI - Neurological injury markers in children with septic shock. AB - OBJECTIVE: To determine whether known serum markers of neurologic injury are increased in children with septic shock. DESIGN: Prospective, observational study. SETTING: Tertiary-care, pediatric intensive care unit. PATIENTS: Two cohorts of children (n = 24) with septic shock were prospectively enrolled within 24 hrs of their diagnosis. In cohort 1, serum markers (S100beta, neuron-specific enolase [NSE], and glial fibrillary acidic protein [GFAP]) were determined (n = 18). In cohort 2, in addition to serum markers, urine S100beta and GFAP were determined, and continuous electroencephalography (cEEG) was performed. Children who presented to the emergency room with a fever served as controls (n = 32). Children with known neurologic conditions were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum and urine were collected daily for up to 7 days or until pediatric intensive care unit discharge. Biomarker concentrations were determined by commercially available enzyme-linked immunosorbent assays. cEEG was performed on days 1, 2, 4, and 7 in a 16-channel montage for at least 6 hrs. Physical examinations did not reveal focal neurologic deficits. Children with septic shock demonstrated increased serum S100beta and NSE compared with controls (mean +/- SEM: 10.5 microg/L +/- 2.4 vs. .9 microg/L +/- .1, p < .001; 96.6 microg/L +/- 8.9 vs. 4.0 microg/L +/- 1.3, p < .001, respectively). Serum GFAP was detectable in five septic children and none of the controls. In cohort 2, urine of four patients demonstrated measurable S100beta levels, and GFAP was detected in one child (nonsurvivor). cEEG demonstrated moderate to severe encephalopathy in all children studied. CONCLUSIONS: Markers of neurologic injuries are increased in children with septic shock. This may indicate subclinical injuries that are either transient or permanent. Studies that correlate the long-term neurologic outcome of children with these markers are needed to identify children at risk for neurologic injuries from septic shock. PMID- 18446105 TI - Changes in outcomes (1996-2004) for pediatric oncology and hematopoietic stem cell transplant patients requiring invasive mechanical ventilation. AB - OBJECTIVE: To assess the following hypotheses regarding mechanically ventilated pediatric oncology patients, including those receiving hematopoietic stem cell transplant (HSCT) and those not receiving HSCT: 1) outcomes are more favorable for nontransplant oncology patients than for those requiring HSCT; 2) outcomes have improved for both populations over time; and 3) there are factors available during the time of mechanical ventilation that identify patients with a higher likelihood of dying. DESIGN: Retrospective review. SETTING: Free-standing, tertiary care, pediatric hematology oncology hospital. PATIENTS: All patients requiring invasive mechanical ventilation with a diagnosis of cancer or following HSCT from January 1996 to December 2004. INTERVENTIONS: Bivariate and multivariate analysis. Dates of admission were grouped into time periods for analysis: 1996-1998, 1999-2001, and 2002-2004. MEASUREMENTS AND MAIN RESULTS: There were 401 courses of mechanical ventilation (329 patients) analyzed. Forty five percent of HSCT admissions (92 of 206) vs. 75% of non-HSCT oncology admissions (146 of 195) were extubated and discharged from the pediatric intensive care unit (p < .0001). Twenty-five percent of HSCT vs. 60% of non-HSCT admissions survived 6 months (p < .0001). Among admissions with an abnormal chest radiograph and a PaO2/FiO2 ratio <200, pediatric intensive care unit survival increased for each successive time period, with 45% of HSCT and 83% of non-HSCT admissions surviving during 2002-2004. In multivariate analysis of all study patients, Pediatric Risk of Mortality scores on the day of intubation, allogeneic HSCT, cardiovascular failure, hepatic failure, neurologic failure, a previous course of mechanical ventilation within 6 months, and the time period intubated were associated with mortality. With the exception of time period, these same variables were associated with mortality in multivariate analysis of only HSCT patients. CONCLUSIONS: HSCT patients who require mechanical ventilation have worse outcomes than non-HSCT oncology patients. Outcomes for both groups have improved over time. Allogeneic transplant, higher Pediatric Risk of Mortality scores, need for repeated mechanical ventilation, and concomitant organ system dysfunction are risk factors for death. PMID- 18446106 TI - Assessment of cardiac output in children: a comparison between the pressure recording analytical method and Doppler echocardiography. AB - OBJECTIVE: To assess cardiac output in pediatric patients with the pressure recording analytical method (PRAM) and the Doppler echocardiography method. PRAM derives cardiac output from beat-by-beat analysis of the arterial pressure profile (systolic and diastolic phase) in the time domain. DESIGN: A prospective observational study. SETTING: Pediatric intensive care unit at a tertiary care children's hospital. PATIENTS: Forty-eight patients between the ages of 1 month and 18 yrs. INTERVENTIONS: Femoral or radial artery catheterization and mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Cardiac output was simultaneously estimated by Doppler echocardiography and PRAM. Cardiac output values obtained by Doppler echocardiography (2.7 +/- 1.6 L/min, range 0.92-8.20) were significantly correlated with those estimated by PRAM (2.6 +/- 1.7 L/min, range 0.89-7.48; r2 = .99, p < .01). The mean difference between the two estimates was 0.12 +/- 0.27 L x min(-1) (95% confidence interval, -0.54 to 0.77 L x min(-1)). CONCLUSIONS: In the range of ages evaluated, PRAM provides reliable estimates of cardiac output when compared with noninvasive techniques. PMID- 18446107 TI - Developing the Children's Critical Illness Impact Scale: capturing stories from children, parents, and staff. AB - OBJECTIVE: With the evolution of pediatric critical care medicine has come an awareness of the ethical imperative of healthcare professionals to attend to the psychological sequelae of technologically intensive care. Recent attempts to measure psychological outcomes in these children have been limited. The purpose of this study was to develop a measure of posthospitalization distress, the Children's Critical Illness Impact Scale (CCIIS), for children aged 6-12 yrs following pediatric intensive care unit hospitalization. DESIGN: A measurement development study consisting of two phases: 1) item generation and scale formatting; and 2) item reduction and scale revisions. Items were generated following thematic analysis of qualitative data from focus groups and individual interviews with children, parents, and healthcare professionals. Children reviewed items for interpretability and importance and assessed scaling technique and item presentation; healthcare professionals further evaluated item relevance. SETTING: The pediatric intensive care units of three quaternary care, Canadian pediatric teaching hospitals. PATIENTS: Phase 1 included 18 children, 22 parents, and 12 healthcare professionals (n = 52). Phase 2 included eight children and four healthcare professionals (n = 12). MEASUREMENTS AND MAIN RESULTS: Five key domains were identified in the thematic analyses: worries, fears, friends and family, sense of self, and behaviors. Thirty-six items were initially generated, and subsequent item reduction resulted in 23 items that were retained on the final scale. Items were generally rated extremely relevant and were judged to capture the content area (content validity index = 0.87). The CCIIS was easily understood, and the scaling format worked well. Older children preferred written items, while younger children will require a modified, pictorial version. CONCLUSIONS: The CCIIS is a new self-report measure with demonstrated content validity and specific relevance for young school-aged children following pediatric intensive care unit hospitalization. Valid, accessible, and developmentally appropriate measures are essential to identify high-risk children and, ultimately, promote healthy growth and development. PMID- 18446108 TI - Cerebral edema in diabetic ketoacidosis. AB - OBJECTIVE: To review the causes of cerebral edema in diabetic ketoacidosis (CEDKA), including pathophysiology, risk factors, and proposed mechanisms, to review the diagnosis, treatment, and prognosis of CEDKA and the treatment of diabetic ketoacidosis as it pertains to prevention of cerebral edema. DATA SOURCE: A MEDLINE search using OVID was done through 2006 using the search terms cerebral edema and diabetic ketoacidosis. RESULTS OF SEARCH: There were 191 citations identified, of which 150 were used. An additional 42 references listed in publications thus identified were also reviewed, and two book chapters were used. STUDY SELECTION: The citations were reviewed by the author. All citations identified were used except 25 in foreign languages and 16 that were duplicates or had inappropriate titles and/or subject matter. Of the 194 references, there were 21 preclinical and 40 clinical studies, 35 reviews, 15 editorials, 43 case reports, 29 letters, three abstracts, six commentaries, and two book chapters. DATA SYNTHESIS: The data are summarized in discussion. CONCLUSIONS: The causes and mechanisms of CEDKA are unknown. CEDKA may be due as much to individual biological variance as to severity of underlying metabolic derangement of the child's state and/or treatment risk factors. Treatment recommendations for CEDKA and diabetic ketoacidosis are made taking into consideration possible mechanisms and risk factors but are intended as general guidelines only in view of the absence of conclusive evidence. PMID- 18446109 TI - Tadalafil improves oxygenation in a model of newborn pulmonary hypertension. AB - OBJECTIVES: Sildenafil, a phosphodiesterase-5 inhibitor, significantly improves oxygenation when used in animal models and patients with pulmonary hypertension. Tadalafil is a new and clinically available phosphodiesterase-5 inhibitor that, aside from causing pulmonary vasodilation, has been shown to increase cardiac output in pulmonary hypertensive adults. Its hemodynamic effects on the newborn, however, have not been tested. The objective was to evaluate the effect of tadalafil on central hemodynamics and arterial oxygenation in a piglet model of acute pulmonary hypertension. DESIGN: Laboratory experiment. SETTING: University laboratory. SUBJECTS: Seven anesthetized and mechanically ventilated newborn piglets. INTERVENTIONS: Pulmonary hypertension was induced and maintained in seven anesthetized and mechanically ventilated newborn piglets following acute exposure to 11% oxygen. The experimental animals received orla tadalafil (1 mg/kg), whereas the control animals were given an equal volume of normal saline. Systemic and pulmonary hemodynamic variables were measured, and the cardiac output and ejection fraction were obtained from two-dimensional echocardiogram and Doppler measurements in all animals. Serial arterial blood gases were also obtained, and the alveolar-arterial oxygen gradient was calculated. MEASUREMENTS AND MAIN RESULTS: In contrast with the control animals, in which no significant changes were noted, in the experimental animals pulmonary arterial pressure decreased on average by 54% and cardiac output increased by 88% following tadalafil administration (p < .05). Tadalafil increased the PaO2 by 48% +/- 21% (p < .01), likely as a result of a 74% +/- 13% reduction in the alveolar-arterial oxygen gradient (p < .01). CONCLUSIONS: In a newborn animal model of acute pulmonary hypertension, oral tadalafil administration reduces pulmonary vascular resistance and increases arterial oxygenation by increasing cardiac output and reducing the lung shunt fraction. This previously untested compound deserves additional investigation in laboratory models of persistent pulmonary hypertension of the newborn. PMID- 18446110 TI - Pediatric critical care nurses' perceptions, knowledge, and attitudes regarding organ donation after cardiac death. AB - OBJECTIVE: Donation after cardiac death (DCD) is being implemented nationwide in the United States to increase the number of organ donors. Pediatric critical care nurses (PCRNs) are key facilitators in the organ donation process. This study assesses their perception, level of knowledge, and understanding of DCD and the effect of an educational intervention. DESIGN: Anonymous questionnaire administered before and after an educational intervention. SETTING: Children's hospital with 39 pediatric and cardiac/transplant intensive care unit beds. SUBJECTS: PCRNs in these intensive care units. INTERVENTIONS: DCD education. MEASUREMENTS AND MAIN RESULTS: Response to the initial questionnaire was 93 of 123 (76%): 63% of PCRNs supported organ donation, 69% felt it gives meaning and worth to death, and 76% felt that it contributes positively to the donating family's grieving process. Ninety-five percent agreed that DCD patients have a right to pain medications, and 92% supported such medications even if they hasten death. However, 11% feared that the DCD donor feels pain and suffering. Fourteen percent felt that a 5-min observation period after asystole is insufficient to pronounce death, and 8% feared legal repercussions. PCRNs scored lower on questions assessing their knowledge (p < .01), their comfort answering family questions (p < .05), and their comfort in calling the organ procurement agency about DCD donors compared with similar questions about brain-dead donors. One month after 104 PCRNs attended the educational intervention, 64 (62%) completed a follow-up survey. Correct identification of the DCD process improved from 20% to 79%. Confidence with knowledge, comfort answering family questions, and comfort in calling the organ procurement agency about DCD donors improved by 41%, 25%, and 18%, respectively. CONCLUSIONS: PCRNs are generally supportive of organ donation but have a self-perceived and objectively identified knowledge deficit regarding DCD, resulting in their being unprepared to identify potential DCD donors or handle family questions. A simple educational intervention can improve PCRNs' knowledge of the DCD process and their confidence and comfort with this process. As DCD policies are implemented, specific interventions should target these key members of the intensive care unit team. PMID- 18446111 TI - Validation of transpulmonary thermodilution cardiac output measurement in a pediatric animal model. AB - OBJECTIVE: This study was undertaken to validate the transpulmonary thermodilution cardiac output measurement (CO(TPTD)) in a controlled newborn animal model under various hemodynamic conditions with special emphasis on low cardiac output. DESIGN: Prospective, experimental, pediatric animal study. SETTING: Animal laboratory of a university hospital. SUBJECTS: Twelve lambs. INTERVENTIONS: We studied 12 lambs under various hemodynamic conditions. Cardiac output was measured using the transpulmonary thermodilution technique with central venous injections of ice-cold saline. An ultrasound transit time perivascular flow probe around the main pulmonary artery served as the standard reference measurement (CO(UFP)). During the experiment, animals were resuscitated from hemodynamic shock using fluid boluses. Cardiac output measurements were performed throughout the experiment. MEASUREMENTS AND MAIN RESULTS: The correlation coefficient between CO(TPTD) and CO(UFP)was .97 (95% confidence interval .94-.98, p < .0001). Bland-Altman analysis showed a mean bias of 0.19 L/min with limits of agreement of -0.04 and 0.43 L/min (12.0% and +/-14.7%, respectively). The correlation coefficient between changes in CO(TPTD) and CO(UFP) during volume loading was .95 (95% confidence interval .91-.96, p < .0001). There was a significant correlation between changes in global end diastolic volume and changes in stroke volume (r = .59) but not between changes in central venous pressure and changes in stroke volume (r = .03). CONCLUSIONS: The transpulmonary thermodilution technique is a reliable method of measuring cardiac output in newborn animals. It is also capable of tracking changes in cardiac output. PMID- 18446112 TI - Serial blood lactate levels as a predictor of mortality in children after cardiopulmonary bypass surgery. AB - OBJECTIVE: To assess the role of serial lactate levels in determining outcome after cardiopulmonary bypass surgery in children. DESIGN: Analysis of retrospectively collected data. SETTING: Cardiac intensive care unit of a tertiary care children's hospital. PATIENTS: Patients were 129 children who underwent surgery for congenital cardiac defects. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Patients were categorized for disease severity using the Risk Adjustment for Congenital Heart Surgery method. Blood lactate levels were obtained at admission to the cardiac intensive care unit and then serially until they were <2 mmol/L. Lactime, time during which the lactate remains >2 mmol/L, was noted for each patient. The primary outcome measured was mortality. Secondary outcomes measured were ventilator days and hospital days. Six patients died, and of these five were neonates. Nonsurvivors had higher initial postoperative lactate concentration (p = .01), peak postoperative lactate concentration (p = .003), and lactime (p = .05). In binomial logistic regression analysis, lactime was the strongest predictor of mortality (p = .03). The positive predictive value for all age groups was highest for lactime >48 hrs, with a positive predictive value of 60%, and among the neonates it was 75%. Initial lactate level >6 mmol/L had a positive predictive value of only 6%, and the peak lactate level >6 mmol/L had a positive predictive value of only 15%. Lactime also had a significant association with ventilator days and hospital days among the survivors (p = .001). CONCLUSIONS: Lactime was a useful predictor of mortality in children undergoing repair or palliation of congenital cardiac defects under cardiopulmonary bypass. Initial and peak lactate levels had a poor positive predictive value for mortality. Lactime also was associated with the number of ventilator days and hospital days in those who survived. PMID- 18446113 TI - Worsening renal function in children hospitalized with decompensated heart failure: evidence for a pediatric cardiorenal syndrome? AB - OBJECTIVES: The purpose of this study was to determine the incidence of renal insufficiency in children hospitalized with acute decompensated heart failure and whether worsening renal function is associated with adverse cardiovascular outcome. DESIGN: Prospective observational cohort study. SETTING: Single-center children's hospital. PATIENTS: All pediatric patients from birth to age 21 yrs admitted to our institution with acute decompensated heart failure from October 2003 to October 2005. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute decompensated heart failure was defined as new-onset or acute exacerbation of heart failure signs or symptoms requiring hospitalization and inpatient treatment. We required that heart failure be attributable to ventricular dysfunction only. Worsening renal function was defined as an increase in serum creatinine by > or = 0.3 mg/dL during hospitalization. Sixty-three patients (35 male, 28 female) comprised 73 patient hospitalizations. Median age at admission was 10 yrs (range 0.1-20.3 yrs). Median serum creatinine at admission was 0.6 mg/dL (range 0.2-3.5 mg/dL), and median creatinine clearance was 103 mL/min/1.73 m2 (range 22-431 mL/min/1.73 m2). Serum creatinine increased during 60 of 73 (82%) patient hospitalizations (median increase 0.2 mg/dL, range 0.1-2.7 mg/dL), and worsening renal function occurred in 35 of 73 (48%) patient hospitalizations. Clinical variables associated with worsening renal function included admission serum creatinine (p = .009) and blood urea nitrogen (p = .04) and, during hospitalization, continuous infusions of dopamine (p = .028) or nesiritide (p = .007). Worsening renal function was independently associated with the combined end point of in-hospital death or need for mechanical circulatory support (adjusted odds ratio 10.2; 95% confidence interval 1.7-61.2, p = .011). Worsening renal function was also associated with longer observed length of stay (33 +/- 30 days vs. 18 +/- 25 days, p < .03). CONCLUSIONS: These data suggest that an important cardiorenal interaction occurs in children hospitalized for acute decompensated heart failure. Renal function commonly worsens in such patients and is associated with prolonged hospitalization and in-hospital death or the need for mechanical circulatory assistance. PMID- 18446114 TI - Cerebrospinal fluid values in very low birth weight infants with suspected sepsis at different ages. AB - OBJECTIVES: Lumbar puncture can be an essential part of the septic work-up in premature infants who are at risk for sepsis and meningitis. Cerebrospinal fluid (CSF) values for cell counts, protein concentrations, and glucose concentrations in children and full-term infants are well established. CSF values in premature infants, however, have not been well studied. We sought to determine CSF values in very low birth weight premature infants at different ages (birth, postmenstrual age, and postnatal age). DESIGN: Medical records of all very low birth weight premature infants with suspected sepsis who were admitted to our neonatal intensive care unit between 1991 and 2005 were reviewed. Infants were excluded if they had evidence of intraventricular hemorrhage, sepsis/meningitis, or major congenital abnormalities or had a traumatic lumbar puncture. SETTING: Neonatal intensive care unit. PATIENTS: Patients were 455 infants who underwent lumbar puncture. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records of 455 infants who underwent 648 lumbar punctures were reviewed. Of these, 243 infants met our inclusion criteria, and 88 patients underwent lumbar puncture only at birth. Patients' mean gestational age and birth weight were 28.8 +/- 2.6 wks and 1080 +/- 279 g, respectively. There were no correlations between gestational age and CSF white blood cell (WBC) count or between gestational age and CSF protein concentrations at birth. CSF WBC count remained unchanged at different postmenstrual ages. However, CSF protein concentration decreased with advancing postmenstrual age (Spearman's rho correlation coefficient, r = -.29; p < .01), and both CSF WBC count and CSF protein concentration decreased with advancing postnatal age (Spearman's rho correlation coefficient, r = -.319 and r = -.376, respectively; p < .01). A subgroup analysis revealed differences in CSF WBC count and CSF protein concentrations between infants who had a lumbar puncture at birth, at 2 wks, and at 3 wks of life at the same postmenstrual age. CONCLUSIONS: In very low birth weight premature infants, CSF WBC count and CSF protein concentrations vary with advancing postnatal and postmenstrual ages. PMID- 18446115 TI - Endovascular aneurysm repair with Zenith graft. Complications caused by leg extensions. AB - AIM: A large amount of Zenith endovascular stent complications is due to problems with the leg extensions. This kind of complication has never been reported in literature. The aim of this study was to monitor the complications of endovascular abdominal aneurysm repair (EVAR) performed with the Zenith endovascular graft occurred in the Amphia Ziekenhuis in Breda to see how many recurrences were due to leg extension. METHODS: The study enrolled all patients (N.=66) treated with the Zenith endograft in the period between October 2000 and September 2006. Mortality, complications and the number of reinterventions were analysed. Average age of the patients was 73.4 years, average follow-up was 24.5 months and average aneurysm size was 61.5 mm. Radiologic follow-up was performed by computed tomography scans and X-rays. RESULTS: Postoperative mortality rate was 0%. The overall mortality rate during follow-up was 3%. Ten patients required a total number of 12 reinterventions (15%). The average time for reintervention was 10 months after the primary operation. Mortality, complication and reintervention rates were comparable with those reported in the literature, but 75% of these reinterventions were related to the leg extensions. CONCLUSION: Authors observed that nine out of 12 complications which required reintervention were due to problems with one of the leg extensions. This is the first study that specifies clearly the percentage of problems with leg extensions in EVAR (75%). When placing a Zenith endovascular graft extra attention should be paid to optimal placement of the leg extensions. PMID- 18446116 TI - Top-fenestrating technique in stentgrafting of aortic diseases with mid-term follow-up. AB - AIM: As a consequence of the rapid growth of thoracic and abdominal endovascular aneurysm repair management of aortic branches has come into focus. The top fenestrating technique can be used where one or two of the renal arteries, the left carotid artery or the left subclavian artery, have deliberately been covered by a stent-graft and immediately reopened by a preplaced stent. The aim of this study is to evaluate whether this technique is feasible and durable. METHODS: Registry study on 24 patients endovascular repaired with the top-fenestrating technique between September 2004 and January 2008. Elective operations were performed in 15 patients and acute procedures in nine. The median neck length for the patients having a carotid stent was 0 mm, range -18-15, related to the left subclavian artery and median 11 mm, range 0-31 mm, for those having a renal stent. Altogether 25 stents were used. RESULTS: There were two postoperative deaths. One patient died from a cardiac infarction and the other, a ruptured thoracic aortic aneurysm, had a major stroke. Median follow-up time was 17 months (range 1-40 months). Two patients died during follow-up from no-aneurysm related reasons. One type I endoleak was solved with a secondary intervention. Two patients had type II endoleak, which was not treated. After 12 months, 71% of the aneurysms had significantly decreased in size. None of the aneurysms had increased. There were no stent-graft migrations in the entire group. None of the stented branches was lost during follow-up. CONCLUSION: The top-fenestrating technique is feasible in short aortic necks and results are durable in a mid-term follow-up perspective. PMID- 18446117 TI - Surgical treatment of tumors involving the inferior vena cava. Personal experience. AB - AIM: Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor that frequently produces non-specific symptoms. Surgical treatment is complex. In this review of our experience, we highlight replacement modalities of the vena cava or other vessels after complete tumor resection. METHODS: During the last 20 years, we treated 12 patients (6 women and 6 men; age range, 38-72 years) with IVC leiomyosarcoma, all apparently free of distant metastases. Tumor location, graft patency, long-term survival and tumor recurrence were recorded. The tumor arose from the IVC in 8 patients; in 2 cases the intracaval mass reached the right atrium; in 4 patients the tumor arose from the femoroiliac axis. Surgical approach was by sternolaparotomy in 5 cases and by median xyphopubic access in 7. Extracorporeal circulation (ECC) was needed in 2 cases. All tumors were removed by en bloc resection. The IVC was directly sutured in 2 patients and patched in 4; no reconstruction was necessary in 2 patients; the IVC was replaced in the remaining cases. Four patients had an additional arteriovenous fistula. One patient underwent bifurcated Dacron graft replacement of the aortic carrefour involved by tumor. RESULTS: Two patients died postoperatively. One patient developed late stenosis of the polytetrafluoroethylene (PTFE) graft, which was treated by stenting. The mean follow-up period was 35 months. The 4-year survival rate was 51% and survival free of recurrence was 63%. CONCLUSION: Leiomyosarcoma of the IVC is an uncommon tumor that produces non-specific symptoms. In the absence of distant malignancy, an aggressive approach can obtain late survival free of recurrence. PMID- 18446118 TI - Excimer laser assisted angioplasty for complex infrainguinal peripheral artery disease: a 2008 update. AB - Conventional percutaneous transluminal angioplasty (PTA) for complex or long segment infrainguinal occlusive arterial disease is limited by elastic recoil, dissection and restenosis, with high rates of intermediate and long term restenosis . Debulking with excimer laser has been advocated as a useful adjunctive strategy to improve procedural success and long term patency. This paper reviews the technological development of excimer laser, the studies supporting its use in infrainguinal arterial disease, effective and safe lasing techniques, its advantages, limitations and disadvantages. Case examples will be presented to illustrate its use in infrainguinal arterial disease. Although randomized controlled trials are lacking, existing registry and case series studies suggest efficacy of the excimer laser-assisted PTA for complex infrainguinal arterial disease, including patients with critical limb ischemia. PMID- 18446119 TI - First report of an ilio-popliteal bypass through the greater sciatic foramen. Case report. AB - A 47 year-old man, who had a history of pelvic radiotherapy for the treatment of testicular tumour 30 years ago, was referred with minor tissue loss of the right lower extremity, grade III, category 5 of the Rutherford classification. His groin region presented with severe radiation damage. Arteriography demonstrated the occlusion of external iliac and femoral arteries. Revascula-risation was performed in the lateral decubitus position, with a ringed polytetrafluoroethylene (PTFE) graft bypass between normal common iliac and popliteal arteries through the greater sciatic foramen. Quick healing was observed. Patient is well 6 months postoperatively. Immediate and 6 month postoperative imaging demonstrated the good patency of the graft. A duplex ultrasound performed 6 month postoperatively showed no significant compression while the patient was in the sitting position. PMID- 18446121 TI - Extending the boundaries of no-touch aorta technique usage for coronary artery bypass grafting in patients with diseased ascending aorta. AB - AIM: Atherosclerosis of the ascending aorta is a leading cause of cerebrovascular accidents (CVA) in patients who undergo coronary artery bypass grafting (CABG). However, the ascending aorta is considered untouchable only in cases of severe calcification. The aim of this study is to evaluate the effect of the no-touch aorta technique (NAT) on morbidity and mortality with an extension of indication to any degree of atherosclerotic disease is detected on the ascending aorta. METHODS: From March 2001 to March 2006, data were prospectively collected from 101 patients with ascending aorta atherosclerosis who underwent either on- or off pump CABG with NAT. Demographic data from these 101 patients were compared with those of 1 473 patients who underwent conventional CABG with aortic cross clamping during the same time period. All preoperative variables were assessed with stepwise logistic regression to determine predictors of ascending aortic disease. RESULTS: Age, hypertension, hyperlipidemia, peripheral vascular disease, EuroSCORE and unstable and redo rates were significantly higher in the NAT group than in the control group (P<0.05). Logistic regression analysis of preoperative variables for all 1 574 cases identified age, peripheral vascular disease, history of smoking, EuroSCORE, and reoperation as independent predictors of atherosclerotic disease of the ascending aorta. No operative or hospital CVA occurred in the study group. Hospital mortality was observed in 2 (1.9%) patients. During the follow-up period of 27.9 +/- 13 months, no patient was re admitted with angina recurrence or CVA. CONCLUSION: Any degree of atherosclerotic disease on the ascending aorta can potentially cause CVA upon manipulation during CABG. Use of CABG with NAT to eliminate the risk of CVA is associated with low rates of morbidity, stroke and mortality during hospital stay and at mid-term follow-up. PMID- 18446120 TI - Use of percutaneous closure devices in the removal of central venous catheters from inadvertent arterial catheterizations. AB - Although rare, misplacement of central venous catheters in supra-aortic arteries is potentially fatal. Five patients had safe catheters removal using percutaneous closure devices. Three patients were coagulopathic, 3 under intensive care and 1 in immediate postoperative limb amputation. Patients were treated successfully, with immediate hemostasis and without complications in a mean follow-up of 12.5 months. Although the number of patients is small, the closure devices proved to be safe. This is a minimally invasive alternative technique in the management of large bore catheters removed from non-compressible puncture sites such as subclavian and brachiocephalic arteries. PMID- 18446122 TI - An assessment of the potential use of transthoracic impedance measurement for the non-invasive monitoring of lung injury following cardiac surgery. AB - AIM: Lung injury commonly occurs following cardiac surgery. More severe forms are associated with a high mortality. In order to diagnose it and monitor its progress with treatment, measurement of extravascular lung water is necessary. This is usually measured using either a double-indicator dilution or single indicator technique. Both require intravascular lines and expensive consumables which make them unsuitable for the routine monitoring of cardiac surgical patients. It has been suggested that the measurement of bioelectrical impedance could provide a non-invasive alternative which would allow routine measurement in these patients. METHODS: Extravascular lung water (EVLW) and index (EVLWI) were measured in 23 patients undergoing elective coronary artery bypass graft surgery at 3 time points before and after surgery using the PiCCO system. At the same times the Transthoracic Impedance ratio (TTIr) was also measured using the Bodystat Dual Scan 2005. RESULTS: The corresponding measurements of TTIr were compared statistically with both EVLW and EVLWI. The resulting correlation coefficients were very low (<0.1). CONCLUSION: Transthoracic Impedance does not appear to reflect extravascular lung water and is therefore unlikely to be useful in the routine monitoring of cardiac surgical patients. PMID- 18446123 TI - Reduced transfusion requirements with a closed cardiopulmonary bypass system. AB - AIM: The aim of this investigation is to reduce blood transfusion in cardiac surgery patients with preoperative conditions predictive for transfusion requirements. We compared the amount of blood transfused in two groups of patients undergoing cardiopulmonary bypass (CPB) with two different circuit systems. METHODS: Sixty patients undergoing cardiac surgery were randomly assigned to two groups: in group A (N=30) cardiopulmonary bypass was accomplished with an open circuit and in group B (N=30) with a closed circuit. The open circuit consisted of a cardiotomy reservoir, a membrane oxygenator and an arterial line filter, while the closed circuit was made up of a collapsible venous reservoir, a membrane oxygenator, an arterial line filter and a cardiotomy reservoir. The amount of transfused packed red cells in each patient was measured until discharge from the hospital. RESULTS: Groups were similar regarding age, gender, body surface area (BSA), New York Heart Association (NYHA) class and comorbidity risk factors. Moreover, there were no significant differences between groups regarding the type of procedures, CPB and aortic cross-clamp times, total amount of cardioplegia and urinary output during CPB. Priming volume was 1180+/ 84 mL (group A) and 760+/-72 mL (group B) (P<0.001). Significant differences in transfusion requirements emerged in the two groups: the total volume of packed red cells transfused for each patient was significantly higher in the open system group compared to the closed system group (717+/-486 mL versus 378+/-364 mL) (P=0.003). Clinical outcomes were similar in both groups. CONCLUSION: In patients with preoperative conditions predictive for the need of transfusions, the use of a closed cardiopulmonary bypass circuit can diminish the amount of transfused blood products. PMID- 18446124 TI - Comparison of harmonic scalpel and high-frequency electrocautery in radial artery harvesting. AB - AIM: We evaluated the effects of the radial artery on the functional outcomes and endothelium when the harvest was made either by harmonic scalpel or by high frequency electrocautery. METHODS: Between 2002 and 2007, 982 patients with coronary artery diseases were operated for coronary artery revascularization. The radial arteries were harvested for 101 of these patients and divided into two groups depending on the use of the harmonic scalpel (Group A; N=51) and the high frequency electrocautery (Group B; N=50). Harvesting time, use of hemostatic clips, frequency of spasm, in situ free flow, and endothelial damage were compared between the two groups. RESULTS: Conventional high-frequency electrocautery technique used 8.7+/-3.9 hemostatic clips versus 1.5+/-1 clips (P<0.001). In situ free blood flow was 85+/-5.5 mL/min for Group B versus 114+/ 21.7 mL/min for Group A (P<0.006). The endothelial damage of the radial arteries taken down with the harmonic scalpel was significantly less than when taken down with the high-frequency electrocautery (P<0.05). There was no statistically significant difference in terms of harvesting time and spasm between the two groups (P>0.05). CONCLUSION: Ultrasonic dissection with harmonic scalpel of the radial artery is associated with a decreased use of hemostatic clips. Moreover, the harmonic scalpel has a positive effect on endothelial preservation and it was associated with increased free blood flow of the radial artery. PMID- 18446125 TI - A retrospective analysis of Terlipressin infusion in patients with refractory hypotension after cardiac surgery. AB - AIM: The aim of this retrospective study was to evaluate the effectiveness of Terlipressin in the treatment of severe hypotension in cardiosurgical patients and to assess the differences between the groups of survivors and nonsurvivors. METHODS: The study population was 27 patients who developed hypotension after cardiac surgery. RESULTS: All surviving patients developed refractory hypotension early after extracorporeal circulation. Of the 9 nonsurvivors, 3 also experienced postcardiotomy hypotension, while the remaining 6 developed severe hypotension during sepsis. Terlipressin given continuously significantly increased the mean arterial pressure and reduced the heart rate in both groups. Norepinephrine requirements decreased significantly among survivors only. The mean pulmonary artery pressure and pulmonary capillary wedge pressure levels remained unchanged or increased insignificantly, while several liver markers in the survivor group significantly increased. CONCLUSION: Terlipressin given continuously is a potent vasopressor in patients with norepinephrine-resistant postcardiotomy hypotension; however, Terlipressin treatment failed in patients who developed refractory hypotension during sepsis. We cannot recommend this therapy in such patients as it proved to be hemodynamicaly ineffective and may even worsen the circulatory situation. PMID- 18446126 TI - Should pregnancy be considered a risk factor for aortic dissection? Two cases of acute aortic dissection following cesarean section in non-Marfan nor bicuspid aortic valve patients. AB - Acute aortic dissection in pregnancy is a rare event and rarer still in healthy young women; however, women with a bicuspid aortic valve or the Marfan syndrome are at a higher risk of dissection. The relationship between pregnancy and aortic dissection is still unclear. We describe the cases of two women with no history of cardiovascular disease who developed an acute aortic type A dissection within a few days after term delivery. Surgical repair was performed with ascending aorta replacement and aortic valve sparing. In both cases, the dissection was diagnosed within a few days following cesarean section done neither because of fetal or maternal distress. To date, only one case of type A and two cases of type B aortic dissection following cesarean section have been reported. Compared with spontaneous delivery, scheduled cesarean section, as in our cases, allows for better control of hemodynamic parameters and should protect against aortic dissection. Postoperative screening for inherent connective tissue disorders detected no mutations within the fibrillin and collagen gene chromosome in either patient. Postoperative recovery was uneventful, and the patients were discharged on postoperative days 7 and 8, respectively. PMID- 18446127 TI - Aortic tube grafts wrapping with hemostatic fleeces reduces postoperative pericardial effusions. AB - Pericardial effusions often complicate the postoperative course of ascending aortic surgery. We evaluated whether an unconventional use of hemostatic fleeces (TachoSil, Nycomed; Austria), wrapped around aortic tube grafts, may reduce such complication. Twenty-nine consecutive patients undergoing button-Bentall were submitted - according to surgeon's choice - to 360 degrees wrapping of the aortic grafts with hemostatic fleeces immediately before sternal wiring (11 patients - group A) or sternal wiring without any wrapping of the prosthesis (18 patients - group B). Hospital outcome was recorded. No differences were recorded in hospital mortality and major organ morbidity. When pericardial complications were considered, group A showed lower chest drains (P=0.0001), time of chest drainage (P=0.002), pretamponade/tamponade with need for pericardiocentesis (P=0.039), predischarge echocardiographic amount of pericardial effusion (P=0.026), fever (P=0.029), need for anti-inflammatory (P=0.05) or antibiotic drugs (P=0.007), hospital stay (P=0.010) and white blood cell count (P=0.016 on postoperative day 3; P=0.014 on day 6). Wrapping of aortic tube grafts with hemostatic fleeces is effective in reducing pericardial effusion and its deleterious effects following aortic surgery. PMID- 18446128 TI - Primary malignant tumors of the aorta: clinical and prognostic aspects of two treated cases. PMID- 18446129 TI - Percutaneous treatment of aortic graft infection. PMID- 18446130 TI - Can radical prostatectomy prevent and improve lower urinary tract symptoms? PMID- 18446131 TI - Is nephron-sparing surgery as safe and effective as radical nephrectomy in patients with locally advanced RCC? PMID- 18446132 TI - Can patients with low-grade papillary bladder tumors be followed up with a cystoscopy interval of 6 months? PMID- 18446133 TI - Papillary fibroelastoma of the aortic valve and coronary artery disease visualized by 64-slice CT. AB - BACKGROUND: A 75-year-old male with a history of myocardial infarction and recent transient ischemic attack was referred to a cardiology clinic for preoperative evaluation before a cystectomy. Transthoracic and transesophageal echocardiography revealed a mobile mass on the right coronary cusp of the aortic valve. Multislice CT demonstrated a significant narrowing in the proximal left anterior descending coronary artery. INVESTIGATIONS: Physical examination, chest radiography, laboratory testing, electrocardiography, transthoracic and transesophageal echocardiography, multislice-CT coronary angiography, pathological and histological examination of the surgically excised tissue. DIAGNOSIS: Papillary fibroelastoma of the aortic valve in conjunction with coronary artery disease. MANAGEMENT: Surgical excision of the mobile lesion and an end-to-side anastomosis of the left internal mammary artery to the left anterior descending coronary artery. PMID- 18446134 TI - Right atrial thrombus attached to the defibrillator lead. PMID- 18446135 TI - What are the effects of patient age and blood pressure on the cholesterol-related risk of vascular mortality? PMID- 18446136 TI - Solving the paradox of self blood-pressure measurement. PMID- 18446137 TI - A call for pragmatic treatment trials in rheumatoid arthritis. PMID- 18446138 TI - Discussion of the 2007 British Society for Rheumatology guidelines for management of ANCA-associated vasculitis. PMID- 18446139 TI - Primer: Toll-like receptor signaling pathways--what do rheumatologists need to know? AB - Toll-like receptors (TLRs) have caught the attention of rheumatologists searching for additional therapeutic targets for diseases such as rheumatoid arthritis and systemic lupus erythematosus. Signaling from these molecules can induce the expression of cytokines such as tumor necrosis factor and interferon alpha. Strategies that target TLRs and their co-receptors (such as MD2 for TLR4 or CD36 for TLR2) might be a more-selective approach than inhibition of global signals such as nuclear factor kappaB or p38 mitogen-activated protein kinase. TLR signaling requires adaptor proteins, including MyD88, Mal, TRIF and TRAM, which are recruited to specific receptors: Mal is used only by TLR2 and TLR4, TRIF is used by TLR3 and TLR4, and TRAM is recruited by TLR4 alone. Mal and TRAM are subject to complex biochemical regulation. Inhibition of Mal or MyD88 blocks the production of inflammatory mediators in synovial tissue. Another possible intracellular target is Unc93b, a protein involved in signaling from TLR3, TLR7 and TLR9. Inhibition of TLR4, TLR7 and TLR9 has produced intriguing results, which indicate that TLRs and their signaling pathways might indeed have great potential as novel targets for the treatment of inflammatory joint disease. PMID- 18446140 TI - Late-night salivary cortisol measurement in the diagnosis of Cushing's syndrome. AB - Making a definite diagnosis of Cushing's syndrome is a challenging problem. Unsuspected Cushing's syndrome occurs in 2-3% of patients with poorly controlled diabetes, 0.5-1% with hypertension, 6-9% with incidental adrenal masses, and 11% with unexplained osteoporosis and vertebral fractures. The increasing recognition of this syndrome highlights the need for a simple, sensitive, and specific diagnostic test. Patients with Cushing's syndrome consistently do not reach a normal nadir of cortisol secretion at night. The measurement of late-night salivary cortisol levels might, therefore, provide a new diagnostic approach for this disorder. Salivary cortisol concentrations reflect those of active free cortisol in plasma and saliva samples can easily be obtained in a nonstressful environment (e.g. at home). Late-night salivary cortisol measurement yields excellent overall diagnostic accuracy for Cushing's syndrome, with a sensitivity of 92-100% and a specificity of 93-100%. Several factors can, however, make interpretation of results difficult; these factors include disturbed sleep-wake cycles, contamination of samples (particularly by topical corticosteroids), and illnesses known to cause physiologic activation of the pituitary-adrenal axis. In this Review, we discuss the methods and value of measuring salivary cortisol for the diagnosis of Cushing's syndrome, and put forward some recommendations to maximize accuracy of results. PMID- 18446141 TI - Prevention of type 1 diabetes: the time has come. AB - Improved understanding of the pathogenesis of type 1 diabetes mellitus has completely changed our view of this disease in the past 25 years-from an acute, fulminant disease, to a chronic, autoimmune process. Information on genetic and serologic markers has increased our ability to identify individuals at risk. Prospectively gathered data indicate that, with a combination of immunologic and metabolic studies, children with a 6-year risk of disease higher than 90% can be identified due to an ongoing immune process. They differ from children with overt disease only in the time it will take for glucose levels to rise above a diagnostic threshold. Therapies to change the progression of beta-cell loss have been tested in patients with newly diagnosed type 1 diabetes. With improved predictive capabilities and agents that can have longer-lasting effects than those tested more than 10 years ago, new prevention studies are underway. These studies are large and costly but the risks posed by such interventions compare favorably with those of developing hyperglycemia and of future complications portended by the diagnosis of diabetes. In this Review we discuss risk stratification techniques and how they are applied, other diagnostic criteria, and outcomes from diabetes-prevention trials. PMID- 18446142 TI - Comparison of gemcitabine plus platinum analog with gemcitabine alone in advanced pancreatic cancer. PMID- 18446143 TI - Updated follow-up of patients treated with bortezomib for relapsed multiple myeloma. PMID- 18446144 TI - Primer: first do no harm--when is it appropriate to plan a cancer prevention clinical trial? AB - Abundant preclinical and clinical data suggest that cancer is a preventable disease; however, few, if any, of the medical interventions available are completely without adverse effects or risk to the patient. This statement is especially true with regard to phenotypically healthy but high-risk populations. Balancing the risks from interventions with the risk of future life-threatening disease is particularly challenging because no standardized methodologies to perform such calculations exist. It is critical, therefore, to establish a framework for determining when interventions show sufficient promise of efficacy and sufficient safety to justify their testing in clinical trials. Systematic review of all available preclinical, epidemiological, and clinical data, along with a mechanistic understanding of the biology of the disease under study, is mandatory before clinical trials are embarked upon. This Review identifies the issues that are critical for decision-making when clinical trials in human beings are being contemplated and provides a framework that can be applied in making these decisions. PMID- 18446145 TI - How safe and effective is a nitinol self-expanding metallic stent for palliation of malignant colonic obstruction? PMID- 18446146 TI - Early or late surgery for patients with ileocecal Crohn's disease? PMID- 18446148 TI - Early use of renin-angiotensin-aldosterone system inhibitors after renal transplantation. PMID- 18446147 TI - New concepts of resistance in the treatment of Helicobacter pylori infections. AB - The prevalence of antimicrobial drug resistance is now so high that all patients infected with Helicobacter pylori should be considered as having resistant infections. Ideally, therapy should be based on pretreatment antibiotic susceptibility testing but this strategy is not currently practical. At present, clarithromycin-containing triple therapies do not reliably produce a > or =80% cure rate on an intention-to-treat basis and are, therefore, no longer acceptable as empiric therapy. In this Review, we discuss concepts of resistance that have become part of mainstream thinking for other infectious diseases but have not yet become so with regard to H. pylori. We also put data on the pharmacokinetics and pharmacodynamics of the drugs used in H. pylori therapy and the effect of host cytochrome P450 genotypes in context with treatment outcomes. Our primary focus is to address the problem of H. pylori resistance from a novel perspective, which also attempts to anticipate the direction that research will need to take to provide clinicians with reliable approaches to this serious infection. We also discuss current therapies that provide acceptable cure rates when used empirically (i.e. sequential therapy; four-drug, three-antibiotic, non-bismuth containing 'concomitant' therapy; and bismuth-containing quadruple therapy) and how they might be further improved. PMID- 18446149 TI - Renal tract malformations: perspectives for nephrologists. AB - Renal tract malformations are congenital anomalies of the kidneys and/or lower urinary tract. One challenging feature of these conditions is that they can present not only prenatally but also in childhood or adulthood. The most severe types of malformations, such as bilateral renal agenesis or dysplasia, although rare, lead to renal failure. With advances in dialysis and transplantation for young children, it is now possible to prevent the early death of at least some individuals with severe malformations. Other renal tract malformations, such as congenital pelviureteric junction obstruction and primary vesicoureteric reflux, are relatively common. Renal tract malformations are, collectively, the major cause of childhood end-stage renal disease. Their contribution to the number of adults on renal replacement therapy is less clear and has possibly been underestimated. Renal tract malformations can be familial, and specific mutations of genes involved in renal tract development can sometimes be found in affected individuals. These features provide information about the causes of malformations but also raise questions about whether to screen relatives. Whether prenatal decompression of obstructed renal tracts, or postnatal initiation of therapies such as prophylactic antibiotics or angiotensin blockade, improve long-term renal outcomes remains unclear. PMID- 18446150 TI - Sleep medicine education: are medical schools and residency programs napping on the job? PMID- 18446151 TI - Recurrent aneurysmal hemorrhage is closely linked with percent of aneurysm occlusion. PMID- 18446152 TI - Is coiling really more costly than clipping in patients with ruptured intracranial aneurysm? PMID- 18446153 TI - Two-photon dual-color imaging using fluorescent proteins. PMID- 18446154 TI - Unexpected failure rates for modular assembly of engineered zinc fingers. PMID- 18446155 TI - BAC to the future: functional genomics in mammals. PMID- 18446156 TI - Metastasis: two assays explore the two roads traveled. PMID- 18446157 TI - Super-resolution light microscopy goes live. PMID- 18446159 TI - Targeting the endocannabinoid system: to enhance or reduce? AB - As our understanding of the endocannabinoids improves, so does the awareness of their complexity. During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals. These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases. When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment. PMID- 18446160 TI - A technicolour approach to the connectome. AB - A central aim of neuroscience is to map neural circuits, in order to learn how they account for mental activities and behaviours and how alterations in them lead to neurological and psychiatric disorders. However, the methods that are currently available for visualizing circuits have severe limitations that make it extremely difficult to extract precise wiring diagrams from histological images. Here we review recent advances in this area, along with some of the opportunities that these advances present and the obstacles that remain. PMID- 18446161 TI - Neonatal mortality: the chance for improvement. PMID- 18446162 TI - Amniotic band syndrome following septostomy in management of twin-twin transfusion syndrome: a case report. AB - Septostomy, a rupture of the diamniotic membrane separating monozygotic twins essentially creating a monoamniotic gestation, is a potential therapeutic modality for twin-twin transfusion syndrome (TTTS). This may be associated with complications including cord entanglement or complete rupture of the membranes. We report a case of severe amniotic band syndrome with cord amputation after septostomy. A 33-year-old woman with a Mo-Di twin pregnancy was diagnosed with TTTS at 18 weeks of gestation. Septostomy as well as amnioreduction were performed at 24 weeks of gestation. A repeat cesarean delivery was performed at 31 weeks resulting in a live recipient baby of 1340 g and a dead donor with amniotic band syndrome. The donor showed pieces of membrane tightening both legs. The right thigh became entangled in the bands connecting to the umbilical cord of the live fetus. The umbilical cord of the dead twin was completely amputated, whereas the umbilical cord of the live infant was also entrapped within the amniotic band resulting in small diameter and some degree of stricture. This is the first report of a rare but serious complication following septostomy. PMID- 18446163 TI - Apple peel small bowel. PMID- 18446165 TI - Emerging trends in neonatal intestinal disease. PMID- 18446166 TI - Neurogenesis after primary intracerebral hemorrhage in adult human brain. AB - Neurogenesis occurs in discrete regions of normal brains of adult mammals including humans, and is induced in response to brain injury and neurodegenerative disease. Whether intracerebral hemorrhage can also induce neurogenesis in human brain is unknown. Specimens were obtained from patients with primary intracerebral hemorrhage undergoing surgical evacuation of an intracerebral hematoma, and evaluated by two-photon laser scanning confocal microscopy. We found that neural stem/progenitor cell-specific protein markers were expressed in cells located in the perihematomal regions of the basal ganglia and parietal lobe of the adult human brain after primary intracerebral hemorrhage (n=5). Cells in this region also expressed cell proliferation markers, which colocalized to the same cells that expressed neural stem/progenitor cell-specific proteins. Our data suggest that intracerebral hemorrhage induces neurogenesis in the adult human brain. PMID- 18446167 TI - Hypoxia and hypotension transform the blood flow response to cortical spreading depression from hyperemia into hypoperfusion in the rat. AB - Cortical spreading depression (CSD) evokes a large cerebral blood flow (CBF) increase in normal rat brain. In contrast, in focal ischemic penumbra, CSD-like periinfarct depolarizations (PID) are mainly associated with hypoperfusion. Because PIDs electrophysiologically closely resemble CSD, we tested whether conditions present in ischemic penumbra, such as tissue hypoxia or reduced perfusion pressure, transform the CSD-induced CBF response in nonischemic rat cortex. Cerebral blood flow changes were recorded using laser Doppler flowmetry in rats subjected to hypoxia, hypotension, or both. Under normoxic normotensive conditions, CSD caused a characteristic transient CBF increase (74+/-7%) occasionally preceded by a small hypoperfusion (-4+/-2%). Both hypoxia (pO(2) 45+/-3 mm Hg) and hypotension (blood pressure 42+/-2 mm Hg) independently augmented this initial hypoperfusion (-14+/-2% normoxic hypotension; -16+/-6% hypoxic normotension; -21+/-5% hypoxic hypotension) and diminished the magnitude of hyperemia (44+/-10% normoxic hypotension; 43+/-9% hypoxic normotension; 27+/ 6% hypoxic hypotension). Hypotension and, to a much lesser extent, hypoxia increased the duration of hypoperfusion and the DC shift, whereas CSD amplitude remained unchanged. These results suggest that hypoxia and/or hypotension unmask a vasoconstrictive response during CSD in the rat such that, under nonphysiologic conditions (i.e., mimicking ischemic penumbra), the hyperemic response to CSD becomes attenuated resembling the blood flow response during PIDs. PMID- 18446168 TI - In situ mouse carotid perfusion model: glucose and cholesterol transport in the eye and brain. AB - The in situ mouse brain perfusion method for measuring blood-brain barrier permeability was adapted to assess transport of solutes at the blood-brain and blood-eye barriers. The procedure was checked with radiolabeled markers in oxygenated bicarbonate-buffered fluid infused for 30 to 120 sec via a carotid artery. Vascular flow estimated with diazepam was 2.2-fold lower in the eye than in the brain. The vascular volume and the integrity markers sucrose and inulin indicated that a perfusion flow rate of 2.5 mL/min preserved the physical integrity of these organs. However, the brain vasculature integrity was more sensitive to acute perfusion pressure than the eye vasculature. The functional capacities of blood barriers were assessed with D-glucose; its transport followed Michaelis-Menten kinetics with an apparent K(m) of 7.6 mmol/L and a V(max) of 23 micromol/sec per g in the brain, and a K(m) of 22.9 mmol/L and a V(max) of 40 micromol/sec per g in the eye. The transport of cholesterol to the brain and eye was significantly enhanced by adding the Abca1 inhibitor probucol, suggesting an Abca1-mediated efflux at the mouse brain and eye blood barriers. Thus in situ carotid perfusion is suitable for elucidating transport processes at the blood brain and blood-eye barriers. PMID- 18446169 TI - Evidence vs experience in neonatal practices. Proceedings of the 4th Annual Conference. June 2007. Chicago, Illinois, USA. PMID- 18446171 TI - Feeding strategies in the ELBW infant. AB - Necrotizing enterocolitis (NEC) remains a common emergency that carries high morbidity and mortality for extremely low birth weight infants. To date there have been no multicenter randomized controlled trials to evaluate different feeding strategies and NEC. Clinicians must weigh their experience against small amounts of data in deciding the best way to feed their patients. Currently published feeding protocols and evidence for the same will be reviewed. Also reviewed is the evidence for use of human milk, initiation and advancement of feedings, and the use of probiotics. PMID- 18446170 TI - Evidence vs experience in the surgical management of necrotizing enterocolitis and focal intestinal perforation. AB - INTRODUCTION: Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are neonatal intestinal emergencies that affect premature infants. Although most cases of early NEC can be successfully managed with medical therapy, prompt surgical intervention is often required for advanced or perforated NEC and FIP. METHODS: The surgical management and treatment of FIP and NEC are discussed on the basis of literature review and our personal experience. RESULTS: Surgical options are diverse, and include peritoneal drainage, laparotomy with diverting ostomy alone, laparotomy with intestinal resection and primary anastomosis or stoma creation, with or without second-look procedures. CONCLUSIONS: The optimal surgical therapy for FIP and NEC begins with prompt diagnosis and adequate fluid resuscitation. It appears that there is no significant difference in patient outcome based on surgical management alone. However, the infant's weight, comorbidities, surgeon preference and timing of intervention should be taken into account before operative intervention. PMID- 18446172 TI - Evidence vs experience in neonatal medicine. PMID- 18446173 TI - Antenatal inflammation and lung injury: prenatal origin of neonatal disease. AB - INTRODUCTION: Antenatal inflammation in utero may be associated with lung injury and subsequent aberrant lung development resulting in bronchopulmonary dysplasia (BPD). BPD has become a developmental disease with a uniform arrest in lung development. STUDY DESIGN: The role of antenatal inflammation in the induction of lung injury was explored in a sheep model suitable for the study of lung development with respect to human development. Chorioamnionitis was induced by a single injection of endotoxin into the amniotic cavity under ultrasound guidance. RESULT: Endotoxin-induced chorioamnionitis caused a cascade of lung injury, pulmonary inflammation and remodeling in the fetal lung similar to lung injury previously described in adult animal models. The structural changes in the fetal lung after chorioamnionitis showed little to no fibrosis and alveolar/microvascular simplification similar to new BPD. The identified cytokine networks and regulators may explain the absence of fibrosis and lung simplification after strictly intra-uterine inflammation. CONCLUSION: The mechanisms of antenatal inflammation in the fetal lung were multifactorial and could be antenatally modulated. Fetal pulmonary inflammation was temporarily suppressed by maternal glucocorticoid therapy. However, pulmonary inflammation could be augmented postnatally by resuscitation, oxygen toxicity, mechanical ventilation and pulmonary and systemic infection, which opens a broad window of clinical options. PMID- 18446174 TI - Clinical practices in neonatal oxygenation: where have we failed? What can we do? AB - INTRODUCTION: Oxygen is among the most frequently used therapies in neonates worldwide. Nevertheless, many times it is used unnecessarily. Neonatal practices have changed over the last several years; treatments originally believed to be beneficial have been discarded. STUDY DESIGN: Oxygen utilized 'just in case' or 'prophylactically' can lead to great damage previously ignored and/or unseen by healthcare providers. It is imperative to improve education on neonatal oxygenation and saturation monitoring. It is also important not to depend on old assumptions, which were not based on evidences. The potential for unseen damage at the cellular and tissue levels cannot be ignored. Therapies that prove to be outdated or even dangerous must be eliminated while further research and confirmation of the best practices are determined. Freedom to choose can come at a price. PMID- 18446175 TI - Moving from experience to evidence: changes in US Neonatal Resuscitation Program based on International Liaison Committee on Resuscitation Review. AB - The Neonatal Workgroup of the International Liaison Committee on Resuscitation recently made available their rigorous review of the scientific evidence base for selected neonatal resuscitation issues. The Neonatal Resuscitation Program guidelines have been recently revised based on that review and published as the Textbook of Neonatal Resuscitation, 5th edn. This review article highlights pertinent changes in recommendations, including revisions in: oxygen use; CO(2) detectors for confirmation of intubation; management of the infant born through meconium-stained amniotic fluid; initial ventilation devices and strategies; thermal protection of very small preterm infants; medications, including doses and routes of delivery; postresuscitation therapies for consideration and ethical issues in initiation and discontinuation of resuscitation. Journal of Perinatology (2008) 28, S35-S40; doi:10.1038/jp.2008.48. PMID- 18446176 TI - Limits of viability: definition of the gray zone. AB - INTRODUCTION: As survival and long-term morbidity of very preterm infants have improved over the past decade, the limits of infant viability, the level of maturity below which survival and/or acceptable neurodevelopmental outcome are extremely unlikely, have also decreased. STUDY DESIGN: In an effort to define the current limits of infant viability, the data in the literature on survival and long-term neurodevelopmental outcome in very preterm neonates have been reviewed. RESULT: The gestational age and birth weight below which infants are too immature to survive, and thus provision of intensive care is unreasonable, appears to be at <23 weeks and <500 g, respectively. Infants born at > or =25 weeks' gestation and with a birth weight of > or =600 g are mature enough to warrant initiation of intensive care, as the majority of these patients survive, and at least 50% do so without severe long-term disabilities. Finally, for infants born between 23(0/7) and 24(6/7) weeks' gestation and with a birth weight of 500 to 599 g, survival and outcome are extremely uncertain. For these infants born in the so-called 'gray zone' of infant viability, the line between patient autonomy and medical futility is blurred, and medical decision-making becomes even more complex and needs to embrace careful consideration of several factors. These factors include appraisal of prenatal data and the information obtained during consultations with the parents before delivery; evaluation of the patient's gestational age, birth weight and clinical condition upon delivery; ongoing reassessment of the patient's response to resuscitation and intensive care and continued involvement of the parents in the decision-making process after delivery. CONCLUSION: Based on these findings an algorithm is offered for consideration for neonatologists managing infants born in the 'gray zone' of infant viability. However, caution must be exercised when one considers incorporating this guideline into clinical practice because the algorithm is based on the analysis of the findings in the literature and the authors' experience rather than direct evidence. PMID- 18446177 TI - Lung protective ventilatory strategies in very low birth weight infants. AB - Respiratory distress syndrome (RDS) is the most common respiratory diagnosis in preterm infants. Surfactant therapy and mechanical ventilation using conventional or high-frequency ventilation have been the standard of care in the management of RDS. Bronchopulmonary dysplasia (BPD) continues to remain as a major morbidity in very low birth weight infants despite these treatments. There is no significant difference in pulmonary outcome when an optimal lung volume strategy is used with conventional or high-frequency ventilation. Lung injury is directly related to the duration of invasive ventilation via the endotracheal tube. Studies using noninvasive ventilation, such as nasal continuous positive airway pressure and noninvasive positive pressure ventilation, have shown to decrease postextubation failures as well as a trend toward reduced risk of BPD. Lung protective ventilatory strategy may involve noninvasive ventilation as a primary therapy or following surfactant administration in very preterm infants with RDS. Initial steps in the management of preterm infants may also include sustained inflation to establish functional residual capacity, followed by noninvasive ventilation to minimize lung injury and subsequent development of BPD. PMID- 18446178 TI - Surfactants: past, present and future. AB - In 1929 Kurt von Neergaard performed experiments suggesting the presence of pulmonary surfactant and its relevance to the newborn's first breath. Almost 25 years later, Richard Pattle, John Clements and Chris Macklin, each working on the effects of nerve gases on the lungs, contributed to the understanding of the physiology of pulmonary surfactant. About 5 years later Mary Ellen Avery and Jere Mead published convincing evidence that preterm neonates dying of hyaline membrane disease (respiratory distress syndrome, RDS) had a deficiency of pulmonary surfactant. The first trials of nebulized synthetic (protein-free) surfactant to prevent RDS were published soon after Patrick Bouvier Kennedy (son of President John F Kennedy) died of this disorder after treatment in Boston. These trials were unsuccessful; however, Goran Enhorning and Bengt Robertson in the early 1970s demonstrated that natural surfactants (containing proteins) were effective in an immature rabbit model of RDS. Soon after this Forrest Adams showed that a natural surfactant was also effective in an immature lamb model. Working with him was Tetsuro Fujiwara who 2 years later, after returning to Japan, published the seminal article reporting the responses of 10 preterm infants with RDS to a bolus of modified bovine surfactant. During the 1980s there were numerous randomized controlled trials of many different natural and synthetic surfactants, demonstrating reductions in pulmonary air leaks and neonatal mortality. Subsequently natural surfactants were shown to be superior to the protein-free synthetic products. Recently there have been a number of randomized trials comparing different natural surfactant preparations. Commercially available bovine surfactants may have similar efficacy but there is some evidence that a porcine surfactant used to treat RDS with an initial dose of 200 mg per kg is more effective than a bovine surfactant used in an initial dose of 100 mg per kg. Bovine and porcine surfactants have not been compared in trials of prophylaxis. Very recently a new synthetic surfactant with a surfactant protein mimic has been compared with other commercially available natural and synthetic surfactants in two trials. The new surfactant may be superior to one of the older protein-free synthetic surfactants but there is no evidence of its superiority over established natural products and it is currently not approved for clinical use. A number of other new synthetic surfactants have been tested in animal models or in treatment of adults with ARDS, but so far there have been no reports of treatment of neonatal RDS. Natural surfactants work best if given by a rapid bolus into the lungs but less invasive methods such as a laryngeal mask, pharyngeal deposition or rapid extubation to CPAP have showed promise. Unfortunately, delivery of surfactant by nebulization has so far been ineffective. Surfactant treatment has been tried in a number of other neonatal respiratory disorders but only infants with meconium aspiration seem to benefit although larger and more frequent doses are probably needed to demonstrate improved lung function. A surfactant protocol based upon early treatment and CPAP is suggested for very preterm infants. Earlier treatment may improve survival rates for these infants; however, there is a risk of increasing the prevalence of milder forms of chronic lung disease. Nevertheless, surfactant therapy has been a major contribution to care of the preterm newborn during the past 25 years. PMID- 18446179 TI - Heat loss prevention in neonates. AB - Maintaining a neutral thermal environment is one of the key physiologic challenges a newborn infant faces after delivery. Attention to detail regarding the management of an infant's neutral thermal environment may lead to improvement in clinical outcome, including improved survival. The details of this management cover a broad spectrum of interventions, from attention to the general environment (such as delivery room temperature) to specific individualized therapies, such as the use of polyethylene occlusive skin wrap. Although an integral part of the routine care of all newborns (whether term or preterm), these interventions have unfortunately received little attention and study. A commitment to greater understanding of these issues and their impact on newborns is essential if we hope to improve their outcome. PMID- 18446180 TI - Treatment of patent ductus arteriosus: indomethacin or ibuprofen? AB - Persistent patent ductus arteriosus (PDA) in preterm infants can result in serious hemodynamic changes causing respiratory, gastrointestinal and renal morbidities if not treated within the first week of life. The treatment options available are a conservative approach, pharmacological treatment with cyclo oxygenase (COX) inhibitors and surgical ligation. The COX inhibitors approved for use in the United States are indomethacin and ibuprofen lysine. Both of these drugs are equally effective in closing the PDA. Subtle differences exist between these two preparations. Indomethacin has a protective effect on the incidence of intraventricular hemorrhage (IVH) but reduces the blood flow to the kidneys and the brain. Ibuprofen is less toxic but has no effect on IVH. Efficacy of pharmacological treatment is influenced by timing of initiation of therapy. Surgical treatment is the only option when pharmacological treatment fails to close the PDA in symptomatic infants. Long-term neurological and respiratory morbidities are associated with surgical ligation. This paper reviews these medical considerations in the treatment options for PDA in premature infants. PMID- 18446181 TI - Evidence vs experience in neonatal practices in necrotizing enterocolitis. AB - INTRODUCTION: Necrotizing enterocolitis (NEC) has been recognized for over 40 years as a cause of inflammation and necrosis of the small and large intestine of infants born at less than 36 weeks of gestation. NEC remains a significant health problem for infants born prematurely and may become the leading cause of morbidity and mortality among these infants worldwide. The sequence of events leading to NEC is complex and multifactorial, although damage to the intestinal epithelium and invasion by bacteria are known to play central roles in disease pathogenesis. STUDY DESIGN: Bacteria initiate a cascade of inflammation that may progress to intestinal necrosis and perforation with sepsis and death. RESULT: Treatment of infants at risk for NEC with probiotic bacteria may be an area of great potential, as probiotic bacteria may promote maturation of the epithelial barrier and function to exclude bacterial pathogens from critical niches in the intestine, thereby disrupting a primary pathway in disease pathogenesis. CONCLUSION: Understanding how probiotic bacteria, or other novel therapies, prevent or limit disease propagation in NEC will be paramount in limiting the impact of disease in a growing population of premature newborns. PMID- 18446182 TI - Revealing cryptic spatial patterns in genetic variability by a new multivariate method. AB - Increasing attention is being devoted to taking landscape information into account in genetic studies. Among landscape variables, space is often considered as one of the most important. To reveal spatial patterns, a statistical method should be spatially explicit, that is, it should directly take spatial information into account as a component of the adjusted model or of the optimized criterion. In this paper we propose a new spatially explicit multivariate method, spatial principal component analysis (sPCA), to investigate the spatial pattern of genetic variability using allelic frequency data of individuals or populations. This analysis does not require data to meet Hardy-Weinberg expectations or linkage equilibrium to exist between loci. The sPCA yields scores summarizing both the genetic variability and the spatial structure among individuals (or populations). Global structures (patches, clines and intermediates) are disentangled from local ones (strong genetic differences between neighbors) and from random noise. Two statistical tests are proposed to detect the existence of both types of patterns. As an illustration, the results of principal component analysis (PCA) and sPCA are compared using simulated datasets and real georeferenced microsatellite data of Scandinavian brown bear individuals (Ursus arctos). sPCA performed better than PCA to reveal spatial genetic patterns. The proposed methodology is implemented in the adegenet package of the free software R. PMID- 18446183 TI - Cross-species replication of a resistin mRNA QTL, but not QTLs for circulating levels of resistin, in human and baboon. AB - Resistin has been associated with inflammation and risk for cardiovascular disease. We previously reported evidence of a QTL on chromosome 19p13 affecting the abundance of resistin (RETN) mRNA in the omental adipose tissue of baboons (L0D score 3.8). In this study, whole genome transcription levels were assessed in human lymphocyte samples from 1240 adults participating in the San Antonio Family Heart Study, using the Sentrix Human-6 Expression Beadchip. Lymphocytes were surveyed, as it has been proposed that their expression levels may reflect those in harder to ascertain tissues, such as adipose tissue, that are thought to be more directly relevant to disease procesn was conducted to detect loci affecting RETN mRNA levels. We obtained significant evidence for a QTL influencing the RETN expression (LOD score 10.7) on chromosome 19p. This region is orthologous/homologous to the region previously localized on baboon chromosome 19. The strongest positional candidate gene in this region is the structural gene for resistin, itself. We also found evidence for a QTL influencing resistin protein levels (LOD score 5.3) on chromosome 14q. This differs from our previously reported QTL on chromosome 18 in baboons. The different QTLs for circulating protein suggests that post-translational processing and turnover may be influenced by different or multiple genes in baboons and humans. The parallel findings of a cis-eQTL for RETN mRNA in baboon omental tissue and human lymphocytes lends support to the strategy of using lymphocyte gene expression levels as a surrogate for gene expression levels in other tissues. PMID- 18446184 TI - A simple method for calculating the statistical power for detecting a QTL located in a marker interval. AB - We developed a simple method for calculating the statistical power for detecting a QTL located in an interval flanked by two markers. The statistical method for QTL detection is assumed to be the Haley and Knott's simple regression method of interval mapping. This method allows us to answer one of the fundamental questions in designing a QTL mapping experiment: What is the minimum marker density required to detect a QTL explaining a certain heritable proportion of the phenotypic variance (denoted by h(2)) with a power gamma under a Type I error alpha in an F(2) or other mating designs with a sample size n? Computing the statistical power only requires the ability to evaluate a non-central F distribution function and the inverse function of this distribution. PMID- 18446186 TI - Biological monitoring of smoke exposure among wildland firefighters: a pilot study comparing urinary methoxyphenols with personal exposures to carbon monoxide, particular matter, and levoglucosan. AB - Urinary methoxyphenols (MPs) have been proposed as biomarkers of woodsmoke exposure. However, few field studies have been undertaken to evaluate the relationship between woodsmoke exposure and urinary MP concentrations. We conducted a pilot study at the US Forest Service-Savannah River Site, in which carbon monoxide (CO), levoglucosan (LG), and particulate matter (PM(2.5)) exposures were measured in wildland firefighters on prescribed burn days. Pre- and post-shift urine samples were collected from each subject, and cross-shift changes in creatinine-corrected urinary MP concentrations were calculated. Correlations between exposure measures and creatine-adjusted urinary MP concentrations were explored, and regression models were developed relating changes in urinary MP concentrations to measured exposure levels. Full-shift measurements were made on 13 firefighters over 20 work shifts in winter 2004 at the US Forest Service Savannah River site, a National Environmental Research Park. The average workshift length across the 20 measured shifts was 701+/-95 min. LG and CO exposures were significantly correlated for samples where the filter measurement captured at least 60% of the work shift (16 samples), as well as for the smaller set of full-shift exposure samples (n=9). PM(2.5) and CO exposures were not significantly correlated, and LG and PM(2.5) exposures were only significantly correlated for samples representing at least 60% of the work shift. Creatinine-corrected urinary concentrations for 20 of the 22 MPs showed cross-shift increases, with 14 of these changes showing statistical significance. Individual and summed creatinine-adjusted guaiacol urinary MPs were highly associated with CO (and, to a lesser degree, LG) exposure levels, and random effects regression models including CO and LG exposure levels explained up to 80% of the variance in cross-shift changes in summed creatinine-adjusted guaiacol urinary MP concentrations. Although limited by the small sample size, this pilot study demonstrates that urinary MP concentrations may be effective biomarkers of occupational exposure to wood smoke among wildland firefighters. PMID- 18446185 TI - Passive dosimeters for nitrogen dioxide in personal/indoor air sampling: a review. AB - Accurate measurement of nitrogen dioxide concentrations in both outdoor and indoor environments, including personal exposures, is a fundamental step for linking atmospheric nitrogen dioxide levels to potential health and ecological effects. The measurement has been conducted generally in two ways: active (pumped) sampling and passive (diffusive) sampling. Diffusion samplers, initially developed and used for workplace air monitoring, have been found to be useful and cost-effective alternatives to conventional pumped samplers for monitoring ambient, indoor and personal exposures at the lower concentrations found in environmental settings. Since the 1970s, passive samplers have been deployed for ambient air monitoring in urban and rural sites, and to determine personal and indoor exposure to NO2. This article reviews the development of NO2 passive samplers, the sampling characteristics of passive samplers currently available, and their application in ambient and indoor air monitoring and personal exposure studies. The limitations and advantages of the various passive sampler geometries (i.e., tube, badge, and radial type) are also discussed. This review provides researchers and risk assessors with practical information about NO2 passive samplers, especially useful when designing field sampling strategies for exposure and indoor/outdoor air sampling. PMID- 18446188 TI - Flat polyps depress gastroenterologists. PMID- 18446187 TI - Biomarkers of selenium status in the Amazonian context: blood, urine and sequential hair segments. AB - Selenium (Se) is an essential element and deficit or excess of dietary Se is associated with health disorders. Relatively elevated Se levels have been reported in the Brazilian Amazon, where there are also important annual variations in the availability of different foods. The present study was conducted among six riparian communities of the Tapajos River to evaluate seasonal variations in blood and sequential hair cm Se concentrations, and to examine the relationships between Se in blood and hair, and blood and urine. Two cross-sectional studies were conducted, at the descending water (DWS, n=259) and the rising water (RWS, n=137) seasons, with repeated measures for a subgroup (n=112). Blood Se (B-Se), hair Se (H-Se) and urine Se (U-Se) were determined. Match-paired analyses were used for seasonal comparisons and the method of best fit was used to describe the relationships between biomarkers. B-Se levels presented a very large range (142-2447 microg/l) with no overall seasonal variation (median 284 and 292 microg/l, respectively). Sequential analysis of 13 cm hair strands showed significant variations over time: Se concentrations at the DWS were significantly lower compared with the rising water season (medians: 0.7 and 0.9 microg/g; ranges: 0.2-4.3 microg/g and 0.2-5.4 microg/g, respectively). At both seasons, the relationships between B-Se and H-Se were linear and highly significant (r(2)=67.9 and 63.6, respectively), while the relationship between B Se and U-Se was best described by a sigmoid curve. Gender, age, education and smoking did not influence Se status or biomarker relationships. Variations in H Se suggest that there may be seasonal availability of Se sources in local food. For populations presenting a large range and/or elevated Se exposure, sequential analyses of H-Se may provide a good reflection of variations in Se status. PMID- 18446190 TI - Secondary chromosomal attachment site and tandem integration of the mobilizable Salmonella genomic island 1. AB - BACKGROUND: The Salmonella genomic island 1 is an integrative mobilizable element (IME) originally identified in epidemic multidrug-resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) DT104. SGI1 contains a complex integron, which confers various multidrug resistance phenotypes due to its genetic plasticity. Previous studies have shown that SGI1 integrates site-specifically into the S. enterica, Escherichia coli, or Proteus mirabilis chromosome at the 3' end of thdF gene (attB site). METHODOLOGY/PRINCIPAL FINDINGS: Here, we report the transfer of SGI1 to a Delta thdF mutant of S. Typhimurium LT2. In the absence of thdF, the frequency of transconjugant formation was reduced by around thirty times of magnitude. Through DNA sequencing SGI1 was shown to integrate specifically into a secondary attachment site (2(nd)attB), which is located in the intergenic region between the chromosomal sodB and purR genes. At this 2(nd)attB site, we found that a significant fraction of SGI1 transconjugants (43% of wild type and 100% of Delta thdF mutant) contained tandem SGI1 arrays. Moreover, in wild type S. Typhimurium LT2 transconjugants, SGI1 integrated into both attachment sites, i.e., thdF and sodB-purR. The formation of SGI1 tandem arrays occurred in both specific attB sites. There was heterogeneity in the size of the SGI1 tandem arrays detected in single transconjugant colonies. Some arrays consisted as far as six SGI1s arranged in tandem. These tandem arrays were shown to persist during serial passages with or without antibiotic selection pressure. CONCLUSIONS/SIGNIFICANCE: The ability of integration into two distinct chromosomal sites and tandem array formation of SGI1 could contribute to its spread and persistence. The existence of a secondary attachment site in the Salmonella chromosome has potential implications for the mobility of SGI1, which may integrate in other attachment sites of other bacterial pathogens that do not possess the 1(st) or 2(nd) specific SGI1 attB sites of Salmonella. PMID- 18446191 TI - C. albicans colonization of human mucosal surfaces. AB - BACKGROUND: Candida albicans is a low level commensal organism in normal human populations with the continuous potential to expand and cause a spectrum of clinical conditions. METHODOLOGY/PRINCIPAL FINDINGS: Using ex vivo human organ cultures and populations of primary human cells, we have developed several related experimental systems to examine early-stage interactions between C. albicans and mucosal surfaces. Experiments have been conducted both with exogenously added C. albicans and with overtly normal human mucosal surfaces supporting pre-existing infections with natural isolates of Candida. Under different culture conditions, we have demonstrated the formation of C. albicans colonies on human target cells and filament formation, equivalent to tissue invasion. CONCLUSIONS/SIGNIFICANCE: These organ culture systems provide a valuable new resource to examine the molecular and cellular basis for Candida colonization of human mucosal surfaces. PMID- 18446193 TI - An NF-Y-dependent switch of positive and negative histone methyl marks on CCAAT promoters. AB - BACKGROUND: Histone tails have a plethora of different post-translational modifications, which are located differently in "open" and "closed" parts of genomes. H3K4me3/H3K79me2 and H4K20me3 are among the histone marks associated with the early establishment of active and inactive chromatin, respectively. One of the most widespread promoter elements is the CCAAT box, bound by the NF-Y trimer. Two of NF-Y subunits have an H2A-H2B-like structure. PRINCIPAL FINDINGS: We established the causal relationship between NF-Y binding and positioning of methyl marks, by ChIP analysis of mouse and human cells infected with a dominant negative NF-YA: a parallel decrease in NF-Y binding, H3K4me3, H3K79me2 and transcription was observed in promoters that are dependent upon NF-Y. On the contrary, changes in the levels of H3K9-14ac were more subtle. Components of the H3K4 methylating MLL complex are not recruited in the absence of NF-Y. As for repressed promoters, NF-Y removal leads to a decrease in the H4K20me3 mark and deposition of H3K4me3. CONCLUSIONS: Two relevant findings are reported: (i) NF-Y gains access to its genomic locations independently from the presence of methyl histone marks, either positive or negative; (ii) NF-Y binding has profound positive or negative consequences on the deposition of histone methyl marks. Therefore NF-Y is a fundamental switch at the heart of decision between gene activation and repression in CCAAT regulated genes. PMID- 18446192 TI - Cooperative stimulation of dendritic cells by Cryptococcus neoformans mannoproteins and CpG oligodeoxynucleotides. AB - While mannosylation targets antigens to mannose receptors on dendritic cells (DC), the resultant immune response is suboptimal. We hypothesized that the addition of toll-like receptor (TLR) ligands would enhance the DC response to mannosylated antigens. Cryptococcus neoformans mannoproteins (MP) synergized with CpG-containing oligodeoxynucleotides to stimulate enhanced production of proinflammatory cytokines and chemokines from murine conventional and plasmacytoid DC. Synergistic stimulation required the interaction of mannose residues on MP with the macrophage mannose receptor (MR), CD206. Moreover, synergy with MP was observed with other TLR ligands, including tripalmitoylated lipopeptide (Pam3CSK4), polyinosine-polycytidylic acid (pI:C), and imiquimod. Finally, CpG enhanced MP-specific MHC II-restricted CD4(+) T-cell responses by a mechanism dependent upon DC expression of CD206 and TLR9. These data suggest a rationale for vaccination strategies that combine mannosylated antigens with TLR ligands and imply that immune responses to naturally mannosylated antigens on pathogens may be greatly augmented if TLR and MR are cooperatively stimulated. PMID- 18446194 TI - Characterization of clinically-attenuated Burkholderia mallei by whole genome sequencing: candidate strain for exclusion from Select Agent lists. AB - BACKGROUND: Burkholderia mallei is an understudied biothreat agent responsible for glanders which can be lethal in humans and animals. Research with this pathogen has been hampered in part by constraints of Select Agent regulations for safety reasons. Whole genomic sequencing (WGS) is an apt approach to characterize newly discovered or poorly understood microbial pathogens. METHODOLOGY/PRINCIPAL FINDINGS: We performed WGS on a strain of B. mallei, SAVP1, previously pathogenic, that was experimentally infected in 6 equids (4 ponies, 1 mule, 1 donkey), natural hosts, for purposes of producing antibodies. Multiple high inocula were used in some cases. Unexpectedly SAVP1 appeared to be avirulent in the ponies and mule, and attenuated in the donkey, but induced antibodies. We determined the genome sequence of SAVP1 and compared it to a strain that was virulent in horses and a human. In comparison, this phenotypic avirulent SAVP1 strain was missing multiple genes including all the animal type III secretory system (T3SS) complex of genes demonstrated to be essential for virulence in mice and hamster models. The loss of these genes in the SAVP1 strain appears to be the consequence of a multiple gene deletion across insertion sequence (IS) elements in the B. mallei genome. Therefore, the strain by itself is unlikely to revert naturally to its virulent phenotype. There were other genes present in one strain and not the other and vice-versa. CONCLUSION/SIGNIFICANCE: The discovery that this strain of B. mallei was both avirulent in the natural host ponies, and did not possess T3SS associated genes may be fortuitous to advance biodefense research. The deleted virulence-essential T3SS is not likely to be re-acquired naturally. These findings may provide a basis for exclusion of SAVP1 from the Select Agent regulation or at least discussion of what else would be required for exclusion. This exclusion could accelerate research by investigators not possessing BSL-3 facilities and facilitate the production of reagents such as antibodies without the restraints of Select Agent regulation. PMID- 18446195 TI - Utilization of a deoxynucleoside diphosphate substrate by HIV reverse transcriptase. AB - BACKGROUND: Deoxynucleoside triphosphates (dNTPs) are the normal substrates for DNA synthesis catalyzed by polymerases such as HIV-1 reverse transcriptase (RT). However, substantial amounts of deoxynucleoside diphosphates (dNDPs) are also present in the cell. Use of dNDPs in HIV-1 DNA synthesis could have significant implications for the efficacy of nucleoside RT inhibitors such as AZT which are first line therapeutics for treatment of HIV infection. Our earlier work on HIV-1 reverse transcriptase (RT) suggested that the interaction between the gamma phosphate of the incoming dNTP and RT residue K65 in the active site is not essential for dNTP insertion, implying that this polymerase may be able to insert dNDPs in addition to dNTPs. METHODOLOGY/PRINCIPAL FINDINGS: We examined the ability of recombinant wild type (wt) and mutant RTs with substitutions at residue K65 to utilize a dNDP substrate in primer extension reactions. We found that wild type HIV-1 RT indeed catalyzes incorporation of dNDP substrates whereas RT with mutations of residue K65 were unable to catalyze this reaction. Wild type HIV-1 RT also catalyzed the reverse reaction, inorganic phosphate-dependent phosphorolysis. Nucleotide-mediated phosphorolytic removal of chain-terminating 3'-terminal nucleoside inhibitors such as AZT forms the basis for HIV-1 resistance to such drugs, and this removal is enhanced by thymidine analog mutations (TAMs). We found that both wt and TAM-containing RTs were able to catalyze Pi-mediated phosphorolysis of 3'-terminal AZT at physiological levels of Pi with an efficacy similar to that for ATP-dependent AZT-excision. CONCLUSIONS: We have identified two new catalytic functions of HIV-1 RT, the use of dNDPs as substrates for DNA synthesis, and the use of Pi as substrate for phosphorolytic removal of primer 3'-terminal nucleotides. The ability to insert dNDPs has been documented for only one other DNA polymerase, the RB69 DNA polymerase and the reverse reaction employing inorganic phosphate has not been documented for any DNA polymerase. Importantly, our results show that Pi-mediated phosphorolysis can contribute to AZT resistance and indicates that factors that influence HIV resistance to AZT are more complex than previously appreciated. PMID- 18446196 TI - Baseline morbidity in 2,990 adult African volunteers recruited to characterize laboratory reference intervals for future HIV vaccine clinical trials. AB - BACKGROUND: An understanding of the health of potential volunteers in Africa is essential for the safe and efficient conduct of clinical trials, particularly for trials of preventive technologies such as vaccines that enroll healthy individuals. Clinical safety laboratory values used for screening, enrolment and follow-up of African clinical trial volunteers have largely been based on values derived from industrialized countries in Europe and North America. This report describes baseline morbidity during recruitment for a multi-center, African laboratory reference intervals study. METHODS: Asymptomatic persons, aged 18-60 years, were invited to participate in a cross-sectional study at seven sites (Kigali, Rwanda; Masaka and Entebbe, Uganda; Kangemi, Kenyatta National Hospital and Kilifi, Kenya; and Lusaka, Zambia). Gender equivalency was by design. Individuals who were acutely ill, pregnant, menstruating, or had significant clinical findings were not enrolled. Each volunteer provided blood for hematology, immunology, and biochemistry parameters and urine for urinalysis. Enrolled volunteers were excluded if found to be positive for HIV, syphilis or Hepatitis B and C. Laboratory assays were conducted under Good Clinical Laboratory Practices (GCLP). RESULTS AND CONCLUSIONS: Of the 2990 volunteers who were screened, 2387 (80%) were enrolled, and 2107 (71%) were included in the analysis (52% men, 48% women). Major reasons for screening out volunteers included abnormal findings on physical examination (228/603, 38%), significant medical history (76, 13%) and inability to complete the informed consent process (73, 13%). Once enrolled, principle reasons for exclusion from analysis included detection of Hepatitis B surface antigen (106/280, 38%) and antibodies against Hepatitis C (95, 34%). This is the first large scale, multi-site study conducted to the standards of GCLP to describe African laboratory reference intervals applicable to potential volunteers in clinical trials. Approximately one-third of all potential volunteers screened were not eligible for analysis; the majority were excluded for medical reasons. PMID- 18446197 TI - Calmodulin activation by calcium transients in the postsynaptic density of dendritic spines. AB - The entry of calcium into dendritic spines can trigger a sequence of biochemical reactions that begins with the activation of calmodulin (CaM) and ends with long term changes to synaptic strengths. The degree of activation of CaM can depend on highly local elevations in the concentration of calcium and the duration of transient increases in calcium concentration. Accurate measurement of these local changes in calcium is difficult because the spaces are so small and the numbers of molecules are so low. We have therefore developed a Monte Carlo model of intracellular calcium dynamics within the spine that included calcium binding proteins, calcium transporters and ion channels activated by voltage and glutamate binding. The model reproduced optical recordings using calcium indicator dyes and showed that without the dye the free intracellular calcium concentration transient was much higher than predicted from the fluorescent signal. Excitatory postsynaptic potentials induced large, long-lasting calcium gradients across the postsynaptic density, which activated CaM. When glutamate was released at the synapse 10 ms before an action potential occurred, simulating activity patterns that strengthen hippocampal synapses, the calcium gradient and activation of CaM in the postsynaptic density were much greater than when the order was reversed, a condition that decreases synaptic strengths, suggesting a possible mechanism underlying the induction of long-term changes in synaptic strength. The spatial and temporal mechanisms for selectivity in CaM activation demonstrated here could be used in other signaling pathways. PMID- 18446198 TI - Localization and characterization of STRO-1 cells in the deer pedicle and regenerating antler. AB - The annual regeneration of deer antlers is a unique developmental event in mammals, which as a rule possess only a very limited capacity to regenerate lost appendages. Studying antler regeneration can therefore provide a deeper insight into the mechanisms that prevent limb regeneration in humans and other mammals, and, with regard to medical treatments, may possibly even show ways how to overcome these limitations. Traditionally, antler regeneration has been characterized as a process involving the formation of a blastema from de differentiated cells. More recently it has, however, been hypothesized that antler regeneration is a stem cell-based process. Thus far, direct evidence for the presence of stem cells in primary or regenerating antlers was lacking. Here we demonstrate the presence of cells positive for the mesenchymal stem cell marker STRO-1 in the chondrogenic growth zone and the perivascular tissue of the cartilaginous zone in primary and regenerating antlers as well as in the pedicle of fallow deer (Dama dama). In addition, cells positive for the stem cell/progenitor cell markers STRO-1, CD133 and CD271 (LNGFR) were isolated from the growth zones of regenerating fallow deer antlers as well as the pedicle periosteum and cultivated for extended periods of time. We found evidence that STRO-1(+) cells isolated from the different locations are able to differentiate in vitro along the osteogenic and adipogenic lineages. Our results support the view that the annual process of antler regeneration might depend on the periodic activation of mesenchymal progenitor cells located in the pedicle periosteum. The findings of the present study indicate that not only limited tissue regeneration, but also extensive appendage regeneration in a postnatal mammal can occur as a stem cell-based process. PMID- 18446199 TI - A new concept for medical imaging centered on cellular phone technology. AB - According to World Health Organization reports, some three quarters of the world population does not have access to medical imaging. In addition, in developing countries over 50% of medical equipment that is available is not being used because it is too sophisticated or in disrepair or because the health personnel are not trained to use it. The goal of this study is to introduce and demonstrate the feasibility of a new concept in medical imaging that is centered on cellular phone technology and which may provide a solution to medical imaging in underserved areas. The new system replaces the conventional stand-alone medical imaging device with a new medical imaging system made of two independent components connected through cellular phone technology. The independent units are: a) a data acquisition device (DAD) at a remote patient site that is simple, with limited controls and no image display capability and b) an advanced image reconstruction and hardware control multiserver unit at a central site. The cellular phone technology transmits unprocessed raw data from the patient site DAD and receives and displays the processed image from the central site. (This is different from conventional telemedicine where the image reconstruction and control is at the patient site and telecommunication is used to transmit processed images from the patient site). The primary goal of this study is to demonstrate that the cellular phone technology can function in the proposed mode. The feasibility of the concept is demonstrated using a new frequency division multiplexing electrical impedance tomography system, which we have developed for dynamic medical imaging, as the medical imaging modality. The system is used to image through a cellular phone a simulation of breast cancer tumors in a medical imaging diagnostic mode and to image minimally invasive tissue ablation with irreversible electroporation in a medical imaging interventional mode. PMID- 18446200 TI - Dental microwear and diet of the Plio-Pleistocene hominin Paranthropus boisei. AB - The Plio-Pleistocene hominin Paranthropus boisei had enormous, flat, thickly enameled cheek teeth, a robust cranium and mandible, and inferred massive, powerful chewing muscles. This specialized morphology, which earned P. boisei the nickname "Nutcracker Man", suggests that this hominin could have consumed very mechanically challenging foods. It has been recently argued, however, that specialized hominin morphology may indicate adaptations for the consumption of occasional fallback foods rather than preferred resources. Dental microwear offers a potential means by which to test this hypothesis in that it reflects actual use rather than genetic adaptation. High microwear surface texture complexity and anisotropy in extant primates can be associated with the consumption of exceptionally hard and tough foods respectively. Here we present the first quantitative analysis of dental microwear for P. boisei. Seven specimens examined preserved unobscured antemortem molar microwear. These all show relatively low complexity and anisotropy values. This suggests that none of the individuals consumed especially hard or tough foods in the days before they died. The apparent discrepancy between microwear and functional anatomy is consistent with the idea that P. boisei presents a hominin example of Liem's Paradox, wherein a highly derived morphology need not reflect a specialized diet. PMID- 18446201 TI - Cyanogenic pseudomonads influence multitrophic interactions in the rhizosphere. AB - In the rhizosphere, plant roots cope with both pathogenic and beneficial bacterial interactions. The exometabolite production in certain bacterial species may regulate root growth and other root-microbe interactions in the rhizosphere. Here, we elucidated the role of cyanide production in pseudomonad virulence affecting plant root growth and other rhizospheric processes. Exposure of Arabidopsis thaliana Col-0 seedlings to both direct (with KCN) and indirect forms of cyanide from different pseudomonad strains caused significant inhibition of primary root growth. Further, we report that this growth inhibition was caused by the suppression of an auxin responsive gene, specifically at the root tip region by pseudomonad cyanogenesis. Additionally, pseudomonad cyanogenesis also affected other beneficial rhizospheric processes such as Bacillus subtilis colonization by biofilm formation on A. thaliana Col-0 roots. The effect of cyanogenesis on B. subtilis biofilm formation was further established by the down regulation of important B. subtilis biofilm operons epsA and yqxM. Our results show, the functional significance of pseudomonad cyanogenesis in regulating multitrophic rhizospheric interactions. PMID- 18446202 TI - Calcium triggered L alpha-H2 phase transition monitored by combined rapid mixing and time-resolved synchrotron SAXS. AB - BACKGROUND: Awad et al. reported on the Ca(2+)-induced transitions of dioleoyl phosphatidylglycerol (DOPG)/monoolein (MO) vesicles to bicontinuous cubic phases at equilibrium conditions. In the present study, the combination of rapid mixing and time-resolved synchrotron small-angle X-ray scattering (SAXS) was applied for the in-situ investigations of fast structural transitions of diluted DOPG/MO vesicles into well-ordered nanostructures by the addition of low concentrated Ca(2+) solutions. METHODOLOGY/PRINCIPAL FINDINGS: Under static conditions and the in absence of the divalent cations, the DOPG/MO system forms large vesicles composed of weakly correlated bilayers with a d-spacing of approximately 140 A (L(alpha)-phase). The utilization of a stopped-flow apparatus allowed mixing these DOPG/MO vesicles with a solution of Ca(2+) ions within 10 milliseconds (ms). In such a way the dynamics of negatively charged PG to divalent cation interactions, and the kinetics of the induced structural transitions were studied. Ca(2+) ions have a very strong impact on the lipidic nanostructures. Intriguingly, already at low salt concentrations (DOPG/Ca(2+)>2), Ca(2+) ions trigger the transformation from bilayers to monolayer nanotubes (inverted hexagonal phase, H(2)). Our results reveal that a binding ratio of 1 Ca(2+) per 8 DOPG is sufficient for the formation of the H(2) phase. At 50 degrees C a direct transition from the vesicles to the H(2) phase was observed, whereas at ambient temperature (20 degrees C) a short lived intermediate phase (possibly the cubic Pn3m phase) coexisting with the H(2) phase was detected. CONCLUSIONS/SIGNIFICANCE: The strong binding of the divalent cations to the negatively charged DOPG molecules enhances the negative spontaneous curvature of the monolayers and causes a rapid collapsing of the vesicles. The rapid loss of the bilayer stability and the reorganization of the lipid molecules within ms support the argument that the transition mechanism is based on a leaky fusion of the vesicles. PMID- 18446203 TI - Conceptualizing integration: a framework for analysis applied to neglected tropical disease control partnerships. PMID- 18446204 TI - Associations between active trachoma and community intervention with Antibiotics, Facial cleanliness, and Environmental improvement (A,F,E). AB - BACKGROUND: Surgery, Antibiotics, Facial cleanliness and Environmental improvement (SAFE) are advocated by the World Health Organization (WHO) for trachoma control. However, few studies have evaluated the complete SAFE strategy, and of these, none have investigated the associations of Antibiotics, Facial cleanliness, and Environmental improvement (A,F,E) interventions and active trachoma. We aimed to investigate associations between active trachoma and A,F,E interventions in communities in Southern Sudan. METHODS AND FINDINGS: Surveys were undertaken in four districts after 3 years of implementation of the SAFE strategy. Children aged 1-9 years were examined for trachoma and uptake of SAFE assessed through interviews and observations. Using ordinal logistic regression, associations between signs of active trachoma and A,F,E interventions were explored. Trachomatous inflammation-intense (TI) was considered more severe than trachomatous inflammation-follicular (TF). A total of 1,712 children from 25 clusters (villages) were included in the analysis. Overall uptake of A,F,E interventions was: 53.0% of the eligible children had received at least one treatment with azithromycin; 62.4% children had a clean face on examination; 72.5% households reported washing faces of children two or more times a day; 73.1% households had received health education; 44.4% of households had water accessible within 30 minutes; and 6.3% households had pit latrines. Adjusting for age, sex, and district baseline prevalence of active trachoma, factors independently associated with reduced odds of a more severe active trachoma sign were: receiving three treatments with azithromycin (odds ratio [OR] = 0.1; 95% confidence interval [CI] 0.0-0.4); clean face (OR = 0.3; 95% CI 0.2-0.4); washing faces of children three or more times daily (OR = 0.4; 95% CI 0.3-0.7); and presence and use of a pit latrine in the household (OR = 0.4; 95% CI 0.2-0.9). CONCLUSION: Analysis of associations between the A,F,E components of the SAFE strategy and active trachoma showed independent protective effects against active trachoma of mass systemic azithromycin treatment, facial cleanliness, face washing, and use of pit latrines in the household. This strongly argues for continued use of all the components of the SAFE strategy together. PMID- 18446206 TI - Stigma: the stealth weapon of the NTD. PMID- 18446205 TI - Uncovering cis regulatory codes using synthetic promoter shuffling. AB - Revealing the spectrum of combinatorial regulation of transcription at individual promoters is essential for understanding the complex structure of biological networks. However, the computations represented by the integration of various molecular signals at complex promoters are difficult to decipher in the absence of simple cis regulatory codes. Here we synthetically shuffle the regulatory architecture--operator sequences binding activators and repressors--of a canonical bacterial promoter. The resulting library of complex promoters allows for rapid exploration of promoter encoded logic regulation. Among all possible logic functions, NOR and ANDN promoter encoded logics predominate. A simple transcriptional cis regulatory code determines both logics, establishing a straightforward map between promoter structure and logic phenotype. The regulatory code is determined solely by the type of transcriptional regulation combinations: two repressors generate a NOR: NOT (a OR b) whereas a repressor and an activator generate an ANDN: a AND NOT b. Three-input versions of both logics, having an additional repressor as an input, are also present in the library. The resulting complex promoters cover a wide dynamic range of transcriptional strengths. Synthetic promoter shuffling represents a fast and efficient method for exploring the spectrum of complex regulatory functions that can be encoded by complex promoters. From an engineering point of view, synthetic promoter shuffling enables the experimental testing of the functional properties of complex promoters that cannot necessarily be inferred ab initio from the known properties of the individual genetic components. Synthetic promoter shuffling may provide a useful experimental tool for studying naturally occurring promoter shuffling. PMID- 18446207 TI - The optokinetic reflex as a tool for quantitative analyses of nervous system function in mice: application to genetic and drug-induced variation. AB - The optokinetic reflex (OKR), which serves to stabilize a moving image on the retina, is a behavioral response that has many favorable attributes as a test of CNS function. The OKR requires no training, assesses the function of diverse CNS circuits, can be induced repeatedly with minimal fatigue or adaptation, and produces an electronic record that is readily and objectively quantifiable. We describe a new type of OKR test apparatus in which computer-controlled visual stimuli and streamlined data analysis facilitate a relatively high throughput behavioral assay. We used this apparatus, in conjunction with infrared imaging, to quantify basic OKR stimulus-response characteristics for C57BL/6J and 129/SvEv mouse strains and for genetically engineered lines lacking one or more photoreceptor systems or with an alteration in cone spectral sensitivity. A second generation (F2) cross shows that the characteristic difference in OKR frequency between C57BL/6J and 129/SvEv is inherited as a polygenic trait. Finally, we demonstrate the sensitivity and high temporal resolution of the OKR for quantitative analysis of CNS drug action. These experiments show that the mouse OKR is well suited for neurologic testing in the context of drug discovery and large-scale phenotyping programs. PMID- 18446208 TI - Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. AB - BACKGROUND: Although uterine macrophages are thought to play an important regulatory role at the maternal-fetal interface, their global gene expression profile is not known. METHODOLOGY/PRINCIPAL FINDINGS: Using micro-array comprising approximately 14,000 genes, the gene expression pattern of human first trimester decidual CD14+ monocytes/macrophages was characterized and compared with the expression profile of the corresponding cells in blood. Some of the key findings were confirmed by real time PCR or by secreted protein. A unique gene expression pattern intrinsic of first trimester decidual CD14+ cells was demonstrated. A large number of regulated genes were functionally related to immunomodulation and tissue remodelling, corroborating polarization patterns of differentiated macrophages mainly of the alternatively activated M2 phenotype. These include known M2 markers such as CCL-18, CD209, insulin-like growth factor (IGF)-1, mannose receptor c type (MRC)-1 and fibronectin-1. Further, the selective up-regulation of triggering receptor expressed on myeloid cells (TREM) 2, alpha-2-macroglobulin (A2M) and prostaglandin D2 synthase (PGDS) provides new insights into the regulatory function of decidual macrophages in pregnancy that may have implications in pregnancy complications. CONCLUSIONS/SIGNIFICANCE: The molecular characterization of decidual macrophages presents a unique transcriptional profile replete with important components for fetal immunoprotection and provides several clues for further studies of these cells. PMID- 18446209 TI - Saccadic eye movements minimize the consequences of motor noise. AB - The durations and trajectories of our saccadic eye movements are remarkably stereotyped. We have no voluntary control over these properties but they are determined by the movement amplitude and, to a smaller extent, also by the movement direction and initial eye orientation. Here we show that the stereotyped durations and trajectories are optimal for minimizing the variability in saccade endpoints that is caused by motor noise. The optimal duration can be understood from the nature of the motor noise, which is a combination of signal-dependent noise favoring long durations, and constant noise, which prefers short durations. The different durations of horizontal vs. vertical and of centripetal vs. centrifugal saccades, and the somewhat surprising properties of saccades in oblique directions are also accurately predicted by the principle of minimizing movement variability. The simple and sensible principle of minimizing the consequences of motor noise thus explains the full stereotypy of saccadic eye movements. This suggests that saccades are so stereotyped because that is the best strategy to minimize movement errors for an open-loop motor system. PMID- 18446210 TI - Biomarkers for clinical and incipient tuberculosis: performance in a TB-endemic country. AB - BACKGROUND: Simple biomarkers are required to identify TB in both HIV(-)TB(+) and HIV(+)TB(+) patients. Earlier studies have identified the M. tuberculosis Malate Synthase (MS) and MPT51 as immunodominant antigens in TB patients. One goal of these investigations was to evaluate the sensitivity and specificity of anti-MS and -MPT51 antibodies as biomarkers for TB in HIV(-)TB(+) and HIV(+)TB(+) patients from a TB-endemic setting. Earlier studies also demonstrated the presence of these biomarkers during incipient subclinical TB. If these biomarkers correlate with incipient TB, their prevalence should be higher in asymptomatic HIV(+) subjects who are at a high-risk for TB. The second goal was to compare the prevalence of these biomarkers in asymptomatic, CD4(+) T cell-matched HIV(+)TB(-) subjects from India who are at high-risk for TB with similar subjects from US who are at low-risk for TB. METHODS AND RESULTS: Anti-MS and -MPT51 antibodies were assessed in sera from 480 subjects including PPD(+) or PPD(-) healthy subjects, healthy community members, and HIV(-)TB(+) and HIV(+)TB(+) patients from India. Results demonstrate high sensitivity (approximately 80%) of detection of smear positive HIV(-)TB(+) and HIV(+)TB(+) patients, and high specificity (>97%) with PPD(+) subjects and endemic controls. While approximately 45% of the asymptomatic HIV(+)TB(-) patients at high-risk for TB tested biomarker-positive, >97% of the HIV(+)TB(-) subjects at low risk for TB tested negative. Although the current studies are hampered by lack of knowledge of the outcome, these results provide strong support for the potential of these biomarkers to detect incipient, subclinical TB in HIV(+) subjects. CONCLUSIONS: These biomarkers provide high sensitivity and specificity for TB diagnosis in a TB endemic setting. Their performance is not compromised by concurrent HIV infection, site of TB and absence of pulmonary manifestations in HIV(+)TB(+) patients. Results also demonstrate the potential of these biomarkers for identifying incipient subclinical TB in HIV(+)TB(-) subjects at high-risk for TB. PMID- 18446211 TI - NO dioxygenase activity in hemoglobins is ubiquitous in vitro, but limited by reduction in vivo. AB - Genomics has produced hundreds of new hemoglobin sequences with examples in nearly every living organism. Structural and biochemical characterizations of many recombinant proteins reveal reactions, like oxygen binding and NO dioxygenation, that appear general to the hemoglobin superfamily regardless of whether they are related to physiological function. Despite considerable attention to "hexacoordinate" hemoglobins, which are found in nearly every plant and animal, no clear physiological role(s) has been assigned to them in any species. One popular and relevant hypothesis for their function is protection against NO. Here we have tested a comprehensive representation of hexacoordinate hemoglobins from plants (rice hemoglobin), animals (neuroglobin and cytoglobin), and bacteria (Synechocystis hemoglobin) for their abilities to scavenge NO compared to myoglobin. Our experiments include in vitro comparisons of NO dioxygenation, ferric NO binding, NO-induced reduction, NO scavenging with an artificial reduction system, and the ability to substitute for a known NO scavenger (flavohemoglobin) in E. coli. We conclude that none of these tests reveal any distinguishing predisposition toward a role in NO scavenging for the hxHbs, but that any hemoglobin could likely serve this role in the presence of a mechanism for heme iron re-reduction. Hence, future research to test the role of Hbs in NO scavenging would benefit more from the identification of cognate reductases than from in vitro analysis of NO and O(2) binding. PMID- 18446212 TI - Of mice and men--universality and breakdown of behavioral organization. AB - Mental or cognitive brain functions, and the effect on them of abnormal psychiatric diseases, are difficult to approach through molecular biological techniques due to the lack of appropriate assay systems with objective measures. We therefore study laws of behavioral organization, specifically how resting and active periods are interwoven throughout daily life, using objective criteria, and first discover that identical laws hold both for healthy humans subject to the full complexity of daily life, and wild-type mice subject to maximum environmental constraints. We find that active period durations with physical activity counts successively above a predefined threshold, when rescaled with individual means, follow a universal stretched exponential (gamma-type) cumulative distribution, while resting period durations below the threshold obey a universal power-law cumulative distribution with identical parameter values for both of the mammalian species. Further, by analyzing the behavioral organization of mice with a circadian clock gene (Period2) eliminated, and humans suffering from major depressive disorders, we find significantly lower parameter values (power-law scaling exponents) for the resting period durations in both these cases. Such a universality and breakdown of the behavioral organization of mice and humans, revealed through objective measures, is expected to facilitate the understanding of the molecular basis of the pathophysiology of neurobehavioral diseases, including depression, and lay the foundations for formulating a range of neuropsychiatric behavioral disorder models. PMID- 18446214 TI - Enzyme sequence and its relationship to hyperbaric stability of artificial and natural fish lactate dehydrogenases. AB - The cDNAs of lactate dehydrogenase b (LDH-b) from both deep-sea and shallow living fish species, Corphaenoides armatus and Gadus morhua respectively, have been isolated, sequenced and their encoded products overproduced as recombinant enzymes in E. coli. The proteins were characterised in terms of their kinetic and physical properties and their ability to withstand high pressures. Although the two proteins are very similar in terms of their primary structure, only 21 differences at the amino acid level exist between them, the enzyme from the deep sea species has a significantly increased tolerance to pressure and a higher thermostability. It was possible to investigate whether the changes in the N terminal or C-terminal regions played a greater role in barophilic adaptation by the construction of two chimeric enzymes by use of a common restriction site within the cDNAs. One of these hybrids was found to have even greater pressure stability than the recombinant enzyme from the deep-living fish species. It was possible to conclude that the major adaptive changes to pressure tolerance must be located in the N-terminal region of the protein. The types of changes that are found and their spatial location within the protein structure are discussed. An analysis of the kinetic parameters of the enzymes suggests that there is clearly a trade off between K(m) and k(cat) values, which likely reflects the necessity of the deep-sea enzyme to operate at low temperatures. PMID- 18446213 TI - Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH-oligomannose-3 complex. AB - BACKGROUND: Escherichia coli strains adhere to the normally sterile human uroepithelium using type 1 pili, that are long, hairy surface organelles exposing a mannose-binding FimH adhesin at the tip. A small percentage of adhered bacteria can successfully invade bladder cells, presumably via pathways mediated by the high-mannosylated uroplakin-Ia and alpha3beta1 integrins found throughout the uroepithelium. Invaded bacteria replicate and mature into dense, biofilm-like inclusions in preparation of fluxing and of infection of neighbouring cells, being the major cause of the troublesome recurrent urinary tract infections. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that alpha-D-mannose based inhibitors of FimH not only block bacterial adhesion on uroepithelial cells but also antagonize invasion and biofilm formation. Heptyl alpha-D-mannose prevents binding of type 1-piliated E. coli to the human bladder cell line 5637 and reduces both adhesion and invasion of the UTI89 cystitis isolate instilled in mouse bladder via catheterization. Heptyl alpha-D-mannose also specifically inhibited biofilm formation at micromolar concentrations. The structural basis of the great inhibitory potential of alkyl and aryl alpha-D-mannosides was elucidated in the crystal structure of the FimH receptor-binding domain in complex with oligomannose-3. FimH interacts with Man alpha1,3Man beta1,4GlcNAc beta1,4GlcNAc in an extended binding site. The interactions along the alpha1,3 glycosidic bond and the first beta1,4 linkage to the chitobiose unit are conserved with those of FimH with butyl alpha-D-mannose. The strong stacking of the central mannose with the aromatic ring of Tyr48 is congruent with the high affinity found for synthetic inhibitors in which this mannose is substituted for by an aromatic group. CONCLUSIONS/SIGNIFICANCE: The potential of ligand-based design of antagonists of urinary tract infections is ruled by the structural mimicry of natural epitopes and extends into blocking of bacterial invasion, intracellular growth and capacity to fluxing and of recurrence of the infection. PMID- 18446215 TI - Muscle dystroglycan organizes the postsynapse and regulates presynaptic neurotransmitter release at the Drosophila neuromuscular junction. AB - BACKGROUND: The Dystrophin-glycoprotein complex (DGC) comprises dystrophin, dystroglycan, sarcoglycan, dystrobrevin and syntrophin subunits. In muscle fibers, it is thought to provide an essential mechanical link between the intracellular cytoskeleton and the extracellular matrix and to protect the sarcolemma during muscle contraction. Mutations affecting the DGC cause muscular dystrophies. Most members of the DGC are also concentrated at the neuromuscular junction (NMJ), where their deficiency is often associated with NMJ structural defects. Hence, synaptic dysfunction may also intervene in the pathology of dystrophic muscles. Dystroglycan is a central component of the DGC because it establishes a link between the extracellular matrix and Dystrophin. In this study, we focused on the synaptic role of Dystroglycan (Dg) in Drosophila. METHODOLOGY/PRINCIPAL FINDINGS: We show that Dg was concentrated postsynaptically at the glutamatergic NMJ, where, like in vertebrates, it controls the concentration of synaptic Laminin and Dystrophin homologues. We also found that synaptic Dg controlled the amount of postsynaptic 4.1 protein Coracle and alpha Spectrin, as well as the relative subunit composition of glutamate receptors. In addition, both Dystrophin and Coracle were required for normal Dg concentration at the synapse. In electrophysiological recordings, loss of postsynaptic Dg did not affect postsynaptic response, but, surprisingly, led to a decrease in glutamate release from the presynaptic site. CONCLUSION/SIGNIFICANCE: Altogether, our study illustrates a conservation of DGC composition and interactions between Drosophila and vertebrates at the synapse, highlights new proteins associated with this complex and suggests an unsuspected trans-synaptic function of Dg. PMID- 18446217 TI - Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans. AB - BACKGROUND: Immunity to malaria develops naturally in endemic regions, but the protective immune mechanisms are poorly understood. Many vaccination strategies aim to induce T cells against diverse pre-erythrocytic antigens, but correlates of protection in the field have been limited. The objective of this study was to investigate cell-mediated immune correlates of protection in natural malaria. Memory T cells reactive against thrombospondin-related adhesive protein (TRAP) and circumsporozoite (CS) protein, major vaccine candidate antigens, were measured, as were frequencies of CD4(+) CD25(high) T cells, which may suppress immunity, and CD56(+) NK cells and gammadelta T cells, which may be effectors or may modulate immunity. METHODOLOGY AND PRINCIPAL FINDINGS: 112 healthy volunteers living in rural Kenya were entered in the study. Memory T cells reactive against TRAP and CS were measured using a cultured IFNgamma ELISPOT approach, whilst CD4(+) CD25(high) T cells, CD56(+) NK cells, and gammadelta T cells were measured by flow cytometry. We found that T cell responses against TRAP were established early in life (<5 years) in contrast to CS, and cultured ELISPOT memory T cell responses did not correlate with ex-vivo IFNgamma ELISPOT effector responses. Data was examined for associations with risk of clinical malaria for a period of 300 days. Multivariate logistic analysis incorporating age and CS response showed that cultured memory T cell responses against TRAP were associated with a significantly reduced incidence of malaria (p = 0.028). This was not seen for CS responses. Higher numbers of CD4(+) CD25(high) T cells, potentially regulatory T cells, were associated with a significantly increased risk of clinical malaria (p = 0.039). CONCLUSIONS: These data demonstrate a role for central memory T cells in natural malarial immunity and support current vaccination strategies aimed at inducing durable protective T cell responses against the TRAP antigen. They also suggest that CD4(+) CD25(high) T cells may negatively affect naturally acquired malarial immunity. PMID- 18446216 TI - Counting the founders: the matrilineal genetic ancestry of the Jewish Diaspora. AB - The history of the Jewish Diaspora dates back to the Assyrian and Babylonian conquests in the Levant, followed by complex demographic and migratory trajectories over the ensuing millennia which pose a serious challenge to unraveling population genetic patterns. Here we ask whether phylogenetic analysis, based on highly resolved mitochondrial DNA (mtDNA) phylogenies can discern among maternal ancestries of the Diaspora. Accordingly, 1,142 samples from 14 different non-Ashkenazi Jewish communities were analyzed. A list of complete mtDNA sequences was established for all variants present at high frequency in the communities studied, along with high-resolution genotyping of all samples. Unlike the previously reported pattern observed among Ashkenazi Jews, the numerically major portion of the non-Ashkenazi Jews, currently estimated at 5 million people and comprised of the Moroccan, Iraqi, Iranian and Iberian Exile Jewish communities showed no evidence for a narrow founder effect, which did however characterize the smaller and more remote Belmonte, Indian and the two Caucasus communities. The Indian and Ethiopian Jewish sample sets suggested local female introgression, while mtDNAs in all other communities studied belong to a well-characterized West Eurasian pool of maternal lineages. Absence of sub-Saharan African mtDNA lineages among the North African Jewish communities suggests negligible or low level of admixture with females of the host populations among whom the African haplogroup (Hg) L0-L3 sub-clades variants are common. In contrast, the North African and Iberian Exile Jewish communities show influence of putative Iberian admixture as documented by mtDNA Hg HV0 variants. These findings highlight striking differences in the demographic history of the widespread Jewish Diaspora. PMID- 18446218 TI - Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. AB - The alpha(4) integrin antagonist natalizumab was shown to be effective in patients with immune-mediated disorders but was unexpectedly associated with JC polyomavirus associated progressive multifocal leukoencephalopathy (PML) in two multiple sclerosis (MS) and one Crohn's disease patients. Impaired immune surveillance due to natalizumab treatment may have contributed to the JCV reactivation. As HHV-6 has been suggested to play a role in MS, we asked whether this virus could also have been reactivated during natalizumab therapy. Matched sera and CSF from a limited set of MS patients treated with and without natalizumab were examined for evidence of HHV-6. In addition, we also superinfected a persistent JC virus infected glial cell with HHV-6A to determine if JC virus can be increased. Elevated serum HHV6 IgG and HHV-6A DNA was detected in the CSF of a subset of patients but not controls. We confirmed that superinfection with HHV-6 of a JC virus infected glial cells increased expression of JCV. These results support the hypothesis that treatment with natalizumab may be associated with reduced immune surveillance resulting in reactivation of viruses associated with MS pathogenesis. PMID- 18446219 TI - Network 'small-world-ness': a quantitative method for determining canonical network equivalence. AB - BACKGROUND: Many technological, biological, social, and information networks fall into the broad class of 'small-world' networks: they have tightly interconnected clusters of nodes, and a shortest mean path length that is similar to a matched random graph (same number of nodes and edges). This semi-quantitative definition leads to a categorical distinction ('small/not-small') rather than a quantitative, continuous grading of networks, and can lead to uncertainty about a network's small-world status. Moreover, systems described by small-world networks are often studied using an equivalent canonical network model--the Watts-Strogatz (WS) model. However, the process of establishing an equivalent WS model is imprecise and there is a pressing need to discover ways in which this equivalence may be quantified. METHODOLOGY/PRINCIPAL FINDINGS: We defined a precise measure of 'small-world-ness' S based on the trade off between high local clustering and short path length. A network is now deemed a 'small-world' if S>1--an assertion which may be tested statistically. We then examined the behavior of S on a large data-set of real-world systems. We found that all these systems were linked by a linear relationship between their S values and the network size n. Moreover, we show a method for assigning a unique Watts-Strogatz (WS) model to any real-world network, and show analytically that the WS models associated with our sample of networks also show linearity between S and n. Linearity between S and n is not, however, inevitable, and neither is S maximal for an arbitrary network of given size. Linearity may, however, be explained by a common limiting growth process. CONCLUSIONS/SIGNIFICANCE: We have shown how the notion of a small-world network may be quantified. Several key properties of the metric are described and the use of WS canonical models is placed on a more secure footing. PMID- 18446220 TI - The mych gene is required for neural crest survival during zebrafish development. AB - BACKGROUND: Among Myc family genes, c-Myc is known to have a role in neural crest specification in Xenopus and in craniofacial development in the mouse. There is no information on the function of other Myc genes in neural crest development, or about any developmental role of zebrafish Myc genes. PRINCIPAL FINDINGS: We isolated the zebrafish mych (myc homologue) gene. Knockdown of mych leads to severe defects in craniofacial development and in certain other tissues including the eye. These phenotypes appear to be caused by cell death in the neural crest and in the eye field in the anterior brain. SIGNIFICANCE: Mych is a novel factor required for neural crest cell survival in zebrafish. PMID- 18446221 TI - Processing of genome 5' termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction. AB - Innate immunity is critically dependent on the rapid production of interferon in response to intruding viruses. The intracellular pathogen recognition receptors RIG-I and MDA5 are essential for interferon induction by viral RNAs containing 5' triphosphates or double-stranded structures, respectively. Viruses with a negative-stranded RNA genome are an important group of pathogens causing emerging and re-emerging diseases. We investigated the ability of genomic RNAs from substantial representatives of this virus group to induce interferon via RIG-I or MDA5. RNAs isolated from particles of Ebola virus, Nipah virus, Lassa virus, and Rift Valley fever virus strongly activated the interferon-beta promoter. Knockdown experiments demonstrated that interferon induction depended on RIG-I, but not MDA5, and phosphatase treatment revealed a requirement for the RNA 5' triphosphate group. In contrast, genomic RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus did not trigger interferon induction. Sensitivity of these RNAs to a 5' monophosphate-specific exonuclease indicates that the RIG-I-activating 5' triphosphate group was removed post transcriptionally by a viral function. Consequently, RIG-I is unable to bind the RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus. These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses and define the cleavage of triphosphates at the RNA 5' end as a strategy of viruses to evade the innate immune response. PMID- 18446222 TI - In silico and biochemical analysis of Physcomitrella patens photosynthetic antenna: identification of subunits which evolved upon land adaptation. AB - BACKGROUND: In eukaryotes the photosynthetic antenna system is composed of subunits encoded by the light harvesting complex (Lhc) multigene family. These proteins play a key role in photosynthesis and are involved in both light harvesting and photoprotection. The moss Physcomitrella patens is a member of a lineage that diverged from seed plants early after land colonization and therefore by studying this organism, we may gain insight into adaptations to the aerial environment. PRINCIPAL FINDINGS: In this study, we characterized the antenna protein multigene family in Physcomitrella patens, by sequence analysis as well as biochemical and functional investigations. Sequence identification and analysis showed that some antenna polypeptides, such as Lhcb3 and Lhcb6, are present only in land organisms, suggesting they play a role in adaptation to the sub-aerial environment. Our functional analysis which showed that photo protective mechanisms in Physcomitrella patens are very similar to those in seed plants fits with this hypothesis. In particular, Physcomitrella patens also activates Non Photochemical Quenching upon illumination, consistent with the detection of an ortholog of the PsbS protein. As a further adaptation to terrestrial conditions, the content of Photosystem I low energy absorbing chlorophylls also increased, as demonstrated by differences in Lhca3 and Lhca4 polypeptide sequences, in vitro reconstitution experiments and low temperature fluorescence spectra. CONCLUSIONS: This study highlights the role of Lhc family members in environmental adaptation and allowed proteins associated with mechanisms of stress resistance to be identified within this large family. PMID- 18446223 TI - Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. AB - BACKGROUND: Modifications of the histone amino-terminal tails affect access of regulatory factors and complexes to chromatin and thereby influence biological processes. Cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications. However, the functional roles of the histone methyltransferases (HMT) in cancer remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: We studied RNAi-based inhibition (knockdown, KD) of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the 2 HMTs in PC3 cancer cell line markedly inhibited cell growth and caused profound morphological changes with loss of telomerase activity and shortened telomeres. SUV39H1 KD cells showed substantial increase in G2/M fraction. G9a KD cells showed increased DNA content (1.7-fold in 2 independent clones) compared with FACS analyses to control. Karyotype analyses showed that this was due to an increased number of chromosomes (from 61 to 102) in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in about 25% of the G9a KD cells, while centrosomes were morphologically normal in control cells. Microarray analyses after KD of SUV39H1 or G9a showed very few genes up-regulated among the 39,000 genes. The silenced tumor-suppressor genes p16 and RASSF1A were not activated in KD cells. CONCLUSIONS/SIGNIFICANCE: These data suggest that the 2 HMTs, SUV39H1 and G9a are required to perpetuate the malignant phenotype. Furthermore, G9a plays a critical role in regulating centrosome duplication presumably through chromatin structure rather than through affecting gene expression in cancer cells. Targeting these histone methyltransferases may be of therapeutic benefit in cancers. PMID- 18446224 TI - Ecologic niche modeling of Blastomyces dermatitidis in Wisconsin. AB - BACKGROUND: Blastomycosis is a potentially fatal mycosis that is acquired by inhaling infectious spores of Blastomyces dermatitidis present in the environment. The ecology of this pathogen is poorly understood, in part because it has been extremely difficult to identify the niche(s) it occupies based on culture isolation of the organism from environmental samples. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the ecology of blastomycosis by performing maximum entropy modeling of exposure sites from 156 cases of human and canine blastomycosis to provide a regional-scale perspective of the geographic and ecologic distribution of B. dermatitidis in Wisconsin. Based on analysis with climatic, topographic, surface reflectance and other environmental variables, we predicted that ecologic conditions favorable for maintaining the fungus in nature occur predominantly within northern counties and counties along the western shoreline of Lake Michigan. Areas of highest predicted occurrence were often in proximity to waterways, especially in northcentral Wisconsin, where incidence of infection is highest. Ecologic conditions suitable for B. dermatitidis are present in urban and rural environments, and may differ at the extremes of distribution of the species in the state. CONCLUSIONS/SIGNIFICANCE: Our results provide a framework for a more informed search for specific environmental factors modulating B. dermatitidis occurrence and transmission and will be useful for improving public health awareness of relative exposure risks. PMID- 18446225 TI - The impact of the absence of aliphatic glucosinolates on insect herbivory in Arabidopsis. AB - Aliphatic glucosinolates are compounds which occur in high concentrations in Arabidopsis thaliana and other Brassicaceae species. They are important for the resistance of the plant to pest insects. Previously, the biosynthesis of these compounds was shown to be regulated by transcription factors MYB28 and MYB29. We now show that MYB28 and MYB29 are partially redundant, but in the absence of both, the synthesis of all aliphatic glucosinolates is blocked. Untargeted and targeted biochemical analyses of leaf metabolites showed that differences between single and double knock-out mutants and wild type plants were restricted to glucosinolates. Biosynthesis of long-chain aliphatic glucosinolates was blocked by the myb28 mutation, while short-chain aliphatic glucosinolates were reduced by about 50% in both the myb28 and the myb29 single mutants. Most remarkably, all aliphatic glucosinolates were completely absent in the double mutant. Expression of glucosinolate biosynthetic genes was slightly but significantly reduced by the single myb mutations, while the double mutation resulted in a drastic decrease in expression of these genes. Since the myb28myb29 double mutant is the first Arabidopsis genotype without any aliphatic glucosinolates, we used it to establish the relevance of aliphatic glucosinolate biosynthesis to herbivory by larvae of the lepidopteran insect Mamestra brassicae. Plant damage correlated inversely to the levels of aliphatic glucosinolates observed in those plants: Larval weight gain was 2.6 fold higher on the double myb28myb29 mutant completely lacking aliphatic glucosinolates and 1.8 higher on the single mutants with intermediate levels of aliphatic glucosinolates compared to wild type plants. PMID- 18446226 TI - Echolocating bats cry out loud to detect their prey. AB - Echolocating bats have successfully exploited a broad range of habitats and prey. Much research has demonstrated how time-frequency structure of echolocation calls of different species is adapted to acoustic constraints of habitats and foraging behaviors. However, the intensity of bat calls has been largely neglected although intensity is a key factor determining echolocation range and interactions with other bats and prey. Differences in detection range, in turn, are thought to constitute a mechanism promoting resource partitioning among bats, which might be particularly important for the species-rich bat assemblages in the tropics. Here we present data on emitted intensities for 11 species from 5 families of insectivorous bats from Panama hunting in open or background cluttered space or over water. We recorded all bats in their natural habitat in the field using a multi-microphone array coupled with photographic methods to assess the bats' position in space to estimate emitted call intensities. All species emitted intense search signals. Output intensity was reduced when closing in on background by 4-7 dB per halving of distance. Source levels of open space and edge space foragers (Emballonuridae, Mormoopidae, Molossidae, and Vespertilionidae) ranged between 122-134 dB SPL. The two Noctilionidae species hunting over water emitted the loudest signals recorded so far for any bat with average source levels of ca. 137 dB SPL and maximum levels above 140 dB SPL. In spite of this ten-fold variation in emitted intensity, estimates indicated, surprisingly, that detection distances for prey varied far less; bats emitting the highest intensities also emitted the highest frequencies, which are severely attenuated in air. Thus, our results suggest that bats within a local assemblage compensate for frequency dependent attenuation by adjusting the emitted intensity to achieve comparable detection distances for prey across species. We conclude that for bats with similar hunting habits, prey detection range represents a unifying constraint on the emitted intensity largely independent of call shape, body size, and close phylogenetic relationships. PMID- 18446229 TI - A pre-Hispanic head. AB - This report on a male head revealed biologic rhythms, as gleaned from hydrogen isotope ratios in hair, consistent with a South-American origin and Atomic Mass Spectrometry radiocarbon dating (AMS) compatible with the last pre-Hispanic period (1418-1491 AD, 95.4% probability). Biopsies showed exceptionally well preserved tissues. The hair contained high levels of toxic elements (lead, arsenic and mercury) incompatible with life. There was no evidence for lead deposition in bone consistent with post-mortem accumulation of this toxic element in the hair. We propose that the high content of metals in hair was the result of metabolic activity of bacteria leading to metal complexation in extra cellular polymeric substances (EPS). This is a recognized protective mechanism for bacteria that thrive in toxic environments. This mechanism may account for the tissues preservation and gives a hint at soil composition where the head was presumably buried. Our results have implications for forensic toxicology which has, hitherto, relied on hair analyses as one means to reconstruct pre-mortem metabolism and for detecting toxic elements accumulated during life. Our finding also has implications for other archaeological specimens where similar circumstances may distort the results of toxicological studies. PMID- 18446228 TI - Attomolar detection of botulinum toxin type A in complex biological matrices. AB - BACKGROUND: A highly sensitive, rapid and cost efficient method that can detect active botulinum neurotoxin (BoNT) in complex biological samples such as foods or serum is desired in order to 1) counter the potential bioterrorist threat 2) enhance food safety 3) enable future pharmacokinetic studies in medical applications that utilize BoNTs. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a botulinum neurotoxin serotype A assay with a large immuno-sorbent surface area (BoNT/A ALISSA) that captures a low number of toxin molecules and measures their intrinsic metalloprotease activity with a fluorogenic substrate. In direct comparison with the "gold standard" mouse bioassay, the ALISSA is four to five orders of magnitudes more sensitive and considerably faster. Our method reaches attomolar sensitivities in serum, milk, carrot juice, and in the diluent fluid used in the mouse assay. ALISSA has high specificity for the targeted type A toxin when tested against alternative proteases including other BoNT serotypes and trypsin, and it detects the holotoxin as well as the multi-protein complex form of BoNT/A. The assay was optimized for temperature, substrate concentration, size and volume proportions of the immuno-sorbent matrix, enrichment and reaction times. Finally, a kinetic model is presented that is consistent with the observed improvement in sensitivity. CONCLUSIONS/SIGNIFICANCE: The sensitivity, specificity, speed and simplicity of the BoNT ALISSA should make this method attractive for diagnostic, biodefense and pharmacological applications. PMID- 18446227 TI - Relief of preintegration inhibition and characterization of additional blocks for HIV replication in primary mouse T cells. AB - Development of a small animal model to study HIV replication and pathogenesis has been hampered by the failure of the virus to replicate in non-primate cells. Most studies aimed at achieving replication in murine cells have been limited to fibroblast cell lines, but generating an appropriate model requires overcoming blocks to viral replication in primary T cells. We have studied HIV-1 replication in CD4(+) T cells from human CD4/CCR5/Cyclin T1 transgenic mice. Expression of hCD4 and hCCR5 in mouse CD4(+) T cells enabled efficient entry of R5 strain HIV 1. In mouse T cells, HIV-1 underwent reverse transcription and nuclear import as efficiently as in human T cells. In contrast, chromosomal integration of HIV-1 proviral DNA was inefficient in activated mouse T cells. This process was greatly enhanced by providing a secondary T cell receptor (TCR) signal after HIV-1 infection, especially between 12 to 24 h post infection. This effect was specific for primary mouse T cells. The pathways involved in HIV replication appear to be PKCtheta-, CARMA1-, and WASp-independent. Treatment with Cyclosporin A (CsA) further relieved the pre-integration block. However, transcription of HIV-1 RNA was still reduced in mouse CD4(+) T cells despite expression of the hCyclin T1 transgene. Additional post-transcriptional defects were observed at the levels of Gag expression, Gag processing, Gag release and virus infectivity. Together, these post-integration defects resulted in a dramatically reduced yield of infectious virus (300-500 fold) after a single cycle of HIV-1 replication. This study implies the existence of host factors, in addition to those already identified, that are critical for HIV-1 replication in mouse cells. This study also highlights the differences between primary T cells and cell lines regarding pre-integration steps in the HIV-1 replication cycle. PMID- 18446230 TI - What happens to patients on antiretroviral therapy who transfer out to another facility? AB - BACKGROUND: Long term retention of patients on antiretroviral therapy (ART) in Africa's rapidly expanding programmes is said to be 60% at 2 years. Many reports from African ART programmes make little mention of patients who are transferred out to another facility, yet Malawi's national figures show a transfer out of 9%. There is no published information about what happens to patients who transfer out, but this is important because if they transfer-in and stay alive in these other facilities then national retention figures will be better than previously reported. METHODOLOGY/PRINCIPAL FINDINGS: Of all patients started on ART over a three year period in Mzuzu Central Hospital, North Region, Malawi, those who transferred out were identified from the ART register and master cards. Clinic staff attempted to trace these patients to determine whether they had transferred in to a new ART facility and their outcome status. There were 805 patients (19% of the total cohort) who transferred out, of whom 737 (92%) were traced as having transferred in to a new ART facility, with a median time of 1.3 months between transferring-out and transferring-in. Survival probability was superior and deaths were lower in the transfer-out patients compared with those who did not transfer. CONCLUSION/SIGNIFICANCE: In Mzuzu Central Hospital, patients who transfer-out constitute a large proportion of patients not retained on ART at their original clinic of registration. Good documentation of transfer-outs and transfer-ins are needed to keep track of national outcomes. Furthermore, the current practice of regarding transfer-outs as being double counted in national cohorts and subtracting this number from the total national registrations to get the number of new patients started on ART is correct. PMID- 18446231 TI - Ionic mechanisms of endogenous bursting in CA3 hippocampal pyramidal neurons: a model study. AB - A critical property of some neurons is burst firing, which in the hippocampus plays a primary role in reliable transmission of electrical signals. However, bursting may also contribute to synchronization of electrical activity in networks of neurons, a hallmark of epilepsy. Understanding the ionic mechanisms of bursting in a single neuron, and how mutations associated with epilepsy modify these mechanisms, is an important building block for understanding the emergent network behaviors. We present a single-compartment model of a CA3 hippocampal pyramidal neuron based on recent experimental data. We then use the model to determine the roles of primary depolarizing currents in burst generation. The single compartment model incorporates accurate representations of sodium (Na(+)) channels (Na(V)1.1) and T-type calcium (Ca(2+)) channel subtypes (Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3). Our simulations predict the importance of Na(+) and T type Ca(2+) channels in hippocampal pyramidal cell bursting and reveal the distinct contribution of each subtype to burst morphology. We also performed fast slow analysis in a reduced comparable model, which shows that our model burst is generated as a result of the interaction of two slow variables, the T-type Ca(2+) channel activation gate and the Ca(2+)-dependent potassium (K(+)) channel activation gate. The model reproduces a range of experimentally observed phenomena including afterdepolarizing potentials, spike widening at the end of the burst, and rebound. Finally, we use the model to simulate the effects of two epilepsy-linked mutations: R1648H in Na(V)1.1 and C456S in Ca(V)3.2, both of which result in increased cellular excitability. PMID- 18446232 TI - Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling. AB - DNA hypermethylation is a common epigenetic abnormality in cancer and may serve as a useful marker to clone cancer-related genes as well as a marker of clinical disease activity. To identify CpG islands methylated in prostate cancer, we used methylated CpG island amplification (MCA) coupled with representational difference analysis (RDA) on prostate cancer cell lines. We isolated 34 clones that corresponded to promoter CpG islands, including 5 reported targets of hypermethylation in cancer. We confirmed the data for 17 CpG islands by COBRA and/or pyrosequencing. All 17 genes were methylated in at least 2 cell lines of a 21-cancer cell line panel containing prostate cancer, colon cancer, leukemia, and breast cancer. Based on methylation in primary tumors compared to normal adjacent tissues, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS and NSE1 are candidate biomarkers for prostate cancer (methylation range 50%-85%). The combination of NSE1 or SPOCK2 hypermethylation showed a sensitivity of 80% and specificity of 95% in differentiating cancer from normal. Similarly NKX2-5, SPOCK2, SLC16A12, DPYS and GALR2 are candidate biomarkers for colon cancer (methylation range 60%-95%) and GALR2 hypermethylation showed a sensitivity of 85% and specificity of 95%. Finally, SLC16A12, GALR2, TOX, SPOCK2, EGFR5 and DPYS are candidate biomarkers for breast cancer (methylation range 33%-79%) with the combination of EGFR5 or TOX hypermethylation showing a sensitivity of 92% and specificity of 92%. Expression analysis for eight genes that had the most hypermethylation confirmed the methylation associated silencing and reactivation with 5-aza-2'-deoxycytidine treatment. Our data identify new targets of transcriptional silencing in cancer, and provide new biomarkers that could be useful in screening for prostate cancer and other cancers. PMID- 18446233 TI - Pancreatic insulin content regulation by the estrogen receptor ER alpha. AB - The function of pancreatic beta-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ER alpha and ER beta, are important molecules involved in glucose metabolism, yet their role in pancreatic beta-cell physiology is still greatly unknown. In this report we show that both ER alpha and ER beta are present in pancreatic beta cells. Long term exposure to physiological concentrations of 17beta-estradiol (E2) increased beta-cell insulin content, insulin gene expression and insulin release, yet pancreatic beta-cell mass was unaltered. The up-regulation of pancreatic beta-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ER alpha and ER beta agonists as well as ER alphaKO and ER betaKO mice suggests that the estrogen receptor involved is ER alpha. The up-regulation of pancreatic insulin content by ER alpha activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis. PMID- 18446234 TI - ZAP-70 restoration in mice by in vivo thymic electroporation. AB - Viral and non-viral vectors have been developed for gene therapy, but their use is associated with unresolved problems of efficacy and safety. Efficient and safe methods of DNA delivery need to be found for medical application. Here we report a new monopolar system of non-viral electro-gene transfer into the thymus in vivo that consists of the local application of electrical pulses after the introduction of the DNA. We assessed the proof of concept of this approach by correcting ZAP-70 deficient severe combined immunodeficiency (SCID) in mice. The thymic electro-gene transfer of the pCMV-ZAP-70-IRES-EGFP vector in these mice resulted in rapid T cell differentiation in the thymus with mature lymphocytes detected by three weeks in secondary lymphoid organs. Moreover, this system resulted in the generation of long-term functional T lymphocytes. Peripheral reconstituted T cells displayed a diversified T cell receptor (TCR) repertoire, and were responsive to alloantigens in vivo. This process applied to the thymus could represent a simplified and effective alternative for gene therapy of T cell immunodeficiencies. PMID- 18446235 TI - The Nod-like receptor (NLR) family: a tale of similarities and differences. AB - Innate immunity represents an important system with a variety of vital processes at the core of many diseases. In recent years, the central role of the Nod-like receptor (NLR) protein family became increasingly appreciated in innate immune responses. NLRs are classified as part of the signal transduction ATPases with numerous domains (STAND) clade within the AAA+ ATPase family. They typically feature an N-terminal effector domain, a central nucleotide-binding domain (NACHT) and a C-terminal ligand-binding region that is composed of several leucine-rich repeats (LRRs). NLRs are believed to initiate or regulate host defense pathways through formation of signaling platforms that subsequently trigger the activation of inflammatory caspases and NF-kB. Despite their fundamental role in orchestrating key pathways in innate immunity, their mode of action in molecular terms remains largely unknown. Here we present the first comprehensive sequence and structure modeling analysis of NLR proteins, revealing that NLRs possess a domain architecture similar to the apoptotic initiator protein Apaf-1. Apaf-1 performs its cellular function by the formation of a heptameric platform, dubbed apoptosome, ultimately triggering the controlled demise of the affected cell. The mechanism of apoptosome formation by Apaf-1 potentially offers insight into the activation mechanisms of NLR proteins. Multiple sequence alignment analysis and homology modeling revealed Apaf-1-like structural features in most members of the NLR family, suggesting a similar biochemical behaviour in catalytic activity and oligomerization. Evolutionary tree comparisons substantiate the conservation of characteristic functional regions within the NLR family and are in good agreement with domain distributions found in distinct NLRs. Importantly, the analysis of LRR domains reveals surprisingly low conservation levels among putative ligand-binding motifs. The same is true for the effector domains exhibiting distinct interfaces ensuring specific interactions with downstream target proteins. All together these factors suggest specific biological functions for individual NLRs. PMID- 18446236 TI - Of mice, cattle, and humans: the immunology and treatment of river blindness. AB - River blindness is a seriously debilitating disease caused by the filarial parasite Onchocerca volvulus, which infects millions in Africa as well as in South and Central America. Research has been hampered by a lack of good animal models, as the parasite can only develop fully in humans and some primates. This review highlights the development of two animal model systems that have allowed significant advances in recent years and hold promise for the future. Experimental findings with Litomosoides sigmodontis in mice and Onchocerca ochengi in cattle are placed in the context of how these models can advance our ability to control the human disease. PMID- 18446237 TI - An analysis of the abstracts presented at the annual meetings of the Society for Neuroscience from 2001 to 2006. AB - Annual meeting abstracts published by scientific societies often contain rich arrays of information that can be computationally mined and distilled to elucidate the state and dynamics of the subject field. We extracted and processed abstract data from the Society for Neuroscience (SFN) annual meeting abstracts during the period 2001-2006 in order to gain an objective view of contemporary neuroscience. An important first step in the process was the application of data cleaning and disambiguation methods to construct a unified database, since the data were too noisy to be of full utility in the raw form initially available. Using natural language processing, text mining, and other data analysis techniques, we then examined the demographics and structure of the scientific collaboration network, the dynamics of the field over time, major research trends, and the structure of the sources of research funding. Some interesting findings include a high geographical concentration of neuroscience research in the north eastern United States, a surprisingly large transient population (66% of the authors appear in only one out of the six studied years), the central role played by the study of neurodegenerative disorders in the neuroscience community, and an apparent growth of behavioral/systems neuroscience with a corresponding shrinkage of cellular/molecular neuroscience over the six year period. The results from this work will prove useful for scientists, policy makers, and funding agencies seeking to gain a complete and unbiased picture of the community structure and body of knowledge encapsulated by a specific scientific domain. PMID- 18446239 TI - Genomic diversity and evolution of the lyssaviruses. AB - Lyssaviruses are RNA viruses with single-strand, negative-sense genomes responsible for rabies-like diseases in mammals. To date, genomic and evolutionary studies have most often utilized partial genome sequences, particularly of the nucleoprotein and glycoprotein genes, with little consideration of genome-scale evolution. Herein, we report the first genomic and evolutionary analysis using complete genome sequences of all recognised lyssavirus genotypes, including 14 new complete genomes of field isolates from 6 genotypes and one genotype that is completely sequenced for the first time. In doing so we significantly increase the extent of genome sequence data available for these important viruses. Our analysis of these genome sequence data reveals that all lyssaviruses have the same genomic organization. A phylogenetic analysis reveals strong geographical structuring, with the greatest genetic diversity in Africa, and an independent origin for the two known genotypes that infect European bats. We also suggest that multiple genotypes may exist within the diversity of viruses currently classified as 'Lagos Bat'. In sum, we show that rigorous phylogenetic techniques based on full length genome sequence provide the best discriminatory power for genotype classification within the lyssaviruses. PMID- 18446238 TI - High distribution of CD40 and TRAF2 in Th40 T cell rafts leads to preferential survival of this auto-aggressive population in autoimmunity. AB - BACKGROUND: CD40-CD154 interactions have proven critical in autoimmunity, with the identification of CD4(lo)CD40(+) T cells (Th40 cells) as harboring an autoaggressive T cell population shedding new insights into those disease processes. Th40 cells are present at contained levels in non-autoimmune individuals but are significantly expanded in autoimmunity. Th40 cells are necessary and sufficient in transferring type 1 diabetes in mouse models. However, little is known about CD40 signaling in T cells and whether there are differences in that signaling and subsequent outcome depending on disease conditions. When CD40 is engaged, CD40 and TNF-receptor associated factors, TRAFs, become associated with lipid raft microdomains. Dysregulation of T cell homeostasis is emerging as a major contributor to autoimmune disease and thwarted apoptosis is key in breaking homeostasis. METHODOLOGY/PRINCIPAL FINDINGS: Cells were sorted into CD4(hi) and CD4(lo) (Th40 cells) then treated and assayed either as whole or fractionated cell lysates. Protein expression was assayed by western blot and Nf-kappaB DNA-binding activity by electrophoretic mobility shifts. We demonstrate here that autoimmune NOD Th40 cells have drastically exaggerated expression of CD40 on a per-cell-basis compared to non-autoimmune BALB/c. Immediately ex-vivo, untreated Th40 cells from NOD mice have high levels of CD40 and TRAF2 associated with the raft microdomain while Th40 cells from NOR and BALB/c mice do not. CD40 engagement of Th40 cells induces Nf-kappaB DNA-binding activity and anti-apoptotic Bcl-X(L) expression in all three mouse strains. However, only in NOD Th40 cells is anti-apoptotic cFLIP(p43) induced which leads to preferential survival and proliferation. Importantly, CD40 engagement rescues NOD Th40 cells from Fas-induced death. CONCLUSIONS/SIGNIFICANCE: CD40 may act as a switch between life and death promoting signals and NOD Th40 cells are poised for survival via this switch. This may explain how they expand in autoimmunity to thwart T cell homeostasis. PMID- 18446240 TI - Single bead affinity detection (SINBAD) for the analysis of protein-protein interactions. AB - We present a miniaturized pull-down method for the detection of protein-protein interactions using standard affinity chromatography reagents. Binding events between different proteins, which are color-coded with quantum dots (QDs), are visualized on single affinity chromatography beads by fluorescence microscopy. The use of QDs for single molecule detection allows the simultaneous analysis of multiple protein-protein binding events and reduces the amount of time and material needed to perform a pull-down experiment. PMID- 18446241 TI - Rescue of salivary gland function after stem cell transplantation in irradiated glands. AB - Head and neck cancer is the fifth most common malignancy and accounts for 3% of all new cancer cases each year. Despite relatively high survival rates, the quality of life of these patients is severely compromised because of radiation induced impairment of salivary gland function and consequential xerostomia (dry mouth syndrome). In this study, a clinically applicable method for the restoration of radiation-impaired salivary gland function using salivary gland stem cell transplantation was developed. Salivary gland cells were isolated from murine submandibular glands and cultured in vitro as salispheres, which contained cells expressing the stem cell markers Sca-1, c-Kit and Musashi-1. In vitro, the cells differentiated into salivary gland duct cells and mucin and amylase producing acinar cells. Stem cell enrichment was performed by flow cytrometric selection using c-Kit as a marker. In vitro, the cells differentiated into amylase producing acinar cells. In vivo, intra-glandular transplantation of a small number of c-Kit(+) cells resulted in long-term restoration of salivary gland morphology and function. Moreover, donor-derived stem cells could be isolated from primary recipients, cultured as secondary spheres and after re transplantation ameliorate radiation damage. Our approach is the first proof for the potential use of stem cell transplantation to functionally rescue salivary gland deficiency. PMID- 18446243 TI - Effect of Coriolis coupling in chemical reaction dynamics. AB - It is essential to evaluate the role of Coriolis coupling effect in molecular reaction dynamics. Here we consider Coriolis coupling effect in quantum reactive scattering calculations in the context of both adiabaticity and nonadiabaticity, with particular emphasis on examining the role of Coriolis coupling effect in reaction dynamics of triatomic molecular systems. We present the results of our own calculations by the time-dependent quantum wave packet approach for H + D2 and F(2P3/2,2P1/2) + H2 as well as for the ion-molecule collisions of He + H2 +, D(-) + H2, H(-) + D2, and D+ + H2, after reviewing in detail other related research efforts on this issue. PMID- 18446242 TI - A minimal fragment of MUC1 mediates growth of cancer cells. AB - The MUC1 protein is aberrantly expressed on many solid tumor cancers. In contrast to its apical clustering on healthy epithelial cells, it is uniformly distributed over cancer cells. However, a mechanistic link between aberrant expression and cancer has remained elusive. Herein, we report that a membrane-bound MUC1 cleavage product, that we call MUC1*, is the predominant form of the protein on cultured cancer cells and on cancerous tissues. Further, we demonstrate that transfection of a minimal fragment of MUC1, MUC1*(1110), containing a mere forty five (45) amino acids of the extracellular domain, is sufficient to confer the oncogenic activities that were previously attributed to the full-length protein. By comparison of molecular weight and function, it appears that MUC1* and MUC1*(1110) are approximately equivalent. Evidence is presented that strongly supports a mechanism whereby dimerization of the extracellular domain of MUC1* activates the MAP kinase signaling cascade and stimulates cell growth. These findings suggest methods to manipulate this growth mechanism for therapeutic interventions in cancer treatments. PMID- 18446245 TI - A Kirkwood-Buff analysis of local properties of solutions. AB - For decades, the properties of liquid mixtures have been analyzed in terms of excess thermodynamic functions. These functions convey global or macroscopic information on the system. In this work, a complementary view, based on the local properties of the same system is suggested. These properties are richer and more informative regarding the local densities, composition and solvation effect. A few examples ranging from Lennard-Jones particles, to inert gas mixtures, to aqueous solutions are presented, stressing the local information that cannot be obtained directly from global properties. PMID- 18446244 TI - Description of pentacoordinated phosphorus under an external electric field: which basis sets and semi-empirical methods are needed? AB - Phosphate transfer reactions are ubiquitous in nature and play fundamental roles in ATP hydrolysis and protein phosphorylation processes. The mechanisms of these reactions involve a pentacoordinated phosphorus atom that can be an intermediate or a transition state. These structures are very sensitive to both internal and external electrostatic effects and their description with quantum mechanical methods is challenging. We have investigated the variations of geometry an energetics under an external electric field for two different molecules and their transition states of formation. The DFT method, with the mPW1PW91 functional employing several basis sets, and different semi-empirical methods have been tested. Compared to zero-field cases, one needs more extended basis sets to achieve the same precision. A good compromise for large systems is the 6-31+G(d). Many semi-empirical methods are unable to describe polarisation effects in pentacoordinated structures. The best methods to describe geometries are PM6 and AM1/d-PhoT and for energetics AM1/d-PhoT. Methods without d orbitals have poorer performances but the best among those is the AM1 parametrization of Arantes et al (Phys. Chem. Chem. Phys., 2006, 8, 347). PMID- 18446246 TI - Aromaticity in cyclic alkali clusters. AB - Density functional calculations on a hexagonal 1D sodium cluster and a 2D potassium cluster show that the M6 (M = Na, K) rings in the chain present in 3D [Na2MoO3L(H2O)2]n (1) and 2D [K2MoO3L(H2O)3]n (2) are aromatic in character according to the nucleus independent chemical shift (NICS) and multicenter bond indices (MCI) values. The NICS values at the center of the Na6 rings and at the cage center of the K6 rings are comparable to the corresponding values of their polyacene analogues in most cases. The stability and reactivity patterns of the M6 rings also follow a similar trend as their organic analogues. PMID- 18446247 TI - A computational study of the intramolecular deprotonation of a carbon acid in aqueous solution. AB - Proton transfer reactions are the rate-limiting steps in many biological and synthetic chemical processes, often requiring complex cofactors or catalysts to overcome the generally unfavourable thermodynamic process of carbanion intermediate formation. It has been suggested that quantum tunnelling processes enhance the kinetics of some of these reactions, which when coupled to protein motions may be an important consideration for enzyme catalysis. To obtain a better fundamental and quantitative understanding of these proton transfer mechanisms, a computational analysis of the intramolecular proton transfer from a carbon acid in the small molecule, 4-nitropentanoic acid, in aqueous solution is presented. Potential-energy surfaces from gas-phase, implicit and QM/MM (quantum mechanical/molecular mechanical) explicit solvation quantum chemistry models are compared, and the potential of mean force, for the full reaction coordinate, using umbrella-sampling molecular dynamics is analysed. Semi-classical multidimensional tunnelling corrections are also used to estimate the quantum tunnelling contributions and to understand the origin of the primary deuterium kinetic isotope effects (KIEs). The computational results are found to be in excellent agreement with the KIEs and the energetics obtained experimentally. PMID- 18446248 TI - Structural effects of Cu(II)-coordination in the octapeptide region of the human prion protein. AB - The copper-binding ability of the prion protein is thought to be central to its function. The structural effects of copper coordination in the octapeptide region of the human prion protein have been investigated by molecular dynamics simulations. Simulations were performed with the apo state, in order to investigate the behavior of the region without copper ions, as well as with the octapeptide region in the presence of copper ions. While the structure of the apo state is greatly influenced by the interaction between the rings in the histidine, tryptophan and proline residues, the region shows evidence of highly ordered coordination sites in the presence of copper ions. The position of the tryptophan indole ring is stabilized by cation-pi interactions. Two stable orientations of the indole ring with respect to the equatorial coordination plane of copper were observed, which showed that the indole ring can reside on both sides of the coordination plane. The interaction with the indole ring was found to occur without a mediating axial water molecule. PMID- 18446249 TI - Spectroscopic study of the Ne-Xe-NH3 van der Waals trimer. AB - Rotational spectra of the Ne-Xe-NH3 van der Waals trimer were recorded using a pulsed-nozzle, Fourier transform microwave spectrometer. Both a- and b-type transitions of eight isotopologues, namely 20Ne-132Xe-14NH3, 20Ne-129Xe-14NH3, 20Ne-132Xe-15NH3, 20Ne-129Xe-15NH3, 20Ne-131Xe-15NH3, 22Ne-132Xe-15NH3, 22Ne 129Xe-15NH3, and 22Ne-131Xe-15NH3 were measured and assigned. Nuclear quadrupole hyperfine structures arising from the 14N (nuclear spin quantum number I = 1) and 131Xe (I = 3/2) nuclei were detected and analyzed. The determined rotational constants were used to fit structural parameters. A harmonic force field analysis was performed based on centrifugal distortion constants to extract information about vibrational motions of the complex. A comparison of van der Waals bond lengths and stretching force constants between the Ne-Xe-NH3 trimer and the corresponding dimers indicates that non-additive three-body effects are present in the trimer system. Analyses of the 14N and 131Xe nuclear quadrupole coupling constants suggest that the NH3 unit undergoes nearly free internal rotation within the complex and that the presence of Ne has little effect on the orientation of NH3 with respect to the Xe atom. PMID- 18446250 TI - Adsorption of fibrinogen on a biomedical-grade stainless steel 316LVM surface: a PM-IRRAS study of the adsorption thermodynamics, kinetics and secondary structure changes. AB - Polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS) was employed to investigate the interaction of serum protein fibrinogen with a biomedical-grade 316LVM stainless steel surface, in terms of the adsorption thermodynamics, kinetics and secondary structure changes of the protein. Apparent Gibbs energy of adsorption values indicated a highly spontaneous and strong adsorption of fibrinogen onto the surface. The kinetics of fibrinogen adsorption were successfully modeled using a pseudo first-order kinetic model. Deconvolution of the amide I bands indicated that the adsorption of fibrinogen on 316LVM results in significant changes in the protein's secondary structure that occur predominantly within the first minute of adsorption. Among the investigated structures, the alpha-helix structure undergoes the smallest changes, while the beta-sheet and beta-turns structures undergo significant changes. It was shown that lateral interactions between the adsorbed molecules do not play a role in controlling the secondary structure changes. An increase in temperature induced changes in the secondary structure of the protein, characterized by a loss of the alpha-helical content and its transformation into the beta-turns structure. PMID- 18446251 TI - Melting phenomena: effect of composition for 55-atom Ag-Pd bimetallic clusters. AB - Understanding the composition effect on the melting processes of bimetallic clusters is important for their applications. Here, we report the relationship between the melting point and the metal composition for the 55-atom icosahedral Ag-Pd bimetallic clusters by canonical Monte Carlo simulations, using the second moment approximation of the tight-binding potentials (TB-SMA) for the metal-metal interactions. Abnormal melting phenomena for the systems of interest are found. Our simulation results reveal that the dependence of the melting point on the composition is not a monotonic change, but experiences three different stages. The melting temperatures of the Ag-Pd bimetallic clusters increase monotonically with the concentration of the Ag atoms first. Then, they reach a plateau presenting almost a constant value. Finally, they decrease sharply at a specific composition. The main reason for this change can be explained in terms of the relative stability of the Ag-Pd bimetallic clusters at different compositions. The results suggest that the more stable the cluster, the higher the melting point for the 55-atom icosahedral Ag-Pd bimetallic clusters at different compositions. PMID- 18446252 TI - Effect of pore wall model on prediction of diffusion coefficients for graphitic slit pores. AB - The effect of the pore wall model on the self-diffusion coefficient and transport diffusivity predicted for methane in graphitic slit pores by equilibrium molecular dynamics (EMD) and non-equilibrium MD (NEMD) is investigated. Three pore wall models are compared--a structured wall and a smooth (specular) wall, both with a thermostat applied to the fluid to maintain the desired temperature, and a structured wall combined with the diffuse thermalizing scattering algorithm of MacElroy and Boyle (Chem. Eng. J., 1999, 74, 85). Pore sizes ranging between 7 and 35 angstroms and five pressures in the range of 1-40 bar are considered. The diffuse thermalizing wall yields incorrect self-diffusion coefficients and transport diffusivities for the graphitic slit pore model and should not be used. Surprisingly, the smooth specular wall gives self-diffusion coefficients inline with those obtained using the structured wall, indicating that this computationally much faster wall can be used for studying this phenomenon provided the fluid-wall interactions are somewhat weaker than the fluid-fluid interactions. The structured wall is required, however, if the transport diffusivity is of interest. PMID- 18446254 TI - Application of mutually immiscible ionic liquids to the separation of aromatic and aliphatic hydrocarbons by liquid extraction: a preliminary approach. AB - The recently discovered class of ionic liquids--mutually immiscible ionic liquids -are explored in this work for their first practical application: the separation of aromatic and aliphatic hydrocarbons by solvent extraction. For this preliminary approach, benzene and hexane were chosen as representatives of each group of hydrocarbons; the ionic liquids 1-ethyl-3-methylimidazolium bis( (trifluoromethyl)sulfonyl)amide and trihexyl(tetradecyl)phosphonium bis( (trifluoromethyl)sulfonyl)amide, which are both liquid at room temperature and hydrophobic, were selected as potential solvents. Liquid-liquid equilibrium experiments were carried out at 25 degrees C for the quaternary system formed by the two hydrocarbons and the two ionic liquids. Typical extraction parameters were calculated and analysed in order to evaluate the possibilities of the mutual immiscible ionic liquids in accomplishing the separation target. A comparison with the case of using just one of the ionic liquids was made. PMID- 18446253 TI - Which factors determine the acidity of the phytochromobilin chromophore of plant phytochrome? AB - Quantum chemical calculations aimed at identifying the factors controlling the acidity of phytochromobilin, the tetrapyrrole chromophore of the plant photoreceptor phytochrome, are reported. Phytochrome is converted from an inactive (Pr) to an active form (Pfr) through a series of events initiated by a Z --> E photoisomerization of phytochromobilin, forming the Lumi-R intermediate, and much controversy exists as to whether the protonation state of the chromophore (cationic in Pr with all nitrogens protonated) changes during the photoactivation. Here, relative ground (S0) and excited-state (S1) pKa s of all four pyrrole moieties of phytochromobilin in all 64 possible configurations with respect to the three methine bridges are calculated in a protein-like environment, using a recently benchmarked level of theory. Accordingly, the relationships between acidity and chromophore geometry and charge distribution, hydrogen bonding, and light absorption are investigated in some detail, and discussed in terms of possible mechanisms making a proton transfer reaction more probable along the Pr --> Pfr reaction than in the parent cationic Pr state. It is found that charge distribution in the cationic species, intra-molecular hydrogen bonding in the neutral, and hydrogen bonding with two highly conserved aspartate and histidine residues have a significant effect on the acidity, while overall chromophore geometry and electronic state are less important factors. Furthermore, based on the calculations, two processes that may facilitate a proton transfer by substantially lowering the pKa s relative to their Pr values are identified: (i) a thermal Z,anti --> Z,syn isomerization at C5, occurring after formation of Lumi-R; (ii) a perturbation of the hydrogen bonding network which in Pr comprises the nitrogens of pyrroles A, B and C and the two aspartate and histidine residues. PMID- 18446255 TI - Decomposition of hexamethyldisilane on a hot tungsten filament and gas-phase reactions in a hot-wire chemical vapor deposition reactor. AB - To study the effect of an Si-Si bond on gas-phase reaction chemistry in the hot wire chemical vapor deposition (HWCVD) process with a single source alkylsilane molecule, soft ionization with a vacuum ultraviolet wavelength of 118 nm was used with time-of-flight mass spectrometry to examine the products from the primary decomposition of hexamethyldisilane (HMDS) on a heated tungsten (W) filament and from secondary gas-phase reactions in a HWCVD reactor. It is found that both Si Si and Si-C bonds break when HMDS decomposes on the W filament. The dominance of the breakage of Si-Si over Si-C bond has been demonstrated. In the reactor, the abstraction of methyl and H atom, respectively, from the abundant HMDS molecules by the dominant primary trimethylsilyl radicals produces tetramethylsilane (TMS) and trimethylsilane (TriMS). Along with TMS and TriMS, various other alkyl substituted silanes (m/z = 160, 204, 262) and silyl-substituted alkanes (m/z = 218, 276, 290) are also formed from radical combination reactions. With HMDS, an increasing number of Si-Si bonds are found in the gas-phase reaction products aside from the Si-C bond which has been shown to be the major bond connection in the products when TMS is used in the same reactor. Three methyl-substituted 1,3 disilacyclobutane species (m/z = 116, 130, 144) are present in the reactor with HMDS, suggesting a more active involvement from the reactive silene intermediates. PMID- 18446256 TI - Modeling the global potential energy surface of the N + N2 reaction from ab initio data. AB - A new global potential energy surface for the N + N2 exchange reaction has been built from ab initio data. To overcome the difficulty of carrying out ab initio calculations for a large set of geometries the alternative strategy of fitting the minimum energy paths of the surface and their angular dependence using a modified LAGROBO functional form has been adopted. In this way we have been able to reproduce all the main features of the potential using a fairly small set of ab initio values. PMID- 18446257 TI - Decompression syndrome and the evolution of deep diving physiology in the Cetacea. AB - Whales repetitively dive deep to feed and should be susceptible to decompression syndrome, though they are not known to suffer the associated pathologies. Avascular osteonecrosis has been recognized as an indicator of diving habits of extinct marine amniotes. Vertebrae of 331 individual modern and 996 fossil whales were subjected to macroscopic and radiographic examination. Avascular osteonecrosis was found in the Oligocene basal odontocetes (Xenorophoidea) and in geologically younger mysticetes, such as Aglaocetus [a sister taxon to Balaenopteridae + (Balaenidae + Eschrichtiidae) clade]. These are considered as early "experiments" in repetitive deep diving, indicating that they independently converged on their similar specialized diving physiologies. PMID- 18446259 TI - Human cancer risk from the inhalation of formaldehyde in different indoor environments in Guiyang City, China. AB - This study was conducted to estimate the risk of human cancer from the inhalation of formaldehyde in different indoor environments in Guiyang City in China. Offices had the highest mean formaldehyde concentration (0.11 mg/m(3)) and classrooms had the lowest mean formaldehyde concentration (0.04 mg/m(3)). The cancer risk levels in different indoor environments ranged from 6.96 x 10(-6 )to 2.48 x 10(-4) and were greater than the acceptable cancer risk 1 x 10(-6). High human formaldehyde risks imply a critical influence on human health in Guiyang City. The highest cancer risk values occurred in bedrooms (ranging from 1.87 in 10,000 to 2.48 in 10,000). For office workers, offices were the highest risk environment after bedrooms where formaldehyde concentration levels were identified. Students were the most sensitive population, and the highest priority should be given to protecting their health in indoor environments. Regulations and standards for low emission materials and public education in relation to indoor pollution are highly recommended in China to protect human health. PMID- 18446260 TI - Pollution, contamination and future land use at Brookhaven National Laboratory. AB - Scientists interested in contamination normally deal only with pollution itself, not with people's perceptions of pollution or the relationship between pollution and land use. The overall objective of this article was to examine the relationship between people's perceptions of pollution and their views on future land use. People were interviewed at an Earth Day Festival near the Department of Energy's Brookhaven National Laboratory (BNL) on Long Island, New York. On an open-ended question, people thought that BNL should be left as it is, or maintained as a preserve, park or conservation area, or used for environmental research. Almost no one thought that it should be used for housing or industrial purposes. When asked to rate a list of possible future land uses, maintaining BNL as a National Environmental Research Park for research and for recreation were rated the highest (nuclear storage was rated the lowest). This was consistent with the subjects' views that pollution was the greatest concern about BNL. The congruence between perceptions about concerns or problems and future land use preferences suggests a unified view of management of contaminated sites, such as BNL, at least among a group of people whose environmental interests were evident by their presence at the event. PMID- 18446261 TI - A comprehensive genetic study of the proteasomal subunit S6 ATPase in German Parkinson's disease patients. AB - Dysfunction of proteasomal protein degradation is involved in neurodegeneration in Parkinson's disease (PD). Recently we identified the regulatory proteasomal subunit S6 ATPase as a novel interactor of synphilin-1, which is a substrate of the ubiquitin-ligase Parkin (PARK2) and an interacting protein of alpha-synuclein (PARK1). To further investigate a potential role in the pathogenesis of PD, we performed a detailed mutation analysis of the S6 ATPase gene in a large sample of 486 German sporadic and familial PD patients. Direct sequencing revealed two novel intronic variants. An insertion/deletion variant in intron 5 of the S6 ATPase gene was more frequent in patients compared to controls. Moreover, this variant was significantly more frequent in early-onset compared to late-onset PD patients. The identification of a genetic link between a regulatory proteasomal subunit and PD further underscores the relevance of disturbed protein degradation in PD. PMID- 18446262 TI - The Janus-face kynurenic acid. AB - Kynurenic acid is an endogenous product of the tryptophan metabolism. Studies on the mechanism of its action have revealed that kynurenic acid at high concentrations is a competitive antagonist of the N-methyl-D-aspartate receptor and acts as a neuroprotectant in different neurological disorders. This in vitro investigation was designed to show that kynurenic acid acts differently at low concentrations. In vitro electrophysiological examinations on the young rat hippocampus confirmed the well-known finding that kynurenic acid in micromolar concentrations exerts an inhibitory effect. However, in nanomolar concentrations, kynurenic acid does not give rise to inhibition, but in fact facilitates the field excitatory postsynaptic potentials. The results available so far are compatible with the idea that kynurenic acid in the concentration range between a few hundred nanomolar and micromolar displays different effects. Its probable action on different receptors, inducing the different mechanisms, is discussed. The findings strongly suggest the neuromodulatory role of kynurenic acid under both physiological and pathological circumstances. PMID- 18446263 TI - Transmission disequilibrium studies in early onset of obsessive-compulsive disorder for polymorphisms in genes of the dopaminergic system. AB - The dopaminergic system has been shown to be involved in the aetiology of obsessive-compulsive disorder (OCD). Family studies suggest a higher genetic loading in patients with early onset OCD. Our investigation is the first family based association study concerning polymorphisms in genes of the dopaminergic system in early onset OCD. We studied polymorphisms within the dopamine-4 receptor gene (DRD4), the dopamine transporter gene (DAT1) and the catecholamine O-methyltransferase gene (COMT). Associations of alleles of DRD4 and COMT with OCD have previously been reported in adults, while a trend towards an association was found for DAT1 alleles. In our study we observed transmission disequilibrium for the 48-bp repeat polymorphism of the DRD4 gene using the ETDT (P=0.047) in 69 trios comprising patients with early onset OCD and both of their parents. Post hoc TDT analysis of the DRD4 showed reduced transmission of the 4-repeat allele and a slightly increased transmission rate for the 7- and the 2-repeat allele. No evidence of transmission disequilibrium was detected for alleles of the DAT1 and COMT polymorphisms. These polymorphisms do not appear to play a major role in the genetic predisposition to early onset OCD in our study group. PMID- 18446264 TI - MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats. AB - The effect of MKC-231 on acetylcholine (ACh) synthesis and release was studied in the hippocampus of normal and AF64A-treated rats. AF64A (3 nmol/brain, i.c.v.) produced significant reduction of high-affinity choline uptake (HACU) and high K+ induced ACh release in hippocampal synaptosomes. Treatments with MKC-231 (10(-8) and 10(-7) M) showed significant reverse of the decrease in both HACU and ACh release. In hippocampal slices superfused with choline-containing artificial cerebro-spinal fluid (ACSF), high K+-induced ACh release was gradually decreased by repeated alteration of resting and high K+ stimulations in AF64A-treated rats. However, addition of MKC-231 (10(-8) to 10(-7) M) in the superfusate reduces this decrease. In vivo microdialysis studies indicate MKC-231 (10 mg/kg, p.o.) significantly reversed reduction of basal ACh concentrations in AF64A-treated rats, measured by radioimmunoassay without a cholinesterase inhibitor in the perfusate. These results indicate MKC-231 improves AF64A-induced cholinergic hypofunction by enhancing HACU, subsequently facilitating ACh synthesis and release in vitro and in vivo. PMID- 18446265 TI - Incisional hernia at the site of a stoma. AB - OBJECTIVE: Incisional hernia at the site where a patient had previously had a stoma has not been clearly studied. The aim of this study is to determine the incidence and associated factors that may lead to an incisional hernia related to the reversal of an intestinal stoma. PATIENTS AND METHODS: An analysis was made of 70 cases of intestinal reconnection. All patients received Cefotaxime or Ceftazidime during anaesthesia induction and two more doses at 1-8 h in the post operative period. In all of the cases, closure of the stoma site was effected as a primary closure using no. 1 polyglycolic acid continuous suture. There followed wound lavage with iodopovidone, and the skin was closed with simple sutures using polypropylene 3/0. No drain was left in situ in any of the cases. The study considered the following aspects: demographic characteristics of the study group; illnesses giving rise to the need for stoma formation; the stoma site itself; clinical aspects, including body mass index (BMI); the incidence of incisional hernia; and any complications involving the surgical wound. RESULTS: At this hospital, the cause of requiring treatment with stoma formation was diverticular disease of the colon principally, and the age of the patients varied from 36 to 87 years (median 61). The incidence of incisional hernia at the stoma site was 22 cases (31.4%), presenting equally in both sexes and with greater frequency under the following circumstances: during the first year of follow-up and in patients with concomitant illnesses, principally diabetes. Local complications involving the surgical wound occurred in six cases (8.5%). CONCLUSION: The incidence of incisional hernia at the stoma site was found to be 31.4% in this study, which is a high incidence of hernias with simple repair. PMID- 18446266 TI - Iatrogenic diaphragmatic hernia complicating nephrectomy: top-down or bottom-up? AB - Hernias of the diaphragm are rarely reported as a complication of abdominal surgery. We review a case of a 47-year-old female who presented with dyspnoea and chest pain one day after left radical nephrectomy for renal cell carcinoma. Plain and cross-sectional imaging identified a large left-sided diaphragmatic hernia containing omentum, spleen, splenic flexure, and stomach. Our patient underwent a thoracotomy and, after hernia reduction, the diaphragmatic defect was repaired using non-absorbable sutures and a mesh. She made an uneventful recovery. The potential cause is discussed and the published literature on this rare complication is reviewed briefly. PMID- 18446267 TI - Accuracy of recall of the items included in disease activity forms of Behcet's disease: comparison of retrospective questionnaires with a daily telephone interview. AB - The assessment of disease activity in Behcet's disease (BD), either by BD Current Activity Form (BDCAF) or Iranian BD Dynamic Measure (IBDDAM), depends largely on the history of the clinical features. Accuracy of recall of a retrospective questionnaire might influence its reliability to some extent. The aim of this study was to investigate whether patients with BD can recall the items included in both of the disease activity forms accurately. Twenty patients with BD completed a retrospective questionnaire that included BDCAF and IBDDAM, twice, 1 month apart. We made some modifications in the IBDDAM, while the BDCAF (revised 8.5.2002, GL) was applied in its original structure. In contrast to the original application of IBDDAM, in which the history obtained depends on the variable time period, all items of IBDDAM in the present study asked subjects to report their symptoms over the preceding 4 weeks. Furthermore, those IBDDAM items for which the operational definitions are not clearly provided by the developers, as well as the items that depend on the objective examination rather than the history, were not included. Concurrent daily data were collected for 2 months via telephone interview. The level of agreement between the retrospective responses and those extracted from daily recordings were quantified for each item using intraclass correlation coefficient (ICC). The agreement between the recalled and daily reports was good (ICCs>0.60) for the majority of items (oral and genital ulceration, skin lesions, arthralgia, arthritis, and eye involvement) included in BDCAF. Exceptions were gastrointestinal symptoms (ICCs<0.40) and headache (ICCs 0.40-0.50). With regard to the IBDDAM, all of the items examined had good agreement (ICCs>0.60), except for headache, for which the agreement was moderate (ICCs 0.40-0.50) for the first and poor (ICCs<0.40) for the second month. For most of the BD-related features questioned in the disease activity forms, patients provided reasonably accurate reports in comparison to information obtained from daily records. However, it should be kept in mind that the limitations of the study design need to be considered while interpreting the results of the present study. Notably, unlike its original application in which the assessment depends on the variable time period, IBDDAM used in the present study assessed the symptoms present during the month prior to the date of assessment. Therefore, our findings regarding IBDDAM cannot be applied to its original use. Furthermore, lack of patients in some of the symptom groups, as well as possible manipulation of recall with daily questioning, might have influenced our results to some extent. PMID- 18446268 TI - A rare case of arterial thrombosis in a 37-year-old male with Factor V Leiden mutation. AB - BACKGROUND: The classic triad of symptoms seen in chronic mesenteric ischaemia is post-prandial pain, sitophobia (fear of food) and progressive weight loss. Patients with mesenteric ischaemia secondary to a prothrombotic state such as that rendered by the Factor V Leiden mutation, are substantially younger than the typical elderly patient in whom embolic disease triggered by atrial fibrillation is the main underlying cause. METHOD: This is one such case report documenting arterial thrombosis in a 37-year-old male with a subsequently identified heterozygous Factor V Leiden mutation. CONCLUSION: Factor V Leiden mutation is a contributing risk factor in cases of small bowel infarction. PMID- 18446269 TI - Bending modulus of lipid bilayers in a liquid-crystalline phase including an anomalous swelling regime estimated by neutron spin echo experiments. AB - Membrane fluctuations of dipalmitoylphosphatidylcholine (DPPC) and dimyristoylphosphatidylcholine (DMPC) were investigated by neutron spin echo spectroscopy. The intermediate structure factor was analyzed in terms of the model proposed by Zilman and Granek (Phys. Rev. Lett. 77, 4788 (1996)), and the bending modulus of lipid bilayers was derived. The hardening of a lipid bilayer upon approaching the main transition point in the anomalous swelling regime was observed, which naturally connects the bending modulus in the gel phase below the main transition temperature. PMID- 18446270 TI - Discrete rearranging disordered patterns, part II: 2D plasticity, elasticity and flow of a foam. AB - The plastic flow of a foam results from bubble rearrangements. We study their occurrence in experiments where a foam is forced to flow in 2D: around an obstacle; through a narrow hole; or sheared between rotating disks. We describe their orientation and frequency using a topological matrix defined in the companion paper (F. Graner, B. Dollet, C. Raufaste, and P. Marmottant, this issue, 25 (2008) DOI 10.1140/epje/i2007-10298-8), which links them with continuous plasticity at large scale. We then suggest a phenomenological equation to predict the plastic strain rate: its orientation is determined from the foam's local elastic strain; and its rate is determined from the foam's local elongation rate. We obtain a good agreement with statistical measurements. This enables us to describe the foam as a continuous medium with fluid, elastic and plastic properties. We derive its constitutive equation, then test several of its terms and predictions. PMID- 18446271 TI - Discrete rearranging disordered patterns, part I: robust statistical tools in two or three dimensions. AB - Discrete rearranging patterns include cellular patterns, for instance liquid foams, biological tissues, grains in polycrystals; assemblies of particles such as beads, granular materials, colloids, molecules, atoms; and interconnected networks. Such a pattern can be described as a list of links between neighbouring sites. Performing statistics on the links between neighbouring sites yields average quantities (hereafter "tools") as the result of direct measurements on images. These descriptive tools are flexible and suitable for various problems where quantitative measurements are required, whether in two or in three dimensions. Here, we present a coherent set of robust tools, in three steps. First, we revisit the definitions of three existing tools based on the texture matrix. Second, thanks to their more general definition, we embed these three tools in a self-consistent formalism, which includes three additional ones. Third, we show that the six tools together provide a direct correspondence between a small scale, where they quantify the discrete pattern's local distortion and rearrangements, and a large scale, where they help describe a material as a continuous medium. This enables to formulate elastic, plastic, fluid behaviours in a common, self-consistent modelling using continuous mechanics. Experiments, simulations and models can be expressed in the same language and directly compared. As an example, a companion paper (P. Marmottant, C. Raufaste, and F. Graner, this issue, 25 (2008) DOI 10.1140/epje/i2007-10300-7) provides an application to foam plasticity. PMID- 18446272 TI - Epigenetics and pharmaco-epigenetics in the primary headaches. PMID- 18446273 TI - Epigenetics in primary headaches: a new avenue for research. PMID- 18446274 TI - Preface-imaging in cancer. PMID- 18446276 TI - Estimation of intake of zinc, copper and iron in the diet of patients with chronic renal failure treated by haemodialysis. AB - The aim of this study was to analyse the dietary zinc, copper and iron intakes in haemodialysis patients and in healthy controls. A statistically significant lower intake of these elements was observed in the patients group. In particular, the copper intake was extremely low in that group, not reaching 40% of the recommended value. PMID- 18446275 TI - Intravital microscopic analysis of vascular perfusion and macromolecule extravasation after photodynamic vascular targeting therapy. AB - PURPOSE: Photodynamic therapy (PDT), involving the combination of a photosensitizer and light, is being evaluated as a vascular disrupting therapy and drug delivery enhancement modality based on its effects on vascular perfusion and barrier function. Since tumor vasculature is the common route for the delivery of both blood and therapeutic agents, it is important to compare the effects of PDT on blood perfusion and substance transport. MATERIALS AND METHODS: Tumor blood cell velocity and the extravasation of high molecular weight dextran molecules were continuously monitored by intravital fluorescence microscopy for up to 60 min after PDT using three doses of verteporfin in the MatLyLu prostate tumor model. RESULTS: PDT induced tumor perfusion disruption via thrombus formation. PDT using a higher dose of verteporfin was more effective in inhibiting blood perfusion while a lower dose verteporfin-PDT was more potent in enhancing dextran extravasation. The increase in dextran extravasation induced by PDT was dependent upon dextran molecular weight. A lower molecular weight dextran obtained a higher tumor accumulation after PDT than a higher molecular weight dextran. CONCLUSIONS: PDT with verteporfin had different effects on tumor vascular perfusion versus the extravasation of macromolecules. Optimal PDT conditions should be adjusted based on the therapeutic application. PMID- 18446277 TI - Adaptive changes in cardiac fibroblast morphology and collagen organization as a result of mechanical environment. AB - There is a growing body of work in the literature that demonstrates the significant differences between 2D versus 3D environments in cell morphologies, spatial organization, cell-ECM interactions, and cell signaling. The 3D environments are generally considered more realistic tissue models both because they offer cells a surrounding environment rather than just a planar surface with which to interact, and because they provide the potential for more diverse mechanical environments. Many studies have examined cellular-mediated contraction of 3D matrices; however, because the 3D environment is much more complex and the scale more difficult to study, little is known regarding how mechanical environment, cell and collagen architecture, and collagen remodeling are linked. In the current work, we examine the spatial arrangement of neonatal cardiac fibroblasts and the associated collagen organization in constrained and unconstrained collagen gels over a 24 h period. Collagen gels that are constrained by their physical attachment to a mold and similar gels, which have been detached (unconstrained) from the mold and subsequently contract, offer two simple mechanical models by which the mechanisms of tissue homeostasis and wound repair might be examined. Our observations suggest the presence of two mechanical regimes in the unconstrained gels: an outer ring where cells orient circumferentially and local collagen aligns with the elongated cells; and a central region where unaligned stellate/bipolar cells are radially surrounded by collagen, similar to that seen throughout constrained gels. The evolving organization of cell alignment and surrounding collagen organization suggests that cellular response may be due to the cellular perception of the apparent stiffness of local physical environment. PMID- 18446279 TI - Molecular dynamics simulations. AB - Molecular simulation is a very powerful toolbox in modern molecular modeling, and enables us to follow and understand structure and dynamics with extreme detail- literally on scales where motion of individual atoms can be tracked. This chapter focuses on the two most commonly used methods, namely, energy minimization and molecular dynamics, that, respectively, optimize structure and simulate the natural motion of biological macromolecules. The common theoretical framework based on statistical mechanics is covered briefly as well as limitations of the computational approach, for instance, the lack of quantum effects and limited timescales accessible. As a practical example, a full simulation of the protein lysozyme in water is described step by step, including examples of necessary hardware and software, how to obtain suitable starting molecular structures, immersing it in a solvent, choosing good simulation parameters, and energy minimization. The chapter also describes how to analyze the simulation in terms of potential energies, structural fluctuations, coordinate stability, geometrical features, and, finally, how to create beautiful ray-traced movies that can be used in presentations. PMID- 18446278 TI - Risk of malignant lymphoma following viral hepatitis infection. AB - We investigated lymphoma risk following hepatitis infection in a case-control study of 274 incident lymphoma cases, defined according to the WHO classification, and 336 population controls in Sardinia, Italy. Part of our study population (198 cases and 219 controls) was included in the EPILYMPH study of Hepatitis C virus (HCV) infection in relation to non-Hodgklin's lymphoma risk. Based on questionnaire information on whether and at what age a diagnosis of hepatitis was posed by a physician, systematic anti-HCV antibodies testing in cases and controls by enzyme-linked immunoassay, and HCV-RNA assessment by PCR analyses in positive samples, we investigated more in detail whether hepatitis non-C is also associated with lymphoma risk, and whether risk varies by clinical form of hepatitis (acute or chronic infection). After adjusting by age, gender, education, and area of birth whether from the study area or elsewhere in Italy, a previous generic diagnosis of hepatitis was associated with a significantly elevated lymphoma risk [odds ratio (OR) = 1.8; 95% CI 1.1, 2.8], which was equally increased for hepatitis B (OR = 1.8; 95% CI 0.9, 3.5), for HCV positive subjects overall (OR = 2.0; 95% CI 0.8, 4.8), and for hepatitis non-B non-C (OR = 1.6; 95% CI 0.7, 3.9). Once concurrent infection from other hepatitis viruses was excluded, acute or chronic hepatitis C was the only one showing a consistent risk increase in all lymphoma subtypes, but follicular lymphoma. Some indications of an excess risk of lymphoma were observed also for acute, but not chronic forms of hepatitis B and hepatitis non-B, non C. Self-limited hepatitis C did not show an association. No significant heterogeneity in the risk of major lymphoma subtype was observed. Our results confirm a role of either acute or chronic active HCV infection in lymphomagenesis. Further studies are warranted to test the hypothesis that acute infection from other hepatitis viruses might also increase lymphoma risk. PMID- 18446280 TI - Monte Carlo simulations. AB - A description of Monte Carlo methods for simulation of proteins is given. Advantages and disadvantages of the Monte Carlo approach are presented. The theoretical basis for calculating equilibrium properties of biological molecules by the Monte Carlo method is presented. Some of the standard and some of the more recent ways of performing Monte Carlo on proteins are presented. A discussion of the estimation of errors in properties calculated by Monte Carlo is given. PMID- 18446281 TI - Hybrid quantum and classical methods for computing kinetic isotope effects of chemical reactions in solutions and in enzymes. AB - A method for incorporating quantum mechanics into enzyme kinetics modeling is presented. Three aspects are emphasized: 1) combined quantum mechanical and molecular mechanical methods are used to represent the potential energy surface for modeling bond forming and breaking processes, 2) instantaneous normal mode analyses are used to incorporate quantum vibrational free energies to the classical potential of mean force, and 3) multidimensional tunneling methods are used to estimate quantum effects on the reaction coordinate motion. Centroid path integral simulations are described to make quantum corrections to the classical potential of mean force. In this method, the nuclear quantum vibrational and tunneling contributions are not separable. An integrated centroid path integral free energy perturbation and umbrella sampling (PI-FEP/UM) method along with a bisection sampling procedure was summarized, which provides an accurate, easily convergent method for computing kinetic isotope effects for chemical reactions in solution and in enzymes. In the ensemble-averaged variational transition state theory with multidimensional tunneling (EA-VTST/MT), these three aspects of quantum mechanical effects can be individually treated, providing useful insights into the mechanism of enzymatic reactions. These methods are illustrated by applications to a model process in the gas phase, the decarboxylation reaction of N-methyl picolinate in water, and the proton abstraction and reprotonation process catalyzed by alanine racemase. These examples show that the incorporation of quantum mechanical effects is essential for enzyme kinetics simulations. PMID- 18446283 TI - Normal modes and essential dynamics. AB - Normal mode analysis and essential dynamics analysis are powerful methods used for the analysis of collective motions in biomolecules. Their application has led to an appreciation of the importance of protein dynamics in function and the relationship between structure and dynamical behavior. In this chapter, the methods and their implementation are introduced and recent developments such as elastic networks and advanced sampling techniques are described. PMID- 18446282 TI - Comparison of protein force fields for molecular dynamics simulations. AB - In the context of molecular dynamics simulations of proteins, the term "force field" refers to the combination of a mathematical formula and associated parameters that are used to describe the energy of the protein as a function of its atomic coordinates. In this review, we describe the functional forms and parameterization protocols of the widely used biomolecular force fields Amber, CHARMM, GROMOS, and OPLS-AA. We also summarize the ability of various readily available noncommercial molecular dynamics packages to perform simulations using these force fields, as well as to use modern methods for the generation of constant-temperature, constant-pressure ensembles and to treat long-range interactions. Finally, we finish with a discussion of the ability of these force fields to support the modeling of proteins in conjunction with nucleic acids, lipids, carbohydrates, and/or small molecules. PMID- 18446284 TI - Calculation of absolute protein-ligand binding constants with the molecular dynamics free energy perturbation method. AB - Reliable first-principles calculations of protein-ligand binding constants can play important roles in the study and characterization of biological recognition processes and applications to drug discovery. A detailed procedure for such a calculation is outlined in this chapter. The methodology is computationally implemented using the molecular dynamics sampling of relevant configurational spaces and free energy perturbation techniques. The procedure is illustrated with the model system of the phosphotyrosine peptide binding to the Src SH2 domain. PMID- 18446285 TI - Free energy calculations applied to membrane proteins. AB - Selected applications of free energy calculations to the realm of membrane proteins are reviewed. The theoretical underpinnings of these calculations are described, focusing on free energy perturbation and the use of thermodynamic integration to determine free energy changes along well-delineated order parameters. Current strategies for improving the reliability of free energy calculations, while making them somewhat more affordable are outlined. Application of the free energy methodology to understand the structure and function of membrane proteins is illustrated in three concrete examples: The binding of an agonist ligand to a G protein-coupled receptor, the assisted transport of a small permeant through a membrane channel, and the recognition and association of transmembrane alpha-helical domains. PMID- 18446286 TI - Molecular dynamics simulations of membrane proteins. AB - Membrane protein structures are underrepresented in the Protein Data Bank (PDB) because of difficulties associated with expression and crystallization. As such, it is one area in which computational studies, particularly molecular dynamics (MD), can provide useful additional information. Recently, there has been substantial progress in the simulation of lipid bilayers and membrane proteins embedded within them. Initial efforts at simulating membrane proteins embedded within a lipid bilayer were relatively slow and interactive processes, but recent advances now mean that the setup and running of membrane protein simulations is somewhat more straightforward, although not without its problems. In this chapter, we outline practical methods for setting up and running MD simulations of a membrane protein embedded within a lipid bilayer and discuss methodologies that are likely to contribute future improvements. PMID- 18446288 TI - Implicit membrane models for membrane protein simulation. AB - Implicit models of membrane environments offer computational advantages in simulations of membrane-interacting proteins and peptides. Such methods are especially useful for studies of long time scale processes, such as folding and aggregation, or very large complexes that are otherwise intractable with explicit lipid environments. Implicit models replace explicit solute-solvent interactions with a mean-field approach. In the most physical models, continuum dielectric electrostatics is combined with empirical formulations for the nonpolar components of the free energy of solvation. The practical use of a number of implicit membrane models ranging from the empirical IMM1 method to generalized Born-based methods with two-dielectric and multidielectric representations of biological membrane characteristics is presented. PMID- 18446287 TI - Membrane-associated proteins and peptides. AB - This chapter discusses the practical aspects of setting up molecular dynamics simulations for membrane-associated proteins and peptides. Special emphasis lies on the analysis of such systems. The main focus is the association between a cationic peptide and an anionic lipid bilayer--a peptide/lipid-bilayer system- but the extension onto more complicated systems is discussed. Topology files for selected lipids and several new analysis tools relevant for protein-membrane simulations are presented, the most important ones of which are: g_helixaxis, to calculate the axis of a helix and its angle with the bilayer; g_arom, to calculate aromatic order parameters; and g_under, to calculate which lipids interact with the protein. A procedure is explained to calculate properties involving peptide-interacting lipids only, as opposed to all lipids. PMID- 18446289 TI - Comparative modeling of proteins. AB - Three-dimensional analysis of protein structures is proving to be one of the most fruitful modes of biological and medical discovery in the early 21st century, providing fundamental insight into many (perhaps most) biochemical functions of relevance to the cause and treatment of diseases. Fully realizing such insight, however, would require analysis of too many distinct proteins for thorough laboratory analysis of all proteins to be feasible, thus, any method capable of accurate, efficient in silico structure prediction should prove highly expeditious. The technique generally acknowledged to provide the most accurate protein structure predictions, called comparative modeling, has, thus, attracted substantial attention and is the focus of this chapter. Although other reviews have reported on the method development and research history of comparative modeling, our discussion herein focuses on the general philosophy of the method and specific strategies for successfully achieving reliable and accurate models. The chapter, thus, relates aspects of template selection, sequence alignment, spatial alignment, loop and gap modeling, side chain modeling, structural refinement, and validation. PMID- 18446290 TI - Transmembrane protein models based on high-throughput molecular dynamics simulations with experimental constraints. AB - Elucidating the structure of transmembrane proteins domains with high-resolution methods is a difficult and sometimes impossible task. Here, we explain the method of combining a limited amount of experimental data with automated high-throughput molecular dynamics (MD) simulations of alpha-helical transmembrane bundles in an explicit lipid bilayer/water environment. The procedure uses a systematic conformational search of the helix rotation with experimentally constrained MDs simulations. The experimentally determined helix tilt and rotational angle of a labeled residue with site-specific infrared dichroism allows us to select a unique high-resolution model from a number of possible energy minima encountered in the systematic conformational search. PMID- 18446291 TI - Nuclear magnetic resonance-based modeling and refinement of protein three dimensional structures and their complexes. AB - Nuclear magnetic resonance (NMR) has become a well-established method to characterize the structures of biomolecules in solution. High-quality structures are now produced, thanks to both experimental and computational developments, allowing the use of new NMR parameters and improved protocols and force fields in structure calculation and refinement. In this chapter, we give a short overview of the various types of NMR data that can provide structural information, and then focus on the structure calculation methodology itself. We discuss and illustrate with tutorial examples both "classical" structure calculation and refinement approaches as well as more recently developed protocols for modeling biomolecular complexes. PMID- 18446292 TI - Conformational changes in protein function. AB - Conformational changes are the hallmarks of protein dynamics and are often intimately related to protein functions. Molecular dynamics (MD) simulation is a powerful tool to study the time-resolved properties of protein structure in atomic details. In this chapter, we discuss the various applications of MD simulation to the study of protein conformational changes, and introduce several selected advanced techniques that may significantly increase the sampling efficiencies, including locally enhanced sampling (LES), and grow-to-fit molecular dynamics (G2FMD). PMID- 18446293 TI - Protein folding and unfolding by all-atom molecular dynamics simulations. AB - Computational protein folding can be classified into pathway and sampling approaches. Here, we use the AMBER simulation package as an example to illustrate the protocols for all-atom molecular simulations of protein folding, including system setup, simulation, and analysis. We introduced two traditional pathway approaches: ab inito folding and high-temperature unfolding. The popular replica exchange method was chosen to represent sampling approaches. Our emphasis is placed on the analysis of the simulation trajectories, and some in-depth discussions are provided for commonly encountered problems. PMID- 18446294 TI - Modeling of protein misfolding in disease. AB - A short review of the results of molecular modeling of prion disease is presented in this chapter. According to the "one-protein theory" proposed by Prusiner, prion proteins are misfolded naturally occurring proteins, which, on interaction with correctly folded proteins may induce misfolding and propagate the disease, resulting in insoluble amyloid aggregates in cells of affected specimens. Because of experimental difficulties in measurements of origin and growth of insoluble amyloid aggregations in cells, theoretical modeling is often the only one source of information regarding the molecular mechanism of the disease. Replica exchange Monte Carlo simulations presented in this chapter indicate that proteins in the native state, N, on interaction with an energetically higher structure, R, can change their conformation into R and form a dimer, R(2). The addition of another protein in the N state to R(2) may lead to spontaneous formation of a trimer, R(3). These results reveal the molecular basis for a model of prion disease propagation or conformational diseases in general. PMID- 18446295 TI - Identifying putative drug targets and potential drug leads: starting points for virtual screening and docking. AB - The availability of three-dimensional (3D) models of both drug leads (small molecule ligands) and drug targets (proteins) is essential to molecular docking and computational drug discovery. This chapter describes an emerging methodology that can be used to identify both drug leads and drug targets using three newly developed web-accessible databases: 1) DrugBank; 2) The Human Metabolome Database; and 3) PubChem. Specifically, it illustrates how putative drug targets and drug leads for exogenous diseases (i.e., infectious diseases) can be readily identified and their 3D structures selected using only the genomic sequences from pathogenic bacteria or viruses as input. It also illustrates how putative drug targets and drug leads for endogenous diseases (i.e., non-infectious diseases or chronic conditions) can be identified using similar databases and similar sequence input. This chapter is intended to illustrate how bioinformatics and cheminformatics can work synergistically to help provide the necessary inputs for computer-aided drug design. PMID- 18446296 TI - Receptor flexibility for large-scale in silico ligand screens: chances and challenges. AB - An important contribution to today's computer-aided drug design is the automated screening of large compound databases against structurally resolved protein receptors targets. The introduction of ligand flexibility has, by now, become a standardized procedure. In contrast, a general approach to treat target degrees of freedom is still to be found, a consequence of the extreme increase of computational complexity, which comes along with the relaxation of protein degrees of freedom. In this chapter, we discuss in some detail both benefits and present limitations of target flexibility for high-throughput in silico database screens. Among the benefits are an improved diversity of binding modes, which allows one to identify a wider class of drug candidates. The limitations are related to a diminishing docking accuracy and an increased number of false hits. Using the thymidine kinase receptor and ten known inhibitors as an example, we describe in detail how target flexibility was implemented and how it affected the screening performance. PMID- 18446297 TI - Molecular docking. AB - Molecular docking is a key tool in structural molecular biology and computer assisted drug design. The goal of ligand-protein docking is to predict the predominant binding mode(s) of a ligand with a protein of known three-dimensional structure. Successful docking methods search high-dimensional spaces effectively and use a scoring function that correctly ranks candidate dockings. Docking can be used to perform virtual screening on large libraries of compounds, rank the results, and propose structural hypotheses of how the ligands inhibit the target, which is invaluable in lead optimization. The setting up of the input structures for the docking is just as important as the docking itself, and analyzing the results of stochastic search methods can sometimes be unclear. This chapter discusses the background and theory of molecular docking software, and covers the usage of some of the most-cited docking software. PMID- 18446298 TI - [Psychosocial stress in children of somatically ill parents. Perspectives of mental health prevention]. AB - Irrespective of their well-known increased risk for mental health problems, children of somatically ill parents are a clinically underserved as well as under researched group. In this article, the authors introduce the epidemiologic and clinical relevance of this topic and present a theoretical framework for understanding the sequelae of a serious parental illness on minor-age children, based on family dynamics and developmental concepts. This is followed by a comprehensive review of current empirical studies in this field, with a special emphasis on results from a transnational European collaborative study (COSIP = Children of Somatically Ill Parents), which was coordinated by the last author. The most important recommendations from intervention concepts published to date are summarized. Some outlooks for clinical practice as well as future research are presented. PMID- 18446299 TI - [Bronchial asthma in children. Furthering compliance]. AB - Success in treating and managing bronchial asthma in children and adolescents is known to rely on active cooperation on behalf of both the patients and their parents. Compliance in terms of pharmaceutical or behavioural intervention is often insufficient to prevent further aggravation and exacerbation. Specific measures for enhancing therapy compliance have been well received in the German Health Care System, and research results indicate their effectiveness in reducing health care utilization and in improving quality of life. Studies that would ascribe such effects to regular medication intake or reduced exposure to allergic elicitors, however, are still lacking. PMID- 18446300 TI - [Attention-deficit hyperactivity disorder: risk factors, protective factors, health supply, quality of life. A brief review]. AB - Attention-deficit hyperactivity disorder (ADHD) is a chronic behavioural disorder diagnosed in 4.8 % of German children and adolescents. Although many studies indicate primarily a neurobiological etiology, the disorder cannot be diagnosed on the basis of specific markers. The principal aspect of diagnosis is the experienced clinician who must also take the differentiation of other behavioural disorders into account. In addition to inheritance, other known risk factors are nicotine exposition in pregnancy, adverse psychosocial conditions and birth complications. Protective factors are cognitive abilities, positive social contacts, and early treatment. The necessary structures in community support are developing; however, substantial enhancement is needed. Studies on quality of life indicate that ADHD should not be reduced to core symptoms since affected children are impaired in almost all areas of daily life. PMID- 18446301 TI - [Fragility and experiencing limits as a chance for development in old age--the meaning of the particular experiences of the aging body for identification and development as focused on the very old]. AB - The main focus of this article is the meaning of particular experiences of the aging body for identity and development with respect to very old age. This experience of embodiment results from a dynamic development between unpleasant experiences of physical aging, positive bodily experiences of the pleasure of living, and reflections on this direct engagement with the aging body. The interaction of those three dimensions requires a constant rebalancing, which, in view of the frail body, becomes increasingly demanding. Beyond one's own experiences with aging through direct engagement with the body, established social relationships give room for an individual's physical nature and support the maintenance of identity and development. People who look after and care for old aged people have to recognize their own embodiment and have to acknowledge their aging body. This applies not only to contact with old aged people, but also requests that the potential for developing one's own identity be recognised. The inclusion of the body in the discourse on the aging process demands a mindset change in social gerontology and for the individual it means to submit oneself to the ethics of embodied existence. PMID- 18446302 TI - [Sport activities from the lifespan perspective]. AB - Considering lifespan developmental psychology, engagement in sport can be seen as a dynamic process of phases of participation and inactivity that varies from individual to individual. Depending on the individual biography, specific categories and patterns of sport participation evolve over a lifetime. Changes of sport participation rates over the last 30 years are discussed on the basis of general social changes. Six patterns of reasons will be discussed. The focus is set on a heuristic model as a base to explain the individual changes of behavior in sports over the lifespan. This model depicts engagement in sports as a process of dynamic changes (aspect of process and time) influenced by specific determinants in the different phases of changes (aspect of determinants). Finally, three of these determinants--(health) motives, barriers and preferences for sport and exercises--are specified because they seem to be important for adherence to adults' sports activities. PMID- 18446303 TI - [Psychological implications of sport and aging--a neglected research field]. AB - Since the 1990s, sport and aging is increasingly in the focus of psychological research. Besides motivational aspects the main attention lies on the positive influence of sporting activity on physical and psychological health. Thus, ageing and sports is mostly considered under functional aspects. The aim to compensate deficits through sports in the elderly reflects the socially widespread pictures of age (frailness) and sport (capability, youthfulness). In this article the deficit model with the associated cliches is questioned on the background of the latest research. The author argues for a more differentiated and constructive view on sport and aging and to take into consideration the specific needs of older people. PMID- 18446304 TI - [Body and memory--physical diseases and cognitive disorders]. AB - Physiological and pathologic changes of various body functions have a great influence on the cognitive performance of a human being in the course of aging. Knowledge-based neuropsychological abilities do not change much during the physiological aging process. However, the decreasing capacity of the working and sensory memory lead to lesser attention and learning performance in the elderly, compared to younger population groups. Pathological mental function changes correlate with the existence of certain physical diseases, the most important of which show an increasing incidence with old age. Degenerative diseases especially Alzheimer's disease and other demential syndromes as well as vascular diseases of the central nervous system, tumors, inflammation, epilepsy, traumatic as well as metabolic and toxic damages to the central nervous system can affect cognitive and physical function to a high degree. Prevention in old age plays a key role. The therapeutic approach to the cognitive disorder is selected according to the disease stage and should be multiprofessional, including the best applicable medical and nonmedical treatment and support for the patient and his family. PMID- 18446305 TI - Does high field MRI allow an earlier diagnosis of multiple sclerosis? AB - BACKGROUND: High field magnetic resonance imaging (MRI) provides higher lesion load measurements in patients presenting with clinically isolated syndromes (CIS) suggestive of demyelination and has impact upon the classification of these syndromes and potentially, the diagnosis of multiple sclerosis (MS). PURPOSE: To investigate whether high field MRI can provide an earlier diagnosis of definite MS within the International Panel (IP) and Swanton criteria. METHODS: Forty patients presenting with CIS suggestive of MS were included. All patients received multi-sequence MRI at 1.5 Tesla (T) and 3T as well as a neurological assessment at baseline. Follow-up visits including MRI at both field strengths and neurological examinations were scheduled 3-4 and 6-7 months after the first clinical event. Based on MRI and clinical findings, fulfilled IP criteria as well as Swanton criteria were analysed. RESULTS: At baseline, the higher detection rate of inflammatory lesions using high field MRI leads to higher classifications according to the Swanton criteria in 15 % of the patients. One additional patient was diagnosed with dissemination in space according to Swanton and IP criteria. During follow-up, an earlier diagnosis of definite MS could not be accomplished, neither according to the IP nor to the Swanton criteria. CONCLUSION: Although high field MRI shows a higher detection rate of inflammatory brain lesion in CIS and MS patients with an influence according to MRI criteria, this influence does not lead to an earlier diagnosis of lesion dissemination in time and therefore definite MS. PMID- 18446306 TI - Effects of subthalamic nucleus stimulation on striatal dopaminergic transmission in patients with Parkinson's disease within one-year follow-up. AB - The mechanisms by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) leads to clinical benefit in Parkinson's disease (PD), especially with regard to dopaminergic transmission, remain unclear. Therefore, the objective of our study was to evaluate alterations of synaptic dopaminergic signaling following bilateral STN-DBS in advanced PD within a one-year follow-up. We used [(123)I]FP-CIT single-photon emission computed tomography (SPECT) to measure dopamine transporter (DAT) availability and [(123)I]IBZM SPECT to assess dopamine D(2) receptor (D2R) availability (stimulator ON condition).Patients (n=18) showed a tendency towards a better suppression of symptoms after STN-DBS (Unified Parkinson's Disease Rating Scale motor score with medication decreased from 24.1+/-16.1 to 15.4+/-7.45; p=0. 002) while medication was strongly reduced (61% reduction of levodopa equivalent units; p<0. 0001). No changes of striatal [(123)I]FP-CIT binding and an increase of [(123)I]IBZM binding up to 16% (p<0. 05) between pre-surgery and follow-up investigations were noticed. These data show that clinical improvement and reduction of dopaminergic drugs in patients with advanced PD undergoing bilateral STN-DBS are paralleled by stable DAT and recovery of striatal D2R availability 12 months after surgery. PMID- 18446307 TI - Episodic ataxia: SLC1A3 and CACNB4 do not explain the apparent genetic heterogeneity. PMID- 18446308 TI - Identification of internuclear ophthalmoplegia signs in multiple sclerosis patients. Saccade test analysis. AB - BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS), due to the diverse nature of the disease, have many types of eye movement disorders, particularly internuclear ophthalmoplegia (INO). The aim of the study was to evaluate the usefulness of a quantitative statistical saccade test analysis for identification of INO in MS patients. METHODS: Sixty MS patients and 50 volunteers underwent clinical bedside ocularmotor examination and electrooculographic evaluation in a tertiary referral university hospital. Simultaneous electro-oculography recordings of each eye separately were made. In the saccade test, the versional dysconjugacy index (VDI) for saccades velocity and the Z score analysis were applied. RESULTS: Clinical eye movements disorders were found in 32% of patients. In the MS patients saccades velocity was significantly lower compared with the control group. Based on the results of the control group, we established the cut off values for VDI (1.04) and corresponded Z score (4.46) as the criterion indicated the presence of INO signs in MS patients. We confirmed clinical evidence of different degrees of INO in 15% of patients, and found subclinical INO signs in 20% of patients. CONCLUSION: The EOG registration is a sensitive electrophysiological method for detecting subtle deficits of ocular motility. Saccade test analysis with calculation of the VDI and the Z-test score is a valuable method for identifying subclinical INO signs in MS patients. PMID- 18446310 TI - Mutations in the POLG1 gene are not a relevant cause of cerebellar ataxia in Italy. PMID- 18446309 TI - The renin-angiotensin-aldosterone system in cerebral small vessel disease. AB - INTRODUCTION: Cerebral small vessel disease (SVD) appears on magnetic resonance imaging (MRI) as leukoaraiosis (LA), etat crible (EC), and multiple lacunar infarctions (MLI). Although the pathophysiology of SVD is poorly understood, there is evidence of a genetic contribution. We sought to analyze the influence of the renin-angiotensin-aldosterone system (RAAS) on SVD in symptomatic patients from the Genetique de l'Infarctus Cerebral (GENIC) study, including RAAS polymorphisms and circulating angiotensin converting enzyme (ACE). METHODS: Caucasian patients (n=510) with acute brain infarction (BI) were recruited and MRIs were evaluated for SVD, including LA, EC, and MLI. We considered ACE levels and several polymorphisms, including ACE, angiotensinogen, aldosterone synthase CYP11B2, and angiotensin II receptor type I. RESULTS: Among the polymorphisms, there were marginal negative associations between aldosterone synthase CYP11B2 344C against severe EC (adjusted OR, 0.57; 95% CI, 0.31-1.05) and severe LA (adjusted OR, 0.54; 95% CI, 0.30-0.95), both considering -344C dominant. In addition, the frequency of -344C decreased with the number of SVD abnormalities (p=0.016). Mean plasma ACE was elevated in patients with MLI, but not with LA or EC. The risk of MLI increased gradually with increasing plasma ACE (adjusted OR, 1.25; 95% CI, 1.02-1.53). CONCLUSIONS: This exploratory study found no strong evidence for RAAS involvement in severe SVD in this population. The whole spectrum of SVD, including EC, MLI, and LA, can be considered as phenotypes for genetic studies. PMID- 18446311 TI - Highly skewed inactivation of the wild-type X-chromosome in asymptomatic female carriers of spinal and bulbar muscular atrophy (Kennedy's disease). AB - We examined families with a history of spinal and bulbar muscular atrophy (SBMA) and found that six out of eight female carriers had a skewed inactivation of the wild-type chromosome. Under these genetic conditions, disease manifestations should be expected and therefore we sought neurological and other symptoms of subclinical SBMA. We did not find either clinical symptoms or electrophysiological signs of mutated AR gene in female carriers, despite skewed methylation of the wild-type allele. These findings suggest that skewed methylation of AR genes are not necessarily associated to clinical manifestations in female carriers of the expanded SBMA allele. PMID- 18446312 TI - Brain hemorrhage as a complication of chronic hepatitis C virus-related vasculitis. PMID- 18446313 TI - Incidence of central nervous system involvement in chronic lymphocytic leukemia and outcome to treatment. AB - Leptomeningeal involvement in patients with CLL is relatively rare and the prognosis is usually considered to be poor. The authors reviewed all CLL patients treated in a tertiary referral center to assess the incidence and outcome of leptomeningeal involvement (LI) in CLL. They found an incidence of 1-2% of LI. Most of the patients with LI had a longterm survival, despite failure to clear the cerebrospinal fluid from tumor cells. PMID- 18446314 TI - Diagnosis of cerebral toxoplasmosis by detection of Toxoplasma gondii tachyzoites in cerebrospinal fluid. PMID- 18446315 TI - Extending the clinical spectrum of SPG3A mutations to a very severe and very early complicated phenotype. PMID- 18446316 TI - Discovery and genetic mapping of single nucleotide polymorphisms in candidate genes for pathogen defence response in perennial ryegrass (Lolium perenne L.). AB - Susceptibility to foliar pathogens commonly causes significant reductions in productivity of the important temperate forage perennial ryegrass. Breeding for durable disease resistance involves not only the deployment of major genes but also the additive effects of minor genes. An approach based on in vitro single nucleotide polymorphism (SNP) discovery in candidate defence response (DR) genes has been used to develop potential diagnostic genetic markers. SNPs were predicted, validated and mapped for representatives of the pathogenesis-related (PR) protein-encoding and reactive oxygen species (ROS)-generating gene classes. The F(1)(NA(6) x AU(6)) two-way pseudo-test cross population was used for SNP genetic mapping and detection of quantitative trait loci (QTLs) in response to a crown rust field infection. Novel resistance QTLs were coincident with mapped DR gene SNPs. QTLs on LG3 and LG7 also coincided with both herbage quality QTLs and candidate genes for lignin biosynthesis. Multiple DR gene SNP loci additionally co-located with QTLs for grey leaf spot, bacterial wilt and crown rust resistance from other published studies. Further functional validation of DR gene SNP loci using methods such as fine-mapping and association genetics will improve the efficiency of parental selection based on superior allele content. PMID- 18446317 TI - Impaired stroke volume and aerobic capacity in female adolescents with type 1 and type 2 diabetes mellitus. AB - AIM/HYPOTHESIS: This study was designed to determine whether type 2 diabetic adolescents have reduced aerobic capacity and to investigate the role of cardiac output and arteriovenous oxygen difference (a-vO(2)) in their exercise response. METHODS: Female adolescents (age 12-18 years) with type 2 diabetes mellitus (n = 8) and type 1 diabetes mellitus (n = 12) and obese (n = 10) and non-obese (n = 10) non-diabetic controls were recruited for this study. Baseline data included maximal aerobic capacity (cycle ergometer) and body composition. Cardiac output and a-vO(2) were determined at rest and during submaximal exercise. RESULTS: Diabetic groups had lower aerobic capacity than non-diabetic groups (p < 0.05). Adolescents with type 2 diabetes had lower aerobic capacity than the type 1 diabetic group. Maximal heart rate was lower in the type 2 diabetic group (p < 0.05). Exercise stroke volume was 30-40% lower at 100 and 120 beats per min in the diabetic than in the non-diabetic groups (p < 0.05). The a-vO(2) value was not different in any condition. CONCLUSIONS AND INTERPRETATION: Type 2 diabetic adolescents have reduced aerobic capacity and reduced heart rate response to maximal exercise. Furthermore, type 2 and type 1 diabetic adolescent girls have a blunted exercise stroke volume response compared with non-diabetic controls. Central rather than peripheral mechanisms contribute to the reduced aerobic capacity in diabetic adolescents. Although of short duration, type 2 diabetes in adolescence is already affecting cardiovascular function in adolescents. PMID- 18446318 TI - AIDS is coming to your ICU: be prepared for acute bowel injury and acute intestinal distress syndrome... PMID- 18446319 TI - Primary and secondary intra-abdominal hypertension--different impact on ICU outcome. AB - OBJECTIVE: To investigate the differences in incidence, time course and outcome of primary versus secondary intra-abdominal hypertension (IAH), and to evaluate IAH as an independent risk factor of mortality in a presumable risk population of critically ill patients. DESIGN: Prospective observational study. SETTING: General intensive care unit of a university hospital. PATIENTS: A total of 257 mechanically ventilated patients at presumable risk for the development of IAH were studied during their ICU stay and followed up for 90-day survival. INTERVENTIONS: Repeated measurements of intra-abdominal pressure (IAP). MEASUREMENTS AND RESULTS: IAP was measured intermittently, via bladder. IAH (sustained or repeated IAP > or = 12 mmHg) developed in 95 patients (37.0%). Primary IAH was observed in 60 and secondary IAH in 35 patients. Patients with secondary IAH demonstrated a significant increase of mean IAP during the first three days (mean DeltaIAP was 2.2 +/- 4.7 mmHg), whilst IAP decreased (mean DeltaIAP -1.1 +/- 3.7 mmHg) in the patients with primary IAH. The patients with IAH had a significantly higher ICU- (37.9 vs. 19.1%; P = 0.001), 28-day (48.4 vs. 27.8%, P = 0.001), and 90-day mortality (53.7 vs. 35.8%, P = 0.004) compared to the patients without the syndrome. Patients with secondary IAH had a significantly higher ICU mortality than patients with primary IAH (P = 0.032). Development of IAH was identified as an independent risk factor for death (OR 2.52; 95% CI 1.23-5.14). CONCLUSIONS: Secondary IAH is less frequent, has a different time course and worse outcome than primary IAH. Development of IAH during ICU period is an independent risk factor for death. PMID- 18446320 TI - Apoptosis in the traumatic and degenerative tears of human meniscus. AB - The apoptotic bodies were observed aging in osteoarthritic cartilage and meniscus but there is still a lack of knowledge in the literature about the relationship between meniscal injury and apoptosis. The aim of this study is to investigate the apoptotic changes on meniscal tears caused by degeneration and trauma. Thirty eight specimens of human meniscal tissues harvested from cadavers and patients were selected from groups below the age of 40. There were 14 normal meniscal tissues from cadavers in the control group. There were 24 meniscal tissues harvested from patients who had had arthroscopic operations for meniscal tear due to degeneration or trauma. The torn meniscal samples were divided into two groups according to their etiologies, either degenerative or traumatic. Apoptotic cells were investigated in each of the three groups in the histopathological examination. There was statistically significant difference among the groups according to apoptotic index (p < 0.01). The mean indexes of apoptosis in both groups of torn meniscus (group 2 = 0.497 and group 3 = 0.725) were significantly higher than that in the normal tissue (group 1 = 0.237) (p < 0.01) but the difference between groups 2 and 3 was not significant (p > 0.001). This study indicates that an increase in the amount of apoptosis appeared to have a close relationship with meniscal tear caused by either trauma or degenerative changes. PMID- 18446321 TI - A long-term clinical follow-up study after arthroscopic intra-articular Bankart repair using absorbable tacks. AB - The aim of the study was to perform an independent long-term evaluation after arthroscopic Bankart repair using absorbable tacks. We hypothesise that arthroscopic Bankart repair using absorbable tacks will result in stable shoulders. Eighty-one consecutive patients (84 shoulders) with symptomatic, recurrent, anterior, post-traumatic shoulder instability were included in the study. All the patients had a Bankart lesion. The age of the patients was 28 (15 62) years. The number of dislocations prior to surgery was five (sublux-50). The operation was performed 28 (3-360) months after the index injury by one of three surgeons with a special interest in shoulder surgery using an intra-articular arthroscopic Bankart procedure involving absorbable Suretac fixators. Seventy six/84 (90%) of the shoulders (50 male, 23 female patients) were re-examined by two independent observers, after a follow-up period of 98 (46-129) months. In the long-term, the failure rate in terms of stability was 8/76 (11%) dislocations and a further 6/76 (8%) had experienced or had clinical signs of subluxation. The Rowe score was 91 (38-98) points at follow-up and the Constant score was 90 (56 100) points. The Constant score for the contralateral shoulder was 93 (69-100) points (P < 0.001). In the long-term, the arthroscopic Bankart procedure using Suretac fixators resulted in stable, well-functioning shoulders in the majority of patients. Eighteen per cent of the patients had experienced signs of instability during the follow-up period in terms of dislocations or subluxations. PMID- 18446323 TI - Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. AB - RATIONALE: Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that induces anxiolytic effects. However, the brain sites and mechanisms of these effects remain poorly understood. The dorsolateral periaqueductal gray (dlPAG) is a midbrain structure related to anxiety that contains receptors proposed to interact with CBD such as 5HT1A. In addition, since CBD has been shown to inhibit anandamide metabolism, CB1 receptors could also be involved in the effects of this cannabinoid. OBJECTIVES: To investigate if the dlPAG could be a possible site of the anxiolytic effects induced by CBD and if these effects depend on CB1 or 5HT1A receptors. MATERIALS AND METHODS: Male Wistar rats with cannulae aimed at the dlPAG were tested in the elevated plus maze (EPM) and the Vogel conflict test (VCT). RESULTS: CBD injected into the dlPAG produced anxiolytic-like effects in the EPM with a bell-shaped dose response curve. The anxiolytic effect of CBD was confirmed in the VCT. These effects were prevented by WAY100635, a 5HT1A receptor antagonist, but not by AM251, an antagonist of CB1 receptors. CONCLUSION: These results suggest the CBD interacts with 5HT1A receptors to produce anxiolytic effects in the dlPAG. PMID- 18446322 TI - Permanent improvement in deficient sensory inhibition in DBA/2 mice with increased perinatal choline. AB - RATIONALE: Schizophrenia patients and certain inbred mouse strains (i.e., DBA/2) show deficient sensory inhibition which has been linked to reduced numbers of hippocampal alpha7 nicotinic receptors and to underlying polymorphisms in the promoter region for the alpha7 gene. Increasing maternal dietary choline, a selective alpha7 agonist, during gestation has been shown to produce long-term changes in adult offspring behavior (i.e., improved learning and memory in rats). OBJECTIVES: The objective of this study is to improve sensory inhibition in DBA/2 mice through maternal choline supplementation. MATERIALS AND METHODS: DBA/2 dams were placed on normal (1.1 g/kg) or supplemented (5 g/kg) choline diet throughout gestation and lactation. Offspring were placed on normal diet at weaning and were assessed for sensory inhibition parameters at adulthood. Evoked EEG responses to identical paired auditory stimuli were compared. At the end of the study, the brains were collected for autoradiographic assessment of hippocampal levels of alpha-bungarotoxin binding to visualize alpha7 nicotinic receptors. RESULTS: Offspring mice which were choline supplemented during gestation showed significantly improved sensory inhibition compared to mice gestated on the normal choline diet. The improvement was produced by a significant reduction in the response to the second stimulus, demonstrating improved inhibition to that stimulus. There was a concurrent increase in alpha7 receptor numbers in both the CA1 and dentate gyrus regions of the hippocampus suggesting that this increase may be responsible for the improved inhibition. CONCLUSIONS: These data show that gestational choline supplementation produces permanent improvement in a deficit associated with schizophrenia and may have implications for human prenatal nutrition. PMID- 18446324 TI - Cataleptic effects of gamma-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABA(B) receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists. AB - RATIONALE: Gamma-hydroxybutyrate (GHB) is a gamma-aminobutyric acid (GABA) analog that is used to treat narcolepsy but that is also abused. GHB has many actions in common with the GABA(B) receptor agonist baclofen, but their underlying GABA(B) receptor mechanisms may be different. OBJECTIVE: The aim of this study is to further investigate a possible differential role of glutamate in GABA(B) receptor mediated effects of GHB and baclofen. MATERIALS AND METHODS: The experiments examined the effects of non-competitive antagonists at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors on GHB-induced catalepsy and compared these effects with those on baclofen-induced catalepsy. RESULTS: In C57BL/6J mice, ketamine, phencyclidine (PCP), and dizocilpine (MK-801) all enhanced GHB-induced catalepsy. They did so with a potency order (i.e., MK-801 > PCP > ketamine) consistent with their relative potencies as NMDA antagonists but not as inhibitors of dopamine or organic cation transporters. Ketamine, PCP, and MK-801 enhanced catalepsy along inverted U-shaped dose-response curves likely because higher doses affected motor coordination, which limited their catalepsy-enhancing effects. Doses that were maximally effective to enhance GHB-induced catalepsy did not affect the cataleptic effects of baclofen. CONCLUSIONS: The finding that NMDA receptor antagonists enhance the cataleptic effects of GHB but not those of baclofen is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and GABA(B) agonists are not identical. Differential interactions of glutamate with the GABA(B) receptor mechanisms mediating the effects of GHB and baclofen may explain why GHB is effective for treating narcolepsy and is abused, whereas baclofen is not. PMID- 18446325 TI - Activation of CB1 cannabinoid receptors in the dorsolateral periaqueductal gray reduces the expression of contextual fear conditioning in rats. AB - RATIONALE: Conditioned fear to context causes freezing and cardiovascular changes in rodents and has been used to measure anxiety. It also activates the dorsolateral column of the periaqueductal gray (dlPAG). Microinjections of cannabinoid agonists into the dlPAG produced anxiolytic-like effects in the elevated plus maze, but the effects of these treatments on fear conditioning remains unknown. OBJECTIVE: The objective of this study was to verify if intra dlPAG injection of the CB1 cannabinoid receptor agonist anandamide (AEA) or the anandamide transport inhibitor AM404 would attenuate behavioral (freezing) and cardiovascular (increase of arterial pressure and heart rate) responses of rats submitted to a contextual fear-conditioning paradigm. MATERIALS AND METHODS: Male Wistar rats with cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Fifteen minutes before the test, the animals received a first intra-dlPAG injection of vehicle or AM251, a CB1 receptor antagonist (100 pmol/200 nl), followed 5 min later by vehicle, AEA (5 pmol/200 nl) or AM404 (50 pmol/200 nl). Freezing and cardiovascular responses were recorded for 10 min. RESULTS: Freezing and cardiovascular responses were reduced by administration of either AEA or AM404 into the dlPAG before re exposition to the aversively conditioned context. These effects were abolished when the animals were locally pretreated with AM251. The latter drug, even at a higher dose (300 pmol), was ineffective when administered alone into the dlPAG. CONCLUSION: The results suggest that facilitation of endocannabinoid-mediated neurotransmission in the dlPAG, through activation of local CB1 receptors, attenuates the expression of contextual fear responses. PMID- 18446326 TI - Effects of acute systemic and intra-cerebral stimulation of cannabinoid receptors on sensorimotor gating, locomotion and spatial memory in rats. AB - RATIONALE: Cannabinoid CB(1) receptors in the brain are targets of both endocannabinoid signalling and the psychoactive compounds of the hemp plant. They mediate neuronal effects of their ligands in various corticolimbic and striatal circuits by presynaptic regulation of transmitter release. OBJECTIVES/METHODS: This study investigates acute systemic effects of the full CB(1) receptor agonist WIN 55,212-2 (WIN) on prepulse inhibition (PPI) of the acoustic startle response (ASR), locomotor activity and spatial memory retrieval in an eight-arm radial maze task. Furthermore, we tested the effect of local intra-cerebral micro infusions of WIN into the nucleus accumbens (NAc), ventral tegmental area (VTA), dorsal (dHIP) and ventral (vHIP) hippocampus and medial prefrontal cortex (mPFC). RESULTS: Systemic WIN (1.2 mg/kg) reduced PPI without affecting ASR, had no effect on locomotion in the open field, but impaired retrieval of spatial memory. Infusions of 5 microg/0.3 microl WIN into either NAc (core or shell), dHIP or VTA did not affect PPI and locomotion immediately afterwards. However, PPI was significantly reduced after intra-mPFC and intra-vHIP infusion of WIN. Furthermore, WIN infusion into dHIP increased the number of reference memory errors in the maze, suggesting impairment of memory retrieval. CONCLUSIONS: Our data support the notion that CB(1) receptor stimulation impairs sensorimotor gating most likely by modulation of neurotransmitter release in mPFC and vHIP. The lack of effects of local WIN infusions in NAc and VTA might be due to low receptor abundance in these regions. Additionally, CB(1) receptor activation in dHIP impairs spatial memory retrieval. Taken together, cortico-hippocampal cannabinoid receptors play an essential role in the regulation of cognitive and behavioural processes. PMID- 18446327 TI - Alprazolam potentiates the antiaversive effect induced by the activation of 5 HT(1A) and 5-HT (2A) receptors in the rat dorsal periaqueductal gray. AB - RATIONALE: Serotonin in the dorsal periaqueductal gray (DPAG) through the activation of 5-HT(1A) and 5-HT(2A) receptors inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with antipanic drugs that nonselectively or selectively blocks the reuptake of serotonin (e.g., imipramine and fluoxetine, respectively) enhances the inhibitory effect on escape caused by intra-DPAG injection of 5-HT(1A) and 5-HT(2A) receptor agonists. It has been proposed that these compounds exert their effect on panic by facilitating 5 HT-mediated neurotransmission in the DPAG. OBJECTIVES: The objective of this study was to investigate whether facilitation of 5-HT neurotransmission in the DPAG is also observed after treatment with alprazolam, a pharmacologically distinct antipanic drug that acts primarily as a high potency benzodiazepine receptor agonist. MATERIALS AND METHODS: Male Wistar rats, subchronically (3-6 days) or chronically (14-17 days) treated with alprazolam (2 and 4 mg/kg, i.p.) were intra-DPAG injected with (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), (+/-)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI), and midazolam, respectively, 5-HT(1A), 5-HT(2A/2C), and benzodiazepine receptor agonists. The intensity of electrical current that needed to be applied to the DPAG to evoke escape behavior was measured before and after the microinjection of these agonists. RESULTS: Intra-DPAG injection of the 5-HT agonists and midazolam increased the escape threshold in all groups of animals tested, indicating a panicolytic-like effect. The inhibitory effect of 8-OH-DPAT and DOI, but not midazolam, was significantly higher in animals receiving long-, but not short-term treatment with alprazolam. CONCLUSIONS: Alprazolam as antidepressants compounds facilitates 5-HT(1A)- and 5-HT(2A)-receptor-mediated neurotransmission in the DPAG, implicating this effect in the mode of action of different classes of antipanic drugs. PMID- 18446328 TI - Rivastigmine effects on EEG spectra and three-dimensional LORETA functional imaging in Alzheimer's disease. AB - OBJECTIVE: The objective of the study is to investigate the electrocortical and the global cognitive effects of 3 months rivastigmine medication in a group of mild to moderate Alzheimer's disease patients. MATERIALS AND METHODS: Multichannel EEG and cognitive performances measured with the Mini Mental State Examination in a group of 16 patients with mild to moderate Alzheimer's Disease were collected before and 3 months after the onset of rivastigmine medication. RESULTS: Spectral analysis of the EEG data showed a significant power decrease in the delta and theta frequency bands during rivastigmine medication, i.e., a shift of the power spectrum towards 'normalization'. Three-dimensional low resolution electromagnetic tomography (LORETA) functional imaging localized rivastigmine effects in a network that includes left fronto-parietal regions, posterior cingulate cortex, bilateral parahippocampal regions, and the hippocampus. Moreover, a correlation analysis between differences in the cognitive performances during the two recordings and LORETA-computed intracortical activity showed, in the alpha1 frequency band, better cognitive performance with increased cortical activity in the left insula. CONCLUSION: The results point to a 'normalization' of the EEG power spectrum due to medication, and the intracortical localization of these effects showed an increase of cortical activity in frontal, parietal, and temporal regions that are well-known to be affected in Alzheimer's disease. The topographic convergence of the present results with the memory network proposed by Vincent et al. (J. Neurophysiol. 96:3517-3531, 2006) leads to the speculation that in our group of patients, rivastigmine specifically activates brain regions that are involved in memory functions, notably a key symptom in this degenerative disease. PMID- 18446330 TI - Bioanalysis and environmental analysis in Spain. PMID- 18446329 TI - Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat. AB - RATIONALE: A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse related behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors. OBJECTIVE: Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists. MATERIALS AND METHODS: URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbine- and cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self administration was also tested. RESULTS: Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress- and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration. CONCLUSIONS: Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators. PMID- 18446331 TI - Stretch reflex coupling between the hip and knee: implications for impaired gait following stroke. AB - Individuals with hemiparetic stroke often exhibit an abnormal coupling between the frontal plane of the hip and saggital plane of the knee during gait. The purpose of this study was to determine if stretch sensitive reflexes, which are known to be altered following stroke, exhibit similar coupling between the muscles of the hip and knee in the post-stroke population. Eighteen subjects were recruited for this study including ten with hemiparesis resulting from stroke and eight unimpaired, age-matched controls. A servomotor was used to apply ramp and hold perturbations to both the hip and knee joints in separate sessions and electromyographic activity was recorded in eight muscles of the lower limb. Hip abduction perturbations elicited abnormal activation in rectus femoris (RF) in seven of ten stroke subjects with amplitudes ranging from 3.2 to 12.5% of the maximum voluntary contraction (MVC). Only two of eight control subjects exhibited any activity in RF and these responses were only 2.1 and 2.7% of MVC. To determine if the responses in the stroke group were a result of muscle stretch, a musculoskeletal model was used to simulate the experimental abduction perturbations and estimate muscle length changes. The simulation revealed that RF should be shortened by the perturbations and this suggests that the response was not likely due to direct stretch. Moreover, knee flexion perturbations elicited responses in the hip adductors (AL) with a mean amplitude of 5.1 +/- 3.8% of MVC across all stroke subjects while no significant responses were recorded in controls. The presence of a reciprocal, reflex-mediated coupling between RF and AL following stroke suggests that changes in the excitability of spinal networks may contribute to the development of abnormal inter-joint coordination patterns observed during hemiparetic gait. PMID- 18446333 TI - Craniofacial and temporal bone CT findings in cleidocranial dysplasia. AB - Cleidocranial dysplasia (CCD) is a multistructural polyostotic genetic disorder that results from mutation of the CBFA1 gene. Hearing loss is a frequent finding in CCD. We describe the CT craniofacial findings in CCD and provide a comprehensive discussion of the CT temporal bone findings in these patients. PMID- 18446332 TI - The haptic perception of spatial orientations. AB - This review examines the isotropy of the perception of spatial orientations in the haptic system. It shows the existence of an oblique effect (i.e., a better perception of vertical and horizontal orientations than oblique orientations) in a spatial plane intrinsic to the haptic system, determined by the gravitational cues and the cognitive resources and defined in a subjective frame of reference. Similar results are observed from infancy to adulthood. In 3D space, the haptic processing of orientations is also anisotropic and seems to use both egocentric and allocentric cues. Taken together, these results revealed that the haptic oblique effect occurs when the sensory motor traces associated with exploratory movement are represented more abstractly at a cognitive level. PMID- 18446334 TI - Multimodality imaging in the diagnosis of deep vein thrombosis and popliteal pseudoaneurysm complicating a sessile osteochondroma. AB - Synergistic use of ultrasonography, radiography, multidetector CT (MDCT) and MRI enabled a prompt and accurate diagnosis of a nonocclusive popliteal vein thrombus (deep venous thrombosis, DVT) and a pseudoaneurysm complicating a sessile osteochondroma in an 11-year-old boy who presented in the emergency department with sudden-onset nontraumatic pain in the posterior aspect of the knee. PMID- 18446335 TI - Pediatric neurodegenerative white matter processes: leukodystrophies and beyond. AB - Pediatric neurodegenerative white matter processes are complex, numerous and result from a vast array of causes ranging from white matter injury or inflammation to congenital metabolic disorders. When faced with a neurodegenerative white matter process on neuroimaging, the first step for the radiologist is to determine whether the findings represent a congenital metabolic leukodystrophy or one of various other white matter processes. In this review we first describe a general approach to neurodegenerative white matter disorders. We will briefly describe a few white matter diseases that mimic metabolic leukodystrophies. In the second half of the review we discuss an approach to distinguishing and classifying white matter leukodystrophies. PMID- 18446336 TI - A novel CD4 T-cell epitope described from one of the cervical cancer patients vaccinated with HPV 16 or 18 E7-pulsed dendritic cells. AB - Previously, safety and immunogenicity of human papillomavirus type 16 (HPV16) or 18 E7-pulsed dendritic cells (DC) vaccinations were demonstrated in a dose escalation Phase I clinical trial which enrolled ten patients diagnosed with stage IB or IIA cervical cancer (nine HPV 16-positive, one HPV 18-positive). The goal of the study was to define the T-cell epitopes of HPV 16 or 18 E7 protein in these patients in order to develop new strategies for treating HPV-associated malignancies. This was accomplished through establishing T-cell lines by stimulating peripheral blood mononuclear cells with autologous mature DC pulsed with the HPV 16 or 18 E7 protein, examining the T-cell responses using ELISPOT assays, and isolating E7-specific T-cell clones based on IFN-gamma secretion. Then, the epitope was characterized in terms of its core sequence and the restriction element. Twelve T-cell lines from eight subjects (seven HPV 16 positive, one HPV 18-positive) were evaluated. Positive T-cell responses were demonstrated in four subjects (all HPV 16-positive). All four were positive for the HPV 16 E7 46-70 (EPDRAHYNIVTFCCKCDSTLRLCVQ) region. T-cell clones specific for the E7 47-70 region were isolated from one of the subjects. Further analyses revealed a novel, naturally processed, CD4 T-cell epitope, E7 58-68 (CCKCDSTLRLC), restricted by the HLA-DR17 molecule. PMID- 18446337 TI - Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. AB - Abnormal accumulation of myeloid-derived suppressor cells (MDSC) is an important mechanism of tumor immune evasion. Cyclophosphamide (CTX) has also been shown in non-tumor bearing animals to cause transient surges in MDSC. Knowledge of MDSC is primarily based on preclinical work, and to date only few published studies have involved cancer patients. The goal of this study was to test the hypothesis that circulating MDSC levels correlate with clinical cancer stage, CTX-based chemotherapy, and metastatic tumor burden. Whole blood was collected from 106 newly diagnosed solid tumor patients (stages I-IV). Percentages of circulating MDSC (Lin(-/Lo), HLA DR-, CD33(+)CD11b(+)) were determined prior to initiation of systemic therapy. In 17 early stage breast cancer patients receiving doxorubicin cyclophosphamide chemotherapy every 14 days (ddAC) blood was collected on day 1 of each cycle. Circulating MDSC were significantly increased in cancer patients of all stages relative to healthy volunteers. A significant correlation between circulating MDSC and clinical cancer stage was also observed. Moreover, among stage IV patients, those with extensive metastatic tumor burden had the highest percent and absolute number of MDSC. Significant increases in circulating MDSC were observed with ddAC when compared with pretreatment levels. Circulating MDSC levels correlate with clinical cancer stage, ddAC, and metastatic tumor burden. This information must be incorporated into the design of future trials exploring immune-based therapeutic strategies. Pharmacologic modulation of MDSC should also be tested in future clinical trials. PMID- 18446338 TI - Phase I dose escalation study of weekly ixabepilone, an epothilone analog, in patients with advanced solid tumors who have failed standard therapy. AB - PURPOSE: To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and recommended Phase II dose of ixabepilone, administered weekly as an intravenous (IV) infusion to patients with solid tumors who have failed standard therapy. METHOD: This was an open-label, single-arm, Phase I, dose escalation study. RESULTS: The MTD of ixabepilone [30-min, weekly IV infusion on a 21-day schedule (N = 33)] was established at 25 mg/m(2). Grade 3 fatigue was the DLT in 2/4 patients treated at 30 mg/m(2). Ixabepilone was well tolerated at the MTD. Myelosuppression was rare, with no Grade 3/4 neutropenia. Due to the potential for cumulative neurotoxicity, the protocol was amended to a 1-h infusion, weekly for 3 weeks with a 1-week break. No DLT occurred at starting doses of 15, 20 and 25 mg/m(2) on this modified schedule (N = 51), although overall toxicity was less at 15 and 20 mg/m(2) than 25 mg/m(2). Five patients (2 on the 30-min/21-day schedule and 3 on the 60-min/28-day schedule) achieved durable objective partial responses across a variety of tumor types. CONCLUSIONS: Ixabepilone had an acceptable safety profile at the MTD of 25 mg/m(2) (as a 30 min weekly infusion on a continuous 21-day schedule) and at 20 mg/m(2) (as a 1-h weekly infusion on a modified 28-day schedule). The clinical activity and acceptable tolerability profile warrant further single- or combination-agent evaluation. PMID- 18446340 TI - Significance of risk factors for osteoporosis is dependent on gender and menopause in rheumatoid arthritis. AB - The aim of our study was to compare the significance of risk factors for osteoporosis according to gender and menopausal state in patients with rheumatoid arthritis (RA). Bone mineral density (dual X-ray absorptiometry), cumulative glucocorticoid dose, age, disease duration, body mass index (BMI) and parameters of disease activity and bone turnover were registered in 343 postmenopausal women, 100 premenopausal women and 108 men with RA. Osteoporosis was found in a significantly higher percentage in postmenopausal women (55.7%) and in men (50.5%) in comparison with premenopausal women (18%; P < 0.001). The following risk factors for osteoporosis were found: older age, low BMI and high cumulative glucocorticoid dose in postmenopausal women, low BMI and high cumulative glucocorticoid dose in men and low BMI in premenopausal women. There is a very high prevalence of osteoporosis not only in postmenopausal women but also in men with RA. Osteoporosis risk factors are strongly dependent from gender and menopausal state. PMID- 18446341 TI - Cutaneous application of local anaesthetic--a useful help in galactography. AB - Galactography is an important step in the diagnostic workup of abnormal nipple discharge. At times it is impossible to insert the cannula in the secreting duct and galactography cannot be performed. In such cases we tried applying local anaesthetic spray (LA) cutaneously to the nipple followed by a further insertion attempt. LA has enabled us to insert the galactography cannula in all patients so far. We concluded that after previous unsuccessful attempts, the presented technique may relax the duct orifice and therefore permit insertion of the galactography cannula into the secreting duct. PMID- 18446342 TI - Functional CT of squamous cell carcinoma in the head and neck: repeatability of tumor and muscle quantitative measurements, inter- and intra-observer agreement. AB - Our purpose was to determine the repeatability of squamous cell cancer in head and neck (SCCHN) and muscle tissue vascularity measurements as well as the inter- and intra-observer agreement using dynamic contrast-enhanced (DCE) multi-detector CT (MDCT). Twelve patients with histologically proven SCCHN were twice examined within 46 h. Measurement error and repeatability were assessed for each of the four functional parameters using the Bland-Altman plots. Two independent observers recorded the vascularity values of the tumor tissue; inter- and intra observer agreement was assessed using the Bland-Altman plot analysis and intraclass correlation coefficients. For the tumor, the mean difference (95% limits of agreement) was 0.40 ml/min/100 g tissue (-6.80, 9.60); 0.01 (-0.96, 0.97) ml/100 g tissue; 0.20 (-1.80, 2.30) s; and 0.40 (-2.00, 2.80) ml/min/100 g tissue for BF, BV, MTT, and PS, respectively. For the muscle, the mean difference (95% limits of agreement) was -0.18 (-1.70, 1.35), 0.04 (-1.17, 1.35), -0.10 ( 5.80, 5.60), and -0.10 (-2.20, 2.00), respectively. Measurement changes of at least +/-8%, 30%, 36%, and 13% were found to be significant for BF, BV, MTT, and PS, respectively. There was better intra- than inter-observer agreement. PMID- 18446343 TI - In vivo Gd-DTPA concentration for MR lung perfusion measurements: assessment with computed tomography in a porcine model. AB - A linear relationship between MR signal and contrast-agent concentration (CAC) of the arterial-input function (AIF) is crucial for MR lung-perfusion quantification. The aim was to determine the in-vivo real maximum CAC of the AIF, using cine CT measurements in a porcine model. A dilution series (Gd-DTPA, 0-20 mM) was examined by clinical time-resolved 3D-GRE MRI and by MDCT in cine CT mode. Using the CT setup, data were acquired in five pigs immediately after the injection of 0.05 mmol and 0.07 mmol/kg BW Gd-DTPA. For phantom measurements, mean signal values were determined using a region-of-interest (ROI) analysis and for animal measurements, a ROI was placed in the pulmonary trunk of the cine CT perfusion data sets. The CT phantom measurements were used to calculate the in vivo maximum CAC corresponding to the HU values obtained in the pulmonary trunk by the cine CT study. Linearity of the AIF of the CT perfusion measurements was verified using the MR phantom measurement results. MR phantom measurements demonstrated linearity for concentrations of 0-4 mM. CT phantom measurements showed linear relation for the entire CAC range. Comparing in-vivo and in-vitro measurements, three of five CA injections at 0.05 mmol/kg and all 0.07 mmol/kg injections exceeded the range of linearity in MRI. The CA dose for quantification of lung perfusion with time-resolved MR studies must be chosen carefully since even with low doses (0.05 mmol/kg) the CAC may exceed the range of linearity in the AIF. PMID- 18446344 TI - Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS): features and potential applications in oncology. AB - Diffusion-weighted magnetic resonance imaging (DWI) provides functional information and can be used for the detection and characterization of pathologic processes, including malignant tumors. The recently introduced concept of "diffusion-weighted whole-body imaging with background body signal suppression" (DWIBS) now allows acquisition of volumetric diffusion-weighted images of the entire body. This new concept has unique features different from conventional DWI and may play an important role in whole-body oncological imaging. This review describes and illustrates the basics of DWI, the features of DWIBS, and its potential applications in oncology. PMID- 18446345 TI - Nonmalignant papillary lesions of the breast at US-guided directional vacuum assisted removal: a preliminary report. AB - This study was conducted to assess the accuracy of US-guided directional vacuum assisted removal (US-DVAR) in evaluating nonmalignant papillary breast lesions. This retrospective study was approved by the institutional review board at our institution; patient consent was not required. We reviewed the clinical and pathology findings from a total of 39 papillary lesions diagnosed at vacuum assisted removal in 37 patients (age range, 26-60 years; mean age, 44.5 years). Over the follow-up period, we evaluated whether any histologic upgrade occurred and whether or not residual lesions were detected on follow-up imaging. US-DVAR of 39 lesions yielded tissue that was classified as benign in 35 and atypical in 4. Of the 35 lesions that were diagnosed as histologically benign at US-DVAR, 2 were surgically excised. Both of them yielded benign results. Of the 33 benign lesions that were not surgically excised, 28 (85%) were not seen at radiographic follow-up. Of the four lesions diagnosed as atypical at US-DVAR that were surgically excised, all the four were benign. None proved to be malignant. The upgrade rate was 0.0% (95% confidence interval, 0-9%). Among our patients, diagnosis by US-DVAR of benign papillary lesions proved to be accurate, and benign papillary lesions at US-DVAR did not need to be surgically excised for accurate diagnosis. PMID- 18446346 TI - Reference values for quantitative left ventricular and left atrial measurements in cardiac computed tomography. AB - To assess reference values for left ventricular (LV) and left atrial (LA) dimensions, global LV function, and LV-myocardial mass for cardiac CT. We examined 120 subjects undergoing a coronary angiography using 64-slice and dual source CT. All individuals had a low cardiovascular risk, normal ECG, negative biomarkers, and a normal cardiac CT examination. All subjects had a negative medical history of cardiovascular disease both on admission and at clinical 6 month follow-up. The following measurements were obtained: septal wall thickness (SWT), posterior wall thickness (PWT), LV inner diameter (LVID), LA anterior posterior diameter (LAD(sys)), end-systolic volume (ESV), and end-diastolic volume (EDV), LV-myocardial mass (LVMM). We found significant gender-related differences for all LV dimensions (SWT(sys), SWT(dia),PWT(sys),PWT(dia),LVID(sys),LVID(dia)). LAD(sys) showed no significant difference between males and females. Significant differences were found for global LV functional parameters including ESV, EDV, and SV, whereas no significant differences were found for the EF. LV-myocardial mass parameters showed significant gender-related differences. No significant correlation was found between any of these parameters and age. All data were transferred to percentile ranks. This study provides gender-related reference values and percentiles for LV and LA quantitative measurements for cardiac CT and should assist in interpreting results. PMID- 18446347 TI - Prospective comparison of high- and low-spatial-resolution dynamic MR imaging with sensitivity encoding (SENSE) for hypervascular hepatocellular carcinoma. AB - The purpose of this study was to prospectively evaluate the efficacy of high spatial-resolution dynamic MRI using sensitivity encoding (SENSE) in detection of hypervascular hepatocellular carcinoma (HCC). Thirty-five patients were included in this prospectively planned study, and 25 patients with 31 HCCs were assigned into three groups and underwent the following sequences: group A (n=11): three dimensional fast-gradient-echo (3D-FGE) high-spatial-resolution dynamic MRI (HR MRI) with SENSE; group B (n=10): 3D-FGE low-spatial-resolution dynamic MRI (LR MRI) with SENSE; and group C (n=14): 3D-FGE/LR-MRI without SENSE. For the quantitative analysis, the lesion-to-liver contrast-to-noise ratio (CNR) between the liver and HCCs was measured. For the qualitative analysis, overall image quality for each group was evaluated with a five-point scale analysis. The sensitivities for detection of HCCs were evaluated. The overall image quality in group A was significantly greater than both groups B and C (P<0.01). The sensitivity of lesion detection on HAP was not significantly higher in group A (100%) than group C (69.2%; P>0.05). In our pilot study on a small number of patients, image quality in HR-MRI with SENSE was superior to LR-MRI. A high detection rate was seen with HR-MRI with SENSE in the patients with hypervascular HCCs. PMID- 18446348 TI - Swim pacemakers in box jellyfish are modulated by the visual input. AB - A major part of the cubozoan central nervous system is situated in the eye bearing rhopalia. One of the neuronal output channels from the rhopalia carries a swim pacemaker signal, which has a one-to-one relation with the swim contractions of the bell shaped body. Given the advanced visual system of box jellyfish and that the pacemaker signal originates in the vicinity of these eyes, it seems logical to assume that the pacemakers are modified by the visual input. Here, the firing frequency and distribution of inter-signal intervals (ISIs) of single pacemakers are examined in the Caribbean box jellyfish, Tripedalia cystophora. It is shown that the absolute ambient light intensity, if kept constant, has no influence on the signal, but if the intensity changes, it has a major impact on both frequency and ISIs. If the intensity suddenly drops there is an increase in firing frequency, and the ISIs become more homogeneously distributed. A rise in intensity, on the other hand, produces a steep decline in the frequency and makes the ISIs highly variable. These electrophysiological data are correlated with behavioral observations from the natural habitat of the medusae. PMID- 18446349 TI - Prof. Dr. Luciano Basauri, M.D. (1932-2008)--ISPN President 1980-1981. PMID- 18446350 TI - Proximal colon cancer in patients aged 51-60 years of age should be tested for microsatellites instability. A comment on the Revised Bethesda Guidelines. AB - PURPOSE: The Bethesda guidelines suggest to perform microsatellite instability (MSI) test in early onset rectal cancer and not in patients>50 years with proximal colon cancer. The aim of the study was to evaluate whether the risk of high MSI (MSI-H) is greater in proximal colon cancer of patients 51-60 years old than in early-onset rectal cancer. METHODS: Consecutive colorectal cancer (CRC) patients were evaluated. Tumor location, cancer family history, MSI status and histology were recorded. Mutations in MLH1/MSH2 were investigated in MSI-H tumors. Patients were subdivided into groups: group A, proximal colon cancer patients 51-60 years old and groups B, C and D, patientsor=7 mg/dL, total bilirubin >or=0.9 mg/dL or aspartate aminotransferase >or=200 IU/L). Sixty-six percent (95% confidence interval [CI] 54-78%) of patients had a prompt defervescence in the mPSL+IVIG group compared with 44% (95% CI 26-62%) for the IVIG group (p=0.048). Coronary artery lesions were observed in 24.2% (95% CI 13.2-35.2%) and 46.9% (95% CI 28.6 65.2%) of patients in the mPSL+IVIG and IVIG groups, respectively (p=0.025). This is the first report showing that mPSL+IVIG is effective and safe as a primary treatment for high-risk KD patients. PMID- 18446366 TI - Drug utilisation profile in the Italian paediatric population. AB - OBJECTIVE: In order to evaluate the prescribing pattern in the Italian paediatric population, prescriptions involving 923,353 children under 14 years old and dispensed during 2006 by the retail pharmacies of 22 Italian local health units were analysed. MATERIALS AND METHODS: A total of 561,237 children (61%) received at least one drug prescription. The prescription prevalence rate was highest in children 3 years of age (78%), decreased with increasing age and was higher in boys than in girls (chi(2)=655; p<<0.001). Each treated child received an average of 3.2 prescriptions and 4.8 boxes. RESULTS: Antibiotics and anti-asthmatics were the more prescribed therapeutic classes and represented 80% of prescriptions. Amoxicillin+clavulanic acid was the most prescribed drug (24% of the overall population; 17% of all boxes), followed by inhaled beclometasone and amoxicillin. A total of 620 different drugs were prescribed and the ten leading drugs represented 64% of the prescribed boxes. Six of the ten most prescribed drugs were the same in all age groups. Wide differences were found in the prevalence rate between the different local health units; these ranged between 50.1 and 68.4% (p<<0.001). The prescription prevalence increased in the 2000-2002 period (from 62.2 to 68.3%) and slightly decreased afterwards. CONCLUSION: Despite some limitations, the systematic monitoring of prescriptions is a valuable tool for evaluating the appropriateness of the care. PMID- 18446367 TI - The use of prostate specific antigen (PSA) density in detecting prostate cancer in Chinese men with PSA levels of 4-10 ng/mL. AB - AIM: To investigate the utility of prostate specific antigen density for detecting prostate cancer in men with serum PSA levels of 4-10 ng/mL. METHODS: Between January 2003 and November 2007, 237 men (aged 48-84 years, median 71) with total PSA levels of 4-10 ng/mL participated in a protocol for prostate cancer screening. Eligible patients were recommended for transrectal ultrasonography (TRUS)-guided prostate biopsies after measuring prostate volumes transrectally. The diagnostic value of PSA levels and the free-to-total PSA ratio (f/tPSA), PSA densities (PSAD) were compared using receiver operating characteristic analysis. RESULTS: Prostate cancer was diagnosed in 44 (18.6%) of the 237 men who had biopsies. There were significant differences between the groups in the prostate volumes determined by TRUS, PSAD, PSA levels and f/tPSA, whereas there was no significant difference in patient age. The area under the curve (AUC) of PSA (0.6786) and PSAD (0.717) was similar and significantly greater than that of f/tPSA (AUC 0.329). PSAD was a significantly better indicator of prostate cancer than f/tPSA. The sensitivity and specificity of PSA density at a cutoff of 0.134 ng/mL(2) was 90 and 33.7%, respectively. CONCLUSION: PSAD was a better predictor of prostate cancer in Chinese men with PSA levels of 4-10 ng/mL, especially those who have had prior ultrasound-determined measurements of prostate volume. Our data suggest that different PSAD cutoffs may need to be defined for Chinese. PMID- 18446368 TI - Germline mutations in the von Hippel-Lindau disease (VHL) gene in mainland Chinese families. AB - BACKGROUND: von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. To date, more than 500 VHL families have been reported worldwide. However, few information is available about VHL germline mutations in mainland Chinese families. OBJECTIVE: To provide some preliminary information about the germline VHL mutations in mainland Chinese population. METHODS: A total of 27 index patients suspected of having VHL disease from unrelated Chinese families were studied by using direct DNA sequencing analysis and universal primer quantitative fluorescent multiplex polymerase chain reaction. RESULTS: The VHL germline mutations were detected in 26 (96%) probands. A total of 20 intragenic mutations (77%) were identified consisting of 12 missenses, 5 nonsenses, 2 micro-deletions and 1 novel intron mutation (IVS1 38C>T). Six large deletions (23%) were detected including four partial deletions and two complete deletions. Furthermore, a C>T substitution at nucleotide 470 (Pro86Leu) was observed in two unrelated Chinese families. Of note, two mutations (Asn78Ser and Ser80Ile) previously characterized as VHL type I mutations in Western VHL were associated with the type II Chinese family. In addition, a VHL germline mutation was also identified in a proband who did not fulfill the clinical diagnostic criteria for VHL disease. CONCLUSIONS: The spectrum of VHL germline mutations in mainland Chinese population is similar to that observed in Western population, and Genetic testing can be powerful in diagnosis and clinical management of VHL disease. PMID- 18446369 TI - Identification of transgelin as a potential novel biomarker for gastric adenocarcinoma based on proteomics technology. AB - PURPOSE: To find a biomarker for gastric adenocarcinomas (GA). METHODS: Ten protein expression profiles of GA and paired non-neoplastic mucosa tissues were analyzed by two-dimensional gel electrophoresis. Forty-two protein spots that were differentially expressed by twofold or greater between cancer and normal mucosa tissue were excised and identified by MALDI-TOF/TOF MS. One of the over expressed proteins identified in GA was transgelin, which was chosen for further verification by immunohistochemistry and western blotting. RESULTS: Forty-two distinct proteins that were differentially expressed at least twofold between the tissues were identified. Expression of 29 of these proteins was decreased (ratio >or= 2, P < 0.01), including adenosine deaminase; and 13 proteins displayed over expression in cancer tissue (ratio >or= 2, P < 0.01), including transgelin. The results of immunohistochemistry confirmed that transgelin was indeed over expressed in 22 cases of GA (22/41, 53.66%), with strong cytoplasmic staining in cancer cells of positive samples, this was absent in most paired non-neoplastic mucosa cells or gastric ulcer tissues (n = 20). Transgelin was found over expressed in 21 samples of cancer tissue (21/41, 51.22%) when detected by western blot. CONCLUSION: This work demonstrates that differentially expressed proteins can be identified by proteomics technology combined with immunohistochemistry and western blot analyses. We have identified one such protein, transgelin, as a novel biomarker for GA. PMID- 18446370 TI - Differential expression of cancer-related genes by single and permanent exposure to bone morphogenetic protein 2. AB - PURPOSE: Bone morphogenetic proteins (BMPs) are multifunctional regulators of various cell functions. The BMP-signalling network plays a pivotal role during embryogenesis and tumorigenesis. BMPs, e.g. BMP-2 exert their biological function in a time and concentration-dependent manner but also modulated by the context of the cellular microenvironment. In this study, we investigated the effect of a steady high level of BMP-2 versus a single application of BMP-2 on the breast cancer cell line MCF-7. METHODS: The effect of the incubation regimes was analysed by DNA microarray expression profiling. Data were verified by real-time PCR. The protein expression of apoptosis-related genes was studied by western blot analysis. RESULTS: We found a clear difference in the altered gene expression between the constant high level and the single application of BMP-2. After grouping the genes of interest into the biological processes of Gene Ontology, the group of apoptosis-related genes like BAX, BAG5 or PKR, was predominantly affected under the single-application regime of BMP-2. Among these protein kinase R was the most prominently regulated. Further studies on the protein level showed activation of PKR after 4 h with a subsequent enhanced phosphorylation of the PKR substrate eIF2alpha for several hours. CONCLUSIONS: The duration of treatment and the concentration of BMP-2 affect the global expression pattern of MCF-7 cells. Among the regulated cancer-related genes, the cohort of the apoptosis-related genes showed the pronounced alterations. Our data point to a novel role of BMP-2 in the regulation of the PKR pathway in tumorigenesis. PMID- 18446371 TI - Modification of a human monoclonal antibody Fab fragment specific for Plasmodium falciparum 19-kDa C-terminal merozoite surface protein 1 by site-directed mutagenesis. AB - We recently produced human monoclonal antibody Fab fragments specific for the 19 kDa C-terminal merozoite surface protein 1 of Plasmodium falciparum in a bacterial expression system. The effect of single amino acid modifications in the third complementarity-determining regions of the heavy and light chains on affinity was examined in one of the Fab fragments, Pf25. Recombination polymerase chain reaction was used to modify Tyr(92) or Ile(97) in the light chain and Val(101) or Trp(107) in the heavy chain. No effective replacements for Tyr(92) and Val(101) were found, but possible substitutions of Ile(97) with Gly, Leu, Glu, Ala and Ser, and of Trp(107) with Arg and Ser were demonstrated. Of these modified Fab fragments, the affinities of Fabs with Ile(97)-Leu and Trp(107)-Ser mutations were slightly higher than that of the original Fab. The effects of these modifications on the antigen-antibody interaction are discussed. PMID- 18446373 TI - Diversification of the barley and wheat blt101/wpi6 promoters by the Xumet element without affecting stress responsiveness. AB - BLT101-family plasma membrane proteins are found in a wide range of organisms from bacteria to nematodes and are involved in the regulation of cellular cation concentration under stress conditions. A comparison of the promoter regions of barley blt101 and its wheat ortholog, wpi6, revealed highly conserved nucleotide sequences between both genes and a unique insertion of a Xumet element in the blt101 promoter. The Xumet insertion occurred between a putative abscisic acid responsive element (ABRE) and the dehydration-responsive element/c-repeat (DRE/CRT) within the blt101 promoter. However, blt101 and wpi6 were induced similarly in response to ABA, drought and low temperature, suggesting that the insertion does not affect promoter functions. The Xumet insertion in the blt101/wpi6 promoter region was detected in five barley cultivars, but absent in two wheat cultivars tested, suggesting that the insertion is barley-specific. Genomic Southern blot analysis revealed a large number of Xumet sequences interspersed in the barley genome, whereas only one or very few copies are present in the wheat genome. The data suggested that an expansion in copy number of Xumet elements occurred in the barley genome through evolution. PMID- 18446372 TI - Global consequences of phosphatidylcholine reduction in Bradyrhizobium japonicum. AB - Phosphatidylcholine (PC) is the major phospholipid in eukaryotic membranes. In contrast, it is found in only a limited number of bacteria including members of the Rhizobiales. Here, PC is required for pathogenic and symbiotic plant-microbe interactions, as shown for Agrobacterium tumefaciens and Bradyrhizobium japonicum, respectively. Two different phospholipid N-methyltransferases, PmtA and PmtX1, convert phosphatidylethanolamine (PE) to PC by three consecutive methylation reactions in B. japonicum. PmtA mainly catalyzes the first methylation reaction converting PE to monomethyl PE, which then serves as substrate for PmtX1 performing the last two methylation reactions. Disruption of the pmtA gene results in a significantly reduced PC content causing a defect in symbiosis with the soybean host. A genome-wide survey for differentially expressed genes in the pmtA mutant with a custom-made Affymetrix gene chip revealed that PC reduction affects transcription of a strictly confined set of genes. Among the 11 up regulated genes were pmtX3 and pmtX4, which code for isoenzymes of PmtA. The expression of two typical two-component systems, a MarR like regulator and two proteins of a RND-type (resistance nodulation cell division) efflux system were differentially expressed in the pmtA mutant. Our data suggests that a decrease in the PC content of B. japonicum membranes induces a rather specific transcriptional response involving three different transcriptional regulators all involved in the regulatory fine-tuning of a RND type transport system. PMID- 18446374 TI - Beyond the reaction progress variable: the meaning and significance of isotopic incorporation data. AB - Ecologists conduct isotopic incorporation experiments to determine the residence time of various stable isotopes in animal tissues. These experiments permit determining the time window through which isotopic ecologists perceive the course of diet changes, and therefore the scale of the inferences that we can make from isotopic data. Until recently, the results of these experiments were analyzed using first-order, one-compartment models. Cerling et al. (Oecologia 151:175-189, 2007) proposed an approach they named the reaction progress variable to: (1) determine how many compartments are needed to describe a pattern of istopic incorporation, and (2) to estimate the size and rate constant of each pool. We elaborate on the approach described by Cerling et al. (Oecologia 151:175-189, 2007) by providing a way to estimate average retention times for an isotope in a tissue (and its associate error) for multi-compartment models. We also qualify the interpretation of the parameters in multi-compartment models by showing that many possible mechanisms yield models with the same functional form. Multi compartment models are phenomenological, rather than mechanistic descriptions, of incorporation data. Finally, we propose the use of information theoretic criteria to assess the number of compartments that must be included in models of isotopic incorporation. PMID- 18446375 TI - Virgins in the wild: mating status affects the behavior of a parasitoid foraging in the field. AB - In haplodiploid organisms, virgin females can produce offspring, albeit only sons. They may therefore face a trade-off between either: (1) searching for hosts and producing sons immediately; or (2) searching for mates and perhaps producing both sons and daughters later in life. Although this trade-off raises a theoretical interest, it has not been approached experimentally. The objective of this article is thus to document the effect of mating status on the foraging behavior of a haplodiploid parasitoid. For this, we recorded the behavior of virgin and mated female Lysiphlebus testaceipes (Hymenoptera: Braconidae) after being released, in the field, on a colony of their aphid hosts. Half of the virgin females were mated by a wild male after less than 10 min of foraging. Evidently, virgin females attract males while foraging on host patches, so that the two activities are not mutually exclusive. Nonetheless, virgin females stayed motionless more often and for longer periods than mated females. Consequently, they attacked aphids at a lower rate, and in turn, attacked fewer aphids on each patch. Moreover, contrary to mated females, virgins did not aggregate their progeny on large patches. We conclude that in L. testaceipes, the trade-off may not be as hypothesized. By dispersing across patches more than mated females, virgins could promote future mating opportunities for their sons and increase their inclusive fitness. However, by moving too frequently, females may lose immediate mating opportunities for themselves and the immediate advantage of producing offspring of both sexes. The observed behavior of virgin L. testaceipes females on host patches could reflect an optimal solution to such a trade-off. PMID- 18446376 TI - Oral-ibuprofen-induced acute renal failure in a preterm infant. AB - The side effects of indomethacin for ductal closure in preterm neonates (e.g. increased incidence of necrotizing enterocolitis, decreased cerebral blood volume and transient renal failure) have led clinicians to seek a safer alternative. Intravenous indomethacin and ibuprofen appear to be equally effective for patent ductus arteriosus closure, but oral ibuprofen remains an experimental option with theoretical advantages yet with potential side effects. We herein report a case of transient but severe acute renal failure developing in a preterm infant in whom oral ibuprofen was used and discuss the safety of this drug in relation to its pharmacokinetics. PMID- 18446377 TI - Glomerular tip changes in childhood minimal change nephropathy. AB - Segmental glomerular lesions at the tubular opening, or tip changes, are found in the renal biopsies of adults in many disorders, including some initially considered to show minimal change nephropathy. The hypothesis was that similar tip changes occurred in children. We reviewed a consecutive series of 50 biopsies, diagnosed as minimal change nephropathy, from 49 children. Segmental lesions were found in five biopsies. One biopsy showed lesions at the glomerular hilum. The patient was in remission at follow-up. Four biopsies showed only tip changes. Three patients were in remission, two on no treatment at follow-up, and one on ciclosporin. The other had chronic hepatitis B infection, with persistent proteinuria and segmental lesions at different sites in glomeruli. The other 44 children were nearly all in remission, 18 without treatment at follow-up, and the rest on various immunosuppressants, but one had persistent proteinuria and multiple segmental lesions. Series of childhood minimal change nephropathy, similar to this one, are likely to include cases of the glomerular tip lesion, under the original definition of minimal change nephropathy plus tip changes. This should make little difference in clinical practice, because the clinical course should resemble that of minimal change nephropathy. PMID- 18446378 TI - Successfully treated bilateral xanthogranulomatous pyelonephritis in a child. PMID- 18446379 TI - Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease. AB - Bone morphogenic protein-7 (BMP7) is a morphogen that is important for kidney development and which is also an integral part of the kidney's physiological response to repair of acute kidney injury. Several studies demonstrate that preexisting renal BMP7 pathways can be utilized by administering recombinant BMP7 to protect the kidney in experimental models of chronic kidney disease (CKD). Effectiveness of recombinant BMP7 in animal studies raises the possibility that the BMP7 pathway could be equally utilized to treat patients with CKD and interstitial fibrosis. However, regulation of BMP7 activity in the kidney is complex. BMP7 activity in the kidney is not only determined by availability of BMP7 itself, but also by a balance of agonists, such as Kielin/chordin-like protein (KCP) or BMP receptors, and antagonists including gremlin, noggin, or uterine sensitization-associated gene-1 (USAG-1). Presence of BMP7 agonists and antagonists has to be considered when recombinant BMP7 is supplemented to treat injured kidneys. Here we summarize recent insights into the role of BMP7 in acute and chronic kidney injury and discuss the implications for future directions of antifibrotic therapies. PMID- 18446380 TI - Saccharomyces boulardii prevents oral-poliovirus vaccine-induced IgA nephropathy in mice. AB - Immunoglobulin A nephropathy (IgAN) is associated with mucosal IgA defect. Probiotics regulate specific and innate immunity. We evaluated the effect of Saccharomyces boulardii on experimental IgAN in mice. Four groups of BALB/c mice (eight for each) were formed. Group 1 was immunized by oral poliovirus vaccine (OPV) at 0, 14, and 28 days. Group 2 was also given S. boulardii in addition to OPV. Group 3 was given only S. boulardii, whereas group 4 received no treatment. At week 6, after urine and serum samples were obtained for urinalysis and serum creatinine and IgA measurements, all animals were sacrificed to get their kidneys for histopathological evaluation. Urinalysis and serum creatinine levels were normal in all groups. Serum IgA level was increased only in group 1. Whereas group 1 had mesangial proliferation, histology was normal in the other groups. Predominant IgA deposition was universal in group 1, whereas it was either not present or minimal in other groups. Three mice in group 1 also had C3 deposition, which was absent in other groups. Electron microscopy revealed mesangial proliferation, matrix expansion, focal glomerular basement membrane thickening and electron-dense deposits in group 1 only, whereas the other groups were normal. In conclusion, enteral S. boulardii prevented OPV-induced IgAN in mice. PMID- 18446381 TI - The kidney in leptospirosis. AB - Leptospirosis is a worldwide zoonosis. Typically, patients are young men, although children can be affected. In children, this disease causes mainly alterations of sensorium. Acute renal failure and jaundice (Weil's syndrome) are less common in children than in adults. The main renal histological findings are acute interstitial nephritis and acute tubular necrosis. Acute renal failure is characterized by hypokalemia and nonoliguria. Many factors are involved in its physiopathology: hypotension, hypovolemia, rhabdomyolysis, hyperbilirubinemia, and, primarily, the direct action of leptospiral proteins. Antibiotic administration (especially early administration) reduces length of hospitalization and leptospiruria. For children, even late antibiotic treatment has been shown to reduce the extent of acute renal failure and thrombocytopenia. Although the best method of dialysis is not yet established, early and intensive dialysis can decrease mortality. Mortality in patients with acute renal failure is approximately 15-20% in association with the presence of oliguria, higher levels of creatinine, and older age. Functional recovery is fast and complete; however, abnormal urinary concentration can persist. PMID- 18446383 TI - Study of the effect of donor source on graft and patient survival in pediatric renal transplant recipients. AB - Evaluation of the impact of live unrelated kidney donor (LURD) source on the outcome of renal transplantation is not adequately studied. We aimed to compare the long-term outcome of kidney transplantation from LURDs to that from living related donors (LRDs) among a pediatric recipient population. This study comprised 235 pediatric recipients who received their kidney grafts between 1976 and 2005 at our center. These patients were further subdivided into two groups according to donor source (211 with LRDs) and (24 with LURDs). All patients' data were assessed with special emphasis on graft and patient survival as well as posttransplant medical complications. Both groups were comparable regarding graft and patient survival at 1, 5, and 10 years. Despite higher incidence of acute vascular rejection among recipients with LURD (12%) vs. LRD (2.8%) (P = 0.03), there was no difference in the incidence of chronic allograft nephropathy. Moreover, the overall incidence of posttransplant complications was comparable among the two groups. In our series, kidney survival was poorer in LURDs compared with LRDs. However, the number of patients with LURD was small, and the difference in results was also small and justifies LURD in exceptional cases when LRD is not possible. PMID- 18446382 TI - Genetic causes of hypercalciuric nephrolithiasis. AB - Renal stone disease (nephrolithiasis) affects 3-5% of the population and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in over 35% of patients and may occur as a monogenic disorder that is more likely to manifest itself in childhood. Studies of these monogenic forms of hypercalciuric nephrolithiasis in humans, e.g. Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) co-transporter, the renal outer medullary potassium (ROMK) channel, the voltage-gated chloride channel, CLC-Kb, the CLC-Kb beta subunit, barttin, or the calcium-sensing receptor (CaSR). Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due to mutations of the chloride/proton antiporter 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium phosphate co-transporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to hypercalciuria and nephrolithiasis. PMID- 18446384 TI - Cerebral glucose metabolic abnormality in patients with congenital scoliosis. AB - A possible association between congenital scoliosis and low mental status has been recognized, but there are no reports describing the mental status or cerebral metabolism in patients with congenital scoliosis in detail. We investigated the mental status using a mini-mental status exam as well as the cerebral glucose metabolism using F-18 fluorodeoxyglucose brain positron emission tomography in 12 patients with congenital scoliosis and compared them with those of 14 age-matched patients with adolescent idiopathic scoliosis. The mean mini mental status exam score in the congenital scoliosis group was significantly lower than that in the adolescent idiopathic scoliosis group. Group analysis found that various brain areas of patients with congenital scoliosis showed glucose hypometabolisms in the left prefrontal cortex (Brodmann area 10), right orbitofrontal cortex (Brodmann area 11), left dorsolateral prefrontal cortex (Brodmann area 9), left anterior cingulate gyrus (Brodmann area 24) and pulvinar of the left thalamus. From this study, we could find the metabolic abnormalities of brain in patients with congenital scoliosis and suggest the possible role of voxel-based analysis of brain fluorodeoxyglucose positron emission tomography. PMID- 18446385 TI - Revision strategies for complications and failure of vertebroplasties. AB - Percutaneous vertebroplasty is widely discussed in the management of osteoporotic spinal compression fracture, but few reports are available concerning salvage procedures after failure of this technique. We studied 22 percutaneous vertebroplasty patients who required revision surgery upon presentation of new symptoms postoperatively. The indications for revision surgery included recurrent intractable back pain with no response to medical treatment, infectious spondylitis, cement leakage with neurologic deficit, and cement dislodgement and/or fragmentation. Five patients underwent repeated percutaneous vertebroplasty of the initially cemented vertebrae. Seventeen patients underwent anterior, posterior, or combined anterior and posterior surgery. Four patients required a third surgical procedure because of poor augmentation with cement, subsidence of the anterior bone graft, or pullout of the instrumentation. Finally, four (18%) patients underwent repeat vertebroplasty, two (9%) patients underwent anterior surgery only, one (5%) patient underwent posterior surgery only, and 15 (68%) patients underwent combined anterior and posterior surgery; all but one regained ambulatory status equivalent to that prior to surgery. In conclusion, percutaneous vertebroplasty is a simple and effective, but not risk- or complication-free procedure for the treatment of osteoporotic spinal compression fracture. The spine surgeon should be familiar with varied approaches and techniques for revision surgery. Combined anterior and posterior surgery seems to be the most secure salvage method to treat severely osteoporotic patients in whom percutaneous vertebroplasty initially failed. PMID- 18446386 TI - The international spine registry SPINE TANGO: status quo and first results. AB - With an official life time of over 5 years, Spine Tango can meanwhile be considered the first international spine registry. In this paper we present an overview of frequency statistics of Spine Tango for demonstrating the genesis of questionnaire development and the constantly increasing activity in the registry. Results from two exemplar studies serve for showing concepts of data analysis applied to a spine registry. Between 2002 and 2006, about 6,000 datasets were submitted by 25 centres. Descriptive analyses were performed for demographic, surgical and follow-up data of three generations of the Spine Tango surgery and follow-up forms. The two exemplar studies used multiple linear regression models to identify potential predictor variables for the occurrence of dura lesions in posterior spinal fusion, and to evaluate which covariates influenced the length of hospital stay. Over the study period there was a rise in median patient age from 52.3 to 58.6 years in the Spine Tango data pool and an increasing percentage of degenerative diseases as main pathology from 59.9 to 71.4%. Posterior decompression was the most frequent surgical measure. About one-third of all patients had documented follow-ups. The complication rate remained below 10%. The exemplar studies identified "centre of intervention" and "number of segments of fusion" as predictors of the occurrence of dura lesions in posterior spinal fusion surgery. Length of hospital stay among patients with posterior fusion was significantly influenced by "centre of intervention", "surgeon credentials", "number of segments of fusion", "age group" and "sex". Data analysis from Spine Tango is possible but complicated by the incompatibility of questionnaire generations 1 and 2 with the more recent generation 3. Although descriptive and also analytic studies at evidence level 2++ can be performed, findings cannot yet be generalised to any specific country or patient population. Current limitations of Spine Tango include the low number and short duration of follow-ups and the lack of sufficiently detailed patient data on subgroup levels. Although the number of participants is steadily growing, no country is yet represented with a sufficient number of hospitals. Nevertheless, the benefits of the project for the whole spine community become increasingly visible. PMID- 18446387 TI - "Iron priming" guides folding of denatured aporubredoxins. AB - The relationship between iron uptake by aporubredoxins (apoRds) and formation of native holorubredoxins (holoRd), including their Fe(SCys)(4) sites, was studied. In the absence of denaturants, apoRds exhibited spectroscopic features consistent with structures very similar to those of the folded holoRds. However, additions of either ferric or ferrous salts to the apoRds in the absence of denaturants gave less than 40% recovery of the native holoRd circular dichroism and UV-vis spectroscopic features. In the presence of either 6 M urea or 6 M guanidine hydrochloride, the nativelike structural features of the apoRds were absent. Nevertheless, nearly quantitative recoveries of the native holoRd spectroscopic features were achieved by addition of either ferric or ferrous salts to the denatured apoRds without diluting the denaturant. Consistent with this observation, the native spectroscopic features were unaffected by addition of the same denaturant concentrations to the as-isolated holoRds. Denaturing concentrations of urea or guanidine hydrochloride also increased the rates of holoRd recoveries from apoRds and ferrous salts. Mass spectrometry confirmed that ferric iron binding to the denatured apoRds precedes the recoveries of protein secondary structures and Fe(SCys)(4) sites. Thus, iron binding to the apoRds guides, both kinetically and thermodynamically, refolding to the native holoRd structures. Our results imply that the ferrous oxidation state would more efficiently drive formation of the native holoRd structure from the nascent apoprotein in vivo, but that the Fe(SCys)(4) site must attain the ferric state in order to achieve its native structure. PMID- 18446388 TI - Long-range charge transport through double-stranded DNA mediated by manganese or iron porphyrins. AB - Guanine oxidation by electron transfer results in the formation of a guanine radical cation, which is at the origin of long-range charge transport through double-stranded DNA. It is possible to observe guanine lesions at a long distance from the oxidative reagent covalently bound to DNA owing to the migration of the positive hole in the DNA pi-stacks. This phenomenon of long-range hole transport is classically studied in the literature with photosensitizers used as one electron oxidants. It is shown in the present work that the process of long-range charge transport and the concomitant formation of guanine lesions at a long distance can be observed also in the case of two-electron oxidants. This is the signature of the formation of a transient guanine radical cation in the course of the two-electron abstraction process and consequently evidence of the separated one plus one electron abstraction steps. Long-range charge transport is likely to be a universal mechanism for any two-electron oxidant acting by electron abstraction provided that the second electron abstraction is slower than hole transfer. PMID- 18446389 TI - The effect of periodontal treatment on metabolic control of type 1 diabetes mellitus. AB - The objective of this investigation was to study the effect of nonsurgical periodontal treatment, with or without systemic administration of doxycycline, on the metabolic control of patients with type 1 diabetes. Sixty type 1 diabetic subjects with moderate to severe periodontitis were recruited. Periodontal parameters were measured, and blood samples were obtained to evaluate glycosylated hemoglobin (HbA1c). Group 1 (30 patients) was treated with scaling, root planning, and chlorhexidine rinses for 3 months in conjunction with systemic administration of doxycycline (100 mg once a day for 15 days). Group 2 (30 patients) received the same periodontal treatment but without the use of doxycycline. The paired Student t-test was used to detect differences between glycosylated hemoglobin means before and 3 months after periodontal treatment in group 1 and group 2 separately. Changes in mean HbA1c after treatment were 0.07% in group 1 and -0.06% in group 2, which were not statistically significant after 3 months. Significant changes were not found even in patients with the best response to periodontal treatment. Periodontal treatment in type 1 diabetic patients after 3 months follow-up did not improve metabolic control of diabetes as measured by glycosylated hemoglobin. PMID- 18446391 TI - Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children. AB - The objective of this study is to evaluate the safety and efficacy of vagus nerve stimulation (VNS) in very young children suffering from catastrophic epilepsy and status epilepticus. We reviewed files of 60 VNS-implanted children at our institution and we selected six very young patients, less than 3 years old (mean age at implant 1.6 years). All patients suffered from severe cognitive impairment and catastrophic epilepsy with underlying diagnosis of hemimegalencephaly (1), hypoxic-ischemic encephalopathy (1), tuberous sclerosis complex (1), and malignant migrating partial epilepsy of infancy (3). Three patients were VNS implanted during admission at intensive care unit (ICU) after developing life threatening status epilepticus. The mean follow-up time was 41.6 months. The VNS was implanted using a single cervical incision. No surgery-related complications were observed. Four of six children have shown a significant, persistent improvement in seizure control (range, 60-90%). In patients with status, insertion of the vagal nerve stimulator allowed early cessation of status and discharge from ICU. Quality of life and parental satisfaction improved and for three children there was some milestone evolution. Catastrophic epilepsy in infancy can be devastating and difficult to treat with drugs and surgery. If resective surgery is inappropriate or refused, VNS can be considered as a well tolerated and effective procedure even in toddlers affected by severe epilepsy and multiple developmental disabilities. PMID- 18446390 TI - Preoperative imaging procedures for lower wisdom teeth removal. AB - The aims of this paper were to critically review the role of radiographic imaging before lower third molar removal and to suggest a strategy for preoperative imaging based on available scientific evidence and clinical experience. Original articles and reviews including the MESH terms "third molar" and "radiography" were selected from the Medline database. Other sources were taken from references of selected papers. It was found that the scientific evidence on the usefulness of different preoperative imaging techniques of wisdom teeth is low. Therefore, information gathered from the literature was combined with the authors' clinical experience to suggest a strategy for preoperative imaging of lower third molars. Currently available radiological techniques used for preoperative imaging of lower third molars are also presented. It is suggested that panoramic and/or intraoral radiographs are sufficient as preoperative imaging in the vast majority of cases where there is no overlap between the mandibular canal and the wisdom tooth. Supplement with a posteroanterior open mouth projection will solve most of the remaining cases. In a restricted number of cases where there is an intimate relationship between the mandibular canal and the wisdom tooth, volume tomography such as cone beam computed tomography or low-dose computed tomography is indicated. PMID- 18446392 TI - An economic evaluation of a perindopril-based blood pressure lowering regimen for patients who have suffered a cerebrovascular event. AB - OBJECTIVES: Cerebrovascular disease (or stroke) is one of the main causes of long term disability and the second leading cause of death worldwide. The economic impact of stroke is clearly seen, as it is the largest single cause of bed occupancy in hospitals in England and accounts for 6% of hospital costs. This analysis is the first to quantify the economic consequences of a blood pressure lowering regimen based on the PROGRESS study (perindopril-based regimen), for reducing future cardiovascular events. DESIGN: A Markov decision analytical model was used to estimate the cost per quality adjusted life year (QALY) of blood pressure lowering in the treatment of patients presenting with a cerebrovascular event. The health states are based upon Barthel indices for which resource utilisation and health benefits have previously been estimated. SETTING: The participants for the economic analysis were obtained from the PROGRESS study database. 6,105 clinical study participants were recruited through both primary and secondary care centres. PARTICIPANTS: The mean age was 64 years; 70% were male in the original study. INTERVENTIONS: In the PROGRESS study, blood pressure lowering by a perindopril-based regimen was compared to standard care. MAIN OUTCOME MEASURES: Cost per quality adjusted life year for the duration of the study (4 years) and for a time span of 20 years. RESULTS: Using only direct hospital medical costs, the cost per QALY for a perindopril based regimen is pound 6,927 for the base study period and pound 10,133 for a 20-year time period. These results are sensitive to the cost of perindopril, the cost of the stroke unit, length of stay, and to a lesser extent, the cost of indapamide. CONCLUSIONS: This analysis demonstrates a cost-effective treatment for patients suffering a cerebrovascular event with a blood pressure lowering regimen. The findings of this study are in line with current decisions and guidance by the national institute for health and clinical excellence (NICE) in England. PMID- 18446393 TI - Regulatory mechanisms controlling antibiotic production in Streptomyces clavuligerus. AB - Streptomyces clavuligerus produces a large array of natural compounds with antibiotic, antitumor, beta-lactamase inhibition or inmunomodulating activities. The production of cephamycin C, clavulanic acid and other compounds with a clavam structure has been studied for many years. A network of regulatory mechanisms is present in S. clavuligerus to control the formation of different compounds by pathway-specific regulators or pleiotropic regulators. The possible existence of a gamma-butyrolactone signaling system in this streptomycete is emerging. In addition, S. clavuligerus possesses a stringent control mechanism somehow different from those previously reported in other Streptomyces species. PMID- 18446395 TI - A novel selective-excitation RF pulse for magnetic resonance imaging. AB - OBJECT: A selective-excitation radiofrequency (RF) pulse that uses hard pulses composed of a sequence of composite pulses with positive and negative phases (P/N pulse) is proposed herein. Because the amplitude of the RF signal is unchanged during the excitation, RF amplification can be accomplished using a nonlinear RF power amplifier (i.e., class C or D type). MATERIALS AND METHODS: In this article, Fourier series have been first used to analyze the equivalence between the proposed P/N pulse and the conventional soft pulse on selective excitation. Subsequently, computer simulations based on density-matrix theory are used to compare the excitation profiles of both the soft and the P/N pulses. RESULTS: The excitation profiles of the P/N pulses have been measured experimentally through a home-built 0.3-T magnetic resonance imaging (MRI) system. In addition, several slices of images have been obtained as proofs by using the multislice two dimensional spin echo sequence through replacement of the conventional soft pulse by the proposed P/N pulse. CONCLUSION: Because the perfect selectivity of the proposed P/N pulse, it can be used for imaging studies to improve the efficiency of amplification at the lowest cost. PMID- 18446394 TI - P846, a new gadolinium based low diffusion magnetic resonance contrast agent, in characterizing occlusive infarcts, reperfused ischemic myocardium and reperfused infarcts in rats. AB - OBJECT: This study has two objectives: (1) to compare the kinetics of low diffusion P846 with Gd-DOTA using inversion recovery echo planar (IR-EPI) magnetic resonance (MR) imaging and (2) to determine the potential of P846 in defining myocardial viability in hearts subjected to various injuries using T1 weighted spin echo (T1-SE). MATERIALS AND METHODS: Rats were subjected to (1) occlusive infarcts (n = 16), (2) reperfused ischemic injuries (n = 8) or (3) reperfused infarcts (n = 16). A dose of 0.05 mmol/kg P846 was compared to 0.1 mmol/kg Gd-DOTA. IR-EPI and T1-SE images were obtained during 60 min. T(1), DeltaR(1) and DeltaR(1) ratio were measured on IR-EPI. Infarct extents were evaluated on T1-SE and compared with histochemical staining. RESULTS: Blood DeltaR(1) was higher at 5 min after P846 (6.36 +/- 0.32 s(-1)) than after Gd-DOTA (1.30 +/- 0.14 s(-1); P < 0.001). With P846, occlusive infarcts appeared as a hypoenhanced region surrounded by a hyperenhanced rim that lasted for 60 min. The increase in the DeltaR(1) ratio value was slower after P846 than with Gd-DOTA in the reperfused infarcts, suggesting low diffusion/convection of P846. Gd-DOTA homogenously enhanced both occlusive and reperfused infarcts at 30 min. CONCLUSION: P846 provides better contrast and extended discrimination between occlusive and reperfused infarcts compared with Gd-DOTA. The gadolinium dose could be reduced with P846. PMID- 18446396 TI - Human oscillatory potentials: intensity-dependence of timing and amplitude. AB - Oscillatory potentials (OPs) have been described as reduced in amplitude or delayed in diabetic retinopathy, glaucoma, and vascular occlusions. Although OPs are thought to have useful diagnostic applications, some of their basic physiologic properties remain to be fully described. In the present study, we examined the relationship between the timing and amplitude of OPs and stimulus intensity. Five normal volunteers had one eye anesthetized and dilated. Dark adapted full-field ERGs were recorded to white stimuli of 0.0125-40 cd s/m(2). The timing of the OPs was measured as the sum of the time to the peak (TTP) of four peaks beginning at 15 ms after the stimulus. The amplitude was taken as the sum of the amplitudes of those same peaks. As an alternative value, OP strength was represented by the area under the OP curve or power around 150 Hz (+/-30 Hz) in the frequency domain. The OP timing, as measured by TTP, was found to be inversely related to stimulus intensity. OP-amplitudes grew with intensity, but then declined for stimulus intensities above about 4 cd s/m(2). At bright light intensities, the TTP continued to shorten, yet amplitudes, power, and area all declined. Individual OPs behaved similarly and reflected the overall response pattern of the group as a whole. Brighter stimuli produced larger, faster OPs for stimulus strengths up to the intensity standard used to produce OPs (3.5 cd s/m(2)). We have extended the range of stimuli to some 10-fold higher than the ISCEV standard for producing OPs and found that the timing continued to accelerate but that OP-amplitudes, OP-area, and OP-power all decline at higher stimulus intensities. These alternative measures of OP energy are easily measured and may be useful for further studies. PMID- 18446397 TI - Correlation between retroglossal airway size and body mass index in OSA and non OSA patients using cone beam CT imaging. AB - Most obstructive sleep apnea (OSA) patients are overweight, and OSA is substantially more common in obese individuals. In morbidly obese patients, at least 70% suffer from OSA. However, the exact mechanism by which obesity causes OSA is unclear. The aim of this study is to evaluate the retroglossal airway configuration quantitatively and to make clear the relationship between Body mass index (BMI) and airway configuration. This retrospective study included 15 OSA patients (male = 11; female = 4) and 14 normal controls (male = 8; female = 6). We studied the airway configuration on an axial slice at the level of the anterior-inferior corner of the second cervical vertebra. Maximum anterior posterior diameter (AP) and lateral width (LW) of the airway were measured, and the square area (SA) was calculated. The airway cross-section area (AWA) was also measured, and then the AWA/SA ratio was calculated. AP, LW, and AWA were not statistically significantly different between controls and OSA patients. On the other hand, the AWA/SA ratio in OSA patients was 8.8% statistically significantly smaller than in controls after adjusting for sex, age, and BMI. In this sample, there was a negative correlation between age and the AWA/SA ratio but only in the OSA group. The AWA/SA ratio was significantly negatively correlated with OSA status (R = -0.5; p = 0.008) after adjusting for BMI and age. In this present study, we could evaluate the retroglossal airway configuration quantitatively. The AWA/SA ratio was correlated with OSA status after adjusting for BMI and age. PMID- 18446398 TI - Multiscale analysis of reaction networks. AB - In most natural sciences there is currently the insight that it is necessary to bridge gaps between different processes which can be observed on different scales. This is especially true in the field of chemical reactions where the different abilities to form bonds between different types of atoms and molecules create much of the properties we experience in our everyday life, especially in all biological activity. There are essentially two types of processes related to biochemical reaction networks, the interactions among molecules and interactions involving their conformational changes, so in a sense, their internal state. The first type of processes can be conveniently approximated by the so-called mass action kinetics, but this is not necessarily so for the second kind: here molecular states do not define any kind of density or concentration. In this paper, we demonstrate the necessity to study reaction networks in a stochastic formulation for which we can construct a coherent approximation in terms of specific space-time scales and the number of particles. The continuum limit procedure naturally creates equations of Fokker-Planck type where the evolution of the concentration occurs on a slower time scale when compared to the evolution of the conformational changes, for example triggered by binding or unbinding events with other (typically smaller) molecules. We apply the asymptotic theory to derive the effective, i.e. macroscopic dynamics of a general biochemical reaction system. The theory can also be applied to other processes where entities can be described by finitely many internal states, with changes of states occurring by arrival of other entities described by a birth-death process. PMID- 18446399 TI - Imaging of peritoneal carcinomatosis with FDG PET-CT: diagnostic patterns, case examples and pitfalls. AB - Early diagnosis of peritoneal spread in malignant disease is essential to prevent unnecessary laparotomies and to select the patients in whom complete cytoreduction is feasible. Although anatomic imaging is the mainstay for evaluating peritoneal seeding, small neoplastic implants can be difficult to detect with CT and MR imaging. FDG PET-CT has the potential to improve detection of peritoneal metastases as lesion conspicuity is high at PET due to low background activity and fused PET-CT offers the combined benefits of anatomic and functional imaging. Correlation of uptake modalities with the pathogenesis of intraperitoneal spread of malignancies, provides a rational system of analysis and is essential to define disease. Distinct patterns appear to predict the presence of either nodular or diffuse peritoneal pathology. Main pitfalls are related to normal physiologic activity in bowel loops and blood vessels or focal retained activity in ureters and urinary bladder. PET-CT is most suitable in patients with high tumor markers and negative or uncertain conventional imaging data and in selecting patients for complete cytoreduction. FDG PET-CT adds to conventional imaging in the detection and staging of peritoneal carcinomatosis and is a useful diagnostic tool in monitoring response to therapy and in long term follow-up. PMID- 18446400 TI - CT enterography vs. capsule endoscopy. AB - Small bowel imaging has been revolutionized by CT enterography and capsule endoscopy. We present an overview of both imaging modalities, discuss advantages and disadvantages of each, and compare findings in Crohn's disease, occult gastrointestinal bleeding, and small bowel tumors. Both methods complement each other often providing information that the other one cannot. PMID- 18446401 TI - Colonic perforation during screening CT colonography using automated CO2 insufflation in an asymptomatic adult. AB - CT colonography has become a potential alternative technique to optical colonoscopy for the detection of colorectal polyps and cancer. While considered safer than optical colonoscopy, CT colonography is not without risk. We report a case of colonic perforation during CT colonography using automated CO(2) insufflation and present procedural changes to help minimize the adverse effects of perforation when it occurs. PMID- 18446402 TI - Results of long-term follow-up observations of blepharoptosis correction using the palmaris longus tendon. AB - BACKGROUND: The frontalis sling procedure is a useful approach for correcting severe blepharoptosis. However, blepharoptosis often recurs after corrective surgery using the tensor fascia lata. Good results without recurrence after a modified Fox method were obtained using the palmaris longus tendon. This study examined the safety and validity of the surgical method using the palmaris longus tendon through long-term follow-up observations. METHODS: To reduce the rate of recurrence, the highest point on the pentagon of the Fox method was fixed to the frontalis fascia and frontalis muscle. It was fixed once again to the area 1 cm above the highest point. This approach remarkably reduces the incidence of recurrence by fixing the pentagon of the Fox method not only to the palmaris longus tendon but also to the frontalis fascia and again to the frontalis muscle. A modified Fox method using the palmaris longus tendon was used to treat 16 eyelids of 10 patients. A senior surgeon performed the procedure in all cases under local anesthesia. RESULTS: The mean follow-up period was 51 months (range = 18-86 months). There was no case of blepharoptosis recurrence and a good field of view was secured after surgery. Long-term follow-up revealed that the visual field had been well secured with a mean MRD1 of 3.1 mm. The eyelids were well maintained without any postoperative adverse reaction such as exposure keratitis. CONCLUSION: The palmaris longus tendon as useful donor material does not lead to recurrence of blepharoptosis, which is often encountered when the tensor fascia lata is used. The modified Fox method using the palmaris longus tendon can be an effective and valid surgical approach that produces both immediate and long-term results. PMID- 18446403 TI - Do cosmetic surgeons consider estrogen-containing drugs to be of significant risk in the development of thromboembolism? AB - BACKGROUND: Well-documented evidence shows that estrogen increases the risk of deep vein thrombosis (DVT), and that the effects of DVT are compounded by the stress of surgery and an anesthetic. METHODS: This study sought to determine the current views and practice of plastic surgeons regarding combined oral contraceptive and surgery. In the United Kingdom, 285 consultant plastic surgeons were identified, and postal questionnaires were distributed to each surgeon. RESULTS: Of 286 postal questionnaires distributed to consultant plastic surgeons, 53% were returned and analyzed. Most of the surgeons considered combined oral contraceptive and surgery to be a risk factor for DVT, although only 54% discontinued it before surgery. Approximately 50% believed hormone-replacement therapy (HRT) is a risk, but fewer than a one-fourth of surgeons stopped its use before surgery. There was a range of distribution for the length of time HRT was discontinued for surgery. The majority of consultants discontinue HRT use for 5 to 6 weeks before surgery and until full ambulation after surgery. Data retrieved were used to compare documented evidence relating to combined oral contraceptive and surgery and its association with DVT. CONCLUSION: This survey shows that the management of patients taking estrogen-containing medication before plastic surgery varies, and guidelines regarding this should be sought. PMID- 18446404 TI - A new method to quantify the effect after subcutaneous injection of lipolytic substances. AB - BACKGROUND: Increasing numbers of patients request lipolytic injection therapy for aesthetic indications. However, only the clinical results of these therapies have been published to date. In most cases, pre- and postprocedure photographs and measurements have been presented. As with every other medical procedure, it is necessary to ensure that the results of lipolytic injections are quantified on an objective and scientific basis with comparable data. METHODS: In the past, the size of fat tissue could not be measured properly with conventional ultrasound systems. High-resolution, real-time three-dimensional (RT-3D) ultrasound is a fairly new method for measuring the volume of tissue. Therefore, this study aimed to measure the interscapular fat bodies of New Zealand rabbits before and after lipolytic therapy with Lipostabil, phosphatidycholine and orciprenalin (Alupent). RESULTS: The ultrasound-controlled injection of the lipolytic substances into the interscapular fat body ensured a precise injection. The RT-3D ultrasound data were compared with the magnetic resonance imaging (MRI) measurements performed at the same time. The greatest decrease in volume, up to 44%, was measured with orciprenalin (Alupent). There was a significant correlation between the data from ultrasound imaging and MRI. CONCLUSION: The data suggest that RT-3D ultrasound imaging could be a simple and fast method for proving the effects on volume size after lipolytic procedures. Of the three investigated substances, orciprenalin (Alupent) showed the highest lipolytic effect in our animal model. PMID- 18446405 TI - Detecting temporal change in watershed nutrient yields. AB - Meta-analyses reveal that nutrient yields tend to be higher for watersheds dominated by anthropogenic uses (e.g., urban, agriculture) and lower for watersheds dominated by natural vegetation. One implication of this pattern is that loss of natural vegetation will produce increases in watershed nutrient yields. Yet, the same meta-analyses also reveal that, absent land-cover change, watershed nutrient yields vary from one year to the next due to many exogenous factors. The interacting effects of land cover and exogenous factors suggest nutrient yields should be treated as distributions, and the effect of land-cover change should be examined by looking for significant changes in the distributions. We compiled nutrient yield distributions from published data. The published data included watersheds with homogeneous land cover that typically reported two or more years of annual nutrient yields for the same watershed. These data were used to construct statistical models, and the models were used to estimate changes in the nutrient yield distributions as a result of land-cover change. Land-cover changes were derived from the National Land Cover Database (NLCD). Total nitrogen (TN) yield distributions increased significantly for 35 of 1550 watersheds and decreased significantly for 51. Total phosphorus (TP) yield distributions increased significantly for 142 watersheds and decreased significantly for 17. The amount of land-cover change required to produce significant shifts in nutrient yield distributions was not constant. Small land cover changes led to significant shifts in nutrient yield distributions when watersheds were dominated by natural vegetation, whereas much larger land-cover changes were needed to produce significant shifts when watersheds were dominated by urban or agriculture. We discuss our results in the context of the Clean Water Act. PMID- 18446406 TI - Impediments and solutions to sustainable, watershed-scale urban stormwater management: lessons from Australia and the United States. AB - In urban and suburban areas, stormwater runoff is a primary stressor on surface waters. Conventional urban stormwater drainage systems often route runoff directly to streams and rivers, thus exacerbating pollutant inputs and hydrologic disturbance, and resulting in the degradation of ecosystem structure and function. Decentralized stormwater management tools, such as low impact development (LID) or water sensitive urban design (WSUD), may offer a more sustainable solution to stormwater management if implemented at a watershed scale. These tools are designed to pond, infiltrate, and harvest water at the source, encouraging evaporation, evapotranspiration, groundwater recharge, and re use of stormwater. While there are numerous demonstrations of WSUD practices, there are few examples of widespread implementation at a watershed scale with the explicit objective of protecting or restoring a receiving stream. This article identifies seven major impediments to sustainable urban stormwater management: (1) uncertainties in performance and cost, (2) insufficient engineering standards and guidelines, (3) fragmented responsibilities, (4) lack of institutional capacity, (5) lack of legislative mandate, (6) lack of funding and effective market incentives, and (7) resistance to change. By comparing experiences from Australia and the United States, two developed countries with existing conventional stormwater infrastructure and escalating stream ecosystem degradation, we highlight challenges facing sustainable urban stormwater management and offer several examples of successful, regional WSUD implementation. We conclude by identifying solutions to each of the seven impediments that, when employed separately or in combination, should encourage widespread implementation of WSUD with watershed-based goals to protect human health and safety, and stream ecosystems. PMID- 18446407 TI - Ground-cover measurements: assessing correlation among aerial and ground-based methods. AB - Wyoming's Green Mountain Common Allotment is public land providing livestock forage, wildlife habitat, and unfenced solitude, amid other ecological services. It is also the center of ongoing debate over USDI Bureau of Land Management's (BLM) adjudication of land uses. Monitoring resource use is a BLM responsibility, but conventional monitoring is inadequate for the vast areas encompassed in this and other public-land units. New monitoring methods are needed that will reduce monitoring costs. An understanding of data-set relationships among old and new methods is also needed. This study compared two conventional methods with two remote sensing methods using images captured from two meters and 100 meters above ground level from a camera stand (a ground, image-based method) and a light airplane (an aerial, image-based method). Image analysis used SamplePoint or VegMeasure software. Aerial methods allowed for increased sampling intensity at low cost relative to the time and travel required by ground methods. Costs to acquire the aerial imagery and measure ground cover on 162 aerial samples representing 9000 ha were less than $3000. The four highest correlations among data sets for bare ground--the ground-cover characteristic yielding the highest correlations (r)--ranged from 0.76 to 0.85 and included ground with ground, ground with aerial, and aerial with aerial data-set associations. We conclude that our aerial surveys are a cost-effective monitoring method, that ground with aerial data-set correlations can be equal to, or greater than those among ground based data sets, and that bare ground should continue to be investigated and tested for use as a key indicator of rangeland health. PMID- 18446408 TI - Stability of balloon-retention gastrostomy tubes with different concentrations of contrast material: in vitro study. AB - The purpose of this study was to determine the performance of two balloon retention-type gastrostomy tubes when the balloons are inflated with two types of contrast materials at different concentrations. Two commonly used balloon retention-type tubes (MIC and Tri-Funnel) were inflated to the manufacturer's recommended volumes (4 and 20 cm(3), respectively) with normal saline or normal saline plus different concentrations of contrast material. Five tubes of each brand were inflated with normal saline and 0%, 25%, 50%, 75%, and 100% contrast material dilutions, using either nonionic hyperosmolar contrast, or nonionic iso osmolar contrast. The tubes were submerged in a glass basin containing a solution with a pH of 4. Every week the tubes were visually inspected to determine the integrity of the balloons, and the diameter of the balloons was measured with a caliper. The tests were repeated every week for a total of 12 weeks. The MIC balloons deflated slightly faster over time than the Tri-Funnel balloons. The Tri Funnel balloons remained relatively stable over the study period for the different concentrations of contrast materials. The deflation rates of the MIC balloons were proportionally related to the concentration of saline and inversely related to the concentration of the contrast material. At high contrast material concentrations, solidification of the balloons was observed. In conclusion, this in vitro study confirms that the use of diluted amounts of nonionic contrast materials is safe for inflating the balloons of two types of balloon-retention feeding tubes. High concentrations of contrast could result in solidification of the balloons and should be avoided. PMID- 18446409 TI - Continuous intra-arterial nimodipine for the treatment of cerebral vasospasm. AB - Two patients with refractory symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) were treated by continuous intra-arterial nimodipine infusion via a catheter placed in the internal carotid artery or vertebral artery for 3 and 12 days, respectively. Recovery of the neurological deficits, normalization of MR perfusion, a decrease in the elevated mean flow velocity measured by transcranial duplex sonography, and angiographic recanalization were observed. Continuous intra-arterial nimodipine might be a treatment option in severe refractory vasospasm following SAH. PMID- 18446410 TI - Spontaneous white sectored-mutants in Streptomyces hygroscopicus 111-81: characterization and antibiotic productivity. AB - Spontaneous white mutants from sectors of Streptomyces hygroscopicus 111-81 were isolated. The comparison of morphological, cultural, and biochemical properties of the mutants and ancestor showed the differences in colors of aerial, substrate mycelia, and sporulation. Changes in resistance to antibiotics and sensitivity to lysozyme indicated alterations in cell walls and cell membranes of the mutants. They showed antifungal activity close to that of the parent strain on fermentation medium FM2, with unchanged component composition of the AK-111-81 antibiotic complex. The cells of spontaneous white mutants are characterized with electron-transparent structures, vacuoles, aggregation of ribosomes, intrahyphal growth, and lack of multiple cell septa, which was established by transmission electron microscopy. The appearance of white sectored-mutants in S. hygroscopicus 111-81 is connected with exhausting of nutrients causing the substrate limitation and is a stress response to starvation. PMID- 18446411 TI - A nonribosomal peptide synthetase gene tzw1 is involved in zwittermicin A biosynthesis in Bacillus thuringiensis G03. AB - A 4.20-kb SspI fragment from Bacillus thuringiensis G03 was cloned and sequenced. Sequencing analysis revealed two complete open reading frames (ORF; tzw1 and tzw2), and one incomplete ORF (tzw3) (GenBank accession no. EU293887). Tzw1 encodes a putative nonribosomal peptide synthetase with thiolation and condensation domains localized at the C-termini, whereas tzw2 and tzw3 encode acyl carrier protein and Acyl-CoA dehydrogenase, respectively. To investigate the function of tzw1 in zwittermicin A (ZA) biosynthesis, an in-frame deletion of 1,461 bp within tzw1 was constructed. The mutant abolished ZA production. Complementation of the mutant with cloned tzw1 restored ZA productivity. These results revealed that tzw1 is required for ZA biosynthesis in B. thuringiensis G03. PMID- 18446412 TI - Implementation of a semi-automated post-processing system for parametric MRI mapping of human breast cancer. AB - Magnetic resonance imaging (MRI) investigations of breast cancer incorporate computationally intense techniques to develop parametric maps of pathophysiological tissue characteristics. Common approaches employ, for example, quantitative measurements of T (1), the apparent diffusion coefficient, and kinetic modeling based on dynamic contrast-enhanced MRI (DCE-MRI). In this paper, an integrated medical image post-processing and archive system (MIPAS) is presented. MIPAS demonstrates how image post-processing and user interface programs, written in the interactive data language (IDL) programming language with data storage provided by a Microsoft Access database, and the file system can reduce turnaround time for creating MRI parametric maps and provide additional organization for clinical trials. The results of developing the MIPAS are discussed including potential limitations of the use of IDL for the application framework and how the MIPAS design supports extension to other programming languages and imaging modalities. We also show that network storage of images and metadata has a significant (p < 0.05) increase in data retrieval time compared to collocated storage. The system shows promise for becoming both a robust research picture archival and communications system working with the standard hospital PACS and an image post-processing environment that extends to other medical image modalities. PMID- 18446413 TI - Digital radiography reject analysis: data collection methodology, results, and recommendations from an in-depth investigation at two hospitals. AB - Reject analysis was performed on 288,000 computed radiography (CR) image records collected from a university hospital (UH) and a large community hospital (CH). Each record contains image information, such as body part and view position, exposure level, technologist identifier, and--if the image was rejected--the reason for rejection. Extensive database filtering was required to ensure the integrity of the reject-rate calculations. The reject rate for CR across all departments and across all exam types was 4.4% at UH and 4.9% at CH. The most frequently occurring exam types with reject rates of 8% or greater were found to be common to both institutions (skull/facial bones, shoulder, hip, spines, in department chest, pelvis). Positioning errors and anatomy cutoff were the most frequently occurring reasons for rejection, accounting for 45% of rejects at CH and 56% at UH. Improper exposure was the next most frequently occurring reject reason (14% of rejects at CH and 13% at UH), followed by patient motion (11% of rejects at CH and 7% at UH). Chest exams were the most frequently performed exam at both institutions (26% at UH and 45% at CH) with half captured in-department and half captured using portable x-ray equipment. A ninefold greater reject rate was found for in-department (9%) versus portable chest exams (1%). Problems identified with the integrity of the data used for reject analysis can be mitigated in the future by objectifying quality assurance (QA) procedures and by standardizing the nomenclature and definitions for QA deficiencies. PMID- 18446414 TI - Knowledge retention after an online tutorial: a randomized educational experiment among resident physicians. AB - BACKGROUND: The time course of physicians' knowledge retention after learning activities has not been well characterized. Understanding the time course of retention is critical to optimizing the reinforcement of knowledge. DESIGN: Educational follow-up experiment with knowledge retention measured at 1 of 6 randomly assigned time intervals (0-55 days) after an online tutorial covering 2 American Diabetes Association guidelines. PARTICIPANTS: Internal and family medicine residents. MEASUREMENTS: Multiple-choice knowledge tests, subject characteristics including critical appraisal skills, and learner satisfaction. RESULTS: Of 197 residents invited, 91 (46%) completed the tutorial and were randomized; of these, 87 (96%) provided complete follow-up data. Ninety-two percent of the subjects rated the tutorial as "very good" or "excellent." Mean knowledge scores increased from 50% before the tutorial to 76% among those tested immediately afterward. Score gains were only half as great at 3-8 days and no significant retention was measurable at 55 days. The shape of the retention curve corresponded with a 1/4-power transformation of the delay interval. In multivariate analyses, critical appraisal skills and participant age were associated with greater initial learning, but no participant characteristic significantly modified the rate of decline in retention. CONCLUSIONS: Education that appears successful from immediate posttests and learner evaluations can result in knowledge that is mostly lost to recall over the ensuing days and weeks. To achieve longer-term retention, physicians should review or otherwise reinforce new learning after as little as 1 week. PMID- 18446415 TI - Using a pocket card to improve end-of-life care on internal medicine clinical teaching units: a cluster-randomized controlled trial. AB - BACKGROUND: End-of-life care is suboptimally taught in undergraduate and postgraduate education in Canada. Previous interventions to improve residents' knowledge and comfort have involved lengthy comprehensive educational modules or dedicated palliative care rotations. OBJECTIVE: To determine the effectiveness of a cheap, portable, and easily implemented pocket reference for improving residents' knowledge and comfort level in dealing with pain and symptom management on the medical ward. DESIGN: Cluster-randomized controlled trial conducted from August 2005 to June 2006. SETTING: Medical clinical teaching units (CTUs) in 3 academic hospitals in Toronto, Canada. PARTICIPANTS: All residents rotating through the medical CTUs who consented to participate in the study. INTERVENTION: Residents at 1 hospital received a pocket reference including information about pain and symptom control, as well as 1-2 didactic end-of-life teaching sessions per month normally given as part of the rotation. Residents at the other 2 hospitals received only the didactic sessions. MAIN OUTCOME MEASURES: A 10-question survey assessing knowledge and comfort level providing end-of-life care to medical inpatients, as well as focus group interviews. RESULTS: One hundred thirty-six residents participated on 3 CTUs for a participation rate of approximately 75%. Comfort levels improved in both control (p < .01) and intervention groups (p < .01), but the increase in comfort level was significantly higher in the intervention group (z = 2.57, p < .01). Knowledge was not significantly improved in the control group (p = .06), but was significantly improved in the intervention group (p = .01). Greater than 90% of residents in the intervention group used the card at least once per week, and feedback from the focus groups was very positive. CONCLUSIONS: Our pocket card is a feasible, economical, and educational intervention that improves resident comfort level and knowledge in delivering end-of-life care on CTUs. PMID- 18446416 TI - Total gastrointestinal tract necrosis after ingesting a considerable amount of hydrochloric acid. AB - BACKGROUND: It has not been reported that ingesting large amounts of strong acid resulted in total gastrointestinal tract necrosis. Here we describe a case of a man with total gastrointestinal tract necrosis after ingestion of a considerable amount of hydrochloric acid. DISCUSSION: Computed tomography (CT) scan showed significant free air in the neck, lateral esophagus, and abdominal cavity, which indicated perforation of the esophagus and gastrointestinal tract. In addition, the abdominal CT image showed splenic subcapsular hematorna and swollen pancreatic head caused by strong acid causis. We found the entire gastrointestinal tract from stomach to rectum necrosis in the emergency exploratory laparotomy. Our case suggests that ingestion of a considerable amount (e.g., 500 mL) and concentration of strong acid could result in total gastrointestinal tract necrosis. Emergency laparotomy should be performed as early as possible to benefit this kind of patient. PMID- 18446417 TI - Adult type I choledochal cyst resection. AB - Type I choledochal cysts are characterized by fusiform dilatation of the common bile duct, commonly associated with an anomalous pancreatobiliary duct junction. Most are diagnosed in childhood, but the diagnosis may be delayed until adulthood. All type I choledochal cysts should be resected because of the risk of malignant degeneration. The steps for resecting a type I choledochal cyst are described. Through a right subcostal incision, the cyst is exposed and transected distally as it narrows within the pancreatic parenchyma. A total transmural excision of the extrahepatic biliary tree is performed. A retrocolic Roux-en-Y hepaticojejunostomy restores biliary-enteric continuity. Thirty-day mortality is low and long-term outcomes are excellent. PMID- 18446418 TI - Radical redo surgery for local rectal cancer recurrence improves overall survival: a single center experience. AB - BACKGROUND: To date, the survival benefit of redo surgery in locally recurrent rectal adenocarcinoma remains unclear. STUDY DESIGN: In an institutional study, operations for recurrence were retrospectively analyzed. Survival was calculated using the Kaplan-Meier plot and Cox regression analysis. RESULTS: A total of 72 patients with local recurrence were explored or resected. In 38 patients, there was synchronous distant organ recurrence. Forty-five of 72 were re-resected and in 37 of 45 cases, R0 situations were achieved. In 11 of 38 metastasized patients, both local and distant organ recurrence were successfully removed. For obtaining tumor control, resections of inner genitals, bladder, and sacral bone were necessary in 10, 4, and 11 patients, respectively. Survival was better for patients re-resected with a median overall survival of 54.9 months, as compared with 31.1 months among non-resected patients (p = 0.0047, log-rank test). Subgroup analysis revealed that a benefit of re-resection was observed to a lesser extent in synchronous local and in distant disease. Cox analysis showed that initial Dukes stage and complete resections of local recurrences were independently determining prognosis (relative risk 1.762 and 0.689, p = 0.008 and p = 0.002, respectively). CONCLUSIONS: Radical surgery for local recurrence can improve survival if complete tumor clearance is achieved, and concomitant distant tumor load should not principally preclude re-resection. PMID- 18446419 TI - Prompt treatment of intestinal obstruction after biliopancreatic diversion can save the intestinal loop. AB - Bariatric surgery is becoming an accepted method for weight reduction. Biliopancreatic diversion is reserved for high initial BMI. With the increasing number of these procedures, the reports of complications become more important and prepare a wider range of specialties to deal with them. We report a 62-year old woman who developed a volvulus of the biliopancreatic loop after a biliary diversion operation with a sleeve gastrectomy and antro-ileal anastomosis. Symptoms of biliopancreatic loop obstruction are rather vague, presenting with atypical abdominal pain, nausea, sometimes vomiting, preserved bowel motility, stool, and gas passage and normal upper GI X-ray. Due to the patient's prompt reaction and straight referral to a bariatric surgeon, freeing of the loop was enough to maintain its viability. The patient's further recovery and follow-up were uneventful. With this case, we stress the importance of an expert in such cases and a need to consider familiarizing doctors with these patients and with the peculiarities of their treatment. PMID- 18446420 TI - Bioabsorbable glycolide copolymer staple-line reinforcement decreases internal hernia rate after laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Internal hernias (IHs) can occur after laparoscopic Roux-en-Y gastric bypass (LRYGBP), perhaps because of a lack of adhesion formation at the cut edges of the mesentery and a cutting through of sutures with a decrease in fat from weight loss. In patients undergoing reoperation after LRYGBP, we observed that bioabsorbable glycolide copolymer staple-line reinforcement (SLR) placed to mitigate staple-line bleeding had evoked adhesiogenesis and tissue fusion at the mesentery edges; therefore, we investigated whether use of this material decreases post-LRYGBP IH rates. METHODS: The records of the 43 patients (3%) in whom an IH developed during a mean follow-up time of 2 years in a series of 1,704 LRYGBP procedures were reviewed retrospectively. RESULTS: The IHs were in the Peterson's space (n = 4), the enteroenterostomy (n = 17), or the transverse mesocolon (n = 22). The IH rate was significantly higher in patients who had suture closure of the mesenteric defects at LRYGBP than in those without formal closure of the defects but in whom SLR was applied to the edges of the cut mesentery (P = 0.01). The suture-closure and SLR groups had similar demographic, operative, and follow-up characteristics. When transverse mesocolic IHs were excluded from analysis, patients given SLR remained less likely to have an IH (P = 0.05). CONCLUSION: Use of bioabsorbable polymer SLR may decrease the occurrence of IHs after LRYGBP. Additional studies of the effect of mesentery closure method on IH incidence after LRYGBP are warranted. PMID- 18446421 TI - Orthopaedic surgeons prefer to participate in expertise-based randomized trials. AB - Empiric data and theoretical arguments suggest an alternative randomized clinical trial (RCT) design, called expertise-based RCT, has enhanced validity, applicability, and ethical integrity compared with conventional RCT. Little is known, however, about whether physicians will participate in an expertise-based RCT. In a cross-sectional survey of Canadian orthopaedic surgeons, we evaluated preference for and willingness to participate in an expertise-based versus a conventional RCT if given the opportunity to participate in a trial investigating the effectiveness of high tibial osteotomy versus unicompartmental knee arthroplasty. Using an electronic survey ((c)2005 SurveyMonkey.com), we invited all 767 members of the Canadian Orthopaedic Association (2005) to participate; 276 surgeons completed the questionnaire (37.5% response rate). One hundred two surgeons (53.4%) were willing to participate in an expertise-based RCT compared with 35 surgeons (18.3%) willing to participate in a conventional RCT. Ninety seven surgeons (52.4%) strongly or moderately preferred the expertise-based design compared with 25 (13.5%) who preferred the conventional design. For the clinical example we presented, the majority of Canadian orthopaedic surgeons were willing to participate in and preferred the expertise-based design. The expertise based randomized clinical trial design may overcome some of the barriers to conducting clinical trials in orthopaedic surgery and improve the validity of their conclusions. PMID- 18446423 TI - Seroprevalence distribution of Aichi virus among a French population in 2006 2007. AB - Little is known about the epidemiology of Aichi virus, which is a new member of the family Picornaviridae, in the genus Kobuvirus. We report here on seroprevalence in France. Sera were screened using an enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G. Of 972 sera tested, seroprevalence ranged from 25% for the 7-month-to-9-year-old age group to about 85% for the 30-to-39 year-old age group and older age groups. Our ELISA correlated well with the microneutralization technique. This study shows that Aichi virus is quite frequent in France and that seroconversion occurs before the age of 40. PMID- 18446424 TI - Identification of a recombinant dengue virus type 1 with 3 recombination regions in natural populations in Guangdong province, China. AB - Using recombination analysis, we identified a recombinant dengue virus type 1 strain, namely, GD23/95, with three recombination regions, located within the sequences of the prM/E junction, NS1, and NS3, respectively. The recombinant dengue virus was further confirmed by phylogenetic analysis based on its recombination and non-recombination regions. This appears to be the first study to confirm the existence of three recombination regions in a single dengue virus isolate and to report recombination between parent virus strains isolated from the same geographic area (Guangdong province, China). It is also the first to report breakpoints within the NS3 gene of dengue viruses. PMID- 18446425 TI - Nobel Prizes and the emerging virus concept. AB - The existence of infectious agents smaller than bacteria was demonstrated already during the 1890s. After this discovery it took more than 50 years before a resilient definition of viruses could be given. There were separate developments of knowledge concerning plant viruses, bacterial viruses and animal viruses. In the mid-1930s, Wendell Stanley at the Rockefeller Institute for Medical Research at Princeton described the purification and crystallization of tobacco mosaic virus. The finding of an "infectious protein" led to him receiving a Nobel Prize in Chemistry in 1946. In studies initiated at the end of the 1930s, bacteriophages were used as a model for replicating genes. They led to important insights into the unique characteristics of virus-cell interactions. However, an understanding of the chemical nature of animal virus particles and their mode of replication was slow in coming. Not until the early 1950s did tissue culture techniques become available, which allowed studies also of an extended number of animal viruses. This article discusses the emergence of concepts which eventually allowed a description of viruses. The unique real-time analyses of the state of knowledge provided by the Nobel Prize archives were used in the investigation. These archives remain secret for 50 years. Besides all of the underlying documents of the Prize to Stanley, comprehensive investigations made in the mid 1950s of Seymour E. Cohen, Max Delbruck, Alfred D. Hershey and Salvador D. Luria (the latter three received a Prize in Medicine in 1969) and of Andre Lwoff (he shared a Prize in Medicine with Francois Jacob and Jaques Monod in 1965) were reviewed. The final phase of the evolution of our understanding of the virus concept closely paralleled the eventual insight into the chemical nature of the genetic material. Understanding the principle nature of barriers to the development of new concepts is of timeless value for fostering and facilitating new discoveries in science. PMID- 18446426 TI - Discrimination in hiring under the Americans with Disabilities Act: an overview of the National EEOC ADA Research Project. AB - This article is intended to provide an overview of the National EEOC ADA Research Project. It also previews four subsequent articles pertaining to the issue of hiring discrimination involving Americans with disabilities. PMID- 18446422 TI - Treatment of tendinopathy: what works, what does not, and what is on the horizon. AB - Tendinopathy is a broad term encompassing painful conditions occurring in and around tendons in response to overuse. Recent basic science research suggests little or no inflammation is present in these conditions. Thus, traditional treatment modalities aimed at controlling inflammation such as corticosteroid injections and nonsteroidal antiinflammatory medications (NSAIDS) may not be the most effective options. We performed a systematic review of the literature to determine the best treatment options for tendinopathy. We evaluated the effectiveness of NSAIDS, corticosteroid injections, exercise-based physical therapy, physical therapy modalities, shock wave therapy, sclerotherapy, nitric oxide patches, surgery, growth factors, and stem cell treatment. NSAIDS and corticosteroids appear to provide pain relief in the short term, but their effectiveness in the long term has not been demonstrated. We identified inconsistent results with shock wave therapy and physical therapy modalities such as ultrasound, iontophoresis and low-level laser therapy. Current data support the use of eccentric strengthening protocols, sclerotherapy, and nitric oxide patches, but larger, multicenter trials are needed to confirm the early results with these treatments. Preliminary work with growth factors and stem cells is promising, but further study is required in these fields. Surgery remains the last option due to the morbidity and inconsistent outcomes. The ideal treatment for tendinopathy remains unclear. LEVEL OF EVIDENCE: Level II, systematic review. PMID- 18446427 TI - Drivers of hiring discrimination for individuals with disabilities. AB - INTRODUCTION: Hiring discrimination in the workplace is defined as failure or refusal by an employer to engage a qualified applicant as an employee due to the existence or consequence of disability. The specific intent of this study is to determine what differentiates an allegation (perception of discrimination) from an actual discriminatory event (Merit Resolution). METHODS: Researchers used a data-mining approach, the Chi-square Automatic Interaction Detector (CHAID), to examine 19,527 resolved allegations of hiring discrimination in order to differentiate between Merit Resolution and Non-Merit Resolution outcomes. RESULTS: CHAID analysis confirmed that hiring discrimination is a complex matter with a variety of influences. Primary among these is the age of the Charging Party, with younger applicants (16-34) prevailing in their allegations 34% of the time. Within this subgroup, the sequence of predictor variables involves the Charging Party's impairment, followed by the Employer's industry classification. Behavioral disabilities, even among the young, result in generally lower Merit Resolution rates in hiring discrimination. CONCLUSIONS: Providers of training and technical assistance regarding hiring and disability may be able to adjust their services accordingly on the basis of findings such as these. PMID- 18446428 TI - Approaches to handling pharmacodynamic baseline responses. AB - A few approaches for handling baseline responses are available for use in pharmacokinetic (PK)-pharmacodynamic (PD) analysis. They include: (method 1-B1) estimation of the typical value and interindividual variability (IIV) of baseline in the population, (B2) inclusion of the observed baseline response as a covariate acknowledging the residual variability, (B3) a more general version of B2 as it also takes the IIV of the baseline in the population into account, and (B4) normalization of all observations by the baseline value. The aim of this study was to investigate the relative performance of B1-B4. PD responses over a single dosing interval were simulated from an indirect response model in which a drug acts through stimulation or inhibition of the response according to an Emax model. The performance of B1-B4 was investigated under 22 designs, each containing 100 datasets. NONMEM VI beta was used to estimate model parameters with the FO and the FOCE method. The mean error (ME, %) and root mean squared error (RMSE, %) of the population parameter estimates were computed and used as an indicator of bias and imprecision. Absolute ME (|ME|) and RMSE from all methods were ranked within the same design, the lower the rank value the better method performance. Average rank of each method from all designs was reported. The results showed that with B1 and FOCE, the average of |ME| and RMSE across all typical individual parameters and all conditions was 5.9 and 31.8%. The average rank of |ME| for B1, B2, B3, and B4 was 3.7, 3.8, 3.3, and 5.2 for the FOCE method, and 4.6, 4.3, 4.7, and 6.4 for the FO method. The smallest imprecision was noted with the use of B1 (rank of 3.1 for FO, and 2.9 for FOCE) and increased, in order, with B3 (3.9-FO and 3.6-FOCE), B2 (4.8-FO; 4.7-FOCE), and B4 (6.4-FO; 6.5-FOCE). We conclude that when considering both bias and imprecision B1 was slightly better than B3 which in turn was better than B2. Differences between these methods were small. B4 was clearly inferior. The FOCE method led to a smaller bias, but no marked reduction in imprecision of parameter estimates compared to the FO method. PMID- 18446430 TI - Validation of a method for collecting annual, population-based oral health data for the MCH Title V Block Grant. AB - OBJECTIVES: This study sought to determine whether estimates of oral health related indicators generated using a relatively small purposive sample of schools were reasonable. METHODS: We collected and analyzed data from two open-mouth school oral health surveys conducted in Ohio in 2004-2005. In each survey, data were gathered for nine indicators using direct observation and a questionnaire. The first survey used unweighted data from 23 sentinel schools purposively selected to represent the state based on the findings of a large 1998-1999 oral health survey (337 schools). The second survey used weighted data aggregated from 374 schools randomly selected to represent each of Ohio's 88 counties. The point estimates from the first data set were compared with 95% confidence intervals (CIs) from the second and Chi-square measures were estimated to determine statistically significant differences. RESULTS: For six of nine indicators, point estimates for the sentinel schools fell within the relatively narrow 95% CIs generated for the 374 schools sampled at the county level. Only one indicator (history of tooth decay) was found to be significantly different according to Chi square analysis. CONCLUSIONS: Ohio's sentinel schools approach provided reasonable estimates suitable for annual reporting as required for the Title V Maternal and Child Health Block Grant. Data collected in this manner are likely to be reasonable population estimates and less costly than larger surveys. PMID- 18446431 TI - Prenatal screening for infectious diseases: an analysis of disparities and adherence to policy in California. AB - OBJECTIVES: Prenatal infectious diseases are a major cause of mortality and morbidity among newborns, but many are preventable with proper maternal screening and treatment. METHODS; Adherence to prenatal infectious disease screening guidelines and demographic factors that influence adherence were determined utilizing existing data on 1837 live births from 1999-2003. RESULTS: We found higher rates of testing for syphilis (94.54%), rubella (92.69%) and hepatitis B (94.23%) than for HIV (73.82%) and GBS (69.05%). Adherence to testing guidelines varied by both disease and maternal factors. Lack of insurance, geographic location, inadequate prenatal care and incarceration were the main maternal factors associated with lack of testing. CONCLUSIONS: Disease screening rates may be improved by reducing socioeconomic barriers to prenatal testing, supporting access to insurance, eliminating provider biases and providing adequate prenatal care. PMID- 18446433 TI - A response to Dreger's defense of the Bailey book. PMID- 18446432 TI - Path-finding in real and simulated rats: assessing the influence of path characteristics on navigation learning. AB - A large body of experimental evidence suggests that the hippocampal place field system is involved in reward based navigation learning in rodents. Reinforcement learning (RL) mechanisms have been used to model this, associating the state space in an RL-algorithm to the place-field map in a rat. The convergence properties of RL-algorithms are affected by the exploration patterns of the learner. Therefore, we first analyzed the path characteristics of freely exploring rats in a test arena. We found that straight path segments with mean length 23 cm up to a maximal length of 80 cm take up a significant proportion of the total paths. Thus, rat paths are biased as compared to random exploration. Next we designed a RL system that reproduces these specific path characteristics. Our model arena is covered by overlapping, probabilistically firing place fields (PF) of realistic size and coverage. Because convergence of RL-algorithms is also influenced by the state space characteristics, different PF-sizes and densities, leading to a different degree of overlap, were also investigated. The model rat learns finding a reward opposite to its starting point. We observed that the combination of biased straight exploration, overlapping coverage and probabilistic firing will strongly impair the convergence of learning. When the degree of randomness in the exploration is increased, convergence improves, but the distribution of straight path segments becomes unrealistic and paths become 'wiggly'. To mend this situation without affecting the path characteristic two additional mechanisms are implemented: a gradual drop of the learned weights (weight decay) and path length limitation, which prevents learning if the reward is not found after some expected time. Both mechanisms limit the memory of the system and thereby counteract effects of getting trapped on a wrong path. When using these strategies individually divergent cases get substantially reduced and for some parameter settings no divergence was found anymore at all. Using weight decay and path length limitation at the same time, convergence is not much improved but instead time to convergence increases as the memory limiting effect is getting too strong. The degree of improvement relies also on the size and degree of overlap (coverage density) in the place field system. The used combination of these two parameters leads to a trade-off between convergence and speed to convergence. Thus, this study suggests that the role of the PF-system in navigation learning cannot be considered independently from the animals' exploration pattern. PMID- 18446434 TI - A space odyssey: experimental manipulation of threat perception and anxiety related interpretation bias in children. AB - This study provides a first test of an experimental method, the "space odyssey" paradigm, that was designed to manipulate interpretation bias in children. Seventy non-clinical children aged 8-12 years first completed a standardized anxiety questionnaire. Following this, they completed the space odyssey paradigm to induce either a negative or a positive interpretation bias. After this stage of interpretation training, children were presented with a series of ambiguous vignettes for which they had to rate perceived levels of threat as an index of interpretation bias. Results indicated that the space odyssey paradigm was successful in training interpretations: children in the negative training condition quickly learned to choose negative outcomes, while children in the positive training condition rapidly learned to select positive outcomes. Most importantly, children's subsequent threat perception scores for the ambiguous vignettes were affected by the manipulation. That is, children in the negative training condition perceived more threat than children in the positive training condition. Interestingly, the effects of training were most pronounced in high anxious children. Directions for future research with this paradigm are briefly discussed. PMID- 18446435 TI - Symptoms of anxiety, depression, and aggression in non-clinical children: relationships with self-report and performance-based measures of attention and effortful control. AB - This study investigated the relation between the regulative trait of effortful control, and in particular attention control, and psychopathological symptoms in a sample of 207 non-clinical children aged 8-12 years. For this purpose, children completed self-report scales for measuring regulative traits and various types of psychopathological symptoms (i.e., anxiety, depression, and aggression) and were tested with a neuropsychological battery for measuring attention/effortful control capacity. Results indicated that self-report and performance-based measures of attention/effortful control were at best moderately correlated. Further, it was found that self-report indexes of attention/effortful control were clearly negatively related to psychopathological symptoms, which provides support for the notion that low regulation is associated with higher levels of psychopathology. Finally, the performance-based measure of attention/effortful control was not convincingly related to psychopathological symptoms. PMID- 18446436 TI - The prevalence of PALB2 germline mutations in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives. AB - PALB2 has been recently identified as breast cancer susceptibility gene in western populations. To investigate the contribution of PALB2 mutations to Chinese non-BRCA1/BRCA2 hereditary breast cancer, we screened all coding exons and intron-exon boundaries of PALB2 in 360 Chinese women with early-onset breast cancer or affected relatives from five breast disease clinical centers in China by utilizing PCR-DHPLC and DNA sequencing analysis. Some genetic variants identified in the cases were then studied in 864 normal controls with no personal or family history of breast cancer. Two protein-truncating PALB2 mutations, 751C>T and 1050_1051delAAinsTCT, were identified in three separate families, and 751C>T was a recurrent mutation. Neither of them, however, were present in the controls (P=0.025). All the truncating mutations occurred in exon 4 of PALB2, and there were still three unclassified variants were detected in the same fragment. We found that exon 4 accounted for 44.1% (15/34) of the person-times carrying with any variant in our study. PALB2 mutations were responsible for approximately 1% of Chinese women with early-onset breast cancer and affected relatives. Our results suggested that a detection of exon 4 before the assay of the whole PALB2 gene might be a cost-effective approach to the screening of Chinese population. PMID- 18446437 TI - Kampo medicine "Dai-kenchu-to" prevents bacterial translocation in rats. AB - Kampo medicine "Dai-kenchu-to" (DKT) has been used for treatment of ileus. The aim of this study was to evaluate the role of DKT on the bacterial translocation (BT) model in rats. Rats were divided into the following four groups: group 1, receiving only water, and groups 2, 3, and 4, receiving 100, 300, and 1,000 mg/kg/day of DKT. Rats were sacrificed 6 days after the beginning of the fast, and then the mesenteric lymph node was cultured. Inflammatory cytokines, intestinal integrity, and apoptosis were assessed. Incidence of BT in groups 3 (33%) and 4 (16%) was lower than in group 1 (66%). Interferon-gamma expression in groups 2, 3, and 4 was significantly lower than in group 1. Villous height and number of villus in groups 2, 3, and 4 were significantly taller and greater than in group 1. Apoptotic index in groups 2, 3, and 4 was significantly lower than in group 1. This is the first evidence that DKT prevents BT by reducing inflammatory reaction and maintaining intestinal integrity. PMID- 18446439 TI - Quality of provider-participant relationships and enhancement of adolescent social skills. AB - This study adds to the limited research on the potential importance of the quality of the relationship between adult prevention service providers and youth participants in enhancing social skills and strengthening prevention outcomes. Study subjects were drawn from seven prevention programs funded under a Youth Mentoring Initiative by the Center for Substance Abuse Prevention in the Substance Abuse and Mental Health Services Administration. These programs maintain a relationship-based service focus but use a variety of one-on-one, group, volunteer, and paid staff service formats. Study results showed that youth who perceived a higher level of trust, mutuality and empathy in their relationship with providers experienced significantly greater improvements in social skills (i.e., cooperation, self-control, assertiveness, and empathy) than program participants who perceived a lower quality relationship with adult providers. These findings underscore the importance of recruitment, training and supervisory practices that promote staff and volunteer skills in achieving high quality relationships with youth participants regardless of the specific intervention strategy. Editors' Strategic Implications: Practitioners and policymakers should review the authors' findings about the importance of individual adult skills in building protective mentoring relationships. The impact of relationship quality, rather than setting, suggests that the scope of effective prevention practice can be broadened beyond the confines of formal prevention programming to any place in which caring and skilled adults interact with youth. PMID- 18446438 TI - A health behaviour cross-sectional study of immigrants and non-immigrants in a Swiss urban general-practice setting. AB - BACKGROUND: Little is known about smoking, unhealthy use of alcohol, and risk behaviours for sexually transmitted diseases (STDs) in immigrants from developed and developing countries. METHOD: We performed a cross-sectional study of 400 patients who consulted an academic emergency care centre at a Swiss university hospital. The odds ratios for having one or more risk behaviours were adjusted for age, gender, and education level. RESULTS: Immigrants from developing countries were less likely to use alcohol in an unhealthy manner (OR = 0.35, 95% CI 0.22-0.57) or practise risk behaviours for STDs (OR = 0.31, 95% CI 0.13-0.74). They were also less likely to have any of the three studied risk behaviours (OR = 2.5, 95% CI 1.5-4.3). DISCUSSION: In addition to the usual determinants, health behaviours are also associated with origin; distinguishing between immigrants from developing and developed countries is useful in clinical settings. Surprisingly, patients from developing countries tend to possess several protective characteristics. PMID- 18446440 TI - Parent training: implementation strategies for adventures in parenting. AB - Adventures in Parenting, an informational booklet published by the National Institute of Child Health and Human Development, offers five principles that parents can use to develop a mental model of parenting: Responding, Preventing, Monitoring, Mentoring, and Modeling (RPM3). The current study was designed to assess the differential impact of three intervention conditions utilizing Adventures in Parenting on knowledge of RPM3 principles. Significant intervention effects were found for measures of knowledge of RPM3 principles; the more intensive interventions (i.e., face-to-face groups and web-based sessions) were associated with increased knowledge of RPM3 principles over 3 months. Results are discussed in terms of their contribution to new approaches of parent education, particularly the use of web-based training. Editors' Strategic Implications: Parent educators should review the promising findings regarding the RPM3 model. Preventionists, more broadly, may be interested in the effect of the program's delivery mechanism, with a comparison of participants who were randomly assigned to web-based, group-based, and booklet only conditions. PMID- 18446441 TI - Mixing behavior of the rhombic micromixers over a wide Reynolds number range using Taguchi method and 3D numerical simulations. AB - A planar micromixer with rhombic microchannels and a converging-diverging element has been systematically investigated by the Taguchi method, CFD-ACE simulations and experiments. To reduce the footprint and extend the operation range of Reynolds number, Taguchi method was used to numerically study the performance of the micromixer in a L(9) orthogonal array. Mixing efficiency is prominently influenced by geometrical parameters and Reynolds number (Re). The four factors in a L(9) orthogonal array are number of rhombi, turning angle, width of the rhombic channel and width of the throat. The degree of sensitivity by Taguchi method can be ranked as: Number of rhombi > Width of the rhombic channel > Width of the throat > Turning angle of the rhombic channel. Increasing the number of rhombi, reducing the width of the rhombic channel and throat and lowering the turning angle resulted in better fluid mixing efficiency. The optimal design of the micromixer in simulations indicates over 90% mixing efficiency at both Re > or = 80 and Re < or = 0.1. Experimental results in the optimal simulations are consistent with the simulated one. This planar rhombic micromixer has simplified the complex fabrication process of the multi-layer or three-dimensional micromixers and improved the performance of a previous rhombic micromixer at a reduced footprint and lower Re. PMID- 18446442 TI - Village chicken production in Turkey: Tokat province example. AB - The aim of this work was to reveal the current form of village chicken production in Tokat province of Turkey. A survey was applied to 153 randomly selected farmers of 5 subdistricts in Tokat province. The ratios of domestic fowls in the survey region were as follows: hen 98.83%, goose 0.65%, turkey 0.29% and duck 0.16% (P < 0.01). Feather colours of laying hens were white (2.76%), brown (8.63%) and mixed color (88.60%). The hen farms in this region consisted of native breeds (91.42%), commercial breeds (5.71%) and their crosses (2.85%). The mean egg weight of the village hens was between 30 and 40 g. Wheat (65.73%) and mixed (wheat, barley, maize and kitchen refuse) feed (34.22%) were used to supplement the hens (P < 0.01). For producing natural chicks, the hens were brooded between 1.10 and 1.46 times/year, 1.31 on average. For each brooding, the number of placed eggs under the broody hens was between 11.39 and 12.42 (P < 0.05). PMID- 18446443 TI - Identification of the cyclin D1b mRNA variant in mouse. AB - Cyclin D1 plays a key regulatory role during the G1 phase of the cell cycle and its gene is amplified and over-expressed in many cancers. The cyclin D1b mRNA variant was established in human cells and recent functional analyses revealed that its protein product harbors unique activities in human cancer cells. By performing reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) experiments, we identified the cyclin D1b mRNA variant in mouse. Similar to its human counterpart, the mouse cyclin D1b transcript consists of exon 1, 2, 3, 4 and part of intron 4, and contains a long open reading frame (ORF). The predicted peptide from this ORF is 34-amino acid longer than the human cyclin D1b. The expression of this mouse mRNA variant was investigated. It appears to be expressed ubiquitously and differentially in various mouse cell lines and tissues and its level might be proportional to that of the canonical endogenous cyclin D1a mRNA. PMID- 18446444 TI - Comparative study of interspecific genetic divergence and phylogenic analysis of genus Jatropha by RAPD and AFLP: genetic divergence and phylogenic analysis of genus Jatropha. AB - Genus Jatropha with 172 species having significant economic importance belongs to the family Euphorbiaceae. There are no reports on molecular characterization and phylogenetic relationship among the species of Jatropha. Hence, the present study was undertaken to assess the extent of genetic variability that exist and also to establish phylogenetic relationship among Jatropha curcas, J. glandulifera, J. gossypifolia, J. integerrima, J. multifida, J. podagrica and J. tanjorensis using RAPD and AFLP. The percentage of loci that are polymorphic among the species studied was found to be 97.74% by RAPD and 97.25% by AFLP. The mean percentage of polymorphism (PP) was found to be 68.48 by RAPD and 71.33 by AFLP. The phylogram generated with RAPD and AFLP data showed maximum similarity. With the generated data maximum relatedness was found between J. curcas and J. integerrima this may be the reason for the success of inter hybrid crosses between these two species. Neither RAPD nor AFLP data generated in this study supports the view of J. tanjorensis, a natural interspecific hybrid between J. curcas and J. gossypifolia. The present study concludes that both RAPD and AFLP techniques are comparable in divergence studies of Jatropha species. The markers generated by RAPD and AFLP can be employed efficiently for interspecific hybrids identification, marker assisted selection and genetic resource management. PMID- 18446445 TI - The novel 5bp deletion polymorphism in the promoter region of bovine ACRP30 gene. AB - ACRP30 gene was located nearby the QTL affecting the marbling, ribeye muscle area and fat thickness on the BAT1 in Angus. In this study, a 5bp deletion mutation within the bovine ACRP30 gene was firstly detected and confirmed in 991 cattle by PCR-SSCP, DNA sequencing and direct PCR amplification. The deletion mutation was appeared in Qinchuan, Nanyang, Jiaxian and Hasake, but was not found in Jinnan, Chinese Holsteins and Angus. The association of the deletion polymorphism with growth traits (including birth weight, body weight, average daily gain and body sizes in different growth periods (6/12/18/24 month-old)) was analyzed in 224 Nanyang cattle. No signification association of the deletion polymorphism with growth traits were observed (P > 0.05). The deletion was located in the promoter region and it resulted in a new putative CCAAT/enhancer binding protein-beta response element (C/EBP-RE). PMID- 18446446 TI - A critique of positive responsibility in computing. AB - It has been claimed that (1) computer professionals should be held responsible for an undisclosed list of "undesirable events" associated with their work and (2) most if not all computer disasters can be avoided by truly understanding responsibility. Programmers, software developers, and other computer professionals should be defended against such vague, counterproductive, and impossible ideals because these imply the mandatory satisfaction of social needs and the equation of ethics with a kind of altruism. The concept of social needs is debatable with no one possessing the authority to impose their version of them. Similarly, the notion of "positive responsibility" is difficult to apply, does not effectively change computing practice, and confuses good (i.e., efficient) computer engineering with good (i.e. moral) computer engineering. PMID- 18446447 TI - Cardiac-targeted transgenic mutant mitochondrial enzymes: mtDNA defects, antiretroviral toxicity and cardiomyopathy. AB - Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (Pol gamma) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol gamma and mtDNA replication. Cardiac "dominant negative" murine transgenes (TGs; Pol gamma Y955C, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in "2 x 2" studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs ( approximately 50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass ( approximately 50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy. PMID- 18446449 TI - True adrenal mesothelial cyst in a patient with flank pain and hematuria: a case report. AB - True mesothelial (epithelial) cysts in the adrenal gland are rare lesions. They represent 9% of adrenal cysts and are much less common than vascular adrenal cysts. We report a case of a true adrenal mesothelial cyst in a patient with flank pain and hematuria that was diagnosed on imaging as a renal cyst. Immunohistochemical studies were performed to investigate the nature of the cyst lining. The positive immunostains for calretinin and WT-1 lend support to the postulate of Medeiros et al nearly 20 years ago of a mesothelial origin for these cysts. The clinical presentation and salient radiologic and pathologic features are described. PMID- 18446448 TI - Lysergic acid amide-induced posterior reversible encephalopathy syndrome with status epilepticus. AB - INTRODUCTION: Posterior reversible encephalopathy syndrome (PRES) is known to occur in association with several substances. However, lysergic acid amide (LSA) is not among the previously reported causes of PRES. METHODS: We report on a patient with PRES presenting as convulsive status epilepticus associated with hypertensive encephalopathy after LSA ingestion. Magnetic resonance imaging was performed and catecholamine metabolites assayed. RESULTS: The patient achieved a full recovery after aggressive antihypertensive therapy and intravenous anticonvulsivant therapy. The clinical history, blood and urinary catecholamine levels, and response to treatment strongly suggest that PRES was induced by LSA. CONCLUSION: LSA, a hallucinogenic agent chiefly used for recreational purposes, should be added to the list of causes of PRES. PMID- 18446450 TI - Metastatic small cell carcinoma to the thyroid gland: a pathologic and molecular study demonstrating the origin in the urinary bladder. AB - Small cell carcinomas may occur in the thyroid gland. Infrequently, they are primary tumors, and have been interpreted as variants of medullary thyroid carcinoma. However, the vast majority of small cell carcinomas involving the thyroid gland are metastatic tumors. In some cases, demonstration of the primary tumor is not easy. An example of a small cell carcinoma metastatic to the thyroid is presented in this report. The primary tumor was a small cell carcinoma that occurred as a minor component in a transitional carcinoma of the urinary bladder. The microscopical and immunohistochemical features of both tumors, in the thyroid and the bladder, were identical. Moreover, both tumors exhibited an identical mutation in p53, as well as similar loss of heterozygosity at 10q23 and RASSF1A promoter hypermethylation, clearly indicating that the bladder tumor was the site for the primary tumor of the patient. PMID- 18446451 TI - Signaling for vesicle mobilization and synaptic plasticity. AB - The hypothesis that release of classical neurotransmitters and neuropeptides is facilitated by increasing the mobility of small synaptic vesicles (SSVs) and dense core vesicles (DCVs) could not be tested until the advent of methods for visualizing these secretory vesicles in living nerve terminals. In fact, fluorescence imaging studies have only since 2005 established that activity increases secretory vesicle mobility in motoneuron terminals and chromaffin cells. Mobilization of DCVs and SSVs appears to be due to liberation of hindered vesicles to promote quicker diffusion. However, F-actin and synapsin, which have been featured in mobilization models, are not required for activity-dependent increases in the mobility of DCVs or SSVs. Most recently, the signaling required for sustained mobilization has been identified for Drosophila motoneuron DCVs and shown to increase synaptic transmission. Specifically, presynaptic endoplasmic reticulum ryanodine receptor-mediated Ca2+ release activates Ca2+/calmodulin dependent kinase II to mobilize DCVs and induce post-tetanic potentiation (PTP) of neuropeptide release in the Drosophila neuromuscular junction. The shared signaling for increasing vesicle mobility and PTP links vesicle mobilization and synaptic plasticity. PMID- 18446452 TI - Resistin is expressed in human hepatocytes and induces insulin resistance. AB - Resistin, known as an adipocyte-specific secretory factor (ADSF), is implicated to modulate insulin resistance in rodents. However, the precise role of this factor for human insulin resistance has remained elusive. Here, we investigate the relationship between human resistin and insulin resistance in hepatocytes and the effect of Metformin on resistin. In this study, the expression of resistin in human hepatocytes and hepatic tissues was examined, and the human resistin eukaryotic expression vector was constructed and stably transfected in HepG2 cells. Data showed that resistin is expressed in human hepatocytes and hepatic tissues. Overexpression of human resistin impaired significantly insulin stimulated glucose uptake and glycogen synthesis in HepG2 cells. It also decreased the expression of insulin receptor substrate 2 (IRS-2) and c-cbl associated protein (CAP), whereas increased the expression of glycogen synthetase kinase 3beta (GSK-3beta). The result suggested that human resistin induced insulin resistance in hepatocytes by blocking the two insulin signal transduction pathways of PI-3K/Akt and of CAP/c-cbl. We also concluded that Metformin reversed the effect of resistin and downregulated the expression of resistin in hepatocytes. PMID- 18446453 TI - Management of hypothyroidism after radiotherapy for nasopharyngeal carcinoma. PMID- 18446454 TI - Genes related to chromate resistance by Pseudomonas aeruginosa PAO1. AB - Chromate-hypersensitive mutants of the Pseudomonas aeruginosa PAO1 strain were isolated using transposon-insertion mutagenesis. Comparison of the nucleotide sequences of the regions interrupted in the mutants with the PAO1 genome revealed that the genes affected in three mutant strains were oprE (ORF PA0291), rmlA (ORF PA5163), and ftsK (ORF PA2615), respectively. A relationship of these genes with chromate tolerance has not been previously reported. No other phenotypic changes were observed in the oprE mutant but its resistance to chromate was not fully restored by expressing the ChrA protein, which extrudes chromate ions from the cytoplasm to the periplasmic space. These data suggest that OprE participates in the efflux of chromate from the periplasm to the outside. Increased susceptibility of the rmlA mutant to the metals cadmium and mercury and to the anion-superoxide generator paraquat suggests a protective role of LPS against chromate toxicity. A higher susceptibility of the ftsK mutant to compounds affecting DNA structure (ciprofloxacin, tellurite, mitomycin C) suggests a role of FtsK in the recombinational repair of DNA damage caused by chromate. In conclusion, the P. aeruginosa genome contains diverse genes related to its intrinsic resistance to chromate. Systems pertaining to the outer membrane (OprE), the cell wall (LPS), and the cytoplasm (FtsK) were identified in this work as involved in chromate protection mechanisms. PMID- 18446455 TI - Effect of drying methods on swelling, erosion and drug release from chitosan naproxen sodium complexes. AB - The purpose of this research was to explore theapplication of ionic interactions between naproxen sodium (NS) and chitosan (CH) in complexes (NSC) prepared by tray drying (TD) and spray drying (SD) methods. Drug-polymer ratio (1:1) in the NSC was optimized on the basis of dialysis studies. The particulate systems of NSC were prepared by tray drying (TD) and spray drying (SD) methods. Release retarding polymers were added to the NSC and to the physical mixtures containing NS-CH and their effects on water uptake, matrix erosion and drug release at different pH were compared. Spray dried complexes (SDC) were spherical, free flowing, light and fine amorphous particles in contrast to the crystalline, hard, tenacious, irregularly shaped, denser tray dried complexes (TDC) with poor flowability. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) patterns confirm the conversion of crystalline to high energy amorphous phase suitable for ionic interactions in NSC. Presence of release retarding polymers, kappa carrageenan and hydroxypropylmethylcellulose (HPMC) in the NSC compacts retarded the drug release and improved the matrix integrity. Carrageenan matrices exhibited more retardation than HPMC tablets. FTIR patterns, erosion, swelling and drug release from matrices support ionic interactions between NS and CH in NSC. The reasons for retarded drug release from the chitosan matrices at acidic pH include poor solubility of drug at acidic pH, formation of a rate limiting polymer gel barrier along the periphery of matrices and the ionic interactions between oppositely charged moieties. PMID- 18446457 TI - Selected physical and chemical properties of Feverfew (Tanacetum parthenium) extracts important for formulated product quality and performance. AB - The objectives of this research are: (1) to assess selected formulation-relevant physical properties of several commercial Feverfew extracts, including flowability, hygroscopicity, compressibility and compactibility (2) to develop and validate a suitable extraction method and HPLC assay, and (3) to determine the parthenolide content of several commercial Feverfew extracts. Carr's index, minimum orifice diameter and particle-particle interaction were used to evaluate powder flowability. Hygroscopicity was evaluated by determining the equilibrium moisture content (EMC) after storage at various % relative humidities. Heckle analysis and compression pressure-radial tensile strength relationship were used to represent compression and compaction properties of feverfew extracts. An adapted analytical method was developed based on literature methods and then validated for the determination of parthenolide in feverfew. The commercial extracts tested exhibited poor to very poor flowability. The comparatively low mean yield pressure suggested that feverfew extracts deformed mainly plastically. Hygroscopicity and compactibility varied greatly with source. No commercial feverfew extracts tested contained the label claimed parthenolide. Even different batches from the same manufacturer showed significantly different parthenolide content. Therefore, extract manufactures should commit to proper quality control procedures that ensure accurate label claims, and supplement manufacturers should take into account possible differences in physico-chemical properties when using extracts from multiple suppliers. PMID- 18446456 TI - Design and evaluation of self-microemulsifying drug delivery system (SMEDDS) of tacrolimus. AB - The objective of present investigation was to formulate self-microemulsifying drug delivery systems (SMEDDS) of tacrolimus (FK 506), a poorly water soluble immunosuppressant that exhibits low and erratic bioavailability. Solubility of FK 506 in various oils, surfactants cosurfactants and buffers was determined. Phase diagrams were constructed at different ratios of surfactant/cosurfactant (K(m)) to determine microemulsion existence region. The effect of oil content, pH of aqueous phase, dilution, and incorporation of drug on mean globule size of resulting microemulsions was studied. The optimized SMEDDS formulation was evaluated for in vitro dissolution profile in comparison to pure drug and marketed formulation (Pangraf capsules). The in vivo immunosuppressant activity of FK 506 SMEDDS was evaluated in comparison to Pangraf capsules. Area of o/w microemulsion region in phase diagram was increased with increase in K(m). The SMEDDS yielded microemulsion with globule size less than 25 nm which was not affected by the pH of dilution medium. The SMEDDS was robust to dilution and did not show any phase separation and drug precipitation even after 24 h. Optimized SMEDDS exhibited superior in vitro dissolution profile as compared to pure drug and Pangraf capsules. Furthermore, FK 506 SMEDDS exhibited significantly higher immunosuppressant activity in mice as compared to Pangraf capsules. PMID- 18446458 TI - Granulation by roller compaction and enteric coated tablet formulation of the extract of the seeds of Glinus lotoides loaded on Aeroperl 300 Pharma. AB - The purpose of this research was to improve the hygroscopicity and poor flow properties of the crude dry extract of the seeds of Glinus lotoides and improve the disintegration time of the core-tablets for enteric coated formulation thereof. The liquid crude extract of the plant was adsorbed on granulated colloidal silicon dioxide (Aeroperl 300 Pharma) at 30% w/w and the dry extract preparation (DEP) was dry-granulated with roller-compaction using Micro-Pactor. Hygroscopicity, flow property and disintegration time were improved significantly due to the adsorption and granulation processes. Moreover, the DEP does not become mucilaginous even at higher relative humidity levels (above 65%). Oblong tablets (20 x 8.25 mm) containing 947 mg of the granulated DEP (equivalent to the traditional dose), 363 mg of Avicel PH101 and 90 mg of Ac-di-Sol as disintegrant were formulated using an instrumented eccentric tablet machine at 20 kN. The tablets showed a crushing strength of 195 N, a friability of 0.4% and disintegrated within 9 min. The tablets were then enteric coated using polymethacrylate co-polymers (Eudragit L 100-55 and Kollicoat MAE 100P). The coated tablets resisted disintegration or softening in simulated gastric fluid for a minimum of 2 h and disintegrated within 15 min in intestine simulated fluid at pH 6.8. In addition to controlling the release of the active agents, the enteric coating improved the strength and decreased friability of the core tablets. PMID- 18446459 TI - Study of the RESS process for producing beclomethasone-17,21-dipropionate particles suitable for pulmonary delivery. AB - The purpose of this research was to micronize beclomethasone-17,21-dipropionate (BDP), an anti-inflammatory inhaled corticosteroid commonly used to treat asthma, using the rapid expansion of supercritical solution (RESS) technique. The RESS technique was chosen for its ability to produce both micron particles of high purity for inhalation, and submicron/nano particles as a powder handling aid for use in next generation dry powder inhalers (DPIs). Particle formation experiments were carried out with a capillary RESS system to determine the effect of experimental conditions on the particle size distribution (PSD). The results indicated that the RESS process conditions strongly influenced the particle size and morphology; with the BDP mean particle size decreasing to sub-micron and nanometer dimensions. An increase in the following parameters, i.e. nozzle diameter, BDP mol fraction, system pressure, and system temperature; led to larger particle sizes. Aerodynamic diameters were estimated from the SEM data using three separate relations, which showed that the RESS technique is promising to produce particles suitable for pulmonary delivery. PMID- 18446460 TI - Development of spray dried liposomal dry powder inhaler of Dapsone. AB - This investigation was undertaken to evaluate practical feasibility of site specific pulmonary delivery of liposomal encapsulated Dapsone (DS) dry powder inhaler for prolonged drug retention in lungs as an effective alternative in prevention of Pneumocystis carinii pneumonia (PCP) associated with immunocompromised patients. DS encapsulated liposomes were prepared by thin film evaporation technique and resultant liposomal dispersion was passed through high pressure homogenizer. DS nano-liposomes (NLs) were separated by ultra centrifugation and characterized. NLs were dispersed in phosphate buffer saline (PBS) pH 7.4 containing different carriers like lactose, sucrose, and hydrolyzed gelatin, and 15% L-leucine as antiadherent. The resultant dispersion was spray dried and spray dried formulation were characterized to ascertain its performance. In vitro pulmonary deposition was assessed using Andersen Cascade Impactor as per USP. NLs were found to have average size of 137 +/- 15 nm, 95.17 +/- 3.43% drug entrapment, and zeta potential of 0.8314 +/- 0.0827 mV. Hydrolyzed gelatin based formulation was found to have low density, good flowability, particle size of 7.9 +/- 1.1 microm, maximum fine particle fraction (FPF) of 75.6 +/- 1.6%, mean mass aerodynamic diameter (MMAD) 2.2 +/- 0.1 microm, and geometric standard deviation (GSD) 2.3 +/- 0.1. Developed formulations were found to have in vitro prolonged drug release up to 16 h, and obeys Higuchi's Controlled Release model. The investigation provides a practical approach for direct delivery of DS encapsulated in NLs for site specific controlled and prolonged release behavior at the site of action and hence, may play a promising role in prevention of PCP. PMID- 18446461 TI - Preparation of spherical crystal agglomerates of naproxen containing disintegrant for direct tablet making by spherical crystallization technique. AB - The purpose of this research was to obtain directly compressible agglomerates of naproxen containing disintegrant by spherical crystallization technique. Acetone water containing hydroxypropyl celloluse (HPC) and disintegrant was used as the crystallization system. In this study croscarmellose sodium (Ac-Di-Sol) was employed as disintegrant. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), and scanning electron microscopy and were evaluated for flow, packing and tableting properties and drug release. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to their fragmentation occurred during compression. DSC and XRPD studies showed that naproxen particles, crystallized in the presence of HPC and Ac-Di-Sol did not undergo structural modifications. The dissolution rate of naproxen from tablets made of naproxen-(Ac-Di-Sol) agglomerates was enhanced significantly because of including the disintegrant in to the particles. This was attributed to an increase in the surface area of the practically water insoluble drug is exposed to the dissolution medium. In conclusion the spherical crystallization technique developed in this study is suitable for obtaining agglomerates of drug with disintegrant. PMID- 18446462 TI - Optimization studies on design and evaluation of orodispersible pediatric formulation of indomethacin. AB - In the present study, the aim was to optimize an orodispersible formulation of indomethacin using a combined approach of subliming agent and superdisintegrant. The tablets were made by non-aqueous wet granulation technique with superdisintegrant incorporated both intragranularly and extragranularly. A 2(3) factorial design was used to investigate the effects amount of subliming agents namely camphor and ammonium bicarbonate and taste masking and soothening hydrophilic agent mannitol as independent variables and disintegration time and crushing strength as dependent responses. The volatilization time of eight hours at 50 degrees C was optimized by conducting solid-state kinetic studies of optimized formulations. Optimized orodispersible tablets were evaluated for wetting time, water absorption ratio, porosity and in vitro and in vivo disintegration tests. Results show that higher levels of camphor and mannitol and a lower level of ammonium bicarbonate is desirable for orodispersion. Scanning electron microscopy (SEM) revealed the porous surface morphology and kinetic digital images substantiated the orodispersible property. Differential Scanning Calorimetry (DSC) studies exhibited physiochemical compatibility between indomethacin and various excipients used in the tablet formulation. Stability studies carried out as per ICH Q(1) A guidelines suggested the stable formulations for the tested time period of 6 months. The systematic approach of using subliming and disintegrating agents helped in achieving a stable, optimized orodispersible formulation, which could be industrially viable. PMID- 18446463 TI - Development and characterization of pectinate micro/nanoparticles for gene delivery. AB - The aim of this study was to investigate the possibility of using pectinate micro/nanoparticles as gene delivery systems. Pectinate micro/nanoparticles were produced by ionotropic gelation. Various factors were studied for their effects on the preparation of pectinate micro/nanoparticles: the pH of the pectin solution, the ratio of pectin to the cation, the concentration of pectin and the cation, and the type of cation (calcium ions, magnesium ions and manganese ions). After the preparation, the size and charge of the pectin micro/nanoparticles and their DNA incorporation efficiency were evaluated. The results showed that the particle sizes decreased with the decreased concentrations of pectin and cation. The type of cations affected the particle size. Sizes of calcium pectinate particles were larger than those of magnesium pectinate and manganese pectinate particles. The DNA loading efficiency showed that Ca-pectinate nanoparticles could entrap DNA up to 0.05 mg when the weight ratio of pectin:CaCl(2):DNA was 0.2:1:0.05. However, Mg-pectinate could entrap only 0.01 mg DNA when the weight ratio of pectin:MgCl(2):DNA was 1:100:0.01 The transfection efficiency of both Ca pectinate and Mg-pectinate nanoparticles yielded relatively low levels of green fluorescent protein expression and low cytotoxicity in Huh7 cells. Given the negligible cytotoxic effects, these pectinate micro/nanoparticles can be considered as potential candidates for use as safe gene delivery carriers. PMID- 18446464 TI - Effect of Eudragit RS 30D and talc powder on verapamil hydrochloride release from beads coated with drug layered matrices. AB - The aim of this study was to investigate the effect of Eudragit RS 30D, talc, and verapamil hydrochloride on dissolution and mechanical properties of beads coated with "drug-layered matrices". This was accomplished with the aid of a three factor multiple-level factorial design using percent drug release in 1 and 2 h, T(50), tensile strength, brittleness, stiffness and toughness as the responses. Beads were coated in a fluidized-bed coating unit. Surface morphology and mechanical properties were evaluated by surface profilometry and texture analysis, respectively. No cracks, flaws and fissures were observed on the surfaces. The mechanical properties were dependent on the talc/polymer ratio. The release of verapamil from the beads was influenced by matrix components. Increasing the level of both talc and Eudragit decreased the percent drug released from 67% to 4.8% and from 80.7% to 6.7% in 1 and 2 h, respectively, and increased T(50) from 0.8 to 25.7 h. It was concluded that beads could be efficiently coated with "drug-layered matrices". The release of drug, however, depends on a balance between the levels of drug, talc, and polymer, whereby desired dissolution and mechanical properties could be controlled by the talc/polymer ratio and the level of drug loading. PMID- 18446465 TI - Spreadability measurements to assess structural equivalence (Q3) of topical formulations--a technical note. PMID- 18446466 TI - Modified polysaccharides as fast disintegrating excipients for orodispersible tablets of roxithromycin. AB - The purpose of this study was to develop a dosage form that was easy to administer and provides rapid release of the drug roxithromycin, using modified polysaccharides as rapidly disintegrating excipients. Modified polysaccharides co grinded treated agar (C-TAG) and co grinded treated guar gum (C-TGG) were prepared by subjecting pure polysaccharides namely agar and guar gum respectively to sequential processes of wetting, drying and co grinding with mannitol (1:1). The modified polysaccharides were characterized by Scanning Electron Microscopy and Diffuse Reflectance Spectroscopy and evaluated for particle size distribution, derived properties, swelling index and biodegradability. Optimization studies based on 2(2) factorial designs, with friability and disintegration time as response parameters were used to formulate orodispersible tablets of roxithromycin and evaluated for wetting time, water absorption ratio and in vitro drug release at salivary pH 6.4 and physiological pH 7.4. Results indicated that lower levels of modified polysaccharides namely C-TAG in F(3) and C-TGG in F(7) and higher levels of microcrystalline cellulose, exhibited least disintegration times without friability concerns. In vitro release of optimized formulations F(3) and F(7,) both at salivary pH and physiological pH was found to be more than 90% within 30 min as compared to 27.82% at the same time point of conventional formulation. Stability studies carried out as per ICH Q1A guidelines suggested the formulations to be stable for a period of 6 months. Thus the approach of using modified polysaccharides as fast disintegrating excipient can be used to formulate a stable orodispersible formulation. PMID- 18446467 TI - Use of drifts and PLS for the determination of polymorphs of piroxicam alone and in combination with pharmaceutical excipients: a technical note. PMID- 18446468 TI - Applicability and comparative evaluation of wet granulation and direct compression technology to Rauwolfia serpentina root powder: a technical note. PMID- 18446469 TI - Investigation of PEGylated derivatives of rosin as sustained release film formers. AB - The purpose of the present study was to investigate the potential use of two PEGylated derivatives of rosin (PD) as sustained release film forming materials. The derivatives differed chemically by their acid numbers--PD-1 with 120.93 and PD-2 with 88.19. The derivative films were characterized for surface morphology, water uptake-weight loss, angle of contact, water vapor transmission rate, mechanical properties and permeability study. Dissolution of diclofenac sodium (DS) and propranolol hydrochloride (PHL) as model drugs was studied from coated pellets. The films of derivatives with and without plasticizers were smooth and continuous. PD-2 films developed greater numbers of pores when in contact with phosphate buffer pH 6.8. The low weight loss, low angles of contact and high water vapor transmission rate of PD-2 films were related to presence of higher concentration of PEG esters. Higher tensile strength and percent elongation of PD 2 films was due to greater degree of internal plasticization of the derivative. The permeability of films to model drugs propranolol hydrochloride and diclofenac sodium was inversely proportional to the film thickness and dibutyl phthalate concentration in them; the permeability being greatest in PD-2 films containing 10% PEG 200. Dissolution rate of propranolol hydrochloride was higher from the coated pellets. The dissolution data followed zero order, Baker-Lonsdale equation and Hixon-Crowell equation of release kinetics with high correlation coefficients. The mechanism of drug release from these coated systems however followed class II transport (n > 1.0). The derivatives investigated could successfully retard release of the model drugs and offers an alternative to the conventionally used polymers. PMID- 18446470 TI - Estimating the number of droplets and drug particles emitted from MDIs. AB - The objective of this paper is to assess the number of drug particles or droplets contained in metered dose inhaler (MDI) aerosols. Equations were developed to estimate this. The number of drug particles was estimated to be as high as about 300 million for QVAR solution MDIs and as low as 670,000 for Beclovent MDIs. The number of particles in MDI aerosols was shown to be highly dependent on the mass median aerodynamic diameter (MMAD) and geometric standard deviation, and to a lesser extent the total mass of the aerosol. It was demonstrated that when the number of particles are calculated assuming that the aerosol is monodisperse and using the MMAD as the particle size, the number of particles are significantly underestimated. The number of droplets atomized from HFA-134a MDIs was estimated to range from about 220 million to about 1.1 billion droplets per actuation. For solution MDIs, each of the atomized droplets contains drug and thus the number of drug particles is the same as the number of atomized droplets. However, for suspension MDI formulations many of the droplets do not contain any micronized drug particles and the number of drug particles is much lower than the number of atomized droplets. PMID- 18446471 TI - Development of enteric coated flurbiprofen tablets using Opadry/Acryl-Eze system- a technical note. PMID- 18446472 TI - Formulation and evaluation of microemulsion based delivery system for amphotericin B. AB - The present studies were designed to develop a formulation of amphotericin B in a lipid-based preparation as a microemulsion and to compare its toxicity with the commercial formulation Fungizone. The final product developed is a lyophilized amphotericin B, oil and surfactant blend for reconstitution in water to yield a microemulsion containing 5 mg/ml of the drug. Pseudoternary phase diagrams were constructed to identify areas of existence of microemulsion composed of Peceol (glyceryl monooleate) as oil phase and Mys 40 (polyethylene glycol 40 stearate) and Solutol HS 15 (polyethylene glycol 15 hydroxy stearate) as surfactants. Amphotericin B was co-evaporated with oil - surfactant mixture to produce a microemulsion pre-concentrate. The co-evaporate was diluted in water, filtered for sterilization and lyophilized to obtain the final product. The lyophilized as well as the reconstituted products were separately studied for stability and the latter was also characterized for various physicochemical aspects including droplet size of the dispersed phase, osmolarity and aggregation state of drug. The dispersion showed no evidence of precipitation of drug for 48 h, and resisted destabilization due to freeze-thaw cycles or centrifugation. The dispersed phase globules measured a mean size of 84 nm and uv-spectrophotometric studies indicated the presence of self-aggregated amphotericin B. The present formulation showed a 92% decrease in haemolysis of human RBC in vitro when compared with the commercially available Fungizone. The LD(50) in mice was estimated to be 3.4 mg/kg. The results indicate that the formulation holds promise for development as a safer and efficacious alternative for amphotericin B therapy. PMID- 18446473 TI - Preparation, characterization and evaluation of Marsupsin-phospholipid complex. AB - The aim of this research was to formulate Marsupsin-phospholipid complex (M-P Complex) in attempt to increase the bioavailability of marsupsin and to characterize this new formulation along with its evaluation. Marsupsin phospholipid complex was formulated by mechanical dispersion method. In this new formulation, complex formation was confirmed by carrying out transmission electron microscopy (TEM), IR, (1)H-NMR and RP-HPLC analysis. TEM showed M-P Complex diameter range of 0.05-0.5 microm. The entrapment efficiency of M-P Complex was found to be 44%. In vitro release study revealed its first order release profile. Mean blood serum concentration vs time curve of marsupsin was of first order after oral administration of M-P Complex in albino rabbits which clearly showed remarkably increased bioavailability of M-P Complex than standardized marsupsin. The average value of C(max) and T(max) of M-P Complex were found to be 3.02 mg/ml and 10.2 h, respectively. Hence the findings demonstrate that complexing marsupsin with phospholipids results in better oral bioavailability and improved biological response than free form of standardized marsupsin. PMID- 18446474 TI - Design and evaluation of microemulsions for improved parenteral delivery of propofol. AB - The objective of this investigation was to evaluate the potential of the microemulsions to improve the parenteral delivery of propofol. Pseudo-ternary phase diagrams were plotted to identify microemulsification region of propofol. The propofol microemulsions were evaluated for globule size, physical and chemical stability, osmolarity, in vitro hemolysis, pain caused by injection using rat paw-lick test and in vivo anesthetic activity. The microemulsions exhibited globule size less than 25 nm and demonstrated good physical and chemical stability. Propofol microemulsions were slightly hypertonic and resulted in less than 1% hemolysis after 2 h of storage with human blood at 37 degrees C. Rat paw-lick test indicated that propofol microemulsions were significantly less painful as compared to the marketed propofol formulation. The anesthetic activity of the microemulsions was similar to the marketed propofol formulation indicating that they do not compromise the pharmacological action of propofol. The stability studies indicated that the microemulsions were stable for 3 months when stored at 5 +/- 3 degrees C. Thus, microemulsions appeared to be an interesting alternative to the current propofol formulations. PMID- 18446475 TI - Amorphization alone does not account for the enhancement of solubility of drug co ground with silicate: the case of indomethacin. AB - The solubility advantage of indomethacin amorphized by co-grinding with Neusilin US2 in various media was investigated. Physical mixtures of gamma-indomethacin and Neusilin US2 (in the ratios 1:1, 1:4 and 1:5) were amorphized at room temperature employing 75% RH in a porcelain jar mill using zirconia balls. The crystallinity of the samples was determined using ATR-FTIR and PXRD. The solubility and dissolution profiles of co-ground powders and crystalline counterparts were evaluated in 0.1 N HCl, water and phosphate buffer (pH 6.8) in a USP type II dissolution apparatus at 250 rpm and 37 degrees C. Very high concentrations of dissolved indomethacin as compared to the solubility of gamma indomethacin (approximately 500 times in water and approximately 3.7 times in phosphate buffer) were attained. However, the presence of other polymorphs detected by PXRD and a change in the pH of the medium made interpretation of the results difficult. In 0.1 N HCl the solubility (i.e., the peak in a concentration versus time plot) of the amorphized drug in a 1:5 ratio with Neusilin increased to 109 times the solubility of crystalline gamma-indomethacin alone. An increase in amount of drug and Neusilin in the same ratio added to the dissolution medium also increased peak and plateau dissolution concentrations. The presence of silicic acid and ions (Mg(2+) and Al(3+)) in the dissolution media were found to cause the increase in the plateau concentration of indomethacin. Amorphization alone does not account for all of the dissolution enhancement; acidity, ions, and silicic acid are major contributors to dissolution enhancement. PMID- 18446476 TI - Lipospheres as carriers for topical delivery of aceclofenac: preparation, characterization and in vivo evaluation. AB - The purpose of this study was to prepare lipospheres containing aceclofenac intended for topical skin delivery with the aim of exploiting the favorable properties of this carrier system and developing a sustained release formula to overcome the side effects resulting from aceclofenac oral administration. Lipospheres were prepared using different lipid cores and phospholipid coats adopting melt and solvent techniques. Characterization was carried out through photomicroscopy, scanning electron microscopy, particle size analysis, DSC, In vitro drug release and storage study. The anti-inflammatory effect of liposphere systems was assessed by the rat paw edema technique and compared to the marketed product. Results revealed that liposphere systems were able to entrap aceclofenac at very high levels (93.1%). The particle size of liposphere systems was well suited for topical drug delivery. DSC revealed the molecular dispersion of aceclofenac when incorporated in lipospheres. Both entrapment efficiency and release were affected by the technique of preparation, core and coat types, core to coat ratio and drug loading. Lipospheres were very stable after 3 months storage at 2-8 degrees C manifested by low leakage rate (less than 7%) and no major changes in particle size. Finally, liposphere systems were found to possess superior anti-inflammatory activity compared to the marketed product in both lotion and paste consistencies. Liposphere systems proved to be a promising topical system for the delivery of aceclofenac as they possessed the ability to entrap the drug at very high levels and high stability, and to sustain the anti inflammatory effect of the drug. PMID- 18446477 TI - Development of lapachol topical formulation: anti-inflammatory study of a selected formulation. AB - This study aimed at developing a topical formulation of lapachol, a compound isolated from various Bignoniaceae species and at evaluating its topical anti inflammatory activity. The influence of the pharmaceutical form and different types of emulsifiers was evaluated by in-vitro release studies. The formulations showing the highest release rate were selected and assessed trough skin permeation and retention experiments. It was observed that the gel formulation provided significantly higher permeation and retained amount (3.9-fold) of lapachol as compared to the gel-cream formulation. Antinociceptive and antiedematogenic activities of the most promising formulation were also evaluated. Lapachol gel reduced the increase in hind-paw volume induced by carrageenan injection and reduced nociception produced by acetic acid (0.8% in water, i.p.) when used topically. These results suggest that topical delivery of lapachol from gel formulations may be an effective medication for both dermal and subdermal injuries. PMID- 18446478 TI - Controlled ocular delivery of acyclovir through rate controlling ocular insert of Eudragit: a technical note. PMID- 18446479 TI - Formulation and evaluation of a salted-out isoniazid-loaded nanosystem. AB - The purpose of this study was to develop a drug-loaded nanosystem that has the ability to achieve flexible yet rate-controlled release of model drug isoniazid (INH) employing either an aqueous or emulsion-based salting-out approach. Formulation conditions were aimed at reducing the polymeric size with subsequent rate-modulated INH release patterns from the polymeric nanosystem. The emulsion based salted-out nanosystems had particle sizes ranging from 77-414 nm and a zeta potential of -24 mV. The dispersant dielectric constant was set at 78.5 and a conductivity of 3.99 mS/cm achieved. The reduced nanosystem size of the aqueous based approach has demonstrated an intrinsically enhanced exposure of methacrylic acid-ethyl acrylate to zinc sulphate which was employed as a crosslinking reagent. This resulted in robustly interconnected polymeric supports in which INH was efficiently embedded and subsequently released. The multi-layer perceptron data obtained showed that the aqueous and emulsion-based salting out approaches had Power (law) (MSE = 0.020) and Linear (MSE = 0.038) relationships, respectively. Drug release from the nanosystems occurred in two phases with an initial burst-release in aqueous-based nanosystems (30-100%) and significantly lower bursts observed in emulsion-based nanosystems (20-65%) within the first 2 h. This was followed by a gradual exponential release phase over the remaining 12 h. The nanosystems developed demonstrated the ability to control the release of INH depending on the formulation approach adopted. PMID- 18446480 TI - Development and evaluation of buccoadhesive controlled release tablets of lercanidipine. AB - The purpose of this research was to develop and evaluate buccal mucoadhesive controlled release tablets of lercanidipine hydrochloride using polyethylene oxide and different viscosity grades of hydroxypropyl methylcellulose individually and in combination. Effect of polymer type, proportion and combination was studied on the drug release rate, release mechanism and mucoadhesive strength of the prepared formulations. Buccal mucoadhesive tablets were made by direct compression and were characterized for content uniformity, weight variation, friability, surface pH, thickness and mechanism of release. In order to estimate the relative enhancement in bioavailability one optimized formulation was evaluated in rabbits. Further, placebo tablets were also evaluated for acceptability in human subjects. Results indicated acceptable physical characteristics of designed tablets with good content uniformity and minimum weight variation. Drug release and mucoadhesive strength were found to depend upon polymer type, proportion and viscosity. The formulations prepared using poly ethylene oxide gave maximum mucoadhesion. The release mechanism of most formulations was found to be of anomalous non-Fickian type. In vivo studies of selected formulation in rabbits demonstrated significant enhancement in bioavailability of lercanidipine hydrochloride relative to orally administered drug. Moreover, in human acceptability studies of placebo formulations, the designed tablets adhered well to the buccal mucosa for more than 4 h without causing any discomfort. It may be concluded that the designed buccoadhesive controlled release tablets have the potential to overcome the disadvantage of poor and erratic oral bioavailability associated with the presently marketed formulations of lercanidipine hydrochloride. PMID- 18446481 TI - Design and evaluation of self-emulsifying drug delivery systems (SEDDS) of nimodipine. AB - The ability of self-emulsifying drug delivery systems (SEDDS) to improve solubility, dissolution rate and bioavailability of a poorly water-soluble calcium channel blocker, nimodipine (NM) was evaluated in the present investigation. Solubility of NM in various oils, surfactants and cosurfactants was determined. The influence of the ratio of oil to surfactant + cosurfactant, pH of aqueous phase on mean globule size of resulting emulsions was studied by means of photon correlation spectroscopy. The NM loaded SEDDS selected for the in vitro and in vivo studies exhibited globule size less than 180 nm. In vitro dissolution studies indicated that NM loaded SEDDS could release complete amount of NM irrespective of the pH of the dissolution media. Pharmacokinetics of NM suspension, NM oily solution, NM micellar solution and NM SEDDS were evaluated and compared in rabbits. Relative bioavailability of NM in SEDDS was significantly higher than all the other formulations. NM loaded SEDDS were subjected to various conditions of storage as per ICH guidelines for 3 months. NM SEDDS successfully withstood the stability testing. PMID- 18446482 TI - Evaluation of Sterculia foetida gum as controlled release excipient. AB - The purpose of the research was to evaluate Sterculia foetida gum as a hydrophilic matrix polymer for controlled release preparation. For evaluation as a matrix polymer; characterization of Sterculia foetida gum was done. Viscosity, pH, scanning electronmicrographs were determined. Different formulation aspects considered were: gum concentration (10-40%), particle size (75-420 microm) and type of fillers and those for dissolution studies; pH, and stirring speed were considered. Tablets prepared with Sterculia foetida gum were compared with tablets prepared with Hydroxymethylcellulose K15M. The release rate profiles were evaluated through different kinetic equations: zero-order, first-order, Higuchi, Hixon-Crowell and Korsemeyer and Peppas models. The scanning electronmicrographs showed that the gum particles were somewhat triangular. The viscosity of 1% solution was found to be 950 centipoise and pH was in range of 4-5. Suitable matrix release profile could be obtained at 40% gum concentration. Higher sustained release profiles were obtained for Sterculia foetida gum particles in size range of 76-125 microm. Notable influences were obtained for type of fillers. Significant differences were also observed with rotational speed and dissolution media pH. The in vitro release profiles indicated that tablets prepared from Sterculia foetida gum had higher retarding capacity than tablets prepared with Hydroxymethylcellulose K15M prepared tablets. The differential scanning calorimetry results indicated that there are no interactions of Sterculia foetida gum with diltiazem hydrochloride. It was observed that release of the drug followed through surface erosion and anomalous diffusion. Thus, it could be concluded that Sterculia foetida gum could be used a controlled release matrix polymer. PMID- 18446483 TI - Influence of position and size of substituents on the mechanism of partitioning: a thermodynamic study on acetaminophens, hydroxybenzoic acids, and parabens. AB - The objective of the present investigation was to study the influence of size, nature, and topology of substituents on the thermodynamic characteristics of sublimation, fusion, solubility, solvation, and partitioning processes of some drug and druglike molecules. Thermodynamic functions of sublimation process 2 acetaminophen and 3-acetaminophen were obtained on the basis of temperature dependencies of vapor pressure by the transpiration method. Thermodynamic characteristics of solubility processes in water, n-octanol, and n-hexane were calculated from the temperature dependencies of solubility using the solubility saturation method. For evaluation of fusion parameters, differential scanning calorimetry was used. A new approach to distinguishing specific and nonspecific energetic terms in the crystal lattice was developed. Specific and nonspecific solvation terms were distinguished using the transfer from the "inert" n-hexane to the other solvents. For the acetaminophen compounds and for some related drug molecules, the correlation between melting points and a parameter describing the ratio between specific and nonspecific interaction in the crystal lattices was obtained. A diagram enabling analysis of the mechanism of the partitioning process was applied. It was found that for isomers of benzoic acids and for acetaminophens, the position of substituents affects the mechanism of the partitioning process but not the extent of partitioning (DeltaG(tr)(0) values). In contrast to this, an increased size of substituents (parabens) leads to essential changes in DeltaG(tr)(0) values, but the mechanism of the partitioning process stays the same. PMID- 18446484 TI - Intracellular delivery of nanoparticles of an antiasthmatic drug. AB - The aim of the investigation was to prepare and characterize wheat germ agglutinin(WGA)-conjugated poly(D: ,L-lactic-co-glycolic) acid nanoparticles encapsulating mometasone furoate (MF) as a model drug and assess changes in its fate in terms of cellular interactions. MF loaded nanoparticles were prepared using emulsion-solvent evaporation technique. WGA-conjugation was done by carbodiimide coupling method. The nanoparticles were characterized for size, zeta potential, entrapment efficiency and in-vitro drug release. The intracellular uptake of nanoparticles, drug cellular levels, and anti-proliferative activity studies of wheat germ agglutinin-conjugated and unconjugated nanoparticles were assessed on alveolar epithelial (A549) cells to establish cellular interactions. Prepared nanoparticles were spherical with 10-15 microg/mg of WGA conjugated on nanoparticles. The size of nanoparticles increased after conjugation and drug entrapment and zeta potential reduced from 78 +/- 5.5% to 60 +/- 2.5% and -15.3 +/- 1.9 to -2.59 +/- 2.1 mV respectively after conjugation. From the cellular drug concentration-time plot, AUC was found to be 0.4745, 0.6791 and 1.24 for MF, MF-nanoparticles and wheat germ agglutinin-MF-nanoparticles respectively. The in vitro antiproliferative activity was improved and prolonged significantly after wheat germ agglutinin-conjugation. The results conclusively demonstrate improved availability and efficacy of antiasthmatic drug in alveolar epithelial cell lines. Hence, a drug once formulated as mucoadhesive nanoparticles and incorporated in dry powder inhaler formulation may be used for targeting any segment of lungs for more improved therapeutic response in other lung disorders as well. PMID- 18446486 TI - Formulation and evaluation of gastroretentive dosage forms of Clarithromycin. AB - The purpose of this research was to develop the hydrodynamically balanced delivery system of Clarithromycin (CLA) which, after oral administration should have the ability to prolong gastric residence time with the desired in vitro release profile for the localized action in the stomach, in the treatment of Helicobacter pylori (H.pylori) mediated peptic ulcer. By applying wet granulation technique floating tablets of Clarithromycin were prepared. The proportion of sodium bicarbonate was varied to get the least possible lag time, also the polymer part varied to get the desired release. In vivo radiographic studies were performed with Barium sulphate loaded formulation to justify the increased gastric residence time of the dosage form in the stomach, based on the floating principle. The formulation developed using 66.2% Clarithromycin, 12% HPMC K4M polymer, 8% sodium bicarbonate gave floating lag time less than 3 min with a floating time of 12 h, and an in vitro release profile very near to the desired release. X-ray studies showed the enhanced gastric residence time of the tablet to 220 +/- 30 min. The mechanism of release of Clarithromycin from the floating tablets is anomalous diffusion transport and follows zero order kinetics. In vivo radiographic studies suggest that the tablet has increased gastric residence time for the effective localized action of the antibiotic (Clarithromycin) in the treatment of H.pylori mediated peptic ulcer. PMID- 18446485 TI - Design and development of gliclazide mucoadhesive microcapsules: in vitro and in vivo evaluation. AB - In this study an attempt was made to prepare mucoadhesive microcapsules of gliclazide using various mucoadhesive polymers designed for oral controlled release. Gliclazide microcapsules were prepared using sodium alginate and mucoadhesive polymer such as sodium carboxymethyl cellulose (sodium CMC), carbopol 934P or hydroxy propylmethyl cellulose (HPMC) by orifice-ionic gelation method. The microcapsules were evaluated for surface morphology and particle shape by scanning electron microscope. Microcapsules were also evaluated for their microencapsulation efficiency, in vitro wash-off mucoadhesion test, in vitro drug release and in vivo study. The microcapsules were discrete, spherical and free flowing. The microencapsulation efficiency was in the range of 65-80% and microcapsules exhibited good mucoadhesive property in the in vitro wash off test. The percentage of microcapsules adhering to tissue at pH 7.4 after 6 h varied from 12-32%, whereas the percentage of microcapsules adhering to tissue at pH 1.2 after 6 h varied from 35-68%. The drug release was also found to be slow and extended for more than 16 h. In vivo testing of the mucoadhesive microcapsules in diabetic albino rats demonstrated significant antidiabetic effect of gliclazide. The hypoglycemic effect obtained by mucoadhesive microcapsules was for more than 16 h whereas gliclazide produced an antidiabetic effect for only 10 h suggesting that mucoadhesive microcapsules are a valuable system for the long term delivery of gliclazide. PMID- 18446487 TI - Dissolution variability: comparison of commercial dosage forms with US Pharmacopeia Lot P Prednisone reference standard tablets--a technical note. PMID- 18446488 TI - The influence of sodium hyaluronate, L-leucine and sodium taurocholate on the nebulization of aqueous betamethasone-17-valerate suspensions. AB - The purpose of this research was to evaluate the variables that are suggested to influence the adsorption of the hydrophilic hyaluronic acid (HA) onto the surface of the hydrophobic betamethasone-17-valerate (BV) particles in order to formulate a nebulizable suspension. The adsorption of HA from aqueous solutions (0.04% to 0.16%, w/v) to a fixed BV concentration (0.04%, w/v) under different experimental conditions, was investigated. The method of preparation of HA-BV suspensions involved suspending BV particles either in the hydrated HA solution (method 1) or in water followed by addition of solid HA (method 2). Other variables like the time required for the adsorption to complete and temperature at which adsorption is carried out were studied. The nebulization of the suspensions was tested via an air jet nebulizer connected to a twin stage impinger. In order to improve the nebulization behavior of the optimized suspension, L-leucine or sodium taurocholate was incorporated in increasing concentrations (0.01-0.04%, w/v). The optimized suspension, having a nebulization efficiency of 33.75%, was achieved following the adsorption of HA (0.1%, w/v) onto BV particles adopting method 2 of preparation and extending for three days at 4 degrees C. Incorporation of either l-leucine or sodium taurocholate significantly decreased the aggregate size of the optimized suspension and consequently caused significant increases in the nebulization efficiency to reach 46.87% and 56.25%, respectively. PMID- 18446489 TI - Comparative evaluation of flow for pharmaceutical powders and granules. AB - The objective of the present work was to carry out a systematic evaluation of flow of pharmaceutical powders and granules using compendial and non-compendial methods. Angle of repose, bulk density, tapped density, Carr's compressibility index, and Hausner ratios were evaluated. Additionally, flow was characterized using a powder rheometer in which a sensitive force transducer monitors the forces generated as a result of the sample displacement. The critical attributes such as cohesivity index, caking strength, and flow stability were determined for samples. The samples consisted of different grades of magnesium stearate powder including bovine, vegetable, and food grade, physical mixture powder blend consisting of a model formulation, granules prepared by various methods including slugging, high shear granulator, and fluid bed dryer. Lubricant efficiency was also determined for granules lubricated with various concentrations of magnesium stearate. It was observed that the compendial methods were often non discriminating for minor variations in powder flow. The additional characterization such as cohesivity, and caking strength were helpful in understanding the flow characteristics of pharmaceutical systems. The flow stability test determined that the powders were not affected by the test conditions on the rheometer. The non-compendial tests were discriminating to even minor variations in powder flow. PMID- 18446490 TI - Process analytical technology: application to particle sizing in spray drying. AB - The purpose of this research was to explore the possibility of employing PAT for particle sizing during spray drying with the use of an in-line and at-line laser diffraction system. Microspheres were made using maltodextrin and modified starch as wall material and size results obtained using PAT compared with those determined with off-line laser diffraction and light microscopy. Median particle size results were highest for in-line laser diffraction, followed by at-line and off-line laser diffraction and finally light microscopy. This was due to the presence of agglomerates which were measured as discrete microspheres in the in line set-up. At-line and off-line laser diffraction gave results more closely correlated with individual microsphere sizes due to agglomerate breakdown during the measurement process. Light microscopy allowed direct observation of the particle morphology, however, its use for particle sizing was tedious and sample size was much smaller compared to laser diffraction. Although PAT was found to be an efficient and convenient tool, careful data interpretation was needed taking into account the cohesiveness of the material measured. The at-line set-up appeared to be more suitable in this particular application. PMID- 18446491 TI - Ultrasound transmission technique as a potential tool for physical evaluation of monolithic matrix tablets. AB - The aim of this study was to investigate the effects of tablet porosity and particle size fraction of compacted Starch acetate powders, with and without model drug caffeine, on acoustic properties of tablets. The ultrasound velocity was determined from the transmission measurements. Tablets of starch acetate (SA DS 2.7) powder with two particle size fractions of 0-53 and 0-710 microm were compressed with a compaction simulator. Porosities of tablets varied in the range from 12% to 43% for both particle size fractions. Strong associations were found between the ultrasound velocity and physical properties of the tablets such as porosity and particle size fraction. Interestingly, ultrasound velocity was practically insensitive to inclusion of the model drug caffeine with the concentrations used. Based on this study ultrasound transmission method is a potential non-destructive tool for studying structural changes of tablets and other solid dosage forms. PMID- 18446492 TI - Influence of compression force on the behavior of mucoadhesive buccal tablets. AB - The purpose of this research was to study the compression force influence on polymers, tablet behavior and drug release rate. Several tablet batches were produced by varying the compression force and by using hydroxyethyl cellulose (HEC) and Carbopol 940 in the 1:1 ratio as matrix forming polymers. All batches were characterized by DSC and X-ray analyses and in terms of swelling, ex vivo and in vivo mucoadhesive time, ex vivo mucoadhesion force, and in vitro and in vivo release. No significant excipient-excipient or excipient-drug interactions were observed in any of the batches. All the tablets hydrated quickly and their high hydration percentage showed that the compression forces used did not remarkably affect the water penetration and the polymeric chain stretching. Mucoadhesion performances and drug release were mainly influenced by compression force; its increase produced higher ex vivo and in vivo mucoadhesion and the in vitro and in vivo drug releases were seen to decrease with the increase of the compression force. However tablets fabricated by using the lowest compression force showed the best in vivo mucoadhesive time and hydrated faster when compared to the others. Tablets 4 and 5, prepared with the highest forces, caused pain during in vivo application and gave rise to irritation needing to be detached by the volunteers while tablet 1, prepared with the lowest force, gave the best results because it was able to produce the highest drug salivary concentration and no pain. All tablets exhibited an anomalous release mechanism. PMID- 18446493 TI - A new rapid on-line imaging method to determine particle size distribution of granules. AB - The purpose of this research was to study the feasibility of the new image analysis method in the particle size determination of the granules. The method is capable of forming a three-dimensional topographic image of a sample surface from a digital picture. In the method, a flat granule bed surface was illuminated from three different directions, using the three primary colors (red, green, and blue). One color picture was taken by a digital camera, after which a topographic image of the object surface was constructed. The particle size distribution was then calculated from the image data. The particle size analysis method was tested both off-line and on-line. Off-line particle size measurement results determined by the image analysis method corresponded quite well to those of sieve analysis in the size fraction range 250-1,000 microm. In on-line application, images were successfully retrieved and median granule size trend could be calculated and followed during fluid bed granulations. PMID- 18446494 TI - Development of novel biodegradable polymeric nanoparticles-in-microsphere formulation for local plasmid DNA delivery in the gastrointestinal tract. AB - There is a critical need for development of novel delivery systems to facilitate the translation of nucleic acid-based macromolecules into clinically-viable therapies. The aim of this investigation was to develop and evaluate a novel nanoparticles-in-microsphere oral system (NiMOS) for gene delivery and transfection in specific regions of the gastrointestinal (GI) tract. Plasmid DNA, encoding for the enhanced green fluorescent protein (EGFP-N1), was encapsulated in type B gelatin nanoparticles. NiMOS were prepared by further protecting the DNA-loaded nanoparticles in a poly(epsilon-caprolactone) (PCL) matrix to form microspheres of less than 5.0 microm in diameter. In order to evaluate the biodistribution following oral administration, radiolabeled ((111)In-labeled) gelatin nanoparticles and NiMOS were administered orally to fasted Balb/C mice. The results of biodistribution studies showed that, while gelatin nanoparticles traversed through the GI tract fairly quickly with more than 54% of the administered dose per gram localizing in the large intestine at the end of 2 h, NiMOS resided in the stomach and small intestine for relatively longer duration. Following oral administration of EGFP-N1 plasmid DNA at 100 microg dose in the control and test formulations, the quantitative and qualitative results presented in this study provide the necessary evidence for transfection potential of NiMOS upon oral administration. After 5 days post-administration, transgene expression in the small and large intestine of mice was observed. Based on these results, NiMOS show significant potential as novel gene delivery vehicle for therapeutic and vaccination purposes. PMID- 18446495 TI - Preliminary investigation on the development of diltiazem resin complex loaded carboxymethyl xanthan beads. AB - The objective of this study was to develop a multiunit sustained release dosage form of diltiazem using a natural polymer from a completely aqueous environment. Diltiazem was complexed with resin and the resinate-loaded carboxymethyl xanthan (RCMX) beads were prepared by interacting sodium carboxymethyl xanthan (SCMX), a derivatized xanthan gum, with Al(+3) ions. The beads were evaluated for drug entrapment efficiency (DEE) and release characteristics in enzyme free simulated gastric fluid (SGF, HCl solution, pH 1.2) and simulated intestinal fluid (SIF, USP phosphate buffer solution, pH 6.8). Increase in gelation time from 5 to 20 min and AlCl(3) concentration from 1 to 3% decreased the DEE respectively from 95 to 79% and 88.5 to 84.6%. However, increase in gum concentration from 1.5 to 2.5% increased the DEE from 86.5 to 90.7%. The variation in DEE was related to displacement of drug from the resinate by the gel forming Al(+3) ions. While 75 82% drug was released in 2 h in SGF from various beads, 75 to 98% drug was released in 5 hour in SIF indicating the dependence of drug release on pH of dissolution media. Although the beads maintained their initial integrity throughout the dissolution process in both media, as evident from scanning electron microscopic studies, the faster release in SGF was accounted for higher swelling of the beads in SGF than in SIF. When release data (up to 60%) was fitted in power law expression, the drug release was found to be controlled by diffusion with simultaneous relaxation phenomena. PMID- 18446496 TI - Controlled release matrix tablets of zidovudine: effect of formulation variables on the in vitro drug release kinetics. AB - The purpose of this research was to design oral controlled release (CR) matrix tablets of zidovudine (AZT) using hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC) and carbopol-971P (CP) and to study the effect of various formulation factors on in vitro drug release. Release studies were carried out using USP type 1 apparatus in 900 ml of dissolution media. Release kinetics were analyzed using zero-order, Higuchi's square root and Ritger-Peppas' empirical equations. Release rate decreased with increase in polymer proportion and compression force. The release rate was lesser in formulations prepared using CP (20%) as compared to HPMC (20%) as compared to EC (20%). No significant difference was observed in the effect of pH of dissolution media on drug release from formulations prepared using HPMC or EC, but significant difference was observed in CP based formulations. Decrease in agitation speed from 100 to 50 rpm decreased release rate from HPMC and CP formulations but no significant difference was observed in EC formulations. Mechanism of release was found to be dependent predominantly on diffusion of drug through the matrix than polymer relaxation incase of HPMC and EC formulations, while polymer relaxation had a dominating influence on drug release than diffusion incase of CP formulations. Designed CR tablets with pH independent drug release characteristics and an initial release of 17-25% in first hour and extending the release up to 16-20 h, can overcome the disadvantages associated with conventional tablets of AZT. PMID- 18446497 TI - Physicochemical properties and dissolution studies of dexamethasone acetate-beta cyclodextrin inclusion complexes produced by different methods. AB - Inclusion complexes between dexamethasone acetate (DMA), a poorly water soluble drug, and beta-cyclodextrin (betaCD) were obtained to improve the solubility and dissolution rate of this drug. Phase-solubility profile indicated that the solubility of DMA was significantly increased in the presence of betaCD (33-fold) and was classified as A(L)-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by different methods (kneading, coevaporation, freeze drying) and physical mixture were characterized by differential scanning calorimetry, thermogravimetry, infrared absorption and optical microscopy. Preparation methods influenced the physicochemical properties of the products. The dissolution profiles of solid complexes were determined and compared with those DMA alone and their physical mixture, in three different mediums: simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 7.4) and distilled water. The dissolution studies showed that in all mediums DMA presented an incomplete dissolution even in four hours. In contrast, the complexes formed presented a higher dissolution rate in simulated gastric fluid (SGF pH 1.2), which indicate that these have different ionization characteristics. According to the results, the freeze-dried and kneaded products exhibited higher dissolution rates than the drug alone, in all the mediums. PMID- 18446498 TI - Process optimization, characterization and pharmacokinetic evaluation in rats of ursodeoxycholic acid-phospholipid complex. AB - The purpose of this research was to study whether the bioavailability of ursodeoxycholic acid could be improved by administering ursodeoxycholic acid phospholipid complex (UDCA-PLC) orally to rats. A central composite design approach was used for process optimization in order to obtain the acceptable UDCA PLC. The physicochemical properties of the complex obtained by optimal parameters were investigated by means of scanning electron microscopy and X-ray diffraction. The pharmacokinetic parameters and bioavailability studies were conducted in rats of UDCA after oral administration of UDCA-PLC and UDCA tablet. Multiple linear regression analysis for process optimization revealed that the acceptable UDCA PLC was obtained wherein the optimal values of X(1), X(2) and X(3) were 3, 60 degrees C and 3 h, respectively. The XRD studies of UDCA-PLC obtained by the optimal parameters demonstrated that UDCA and phospholipids in the UDCA-PLC were combined by non-covalent bonds, not form new compounds. But pharmacokinetic parameters of the complex in rats were T(max) 1.6 h, C(max) 0.1346 microg/ml, AUC(0-infinity) 11.437 microg x h/ml, respectively. The relative bioavailability of UDCA of UDCA-PLC was increased by 241%,compared with the reference ursodeoxycholic acid tablet. PMID- 18446499 TI - Gum cordia: a novel matrix forming material for enteric resistant and sustained drug delivery--a technical note. PMID- 18446500 TI - An overview of patent law as applied to the field of veterinary medicine. AB - This article analyzes some of the challenges that can arise when patent law is applied to the field of veterinary medicine. Topics covered in this article include an overview of the different kinds of inventions that can be patented in the veterinary field; a review of recent legal developments that may affect the patenting of veterinary pharmaceuticals; a discussion of some potential issues related to patents covering assays; and an identification of some special situations where the law affecting veterinary pharmaceuticals is actually different from the law affecting human pharmaceuticals. PMID- 18446501 TI - The role of quantitative pharmacology in an academic translational research environment. AB - Translational research is generally described as the application of basic science discoveries to the treatment or prevention of disease or injury. Its value is usually determined based on the likelihood that exploratory or developmental research can yield effective therapies. While the pharmaceutical industry has evolved into a highly specialized sector engaged in translational research, the academic medical research community has similarly embraced this paradigm largely through the motivation of the National Institute of Health (NIH) via its Roadmap initiative. The Clinical and Translational Science Award (CTSA) has created opportunities for institutions which can provide the multidisciplinary environment required to engage such research. A key component of the CTSA and an element of both the NIH Roadmap and the FDA Critical Path is the bridging of bench and bedside science via quantitative pharmacologic relationships. The infrastructure of the University of Pennsylvania/Children's Hospital of Philadelphia CTSA is highlighted relative to both research and educational objectives reliant upon quantitative pharmacology. A case study, NIH-sponsored research program exploring NK1r antagonism for the treatment NeuroAIDS is used to illustrate the application of quantitative pharmacology in a translational research paradigm. PMID- 18446502 TI - Cell cycle checkpoint models for cellular pharmacology of paclitaxel and platinum drugs. AB - A pharmacokinetic-pharmacodynamic mathematical model is developed for cellular pharmacology of chemotherapeutic drugs for which the decisive step towards cell death occurs at a point in the cell cycle, presumably corresponding to a cell cycle checkpoint. For each cell, the model assumes a threshold level of some intracellular species at that checkpoint, beyond which the cell dies. The threshold level is assumed to have a log-normal distribution in the cell population. The kinetics of formation of the lethal intracellular species depends on the drug, and on the cellular pharmacokinetics and binding kinetics of the cell. Specific models are developed for paclitaxel and for platinum drugs (cisplatin, oxaliplatin and carboplatin). In the case of paclitaxel, two separate mechanisms of cell death necessitate a model that accounts for two checkpoints, with different intracellular species. The model was tested on a number of in vitro cytotoxicity data sets for these drugs, and found overall to give significantly better fits than previously proposed cellular pharmacodynamic models. It provides an explanation for the asymptotic convergence of dose response curves as exposure time becomes long. PMID- 18446503 TI - Informatic tools and approaches in postmarketing pharmacovigilance used by FDA. AB - The safety profile of newly approved drugs and therapeutic biologics is less well developed by pre-marketing clinical testing than is the efficacy profile. The full safety profile of an approved product is established during years of clinical use. For nearly 40 years, the FDA has relied on the voluntary reporting of adverse events by healthcare practitioners and patients to help establish the safety of marketed products. Epidemiologic studies, including case series, secular trends, case-control and cohort studies, are used to supplement the investigation of a safety signal. Ideally, active surveillance systems would supplement the identification and exploration of safety signals. The FDA has implemented a number of initiatives to help identify safety problems with drugs and continues to evaluate their efforts. PMID- 18446504 TI - The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AB - Ivermectin is an antiparasitic drug with a broad spectrum of activity, high efficacy as well as a wide margin of safety. Since 1987, this compound has a widespread use in veterinary medicine and it use has been extended in humans. Here we present a brief review of the information available regarding the pharmacokinetics and interactions of ivermectin in humans. Awareness of these characteristics could improve the clinical efficacy of Ivermectin. All Authors declare that they do not have any Conflict of interest and that the work is original. All Authors agree that the contents of the manuscript are confidential and will not be copyrighted, submitted, or published elsewhere (including the Internet), in any language, while acceptance by the Journal is under consideration. PMID- 18446505 TI - Pharmacokinetic interaction between the flavonoid luteolin and gamma hydroxybutyrate in rats: potential involvement of monocarboxylate transporters. AB - Monocarboxylate transporter 1 (MCT1) has been previously reported as an important determinant of the renal reabsorption of the drug of abuse, gamma-hydroxybutyrate (GHB). Luteolin is a potent MCT1 inhibitor, inhibiting the uptake of GHB with an IC(50) of 0.41 microM in MCT1-transfected MDA-MB231 cells. The objectives of this study were to characterize the effects of luteolin on GHB pharmacokinetics and pharmacodynamics in rats, and to investigate the mechanism of the interaction using model-fitting methods. GHB (400 and 1,000 mg/kg) and luteolin (0, 4 and 10 mg/kg) were administered to rats via iv bolus doses. The plasma or urine concentrations of luteolin and GHB were determined by HPLC and LC/MS/MS, respectively. The pharmacodynamic parameter sleep time in rats after GHB administration was recorded. A pharmacokinetic model containing capacity-limited renal reabsorption and metabolic clearance was constructed to characterize the in vivo interaction. Luteolin significantly decreased the plasma concentration and AUC, and increased the total and renal clearances of GHB. Moreover, luteolin significantly shortened the duration of GHB (1,000 mg/kg)-induced sleep in rats (161 +/- 16, 131 +/- 14 and 121 +/- 5 min for control, luteolin 4 and 10 mg/kg groups, respectively, p < 0.01). An uncompetitive inhibition model, with an inhibition constant of 1.1 microM, best described the in vivo pharmacokinetic interaction. The results of this study indicated that luteolin significantly altered the pharmacokinetics of GHB by inhibiting its MCT1-mediated transport. The interaction between luteolin and GHB may offer a potential clinical detoxification strategy to treat GHB overdoses. PMID- 18446506 TI - Pharmacokinetics of 1,4-butanediol in rats: bioactivation to gamma-hydroxybutyric acid, interaction with ethanol, and oral bioavailability. AB - 1,4-Butanediol (BD), a substance of abuse, is bioactivated to gamma hydroxybutyrate (GHB), but its fundamental pharmacokinetics (PK) have not been characterized. Because this bioactivation is partly mediated by alcohol dehydrogenase, we hypothesized that there may also be a metabolic interaction between ethanol (ETOH) and BD. We therefore studied, in rats, the plasma PK of GHB, BD and ETOH each at two intravenous (IV) doses, when each substance was given alone, and when GHB or BD was co-administered with ETOH. Results showed that bioconversion of intravenously administered BD to GHB was complete, and that both GHB and BD exhibited nonlinear PK. Various population PK models were analyzed using NONMEM VI, and the best disposition model was found to include two PK compartments each for BD, an (unmeasured) putative semialdehyde intermediate (ALD), GHB and ETOH, the presence of nonlinear (Michaelis-Menten) elimination for each compound, and several mutual inhibition processes. The most prominent mutual metabolic inhibition was found between ETOH and BD, while that between GHB and ETOH was not significant. In vitro studies using liver homogenates confirmed mutual metabolic inhibitions between GHB and BD. Oral absorption of BD was best described by a first-order process with lag-time and pre-systemic metabolism from BD to ALD. Oral absorption of BD (as BD plus ALD) was rapid and complete. The fraction of the absorbed dose entering the central compartment as BD was 30% for the 1.58 mmol/kg dose and 55% for the 6.34 mmol/kg dose. At 6.34 mmol/kg IV, the onset of loss of righting reflex (LRR) for BD was significantly delayed vs. that produced by GHB (72.0 +/- 9.1 min vs. 6.7 +/- 0.6 min, respectively, p < 0.001), and the total duration of LRR was prolonged for BD vs. GHB (192 +/- 28 min vs. 117 +/- 2 min, respectively, p < 0.05). Relative to IV dosing, oral BD produced similar but more variable LRR effects. These results may provide a quantitative PK framework for the understanding of the toxicokinetics and toxicodynamics of both BD and GHB. PMID- 18446507 TI - A flexible nonlinear feedback system that captures diverse patterns of adaptation and rebound. AB - An important approach to modeling tolerance and adaptation employs feedback mechanisms in which the response to the drug generates a counter-regulating action which affects the response. In this paper we analyze a family of nonlinear feedback models which has recently proved effective in modeling tolerance phenomena such as have been observed with SSRI's. We use dynamical systems methods to exhibit typical properties of the response-time course of these nonlinear models, such as overshoot and rebound, establish quantitive bounds and explore how these properties depend on the system and drug parameters. Our analysis is anchored in three specific in vivo data sets which involve different levels of pharmacokinetic complexity. Initial estimates for system (k(in), k(out), k(tol)) and drug (EC(50)/IC(50), E(max)/I(max), n) parameters are obtained on the basis of specific properties of the response-time course, identified in the context of exploratory (graphical) data analysis. Our analysis and the application of its results to the three concrete examples demonstrates the flexibility and potential of this family of feedback models. PMID- 18446508 TI - Rheological evaluation of silicon/carbopol hydrophilic gel systems as a vehicle for delivery of water insoluble drugs. AB - The present study analyzed the thickening properties of Carbopol 974 and 971 in a 50:50 mixture of water/Silsense A-21, a new cationic silicon miscible in any proportion with water. Samples were prepared by simply dispersing different Carbopol amounts (0.5-4%) at room temperature or at 70 degrees C without neutralizing. Temperature sweep and time sweep analysis did not reveal significant structural changes at increasing temperature in the samples prepared following the first procedure. On the other hand systems obtained at 70 degrees C possessed higher elastic character particularly at polymer concentration higher than 2% (w/v). Analysis of the G' and G'' vs frequency curves by using different fitting equations (linear fitting, power law) gave information about the viscoelastic properties of the systems. The fitting of the frequency spectra and the calculation of the relaxation times from the master curves outlined the structural differences within the samples prepared with the two different procedures, confirming stronger gel-like behaviour for the samples prepared by the heating procedure. High preparation temperature promoted the polymer-solvent interactions, aiding the solvation of Carbopol. Heating facilitated polymer solvent and polymer-polymer interaction, giving rise to a better organised structure typical of gel-like systems. Furthermore this preparation method provided good stability properties as shown by the stress sweeps tests performed during the three months of storage. The interpretation of the rheological results was supported by statistical analysis. A design methodology (screening and optimisation) was also applied in order evaluate the influence on dynamic rheological moduli of several parameters (polymer type and concentration, preparation method, temperature of the tests). This last method showed the relevance of the interaction of two main factors: polymer concentration and preparation procedure. Thus, statistical analysis confirmed that temperature increased the polymer-solvent interaction and improved the viscoelastic properties of the systems, particularly when Carbopols were present in considerable amounts. PMID- 18446510 TI - FDA critical path initiatives: opportunities for generic drug development. AB - FDA's critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document "Critical Path Opportunities for Generic Drugs" that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs. PMID- 18446509 TI - Prodrug approaches for CNS delivery. AB - Central nervous system (CNS) drug delivery remains a major challenge, despite extensive efforts that have been made to develop novel strategies to overcome obstacles. Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which subsequently exerts the desired pharmacological effect. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that overcome barriers to a drug's usefulness. This review provides insight into various prodrug strategies explored to date for CNS drug delivery, including lipophilic prodrugs, carrier- and receptor-mediated prodrug delivery systems, and gene-directed enzyme prodrug therapy. PMID- 18446511 TI - Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. AB - There is limited information describing species related pharmacogenetic differences in animals. Despite the lack of genetic information in veterinary medicine, breed specific responses to endogenous and exogenous substances have been reported across many species. This finding underscores the importance of obtaining insight into the genotypic and phenotypic variation present across breeds. This article provides a summary of the literature pertaining to canine breed differences in physiology, drug response, drug pharmacokinetics, and metabolic idiosyncrasies. The existing knowledge of pedigrees and the known phenotypes and genotypes of dogs provides important information for determining mode of inheritance, penetration, and other major characteristics of heritable traits. Understanding these breed differences will improve canine population predictions (for canine drug products) and may be of value when extrapolating toxicology data from dogs to humans. PMID- 18446513 TI - Nanoparticles containing anti-inflammatory agents as chemotherapy adjuvants: optimization and in vitro characterization. AB - The pre-administration of dexamethasone (DEX) has previously been shown to enhance the anti-tumor efficacy of chemotherapeutic agents. The delivery of anti inflammatory agents specifically to tumors via nanoparticle carriers is expected to promote the effectiveness of chemotherapeutic agents while avoiding systemic toxicities. The process for preparing solid lipid nanoparticles containing anti inflammatory agents using the nanotemplate engineering method was optimized. Due to the solubilization of DEX in the bulk aqueous phase, its more lipophilic palmitate ester was synthesized and incorporated in nanoparticles that included a pegylating agent, PEG6000 mono-stearate, as part of the formulation. The stealth properties of these nanoparticles were demonstrated to be enhanced compared to latex particles by measuring the adsorption of radioiodinated IgG (185 microg vs. 6.7 microg IgG/mg NP). In addition, the uptake of (14)C-labeled nanoparticles by murine macrophages was shown to decrease from 36.6% to 14.7% of the nanoparticles/mg cell protein as the amount of pegylating agent in the formulation increased from 0 to 4 mg/mL. The high loading values and low burst effect observed for these DEX palmitate-containing nanoparticles in addition to their stealth properties are expected to allow for the delivery of sufficient amounts of DEX to tumors to enhance the uptake of chemotherapeutic agents. PMID- 18446514 TI - Evaluation of methods for estimating time to steady state with examples from phase 1 studies. AB - An overview is provided of the methodologies used in determining the time to steady state for Phase 1 multiple dose studies. These methods include NOSTASOT (no-statistical-significance-of-trend), Helmert contrasts, spline (quadratic) regression, effective half life for accumulation, nonlinear mixed effects modeling, and Bayesian approach using Markov Chain Monte Carlo (MCMC) methods. For each methodology we describe its advantages and disadvantages. The first two methods do not require any distributional assumptions for the pharmacokinetic (PK) parameters and are limited to average assessment of steady state. Also spline regression which provides both average and individual assessment of time to steady state does not require any distributional assumptions for the PK parameters. On the other hand, nonlinear mixed effects modeling and Bayesian hierarchical modeling which allow for the estimation of both population and subject-specific estimates of time to steady state do require distributional assumptions on PK parameters. The current investigation presents eight case studies for which the time to steady state was assessed using the above mentioned methodologies. The time to steady state estimates obtained from nonlinear mixed effects modeling, Bayesian hierarchal approach, effective half life, and spline regression were generally similar. PMID- 18446512 TI - Percutaneous permeation enhancement by terpenes: mechanistic view. AB - A popular approach for improving transdermal drug delivery involves the use of penetration enhancers (sorption promoters or accelerants) which penetrate into skin to reversibly reduce the barrier resistance. The potential mechanisms of action of penetration enhancers include disruption of intercellular lipid and/or keratin domains and tight junctions. This results in enhanced drug partitioning into tissue, altered thermodynamic activity/solubility of drug etc. Synthetic chemicals (solvents, azones, pyrrolidones, surfactants etc.) generally used for this purpose are rapidly losing their value in transdermal patches due to reports of their absorption into the systemic circulation and subsequent possible toxic effect upon long term application. Terpenes are included in the list of Generally Recognized As Safe (GRAS) substances and have low irritancy potential. Their mechanism of percutaneous permeation enhancement involves increasing the solubility of drugs in skin lipids, disruption of lipid/protein organization and/or extraction of skin micro constituents that are responsible for maintenance of barrier status. Hence, they appear to offer great promise for use in transdermal formulations. This article is aimed at reviewing the mechanisms responsible for percutaneous permeation enhancement activity of terpenes, which shall foster their rational use in transdermal formulations. PMID- 18446515 TI - Highly variable drugs: observations from bioequivalence data submitted to the FDA for new generic drug applications. AB - INTRODUCTION: It is widely believed that acceptable bioequivalence studies of drugs with high within-subject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions. MATERIALS AND METHODS: We collected data from all in vivo bioequivalence studies reviewed at FDA's Office of Generic Drugs (OGD) from 2003-2005. We used the ANOVA root mean square error (RMSE) from bioequivalence statistical analyses to estimate within subject variability. A drug was considered highly variable if its RMSE for C (max) and/or AUC was > or =0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance. RESULTS AND DISCUSSION: In 2003-2005, the OGD reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 39% were either consistently, borderline, or inconsistently highly variable, respectively. We observed that most of the consistent and borderline highly variable drugs underwent extensive first pass metabolism. Drug product dissolution variability was high for about half of the inconsistently highly variable drugs. We could not identify factors causing variability for the other half. Studies of highly variable drugs generally used more subjects than studies of lower variability drugs. CONCLUSION: About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability. PMID- 18446516 TI - Pharmacokinetically-guided lead optimization of nitrofuranylamide anti tuberculosis agents. AB - In an effort to develop novel and more potent therapies to treat tuberculosis, a new class of chemical agents, nitrofuranylamides, is being developed. The present study examines biopharmaceutic properties and preclinical pharmacokinetics of nitrofuranylamides at early stages of drug discovery to accelerate the optimization of leads into development candidates. The first tested compound, Lee 562, had high anti-tuberculosis activity in vitro, but exhibited poor metabolic stability resulting in a high systemic clearance, a short elimination half-life and low oral bioavailability in vivo in rats. Thus, two follow-up compounds were designed and tested that included structural modifications for increased metabolic stability. Both compounds showed improved metabolic stability compared to Lee 562, with Lee 878 being much more stable than Lee 952. As a consequence, the oral bioavailability of Lee 878 reached approximately 27% compared to 16% for the other two compounds. This observation prompted us to select compounds based on metabolic stability screening and a new set of nine compounds with high in vitro activity were tested for metabolic stability. The most stable compound in the assay, Lee 1106 was selected for further pharmacokinetic evaluation in rats. Surprisingly, Lee 1106 exhibited poor oral bioavailability, 4.6%. Biopharmaceutic evaluation of the compound showed that the compound has poor aqueous solubility and a high clogP. Based on these results, a screening paradigm was developed for optimization of the nitrofuranylamide lead compounds in a timely and cost effective manner that might also be applicable to other classes of anti-infective drugs. PMID- 18446517 TI - Recent advances in blood-brain barrier disruption as a CNS delivery strategy. AB - The blood-brain barrier (BBB) is a complex functional barrier composed of endothelial cells, pericytes, astrocytic endfeets and neuronal cells. This highly organized complex express a selective permeability for molecules that bear, amongst other parameters, adequate molecular weight and sufficient liposolubility. Unfortunately, very few therapeutic agents currently available do cross the BBB and enters the CNS. As the BBB limitation is more and more acknowledged, many innovative surgical and pharmacological strategies have been developed to circumvent it. This review focuses particularly on the osmotic opening of the BBB, a well-documented approach intended to breach the BBB. Since its inception by Rapoport in 1972, pre-clinical studies have provided important information on the extent of BBB permeation. Thanks to Neuwelt and colleagues, the osmotic opening of the BBB made its way to the clinic. However, many questions remain as to the detailed physiology of the procedure, and its best application to the clinic. Using different tools, amongst which MRI as a real time in vivo characterization of the BBB permeability and CNS delivery, we attempt to better define the osmotic BBB permeabilization physiology. These ongoing studies are described, and data related to spatial and temporal distribution of a molecule after osmotic BBB breaching, as well as the window of BBB permeabilization, are discussed. We also summarize recent clinical series highlighting promising results in the application of this procedure to maximize delivery of chemotherapy in the treatment of brain tumor patients. PMID- 18446518 TI - Role of biotransformation studies in minimizing metabolism-related liabilities in drug discovery. AB - Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules. PMID- 18446519 TI - Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AB - SLC5A8 and SLC5A12 are sodium-coupled monocarboxylate transporters (SMCTs), the former being a high-affinity type and the latter a low-affinity type. Both transport a variety of monocarboxylates in a Na(+)-coupled manner. They are expressed in the gastrointestinal tract, kidney, thyroid, brain, and retina. SLC5A8 is localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to neurons and the retinal pigment epithelium. The physiologic functions of SLC5A8 include absorption of short-chain fatty acids in the colon and small intestine, reabsorption of lactate and pyruvate in the kidney, and cellular uptake of lactate and ketone bodies in neurons. It also transports the B complex vitamin nicotinate. SLC5A12 is also localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to astrocytes and Muller cells. SLC5A8 also functions as a tumor suppressor; its expression is silenced in tumors of colon, thyroid, stomach, kidney, and brain. The tumor-suppressive function is related to its ability to mediate concentrative uptake of butyrate, propionate, and pyruvate, all of which are inhibitors of histone deacetylases. SLC5A8 can also transport a variety of pharmacologically relevant monocarboxylates, including salicylates, benzoate, and gamma-hydroxybutyrate. Non-steroidal anti inflammatory drugs such as ibuprofen, ketoprofen, and fenoprofen, also interact with SLC5A8. These drugs are not transportable substrates for SLC5A8, but instead function as blockers of the transporter. Relatively less is known on the role of SLC5A12 in drug transport. PMID- 18446520 TI - Reaction phenotyping: current industry efforts to identify enzymes responsible for metabolizing drug candidates. AB - Reaction phenotyping studies to identify specific enzymes involved in the metabolism of drug candidates are increasingly important in drug discovery efforts. Experimental approaches used for CYP reaction phenotyping include incubations with cDNA expressed CYP enzyme systems and incubations containing specific CYP enzyme inhibitors. Since both types of experiments present specific advantages as well as known drawbacks, these studies are generally viewed as complementary approaches. Although glucuronidation pathways are also known to present potential drug-drug interaction issues as well as challenges related to their polymorphic expression, reaction phenotyping approaches for glucuronidation are generally limited to cDNA expressed systems due to lack of availability of specific UGT inhibitors. This article presents a limited review of current approaches to reaction phenotyping studies used within the pharmaceutical industry. PMID- 18446521 TI - Use of the Biopharmaceutical Classification System in early drug development. AB - The Biopharmaceutics Classification System (BCS) is not only a useful tool for obtaining waivers for in-vivo bioequivalence studies but also for decision making in the discovery and early development of new drugs. Measurement of solubility and permeability in the discovery/development settings is described. These data can be utilized for the preliminary BCS classification of pipeline compounds. A decision tree is described in the prioritization of salt and polymorph screening studies prior to in vivo studies in animals. For BCS class 1 and 3 compounds, polymorphism is less likely to impact on bioavailability. The polymorph screening study may be postponed after animal studies. The BCS classification can also be used in the design of animal and human formulations. A BCS-based animal formulation development decision tree is presented. A compound is triaged based on a series of decision points into one of the five formulation strategies. Human formulation has different requirements than animal formulation. A comparison between animal and human formulation strategies is presented. In conclusion, for non-BCS 1 compounds, the right-first-time polymorph and formulation selection ensures consistent pharmacokinetic performance and avoids bridging BA/BE studies. It is in line with FDA's initiative to reduce R&D cycle time through quality by design for pharmaceutical products. PMID- 18446522 TI - Application of gastrointestinal simulation for extensions for biowaivers of highly permeable compounds. AB - The goal of this study was to apply gastrointestinal simulation technology and integration of physiological parameters to predict biopharmaceutical drug classification. GastroPlus was used with experimentally determined physicochemical and pharmacokinetic drug properties to simulate the absorption of several weak acid and weak base BCS class II compounds. Simulation of oral drug absorption given physicochemical drug properties and physicochemical parameters will aid justification of biowaivers for selected BCS class II compounds. PMID- 18446523 TI - [Emergency physician and AutoPulse--a good duo in preclinical emergency services?: case example and report on experience]. AB - Survival rates after cardiac arrest remain poor despite substantial efforts to advance the cardiopulmonary resuscitation algorithm in the last decades. Recent changes in the resuscitation guidelines in 2005 focused on minimizing interruptions during chest compressions. The aim to provide optimal chest compressions led to the development of automated mechanical chest compression devices, one of which is the AutoPulse resuscitation system. A case of successful use of the AutoPulse system in a 66-year-old patient with sudden cardiac arrest is presented and a review is given of more than 3 years experience in the routine use of this mechanical device for CPR in the emergency medical system in Bonn. Based on this experience, the AutoPulse system is considered to be a safe and effective technical advancement that under certain CPR conditions can be a helpful tool and provide an increased quality of chest compressions. PMID- 18446524 TI - Caffeine-inducible ATP release is mediated by Ca2+-signal transducing system from the endoplasmic reticulum to mitochondria. AB - Adenosine triphosphate (ATP) is released as an autocrine/paracrine signal from a variety of cells. The present study was undertaken to clarify the Ca2+-signal pathway involved in the caffeine-inducible release of ATP from cultured smooth muscle cells (SMC). The release of ATP induced by caffeine (3 mM) was almost completely inhibited by ryanodine and tetracaine, but not by 2-APB, thus being mediated by ryanodine receptors (RyR). The expression of messenger RNA from only RyR-2 was detected in the cells. Furthermore, the induced release was attenuated by mitochondrial inhibitors, rotenone and oligomycin and by Cl- channel blockers, niflumic acid, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid. Increase in Ca2+ signals with fluo 4 and rhod-2 caused by caffeine were reduced by tetracaine and oligomycin plus carbonyl cyanide m-chlorophenylhydrazone, respectively. A close spatial relation between the endoplasmic reticulum (ER) and mitochondria was electromicroscopically observed in the SMC, supporting the existence of a Ca2+ signaling bridge on both the organelli. These results suggest that caffeine stimulates ryanodine receptor (RyR-2) and facilitates a Ca2+-signal transducing system from ER to mitochondria, and then, the signal appears to accelerate the ATP synthesis in mitochondria. In addition, the mitochondrial event may lead further cell signaling to the cell membrane and activates Cl- channels, resulting in the extracellular release of cytosolic ATP. PMID- 18446525 TI - A chemoenzymatic approach to the synthesis of enantiomerically pure (S)-3-hydroxy gamma-butyrolactone. AB - Optically pure (S)-3-hydroxy-gamma-butyrolactone, an important chiral building block in the pharmaceutical industry, was synthesized from L: -malic acid by combining a selective hydrogenation and a lipase-catalyzed hydrolysis. Lipase from Candida rugosa was found to be the most efficient enzyme for the hydrolysis of (S)-beta-benzoyloxy-gamma-butyrolactone. The use of organic solvent-aqueous two-phase system was employed to extract benzoic acid generated from enzymatic hydrolysis of the substrate. Tert-butyl methyl ether as an organic solvent was effective to extract the reaction product, benzoic acid, and stably maintained the enzyme activity of Lipase OF immobilized on polymeric supports Amberlite XAD 7. The immobilization made the recovery of the product simpler and prevented the formation of the emulsion. The pH adjustment was unnecessary with the immobilized Lipase OF. The scale-up of the enzymatic hydrolysis of S-BBL at 1,850-kg scale was carried out without problems to give 728.5 kg of S-HGB at 80% isolated yield. The scale-up results are similar to those of bench scale reactions. Racemic (R,S) beta-benzoyloxy-gamma-butyrolactone was prepared from D-, L: -malic acid and was found to be hydrolyzed nonselectively by the enzyme. PMID- 18446527 TI - Regional fat mass by DXA: high leg fat mass attenuates the relative risk of insulin resistance and dyslipidaemia in obese but not in overweight postmenopausal women. AB - OBJECTIVE: To investigate the influence of regional fat mass (FM) on insulin resistance and dyslipidaemia in obese postmenopausal women (BMI >30 kg/m(2)) compared to overweight women (BMI <30 kg/m(2)). Leg FM may attenuate the increased risk of cardiovascular disease and diabetes imposed by increased trunk FM in normal and overweight postmenopausal women. MATERIAL AND METHODS: Cross sectional and consecutively referred patients comprising 63 obese and 36 overweight postmenopausal women. Body composition and regional FM by dual X-ray absorptiometry (DXA), fasting glucose, fasting insulin and C-peptide, insulin resistance by homeostasis model assessment (HOMA-IR), insulin sensitivity by quantitative insulin sensitivity check index (QUICKI) and metabolic clearance rate (MCRestOGTT), insulin secretion (HOMAsecr) and serum lipids were assessed. RESULTS: In obese subjects, leg FM was favourably associated with HOMA-IR (p<0.05), QUICKI (p<0.05), fasting glucose (p<0.05), fasting insulin (p<0.05), HOMAsecr (p<0.05) and total cholesterol/HDL ratio (p<0.05). Trunk FM was unfavourably associated with MCRestOGTT (p<0.01), QUICKI (p<0.05) and fasting insulin (p<0.05). Compared to leg FM, leg/trunk FM ratio was more strongly associated with fasting insulin (p<0.001), fasting C-peptide (p<0.001), HOMA-IR (p<0.001), MCRestOGTT (p<0.001), QUICKI (p<0.001), HOMAsecr (p<0.001), fasting glucose (p<0.01) and triglycerides (p<0.01). Stepwise multiple regression demonstrated that leg/trunk FM ratio was the most important variable with partial R (2) = 0.26 (p<0.001) for HOMA and R (2) = 0.37 (p<0.001) when QUICKI was used as the dependent variable. In overweight women, no associations between fat mass and parameters of insulin resistance or dyslipidaemia were found. CONCLUSIONS: A high leg/trunk FM ratio as measured by DXA may give relative protection against diabetes and cardiovascular disease in obese postmenopausal women, but not in overweight women. PMID- 18446529 TI - Springing to life. PMID- 18446528 TI - Reference data for distal blood pressure in healthy elderly and middle-aged individuals measured with the strain gauge technique. Part I: resting distal blood pressure. AB - OBJECTIVE: Most patients referred to our department for distal blood pressure (DBP) determination on suspicion of arterial peripheral vascular disease (apvd) are more than 60 years of age, whereas the only available reference data for resting pressure are based on data from healthy individuals aged between 43 and 57 years. Our aim was to investigate whether newly collected reference data for DBP measured using the strain-gauge technique in healthy subjects older than 60 years and in others between 45 and 58 years were significantly different from the old reference data used in daily practice. MATERIAL AND METHODS: . Group I comprised 31 healthy persons aged between 61 and 87 years and group II 14 healthy middle-aged hospital staff members aged between 45 and 58 years. Strict rules of inclusion were followed. RESULTS: For group I, significantly greater gradients (DBP(toe) - systolic arm blood pressure and DBP(toe) - DBP(ankle)) were found in the new reference data compared to the old. No significant difference between the mean values of the gradient (DBP(ankle) - systolic arm blood pressure) was found between the old and new reference data, although the variation was significantly wider in the new reference data; the lower level of normality was therefore -15 mmHg compared to 0 mmHg in the old reference data. For group II, no significant differences between the gradients were found comparing the new and old reference data. CONCLUSION: These new data indicate that reference data gathered from middle-aged subjects should be changed when DBP measurements are used in patients older than 60 years of age. PMID- 18446526 TI - Integrated transcriptomic response to cardiac chronic hypoxia: translation regulators and response to stress in cell survival. AB - Complementary deoxyribonucleic acid microarray data from 36 mice subjected for 1, 2, or 4 weeks of their early life to normal atmospheric conditions (normoxia) or chronic intermittent (CIH) or constant (CCH) hypoxia were analyzed to extract organizational principles of the developing heart transcriptome and determine the integrated response to oxygen deprivation. Although both CCH and CIH regulated numerous genes involved in a wide diversity of processes, the changes in maturational profile, expression stability, and coordination were vastly different between the two treatments, indicating the activation of distinct regulatory mechanisms of gene transcription. The analysis focused on the main regulators of translation and response to stress because of their role in the cardiac hypertrophy and cell survival in hypoxia. On average, the expression of each heart gene was tied to the expression of about 20% of other genes in normoxia but to only 8% in CCH and 9% in CIH, indicating a strong decoupling effect of hypoxia. In contrast to the general tendency, the interlinkages among components of the translational machinery and response to stress increased significantly in CIH and much more in CCH, suggesting a coordinated response to the hypoxic stress. Moreover, the transcriptomic networks were profoundly and differently remodeled by CCH and CIH. PMID- 18446530 TI - Strengthening prevention programs to eliminate cervical cancer in the Nordic countries. AB - Disease trend studies based on birth cohort analysis and serological studies indicate that recent generations have a higher prevalence of oncogenic Human Papilloma Virus (HPV) types, and are likely to be at higher risk of cancer than previous generations. This implies that prevention strategies to protect young populations from HPV-associated cancers need to be strengthened, and hence organized implementation of vaccination and better screening programs are being considered. In this context, randomized large-scale policy evaluations will be instrumental in accelerating disease control and improve effective prevention programs. This report shares experiences from Nordic countries with examples of prevention strategies through vaccination and cervical screening. The same principles as set up for organized programs and new HPV technologies may apply for screening and vaccination as key tools to eliminate cervical cancer in the Nordic countries and globally. PMID- 18446531 TI - Yolk sac volume assessed by three-dimensional ultrasonography using the VOCAL method. AB - OBJECTIVES: Establish normative data for yolk sac volume (YSV) at 7-10 weeks of gestation assessed by transvaginal three-dimensional ultrasonography (3D-US) using the VOCAL method and analyze its correlation with gestational age (GA) and crown-rump length (CRL). METHODS: A cross-sectional study involving 62 normal pregnancies was performed to assess YSV from 7 to 10 weeks of gestational age. An endocavitary volumetric transducer (3D5-8EK) was used for all measurements. The VOCAL (Virtual Organ Computer-aided AnaLysis) method with a 30 degrees rotation angle was used for volumetric calculations. Regression models were constructed to analyze the correlation between YSV and GA or CRL The mean, standard deviation, median, minimum and maximum values were calculated for each gestational age. RESULTS: There was a poor correlation between YSV and GA or CRL. The quadratic regression was the model that best expressed the correlation between these variables: R2=0.188 for GA and R2=0.203 for CRL. The mean YSV went from 0.063 cm(3) (95% CI: 0.047; 0.080) at 7 weeks to 0.164 cm3 (95% CI 0.095; 0.232) at 10 weeks. CONCLUSION: Reference limits were generated for first trimester YSV using 3D-US. There was a poor correlation between YSV and GA or CRL. PMID- 18446532 TI - Moderate neonatal encephalopathy: pre- and perinatal risk factors and long-term outcome. AB - BACKGROUND: The aim was to describe pre- and perinatal data and long-term neurodevelopmental outcome (15-19 years) in children born at term with Apgar score <7 at 5 min and moderate neonatal encephalopathy. METHODS: The study is based on a population-based birth-cohort of children born in Sweden in 1985. Maternal, delivery, neonatal, and neuropaediatric data were compiled. Neurodevelopmental status was classified according to the presence of 1. cerebral palsy or other major impairments, 2. exclusively cognitive impairments, and 3. no impairments. RESULTS: The majority of the children (81%) had cognitive dysfunctions, with or without other impairments, such as cerebral palsy. The rates of post-term birth (19% versus 8%) and breech presentation (12% versus 3%) were significantly higher than in the general Swedish population. Pre- and perinatal data did not differ notably between the three outcome groups. Questionable or suboptimal obstetric care was common (55%). CONCLUSIONS: The study shows that children born at term with moderate neonatal encephalopathy have a high rate of cognitive dysfunctions with or without cerebral palsy at long-term follow-up. Our pre- and perinatal data did not correlate with outcome. PMID- 18446533 TI - Pre-pregnancy body mass index and weight gain during pregnancy in relation to preterm delivery subtypes. AB - BACKGROUND: Associations between preterm delivery (PTD) and pre-pregnancy body mass index (BMI) and pregnancy weight gain may differ across outcome subtypes. METHODS: The authors analyzed data from 2,468 cohort participants in western Washington State, USA (1996-2005) and examined pre-pregnancy BMI and weight gain rate from pre-pregnancy to 18-22 weeks' gestation in relation to spontaneous PTD after preterm labor, spontaneous PTD after preterm premature rupture of membranes (PPROM), and indicated PTD. RESULTS: Each 5 kg/m(2) BMI increase was associated with indicated PTD (adjusted odds ratio [OR] 1.71, 95% confidence interval [CI] 1.40-2.06). The association weakened somewhat after adjustment for hypertension and diabetes before and/or during pregnancy (5 kg/m(2) adjusted OR, 1.40; 95% CI, 1.12-1.75). Associations with spontaneous PTD and PPROM were weaker (5 kg/m(2) adjusted ORs, 0.90 and 1.14, respectively). Weight gain was associated with indicated delivery among women with normal BMI (0.1 kg/week adjusted OR, 1.22; 95% CI, 1.02-1.45) but not among overweight or obese women (adjusted OR, 1.02; 95% CI, 0.87-1.20). Weight gain was inversely associated with spontaneous PTD (0.1 kg/week adjusted OR, 0.87; 95% CI, 0.77-0.99) and not strongly associated with PPROM (adjusted OR, 1.03; 95% CI, 0.90-1.17). CONCLUSIONS: Pre-pregnancy overweight increases indicated PTD risk independently of hypertension and diabetes. High early pregnancy weight gain increases indicated PTD risk in women with a normal BMI. PMID- 18446534 TI - Development and validation of a nomogram to predict the risk of cesarean delivery in macrosomia. AB - OBJECTIVE: To develop and validate a nomogram that predicts individual probability of cesarean delivery in cases of macrosomia (>4,000 g). METHODS: The nomogram was built based on the data from 246 patients who delivered macrosomic infants at Conception Hospital (Marseille, France), and was validated on an external population of 206 patients. Logistic regression was used to construct a model to predict the probability of cesarean section. The calculations were based on actual birth weight. MAIN OUTCOME MEASURES: The accuracy of the model was evaluated by area under the receiver operator curve. RESULTS: In the multivariate analysis performed on the training set, maternal age (p=0.002), parity (p=0.003), and maternal height <1.65 m (p=0.01) were found to be significantly associated with the occurrence of cesarean delivery and included in the nomogram. The final variables included in the nomogram were: age (p=0.01), maternal height (p=0.02), parity (p<0.001), and previous cesarean section (p=0.009). Area under the ROCs was 0.80 and 0.78 in the training set before and after bootstrapping, respectively, and 0.88 in the validation set. The calibration of the nomogram was good. CONCLUSION: We have developed a nomogram based on actual birth weight that accurately predicts the risk of cesarean delivery in cases of macrosomia. This tool might be useful for decision-making. PMID- 18446535 TI - Effects of pre-pregnancy physical activity and maternal BMI on gestational weight gain and birth weight. AB - BACKGROUND: Western women frequently exhibit excessive gestational weight gain (GWG). The effects of maternal physical activity level (PAL) and body mass index (BMI) on the timing of GWG are insufficiently known. PURPOSE: To assess the impact of pre-pregnancy PAL and BMI on GWG during the second and third trimester and on birth weight. METHODS: Body weight was measured in 223 healthy Swedish women in gestational weeks 12, 25 and 33, and GWG during the second (weeks 12-25) and third trimesters (weeks 25-33) was determined (kg/week). PAL was assessed using a questionnaire. Birth weights were obtained from birth records. The results were evaluated by the fitting of linear statistical models. RESULTS: Some 50 and 80% of the women exhibited excessive GWG during the second and third trimesters, respectively. Women with a high pre-pregnancy PAL gained 0.10 kg/week (p=0.04) less weight during the third trimester than women with a medium PAL. A 5 kg/m(2) higher BMI was associated with a 0.06 kg/week lower GWG in the second trimester (p=0.005), but with a 0.05 higher GWG in the third trimester (p=0.03). Maternal BMI (p=0.014) and total GWG (p=0.05) correlated with birth weight. CONCLUSIONS: High BMI and low pre-pregnancy PAL were associated with excessive GWG. BMI and GWG, but not pre-pregnancy PAL, were linked to birth weight. However, together with smoking, parity, education and age, pre-pregnancy PAL and BMI explained only 4% of the variation in GWG. Thus, identification of other factors that could explain excessive GWG is an important area of future research. PMID- 18446536 TI - Breastfeeding in polycystic ovary syndrome. AB - BACKGROUND: To investigate the breastfeeding rate in new mothers with polycystic ovary syndrome (PCOS). METHODS: Case-control study. Thirty-six women with PCOS and 99 controls matched for age, gestational length and parity, answered a questionnaire. Breastfeeding at one-, three- and six-months postpartum was registered and the two groups were compared. In the women with PCOS, androgen levels through pregnancy were analysed and related to breastfeeding rate. RESULTS: At one-month postpartum, 27 (75%) of the women with PCOS were breastfeeding exclusively, whereas five (14%) did not breastfeed at all. Among controls, 88 (89%) were breastfeeding exclusively and two (2%) did not breastfeed (p=0.001). At three- and six-months postpartum, breastfeeding was equal in the two groups. Problems with sore nipples and seeking professional lactation support were also equal. Dehydroepiandrosterone-sulphate levels at gestational week 32 and 36 showed a weak negative association with breastfeeding in PCOS women. Breastfeeding rate was not associated with maternal gestational levels of androstenedione, testosterone, sex-hormone binding globulin, or free testosterone index in PCOS. CONCLUSIONS: Women with PCOS appear to have a reduced breastfeeding rate in the early postpartum period. Possibly, gestational dehydroepiandrosterone-sulphate might negatively influence breastfeeding rate in women with the syndrome. PMID- 18446537 TI - Interobserver agreement in the assessment of intrapartum automated fetal electrocardiography in singleton pregnancies. AB - OBJECTIVE: To study interobserver agreement in the assessment of intrapartum automated fetal electrocardiogram ST interval analysis (STAN). DESIGN: Observational study. SETTING: Labor ward in tertiary level university hospital. Sample. Two hundred (140 reassuring and 60 non-reassuring) STAN recordings on non selected women with singleton, vertex, term pregnancies were selected from our archive. Samples of 60-min were analysed from the end of each recording, excluding the last 30 min before delivery. METHODS: Three consultants, who had undergone STAN training and had clinical experience in using STAN, reviewed the recordings using cardiotocography (CTG) and ST information with no clinical data. The reviewers were asked to follow STAN guidelines and 1 to classify the CTG as normal, intermediary, abnormal, or preterminal, and 2 to make a clinical decision on labor management. MAIN OUTCOME MEASURES: Interobserver agreement evaluated by weighted kappa (kappa(w)) values and the proportion of agreement. RESULTS: In CTG classification, the interobserver agreement between three observers was moderate (kappa(w), 0.47-0.48). The proportion of agreement was 56-59%. In clinical decision-making, kappa(w) values varied from 0.47 to 0.60, and the proportion of agreement was 80-86%. CONCLUSIONS: In non-selected term pregnancies, the interobserver agreement among experienced obstetricians in the classification of CTG and clinical decision-making according to STAN guidelines is moderate at best. PMID- 18446538 TI - Term perinatal mortality and morbidity in monochorionic and dichorionic twin pregnancies: a retrospective study. AB - AIM: Perinatal mortality and morbidity in monochorionic (MC) twins appears to be increasing compared to dichorionic (DC) twins. The aim of our study was to determine the difference in perinatal mortality and morbidity in MC and DC twins born after 37 weeks' gestation. DESIGN: A retrospective, cross-sectional study of medical records. Setting. Large tertiary care centre in the Netherlands. POPULATION: All twins delivered > or =37 gestational weeks at the Leiden University Medical Centre between 1988 and 2004 were included in the study. METHODS: Perinatal outcome was assessed in all term twins. Differentiation between a MC study group and a DC control group was made based on gender, intertwin membrane histology, or first trimester ultrasound. MAIN OUTCOME MEASURES: Perinatal mortality and morbidity was assessed. Morbidity was defined as admission to the neonatal nursery. RESULTS: We included 383 DC and 74 MC twin pregnancies. Three fetuses died in utero in two MC pregnancies at 38 gestational weeks. One surviving MC co-twin had a right-sided hemiparesis due to a large parenchymal defect in the left cerebral hemisphere. Perinatal mortality was 2% (3/148) in MC and 0% (0/766) in DC twins (p=0.004). The admission rate to the neonatal nursery was 27% in MC and 19% in DC twins (p=0.031). CONCLUSIONS: At term, MC twins have a higher risk for perinatal mortality and a higher admission rate to the neonatal nursery compared to DC twins. Given the increased mortality, a prospective study is needed to determine the effects of elective delivery in uncomplicated MC twin pregnancies at around 37 weeks' gestation. PMID- 18446539 TI - Establishment of a national Danish hysterectomy database: preliminary report on the first 13,425 hysterectomies. AB - OBJECTIVE: To describe the concept and early results from the Danish Hysterectomy Database (DHD). DESIGN: Nationwide prospective cohort. SETTING: Denmark. POPULATION: All women who had undergone an elective hysterectomy for benign indication carried out in 2004-2006. METHODS: Structured data are registered prospectively by the surgeons involved in the treatment. Data is reported using the Danish National Patient Registry (LPR) and feedback is provided as clinical indicators with well-defined goals. The DHD concept includes annual plenary meetings, elaboration of national clinical guidelines and parallel causal studies. MAIN OUTCOME MEASURES: Completeness, data validation and department identifiable clinical indicators (surgical volume, method of hysterectomy, use of antibiotic and thromboembolic prophylaxis, postoperative hospitalization and bleeding complications, surgical infections, reoperations, readmissions and death within 30 days postoperatively). RESULTS: A total of 13,425 hysterectomies were performed in Denmark from 2004 to 2006. In 2005, all gynecological departments in Denmark (n=31) were included in the database collaboration and the national response rate was 99%. Data validity was good in general (82-100% agreement and kappa=0.40-1.00) and data completeness was high (92-100% in 2006). From 2004 to 2006, two clinical guidelines were implemented, the postoperative hospitalization was stable at median 2 days, the rate of postoperative surgical infections was reduced from 4 to 2%, the rate of bleeding complications from 8 to 6%, the reoperation rate from 5 to 4%, and the readmission rate from 7 to 5%. CONCLUSIONS: Clinical performance indicators, audit meetings and nationwide collaboration are useful in monitoring and improving outcome after hysterectomy on a national level. In addition, the DHD offers scope for causal studies about perioperative management. PMID- 18446540 TI - LAVH for large uteri by various strategies. AB - BACKGROUND: To study if there are specific problems in laparoscopically assisted vaginal hysterectomy (LAVH) for a certain weight of bulky uteri and the strategies to overcome such problems. METHODS: One hundred and eighty-one women with myoma or adenomyosis, weighing 350-1,590 g, underwent LAVH between August 2002 and December 2005. Key surgical strategies were special sites for trocar insertion, uterine artery or adnexal collateral pre-ligation, laparoscopic and transvaginal volume reduction technique. The basic clinical and operative parameters were recorded for analysis. RESULTS: Based on significant differences in the operative time and estimated blood loss, the patients were divided into medium uteri weighing 350-749 g, n=138 (76%), and large uteri weighing > or =750 g, n=43 (24%). There was no significant difference in terms of age, body mass index, preoperative diagnoses, complications and duration of hospital stay among groups. The operative time and estimated blood loss increased with larger uterine size (p<0.001). The operative time (196+/-53, 115-395 min), estimated blood loss (234+/-200, 50-1,000 ml) and frequency of excessive bleeding (14%) or transfusion (5%) were significantly greater, but in acceptable ranges, for those with large uteri. Conversion to laparotomy was required in a patient (2%) with a large uterus, and the overall conversion rate was 0.6%. There was no re-operation or surgical mortality. CONCLUSION: Using various combinations of special strategies, most experienced gynecologic surgeons can conduct LAVH for most large uteri with minimal rates of complications and conversion to laparotomy. PMID- 18446541 TI - Increasing incidence of anal sphincter tears among primiparas in Sweden: a population-based register study. AB - BACKGROUND: The aim of this study was to examine the incidence and risk factors for anal sphincter tears (ASTs) at delivery. METHODS: A national population-based study was conducted with data from the Medical Birth Register including all primiparas with singleton pregnancy, who gave birth vaginally in Sweden from 1994 to 2004 (n=365,886). Women with a third and fourth degree AST were compared with those who gave birth during the same period without incurring such tears. RESULTS: The incidence of third degree AST increased by >60%, from 3.4% in 1994 to 5.2% in 2004 in spontaneous births, and from 8.7 to 14.8% in instrumental deliveries during the study period. The proportion of fourth degree AST increased from 0.3 to 0.55% in spontaneous births and from 0.8 to 1.4% in instrumental assisted deliveries during the same period. Compared with non-instrumental delivery, vacuum extraction (VE) deliveries were related to an increased risk of AST. An infant birth weight of >4,000 g was also associated with an increased risk for both third and fourth degree AST. In addition, women born in Africa and Asia had significantly higher risk for both third and fourth degree AST compared to women born in Sweden. CONCLUSION: The incidence of third and fourth degree AST increased in both spontaneous births and instrumental deliveries. Instrumental delivery and an infant birth weight >4,000 g are the main risk factors for AST. Women from Africa and Asia have pronounced risks. PMID- 18446542 TI - Complete destruction of urethra and bladder neck following symphysiotomy and results of attempted corrective surgery. AB - Four (0.8%) out of 526 obstetric fistulas were related to a preceding symphysiotomy procedure. Complete destruction of the urethra and bladder neck with retropubic fibrosis was found. Faulty technique is the most probable cause. All women had stillborn babies before the symphysiotomy delivery, and tissue damage due to obstructed labor could have been a predisposing factor. A neo urethra was successfully constructed in three of the four women, but continence in standing position was not obtained. PMID- 18446543 TI - Bowel and omentum prolapse into the vagina after third stage: an unusual presentation of ruptured uterus. PMID- 18446544 TI - Autopsy of bacterial vaginosis: a physiological entity rather than a contagious disease. PMID- 18446545 TI - Laparoscopic boxmodel and surgical dexterity. PMID- 18446546 TI - Comparison of the effectiveness of fissure sealants in Finland, Sweden, and Greece. AB - OBJECTIVE: To evaluate the effectiveness of sealant treatment in preventing dental restorations due to caries in a practice-based research network in Finland, Sweden, and Greece. MATERIAL AND METHODS: Times of tooth emergence, sealing treatment, and dental caries were compiled from the dental charts of 4735 subjects born in 1970-72 in Finland and in 1980-82 in Finland, Sweden, and Greece. Survival time between tooth emergence and placement of first restoration was measured and estimated using survival analysis methodology. RESULTS: At the end of follow-up (7-10+ years), 30-40% of sealed molars and 60-80% of non-sealed molars were restored. Early sealant placement compared to late sealing did not result in significantly higher survival of 1st molars. The strategy of sealing the 1st molars only in high caries risk subjects was as effective as sealing all the molars and premolars routinely without caries risk determination. CONCLUSIONS: The sealing of all molar fissures proved to be no more effective than sealing risk fissures of subjects. Early sealing did not result in any better outcome than late sealing. The effectiveness of sealant treatment in preventing dental restorations is dependent on the caries risk of individuals and caries prevalence of the country. PMID- 18446547 TI - Comparison between regional micropush-out and microtensile bond strength of resin composite to dentin. AB - OBJECTIVE: In this study we compared the micropush-out (micro-PO) and microtensile (micro-TBS) test methods for resin composites on different levels and surfaces of dentin. MATERIAL AND METHODS: Thirty-four sound human molars were divided into two groups in accordance with the dentin surface used (occlusal (O) or mesio-distal (M)), then subdivided into a further two groups in accordance with the test method (micro-PO (P) or micro-TBS (T)). In groups OP and OT, teeth were ground occlusally perpendicular to their axis, and in groups MP and MT, mesio-distally parallel to their axis to expose dentin. Dentin disks were prepared from different regions of the teeth either in an occluso-cervical (group OP) (n=5) or mesio-distal direction (group MP) (n=5) (S, superficial; M, middle; D, deep). One-hundred-and-twenty standardized occlusal cavities were prepared in these dentin disks using a conical-shaped diamond rotary cutting instrument. The adhesive (Adper Scotchbond Multi-Purpose Dental Adhesive) and a composite material (Filtek Z250 Universal Restorative) were applied and polymerized with a LED light curing unit (Elipar FreeLight 2). The disks (n=20/per group) were tested in a universal testing machine and pushed out with a cross-head speed of 1.0 mm/min. In groups OT (n=12) and MT (n=12), the teeth were ground to expose superficial, middle, and deep dentin. Build-ups of resin composite were constructed with the same materials. The specimens were serially sectioned and trimmed to hour-glass shapes, then tested with the micro-TBS tester at a rate of 1 mm/min. Failure modes were examined using a stereomicroscope and scanning electron microscope. RESULTS: ANOVA revealed significant differences among the groups (p<0.001). With the push-out test, no premature failure occurred, the variability of the data distribution was acceptable, and regional differences in bond strength among dentin levels could be assessed. CONCLUSIONS: The micro-PO test method could be an alternative to the micro-TBS technique. PMID- 18446548 TI - Evaluation of three methods assessing the relative value of a dental program. AB - OBJECTIVE: The aim of this study was to evaluate three commonly used methods for preference measurement in medical and dental programs. MATERIAL AND METHODS: In a questionnaire filled in by 156 first-year medical (n=120) and dental (n=36) students, they were asked to evaluate five programs, each costing approximately 2 million euros annually. The programs were helicopter ambulance service, MPR vaccination (measles, parotitis and rubella), breast cancer screening, 250 hip replacement operations, and a dental check-up program for 7-year-olds. RESULTS: The respondents were willing to make the highest donations for running the helicopter ambulance service (39 euros) and least for the dental check-up programme (14 euros) (p<0.01). When using the visual analog scale (VAS) method to evaluate the importance of the five programs, MPR vaccination was considered the most important (score 88), and hip replacement operations and dental check-up the least important (scores 68) (p<0.01). With the rank order (RO) method, MPR vaccinations were ranked the highest (score 1.8) and hip replacement operations (score 4.2) and dental check-up (score 4.0) the lowest (p<0.01). The respondents considered VAS and RO methods significantly easier than the willingness to pay method (p<0.001). CONCLUSIONS: It is concluded that depending on the nature of the information required, each of the three methods can be used for assessing preferences. The willingness to pay method seemed to be the most difficult to comprehend, but it provides more detailed and ready-to-use information for economic evaluations than the other two methods. PMID- 18446549 TI - A follow-up study of subjective symptoms of temporomandibular disorders in patients who received acupuncture and/or interocclusal appliance therapy 18-20 years earlier. AB - OBJECTIVE: To evaluate the presence of symptoms of temporomandibular disorders (TMDs) in patients referred to a specialist clinic because of muscular problems 18-20 years earlier and who had received mainly acupuncture and/or interocclusal appliance therapy. MATERIAL AND METHODS: Sixty-five subjects who had received therapy at a TMD specialist clinic 18-20 years earlier were mailed a questionnaire with questions about TMD symptoms, their attitude towards the therapy, and their opinion about the outcome. Fifty-five subjects (85%) answered and returned the questionnaire. RESULTS: Before therapy, 87% had had severe TMD symptoms, but this figure decreased to 38% at the long-term follow-up. The mean values of the subjects' complaints at worst and at best before treatment, measured with a visual analog scale, were 66 (range 26-100) and 31 (range 0-100), respectively. The corresponding figures at the long-term follow-up were 32 (range 0-96) and 16 (range 0-70). Headache at least once a week was originally reported by 73% of the women and by 77% of the men. Headache prevalence 18-20 years later was 35% in women and 54% in men. The majority of patients were positive about the therapy they had received, and would recommend it to a friend with similar complaints. CONCLUSIONS: A majority of the patients reported a lasting improvement in their symptoms. Patients' overall opinions of the therapy received were positive. PMID- 18446550 TI - Age-dependent external root resorption during tooth movement in rats. AB - OBJECTIVE: To investigate the effect of age on root resorption and distribution along different parts of the root during prolonged light force application. MATERIAL AND METHODS: Orthodontic appliances were placed in two groups of 30 rats (one group 6 weeks old, the other 9-12 months old), with contralateral sides as controls. Groups of animals were killed at 1, 2, 4, 8, and 12 weeks. At the study site, incidence was counted as either 1 (with resorption) or 0 (without); severity was measured as the summed length of all resorption lacunae as a percentage of study total root length. RESULTS: Young and adult rats had the same incidence of root resorption in the early phase (<4 weeks), and both increased in the late phase (4-12 weeks) to the same level. Severity of resorption increased with prolonged tooth movement only in adult rats. However, there was no age related difference in either the early or the late phase. In both groups, the middle part of the root had the highest incidence of resorption; the most severe resorption occurred exclusively at this part. CONCLUSION: Orthodontic intervention even with light forces increased both the incidence and severity of root resorption, the more so in the middle part of the root. Adult rats had increased incidence and severity with prolonged tooth movement. PMID- 18446551 TI - Correlation of parenting style and pediatric behavior guidance strategies in the dental setting: preliminary findings. AB - OBJECTIVE: The aim of this study was to investigate the influence of parenting style on the choice of proper behavior guidance strategies in pedodontics. MATERIAL AND METHODS: Seventy-two children aged between 4 and 6 years (mean 5.12 years) with carious primary mandibular molars were selected. The Primary Caregivers' Practices Report (PCPR) was used to quantify authoritarian, permissive and authoritative aspects of the caregivers' parenting style. After inferior alveolar nerve block, carious lesions were removed and the teeth were restored using amalgam. The children's behavior during operation was assessed according to the sound, eye, and motor (SEM) scale. Communicative guidance, advance behavior guidance, parental separation, and deferred treatment were used for behavior management. RESULTS: The dominant authoritative score was observed in 50% of parents, permissive in 37.5%, and authoritarian in 12.5%. The mean SEM score in children belonging to authoritative parents was significantly lower than in children of permissive and of authoritarian parents (p<0.05). Communicative guidance was necessary for all patients regardless of parenting style. Advanced behavior guidance (protective stabilization) was applied in 16.7% of cases in the authoritative category and in 100% in the permissive and authoritarian categories. The use of restrictive devices (7.4%) and sedation (3.7%) was limited to the permissive category. Parental separation (40.7%) and deferred treatment (3.7%) were performed only in the permissive category. CONCLUSIONS: This study provides preliminary evidence that a child's reaction to restorative dental procedures is influenced by the nature of the caregiver's parenting style. PMID- 18446552 TI - Association of interleukin-6 (IL-6) haplotypes with plaque-induced gingivitis in children. AB - OBJECTIVES: The proinflammatory cytokine interleukin-6 (IL-6) is a key regulator of the host response to microbial infection and major modulator of extracellular matrix catabolism and bone resorption. The aim of this case-control study was to test differences between children with and without gingivitis in the distribution of IL-6 alleles at positions -174, -572, and -597 and their haplotypes. MATERIAL AND METHODS: A total of 455 Caucasian children, aged 11 to 13 years, were enrolled in this study. According to gingival bleeding on probing indices, 183 were classified as healthy subjects and 272 as children with plaque-induced gingivitis. DNA for genetic analysis was obtained from buccal epithelial cells and PCR-RFLP methods were used for genotyping three selected IL-6 promoter polymorphisms. RESULTS: Complex analysis revealed significant differences in haplotype frequencies between patients and healthy subjects (p<0.01). The CGA haplotype was significantly more frequent in children with gingivitis than in healthy subjects (41.5% versus 34.1%). In subanalyses, we found that IL-6 -174C allele was more frequent in patients (44.3%) than in healthy children (36.1%, p=0.016, P(corr)<0.05). Multivariate logistic regression analysis showed that allele C remained a risk factor for gingivitis in children (p=0.03) regardless of plaque or gender. However, the proportions of the IL-6 -597 and -572 genotypes were comparable between the two groups. CONCLUSIONS. Our results indicate that the three promoter polymorphisms in the IL-6 gene act in a cooperative fashion and suggest that IL-6 haplotypes could play a role in the pathogenesis of gingivitis in Caucasian children. PMID- 18446553 TI - Incidence and prevalence of myofascial pain in the jaw-face region. A one-year prospective study on dental students. AB - OBJECTIVE: The aims of this study were to examine the 1-year period prevalence, incidence, and course of myofascial pain in the jaw-face region, and to analyze whether female gender, dental occlusion, and oral parafunctions have any influence on these signs and symptoms. MATERIAL AND METHODS: The study population comprised 308 dental students examined at the start of their dentistry course and re-examined after 1 year. Case histories were collected using a questionnaire. The clinical examination included palpation sites of muscles, a submaximal clenching test, measurements of maximal mandibular mobility, and classification of morphological and functional dental occlusion. RESULTS: The 1-year period prevalence of frequent myofascial symptoms was 19%. The incidence of myofascial pain, according to the Research Diagnostic Criteria for TemporoMandibular Disorders (RDC/TMD), was 4%. The female students presented an almost 4-fold incidence rate of myofascial symptoms compared to the male students. Non symptomatic subjects were found predominantly among men, among those unaware of bruxism with bilateral contact in the retruded contact position (RCP), and among those with a stable intercuspal position (ICP). Variations in morphological occlusion did not show any relation to myofascial symptoms, nor did contact patterns in eccentric positions. CONCLUSIONS: Female dental students were more prone to developing frequent myofascial pain and to perceiving local muscle soreness than were male students during a 1-year period. Both self-reported bruxism and registered mandibular instability in ICP showed association with the 1-year period prevalence of myofascial signs and symptoms in the jaw-face region. PMID- 18446554 TI - Autoclaving and battery capacity influence on laser fluorescence measurements. AB - AIM: To evaluate the influence of probe tip autoclaving and depleted alkaline batteries on laser fluorescence (LF-DIAGNOdent) device performance. MATERIAL AND METHODS: One-hundred-and-twenty occlusal sites were analyzed with an LF device in nine conditions: No autoclaved probe and probe after 5, 10, 15, 20, 25, 30, 40, and 50 autoclaving cycles. Subsequently, the performance of the device was analyzed with: New batteries, batteries with 1.49/1.39 V, 1.38/1.37 V, 1.36/1.34 V, 1.33/1.32 V, and lower than 1.32 V. LF values, sensitivity, specificity, accuracy, and area under the ROC curve were compared. RESULTS: In the probe study, sensitivity was lower after 50 sterilizing cycles, though specificity was higher than the assessment performed using a new tip. In the batteries study, specificity was higher for depleted batteries, but LF performance did not differ significantly among the groups. CONCLUSION: Batteries do not significantly influence device performance, but consecutive sterilization of probes in autoclave alters readings, downgrading its performance. PMID- 18446555 TI - Abstracts of the 12th World Congress on the Menopause. PMID- 18446556 TI - Economic reform in Vietnam. PMID- 18446557 TI - Strategies for the prevention and treatment of reproductive tract infections among women in Vietnam. AB - This paper presents selected findings from a larger study on reproductive tract infections (RTIs) among women seeking abortion in Northern Vietnam. In particular it focuses on women's experience of RTIs within the context of their perceptions of female physiology and what women do to prevent and treat RTIs. The approach used was a combination of the quantitative and the qualitative: 748 structured interviews were undertaken before, and 701 after, abortion; and in-depth interviews were carried out with 20 women and 20 healthcare providers. Both healthcare providers and women believed that RTIs are an essential and normal part of womanhood. Reproductive tract infections were associated with laziness, being unclean and hesitance in using health facilities for help with gynecological problems. Women used various forms of self-treatment, including some that may be medically harmful. Women's preventive and treatment strategies were often supported and sometimes even promoted by healthcare providers. We assess women's strategies for RTI prevention and treatment in the context of the current Vietnamese health system and from a gender perspective. These strategies highlight inadequacies in the public healthcare system, while also pointing to important cultural paradoxes in the understanding of womanhood in contemporary Vietnam. PMID- 18446558 TI - Drugs, sex and AIDS: sexual relationships among injecting drug users and their sexual partners in Vietnam. AB - HIV transmission in Vietnam is strongly linked to drug injection, but there is the potential for an epidemic driven by sexual behaviour. HIV-education programmes to date focus largely on personal responsibility and fail to address adequately other aspects of HIV-related risks in social contexts. Based on ethnographic fieldwork conducted in 2002, this paper examines the association between HIV-related risks (unsafe drug use and unsafe sex) and gender relations among injecting drug users. Three patterns of relationships are analysed: between injecting drug users and their injecting partners; between injecting drug users and their smoking partners; and between injecting drug users and their non-using partners. Data shows that intimate relations play an important role in managing HIV-related risks among injecting drug users. HIV prevention must pay due attention to the specific contexts of injecting drug users' lives. Some implications of these findings are discussed and relevant recommendations are proposed. PMID- 18446559 TI - Male sexual health concerns in Muong Khen, Vietnam. AB - Male sexual health concerns are often construed in the medical literature as linked only to genital and reproductive difficulties and malfunctions. However, in reality, male sexual health concerns encompass a broader range of issues and should not be so narrowly conceived. This paper explores men's perceptions of sexual health concerns in Muong Khen, a rural town in northwestern Vietnam. Data were collected through observation, in-depth interviews and focus group discussions. Findings suggest that men's sexual health concerns are strongly related to worries about economic problems, excessive drinking, men's beliefs about how their bodies work and the hegemonic notion that a man should be responsible for his family's economic well-being. PMID- 18446560 TI - Femininity and sexual agency among young unmarried women in Hanoi. AB - In contemporary Vietnam, young, unmarried, educated women are struggling to negotiate the contradictory expectations of femininity. Qualitative research conducted in Hanoi with 13 unmarried, educated women, aged from 25 to 34 years, explored women's sexual agency in a context of changing discourses on sexuality and gender roles. Interviews were conducted several times with each woman to enable in-depth understanding of sexual experiences and meanings. Either implicitly or explicitly, women in the research were found to resist the power of public discourses on femininity and sexuality. Notions of femininity can be interpreted as a temporary means for women to gain control over sexual relationships. It is crucial to acknowledge the sexual agency of unmarried, educated women and its diverse forms in order to understand complex sexual behaviours and to promote their sexual rights and health. PMID- 18446561 TI - The harmony of family and the silence of women: sexual attitudes and practices among rural married women in northern Viet Nam. AB - Women in Viet Nam have long had to face various sexual and reproductive health problems, ranging from abortion to reproductive tract infections (RTIs) and sexual coercion. These issues have increasingly been addressed by scholars in the fields of public health and social sciences through sexual and reproductive health research and in other ways. Despite this, there remains a lack of in-depth information on attitudes and practices regarding sex and sexuality of Vietnamese women today. This paper in part responds to the knowledge gap by reporting on findings from qualitative research on sexual attitudes and practices among rural married women in a Northern rural community, measured against the broader social and cultural context. Twenty-five women in total were interviewed; and two focus group discussions were conducted. The findings show that women generally believe that men are (or should be) the initiators in sexual relations. Many women feel reluctant to refuse sex to their husbands or communicate openly about sex and sexuality. However, this paper also demonstrates that women are not totally passive in sexual relations. Women in this study used a range of strategies to negotiate their sexual life, and sometimes 'silence' is used as a form of agency in order to maintain harmony and happiness within the family. PMID- 18446562 TI - Sexual coercion within marriage in Quang Tri, Vietnam. AB - Sexual coercion in marriage is not widely talked about in Vietnam. Against this background, the present study aimed to describe how and why non-consensual sex in marital settings occurs in a rural community in Vietnam. Data were collected from 81 married men and women through ethnographic fieldwork, in-depth interviews and focus group discussions. Findings revealed that silence and lack of resistance on the part of women in sex are interpreted as consent, and cultural values often encourage women to accept coercion 'voluntarily'. Lack of information on, and public dialogue about, sexuality make it difficult for sexually inexperienced people to gain knowledge before commencing sexual relationships and often lead to traumatic first experiences. These factors combine to make women develop negative attitudes toward sex or to deny sex altogether. To better understand sexual coercion within marriage, we should look not only at physical acts but also at cultural and gendered perceptions and practices in a specific setting. Findings highlight the need for a comprehensive response to tackling sexual coercion within marriage. PMID- 18446563 TI - Supervisors and accomplices: extra-marital sex among migrant construction workers in Ha Noi, Viet Nam. AB - This study examines the influence of social networks on the sexual relations of migrant construction workers in Ha Noi, Viet Nam. Research included observation and interviews with members of two different groups of workers. The first group, together with their employer (cai), came from the same village; the second group came from different villages. Of interest in the present study was how social relationships among workers and their employers influence extra-marital sexual activity. In the group where workers and their cai came from the same village of origin, fear of acquiring a bad reputation made these workers reluctant to seek sex services, since accounts of their behaviour were transmitted quickly home. In contrast, workers from the group who came from different villages often went out together to purchase sex. The absence of direct links to their villages of origin made it easier for these latter workers to conceal their activity. The implication of these findings for sexual safety and risk are discussed. PMID- 18446564 TI - Internet influences on sexual practices among young people in Hanoi, Vietnam. AB - While the influences of the Internet on adult sexuality are well recognized, research on the potential connection between the Internet and young people's sexuality is still limited. We conducted a qualitative study to examine how young people (aged 15-19 years) in Hanoi, Vietnam used the Internet to develop sexual practices and identities. Our analysis of texts from focus groups, in-depth interviews, chat scripts and field notes reveals how the Internet is used to assemble sexual information that was not available from other sources such as the family and school. Young people's narratives also show how they use the Internet as a medium for expressing sexual identities and desires. In the light of these findings, we suggest expanding sex education to include issues that are important to young people such as emotions and relationships, rather than simply focusing more narrowly on reproduction, public health and other interests of the state. PMID- 18446565 TI - Abstracts of the Second Conference on Drug Delivery and Translational Research, Brooklyn, New York, May 12-13, 2008. PMID- 18446566 TI - Liposomal polyethyleneglycol and polyethyleneglycol-peptide combinations for active targeting to liver in vivo. AB - This report describes the development and evaluation of a range of polyethyleneglycol and polyethyleneglycol-peptide liposome formulations that effectively target liver in vivo. A 19-amino-acid sequence from the N-terminal region of the circumsporozoite protein of Plasmodium berghei was attached to the distal end of di22:1-aminopropane-polyethyleneglycol(3400), and incorporated into liposomes containing di22:1-phosphatidylcholine and di22:1 phosphatidylethanolamine-polyethyleneglycol(5000). By systematically varying the mole fractions of both the lipid-polyethyleneglycol and the lipid polyethyleneglycol-peptide conjugates, and screening for serum-induced aggregation in vitro, a serum-stable range of formulations was established. These stable formulations were tested for binding to Hepa 1-6 liver cells in culture, and from these results three formulations were prepared for intravenous administration in mice. All three formulations exhibited effective liposome targeting to the liver, with approximately 80% of the total injected dose recovered in the liver within 15 min. Uptake by liver cells was more than 600 fold higher than uptake by those in the heart, and more than 200-fold higher than uptake by lung or kidney cells. Effective targeting to liver in vivo was successful after repeated (up to three) administrations to the host at 14-day intervals. All formulations prepared for in vivo administration were stable in the presence of serum, as measured by complete retention of entrapped calcein dye. The formulation with the lowest mole fractions of peptide and polyethyleneglycol was the most cost-effective in terms of encapsulation efficiency and minimal use of peptide and polymer compounds. The in vitro biophysical screening, followed by cell culture testing, reduced the number of animals required to develop an effective set of targeted liposome formulations for in vivo application. PMID- 18446567 TI - Permeation studies and histological examination of sheep nasal mucosa following administration of different nasal formulations with or without absorption enhancers. AB - This study was designed to investigate the possible histological effects of different intranasal (IN) formulations of indomethacin (IND) on nasal mucosa in sheep. For this purpose, oil-in-water (O/W) emulsion (E) and solution (S) formulations including 3 mg/mL of IND were prepared. Penetration enhancers such as polyvinylpyrolidone (PVP), citric acid (CA) and sodium taurocholate (NaT) were added to emulsion (1%) at the final step into the formulations. First, the effect of penetration enhancers on permeation of IND was evaluated by in vitro permeation studies in which sheep nasal mucosa was used. According to the permeation studies PVP showed the highest enhancing effect on the permeation rate of IND from sheep nasal mucosa. Furthermore, the IND permeation from E containing PVP (1.624 +/- 0.045 mg) was significantly higher than that obtained from E (0.234 +/- 0.012 mg) (p < 0.05). For the histological studies, white Karaman sheep of approximately 20 +/- 5 kg, aged 4 to 8 months were used. They were randomly divided into eight groups, each including three sheep. Five experimental groups received different formulations of IND emulsion without/ with penetration enhancers (E-PVP, E-CA, E-NaT, E) and IND solution (S), respectively. Parallel controls were composed of either untreated groups and were given blank emulsion or isotonic sodium chloride solution (0.31 mg/kg). 2 mL of each experimental formulation was applied to both nostrils of sheep, and 1/3 central and lower regions of the nose were dissected and prepared for light microscopy. Specimens stained with hematoxylin and eosin and Gomori's trichrome were examined by light microscopy. No signs of inflammation or erosion were noticed in the nasal mucosa of the control groups. Widened epithelial intercellular spaces were noticed in E CA, E-NaT, and E-PVP groups as well with the E-PVP group showing the largest intraepithelial separations. E-CA and E-NaT groups showed significant decrease in the amount of goblet cells, while hypoplasia was considerably moderate in the E PVP group. Finally, intranasal administration of IND emulsion with PVP may be considered as an alternative to intravenous and per oral administrations of IND to overcome their adverse effects. PMID- 18446568 TI - Penetration-enhancing effect of ethanolic solution of menthol on transdermal permeation of ondansetron hydrochloride across rat epidermis. AB - The aim of this investigation was to study the effect of an ethanol-water solvent system and ehtanolic solution of menthol on the permeation of ondansetron hydrochloride across the rat epidermis in order to select a suitable ethanol water vehicle and optimal concentration of menthol for the development of a transdermal therapeutic system. The solubility of ondansetron hydrochloride in ethanol, water and selected concenetrtaion of ethanol-water vehicles (20:80 v/v, 40:60 v/v and 60:40 v/v) was determined. The effect of these solvent vehicles, containing 1.5% w/v of ondansetron hydrochloride, on the in vitro permeation of the drug was studied across the rat epidermis. The highest permeation was observed from 60% v/v of ethanol-water vehicle that showed highest solubilty. Hence, the hydroxypropyl cellulose (HPC) (2% w/w) gel formulations containing 1.5% w/w of ondansetron hydrochloride and selected concentrations of menthol (0, 2, 4, 8 and 10% w/w) were prepared using 60% v/v of ethanol-water vehicle, and subjected to in vitro permeation of the drug across rat epidermis. The transdermal permeation of ondansetron hydrochloride was enhanced markedly by the addition of menthol to HPC gel drug reservoir formulations. A maximum flux of ondansetron hydrochloride (77.85 +/- 2.85 mu g/cm(2.)h) was observed with a mean enhancement ratio of 13.06 when menthol was incorporated at a concentration of 8% w/w in HPC gels. However, there was no significant increase in the drug flux with 10% w/w menthol when compared to that obtained with 8% w/w of menthol in HPC gel formulations. The results suggest that 2% w/w HPC gel drug reservoir formulation, prepared with 60% v/v ethanol-water, containing 8% w/w of menthol provides an optimal transdermal permeation of ondansetron hydrochloride. PMID- 18446569 TI - The delivery of platinum drugs from thermosensitive hydrogels containing different ratios of chitosan. AB - New thermosensitive hydrogels of poly(N-isopropylacrylamide) (PNIPAAm) with chitosan (CPN) were prepared and evaluated for use in the delivery of the platinum drugs, cisplatin and carboplatin. The effects of polymers containing different ratios of chitosan on the physicochemical and drug release characteristics were examined. The sol-gel transition temperature of the hydrogels was determined by differential scanning calorimetry (DSC) and viscometry. Discrepancies in the transition temperature among the various polymer systems were more pronounced when determined by viscosity compared by DSC, with the CPN showing a higher transition temperature than PNIPAAm. The cross-sectional structure and surface topography of the hydrogels were examined by scanning electronic microscopy (SEM) and atomic force microscopy (AFM), respectively. The incorporation of chitosan further increased the entanglement of the hydrogel network. An increase in the chitosan ratio in the polymers (CPN-H) also increased the cross-linking structure. A smoother surface of hydrogel matrices was observed for CPN compared with PNIPAAm. All hydrogels tested significantly reduced drug release compared with an aqueous solution. The release rate of platinum drugs from PNIPAAm was retarded at the late stage. CPN matrices could continuously deliver platinum drugs during the experiment. The rate of release from CPN-H was generally slower than that from hydrogels and had a lower chitosan ratio (CPN-L), presumably due to the more-tortuous pathways in the hydrogels. Thermosensitive hydrogels like those prepared in this study may be a promising carrier for the delivery of platinum drugs, as the drug release can be controlled and sustained using CPN networks. PMID- 18446571 TI - Molecularly imprinted polymers for alpha-tocopherol delivery. AB - Biomedical applications of antioxidants have increased dramatically since the link between human diseases and oxidative stress was established. This paper focuses on alpha -tocopherol and on the possibility of employing molecularly imprinted polymers as a controlled release device for alpha-tocopherol in gastrointestinal simulating fluids. Polymers were synthesized using methacrylic acid as functional monomer and ethylene glycol dimethacrylate as cross-linker. Considerable differences in recognition characteristics between imprinted and non imprinted polymers, both in organic and in aqueous media, were observed. Imprinted polymers bound much more alpha-tocopherol and showed a controlled/sustained drug release capacity in gastrointestinal simulating fluids. PMID- 18446570 TI - Chitosan-N-acetyl cysteine conjugates: in vitro evaluation of permeation enhancing and P-glycoprotein inhibiting properties. AB - This study evaluated three chitosan-N-acetyl cysteine (CAC) conjugates of increasing molecular mass as a valuable tool to improve the absorption of drugs by assessing its permeation enhancing effect regarding the active P-gp substrate rhodamine-123 in comparison to the trans- and paracellular marker FD 4 both in rat intestine and Caco 2 monolayers. Additional LDH and MTT cytotoxicity tests have attested a non-toxic profile to CAC, which can consequently be seen as a safe and promising novel drug carrier with the ability to enhance drug absorption and to inhibit P-gp efflux transporters. PMID- 18446572 TI - Development of controlled release sildenafil formulations for vaginal administration. AB - Sildenafil is an active substance that has already been approved by FDA for human use. It is known to be an active compound for the treatment of sexual dysfunction in men. Some encouraging results have been published concerning the treatment of infertility with sildenafil in women, but there is no pharmaceutical preparation available. Therefore, various formulations were prepared and the most suitable sildenafil release was found to be with the sildenafil-containing suppositories prepared using Eudragit RS100 and Witepsol H15. The vaginal insert with EVAC 210 polymer containing sildenafil has also provided sildenafil release for a longer period. PMID- 18446573 TI - Economic aspects of a therapy and support service for people with long-term stroke and aphasia. AB - BACKGROUND: This paper considers some economic aspects of a therapy and support service for people with stroke and aphasia. This material was part of a broader evaluation of the service, which is reported elsewhere (van der Gaag et al. 2005, van der Gaag and Mowles 2005). AIMS: The purpose of this part of the study was to investigate the feasibility of undertaking economic appraisal in a voluntary sector service providing therapy for people with aphasia and their families. METHODS & PROCEDURES: The costs of delivering therapy and support services were calculated. These costs were compared with the costs of equivalent services in the National Health Service (NHS). The EQ-5D health-related quality of life instrument was used to calculate quality-adjusted life years (QALYs). OUTCOMES & RESULTS: The cost of delivering therapy was lower than expected for a customized service of this nature. The study generated cost data for delivering therapy services, allowing some comparisons to be made with equivalent services in NHS settings. QALY data were generated for a sample of 25 clients on one of the programmes. CONCLUSIONS: The economics of speech and language therapy service delivery have received scant attention in the published literature. The paper argues that decision-making about methods of service delivery can be aided by the explicit consideration of the costs and consequences of different programmes. PMID- 18446575 TI - Investigating factors related to the effects of time-out on stuttering in adults. AB - BACKGROUND: Response-contingent time-out has been shown to be an effective technique for enhancing fluency in people who stutter. However, the factors that determine individual responsiveness to time-out are not well understood. AIMS: The study investigated the effectiveness of using response-contingent time-out to reduce stuttering frequency in adults who stutter. In addition, it investigated the predictive value of participants' stutter severity, age, previous treatment history, and type of stutter on the responsiveness to time-out conditioning. METHODS & PROCEDURES: Sixty people who stutter participated in the study. Half were exposed to time-out following each moment of stuttering over a 40-min period, the remaining participants acted as controls. OUTCOMES & RESULTS: Results showed that individuals who stutter are highly responsive to time-out, and that the participants with a more severe stutter responded better than those with a mild stutter. To a lesser degree, previous treatment and speech rate also influenced treatment success. Age and type of stutter did not, although the proportion of repetition types of stutters increased over the experiment conditions, with prolongations and blocks decreasing, for the treatment group. CONCLUSIONS: This simple operant conditioning treatment method is effective in reducing stuttering. Individuals respond to time-out regardless of their age, type of stutter, stuttering severity or treatment history, thus it is a treatment methodology potentially suitable for all clients. This study investigated initial responsiveness to time-out; therefore, further research is necessary to determine the durability of fluency over time. PMID- 18446577 TI - Analysis of altered mental status in Turkey. AB - The aim of this study was to determine the frequency and etiology of altered mental status in adults at an Emergency Department. Medical records of 790 patients with altered mental status were reviewed. Out of 790 patients, 414 (52.3%) were male, 376 (47.7%) were female. Mean age was 45.65 +/- 15.5 years. Etiologic factors were neurological (n = 566; 71.6%), head trauma (n = 82; 10.4%), endocrine/metabolic (n = 48; 6.1%), cardiovascular/pulmonary (n = 49; 6.2%), infectious (n = 30; 3.8%), gynecologic and obstetric (n = 2; 0. 4%), toxicologic (n = 12; 1.5%). Of patients, 40% were in deep coma, 11% were confused, 20% were in agitated confusion, 15% were lethargic, and 14% were in stupor. Eighteen percent of were hypertensive. Total mortality rate was 20.1% (n = 159). Common causes of death were cerebrovascular disease and trauma. Most patients presenting with altered mental status seem to be elderly with the most frequent cause being cerebrovascular accidents. Fatality rate is very high. PMID- 18446576 TI - Grammaticality judgements in adolescents with and without language impairment. AB - BACKGROUND: Existing evidence suggests that young children with specific language impairment have unusual difficulty in detecting omissions of obligatory tense marking morphemes, but little is known about adolescents' sensitivity to such violations. AIMS: The study investigated whether limitations in receptive morphosyntax (as measured by grammaticality judgements) were present at age 16 years, and, if so, whether participants' profiles showed less sensitivity to omissions of tense and agreement morphemes than to (1) inappropriate uses (intrusions) of these same morphemes, and (2) omissions of morphemes that do not encode tense and agreement. The study also compared adolescents with language impairment and non-verbal IQ more than 1 standard deviation (SD) below the mean (nonspecific language impairment) to adolescents with specific language impairment. METHODS & PROCEDURES: Adolescents with specific language impairment (n = 48), adolescents with non-specific language impairment (n = 25), and adolescents with normal language development (n = 108) performed speeded grammaticality judgements of sentences presented over headphones. Half the sentences were ungrammatical. They included omissions of non-tense morphemes ( ing and possessive -s), omissions of tense morphemes (-ed and third-person singular present -s), and intrusions of the same tense morphemes. The A' statistic was used as the dependent variable for comparisons across groups and item types. OUTCOMES & RESULTS: Overall, the normal language development group was more sensitive to grammatical violations than the specific language impairment and non-specific language impairment groups, and there was no significant interaction of group and item type. Post-hoc analyses showed that the specific language impairment group was less sensitive to violations than the normal language development group on each item type, and the specific language impairment and non-specific language impairment groups did not differ. Across groups, performance on omission of past tense -ed was lowest, and properties of the items that may have contributed to this difference were explored. CONCLUSIONS: The adolescents with language impairment in this study showed evidence of reduced sensitivity to morphological errors, including both tense marking and non-tense-marking morphemes, but no evidence of any extraordinary difficulty in detecting the omission of tense-marking morphemes, in contrast to results from other research on younger children with specific language impairment. Participants whose non-verbal IQ score was too low to meet the criteria for specific language impairment performed similarly to their peers with specific language impairment. Grammatical competence is compromised in these adolescents with specific language impairment and non-specific language impairment. Neither researchers nor clinicians can assume that adolescents with language impairment have fully mastered grammatical morphology. PMID- 18446578 TI - Bilateral and unilateral hippocampal inactivation did not differ in their effect on consolidation processes in the Morris water maze. AB - Consolidation processes were studied in the rat by using functional inactivation techniques. Previous results showed that unilateral hippocampal inactivation alters consolidation. It is not clear if bilateral treatments increase the impairment. Wistar rats were trained in the Morris water maze during 4 consecutive days. Subjects received saline or tetrodotoxin in the dorsal hippocampus 1 min after training. Results showed that bilateral as well as unilateral treatments impair consolidation to the same degree, as shown by the mean latency to reach the platform. In both cases, the impairment is only visible in the first trial of the session following the blockade. PMID- 18446579 TI - Spontaneous incomplete recovery of peroneal palsy after a sealbite. AB - Incomplete recovery of peroneal palsy, after a sealbite during swimming has not been reported. A 58-year-old woman was bitten into the right knee by a seal during swimming, resulting in incomplete division of the right profound branch of the peroneal nerve and complete division of the superficial branch of the peroneal nerve. Initial drop-foot, absent foot eversion, and hypaesthesia of the lateral lower leg were followed by almost complete clinical recovery of motor functions within four month by spontaneous re-innervation from the proximal nerve stump, despite severely abnormal electrophysiological findings. Re-evaluation 6 years after the accident revealed only discrete weakness for foot and toe extension, slight distal hypaesthesia, but still increased distal latency, reduced compound muscle action potential, slowed nerve conduction velocity of the right peroneal nerve, and neurogenic electromyography of the right anterior tibial and long peroneal muscles. Nerve conduction studies were hampered by co innervation of the extensor digitorum brevis muscles by the tibial nerves. This case shows that peroneal palsy from a sealbite may recover spontaneously almost completely, but may go along with residual, subclinical, electrophysiological abnormalities. The later may be enhanced by innervation variants. PMID- 18446580 TI - Angiotensinogen gene polymorphism predicts hypertension, and iridological constitutional classification enhances the risk for hypertension in Koreans. AB - This study investigated the relationship between iridological constitution and angiotensinogen (AGN) gene polymorphism in hypertensives. In addition to angiotensin converting enzyme gene, AGN genotype is also one of the most well studied genetic markers of hypertension. Furthermore, iridology, one of complementary and alternative medicine, is the diagnosis of the medical conditions through noting irregularities of the pigmentation in the iris. Iridological constitution has a strong familial aggregation and is implicated in heredity. Therefore, the study classified 87 hypertensive patients with familial history of cerebral infarction and controls (n = 88) according to Iris constitution, and determined AGN genotype. As a result, the AGN/TT genotype was associated with hypertension (chi2 = 13.413, p < .05). The frequency of T allele was 0.92 in patients and 0.76 in controls (chi2 = 13.159, p < .05). In addition, iridological constitutional classification increased the relative risk for hypertension in the subjects with AGN/T allele. These results suggest that AGN polymorphism predicts hypertension, and iridological constitutional classification enhances the risk for hypertension associated with AGN/T in a Korean population. PMID- 18446581 TI - Increased tunel positive cells in CA1, CA2, and CA3 subfields of rat hippocampus due to copper and ethanol co-exposure. AB - Copper (Cu) is an essential element for life. However, it is toxic at excessive doses, whereas exposure to ethanol (EtOH) has known to cause morphological changes, degeneration, and neuronal loss in central nervous system. A previous investigation by the authors' group showed that Cu and EtOH co-treatment cause severe hippocampal neuronal loss in CA1, CA2, and CA3 subfields of rat hippocampus. This study was designed to analyze the possible mechanism(s) of action of this effect. In addition, the possible neurogenesis in response to a potent neurodegenerative treatment in rat hippocampus was analyzed. Results demonstrated that Cu and EtOH induced neuronal loss in rat hippocampus was in correlation with the increased cell death analyzed on the basis of TdT-mediated dUTP nick end labeling (TUNEL) assay. On the other hand, neuronal regenerative activity was detectable in analyzed CA1, CA2, and CA3 subfields of the rat hippocampus analyzed on the basis of 5-bromo-2'-deoxy-uridine (BrdU) labeling assay; however, this activity in treated group was not significantly different from that of control group. PMID- 18446582 TI - Near-infrared spectroscopy study of language activated hyper- and hypo oxygenation in human prefrontal cortex. AB - Oxygenation changes in the left prefrontal cortex during language processing were assessed with near-infrared spectroscopy (NIRS). Oxyhemoglobin and deoxyhemoglobin concentrations at the Fp1 site during 5 min of resting with eyes closed (control), followed by 5 min of reading aloud, were monitored. A statistically significant change in the oxyhemoglobin concentration was observed by NIRS in all the subjects after execution of the experimental task. The observations of hyper-oxygenation as well as hypo-oxygenation in the present investigation extend past studies and suggest a complex phenomenon of activation that may be the result of a vascular steal mechanism, attenuated activation baselines, or active cortical deactivation. PMID- 18446583 TI - The effects of antidepressants in Parkinson's disease: a meta-analysis. AB - This study explored the therapeutic effect of antidepressants in Parkinson's disease (PD) using a meta-analysis. Altogether, 24 placebo-controlled trials qualified for inclusion and revealed that tricyclic antidepressants (TCAs) had a greater antidepressant effect relative to selective serotonin reuptake inhibitors (SSRIs), Qb(1) = 8.87, p < .01, and the mono-amine-oxidase inhibitor, selegiline, Qb(1) = 7.90, p < .01. Whereas TCAs produced a significant side effect profile (odds ratio = 3.07), adverse events were negligible with SSRIs (odds ratio = 1.83) and selegeline (odds ratio = 1.63). Antidepressants can be beneficial for patients with PD. However, the choice of antidepressants needs to take depressive symptomatologies into account while monitoring side effects. PMID- 18446584 TI - Reduced energy utilization in the brain is a feature of an animal model of fatigue. AB - Recently, the authors established an animal model of fatigue. The fatigued animals showed reduced 2-[18F]fluoro-2-deoxy-D-glucose uptake in their brain, although their blood glucose level did not differ from that of the control animals. For further clarification, the study measured regional cerebral blood flow, ATP level, and the ability of mitochondria to produce ATP in the brain of the fatigued and control rats. The fatigued animals showed almost equal regional cerebral blood flow, a significantly higher ATP level, and almost equal mitochondria ability to produce ATP. These data suggest that decreased energy utilization in the brain is a feature of fatigue. PMID- 18446585 TI - Effects of nestin-antisense treatment in mice on memory-related performance. AB - Nestin is a neuronal stem cell marker. It has been reported that newly generated adult neurons play a role in murine memory. The purpose of this study was to determine whether nestin itself plays a role in memory function in adult animals. Mice were infused intraventricularly with nestin-selective, morpholino-modified antisense oligodeoxynucleotides for 6 days, after which their ability to perform a new memory-related, food-search task was assessed. Such treatment was found to reduce the training effect on food-search test performance. Immunohistochemical staining revealed that nestin-positive cells within the hippocampal dentate gyrus and subventricular zone were attenuated in these animals. These data support a role for nestin in adult memory and learning. PMID- 18446586 TI - Gaba receptor insecticide non-competitive antagonists may bind at allosteric modulator sites. AB - Results from several studies have shown that a series of chemically distinct insecticide compounds (picrotoxin, BIDN, TBPS, fipronil, lindane, EBOB, and alpha endosulfan) affect GABA A receptor function. In this investigation, docking of this set of insecticides to the GABA receptor identified five potential binding sites. The lowest energy site was found within the base of the transmembrane bundle, interacting with M2 but not in the pore, and includes many of the residues previously experimentally implicated in insecticide binding. Many of the binding modes are suggestive of a non-competitive allosteric mechanism based on interruption of the channel gating mechanism rather than directly blocking the channel. The results also distinguished between isomers of hexachlorohexane (HCH), where gamma-HCH (lindane) binds more favorably than beta-HCH. The results suggest multiple sites for insecticide binding and may suggest further mutagenesis and labeling work to either confirm or rule out these findings. PMID- 18446587 TI - Early maternal separation and chronic variable stress as adults differentially affect Fos expression in the anterodorsal thalami nuclei. AB - The present study examined the participation of the anterodorsal thalamic nuclei (ADTN) in mediating the long-term effects of early maternal separation on the stress/hypothalamic-pituitary-adrenal axis response of adult animals. The study measured Fos and glucocorticoid receptor immunoreactivity (GR-ir) in the ADTN of maternally separated female rats subsequently exposed to variable chronic stress. Maternal separation increased the number of neurons immunoreactive to Fos in the ADTN of chronically stressed adult rats. GR-ir was absent in the ADTN. Linking these results with previous endocrine evidence led the authors to propose a dual role of these nuclei. Maternal separation and chronic stress enhance the neuronal activity of the ADTN, nevertheless it is not regulated, at least directly, via GR. PMID- 18446588 TI - Asthma genetics: personalizing medicine. AB - Asthma is a chronic inflammatory lung disease that leads to significant morbidity, mortality, and economic burden. The clinical symptoms, which are a result of airway inflammation and reversible airway obstruction, have led to the mainstay of therapies for asthma: anti-inflammatory medications and bronchodilators. However, the efficacies of the various classes of medications are not equal among all patients and may be affected by asthma phenotypes, environmental exposures, and genetic differences. Similarly, the risk for developing asthma and the natural history of the disease show great inter individual variability due to these same factors. Over the past few decades, much effort has been focused on the genetics of asthma, and investigators have identified more than one hundred potential asthma susceptibility genes, of which at least ten have been replicated in numerous independent studies. In parallel, researchers have also identified genetic factors that impact the pharmacotherapeutic responses to the major classes of asthma medications. While the results of previous studies have been promising, future investigations need to combine genetics, pharmacogenetics, accurate disease phenotyping, and environmental exposures to build the foundation for personalized and predictive medicine for the 21st century. The ultimate goal is to enable physicians to identify those at risk for asthma, intervene to prevent or attenuate the disease, and select the optimal medical regimen for each individual patient. If successful, the resulting paradigm shift in medical practice will lead to improved clinical outcomes and decreased health care expenditures. PMID- 18446589 TI - Early bronchodilatory effects of budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and albuterol pMDI: 2 randomized controlled trials in adults with persistent asthma previously treated with inhaled corticosteroids. AB - Two identically designed, randomized, multicenter, single-dose, crossover studies were conducted in patients aged > or = 18 years with mild to moderate asthma previously treated with inhaled corticosteroids. After 2 weeks on twice-daily budesonide pressurized metered-dose inhaler (pMDI) 160 microg, patients received a randomized sequence of budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), fluticasone/salmeterol dry powder inhaler (DPI) 250/50 microg x 1 inhalation, albuterol pMDI 90 microg x 2 inhalations (180 microg), and placebo pMDI (3-to 14-day washout periods). Improvements in forced expiratory volume in 1 second (FEV(1)) at 3 minutes were significantly (p < 0.001) greater after treatment with budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and similar to that of albuterol pMDI. In addition, significantly (p < 0.001) more patients treated with budesonide/formoterol pMDI achieved a 15% improvement in FEV(1) within 15 minutes compared with patients treated with fluticasone/salmeterol DPI and placebo. Thus, the early bronchodilatory effects of budesonide/formoterol pMDI were greater than with fluticasone/salmeterol DPI. PMID- 18446590 TI - Normal variation of bronchial reactivity in nonasthmatics is associated with the level of mite-specific IgE. AB - OBJECTIVE: To investigate association between non-specific bronchial reactivity (NBR) and level of mite specific IgE amongst mite-sensitized non-asthmatic subjects. METHODS: Subjects attending occupational check-up were assessed for: respiratory symptoms, atopic status (skin prick testing [SPT], total and specific IgE), spirometry and NBR. Individuals without history of respiratory disease (N = 234) were included into analysis. RESULTS: All subjects had normal spirometry and 99% had normal NBR while 41.8% had detectable specific IgE to mites. Lung function parameters and NBR were significantly lower in mite sensitized subjects. Multiple regression analysis controlling for age, gender, smoking, family history, SPT, IgE, and lung function showed that NBR was significantly associated only with mite specific IgE level (beta = 0.26; 95% CI, 0.05-0.47; p = 0.018). CONCLUSION: Even in subjects without allergic symptoms, IgE-mediated sensitization does not appear to be all or nothing phenomenon influencing the normal variability of underlying airway reactivity. PMID- 18446592 TI - Olfactory receptor gene polymorphisms and nonallergic vasomotor rhinitis. AB - We sought a genotype-phenotype association: between single-nucleotide polymorphisms (SNPs) in olfactory receptor (OR) genes from the two largest OR gene clusters and odor-triggered nonallergic vasomotor rhinitis (nVMR). In the initial pedigree screen, using transmission disequilibrium test (TDT) analysis, six SNPs showed "significant" p-values between 0.0449 and 0.0043. In a second case-control population, the previously identified six SNPs did not re-emerge, whereas four new SNPs showed p-values between 0.0490 and 0.0001. Combining both studies, none of the SNPs in the TDT analysis survived the Bonferroni correction. In the population study, one SNP showed an empirical p-value of 0.0066 by shuffling cases and controls with 10(5) replicates; however, the p-value for this SNP was 0.83 in the pedigree study. This study emphasizes that underpowered studies having p-values between < 0.05 and 0.0001 should be regarded as inconclusive and require further replication before concluding the study is "informative." However, we believe that our hypothesis that an association between OR genotypes and the nVMR phenotype remains feasible. Future studies using either a genomewide association study of all OR gene-pseudogene regions throughout the genome--at the current recommended density of 2.5 to 5 kb per tag SNP--or studies incorporating microarray analyses of the entire "OR genome" in well-characterized nVMR patients are required. PMID- 18446591 TI - Improving care for urban children with asthma: design and methods of the School Based Asthma Therapy (SBAT) trial. AB - The School Based Asthma Therapy (SBAT) trial builds on a pilot study in which we found that school-based administration of preventive asthma medications for inner city children reduced asthma symptoms. However, the beneficial effects of this program were seen only among children not exposed to environmental tobacco smoke (ETS). The current study is designed to establish whether this intervention can be enhanced by more stringent adherence to asthma guidelines through the addition of symptom-based medication dose adjustments, and whether smoke-exposed children benefit from the intervention when it is combined with an ETS reduction program. The intervention consists of both administration of preventive asthma medications in school (with dose adjustments according to NHLBI guidelines) and a home-based ETS reduction program utilizing motivational interviewing principles. This paper describes the methodology, conceptual framework, and lessons learned from the SBAT trial. Results of this study will help to determine whether this type of comprehensive school-based program can serve as a model to improve care for urban children and reduce disparities. PMID- 18446593 TI - Costs and resource use of mild persistent asthma patients initiated on controller therapy. AB - BACKGROUND: The treatment of mild persistent asthma is controversial. OBJECTIVES: A retrospective database approach was used to evaluate different alternatives to treating mild persistent asthma. We hypothesized that treatment with inhaled corticosteroids (ICS) would result in lowest costs than treatment with leukotriene modifiers (LM) and combination therapy with ICS long-acting inhaled beta(2)-agonists (LABA) because it would be associated with fewer acute care visits and hospitalizations than LM and it would have lower drug acquisition costs than both ICS+LABA and LM. METHODS: Costs and resource utilization were compared in 1,283 mild persistent asthma patients initiating regular use of either ICS, ICS+LABA, or LM. Mild persistent asthma patients were identified from a privately insured claims database (1999-2005) using an established algorithm. Wilcoxon rank-sum tests and generalized linear models were used to compare costs. RESULTS: Of the total patients who met study criteria, 319 patients (24.9%) initiated regular ICS use, 414 (32.3%) ICS+LABA use, and 550 (42.9%) LM use. Over the 1 year after controller therapy initiation, asthma-related direct costs were significantly lower with ICS compared with ICS+LABA or LM ($819 for ICS, $1,094 for ICS+LABA, and $869 for LM, p < 0.001 for all comparisons). There were no significant differences in resource use. CONCLUSION: In this analysis, physicians, despite guideline recommendations, chose to treat patients with mild persistent asthma more often with LM and ICS+LABA than with ICS. However, therapy with ICS was less costly than treatment with either LM or ICS+LABA, primarily due to differences in drug costs, and provided similar outcomes. PMID- 18446594 TI - Early respiratory infections and asthma among New York City Head Start children. AB - BACKGROUND: Respiratory infections in neonates have been found to predict wheeze among young children. We hypothesized that among preschool children from low income minority communities in New York City, current asthma would be associated with a history of respiratory infection in the first few months after their birth. METHODS: We asked parents of children in New York City Head Start centers (preschool programs for children of low-income families) to respond to a questionnaire covering demographic factors, lifestyle, home environment, and health history, including a detailed history of respiratory conditions. We used logistic regression to model the association of asthma and asthma severity with history of respiratory infections, controlling for gender, ethnicity, family history of asthma, and other factors. RESULTS: Among 1,022 children (mean age 4+/ 0.6 years) whose parents provided information about their health history, 359 (35%) met our criteria for asthma. Overall, 22% had had a cold by 6 months and 17% an ear infection by 8 months of age. In multivariable models, children with asthma had had more colds (OR = 2.8, 95% confidence interval [CI] 1.4-6.0) and ear infections (OR = 3.4, 95% CI 1.7-6.9) in the past year than other children. Associations of respiratory infections with emergency department use for asthma (as a measure of severity) were similar. In models that did not control for infections in the past year, ages at first cold and first ear infection were associated with asthma and emergency department visits in the past year. CONCLUSIONS: In this sample of preschool children, respiratory infections were common and were associated with asthma and health care utilization for asthma exacerbations. If these findings are confirmed, preventive measures among children who develop such infections at a very early age should be explored to help reduce the burden of asthma in this age group. PMID- 18446596 TI - Characterizing community-based asthma knowledge in Chicago and its high risk neighborhoods. AB - The goal of this study was to characterize asthma knowledge in high risk neighborhoods compared to a random sample of residents in the Chicago area. The Chicago Community Asthma Survey-32 (CCAS-32) was administered to 1006 Chicago area residents and 388 residents in 4 high-risk Chicago inner-city neighborhoods. There was a significant difference in asthma knowledge between groups. The general Chicago-area respondents have an average desirable response rate of 71.6% versus 64.7% for respondents in high-risk communities (p < 0.0001). For some aspects of asthma knowledge, e.g., nocturnal cough, cockroach allergen, and vaporizer use, general knowledge was similarly low. For other aspects, such as the need for asymptomatic asthma visits and chest tightness, there were larger gaps between residents of high risk communities and the general community. High risk neighborhoods in Chicago had lower asthma knowledge compared to the general Chicago community. This discrepancy may be contributing to the disparities seen in asthma morbidity. Public health efforts to increase asthma knowledge in these high risk minority communities may help reduce these disparities. Important misconceptions exist about asthma triggers, signs and symptoms, especially among lower income African American communities, that should be addressed by physicians. PMID- 18446595 TI - Birth-related exposures and asthma and allergy in adulthood: a population-based cross-sectional study of young adults in North Staffordshire. AB - The rise in the prevalence of asthma and other allergic disorders over the past two decades has been well documented, yet this increase has still to be fully explained. One possible hypothesis is that the rise in atopic disease is related to recent changes in obstetric practice. Using a population based survey, with linked general practice and hospital birth records, we investigated the association between 6 birth related exposures (birth weight, mode of delivery, artificial commencement of labour, prematurity, neonatal intensive care unit admission and foetal distress) and asthma, allergic rhinitis, eczema and hay fever in adulthood. No statistically significant associations were demonstrated between any of the birth-related exposures and the 4 allergic conditions studied, although some non-significant trends were noted, especially for those born by Caesarean section (asthma: odds ratio 1.71, 95% confidence interval 0.75, 3.86, eczema: 1.09, 95% CI 0.41, 2.91, hay fever: OR 1.36, 95% CI 0.51, 3.61) (Table 2) or having evidence of foetal distress during labour (asthma: OR 1.45, 95% CI 0.70, 3.02, rhinitis OR 2.82, 95% CI 0.87, 9.15, hay fever OR 1.34, 95% CI 0.57, 3.14). Given the ongoing changes in obstetric practice and the continuing rise in the prevalence of allergic disorders, this area is worthy of further investigation. PMID- 18446597 TI - Parental stress and childhood wheeze in a prospective cohort study. AB - BACKGROUND: Although studies indicate that psychological stress is linked with asthma morbidity, it is unknown whether stress is associated with the incidence of asthma symptoms. METHOD: In a cohort of 5- to 6-year-old school children participating in the southern California Children's Health Study, we evaluated parent-reported wheeze in the child using a standardized questionnaire and perceived parental stress at study entry. Wheeze in the child was evaluated one year later. Analyses were restricted to children without asthma at study entry (N = 2,888, of whom 286 had wheeze at follow-up). RESULTS: There was an increase in wheeze across an interquartile range of parent stress (odds ratio [OR] 1.18; 95% confidence interval [CI] 0.99, 1.42). Parent stress was associated with wheeze among children with no parental asthma (OR 1.24; CI 0.99, 1.55) and among boys (OR 1.34; CI 1.04, 1.74), but not among girls or children with parental asthma. Among boys with no parental asthma there was a strong dose-response relationship, and in the top quartile of stress the OR was 2.76 (CI 1.39, 5.51) compared to the bottom quartile. CONCLUSION: Parental stress increases the risk of childhood wheeze among children with no parental history of asthma, especially among boys. These results suggest that the influence of psychosocial factors on asthma, such as stress and social environment, deserve increased attention. PMID- 18446598 TI - Self-reported home environmental risk factors for childhood asthma: a cross sectional study of children in Buffalo, New York. AB - We present prevalence estimates of indoor and outdoor environmental risk factors for asthma from a cross-sectional study of children 1 to 17 years of age living in Buffalo, New York. A child's primary caretaker completed a questionnaire about the household's demographics, lifestyle habits, housing, indoor and outdoor environment, and the child's activity patterns, family history of asthma, asthma symptoms and treatment, and medical care access. Significant environmental risk factors were presence of smokers in the household, humidifier or vaporizer use, chemical odors indoors, frequent truck traffic, and chemical odors outdoors. Most of these risk factors can be mitigated or controlled. PMID- 18446599 TI - Tolerance mechanisms in response to antigens responsible for baker's asthma in different exposed people. AB - BACKGROUND: Baker's asthma is among the most common occupational disease. The risk factors and immune features that may be important as predictors of tolerance or development of the disease are not completely understood. OBJECTIVE: To study the evolution over time of antigenic reactivity on baker's asthma in Spain and in France, in order to find differences in their allergenic response and evidence of protective or risks mechanisms against this disease. METHODS: Two groups of subjects were randomly selected. A group of bakers with asthma from Spain and a second group from France whose blood was taken 30 years ago: bakers with asthma, bakers without occupational respiratory allergy, and wives and children living close to the bakery. In all subjects skin tests were carried out with cereals, insects and the most common allergens in their area. Specific IgE, IgG(4) and IL 10 measurement were also determined. RESULTS: Spanish patients were mainly sensitized to cereal allergens and presented higher levels of IgE (p < 0.001). French patients are more often sensitised to insects than the Spanish ones: 5.26% versus 80% (p < 0.005). Symptom free or without aggravation at work subjects have higher specific IgG(4) and IL 10 levels than the others (p < 0.01). CONCLUSIONS: Antigens implicated in baker's asthma may change with time. The presence of higher levels of IgG(4), IL10 and diversity of sources of sensitisation in French patients may have helped them to develop a kind of natural hyposensitization. PMID- 18446600 TI - Specialists play a vital role in general practitioners' prescription behavior: a qualitative study of asthma care in Japan. PMID- 18446601 TI - Lung function and cytokine levels in professional athletes. AB - OBJECTIVE: Previous studies have demonstrated that exercise-induced asthma and bronchial hyperresponsiveness commonly occur in athletes. The present study investigates pulmonary function and cytokine levels in professional athletes to explore the impact of various sports on respiratory system function and to evaluate the possible role of systemic anaphylaxis. METHODS: Lung function was measured at rest in professional athletes without a history of smoking. Athletes were recruited from 10 different sports including swimming, water ballet, shooting, volleyball, softball, football, kickboxing, fencing, judo, and track and field. Measurements included forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), vital capacity (VC), peak expiratory flow (PEF), maximal mid-expiratory flow curve (MMEF), and forced expiratory flow rate (FEF(25 75)%). In addition, the medical history of all athletes was recorded. Correlations between lung function measurements and the different sports, age, gender, height and weight were analyzed. In some athletes, serum was sampled to detect IL-4 and IL-10 concentrations. In these subjects, the correlation between pulmonary function and cytokine levels was analyzed. RESULTS: A total of 147 professional athletes and 30 healthy volunteers were enrolled in the study. Allergic rhinitis and asthma were detected only in swimmers with an incidence of 56.52% (13/23) and 8.70% (2/23), respectively. Lung function measures were significantly correlated with sport, age, gender, height, and weight. Ventilation functions (including FVC, FEV(1), FEV(1)/FVC, and MMV) in male athletes were superior to those in females, and the ventilation functions in swimmers were superior to those in others. However, the small airway functions (MMEF, FEF(50), FEF(75)) in swimmers and in track and field athletes were lower than predicted (swimmers: 72%, 70%, and 78%, respectively; track and field athletes: 79%, 75%, and 99%, respectively). Serum analyses for IL-4 and IL-10 revealed that IL-4 concentrations were higher in swimmers 69.34 +/- 22.4 pg/mL relative to non swimmers (p = 0.000). By contrast IL-10 concentrations were lower in swimmers 34.94 +/- 9.71 pg/mL than that in the static group (44.69 +/- 16.32 pg/mL; p = 0.027). IL-4 levels were negatively correlated with FEV(1)%, FEF(25)%, FEF(50)%, and MMEF%. By contrast, IL-10 levels were not correlated with any of these measures. CONCLUSIONS: The lung function measurements were correlated with sport, age, gender, height, and weight in the various athletes. The lung capacity of swimmers was greater than that of other athletes. Small airway dysfunction was observed in some swimmers and endurance athletes. We observed an association between systemic anaphylaxis and small airway dysfunction after prolonged regular training, particularly following swimming and endurance training. PMID- 18446603 TI - Chitosan-mediated orally delivered nucleic acids: a gutful of gene therapy. AB - Gene therapy is rapidly gaining its hold in preclinical drug evaluation. However, upfront, ease of administration and greater patient compliance should strictly drive research efforts for developing modes of gene delivery. It has been a decade since plasmid DNA was first introduced orally in animals. Since then, two main modes of such delivery for potentially therapeutic nucleic acids, chitosan based systems and non-chitosan-based systems, have been developed, at a steady though slow pace. This slow pace is partly due to the various hurdles faced with oral delivery, especially for labile molecules like nucleic acids. The real challenge is to enhance delivery systems that can traverse the gut and gain entry into the bloodstream in sufficient quantities for efficacy in diseased tissues at a distance. This review examines some of the current chitosan-based vehicles used for oral administration of potentially therapeutic nucleic acids, and explores novel ways to better deliver such molecules in the future for non-vaccination applications. PMID- 18446604 TI - Capture of magnetic carriers within large arteries using external magnetic fields. AB - Our overall research goal is to advance the safety and effectiveness of acute ischemic stroke therapy by improving the benefit/risk ratio of thrombolysis and hence, the long-term outcome of acute ischemic stroke victims. Our approach is the development of a novel tissue plasminogen activator (t-PA) delivery system based on t-PA-loaded magnetic nano- and microcarriers guided directly to the site of vascular occlusion by external magnetic fields. Such a t-PA delivery system would conveniently combine the advantages of both intravenous (systemic) and intraarterial (catheter-facilitated) thrombolysis: non-invasiveness - the magnetic t-PA carriers can be injected intravenously and targeted, as drug delivery is magnetically guided to and t-PA focally released at and within the vascular clot to induce lysis. The focus of our discussion are the two necessary, fundamental and interrelated bioengineering steps: the research and development of well-characterized, biocompatible, functionally active and t-PA-loaded (encapsulated) magnetic nano- and microcarriers able to induce effective thrombolysis, and the design of magnetic guidance systems for targeted tPA delivery allowing also the triggered release of the thrombolytic agent at the clot site. In this paper, we theoretically demonstrated magnetic trapping of blood borne magnetic nano- and microcarriers from human large vessels, especially arteries. Then, some preliminary experiments using primate models (monkeys) were done to identify successful in vivo sequestration of magnetic carriers in large and smaller arterial branches after arterial upstream and systemic venous injection. Histology (hematoxylin-eosin stain) verified intraarterial carrier concentration (identified as black carrier agglomerates on H and E staining) at the arterial region above the surface magnet. The results revealed the feasibility of magnetic drug-targeting at arteries and solidified the proposed t PA delivery system. PMID- 18446605 TI - Folate-targeted etoposide-encapsulated lipid nanospheres. AB - Lipid nanospheres (LN) are simple colloidal drug delivery systems, which are proven to be useful for the systemic delivery of lipophilic anticancer drugs. Our previous work shows that the encapsulation of etoposide in LN improved the anticancer activity and a further inclusion of polyethylene glycol distearoylphosphatidylethanolamine (DSPE-PEG) increased the circulation time and stability of LN. The present study is focused on the targeting ability of LN using Folate-PEG-DSPE. Folate-targeted (Fol-LNE) and non-targeted (SLNE) etoposide-encapsulated lipid nanospheres were prepared with the help of soybean oil, egg phosphatidylcholine, and PEG-DSPE with and without Folate-PEG-DSPE. The anticancer activity of these formulations was assessed in KB cell line. Cell uptake studies were carried out in KB cell lines using fluorescent-labeled targeted (Fol-LN) and non-targeted (SLN) lipid nanospheres without etoposide. Confocal microscopy and flow cytometry results found that, Fol-LN was selectively taken up by the KB cells and the addition of 1 mM folic acid completely blocked this uptake. Cytotoxicity results support the above finding, the IC50 values of etoposide solution, Fol-LNE, and Fol-LNE-comp (competition with 1 mM folic acid) were 33, 5, and 19 muM, respectively. Tissue distribution of Fol-LNE was compared with that of SLNE and etoposide commercial formulation (ETP) in normal mice. The studies show that in the kidney etoposide concentration was higher following Fol LNE administration than SLNE and ETP. PMID- 18446606 TI - Efficient in vivo gene transfection by stable DNA/PEI complexes coated by hyaluronic acid. AB - Plasmid DNA was mixed with polyethyleneimine (PEI) and hyaluronic acid (HA) to afford ternary complexes with negative surface charge regardless of the mixing order. They showed reduced non-specific interactions with blood components. When DNA and PEI were mixed at a high concentration such as that used in in vivo experiments, they soon aggregated, and large particles were formed. On the other hand, pre-addition of HA to DNA prior to PEI effectively diminished the aggregation, and 10% (in volume) of the complexes remained as small particles with a diameter below 80 nm. Those negatively charged small ternary complexes induced a much stronger extra-gene expression in tumor than binary DNA/PEI complex after intratumoral or intravenous injection into the mice bearing B16 cells. PMID- 18446607 TI - PLGA microspheres for the delivery of a novel subunit TB vaccine. AB - Biodegradable poly(dl-lactide-co-glycolide) microspheres were prepared using a modified double emulsion solvent evaporation method for the delivery of the subunit tuberculosis vaccine (Ag85B-ESAT-6), a fusion protein of the immunodominant antigens 6-kDa early secretory antigenic target (ESAT-6) and antigen 85B (Ag85B). Addition of the cationic lipid dimethyl dioctadecylammonium bromide (DDA) and the immunostimulatory trehalose 6,6'-dibehenate (TDB), either separately or in combination, was investigated for the effect on particle size and distribution, antigen entrapment efficiency, in vitro release profiles and in vivo performance. Optimised formulation parameters yielded microspheres within the desired sub-10 microm range (1.50 +/- 0.13 microm), whilst exhibiting a high antigen entrapment efficiency (95 +/- 1.2%) and prolonged release profiles. Although the microsphere formulations induced a cell-mediated immune response and raised specific antibodies after immunisation, this was inferior to the levels achieved with liposomes composed of the same adjuvants (DDA-TDB), demonstrating that liposomes are more effective vaccine delivery systems compared with microspheres. PMID- 18446608 TI - The release and analgesic activities of morphine and its ester prodrug, morphine propionate, formulated by water-in-oil nanoemulsions. AB - In this study, we examined the feasibility of water-in-oil (w/o) nanoemulsions as sustained-release systems for morphine, following subcutaneous administration in rats. The ester prodrug of morphine, morphine propionate (MPR), was also utilized in this study. A variety of nanoemulsions were prepared using soybean oil or sesame oil as the external phase. Span 80, Tween 80, Plurol diisostearique and Brij 98 were used as surfactants in the w/o interface. The effects of the formulation variables on the characteristics of the nanoemulsions, such as inner droplet size, zeta potential, viscosity, drug partitioning, drug release and pharmacological effect, were evaluated. Mean sizes of nanoemulsions of 50-200 nm were obtained. The initial surface charge of the emulsions was found to be around - 3 to - 4 mV, except that the Plurol-containing vehicle showed a highly negative charge of - 23 mV. The loading of morphine and MPR into the nanoemulsions resulted in slower sustained-release behavior as compared with the drug/prodrug in aqueous solution. The rate of morphine released across the membrane was found to be highly dependent on the choice of oil and surfactant types. On the other hand, discrepancies in MPR release rates among the various formulations were minimal. The in vivo analgesic duration of morphine by targeting the drug to central nerve system could be prolonged from 1 to 3 h by incorporating the drug into nanoemulsions using Span 80 or Tween 80 as the surfactant. These results suggest that w/o nanoemulsions are well suited to provide sustained morphine delivery for therapeutic purposes. PMID- 18446609 TI - Enhanced mucosal and systemic immune response with squalane oil-containing multiple emulsions upon intranasal and oral administration in mice. AB - The objective of this study was to develop and evaluate squalane oil-containing water-in-oil-in-water (W/O/W) multiple emulsion for mucosal administration of ovalbumin (OVA) as a model candidate vaccine in BALB/c mice. Control and optimized OVA-containing W/O/W emulsion (OVA-Emul) and chitosan-modified W/O/W emulsion (OVA-Emul-Chi) formulations were administered intranasally and orally at an OVA dose of 100 mug. The mucosal and systemic immune responses were evaluated after the first and second immunization. The OVA-Emul formulations resulted in higher immunoglobulin-G (IgG) and immunoglobulin-A (IgA) responses as compared with aqueous solution. In addition, significant IgG and IgA responses were observed after the second immunization dose using the emulsions with both routes of administration. Intranasal vaccination was more effective in generating the systemic OVA-specific IgG response than the mucosal OVA-specific IgA response. Oral immunizations, on the other hand, showed a much higher systemic IgG and mucosal IgA responses as compared with the nasally treated groups. The results of this study show that squalane oil-containing W/O/W multiple emulsion formulations can significantly enhance the local and systemic immune responses, especially after oral administration, and may be adopted as a better alternative in mucosal delivery of prophylactic and therapeutic vaccines. PMID- 18446610 TI - Chloramphenicol-incorporated poly lactide-co-glycolide (PLGA) nanoparticles: formulation, characterization, technetium-99m labeling and biodistribution studies. AB - Chloramphenicol-loaded (CHL) poly-d,l-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were prepared by emulsification solvent evaporation technique either by using polyvinyl alcohol (PVA) as emulsion stabilizer or polysorbate-80 (PS-80) as surfactant and characterised by transmission electron microscopy, zeta potential measurements. The NPs were radiolabeled with technetium-99m ((99m)Tc) by stannous reduction method. Labeling conditions were optimised to achieve high labeling efficiency, in vitro and in vivo (serum) stability. The labeled complexes also showed very low transchelation as determined by DTPA challenge test. Biodistribution studies of (99m)Tc-labeled complexes were performed after intravenous administration in mice. The CHL-loaded PLGA NPs coated with PS-80 exhibited relatively high brain uptake with comparatively low accumulation in bone marrow to that of free drug and CHL-loaded PLGA NPs (PVA, used as emulsion stabilizer) at 24 h post injection time period. This indicates the usefulness of the above delivery system for prolonged use of the antibiotic. PMID- 18446611 TI - Recombinant alpha-fetoprotein C-terminal fragment: the new recombinant vector for targeted delivery. AB - The specific receptor of alpha-fetoprotein (AFP) is a universal tumor marker, being expressed on the surface of many tumor cells, but not in normal human tissues. AFP enters the cell by receptor-mediated endocytosis; its receptor binding site is hypothetically localized in the third domain of AFP. A recombinant C-terminal AFP fragment, which contains all the third and a part of the second domains of hAFP, was produced. This AFP fragment was bound specifically to the AFP receptor on the surface of tumor cells and was accumulated by them with the same efficiency as the full-size hAFP. Similar to hAFP, the recombinant C-terminal fragment inhibited the estradiol-induced growth of hormone-dependent MCF-7 cells in vitro. Hence, the recombinant C-terminal AFP fragment can be used as a protein vector for the targeted delivery of cytostatic drugs to tumor cells. PMID- 18446612 TI - Foreword: trafficking, assembly and regulation of neurotransmitter receptors and ion channels. PMID- 18446613 TI - An overview of trafficking and assembly of neurotransmitter receptors and ion channels (Review). AB - Ionotropic neurotransmitter receptors and voltage-gated ion channels assemble from several homologous and non-homologous subunits. Assembly of these multimeric membrane proteins is a tightly controlled process subject to primary and secondary quality control mechanisms. An assembly pathway involving a dimerization of dimers has been demonstrated for a voltage-gated potassium channel and for different types of glutamate receptors. While many novel C terminal assembly domains have been identified in various members of the voltage gated cation channel superfamily, the assembly pathways followed by these proteins remain largely elusive. Recent progress on the recognition of polar residues in the transmembrane segments of membrane proteins by the retrieval factor Rer1 is likely to be relevant for the further investigation of trafficking defects in channelopathies. This mechanism might also contribute to controlling the assembly of ion channels by retrieving unassembled subunits to the endoplasmic reticulum. The endoplasmic reticulum is a metabolic compartment studded with small molecule transporters. This environment provides ligands that have recently been shown to act as pharmacological chaperones in the biogenesis of ligand-gated ion channels. Future progress depends on the improvement of tools, in particular the antibodies used by the field, and the continued exploitation of genetically tractable model organisms in screens and physiological experiments. PMID- 18446614 TI - Assembly and trafficking of nicotinic acetylcholine receptors (Review). AB - Nicotinic acetylcholine receptors (nAChRs) are members of an extensive super family of neurotransmitter-gated ion channels. In humans, nAChRs are expressed within the nervous system and at the neuromuscular junction and are important targets for pharmaceutical drug discovery. They are also the site of action for neuroactive pesticides in insects and other invertebrates. Nicotinic receptors are complex pentameric transmembrane proteins which are assembled from a large family of subunits; seventeen nAChR subunits (alpha1-alpha10, beta1-beta4, gamma, delta and epsilon) have been identified in vertebrate species. This review will discuss nAChR subunit diversity and factors influencing receptor assembly and trafficking. PMID- 18446615 TI - Trafficking of 5-HT(3) and GABA(A) receptors (Review). AB - The 5-HT(3) and GABA(A) receptors are members of the Cys-loop family of neurotransmitter-gated ion channels that also include receptors for glycine and acetylcholine. The 5-HT(3) and acetylcholine receptors (cationic ion channels) and the GABA(A) and glycine receptors (anionic ion channels) generally depolarize or hyperpolarize, respectively, the neuronal membrane. Within the amino-terminal extracellular region, all members of this family exhibit a similar architecture of ligand binding domains and a number of key residues are completely conserved. The molecular characterization of their ligand binding and gating characteristics has benefited from the existence of a large repertoire of individual subunits that contribute to the pentameric ion channel. Although differences do exist, advances in our knowledge of one member offers valuable insight into the family as a whole. Each member of the Cys-loop receptors (and all other multimeric ion channels) must face the same challenges: How to assemble individual subunits into an ion channel and which subunits to use? How are assembled receptors distinguished from those that are unassembled or misassembled, then exported from the endoplasmic reticulum and delivered to the cell surface? How are they targeted to, and anchored at synaptic and extrasynaptic sites? How and when are they to be removed from these sites to provide long-term regulation of neuronal activity? In this review, we summarize our current knowledge for the 5-HT(3) and GABA(A) receptors that have provided complementary information and helped us build an overall picture of how receptor biogenesis and trafficking occurs. PMID- 18446616 TI - Assembly of GABA(A) receptors (Review). AB - GABA(A) receptors are the major inhibitory transmitter receptors in the central nervous system. They are chloride ion channels that can be opened by gamma aminobutyric acid (GABA) and are the targets of action of a variety of pharmacologically and clinically important drugs. GABA(A) receptors are composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to the formation of a large variety of distinct GABA(A) receptor subtypes in the brain. The majority of GABA(A) receptors seems to be composed of two alpha, two beta and one gamma subunit and the occurrence of a defined subunit stoichiometry and arrangement in alphabetagamma receptors strongly indicates that assembly of GABA(A) receptors proceeds via defined pathways. Based on the differential ability of subunits to interact with each other, a variety of studies have been performed to identify amino acid sequences or residues important for assembly. Such residues might be involved in direct protein-protein interactions, or in stabilizing direct contact sites in other regions of the subunit. Several homo-oligomeric or hetero-oligomeric assembly intermediates could be the starting point of GABA(A) receptor assembly but so far no unequivocal assembly mechanism has been identified. Possible mechanisms of assembly of GABA(A) receptors are discussed in the light of recent publications. PMID- 18446617 TI - Assembly and forward trafficking of NMDA receptors (Review). AB - N-Methyl-D-aspartate (NMDA) receptors are a subclass of the excitatory, ionotropic L-glutamate neurotransmitter receptors. They are important for normal brain function being both primary candidates for the molecular basis of learning and memory and in the establishment of synaptic connections during the development of the central nervous system. NMDA receptors are also implicated in neurological and psychiatric disorders. Their dysfunction which is primarily due to either hypo- or hyper-activity is pivotal to these pathological conditions. There is thus a fine balance between NMDA receptor-mediated mechanisms in normal brain and those in diseased states where receptor homeostasis is perturbed. Receptor activity is due in part to the number of surface expressed receptors. Understanding the assembly and trafficking of this complex, heteromeric, neurotransmitter receptor family may therefore, be pivotal to understanding diseases in which their altered activity is evident. This article will review the current understanding of the mechanisms of NMDA receptor assembly, how this assembly is regulated and how assembled receptors are trafficked to their appropriate sites in post-synaptic membranes where they are integral components of a macromolecular signalling complex. PMID- 18446618 TI - Assembly and trafficking of P2X purinergic receptors (Review). AB - P2X receptors are cation selective ion channels gated by the binding of extracellular ATP. Seven subtypes have been identified and they have widespread and overlapping distributions throughout the body. They form homo- and heterotrimeric complexes that differ in their functional properties and subcellular localization. They form part of larger signalling complexes, interacting with unrelated ion channels and other membrane and cytosolic proteins. Up- or down-regulation of their expression is associated with several disease states. This review aims to summarize recent work on the assembly and trafficking of this family of receptors. PMID- 18446619 TI - Surface expression and distribution of voltage-gated potassium channels in neurons (Review). AB - The last decade has witnessed an exponential increase in interest in one of the great mysteries of nerve cell biology: Specifically, how do neurons know where to place the ion channels that control their excitability? Many of the most important insights have been gleaned from studies on the voltage-gated potassium channels (Kvs) which underlie the shape, duration and frequency of action potentials. In this review, we gather recent evidence on the expression, trafficking and maintenance mechanisms which control the surface density of Kvs in different subcellular compartments of neurons and how these may be regulated to control cell excitability. PMID- 18446620 TI - Measurement and characteristics of neurotransmitter receptor surface trafficking (Review). AB - Neurotransmitter receptor trafficking in and out synapses has emerged as a key process to regulate synaptic transmission during synaptic development and plasticity both at excitatory and inhibitory synapses. Lateral diffusion of surface neurotransmitter receptors has recently emerged as a key pathway to regulate receptor trafficking to and from synapses. Receptors enter and exit synapses mainly by lateral diffusion within the plane of the membrane while their retrieval and addition from and to the plasma membrane by endo and exocytotic processes occur largely at extrasynaptic sites. As a consequence, regulation of receptor surface trafficking is likely to be a major process to regulate receptor numbers at synapses. Measurement of receptor surface diffusion has required the development of new experimental approaches to specifically label and track surface receptor with appropriate time- and space-resolutions. In this review, we first discuss the approaches that have been used to measure receptor surface diffusion, such as the ensemble approach that measure average diffusion of a defined surface receptor population and the single molecule/particle approaches that measure the surface diffusion of isolated receptors. To date, surface diffusion has been described for a variety of neurotransmitter receptors that exhibit common as well as specific features. These points are discussed in a comparative manner and emerging rules of surface trafficking as well as potential interplay between receptor classes are further commented. Because our knowledge on neurotransmitter receptor surface diffusion is fairly recent, open questions and experimental challenges facing the field are highlighted throughout the review. PMID- 18446621 TI - The role of transmembrane AMPA receptor regulatory proteins (TARPs) in neurotransmission and receptor trafficking (Review). AB - AMPA receptors (AMPAR) mediate the majority of fast excitatory neurotransmission in the central nervous system (CNS). Transmembrane AMPAR regulatory proteins (TARPs) have been identified as a novel family of proteins which act as auxiliary subunits of AMPARs to modulate AMPAR trafficking and function. The trafficking of AMPARs to regulate the number of receptors at the synapse plays a key role in various forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Expression of the prototypical TARP, stargazin/TARPgamma2, is ablated in the stargazer mutant mouse, an animal model of absence epilepsy and cerebellar ataxia. Studies on the stargazer mutant mouse have revealed that failure to express TARPgamma2 has widespread effects on the balance of expression of both excitatory (AMPAR) and inhibitory receptors (GABA(A) receptors, GABAR). The understanding of TARP function has implications for the future development of AMPAR potentiators, which have been shown to have therapeutic potential in both psychological and neurological disorders such as schizophrenia, depression and Parkinson's disease. PMID- 18446622 TI - Diagnostic utility of p16INK4a: a reappraisal of its use in cervical biopsies. AB - p16(INK4a), an indirect marker of cell cycle dysregulation, is commonly expressed in cervical dysplasias and carcinomas associated with high risk human papillomavirus (HR-HPV) infections. Although p16(INK4a) immunohistology is routinely used as a cost effective surrogate marker, many of the published articles are confusing and contradictory. The discrepancies can be ascribed to a multitude of factors operating at the molecular, technical and interpretative levels. In the first place, our simplistic model of viral mediated oncogenesis is speculative and fails to account for all the known biomolecular changes. Unresolved technical issues include the variables of tissue fixation, antibody dilution, antibody isotype and clone, and the sensitivity of the particular detection method. Within any controlled staining method, strong diffuse or 'block' immunoreactivity in squamous cells may be found in moderate/severe dysplasia (CIN 2/3) and invasive squamous carcinoma. In contrast, focal or multifocal reactivity in squamous cells may be artefactual, related to low risk or HR-HPV. p16(INK4a) is less reliable when dealing with glandular lesions since considerable overlap exists between reactive and dysplastic lesions. In addition not all glandular dysplasias/carcinomas are HR-HPV related, nor are all p16(INK4a) immunoreactive lesions associated with HR-HPV. We conclude that p16(INK4a) immunoperoxidase shows greater specificity than sensitivity for squamous lesions; in comparison, glandular dysplasias/carcinomas show reduced specificity and sensitivity. Like all cell cycle regulatory proteins, the future diagnostic role of p16(INK4a) is limited. The ideal diagnostic molecular test for cervical dysplasias will detect a HR-HPV related product after, but not before, cell transformation and will reliably predict those cases yet to experience disease progression. PMID- 18446623 TI - Diagnosis of extramammary malignancy metastatic to the breast by fine needle biopsy. AB - AIMS: To review and illustrate the findings in fine needle biopsy (FNB) of extramammary malignancies presenting with breast metastases (MMB). METHODS: We reviewed 32 cases of MMB diagnosed on breast FNB. The clinical data, with particular attention to the history of a known primary malignancy, previous systemic metastatic disease in other sites and presentation with extramammary disease in addition to a breast mass were examined. The morphological appearances were reviewed and are illustrated, focusing on those features which allow the pathologist to recognise the possibility of metastatic disease and undertake appropriate steps to investigate this. RESULTS: The 32 cases included metastases from a wide range of sites, including cutaneous melanoma (10), lung (8), non Hodgkin's lymphoma (5), soft tissue (4), colon (2), endometrium, ovary and bladder. There was a history of extramammary malignancy in 26, while in six patients the breast mass was detected at initial presentation with malignant disease. Of the latter six patients, four had evidence of widespread metastases, while one presented with multiple breast masses. In 16 cases the cytological features allowed the possibility of metastases to be recognised without clinical data, while in the other 16 there was sufficient overlap with primary mammary carcinoma that the possibility of metastases could be missed. Only one case was initially mistaken for a primary tumour, in this case the history of prior malignancy with systemic metastases was not provided to the reporting pathologist. CONCLUSION: The majority (81%) of cases of MMB have a history of primary malignancy, although only a minority have a history of systemic metastases at other sites. Of those patients without known prior malignancy, the majority present with systemic disease or multiple breast lesions. The cytological features allow metastatic disease to be suspected in half of the cases, although in the others, particularly patients with metastatic adenocarcinoma, diagnosis without recourse to immunohistochemistry is difficult or impossible. A combination of complete clinical history, attention to the cytological features and suspicion in cases with metastatic disease beyond the axilla should allow most cases of MMB to be suspected, and suitable material for ancillary confirmatory testing to be obtained. PMID- 18446624 TI - Histopathological features of 'BRCAX' familial breast cancers in the kConFab resource. AB - AIMS: In recent years histopathology has made an important contribution to the study of familial breast cancer, largely on the basis of the distinctive cancer phenotype commonly identified in BRCA1-mutation carriers. The aim of this study was to identify this phenotype amongst index cases from families in the kConFab familial breast cancer resource with no known pathogenic mutation ('BRCAX' families). METHODS: The histopathology of breast cancer from 180 individuals was reviewed: 132 members of individual BRCAX families, 26 BRCA1 and 15 BRCA2 mutation carriers and seven mutation negative individuals from families with a known pathogenic mutation. RESULTS: BRCAX breast cancers were a heterogeneous group with 25.8% grade 1, 37.9% grade 2 and 36.4% grade 3. Overall, 45/180 (25%) cases were designated 'BRCA1-phenotype' including 22/132 (16.7%) BRCAX cases, 18/26 (69.2%) BRCA1 and 5/15 (33.3%) BRCA2 mutation carriers. For BRCAX cases, a BRCA1 phenotype designation was negatively correlated with age. CONCLUSIONS: Characteristic breast cancer pathology is not diagnostic of a germline BRCA1 mutation, but it does indicate a pathogenic mechanism that occurs with increased frequency in BRCA1 mutation carriers. In BRCAX families, BRCA1 tumour phenotype may signal the presence of an unidentified BRCA1 mutation. However, this finding must be interpreted with regard to limits of the association between histopathology and genotype, and the importance of clinical context. PMID- 18446625 TI - Fine needle aspiration cytology in young women with breast cancer: diagnostic difficulties. AB - BACKGROUND: Breast carcinoma is the most common malignancy in women worldwide. Though fine needle aspiration cytology (FNAC) plays an important role in preoperative diagnosis, there may be diagnostic delays in affected young women due to a lower index of suspicion. METHODS: The files of the Departments of Pathology, Singapore General Hospital, Singapore, and Prince of Wales Hospital, Hong Kong, were searched for cases of breast carcinoma in women aged 35 years or less. Those with prior FNA procedures comprised our study group. The FNA smears were reviewed and classified into five categories: inadequate, benign, equivocal, suspicious, malignant. The findings were correlated with subsequent histology. RESULTS: Thirty-four women aged 35 years and below underwent 35 FNACs, with one woman having bilateral FNA procedures. Upon review, one (2.9%) was classified as inadequate, one (2.9%) benign, five (14.3%) equivocal, five (14.3%) suspicious, 21 (60%) malignant and slides were not available for review for two (5.6%) cases. For six benign and equivocal cytological diagnoses, subsequent histology disclosed pure ductal carcinoma in situ (DCIS, 1 case), mucocoele-like lesions with DCIS (2 cases), invasive and in situ ductal carcinoma with neuroendocrine features (1 case) and two cases of invasive ductal carcinoma. CONCLUSION: Diagnostic difficulties in cytological interpretation of aspirates from breast carcinoma in young women may lead to unwanted delays, which occurred in six (17.6%) of 34 women in our series. Low grade cancers posing a pitfall in cytological diagnosis have to be considered. PMID- 18446626 TI - Use of reticulin stain in the diagnosis of intra-uterine gestation. AB - AIMS: The diagnosis of intra-uterine gestation may be problematic when specimens from clinically suspected products of conception lack chorionic villi and/or fetal somatic tissues, since the distinction of intermediate trophoblast from decidual or myometrial elements can be difficult. The placental site is also characterised by stromal changes, including the deposition of a characteristic extracellular fibrinoid matrix. We have noted that these stromal changes may be highlighted by a simple reticulin stain; therefore, we have evaluated reticulin staining in a series of endometrial biopsy specimens from patients with intra uterine and ectopic gestations. METHODS: Reticulin staining was performed in 28 endometrial specimens from patients with first trimester intra-uterine gestations, including 14 cases that lacked chorionic elements. Eight endometrial samples from patients with concurrent histologically verified tubal ectopic pregnancy were also examined. Selected cases were also studied using a Masson trichrome stain, and immunohistochemically with antisera to cytokeratin and HPL. RESULTS: There was a distinct increase in reticulin staining, usually evident at low power magnification, in most areas of decidua showing implantation site. Prominent reticulin staining was present around the decidual and trophoblast cells and there was also accentuation around stromal vessels, glands and myometrial cells. There was no clear difference in staining within areas of decidua including only rare intermediate trophoblast cells but this pattern was seldom seen in isolation. Minimal changes were seen in the placental site using the Masson trichrome stain. CONCLUSION: Reticulin stains may prove useful in the assessment of endometrial specimens from patients with purported intra-uterine gestations when chorionic elements are not identified. Since the staining technique is simple and can be quickly performed, it could be used as an adjunct to conventional H&E assessment and to select appropriate specimen blocks for additional more sensitive studies, including immunohistochemistry. PMID- 18446628 TI - Pathological findings in explanted prosthetic heart valves from ventricular assist devices. AB - AIMS: Ventricular assist devices (VADs) are now a mainstay in the management of patients with end-stage heart failure. An important consideration in the long term durability of these devices is the structural integrity of the prosthetic valves. Herein, we report the morphological findings in inflow and outflow explanted bioprostheses from seven such devices. METHODS: The porcine bioprostheses (n = 7; HeartMate, Novacor) were examined from inflow and outflow valve conduits. Cusp tears were assessed on gross examination. Tissues were then processed for histology and graded for pannus, thrombus, and calcification. Immunohistochemistry was performed using anti-CD68 (macrophages), CD45 (leukocytes) and CD31 (endothelial cells) antibodies to assess inflammation. RESULTS: There was no evidence of infection, host tissue growth, or calcification in either the inflow or the outflow valves in any case. A mild-to-moderate mononuclear cell 'deposit' was present on all porcine bioprostheses, largely on the non-flow surface of the valve cusps. In the case of the longest implant (HeartMate, duration 567 days), a significant mononuclear cell infiltrate was seen on the flow surface, the non-flow surface, as well as the base of the cusp tissue. Variably sized cusp tears were found in all inflow porcine bioprostheses at and beyond 3 months post-implantation, with the longest duration implant showing multiple tears. No tears were identified in the outflow valves. Histology revealed thrombus deposition in all inflow and outflow porcine valves. In addition, inflow valve cusps were characterised by the presence of longitudinally running 'cystic' spaces, which seem to increase in size with increasing implant duration. CONCLUSION: Bioprosthetic heart valves in VADs show significant changes which appear to correlate with duration post-implantation. These changes suggest that haemodynamic forces and the inflammatory reaction may play a significant role in the long-term durability of the porcine bioprostheses in these devices. PMID- 18446627 TI - Histological characteristics of singleton placentas delivered before the 28th week of gestation. AB - AIMS: The placenta is a record of the fetal environment and its examination may provide information about the baby's subsequent growth and development. We describe the histological characteristics of 947 singleton placentas from infants born between 23 and 27 weeks gestation. METHODS: Consent was obtained from mothers who delivered before 28 weeks (clinical estimate). We evaluated the gross and histopathological features of the placenta and assessed pair-wise correlations between variables. RESULTS: Lesions of uteroplacental circulation (abruption, extensive infarction or thrombosis, marked basal or perivillous fibrin deposition, increased syncytial knots) were inversely related to those associated with inflammation of the membranes and cord. Earlier age favoured inflammatory variables, while older age favoured characteristics attributed to impaired blood flow. We observed inflammation of the chorionic plate in 43%, the cord in 19%, and of chorionic plate vessels in 30%. Of the placentas with umbilical cord inflammation, 8% had no inflammation of the chorionic plate. CONCLUSIONS: This study population is unique in its size and recruitment by gestational age rather than birth weight. Inflammation occurred frequently, but not in placentas that had characteristics of vasculopathy. The prevalence of inflammation decreased with increasing gestational age, while vasculopathy increased. Funisitis need not be accompanied by chorionic inflammation. PMID- 18446629 TI - Peripheral vascular disease: who gets it and why? A histomorphological analysis of 261 arterial segments from 58 cases. AB - AIMS: This retrospective study aimed to document and illustrate the histomorphological changes underlying peripheral vascular disease (PVD). More specifically, it aimed to analyse and quantify those changes that lead to lower limb amputations. Histological changes were assessed in relation to various clinical pathologies, and significant correlations were sought thereafter. METHODS: A total of 1305 arterial segments were examined from 58 consecutive patients undergoing a lower limb amputation from January 2002 to December 2003. Serial arterial segments were taken from the femoral, popliteal, anterior tibial, posterior tibial, peroneal, and dorsalis pedis arteries, and the degrees of atherosclerotic stenosis and medial calcification were histologically quantified. RESULTS: Atherosclerosis was associated with severe arterial stenosis. An increased occurrence of severe atherosclerotic narrowing coincided with increasing patient age (p = 0.0166), hypertension (p = 0.0019), and diabetes mellitus (p = 0.0036). The presence of medial calcification was an important pathological feature in patients under 70 years of age (p = 0.0308) and significantly more severe in those with diabetes mellitus (p<0.001). CONCLUSION: Atherosclerosis and medial calcification are significant underlying lesions in diabetic patients undergoing lower limb amputation. Medial calcification can cause significant stiffening of the arterial wall and a reduction in its ability to respond to vasodilator stimuli. PMID- 18446630 TI - Clonal status of fibrous dysplasia. AB - AIM: The purpose of this study was to elucidate the clonality of fibrous dysplasia based on X-chromosome inactivation mosaicism and polymorphism in female somatic cells at the phosphoglycerate kinase (PGK) and androgen receptor (AR) loci using microdissection technology. MATERIALS AND METHODS: Nine patients with fibrous dysplasia were examined using clonality assays based on X-chromosome inactivation mosaicism. Lesions and surrounding soft tissues were microdissected from paraffin sections, and genomic DNA was extracted, pretreated with Hpa II or Hha I, and the PGK and AR genes were amplified by nested PCR. The single nucleotide polymorphism (SNP) at the PGK locus was identified by incubation with Bst XI and agarose gel electrophoresis. The CAG repeat length polymorphism at the AR locus was revealed on denaturing polyacrylamide gels and visualised by silver staining. RESULT: Microscopically, typical histological characteristics were seen in each sample. Lesions consisted of varying proportions of fibrous tissue and immature trabecular bone. Tissue consisted of collagenous fibres and fish-hook or comma-shaped trabecular bone without rows of cuboidal appositional osteoblasts on the surface. Restriction fragment length polymorphism (RFLP) of AR was found in seven of nine cases. The results of clonality assays demonstrated that seven cases of fibrous dysplasia were monoclonal, suggesting that they are neoplastic lesions. CONCLUSION: We conclude that fibrous dysplasia may not be a hyperplastic lesion, but a neoplastic lesion. Additional studies with larger sample sizes will be needed to conclusively prove our hypothesis. PMID- 18446631 TI - Juvenile nasopharyngeal angiofibroma: an immunohistochemical characterisation of the stromal cell. AB - AIMS: Juvenile nasopharyngeal angiofibroma (JNA) is a rare tumour occurring almost exclusively in young adult males. Although histologically benign, it can be locally aggressive with a significant recurrence rate. The finding of activating beta-catenin gene mutations in the stromal cells indicates these are the neoplastic cells and supports the association of JNA and familial adenomatous polyposis (FAP). Previous immunohistochemical studies have demonstrated a null or focal myoepithelial immunophenotype in the stromal cells. Recently, expression of several growth factors and oncoproteins including CD117 (c-kit) in the stromal cells has been demonstrated. Our objective is to evaluate the immunohistochemical phenotype of the stromal cell of JNA, particularly within the proliferative zone of the tumour, by application of antibodies against MNF116, CAM5.2, S-100, CD31, CD34, CD99, CD68, vimentin, EMA, SMA, desmin, calponin, Bcl-2 and (CD117) c-kit in a series of 54 cases. METHODS: A routine immunohistochemical protocol was applied to representative paraffin sections of 54 JNAs collected from the Port Moresby General Hospital, Papua New Guinea, and Princess Alexandra and Royal Brisbane Hospitals, Queensland, Australia. Immunoexpression of each antigen was assessed in the stromal cells and the vessels. RESULTS: The majority of stromal cells in more than half of the cases demonstrated no staining with any of the 14 antibodies other than vimentin. Of 54 cases, 22 contained a microvascular component (usually peripherally located and indicating the active growth front of the tumour) in which the stromal cells demonstrated a hybrid immunophenotype with both smooth muscle and endothelial differentiation. c-kit was negative in all cases. CONCLUSIONS: The majority of stromal cells have an undifferentiated immunophenotype with no evidence of epithelial, myoid, endothelial or other lineage specific differentiation. In the microvascular component the stromal cells appear able to show smooth muscle or endothelial differentiation. No c-kit expression was identified. PMID- 18446632 TI - Partial and severe factor XI deficiency in South Australia and the usefulness of factor XI mutation analysis for diagnosis. AB - AIMS: To correlate the presence or absence of a factor XI gene mutation with factor XI activity in patients with severe or partial reduction in factor XI. METHODS: Patients previously found to have reduced factor XI levels were recalled for repeat testing and factor XI genetic analysis. Also, during the 18 month study period, any routine patient found to have an isolated reduced or low normal factor XI level had factor XI genetic analysis. RESULTS: Twenty-two cases were studied and 11 with factor XI from <2 to 57 U/dL (reference 55-130 U/dL), were found to have a factor XI gene mutation. Gene sequencing identified 15 different mutations, with four patients found to be compound heterozygotes. One patient with no bleeding history had a novel polymorphism which family studies showed was not associated with his low factor XI. No factor XI gene abnormality was detected in 10 patients and they have either acquired causes of deficiency or factor XI levels in the lower portion of the normal range. CONCLUSION: Genetic analysis of the factor XI gene is important to confirm or exclude inherited causes of factor XI deficiency, especially when the reduction is mild. PMID- 18446633 TI - Test and Teach. Abnormal glands in the uterine cervix Part 1. Diagnosis: Ectopic prostate tissue in the uterine cervix. PMID- 18446634 TI - First Australian description of Eggerthella lenta bacteraemia identified by 16S rRNA gene sequencing. PMID- 18446635 TI - A case of acute necrotising eosinophilic myocarditis with an associated raised myoplasma serology: an incidental finding or a causal association? PMID- 18446636 TI - Adenoid cystic breast carcinoma: a salivary gland-type tumour with excellent prognosis and implications for management. PMID- 18446637 TI - Oncocytic epithelial-myoepithelial carcinoma: an evolving new variant with comparative immunohistochemistry. PMID- 18446638 TI - Aggressive psammomatoid ossifying fibroma (APOF): two cases with short review. PMID- 18446639 TI - Disappearing bones: a case of Gorham-Stout disease. PMID- 18446640 TI - Acute neutropenic diverticulitis: a case report. PMID- 18446641 TI - Eruptive haemangioma associated with HIV therapy and mitochondrial pathology. PMID- 18446642 TI - Bilateral adrenal haemangioblastoma in a patient with von Hippel-Lindau disease. PMID- 18446643 TI - Malignant salivary gland-type mixed tumour of the kidney. PMID- 18446644 TI - The use of immunohistochemistry in the diagnosis of primary salivary duct carcinoma: three case reports. PMID- 18446645 TI - Re: Acceptability of CoaguChek S and CoaguChek XS generated international normalised ratios against a laboratory standard in a paediatric setting. PMID- 18446647 TI - Proteins involved in meiotic recombination: a role in male infertility? AB - Meiotic recombination results in the formation of crossovers, by which genetic information is exchanged between homologous chromosomes during prophase I of meiosis. Recombination is a complex process involving many proteins. Alterations in the genes involved in recombination may result in infertility. Molecular studies have improved our understanding of the roles and mechanisms of the proteins and protein complexes involved in recombination, some of which have function in mitotic cells as well as meiotic cells. Human gene sequencing studies have been performed for some of these genes and have provided further information on the phenotypes observed in some infertile individuals. However, further studies are needed to help elucidate the particular role(s) of a given protein and to increase our understanding of these protein systems. This review will focus on our current understanding of proteins involved in meiotic recombination from a genomic perspective, summarizing our current understanding of known mutations and single nucleotide polymorphisms that may affect male fertility by altering meiotic recombination. PMID- 18446648 TI - Lipid peroxidation in human spermatozoa from men with genitourinary infections. AB - A fluorescent assay was used to reveal the presence of lipid peroxidation (LPO) in spermatozoa from individuals with genitourinary infections (GI). The incidence of LPO was compared with sperm pathologies (apoptosis, immaturity, necrosis) evaluated by transmission electron microscopy (TEM) and motility. A C11 BODIPY(581/591) probe was used to detect and localize LPO in sperm from 34 individuals. The sperm morphological characteristics were studied by TEM and the results were mathematically assessed. Using the LPO percentage we divided the patients into four groups. Group 1 included ten patients with GI with almost normal progressive motility, a very low percentage of LPO and sperm pathology values that were not far from the standard ranges. Group 2 had eleven infected patients showing reduced motility, LPO of 10 to 20% and sperm pathologies that were just out of normal range. Group 3 included 6 infected patients with progressive motility < or =22%, low levels of LPO with a higher percentage of apoptosis and necrosis. Group 4 had 7 patients showing normal semen parameters, without GI, LPO ranged from 0% to 1% and a normal incidence of sperm pathologies. In all groups, LPO was inversely correlated with sperm motility and directly correlated with low semen quality. However, the LPO percentage was low in Group 3, in which sperm necrosis, concomitant with GI, was the predominant pathology. C11-BODIPY(581/591) is a useful labeling method for quantifying and localizing LPO in spermatozoa from patients with GI. The detection of LPO could be questionable in cases of sperm necrosis because in this pathology the plasma membrane is often disrupted and the lipidic probe is unable to intercalate within the phospholipidic bilayer. PMID- 18446649 TI - Evaluation of effects of methamphetamine repeated dosing on proliferation and apoptosis of rat germ cells. AB - Methamphetamine (MAMP) is a central nervous system stimulant that is increasingly abused especially by teenagers and young adults, a group in its reproductive age. MAMP effects on the male reproductive system are not clear. In this experimental study, we evaluated the effects of MAMP administration on proliferation and apoptosis in seminiferous tubules of rat testis. Methamphetamine hydrochloride was synthesized by iodination of norephedrine hydrochloride and reduction to methamphetamine. Mature male rats were randomly divided into four groups (n=7) and were injected intraperitoneally with MAMP (1, 5 or 10 mg/kg) or saline at the same time, once daily for 14 consecutive days. Twenty four hs after the last injection, perfused testis were fixed, sectioned and stained by TUNEL labeling or proliferating cell nuclear antigen (PCNA) immunostaining. Apoptotis and proliferation indices were calculated and ratios of proliferation/apoptosis in the seminiferous tubules were obtained. Cell proliferation and the ratio of proliferation to apoptosis decreased significantly in all experimental groups compared to the control group. Conversely, apoptosis was increased in these groups. Such differences were observed in both spermatogonia and primary spermatocytes. In the control group, more than 95% of spermatogonia were PCNA positive. However, 10 mg/kg of MAMP caused a reduction to approximately 75% PCNA staining in spermatogonia. In some tubules of the experimental groups, more than 10 TUNEL-positive germ cells were seen, although in the control group, the tubules with 3 TUNEL-positive germ cells were rarely observed and the majority of tubules were without such cells. There were significant differences in the indices between the 1 mg/kg group and the higher dose groups, but there was no such difference between the 5 mg/kg and 10 mg/kg groups. In some tubules of the experimental groups, significant gaps in the epithelium between the spermatogonia layer and other cell layers were observed. These results show that repeated administration of MAMP, especially at higher doses, may cause a decrease in cellular proliferation, induce apoptosis and change the proliferation/apoptosis ratio in testis. This might explain the MAMP effect on the spermatogenesis process. It is suggested that studies on the consequence of MAMP consumption on male fertility is warranted. PMID- 18446650 TI - The KLAB Toolbox: a suite of in-house software applications for epigenetic analysis. AB - Systems biology presents a new paradigm for elucidating the processes required to organize and sustain life. We now have access to whole genome sequences, gene expression data for multiple cell types, and databases for regulatory elements governing these genes. These resources make it feasible to identify conserved genomic sequences across multiple species, transcription factors regulating the expression of genes with similar expression patterns within a given cell type and to compare expression levels of specific genes between normal and diseased cellular states. In order to utilize this wealth of information, new computational tools that integrate these datasets in a genome-wide context are required. Using the protamine cluster as an example, we present a series of in house applications that we have developed to integrate, contextualize and visualize datasets across multiple hierarchies. PMID- 18446653 TI - Recurrence of preterm birth in twin pregnancies in the presence of a prior singleton preterm birth. AB - OBJECTIVE: We examined recurrence of preterm birth in twin pregnancy in the presence of a previous singleton preterm pregnancy, and assessed if these recurrence risks differed for medically indicated and spontaneous preterm birth. METHODS: A retrospective cohort study was designed using the maternally-linked data of women who delivered a first singleton live birth followed by a twin birth in the second pregnancy (n = 2329) in Missouri (1989--97). We examined preterm birth recurrence at <37 in the second twin pregnancy among women with a prior singleton preterm birth. Recurrence risks were based on hazard ratios (HR) and 95% confidence intervals (CI) estimated from Cox proportional hazards models after adjusting for potential confounders. RESULTS: Preterm birth rates in the second twin pregnancy were 69.0% and 49.9% among women who had a previous preterm and term singleton birth, respectively (HR 1.8, 95% CI 1.6-2.1). The preterm birth rate in the second pregnancy was about 95% when the first singleton pregnancy ended at <30 weeks. Women delivering preterm following a medical intervention in the first pregnancy had increased recurrence for both spontaneous (HR 1.4, 95% CI 1.1-2.0) and indicated (HR 2.4, 95% CI 1.8-3.2) preterm birth; similarly among women with a prior spontaneous preterm birth, hazard ratios were 1.8 (95% CI 1.5-2.1) and 1.6 (95% CI 1.3-1.9), for spontaneous and indicated preterm birth in the second twin pregnancy, respectively. CONCLUSIONS: Women with a singleton preterm birth carry increased risk of preterm birth in the subsequent twin pregnancy. A history of a singleton preterm birth has an independent and additive contribution to risk of preterm birth in the subsequent twin gestation. PMID- 18446652 TI - The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age. AB - INTRODUCTION: An imbalance between angiogenic and anti-angiogenic factors has been proposed as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well as lower plasma concentrations of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters are associated with a high risk for the subsequent development of PE and/or delivery of an SGA neonate. METHODS: This longitudinal case-control study included 402 singleton pregnancies in the following groups: (1) normal pregnancies with appropriate for gestational age (AGA) neonates (n = 201); (2) patients who delivered an SGA neonate (n = 145); and (3) patients who developed PE (n = 56). Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. In this study, we included two samples per patient: (1) first sample obtained between 6 and 15 weeks of gestation ('first trimester' sample), and (2) second sample obtained between 20 and 25 weeks of gestation ('second trimester' sample). Plasma concentrations of s-Eng, sVEGFR-1, and PlGF were determined by specific and sensitive immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related factors were compared among normal patients and those destined to develop PE or deliver an SGA neonate while adjusting for maternal age, nulliparity, and body mass index. General linear models and polytomous logistic regression models were used to relate the analyte concentrations, ratios, and product to the subsequent development of PE and SGA. RESULTS: (1) An increase in the maternal plasma concentration of s-Eng between the first and second trimesters conferred risk for the development of preterm PE and SGA (OR 14.9, 95% CI 4.9-45.0 and OR 2.9, 95% CI 1.5-5.6, respectively). (2) An increase in the maternal plasma concentration of sVEGFR-1 between the first and second trimester conferred risk for the development of preterm PE (OR 3.9, 95% CI 1.2-12.6). (3) A subnormal increase in maternal plasma PlGF concentration between the first and the second trimester was a risk factor for the subsequent development of preterm and term PE (OR 4.3, 95% CI 1.2-15.5 and OR 2.7, 95% CI 1.2-5.9, respectively). (4) In addition, the combination of the three analytes into a pro-angiogenic versus anti-angiogenic ratio (PlGF/(s-Eng x VEGFR-1)) conferred risk for the subsequent development of preterm PE (OR 3.7, 95% CI 1.1-12.1). (5) Importantly, patients with a high change in the s-Eng x sVEGFR-1 product had an OR of 10.4 (95% CI 3.2-33.8) for the development of preterm PE and 1.6 (95% CI 1.0-2.6) for the development of SGA. CONCLUSIONS: Changes in the maternal plasma concentrations of s-Eng, sVEGFR 1, PlGF or their ratios between the first and second trimesters of pregnancy confer an increased risk to deliver an SGA neonate and/or develop PE. PMID- 18446655 TI - The role of continuous fetal monitoring in the management of preterm premature rupture of membranes. AB - OBJECTIVE: Continuous fetal monitoring (CFM) is often used in the management of preterm premature rupture of membranes (PPROM) but there is little evidence to support this approach. The objective of this study was to evaluate the clinical outcome of PPROM when managed by CFM. METHODS: A retrospective review was conducted of 129 cases PPROM outcomes for the period January 1, 1998 to December 31, 2003. All women underwent CFM. Delivery was carried out for non-reassuring fetal testing, vaginal bleeding, evidence of infection, positive vaginal pool phosphatidylglycerol when available, and spontaneous labor. RESULTS: Delivery was carried out because of an abnormal fetal heart tracing in 15 women (11.7%). The mean gestational age at admission was 32.2 weeks (95% CI 31.7-32.7), the mean gestational age at delivery was 32.7 weeks (95% CI 32.2-33.1), and the mean latency period was 3.3 days (95% CI 1.5-5.0). Gestational age at rupture of membranes was inversely correlated with latency period (n = 128, r = -0.372, p < 0.001). With regard to gestational age, gravidity, and latency period there was no significant difference noted with respect to why the subjects delivered. No intrauterine deaths occurred in the study. CONCLUSION: In our series, fetal heart rate tracing abnormalities were the indication for delivery in a small but significant percentage of conservatively managed PPROM cases. Our review suggests that a prospective trial of CFM versus intermittent monitoring techniques should be carried out. PMID- 18446656 TI - Comparison of three neonatal pain scales during minor painful procedures. AB - OBJECTIVE: There is no single or widely accepted method to define pain in neonates. The aim of this study was to compare three different neonatal pain scales in the estimation of the pain response to minor painful stimuli in healthy term neonates. METHOD: Thirty healthy neonates were included in the study. Video recordings of infants during heel prick blood sampling were evaluated by two observers according to the Neonatal Infant Pain Scale (NIPS), the Neonatal Facial Coding System (NFCS), and the Douleur Aigue du Nouveau-ne (DAN). Crying times of infants were recorded, and the correlation between the three pain scales and crying time was calculated. The pain scores and inter-observer variability were analyzed. RESULTS: The highest correlation between the crying time and each of the three different neonatal pain scales was found for NIPS (r = 0.74, p<0.001), while similar results were found for the DAN scale (r = 0.67, p <0.001) and the NFCS (r = 0.67, p<0.001). Inter-observer variability was similar for the three scales (NFCS r = 0.95; DAN r = 0.97; NIPS r = 0.96). NFCS had a coefficient of variation (CV) of 59.8 +/- 32.2%. The DAN scale and NIPS had similar CV values (41.5 +/- 26.1% and 43.2 +/- 31.6%, respectively), but these values were significantly lower than that of NFCS. CONCLUSION: All three scales provided comparable results, with a slight difference favoring NIPS. Therefore, NIPS can be used to evaluate pain during minor painful procedures in neonates. PMID- 18446657 TI - A comparison of lispro and regular insulin for the management of type 1 and type 2 diabetes in pregnancy. AB - OBJECTIVE: To describe perinatal outcomes of women with pregestational diabetes treated with short-acting, regular insulin and the short-acting insulin analogue, lispro. STUDY DESIGN: This was a prospective observational study of women with pregestational diabetes maintained on short-acting insulin regimens over a 3-year period. Clinical characteristics, aspects of diabetic therapy, and perinatal/neonatal outcomes were collected. RESULTS: Of 107 women, 49 were maintained on regular insulin and 58 utilized the insulin analogue, lispro. Frequency of type 1 diabetes, maternal age, overweight/obese pregravid body mass index (> or =25 kg/m2), preexisting hypertension, and presence of vascular disease were similar between groups. Women treated with lispro had a longer duration of diabetes (11.4 vs. 8.3 years, p = 0.04). Glycemic control was improved in women managed with lispro compared to regular insulin (HgbA1c 5.9 vs. 6.7, p = 0.009). Total insulin requirements were lower in the lispro group in the first (0.58 vs. 0.79 units/kg, p = 0.02), second (0.75 vs. 1.10 units/kg, p = 0.002), and third (0.98 vs. 1.25 units/kg, p = 0.03) trimesters of pregnancy. Mean infant birth weight was greater in the lispro group, whereas the rate of large for gestational age infants and ponderal indices were similar between groups. Malformation rate, gestational age at delivery, neonatal intensive care unit admission, neonatal length of stay, rates of respiratory distress syndrome, and hypoglycemia were similar. CONCLUSIONS: Women treated with lispro demonstrated improved glycemic control and lower total insulin requirements during pregnancy compared to those receiving regular insulin. Perinatal outcomes were similar between women treated with both types of insulin. PMID- 18446654 TI - Insulin-like growth factor-binding protein-1 (IGFBP-1) in cervical secretions as a predictor of preterm delivery. AB - OBJECTIVE: The objective of this study was to investigate the level of insulin like growth factor-binding protein-1 (IGFBP-1) in cervical secretions and Bishop score as predictors of preterm delivery in asymptomatic pregnant women. METHODS: This was a prospective study at the Clinic for Gynecology and Obstetrics at the University Clinical Center in Tuzla, on a sample of 80 healthy pregnant women at between 24 and 34 gestational weeks. After interview every woman underwent IGFBP 1 concentration measurement by the 'Actim Partus' test. The Bishop score was determined by the author (A.L) during vaginal examination. Rates among groups were compared using arithmetic mean and standard deviation, Student's t-test, Mann-Witney U-test, and Spearman-Rank correlation test. Statistical importance was determined at the variation levels of 5% and 1%. RESULTS: Eight (10.00%) women in the study group had a positive Actim Partus test and six (7.50%) of them had a preterm delivery. The positive predictive value was 44.44% and negative predictive value was 98.59%. The specificity of the Bishop score in the study group was 83.78% and the sensitivity was 50.00%. The positive predictive value of the Bishop score in this group was 20.00% and the negative predictive value was 95.36%. There was no correlation between the Bishop score and Actim Partus test (p = 0.15). CONCLUSIONS: If the concentration of IGFBP-1 is <10 microg/L (negative Actim Partus test) in asymptomatic pregnant women, the risk of preterm delivery is low. The Actim Partus test could be used as a screening test for preterm delivery in asymptomatic pregnant women. PMID- 18446658 TI - Obstetric outcomes with a false-positive one-hour glucose challenge test by the Carpenter-Coustan criteria. AB - OBJECTIVE: Pregnancies complicated by a false-positive one-hour glucose challenge test (GCT), as determined by the National Diabetes Data Group (NDDG) criteria, have higher rates of adverse maternal and neonatal outcomes. This study was conducted to determine if pregnancies complicated by a false-positive GCT, as determined by the Carpenter-Coustan (CC) criteria, also have higher rates of adverse maternal and neonatal outcomes. STUDY DESIGN: In this retrospective case control study, we compared 165 patients with a false-positive GCT, as determined by the Carpenter-Coustan criteria, to a cohort of 165 pregnant controls with a normal screening GCT. Multiple variables for maternal and neonatal outcomes were compared between the two groups. RESULTS: The racial distribution and gestational age of delivery were similar in both groups. The study group had a higher one hour GCT (148.2 mg/dl vs. 95.3 mg/dl, p < 0.001), was older (27.4 yrs vs. 23.8 years, p < 0.001), was more likely to be multiparous (71.5% vs. 58.2%, p = 0.011), and had a higher BMI (26.7 kg/m2 vs. 24.6 kg/m2, p = 0.002). There were no differences between the two groups in mode of delivery, birth weight, rates of macrosomia, shoulder dystocia, antenatal death and maternal laceration. There were also no differences between the two groups in rates of preeclampsia, chorioamnionitis, endometritis, ICN admission, neonatal hypoglycemia, Erb's palsy, clavicular fracture, neonatal sepsis, neonatal death or use of phototherapy. CONCLUSION: Women with a false-positive one-hour GCT by the Carpenter-Coustan criteria do not have higher rates of adverse perinatal outcomes. Using the Carpenter-Coustan criteria to diagnose GDM appears to be superior to NDDG criteria in terms of avoiding adverse maternal and neonatal outcomes. PMID- 18446659 TI - Screening for postpartum depression with the Edinburgh Postnatal Depression Scale in an indigent population: does a directed interview improve detection rates compared with the standard self-completed questionnaire? AB - BACKGROUND: The Edinburgh Postnatal Depression Scale (EPDS) is a well-validated screening tool for the detection of patients at risk for postpartum depression. It was postulated that screening utilizing the EPDS in a directed interview would increase the detection rate compared with a self-completed EPDS in an indigent population. OBJECTIVE: To compare the results of a self-completed EPDS with those of a directed interview utilizing the EPDS in the identification of patients at increased risk for postpartum depression. METHODS: All patients undergoing a 6 week postpartum evaluation in the obstetric clinic at a community teaching hospital between November 1, 2003 and March 31, 2004 were screened for postpartum depression using the self-completed EPDS. This was followed by a directed interview, which consisted of a verbally administered EPDS by a social worker blinded to the results of the self-completed EPDS. A positive screen was defined as an EPDS score of > or =12 by either method. The number of patients with a positive screen to either the self-completed EPDS, the directed interview EPDS, or both were recorded. The two techniques were compared by the McNemar Chi-square test. The self-completed and directed interview EPDS scores were compared by Pearson's correlation coefficient to examine differences in screening techniques. Demographic data and characteristics in each group were examined. RESULTS: Among the 134 patients evaluated, 24 (17.9%) screened positively for being at an increased risk of having postpartum depression. The self-completed EPDS and the directed interview EPDS screening detection rates were not different, identifying 23 (17.2%) and 22 (16.4%) patients, respectively (p = 1.0). The use of the self completed EPDS and the directed interview EPDS in parallel detected one additional subject (0.7%; p = 0.99). The self-completed EPDS and directed interview EPDS scores correlated significantly (r = 0.94; p = 0.01). The demographics and characteristics of patients with a positive screen were not different from those with a negative screen. CONCLUSIONS: The self-completed EPDS and directed interview EPDS are equivalent screening techniques for postpartum depression. There is no evidence to suggest that parallel screening improves detection. Either technique should be incorporated into the postpartum visit to screen for postpartum depression. PMID- 18446660 TI - Comparative study on the outcome of obstetric cholestasis. AB - OBJECTIVES: The aim of this study was to determine the characteristics and outcomes of obstetric cholestasis (OC) and the significance of measuring total bile acid (TBA) to aid diagnosis. METHODS: This study was conducted over a 27 month period at a tertiary referral maternity hospital (>8000 deliveries annually). In the study period, 753 women presented with pruritus of no specific origin. This group was divided into OC (TBA > or =6 micromol/L, N=151) and idiopathic pruritus of pregnancy (TBA <6 micromol/L, N=602). The latter group served as controls. Data were collected retrospectively and analyzed using SPSS 11.4 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS: Patients were matched for age, ethnicity, parity, and smoking status, sex of baby, and Apgar scores at 1 and 5 minutes. OC was noted to be higher in twin pregnancies. Twice as many mothers in the OC group were induced compared to controls. Of the OC group, 18.0% delivered preterm versus 7.7% of controls. Of the mothers with OC, 48.3% had a TBA in the range of 11-39.9 micromol/L, 21.2% had a TBA >40 micromol/L, and the remaining 30.5% had a TBA between 6 and 10.9 micromol/L. Of the OC group with preterm delivery, all had a raised TBA >11 micromol/L. CONCLUSIONS: The presence of OC increases preterm delivery, both idiopathic and iatrogenic. Increasing induction, admission to the neonatal intensive care unit, and low birth weight were also noted. A TBA cut-off value of >11 micromol/L will more accurately aid the diagnosis of OC in the absence of raised liver function test results, reducing the over-diagnosis of this condition. PMID- 18446661 TI - Idiopathic bleeding during the second half of pregnancy as a risk factor for adverse perinatal outcome. AB - OBJECTIVE: To investigate pregnancy outcome in women suffering from idiopathic vaginal bleeding (IVB) during the second half of pregnancy. METHODS: A comparison between patients admitted to the hospital due to bleeding during the second half of pregnancy and patients without bleeding was performed. Patients lacking prenatal care as well as multiple gestations were excluded from the analysis. Stratified analyses using the Mantel-Haenszel technique and a multiple logistic regression model were performed to control for confounders. RESULTS: During the study period, 173,621 singleton deliveries occurred at our institute. Of these, 2077 (1.19%) were complicated with bleeding upon admission during the second half of pregnancy. After excluding cases with bleeding due to placental abruption, placenta previa, cervical problems, etc., 67 patients were classified as having IVB (0.038%). Independent risk factors associated with IVB, using a backward, stepwise multivariable analysis were oligohydramnios (OR=6.2; 95% CI 3.1-12.7; p < 0.001), premature rupture of membranes (OR=3.4; 95% CI 1.8-6.2; p < 0.001), intrauterine growth restriction (IUGR, OR 5.6; 95% CI 2.5-12.2; p < 0.001), and Jewish ethnicity (OR=1.9; 95% CI 1.0-3.5; p=0.036). These patients subsequently were more likely to deliver preterm (<37 weeks, 56.7% vs. 7.3%; mean gestational age of 33.6+/-5.7 weeks vs. 39.2+/-2.1 weeks; p < 0.001) and by cesarean delivery (CD, 35.8% vs. 12.1%, OR=4.0; 95% CI 2.4-6.6; p < 0.001). Higher rates of low Apgar scores (<7) at 1 and 5 minutes were noted in these patients (OR=10.3; 95% CI 5.9-17.8; p < 0.001 and OR=17.8; 95% CI 7.1-44.5; p < 0.001, respectively). Moreover, perinatal mortality rate among patients admitted due to idiopathic bleeding was significantly higher as compared to patients without bleeding (9.6% vs. 1.2%, OR=8.4; 95% CI 3.3-21.2; p < 0.001). However, when controlling for preterm delivery, using the Mantel-Haenszel technique, the association lost its significance. CONCLUSION: Idiopathic vaginal bleeding during the second half of pregnancy is a risk factor for adverse perinatal outcome, mostly due to its significant association with preterm delivery. Careful surveillance, including fetal monitoring, is suggested in these cases in order to reduce the adverse perinatal outcome. PMID- 18446662 TI - The incidence of birth trauma among live born term neonates at a referral hospital in Rafsanjan, Iran. AB - BACKGROUND: Some special problems of neonates are related to the adverse effects of delivery such as birth trauma with high mortality and morbidity. The aim of this study was to determine the incidence of birth trauma and related risk factors in a referral hospital in Rafsanjan, a city in the south of Iran. MATERIALS AND METHODS: In this cross-sectional study, we reviewed medical records of all 3340 live neonates that were born between March 2004 and March 2005 at Nicknafs maternity center. Special questionnaires of study were completed and data was analyzed. RESULTS: Among all neonates, 0.8% of them had birth trauma. The most common types of trauma were cephalohematoma 37.03%, massive hematoma 37.03%, and clavicular fracture 11.2%. The incidence of brachial plexus injury and clavicular fracture was higher in macrosomic neonates, whereas cephalhematoma, skin injury and massive hematoma were more prevalent in microsomic neonates. Neonatal birth trauma was more frequent in vaginal delivery than cesarean section (1.3% vs 0.1%, p = 0.0001). However, the incidence of birth trauma in instrumental delivery and normal vaginal delivery were similar (2.8% vs 1.3%, p = 0.303). CONCLUSION: The incidence of birth trauma in this region is 0.8% and birthweight and normal vaginal delivery are strong predictors for birth injuries. PMID- 18446663 TI - Complete hydatidiform mole with co-existing healthy fetus: a case report. AB - A twin pregnancy is described consisting of a complete hydatiform mole (CHM) with coexisting healthy fetus. Pregnancy occurred after IVF-ICSI. The couple wished to continue the pregnancy and a decision to accept was taken after having consulted the available literature, but at 18 weeks gestation pregnancy termination was inevitable for severe vaginal bleeding. A rising HCG, 25 days after the curettage made methotrexate treatment necessary and 24 months later there is no evidence of disease. PMID- 18446664 TI - Differentiating undifferentiated and poorly differentiated sarcomas--a multidisciplinary approach: the 2007 Society for Ultrastructural Pathology companion meeting. PMID- 18446665 TI - Undifferentiated sarcomas: what to do? And does it matter? A surgical pathology perspective. PMID- 18446666 TI - Molecular profiling in the diagnosis and treatment of high grade sarcomas. AB - High-density microarrays are used to measure in a comprehensive manner large scale ("profile") gene expression patterns (when tumor RNA is tested) or gene copy number changes (when tumor genomic DNA is tested). Microarray-based studies are increasingly useful in addressing a wide variety of questions in sarcoma biology. This review includes a brief description of the microarray methodology and data analysis, followed by few examples of the recent applications of gene expression in the diagnosis, classification, and treatment of sarcomas. PMID- 18446668 TI - Recognizing hidden phenotypes in sarcomas through the electron microscope. AB - Differentiation along a distinct cell lineage can be identified either morphologically or with the adjunct of different ancillary techniques. While immunohistochemistry has progressively supplanted electron microscopy as the method of choice to characterize the phenotype of neoplastic cells in soft tissue tumors and in solving most differential diagnoses, a number of lesions still lack reliable specific markers or show overlapping antigen expression, which can be categorized by ultrastructural analysis through the recognition of submicroscopic features indicative of a specific line of differentiation. This review discusses the role of electron microscopy in the identification of the phenotype of neoplastic cells in soft tissue sarcomas, with particular reference to the diagnostic aspects. Sarcomas in which the cellular phenotype that can be better recognized by electron microscopy include those belonging to the fibroblastic/myofibroblastic group, particularly those displaying a poorly differentiated/pleomorphic morphology. Occasionally, in tumors with smooth muscle, skeletal muscle, adipocytic, vascular endothelial, and Schwann cell differentiation electron microscopy may help in the differential diagnosis. PMID- 18446667 TI - Sarcoma and look-alikes: the important role of ultrastructural evaluation. AB - Due to the variable light microscopic appearance of sarcomas, a large number of neoplasms may need to be considered in the differential diagnosis in some situations. In difficult cases, the surgical pathologist must approach the differential diagnosis using ancillary diagnostic techniques and should do so in an orderly fashion, recognizing that arriving at the correct diagnosis is without a doubt the most important goal. It is also imperative to take into account the expense and time that may be involved in arriving to the definitive diagnosis, which could influence how the workup is conducted. Therefore, the most reasonable route to address the differential diagnosis in order to make a final solid diagnostic assessment should be taken. Whether immunohistochemistry, electron microscopy, cytogenetics, and/or molecular diagnostics should be employed in a given case becomes the dilemma. In some instances a combination of the above mentioned techniques is important not only to obtain an unequivocal diagnosis, but also to provide important additional information regarding prognosis and to facilitate the patient's management. PMID- 18446669 TI - Contribution of cytogenetics to the management of poorly differentiated sarcomas. AB - Sarcomas constitute a heterogeneous group of rare tumors that in recent years have been shown by cytogenetic analysis to have a remarkably high incidence of specific and primary alterations. These genetic alterations not only have guided molecular studies in establishing the underlying genes involved, thereby yielding important pathogenetic information, but have also provided clinicians with a valuable tool to add to their diagnostic armamentarium. The addition of molecular cytogenetic (fluorescence in situ hybridization [FISH]) and molecular approaches (reverse transcriptase-polymerase chain reaction [RT-PCR]) has further enhanced the sensitivity and accuracy of detecting nonrandom chromosomal imbalances and/or structural rearrangements in sarcomas, including assessment in formalin-fixed, paraffin-embedded tissues. Poorly differentiated sarcomas represent a significant challenge to the pathologist as these neoplasms lack an identifiable hematoxylin and eosin-stained phenotype and often have lost diagnostic immunohistochemical or ultrastructural features as well. In contrast, primary cytogenetic changes and associated molecular events such as the 11;22 translocation in Ewing sarcoma are retained as a given tumor metastasizes or becomes less differentiated, as their presence appears to be vital for sustaining neoplastic transformation. Consequently, demonstration of characteristic, tumor-specific chromosomal aberrations is especially useful in the management of poorly differentiated sarcomas. PMID- 18446671 TI - Constituents from Hoya parasitica and their cell growth inhibitory activity. AB - An androstanoid, hoyasterone (1), a sesquiterpene, 15-bulnesolic acid (2), and a phenolic compound, 1-(4-hydroxy-3-methoxyphenyl)-1-methoxypropan-2-ol (3), together with a known triterpene, dihydrocanaric acid, were isolated from Hoya parasitica. Structures were elucidated by 1 D and 2 D NMR and mass spectroscopic analysis. Among the isolated compounds, only dihydrocanaric acid exhibited growth inhibitory activity against both HeLa and SW480 cells. PMID- 18446673 TI - Phytochemicals for bacterial resistance--strengths, weaknesses and opportunities. AB - This review covers some of the opportunities which currently exist to exploit plants for their natural products as templates for new antibacterial substances. This is a timely exercise given the continuing and developing problems of bacterial resistance, and in particular multidrug-resistance (MDR). Some of the challenges which are evident with bacterial resistance will be described and the strengths and weaknesses of plant natural products are highlighted. Opportunities to characterise antibacterial compounds from several key taxa are described with activity against methicillin-resistant STAPHYLOCOCCUS AUREUS (MRSA), MDR variants of this species and MYCOBACTERIUM TUBERCULOSIS (MTB). These pathogens continue to cause problems in terms of their eradication and spread and MTB strains which are extremely-drug resistant (XDR) promise to afford an additional challenge for clinicians. The review also covers plant natural products that modulate or modify bacterial resistance. Specific examples include plant-derived efflux pump inhibitors (EPIs) which inhibit bacterial antibiotic efflux mechanisms that are problematic due to their broadness in substrate specificity. A summary on future trends and directions in this fruitful and interesting area is also given. PMID- 18446672 TI - Radioprotective effects of Gentianella austriaca fractions and polyphenolic constituents in human lymphocytes. AB - The aim of this study was to identify active principles of Gentianella austriaca responsible for the reduction of the incidence of micronuclei in irradiated lymphocytes in vitro. The radioprotective effects of ether (EF) and methanolic (MeF) fractions, water-soluble xanthones demethylbellidifolin (1), demethylbellidifolin 8-O-glucoside (2), bellidifolin 8-O-glucoside (3), and flavonoid swertisin (4) against chromosomal damage induced by gamma-rays were determined using the micronucleus test. EF and MeF showed better protection in treatment of human lymphocytes after gamma-irradiation than did isolated compounds. Among the isolated compounds, the effectiveness in reduction of the frequency of micronuclei followed the order 4>3>2>1. The anti-lipoperoxidant activity was in the order 2>4>1, while 3 slightly increased the level of malondialdehyde. In addition, the effectiveness in induction of apoptosis followed the order, 3>2>4, while 1 had no proapoptotic effect. These results suggest that the antioxidative properties of the polyphenols tested may contribute to the radioprotective effects of G. austriaca. PMID- 18446674 TI - Resveratrol from red grapes - pedestrian polyphenol or useful anticancer agent? AB - Resveratrol is a phytoalexin with cancer chemopreventive properties in preclinical models of carcinogenesis. The mechanisms via which resveratrol is thought to exert chemopreventive efficacy are inhibition of cyclooxygenase enzymes, inhibition of angiogenesis, modulation of drug metabolising enzymes, antioxidation and alterations of cell cycle components and apoptotic machinery. Pharmacokinetic evidence in rodents and humans suggests that the bioavailability of resveratrol is very low and that resveratrol conjugates are the major circulating agent-derived species. The recent realisation that resveratrol can mimic caloric restriction in several species has generated a lot of interest. Attempts to design analogues with the aim of optimising resveratrol pharmacology have furnished stilbenes with different aryl subtituents, e. g., methoxy instead of hydroxy. Some of these derivatives possess more potent pharmacological properties than the lead compound. More work is required to elucidate the role of metabolites in the pharmacological activity of resveratrol. PMID- 18446675 TI - [Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in patients in long-term care in hospitals, rehabilitation centers and nursing homes of a rural district in Germany]. AB - BACKGROUND: In recent years multi-resistant pathogens, particularly methicillin resistant Staphylococcus aureus (MRSA) have been causing increasing problems in hospitals and nursing homes. In Germany area-wide and interdisciplinary studies of prevalence of MRSA have not previously been conducted. For this reason we investigated the its prevalence in a cross-sectional study, which included patients in hospitals, rehabilitation centers and nursing homes in a rural district in Germany. METHODS AND PATIENTS: The MRSA prevalence was determined by obtaining cultures from the nose, throat and any existing skin lesions of each patient in medical institutions and nursing homes in the the Hoxter district. The presence of methicillin resistance, Panton-Valentine leukocidin (PVL) gene were determined and and staphylococcal protein A (spa) typing was done. Potential risk factors for MRSA colonization were also determined. RESULTS: S. aureus was isolated from 319 of 1 083 patients (614 females, 469 males; median age 68,2 years) from five hospitals, five nursing homes und three rehabilitation centers. The MRSA prevalence was 2,5% (95% confidence interval (CI) 1,7-3,7%). In hospitals the MRSA prevalence was 3,4%, in the nursing homes 2,3% and in rehabilitation centers 1,2%, without any significant difference between these three establishments. The proportion of MRSA in all S. aureus isolates was 8,5%. The PVL gene was not detected. It was found by multivariate analysis that variables independently associated with evidence of MRSA were haemodialysis (odds ratio (OR) 11,2; 95% CI 1,9-67,4) and an acute infection in the six months before hospital admission (OR 6,5; 95% CI 1,5-29,2). The spa typing showed different regional distribution of the MRSA subtypes. With 30% the spa type t003 (ST225 clone; in Germany called "Rhine-Hessen strain") occurred most frequently, followed by t032 with 22,2% (ST22 clone, also called "Barnimer strain"). CONCLUSIONS: This first regional cross-sectional study provides supportive data for MRSA surveillance in Germany and the data provide a basis for additional preventative measures. PMID- 18446676 TI - [Factitious disorder--fever and delayed wound healing]. AB - HISTORY AND ADMISSION FINDINGS: A 23-year-old woman was admitted to the department of rheumatology for detailed diagnostic tests for a suspected immune deficiency. Over the past 3 years, she has had repeated unexplained febrile episodes and impaired wound healing, which required permanent antibiotic treatment. INVESTIGATIONS AND DIAGNOSIS: Extensive tests initially showed no definitively diagnostic findings. Based on various clinical and inconsistencies in biochemic tests, the suspicion of a self-inflicted cause increased. In several interviews with a psychologist of the psychosomatic consultation service, the patient finally admitted manipulation by means of i. v. application of bacterially contaminated water. THERAPY AND CLINICAL COURSE: The self-inflicted injuries were interpreted as the consequence of a serious psychological trauma, as well as a self-healing attempt to prevent an emotional breakdown. The trust which the patient developed in her specialist carers after admitting the deception, made it possible to motivate her to continue psychotherapy. CONCLUSION: If a factitious disorder is suspected, the doctor should not be too precipitous in confronting the patient without expression of empathy, but rather respect the self-inflicted injury as a measure of self-preservation. Such non confrontational behavior on the part of the carer enables the patient to accept the offer of psychotherapy without losing face. PMID- 18446678 TI - [Sigmoid colon diverticular empyema]. PMID- 18446679 TI - [Pulmonary arterial hypertension]. PMID- 18446680 TI - [Treatment of adult men with congenital adrenal hyperplasia syndrome due to 21 hydroxylase deficiency]. AB - Information about the treatment of males with congenital adrenal hyperplasia (CAH) is scarce and there are no therapeutical guidelines. The aim of this review is to provide a survey of the current data. An extensive literature research was performed in PubMed for relevant articles published in the last ten years. The aim in the treatment of adult male CAH patients is preservation of fertility, prevention of an addisonian crisis, blood pressure management, prevention of testicular adrenal rest tumors (TART), maintaining well-being and good quality of life, satisfactory sexual function and prevention of long-term side effects of gluco- and mineralocorticoid therapy. The change from paediatric to adult medicine should be handled in a transition outpatient clinic organized by paediatric and adult endocrinologists. Most studies have included only small numbers of patients. The steroid therapy is usually orientated on an individual basis; but, general guidelines are lacking. It is reported that fertility is often impaired and related to the occurrence of TART. Some of these tumors are responsive to altered glucocorticoid therapy. However, glucocorticoid-resistant TART have been described, and testis-sparing surgery seems to be a treatment option. A future system of regular follow-up visits and standardized therapy guidelines are essential to provide a better medical care and a higher quality of life for male patients with CAH. PMID- 18446681 TI - [Requirements for an internal hospital emergency management system]. PMID- 18446682 TI - Use of flap based on anterior tibial artery for free transfer. AB - Free flap transfer can be a challenge because of the risk of anastomotic failure, especially in microvascular tissue transfers. Free lateral crural flap based on the anterior tibial artery has good vascular condition that results in a low rate of failure. To avoid loss of the anterior tibial artery of the donor, we reconstructed the anterior tibial artery after the flap was harvested with a "half-half" technique in a simple way. Ten patients underwent this type of flap transfer and succedent artery reconstruction. All flaps survived. In no case was a subsequent anastomosis thrombosis operation required. Donor site morbidities were negligible. By contrast, the vessels of the free lateral crural flap were in better condition than that of other flaps. The flap can be used reliably and successfully without loss of the major artery trunk. We believe that the flap has special characteristics that may be useful in selected instances. PMID- 18446683 TI - A single-stage reconstruction of a complex Achilles wound with modified free composite lateral arm flap. AB - Composite defect of the posterior aspect of the heel, including the Achilles tendon, usually is very difficult to reconstruct as we face the problems of controlling infection, resurfacing the deficient skin defect, and restoring plantar flexion. With the latest advances in microsurgery, several free composite flaps have been used to reconstruct the defect in the Achilles tendon region to achieve stable and functional soft tissue coverage. We report such a single-stage reconstruction of a complex Achilles wound using the modified neurosensory lateral arm free flap including the triceps tendon strip and the posterior cutaneous nerve. Authors' rolled-up triceps tendon strip method is presented for the one-stage reconstruction of the Achilles tendon and soft tissue defect, providing good contour, strong tension, and protective sensation. The follow-up has proved a satisfactory outcome. PMID- 18446684 TI - The vascular pedicle of the anterolateral thigh flap as an alternative recipient site for thigh free flaps. AB - The indications for a free flap for thigh defects are relatively uncommon. Regardless, a reasonable recipient site will always be of paramount importance. The major femoral vessels, usually accessed via the medial thigh, would be a conventional selection. If these are at risk within the zone of injury, or if the defect is more lateral, the descending branch of the lateral circumflex femoral vessels might be a more suitable alternative. The surgical approach is virtually identical to that used to raise the familiar anterolateral thigh flap, where in a similar fashion a long pedicle of large caliber can be obtained to simplify end to-end microanastomoses. This has proven to be an invaluable resource as demonstrated in two clinical cases. PMID- 18446685 TI - Adrenocortical dysfunction in obesity and the metabolic syndrome. AB - Recently, it has become evident that the adrenals play a key role in obesity as well as in the metabolic syndrome and their complications. On the one hand, adrenal steroids are involved in physiological regulation of adipose tissue and energy homeostasis and in the pathogenesis of cardiometabolic complications. On the other hand, fat cell-derived factors, adipocytokines, and lipids released from adipose tissue are involved in the modulation of adrenal steroidogenesis. Aldosterone plasma levels are elevated in obesity and in patients with the metabolic syndrome. Recent research has provided evidence that adipocytes secrete factors that stimulate adrenal mineralocorticoid release and sensitize the adrenal cortex to angiotensin II. PMID- 18446686 TI - Circulating pro- and anti-inflammatory cytokines in Polish women with gestational diabetes. AB - In this study we measured serum concentrations of proinflammatory interleukin-6, interleukin-8, and interleukin-18 as well as anti-inflammatory interleukin-10 in 30 pregnant women with normal glucose tolerance, in 32 women with abnormal results of a 50-g glucose challenge test, and in 57 patients with gestational diabetes mellitus. Patients with gestational diabetes had significantly higher IL 6 (median 1.0 [0.7-1.5] vs. 0.7 [0.4-0.8] pg/ml, p=0.001), IL-8 (2.1 [1.1-4.2] pg/ml vs. 0.7 [0.4-0.9] pg/ml, p<0.0001), and IL-18 (249.3 [188.5-318.7] pg/ml vs. 186.7 [139.9-243.9] pg/ml, p=0.005) as well as lower IL-10 levels than healthy pregnant women (0.6 [0.5-1.5] pg/ml vs. 2.9 [1.8-3.2] pg/ml, p<0.0001). After adjusting for glucose, insulin, and BMI values, the differences in IL-8 and IL-18 became insignificant, whereas the differences in IL-6 and IL-10 levels remained highly significant (p<0.0001). The subjects with abnormal glucose challenge test results had higher IL-6 levels (0.9 [0.7-1.3] pg/ml, p=0.005) and similar levels of other cytokines as compared with the women with normal glucose tolerance. Our results suggest an impaired balance between circulating pro- and anti-inflammatory cytokines in patients with gestational diabetes; however, a significant contribution of maternal obesity to the increased levels of IL-8 and IL-18 should be underlined. PMID- 18446689 TI - [The worry-lines incision for frontal sinus surgery]. PMID- 18446690 TI - Properties of the amniotic membrane for potential use in tissue engineering. AB - An important component of tissue engineering (TE) is the supporting matrix upon which cells and tissues grow, also known as the scaffold. Scaffolds must easily integrate with host tissue and provide an excellent environment for cell growth and differentiation. Most scaffold materials are naturally derived from mammalian tissues. The amniotic membrane (AM) is considered an important potential source for scaffolding material. The AM represents the innermost layer of the placenta and is composed of a single epithelial layer, a thick basement membrane and an avascular stroma. The special structure and biological viability of the AM allows it to be an ideal candidate for creating scaffolds used in TE. Epithelial cells derived from the AM have the advantages of stem cells, yet are a more suitable source of cells for TE than stem cells. The extracellular matrix components of the basement membrane of the AM create an almost native scaffold for cell seeding in TE. In addition, the AM has other biological properties important for TE, including anti-inflammatory, anti-microbial, anti-fibrosis, anti-scarring, as well as reasonable mechanical property and low immunogenicity. In this review, the various properties of the AM are discussed in light of their potential use for TE. PMID- 18446691 TI - [Characteristics of falls of neurological cause in the elderly]. AB - INTRODUCTION: Falls are a cause of disability and death in geriatric population. Third part of the elderly suffer at least one fall per year. Neurological illness are a very important risk factor in developing falls. AIM: To establish the differences between neurological and not neurological patients with recurrent falls. PATIENTS AND METHODS: We select 113 patients over 65 years-old with two or more falls in the last six months, collecting demographic and medical data, as well as a functional, mental and social evaluation, gait and balance tests and posturography. Complementary examinations were done to clarify the diagnosis in each case. RESULTS: Average age was 78 years-old. We define a group A, patients in which the main cause of falls is a neurological disease and group B with a non neurological cause. Group A shows more number of falls (p < 0.053), worse functional (p < 0.002) and mental (p < 0.001) situation and more comorbility (p = 0.05), as well as worse scores in gait tests. CONCLUSIONS: Neurological illness are a very important risk factor in falls due to the disturbances in gait and balance that they produce. Dementia, parkinsonism and cerebrovascular diseases are frequently found in elderly patients with recurrent falls. Patients with falls due to neurological illness tend to fall oftener and have worse mental and functional situation. Evaluating neurological risk factors in geriatric patients with recurrent falls is essential to establish appropriate prevention strategies. PMID- 18446693 TI - [Abnormalities in the central nervous system and alterations in the upper limbs in patients with myelomeningocele]. AB - INTRODUCTION: Myelomeningocele is a neural tube defect resulting in motor and sensory deficit below the level of the lesion, bowel and neurogenic bladder, sexual dysfunction, cognitive dysfunction, neurodevelopment delay and motor skills disability. During the past decades, hand function impairment has been described in myelomeningocele patients, probably due to central nervous system abnormalities. AIM. To determine the occurrence of upper limb impairment and additional central nervous system abnormalities in patients with myelomeningocele. SUBJECTS AND METHODS: A transversal study including 33 patients with myelomeningocele, 6 years and older, referred to pediatric rehabilitation program at Sarah Network of Rehabilitation Hospital (Fortaleza, Brazil), and 33 control subjects. All patients underwent brain and spinal cord magnetic resonance imaging. RESULTS: Hydrocephalus, Chiari type II malformation with or without kinking of the medullocervical junction, hydrosyringomyelia, spinal cord and brain atrophy were the most common central nervous system abnormalities. Dysmetria, evaluated by the Index-Index Test, was exhibited by 87.9% of the patients and 21.2% of them exhibited dysdiadochokinesia. The mean hand grip strength of the myelomeningocele group was significantly lower compared with the control group (p < 0,001). CONCLUSIONS: High occurrence of upper limb dysfunction and additional central nervous system abnormalities was detected in patients with myelomeningocele, supporting previous studies. Further investigation is still necessary to elucidate the upper limb impairment impact on the daily live activities of the patient with myelomeningocele. PMID- 18446692 TI - [A comparative study of the effectiveness and tolerability of a procedure involving slow dose-escalation of rivastigmine in patients with mild or moderate Alzheimer-type dementia: the SCALEX study]. AB - AIMS: To determine and to compare the tolerability and effectiveness of a slow escalation of the dose of rivastigmine in patients with Alzheimer's disease with respect to using it with a faster escalation. PATIENTS AND METHODS: We conducted a multi-centre, naturalistic, open-label, randomised trial with 429 hospital outpatients diagnosed with Alzheimer-type dementia (according to DSM-IV and NINCDS-ADRA criteria) and in whom treatment with rivastigmine was clinically indicated. Two study groups were established: slow escalation and fast escalation (in accordance with usual clinical practice); effectiveness and tolerability variables were analysed in the two groups, as was the proportion of patients who reached therapeutic doses (> 6 mg/day). The scores obtained on the CGI, MMSE, NPI and Barthel index scales were analysed, together with adverse events and reactions concerning spontaneous communication, and scores on the UKU scale. RESULTS: The slow escalation group displayed slightly higher percentages of sub therapeutic anticipated interruptions than the fast escalation group (chi-square test; p < 0.05). On comparing the two treatment groups, no statistically significant differences were observed for the evolution of the scores on the different scales of effectiveness; no statistically significant differences were found between the two groups in the safety and tolerability analyses (chi-square test, exact test; p > 0.05) for most of the parameters that were studied (adverse reactions in spontaneous communication and the modified UKU scale). CONCLUSION: Slow escalation of the dose of rivastigmine did not display greater effectiveness or tolerability in comparison to an escalation applied in accordance with usual clinical practice. PMID- 18446694 TI - [Neurofibromatosis type 1 and optic pathway gliomas. A series of 80 patients]. AB - PATIENTS AND METHODS: From a series of 530 patients with neurofibromatosis type 1 (NF1), we performed a retrospective assessment of the long-term neurologic, visual, neuroimaging and evolution of 80 patients (15%) with optic pathway gliomas (OPG). All the 80 patients, 58 (72.5%) females and 22 (27.5%) males were diagnosed during childhood (below age 16 years), range 13 months to 15 years (average: 4.6 years). RESULTS: Image studies showed the distribution of the lesions among optic nerves, chiasm, tracts and radiations demonstrated that only 25% of the tumors involved only one optic nerve and 11.5% were located only in the chiasm, while 40% involved one or both optic nerves and chiasm, tracts and radiations. Two patients showed pilocytic astrocytoma in the histological study. Late diagnosis (after 7 years of age) of OPG was made in three patients and late progression was evident in three others who required surgical resection, radiotherapy or chemotherapy. CONCLUSIONS: All patients were diagnosed during childhood (below 16 years of age). Incidence was double in girls than in boys. Despite the apparent tumoral agressivity of the magnetic resonance and magnetic resonance spectroscopy images, histological findings corresponded to benign pilocytic astrocytoma. Some tumors follow the growth after 7 years. Continued monitoring of patients with NF1 into adulthood is advisable. PMID- 18446695 TI - [Hyperammonaemic encephalopathy due to valproic acid]. AB - INTRODUCTION: One of the less frequent idiosyncratic side effects of valproic acid (VPA) is encephalopathy. Here we report one case. CASE REPORT: An 83-year old female with no relevant past history, who received treatment with VPA following a post-traumatic subarachnoid haemorrhage and two convulsive seizures. A few days later, she was admitted to the Emergency Department because of a progressive clinical picture of mental slowness, nauseas and apathy. The systemic examination was normal. Neurologically, the most striking features were inattention and disorientation, despite her having a good level of consciousness, and mental confusion. Levels of VPA were within the below-therapeutic range and the basic lab findings (including hepatic profile) were normal, except for hyperammonaemia. Neuroimaging studies and cerebrospinal fluid analysis were also normal. An electroencephalogram (EEG) showed signs of severe diffuse encephalopathy with slow, triphasic waves and a non-convulsive epileptic status was therefore ruled out. After withdrawing the VPA, the patient's condition improved until her basal situation was reached in 48 hours and the EEG became normal, as did her ammonium levels. CONCLUSION: When faced with a patient who has recently been taking VPA and who presents a clinical picture of mental confusion, the possibility of encephalopathy due to said drug must be taken into consideration. PMID- 18446696 TI - [Idiopathic spinal epidural hematoma in patients with sudden paraplegia: a case report]. AB - INTRODUCTION: Spontaneous spinal epidural hematoma (SEH) represents 0.3-0.9% of spinal epidural space-occupying lesions, and most surgeons advocate aggressive and early surgical intervention. In this paper we describe a patient with SEH with sudden paraplegia. CASE REPORT: This 30-year-old man had experienced one prior episode of sudden dorsal pain two days before the current admission and while he waited medical attendance, his legs suddenly became weak, and immediately afterwards, he became completely paraplegic in minutes. The patient had complete paraplegia, analgesia below the T4 level and urinary retention. He had no anticoagulant agent and no coagulopathic disease. He was submitted to computerized tomography that demonstrated a dorsally located epidural hematoma extending from the T3 to the T6 level with spinal cord compression. A laminectomy from T3 to T7 was performed four hours after the onset of the symptom. In postoperative time the patient presented the partial sensorial recovery and motor force grade II. The patient was directed to a neurorehabilitation program and in the last medical evaluation he presented recovery for motor grade III-IV, without pain. CONCLUSION: The SHE is rare, with severe neurological consequences for patients and early surgical treatment persist as essential for motor recovery. PMID- 18446697 TI - [Learning and implicit memory: mechanisms and neuroplasticity]. AB - INTRODUCTION: Learning and memory are complex processes that researchers have been attempting to unravel for over a century in order to gain a clear view of the underlying mechanisms. AIMS: To review the basic cellular and molecular mechanisms involved in the process of procedural retention, to offer an overall view of the fundamental mechanisms involved in storing information by means of theories and models of memory, and to discuss the different types of memory and the role played by the cerebellum as a modulator of procedural memory. DEVELOPMENT: Experimental results from recent decades have opened up new areas of study regarding the participation of the biochemical and cellular processes related to the consolidation of information in the nervous system. CONCLUSIONS: The neuronal circuits involved in acquiring and consolidating memory are still not fully understood and the exact location of memory in the nervous system remains unknown. A number of intrinsic and extrinsic factors interfere in these processes, such as molecular (long-term potentiation and depression) and cellular mechanisms, which respond to communication and transmission between nerve cells. There are also factors that have their origin in the outside environment, which use the association of events to bring about the formation of new memories or may divert the subject from his or her main focus. Memory is not a singular occurrence; it is sub-divided into declarative and non-declarative or, when talking about the time it lasts, into short and long-term memory. Moreover, given its relation with neuronal mechanisms of learning, memory cannot be said to constitute an isolated process. PMID- 18446698 TI - [Advances in the diagnosis and treatment of narcolepsy-cataplexy syndrome]. AB - INTRODUCTION: Narcolepsy is a disabling sleep disorder that is characterised by excessive daytime sleepiness and abnormal manifestations in REM (rapid eye movement) sleep that include, among other symptoms, cataplexy (the sudden loss of muscle tone triggered by strong emotions). Studies on the prevalence of narcolepsy-cataplexy in Europe and the United States have yielded a figure of 0.013-0.067% in the general population. Although its prevalence is low, it is probably under-diagnosed for a number of different reasons, the most important perhaps being the difficulties involved in its diagnosis. DEVELOPMENT: Because its diagnosis is essentially clinical, complementary tests can often be very helpful. Today, it is one of the most extensively studied sleep disorders at the molecular level. Human narcolepsy is associated with diminished hypocretin/orexin concentrations, unlike the case of canine narcolepsy, where mutations in the Hcrt receptor have been found. The treatment of narcolepsy must be tailored to meet the needs of each patient after an individual analysis of his or her symptoms. Daytime sleepiness can be controlled by drugs that stimulate the central nervous system, the most common being methylphenidate and modafinil. Cataplexy is usually treated with tricyclic antidepressants and selective serotonin reuptake inhibitors. The appearance of new drugs like sodium oxybate sheds a ray of light on the dark horizon of patients with narcolepsy-cataplexy syndrome. CONCLUSION: Early identification of excessive daytime sleepiness by primary care physicians and specialists is essential for a better management and follow-up of these patients. PMID- 18446699 TI - [Can telemedicine re-establish geographic equity in the treatment of acute stroke?]. AB - INTRODUCTION: In acute stroke patients, urgent expert neurologic evaluation and thrombolytic treatment within the first hours alter onset are the only proven effective therapeutic measures. Patients living far from large hospitals do not have access to these measures. DEVELOPMENT: Implementing a telemedicine system allows that patients with suspected acute stroke admitted to a community hospital could be urgently evaluated by a specialized vascular neurologist located in a Reference Stroke Center. This paper reviews the best care access geographic equity imbalances created after the approval of acute stroke treatments and the solutions offered by the new telecommunication technologies. CONCLUSIONS: Telemedicine systems allow around the clock specialized urgent evaluation of those patients arriving to hospitals lacking a neurologist on call. This may lead to the use of thrombolytic treatments in community hospitals under the supervision of an expert physician, reducing time to treatment and the number of unnecessary patient transfers to referral Stroke Centers. PMID- 18446700 TI - [Pontine capillary telangiectasia as an incidentaloma in a cervical magnetic resonance imaging study]. PMID- 18446702 TI - [Cerebrospinal fluid hypotension due to dural fistulas]. PMID- 18446703 TI - [Hyponatraemia, pontine myelinolysis and rhabdomyolysis]. PMID- 18446704 TI - [Transverse myelitis due to human herpesvirus 6]. PMID- 18446705 TI - [The effects of aerobic and isokinetic exercise on the strength, spasticity and functionality of stroke patients]. PMID- 18446706 TI - Better understanding of ADPKD results in potential new treatment options: ready for the cure? AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary disorders. It accounts for 6% of the incidence of end-stage renal disease in Europe. Over the last decade, knowledge of the pathology underlying this disease has increased rapidly. Attributing important roles to tubular cell ciliary functioning, cell proliferation and fluid secretion, subsequent alterations in levels of intracellular calcium, adenosine 3',5'-cyclic monophosphate (cAMP) and activation of a variety of cellular kinases, including mammalian target of rapamycin (mTOR), has laid out the foundations for development of potentially effective treatments. In this editorial, the possible therapeutic roles for vasopressin antagonists, rapamycin, somatostatin and roscovitine are discussed. Clinical trials have been started to investigate the efficacy and safety of these agents for treating ADPKD in humans. PMID- 18446707 TI - Comparative studies of dialysis therapies should reflect real world decision making. AB - The incidence and prevalence of end-stage renal disease (ESRD) continues to rise. While transplantation is the preferred therapy for kidney failure, there is a shortage of donor organs, and the majority of patients will be treated with either peritoneal dialysis (PD) or hemodialysis (HD). Randomized controlled trials comparing patient outcomes on PD and HD are not likely to be successful, as individuals who are educated about their treatment options generally develop a strong preference for one therapy over the other and will not consent to randomization. As a result, prospective cohort studies are frequently the strongest study design available to compare outcomes between dialysis modalities. Previous studies have provided important insights into the relative merits of the 2 therapies. However, they have examined outcomes in relatively heterogeneous groups of ESRD patients and are generally not designed in a manner that mirrors clinical decision-making. We explore several key methodological challenges in the design of observational research in ESRD with a focus on minimizing selection bias and making studies more relevant to the practicing nephrologist. We emphasize that incident patients are preferred in most comparative studies of dialysis modalities. We argue that analyses comparing the outcomes of renal replacement therapy (RRT) modalities should include patients eligible for the therapies being compared and that the way that patients are assigned to treatment groups should reflect decision-making in clinical practice. Finally, the point at which baseline characteristics are measured and we begin tracking patients for the occurrence of outcomes should be chosen carefully. PMID- 18446708 TI - The middle-molecule hypothesis 30 years after: lost and rediscovered in the universe of uremic toxicity? AB - The present review gives an overview of the known and newly detected middle molecules and their biological potential. Since many middle molecules were shown to affect leukocyte, endothelial cell, smooth muscle cell and/or thrombocyte function, the likelihood of their role in cardiovascular damage related to renal failure is described. In addition, the middle-molecule behaviour during dialysis is commented. The impact of dialytic removal by diffusion or convection in clinical studies is extensively discussed reflecting the benefit on patient survival and/or clinical outcome. The continuing search for new culprits will result in therapeutic options including improved removal of uremic solutes and/or the search for pharmacological strategies blocking responsible pathophysiological pathways. PMID- 18446709 TI - Uremic pruritus in chronic hemodialysis patients. AB - Skin itching (pruritus) affects 50%-90% of patients undergoing peritoneal dialysis or hemodialysis and the symptoms range from localized and mild to generalized and severe. Among the dermatological abnormalities associated with end-stage renal disease, pruritus is the most prevalent. Of all systemic disorders, uremia is the most important cause of pruritus. The mechanism underlying uremic pruritus is poorly understood: secondary hyperparathyroidism, divalent-ion abnormalities, histamine, allergic sensitization, proliferation of skin mast cells, iron-deficiency anemia, neuropathy and neurological changes, or a combination of these have been hypothesized. Severe pruritus not only affects the quality of life but is also associated with poor outcome in chronic hemodialysis patients. No specific, effective treatment is currently available for uremic pruritus. Further studies are necessary to evaluate the long-term efficacy and safety of a novel kappa-opioid agonist, nalfurafine. Early diagnosis and treatment of uremic pruritus focusing on general strategies that include the optimization of dialysis dose, erythropoiesis-stimulating agents, and management of secondary hyperparathyroidism is recommended. PMID- 18446710 TI - Are chronic dialysis patients at increased risk for cancer? AB - This review summarizes the plausible mechanisms of carcinogenesis, critically analyzes the literature on cancer risk and discusses issues of cancer screening in chronic dialysis patients. Despite conflicting results among various studies, there is sufficient evidence to conclude that there is a heightened incidence of at least some cancers in dialysis patients. The data most convincingly support an increased risk of genitourinary malignancies. Screening for the common solid organ cancers (prostate, colon, breast and cervix) should be individualized, and is appropriate only for the minority of patients with a life expectancy on dialysis of 10 years or longer. Further research is needed before routine screening for bladder or renal cell cancers can be recommended. PMID- 18446711 TI - Oxidative stress, inflammation and cardiovascular disease in chronic renal failure. AB - Traditional risk factors such as hypertension, diabetes, dyslipidemia, obesity and metabolic syndrome, as well as additional nontraditional risk factors, can damage the kidney directly and by promoting intrarenal atherogenesis. Evidence indicates that increased oxidative stress and inflammation may mediate most of the effects of risk factors on the kidney. Clinical studies have demonstrated a relationship between oxidative stress and inflammatory biomarkers, and a few studies indicate an inverse correlation of oxidative stress biomarkers with estimated glomerular filtration rate (eGFR). Further, surrogate indexes of atherosclerosis such as intima-media thickness and aortic pulse wave velocity have been demonstrated to be related to plasma concentrations of markers of endothelial activation, inflammation and fibrosis in patients with different stages of chronic kidney disease (CKD). Moreover, plasma concentrations of high sensitivity C-reactive protein have been shown to be increased and related to left ventricular mass in CKD individuals having left ventricular hypertrophy. In contrast, in these patients, decreases in fetuin-A plasma levels have been reported. Considering the complex background of the pathophysiological changes characterizing CKD patients, we can consider cardiovascular disease a multifactorial complication of CKD. PMID- 18446712 TI - Cigarette smoking and kidney dysfunction in diabetes mellitus. AB - Type 2 diabetes mellitus is one of the leading causes of end-stage renal disease in the Western world. Smoking can also be seen as a powerful agent, although often underrated, able to induce renal damage and microvascular dysfunction via several different mechanisms, which often overlap with those of diabetic disease, and in concert may eventually worsen the renal redox homeostasis. As a result of this, the association of diabetes with smoking may favor the onset and/or the progression of renal insufficiency toward renal failure, and such a conclusion is supported by an array of epidemiological and physiopathological studies. Consequently, smoking prevention and cessation programs must be strongly encouraged not only to reduce the cardiovascular risk, but also to avoid the deterioration of renal function among diabetic patients. PMID- 18446713 TI - The First European Renal Association-European Dialysis and Transplant Association CKD Anaemia Physician Behaviours Survey: key findings. AB - Anemia in chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease. Maintenance of stable hemoglobin (Hb) levels is necessary to effectively manage CKD anemia. The European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) endorsed the present CKD Anaemia Physician Behaviours Survey conducted among nephrologists who regularly manage CKD patients. The survey included a total of 369 nephrologists from France, Germany, Italy, Spain and the United Kingdom, between May and June 2007. There were several aspects on which most of the nephrologists (independently of their country of origin) agreed, such as the complexity of managing anemia in patients with comorbidities -- particularly, cardiovascular disease and diabetes -- the target Hb levels of 11.00 to 12.99 g/dL and the advantages of the flexibility of weekly and monthly dosing. There was also agreement on the fact that most CKD patients are referred to a nephrologist at a late stage of the disease, which makes it difficult to start therapies to reduce morbidity and mortality. The more general implementation of routine glomerular filtration rate estimates in primary care, together with more education and awareness of CKD among primary health care providers, was considered necessary to improve the management of CKD patients. PMID- 18446714 TI - Body mass index and cardiovascular risk factors and biomarkers in hemodialysis patients. AB - BACKGROUND: Being overweight and obesity are associated with improved survival in hemodialysis (HD) patients, based on mechanisms that are presently uncertain. We compared traditional and uremia-related cardiovascular risk factors in HD patients stratified according to their body mass index (BMI). METHODS: One hundred sixteen HD patients were stratified into 4 groups according to the BMI: underweight (<18.5), normal weight (18.5-24.9), overweight (25.0-29.9) and obese (> or =30). Blood samples were obtained before the HD session to measure serum albumin, high-sensitivity C-reactive protein, fibrinogen, ferritin, total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein A-I and apolipoprotein B-100, apolipoprotein B (apoB) to apolipoprotein A (apoA) ratio and Lp(a) lipoprotein. RESULTS: There were 3 underweight (excluded from the analysis), 58 normal weight, 35 overweight and 20 obese patients. Their mean age was 62.1 +/- 14.1 years. There were 68 men and 45 women. Mean dialytic age was 5.32 +/- 3.2 years. The mean BMI of the study population was 25.2 +/- 4.1. The prevalence of smoking habit was similar in the 3 groups (17.2%, 8.5% and 25%, respectively; p=0.28). The prevalence of hypertension was higher in overweight (77.1%) and obese (65%) patients than in leaner counterparts (53.4%), although the difference was not significant. Conversely, diabetes prevalence was significantly higher in overweight and obese patients (22.8% and 30%, respectively) than in normal weight patients (6.9%; p=0.02). The serum levels of total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a) lipoprotein, apolipoprotein A-I, apolipoprotein B-100, and apoA/apoB ratio were similar in the 3 BMI groups. Triglycerides levels were significantly higher in obese (221.2 +/- 132.7 mg/dL) and overweight (230.5 +/- 119.3 mg/dL) patients than in those of normal weight (154.6 +/- 78.8 mg/dL; p=0.02). Most of the uremia-related cardiovascular risk factors (anemia, hyperparathyroidism, chronic inflammation) were comparable among BMI categories as well as the levels of C-reactive protein, fibrinogen and ferritin. CONCLUSION: The present study suggests that almost all traditional and uremia-related cardiovascular risk factors do not differ significantly among different categories of BMI in hemodialysis patients. PMID- 18446715 TI - Effects of dermatan sulfate for anticoagulation in continuous renal replacement therapy. AB - BACKGROUND: Dermatan sulfate (DS) is a natural glycosaminoglycan with a unique mechanism of action on the coagulation system. Unlike unfractionated heparin (UFH), DS selectively inhibits thrombin, does not inhibit factor Xa, is effective on both free and fibrin-bound thrombin and does not interfere with platelets. This study represents the first experience using DS as anticoagulant in patients on continuous renal replacement therapy (CRRT). METHODS: A total of 147 patients in our intensive care unit who developed acute renal failure after cardiovascular surgery were on CRRT according to the same protocol: machine, Gambro Prisma; filter, AN69, 0.9 m2; QB, 150 ml/min; QD, 2,000 ml/hour; and Q(Infusate), 500 ml/hour. In a retrospective cohort of 100 patients, anticoagulation was performed with UFH (UFH-CRRT): initial bolus of 530 +/- 363 IU, then i.v. infusion of 598 +/- 261 IU/hour. A prospective cohort of 47 patients received DS (DS-CRRT) as a 150-mg bolus followed by a 13.5 +/- 3 mg/hour infusion. Hematology tests were performed at baseline and during CRRT; filter lifetime was measured from the start to filter clotting. RESULTS: Median filter lifetime was 58 hours in DS-CRRT vs. 47 hours in UFH-CRRT (p<0.001). No differences emerged in basal hematology and hemostasis tests between groups. During CRRT, DS produced a smaller activated partial thromboplastin time increase than UFH (p<0.01). Platelet count exhibited a comparable small decline in both DS-CRRT and UFH-CRRT (p<0.01). No significant bleeding episodes occurred during DS-CRRT. In-hospital mortality was similar in the 2 cohorts. CONCLUSIONS: DS can be suggested as an anticoagulant for CRRT in patients who develop acute renal failure following major cardiovascular surgery. PMID- 18446716 TI - An oral adsorbent, AST-120, combined with a low-protein diet and RAS blocker, for chronic kidney disease. AB - BACKGROUND: A low-protein diet and treatment with renin-angiotensin system (RAS) blockers can delay the progression of chronic kidney disease (CKD). The oral adsorbent AST-120 (Kremezin) has a renoprotective effect by reducing serum levels of uremic toxins. We investigated the influence of AST-120 on the preservation of renal function in patients with CKD. METHODS: Twenty-eight patients were randomized to 2 groups: 15 patients receiving 6.0 g of AST-120 daily for 12 months plus a low-protein diet and RAS blocker therapy (group A) and 13 patients who were not given AST-120 (group B). All of them had shown progressive deterioration of renal function with basal treatment. Mean baseline serum creatinine level (+/- standard deviation) was 2.4 +/- 0.8 mg/dL in group A and 2.7 +/- 0.8 mg/dL in group B. There were no significant differences in background parameters before AST-120 therapy. RESULTS: The change in the estimated glomerular filtration rate (eGFR) was significantly smaller in group A than in group B. The change was also significantly smaller in patients with a baseline serum creatinine <2.4 mg/dL and in patients with rapid progression. After 12 months, the slope of the eGFR curve was significantly less steep compared with baseline in group A (-1.77 vs. -0.52 ml/min per month), but there was no significant change in group B. The slope was also significantly less steep in patients with rapid progression. CONCLUSIONS: Adding AST-120 to a low-protein diet and RAS blocker therapy may delay the deterioration of chronic renal failure, especially in patients with early or rapid progression. PMID- 18446717 TI - Pretransplant inflammation: a risk factor for delayed graft function? AB - BACKGROUND: Inflammation plays an important role in the pathogenesis of ischemic acute kidney injury (IAKI). In this study, we hypothesize that transplant recipients with pretransplant inflammation may have a greater chance of developing delayed graft function (DGF), an example of IAKI. PATIENTS AND METHODS: We analyzed 178 patients who had undergone their first transplant using cadaveric donors. Blood samples were extracted from transplant recipients prior to transplantation. C-reactive protein (CRP) (nephelometry); interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) (automatized enzyme chemiluminescence immunometric assay); and pregnancy-associated plasma protein A (PAPP-A) (enzyme linked immunosorbent assay) were determined using the pretransplant blood samples. The risk factors analyzed included cold ischemia, type and time of dialysis, donor and recipient age and HLA compatibility. RESULTS: Sixty-one patients (34.3%) developed DGF. Pretransplant TNF-alpha (9.31 +/- 2.57 vs. 10.56 +/- 3.82 pg/mL; p=0.039) and PAPP-A (1.25 +/- 0.74 vs. 1.90 +/- 1.56 mU/L; p=0.002) were significantly elevated in the group of patients with DGF. Univariate analysis showed that PAPP-A, TNF-alpha, cold ischemia, type of dialysis (hemodialysis) and donor age were associated with DGF. Multivariate analysis showed that PAPP-A (p=0.006), cold ischemia (p=0.009) and type of dialysis (p=0.046) were independent risk factors for DGF. CONCLUSIONS: Pretransplant inflammation (TNF-alpha, PAPP-A) in transplant recipients could be a risk factor for the development of DGF. PMID- 18446718 TI - Ischemic acute renal failure in the rat: effects of L-arginine and superoxide dismutase on renal function. AB - BACKGROUND: Regulation of renal hemodynamics -- especially intraglomerular hemodynamics -- is closely related to the L-arginine (L-Arg)/nitric oxide (NO) pathway, both under basal conditions and in acute renal failure (ARF). Also, superoxide anions -- which may react with NO -- play a role in ischemic ARF. L Arg not only has beneficial effects on glomerular filtration rate (GFR) but also reduces O2(-) production and prevents NO synthase isoform I up-regulation. Thus, it is of interest to elucidate whether the potential beneficial effects of L-Arg in reperfusion can be augmented by additional treatment with superoxide dismutase (SOD). METHODS: ARF was induced by renal artery clamping for 40 minutes. Animals were treated with either L-Arg, SOD, a combination of both, or saline. GFR, renal plasma flow (RPF), filtration fraction (FF) and blood pressure were recorded at baseline, after induction of ARF, during drug infusion and thereafter. RESULTS: Renal artery clamping induces a severe drop of GFR, RPF and FF, which all are improved by L-Arg and SOD. Increasing GFR is mainly due to better renal perfusion. FF fell after reperfusion and increased with L-Arg and SOD, indicating improvement of disturbed intrarenal hemodynamics. Combined administration of L Arg and SOD showed similar effects in comparison with each substance alone, but did not induce additional effects on GFR and RPF. CONCLUSIONS: L-Arg and SOD exert beneficial effects in ischemic ARF. Probably, improvements in reducing NO availability and in enhancing O2(-) formation are both playing a mediating role. The underlying mechanisms regulating the interplay between NO availability and O2(-) formation need to be elucidated in further studies using -- aside from other means -- selective NOS inhibitors, intervention in different experimental phases and treatment for a longer period. PMID- 18446719 TI - Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency. AB - OBJECTIVES: Iron deficiency anemia is a frequent finding in many patients with congestive heart failure (CHF). The purpose of this study was to assess the effect of intravenous (i.v.) iron on the anemia of CHF patients and on cardiac remodeling, New York Heart Association (NYHA) classification and renal function. METHODS: Thirty-two patients with well-treated CHF which was NYHA class III-IV, and with hemoglobin (Hb) persistently <11 g/dL, were treated with i.v. iron over 26 weeks. Echocardiographic, hematological and renal parameters were measured at the beginning and end of the study. RESULTS: Hb increased significantly from 10.7 +/- 0.4 g/dL to 13.7 +/- 0.4 g/dL and from 9.4 +/- 0.6 g/dL to 12.7+/- 0.8 g/dL in the NYHA III and IV groups respectively. Posterior wall thickness, septal thickness (ST), left ventricular (LV) end diastolic volume and diameter, LV end systolic volume and diameter, LV mass index and LV ejection fraction (LVEF) were all abnormal initially. All of these parameters improved significantly in the NYHA III patients, and all but ST and LVEF improved significantly in the NYHA IV patients. NYHA classification improved from III to II in 9 of 19 NYHA III patients (47.4%) (p<0.01) but did not improve in any of the 13 NYHA IV patients. CONCLUSION: Intravenous iron causes a marked increase in hemoglobin in anemic CHF patients, and this is frequently associated with an improvement in cardiac remodeling and NYHA classification. PMID- 18446721 TI - Sickle cell kidney. AB - Acute kidney injury is a rather unusual complication of sickle cell disease. We report a case of acute intrarenal sickling, causing dialysis-dependent acute renal failure, that was diagnosed by nuclear medicine renal imaging. PMID- 18446720 TI - Association of physical activity with mortality in chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is an important risk factor for all cause mortality. In the general population, physical activity is associated with reduced mortality. We examined the association of level of physical activity with mortality in patients with predominantly nondiabetic CKD stage 3-4. METHODS: We studied 811 patients with CKD enrolled in the Modification of Diet in Renal Disease (MDRD) Study, a multicenter clinical trial conducted between 1989 and 1993. Patients completed a survey of their physical activity at baseline, from which we derived 3 physical activity variables: indoor activity, exercise and outdoor activity, using standardized scores. We used Cox proportional hazards modeling to examine the relationship between baseline physical activity and all cause mortality with long-term outcome ascertained through 2000. RESULTS: The mean age of the study population was 52 years, and 61% were male. The mean glomerular filtration rate was 32.5 ml/min per 1.73 m2. A total of 24.6% died during follow-up. After adjustment for other factors significantly associated with mortality, the hazard ratio for all-cause mortality for indoor activity was 0.94 (95% confidence interval [95% CI], 0.77-1.14), exercise 1.01 (95% CI, 0.84 1.10) and outdoor activity 0.94 (95% CI, 0.80-1.10). CONCLUSIONS: Higher levels of physical activity were not significantly associated with a reduction in long term mortality in patients with CKD in this cohort. Additional prospective studies are needed to confirm our finding and determine whether physical activity improves outcomes in patients with CKD. PMID- 18446722 TI - Acute renal failure induced by bentazone: 2 case reports and a comprehensive review. AB - Bentazone is a herbicide widely used in the agrochemical field and acts by interference in photosynthesis in plants. Case reports of bentazone poisoning in humans are rare, but hepatorenal damage and death have been described, though the mechanism of toxicity remains speculative. We describe 2 cases of acute bentazone poisoning and compare these with other literature reports. The clinical picture included nausea, vomiting, diarrhea, abdominal pain with gastrointestinal corrosive injury, dyspnea and acute hepatorenal dysfunction. Respiratory failure, acute hepatitis, acute renal failure requiring hemodialysis, and death occurred following a large ingested dose of 1,764 mg/kg. Bentazone may have direct organ toxicity, especially in liver and kidney, in subjects with renal hypoperfusion, rhabdomyolysis, preexisting renal disease or concomitant nephrotoxic drug consumption. Aggressive supportive therapy, hydration and measures to prevent renal hypoperfusion are essential to reverse acute renal failure. PMID- 18446723 TI - Survival is not enough--quality of life in CKD. PMID- 18446724 TI - Survival is not enough: reflections of a long-term renal patient. AB - A kidney patient recalls his experience of almost 45 years of renal replacement therapy covering nearly 25 years of dialysis and 20 years with a transplant. At the beginning, patient or graft survival was a major goal and symbol of successful treatment. But for the patient, what really matters is the quality of his life, assuming he can survive. PMID- 18446725 TI - How to improve quality of life in patients with chronic kidney disease: a personal view. AB - The quality of life (QoL) of patients affected with chronic kidney disease (CKD) is clearly diminished, especially at the dialysis or renal transplantation stage. To find an equilibrium and improve his/her QoL, the patient should be active and positive regarding his/her own disease. The patient's disease profoundly affects the QoL of spouse and family. The patient and his family are in permanent need of more knowledge and information about the disease. Health professionals should be aware of all these consequences and try to help/advise the patient to reach the goal of a better daily life in his/her own environment. PMID- 18446726 TI - Can we ameliorate quality of life in chronic kidney disease? The nephrologist's point of view. AB - Despite admirable technical progress in dialysis procedure, rehabilitation of dialysis patients is far from optimal, in part because of deficiencies in the dialysis modality, in part because of the limited access to kidney transplantation, which is a superior method of treatment, and in part because of demographic reasons, particularly the ageing of the dialysis population. Chronic dialysis treatment creates a particular "microcosmos" in which interpersonal relations and psychological problems carry particular weight. PMID- 18446727 TI - The philosopher and the malady. A historical reckoning. AB - Phenomenological-existential culture widened our perception of life, health, and illness. In the light of philosophical reflection, the need arose to treat issues related with life and health within a much larger horizon than that allowed by traditional medical practice, adjacent to procedures of anamnesis, diagnosis and therapeutic prescription. The need has emerged to treat them not only in the light of medical competence but also, more specifically, as a social and humanistic issue. At the juncture between medicine and philosophy, of nature and culture, of organic and relational processes, the themes of life and health are seen to link with ethic thought. Bearing in mind this new and much profounder vision of the subject, to continue to think of the medical-sanitary system as a self-referential whole enclosed within itself, with no overture to humanists, exposes it to the danger of de-valuing the importance of lived experience and, consequently to reduce a patient's reactive resources to pathological conditions. PMID- 18446728 TI - On this side of language, pain. AB - Pain and pleasure, when profound, totalizing, leave one without voice. Under the violence of pure suffering, language is annihilated and therefore the protective falseness of its game vanishes. The impenetrable nakedness of our life, as pain and as pleasure, forces the thought, without protection, to the redde rationem and makes it free of the irreparable unrest due to philosophizing. We can say with Hegel that: "Pain is the privilege of living natures (...). One can say that the contradiction is not thinkable, but the living organisms, while suffering, effectively live". The relationship between pain and language assumes a link between death and pain. There would be no anxiety towards our own death if we did not have an idea of its occurrence, and no idea is possible without language. The soul is the human on the move, the continuous flow of symbolic communication, it is history, it is our acting community. Thought, love and joy are faces of this movement and are in a relation of reciprocity. I, you, we have a dialog; I, you, we love each other; I, you and we have delight in each other. Therefore anyone of us has pleasure since the others have pleasure. Physical pain breaks this essential reciprocity. PMID- 18446729 TI - How to support the patient with chronic disease. A philosophical point of view. AB - The patient with chronic disease is influenced by the concept of disease and therapy, their scientific, social, psychological and cultural meaning. He depends on the specific relationship with the physician, his empathy and communication, manifests his individual attitude and behavior in coping with disease, expects understanding and assistance from the social surroundings and can gain essential help from literature, art and philosophy. PMID- 18446730 TI - The legal basis of the right to rehabilitation in the Italian Constitution. PMID- 18446731 TI - To survive is not enough. Quality of life in CKD--the need for a new generation of health-oriented economists. AB - CKD is utilized as a paradigm, a chronic disease which allows decades of life conquered with great effort through a machine, a life with many losses and many dependencies. We must understand the patient's needs, which are not related to availability of drugs and machines and hospitals. We cannot provide good medical care with the limited amount of national product devoted to health care. Society is much older than ever before. We need a new cadre of economists working on health care with vision and ability, keeping in mind that there are no resources and there are no expenses which can be cut in medical care nowadays. We have to switch from curative medicine towards prevention, by implementing clinical research, bearing in mind that in the Western world, democracy was granted through the correct allocation of resources. The search for happiness and good quality of life are old concepts born in the Mediterranean area over the centuries, starting with Hesiod and Homer, and sleep and dreams were being investigated centuries before Freud was born. PMID- 18446732 TI - What is psychonephrology? AB - Patients on forms of dialysis and those who receive kidney transplants face many stresses connected with their illness and forms of treatment. These stresses may result in a variety of psychiatric disorders and other problems. It is the duty of all nephrology personnel to be aware of these problems, and inquire about them so that the appropriate treatment may be instituted. The major stresses of dialysis involve conflicts of dependency and independency, unrealistic expectations, the medical regimen and the many losses these patients sustain. As a consequence of these stresses and other factors, patients experience depression, anxiety, sexual problems, psychosis, problems in rehabilitation and uncooperativeness. The therapies of these disorders include individual and group therapy and the use of psychologically active medications. The pharmacokinetics of medications used to treat these patients require special consideration of the route of elimination, whether or not the medication is dialyzable and the protein binding of the medicine. Renal transplant patients may experience the same psychiatric problems, but usually of a lesser degree. Their special stress is termed "The Sword of Damocles'" that refers to anxiety associated with the wait and worry of organ rejection. PMID- 18446733 TI - Quality of life in patients with end-stage renal disease treated with hemodialysis: survival is not enough! AB - The quality of life (QoL) of end stage renal disease (ESRD) patients is a frequently overlooked yet critical consideration when evaluating the overall medical care of patients. There are a variety of measures used to assess the QoL of ESRD patients. Some of the more frequently used tools include the single question QoL questionnaire, the 36 Item Short Form Health Survey (SF-36), and the Kidney Disease Quality of Life (KDQoL) questionnaire. The best intervention to improve the QoL of ESRD patients is renal transplantation. The role of erythropoietin and intensification of dialysis dose in improving patients' QoL is undergoing review. We have previously shown relationships between patients' perception of quality of life and depressive affect, perception of burden of illness (IEQ), social support (MSP), pain and sleep disturbances. Further studies should focus on interventions that modify patients' perceptions of these psychosocial parameters with the goal of improving their QoL. Treatment of depression, pain and sleep disorders holds particular promise in this regard. PMID- 18446734 TI - Sleep disorders occur very early in chronic kidney disease. AB - BACKGROUND: Recent data suggest that sleep disorders may be common in patients with end-stage renal disease (ESRD) and patients with pre-dialytic chronic kidney disease (CKD). The prevalence of sleep disorders in CKD, its association to kidney function and related factors is still unclear. This study aimed to measure the prevalence of sleep disorders in patients with recent diagnosis of CKD and to assess the relation with indices of kidney function, PTH, anemia, blood pressure status, antihypertensive drug(s) and other comorbidities. METHODS: A standardized questionnaire, Sleep Disorders Questionnaire (SDQ) was administered to 124 patients within 4 weeks of first diagnosis of CKD. Blood samples were analyzed to assess kidney function and related variables. Charlson Comorbidity Index was used to index the number of associated diseases. RESULTS: Of these patients 89.5% reported some sleep disorders (subclinical or insomnia). Prevalence of sleep disorders was not associated with age, creatinine plasma concentration, urea, predicted creatinine clearance, uric acid, PTH, blood pressure status, use of antihypertensive drugs, anemia, and comorbidities. Poor sleep is highly prevalent in early CKD patients. Prevalence of sleep disorders in CKD was not associated with factors considered responsible for sleep disorders in maintenance hemodialysis. CONCLUSIONS: The data are in good keeping with findings in narrative studies in ESRD pointing out that the time of diagnosis is a crucial and disrupting moment in the life of patients since they are made aware of significant future personal changes due to a chronic illness. PMID- 18446735 TI - Sleep disturbances in dialysis patients. AB - Sleep disorders are common in dialysis patients. Insomnia is reported in almost 70% of the dialysed. Old age, presence of common sleep disorders, such as sleep apnea syndrome (SAS) and restless legs syndrome (RLS), comorbid clinical conditions, metabolic parameters and characteristics of dialysis, represent the main risk factors for insomnia. RLS is independently associated with uremia, affecting almost 30% of Caucasians dialysed. Pathophysiology of uremic RLS is still unclear. Although the exact pathogenetic mechanism remains unknown, the efficacy of kidney transplantation on RLS symptoms supports the involvement of renal function in this disturbance. SAS affects 30-80% of dialysis patients. The use of neurophysiological measures is necessary to diagnose SAS. This approach is not applicable in all dialysis patients; consequently, validated questionnaires might be useful to screen patients with a high risk of apnea. Risk of obstructive and central respiratory events are increased by renal failure and dialysis therapy. Excessive daytime sleepiness (EDS) is often reported by the dialysed population. Direct effects of uremic encephalopathy and of somnogenic cytokines have been suggested as the cause of EDS, in addition to the sleep disturbances that increase daytime sleepiness by impairing nocturnal sleep efficiency. Although less frequent, the presence of other sleep disturbances (such as nightmares and narcolepsy) should be carefully evaluated in the uremic population. Several sleep disturbances may potentially be treated but, if left untreated, may impair health status and increase the risk of mortality. However, literature and personal data suggest that undertreatment is common, calling to higher awareness of sleep disturbances among nephrologists. PMID- 18446736 TI - Insomnia on dialysis nights: the beneficial effects of cool dialysate. AB - BACKGROUND: Hemodialysis (HD) induces physiological changes that may affect the ability to dissipate heat and adversely affect sleep on the nights following treatment. We studied the effects of altering dialysate temperature on polysomnographic measures of nocturnal sleep and the time course of proximal skin temperature. METHODS: The sample included seven stable HD patients. The three phase randomized trial was conducted in a research facility. After one acclimatization night, subjects were readmitted in the evening on two additional occasions for 42 hours and received HD the next morning in the warm condition (dialysate--37 degrees C) and cool condition (dialysate--35 degrees C) in random order. Continuous proximal skin temperature (axillary, Tax) and polysomnographic measures of sleep were recorded the nights before and after HD was administered. RESULTS: Highly significant findings included that the course of Tax was markedly affected by the interaction of time and condition. In addition, there was a greater drop of Tax in the early morning following the warm condition than during the baseline nights or in the cool condition. Logistic regression indicated that the odds for the occurrence of sleep and its deeper stages were strongly and positively associated with Tax. Time of sleep onset was earlier in the cool condition (p = 0.032) with trends toward longer total sleep times (p = 0.090) and shorter REM latencies (p = 0.088). CONCLUSIONS: These observations suggest that the use of cool dialysate during HD may improve nocturnal sleep the night following treatment by decreasing sympathetic activation and sustaining the normally elevated nocturnal skin temperature until later into the morning hours. PMID- 18446737 TI - Relation between insomnia mood disorders and clinical and biochemical parameters in patients undergoing chronic hemodialysis. AB - BACKGROUND: Sleep disturbances are usually the outcome of a complex interplay between intrinsic factors and environmental influences. Aim of this study was to investigate the incidence of insomnia and to assess its relation to clinical and laboratory parameters in hemodialysis patients. METHODS: Using Athens Insomnia Scale (AIS), sleeping profile of 45 subjects (32 male, 13 female, mean age 59+/ 16.2 years) was evaluated. According to AIS, patients were divided into two groups. Group A comprised 32 patients with score 0-9 (absence of sleep disorders), whereas group B included 13 patients scoring higher than 9 (clinically assessed disorder). Subjects were compared in terms of socioeconomic, clinical, laboratory parameters and presence of depression (assessed by Hamilton Depression Scale, HAMD). RESULTS: No significant difference was observed with respect to age, sex, family status, education, self-esteem, coffee and alcohol consumption, time in hemodialysis and laboratory parameters. Group B demonstrated significantly lower albumin levels (3.65+/-0.38 and 3.9+/-0.24 g/dL respectively, p<0.01), higher CRP levels (1.88+/-1.9 and 0.92+/-0.64 mg/dL respectively, p<0.01) and exhibited depression (HAMD score 13.4+/-6.4 and 7.8+/-5.9 respectively, p<0.005). Moreover, significant correlation was observed when AIS scores were related to albumin (r=-0.29, p< 0.05), CRP (r=0.38, p<0.01) and HAMD scores (r=0.54, p<0.0001). CONCLUSIONS: Sleep disorders are common in hemodialysis patients. They seem to be related to high CRP and low albumin levels and demonstrate strong correlation to mood disorders, which are equally common to such patients. PMID- 18446738 TI - Co-morbidity and quality of life in chronic kidney disease patients. AB - Chronic kidney disease (CKD) is frequently associated with other chronic medical conditions. Adjusting for potential confounding factors that are associated with the outcome of interest is important both in clinical research and in everyday clinical practice. Comorbidity is such an important co-variable that it is reported to predict different outcomes in patients with ESRD. Health related quality of life (HRQoL) has increasingly been recognized as an important aspect of health care delivery, measure of effectiveness and patient experience, in chronic medical conditions. The progressively older ESRD patient population of industrialized countries is significantly debilitated by the burden of disease and also by the intrusiveness of renal replacement therapies. For these patients simply prolonging life is not enough. Little information has been published about the association of comorbidity and HRQoL. The aim of this review is to summarize the significance of comorbidity in patients with ESRD, with a special focus on the complex relationship between comorbidity and HRQoL. Several frequently used instruments will be described and the current literature, that compared the relative utility and accuracy of these tools, will be reviewed. Finally, the impact of selected medical conditions on HRQoL of patients with end-stage renal disease will be demonstrated. PMID- 18446739 TI - Parathyroidectomy improves the quality of sleep in maintenance hemodialysis patients with severe hyperparathyroidism. AB - Sleeping disorders are very common in patients with chronic kidney disease on dialysis (CKD5D) and are an emerging risk factor able to predict mortality. Parathyroid hormone (PTH) although considered a pivotal uremic toxin has rarely been associated with sleep disorders in uremia. In a study from our laboratory PTH concentrations failed to distinguish patients with sleep disorders from those without. In a study performed by Chou et al a 97% prevalence of insomnia was found in patients undergoing hemodialysis requiring parathyroidectomy. Surgery reduced PTH and increased sleeping hours within 3 months. The aim of this study was to study the effects of parathyroidectomy on the sleep disorders of insomniacs on maintenance hemodialysis. The study was performed in 16 insomniac patients on maintenance hemodialysis who successfully underwent surgery with autotransplantation of autologous parathyroid tissue (40 mg) under the skin of the forearm. Patients (5 F and 11 M) were studied from 1 month before surgery to 1 year after. Sleep disorders were assessed by means of a 27-item questionnaire- Sleep Disorder questionnaire (SDQ)--that identified sleeping disorders according to Diagnostic and Statistical Manual of Mental Disorders - IV Edition (DSM-IV) criteria. The Charlson Comorbidity Index (CCI) was also measured along with systolic and diastolic blood pressure, Hb, PTH, Ca, P. A 95.5% prevalence of sleep disorders was found pre operatively. Patients slept 4.90+/-1.2 hours, Ca averaged 10.09+/-0.54 mg/dL, Phosphate 5.5+/-1.93, CCI 9.8+/-1.1, PTH 1498+/-498 ng/mL. After 1 year follow-up 2 out 16 patients had normal sleep, 6 out 16 patients had subclinical sleep disorders and 8 remained insomniacs (p=0.008, Mc Nemar Test for paired data, insomniacs vs. no disturbance + subclinical disorders). Sleeping hours increased up to 6.0+/-1.24 (p<0.05), PTH was normalized, the Charlson Comorbidity Index was reduced (p<0.05) as were plasma calcium and phosphate (p<0.01). The study indicates that insomnia in patients with severe hyperparathyroidism on maintenance hemodialysis is ameliorated by parathyroidectomy. PMID- 18446740 TI - Renal transplantation and sleep: a new life is not enough. AB - Renal transplantation is associated with better survival and improved quality of life compared to maintenance dialysis. Although many sleep disorders improve or even disappear after a successful transplantation, sleep quality remains low, and the prevalence of sleep complaints, although lower than in dialysis patients, is much higher than in the general population. Few studies have dealt with sleep problems of renal transplant patients: despite reporting obvious differences in the prevalence of the single sleep disorders, all underline the importance of psychological problems in conditioning sleep. In the diagnosis of sleep disorders, the nephrologist must learn to distinguish medical risk factors (pain, pruritus, tremors, drugs) and psychological aspects (depression, anxiety, fear), since they are potentially modifiable with the appropriate treatment. PMID- 18446741 TI - Early identification of kidney disease by eGFR: what is the prevalence of eGFR in the population? AB - The paper deals with the use of estimated glomerular filtration rate (eGFR) as marker of low kidney function in the population. Data were collected on serum creatinine, other laboratory indices, blood pressure, and medical history in a population sample of 2083 men and 2491 women aged between 18-95 years. Estimated GFR was calculated by the equation of Modification Diet in Renal Disease study. Disorders included in the analysis were hypertension, cardiovascular disease, high serum uric acid, high serum phosphorus/low serum calcium, anemia, and high serum potassium. Prevalence of low eGFR (eGFR <60 mL/min per 1.73 m2) increased with age: from <1% for ages 18-24 to >30% for ages > or =75, P<0.001. On the basis of these data, prevalence of low eGFR in the adult Italian population was 5.7% for men (n=1.3 million, 95%CI = 1.1/1.5) and 6.2% for women (n=1.5 million, 95%CI = 1.3/1.8). Disorders associated with kidney dysfunction were two or more in the majority of persons with low eGFR and were more frequent with lower eGFR (p<0.001). Previous diagnosis of kidney disease was reported by less than 5% in people with low eGFR and was progressively higher with higher serum creatinine or with number of associated disorders (p<0.03). Hypertension tended to be more frequently treated but not more frequently controlled in people with low eGFR. Data support the use of eGFR to identify people with or at risk of low kidney function. Awareness of kidney disease is low in people with low eGFR unless serum creatinine is very high or they have many associated disorders. PMID- 18446742 TI - Quality of life assessment and instruments in end-stage renal disease. AB - The main aim of every medical intervention is to improve the "quality of life" of the patients. In recent years, quality of life assessment has become increasingly important as an additional outcome measure in clinical research. The evaluation of quality of life is particularly relevant in patients with end-stage renal disease. The characteristics of the clinical condition in fact--no cure of the pathological state, and the type of the heavy non-stop treatment programs- obviously have an important impact on the patients' quality of life. Mortality, of course, is not an optimal or satisfactory outcome to assess the quality of care provided to these patients. After a general introduction of the current debate on methodological issues in quality of life evaluation, this paper reports several instruments described in the literature to evaluate the quality of life in patients with renal disease. Compared to other medical fields the number of questionnaires available for patients with renal disease is limited. The domains investigated are well defined in terms of generic concepts and disease-specific domains, principal symptoms, and the validity of the questionnaires is generally well documented. PMID- 18446743 TI - Sexual dysfunction in chronic renal failure. AB - Recent studies have shown that testosterone is involved in the pathogenesis of cardiovascular diseases. Moreover, in observational studies blood testosterone concentrations, resulted consistently lower, not only among men with cardiovascular disease but also in men with uremia. In order to correlate the blood level of testosterone with the degree of erectile dysfunction (ED) and chronic renal failure (CRF) (stage I-V) we selected a group of patients with renal failure on conservative treatment, who attended our nephrology outpatients clinic. All the patients had stage II and III renal failure, respectively with a creatinine clearance between 59-30 and 29-15 ml/m'. The sexual evaluation was done using a 15-item questionnaire, i.e. the International Index of Erectile Function (IIEF). Mean score of patients with ED were significantly lower than mean scores for healthy controls for all 15 questions (all p values <0.01). Preliminary results show a direct correlation between -IIEF and glomerular filtration rate (GFR) (R2 0.08); an inverse correlation between testosterone and cholesterol (R2 0.045); a higher number of diabetic patients with lower levels of testosterone, at level 3 of CRF; low levels of testosterone for smokers especially in stage II (GFR). These data confirm the direct correlation between ED and renal failure, and the role of diabetes and smoking in hypotestosteronemia, in patients with different degrees of renal insufficiency. Further prospective studies are needed in order to correlate cardiovascular morbidity and mortality in patients with CRF and blood levels of testosterone. PMID- 18446744 TI - Survival in octogenarian dialysis patients: analysis in two Southern Italian regions. AB - Dialysis for octogenarian and nonagenarian patients has increased dramatically in recent decades. Worldwide Registries of dialysis and transplantations show how the incidence rate of patients older than 80 years of age is almost doubled. This increase is probably due to liberalisation of acceptance criteria for dialysis, together with the ageing population. In recent years, the Sicilian and Campanian Registries of dialysis and transplantations have also observed a progressive increase in the elderly population. In order to study survival in this class of patients, we performed a study on a sample of Sicilian and Campanian patients. Regarding Sicilian patients, we considered a sample of 497 patients and grouped them into 3 categories of risk: in the first group (low risk) patients included were <70 years old without any co-morbidities; in the second group (average risk), we selected patients between 70 and 80 years old with one or more co morbidities: in the third group (high risk patients), we included patients aged more than 80 years or with a high number of co-morbidities. The probabilities of survival in the low risk patients after 48 months of treatment was 96.1%; this probability fell to 82.9% for patients included in the high risk group; while the probability of survival for average risk patients was 91.7%. Given the high risk presented by older patients, we focused the second part of our analysis only on octogenarians, studying both Sicilian and Campanian patients. 64 Sicilian patients (33 males and 31 females--51.56% and 48.43% respectively) were observed: and their survival was 81.25% after 48 months. The sample of Campanian octogenarian patients considered for this study included 26 patients (12 males- 53.85%--and 14 females--46.15%), observed for a shorter period (36 months). The probabilities of survival after 36 months was 84.61%. To sum up, elderly patients represent a growing reality on dialysis registries in Sicily and Campania. Future research concerning this class of patients should be developed in order to individualize suitable stratification risk indices; knowing patterns and probability of survival might help physicians in the dialysis decision-making process. PMID- 18446745 TI - Life without quality. Reflections of a female focus group on life, health and kidney disease. AB - Focus groups are increasingly employed in clinical practice as their flexible structure permits the range and depth of experiences of health service users and chronically ill individuals to be explored and recorded. A focus group workshop on quality of life was held in March 2007 involving a group of patients either awaiting transplantation, following transplantation, or with a family member who had already undergone renal replacement therapy (RRT). After intensive discussion the group produced the following consensus points. Before talking about quality of life, physicians should call us by our names, instead of by the names of our diseases. The true disease is the ignorance of diversity. The life of a person with a chronic disease is entangled with the disease and with the fear of the disease. It is impossible to consider one's disease separately from one's life, loves, failures, families, and dreams. To evaluate the quality of our life means knowing us, as people. We do not need other numbers. Physicians often see us as boxes, with a disease inside. That's not what we are. We need time. Discussions about the quality of life should include the people around us. The disease steals a lot from you, but it also gives you something in return. We do not feel sick. The main result was to highlight the close relationship between quality of life and quality of care. Underlining the importance of a global approach to health, and the role of the physician as a leader in all aspects of care. PMID- 18446746 TI - Vitamins and quality of life in hemodialysis patients. AB - BACKGROUND: Dialysis patients have decreased quality of life compared to healthy controls. In recent years the quality of life in hemodialysis patients has been considered from many points of view. The aim of this retrospective study was to improve quality of life in dialysis patients by supplementing some important vitamins. PATIENTS AND METHODS: Eighty-three patients underwent hemodialysis treatment 3 x 4 hr/weekly using a standard dialyzer with a cellulose membrane. During the investigation of plasma and erythrocyte vitamin E, vitamin E-coated dialyzer was used. Patients who were treated with erythropoietin (EPO) were supplemented over 3 months with Pyridoxine: 20 mg/day, folic acid: 10 mg/week, vitamin C: 60 mg/day. Some erythrocyte and plasma vitamins and plasma malondialdehyde were investigated in all patients. Erythrocyte vitamin B6 was determined by indirect enzymatic method as an effect of pyridoxal-5-phosphate (PLP). Erythrocyte folic acid was determined by radioimmunoassay method, erythrocyte vitamin E and plasma malondialdehyde were determined by fluorometric methods, plasma vitamin C was determined by spectrophotometric method. RESULTS: During above mentioned EPO treatment and supplementation, vitamins significantly increased blood hemoglobin (from 100+/-5 to 110+/-4 g/L, p<0.05), erythrocyte vitamin B6 that means decreased effect of PLP (from 30.4+/-2.4 to 16.4+/-1.9%, p<0.01), increased erythrocyte folic acid (from 343.3+/-72 to 734.5+/-98 ng/mL) and plasma vitamin C (from 63.5+/-15 to 88.3+/-10 micromol/L). Three-month use of vitamin E-coated dialyzer led to the increase of erythrocyte vitamin E (from 6.7+/-0.5 to 7.4+/-0.4 micromol/L, p<0.05) and to the significant decrease of plasma malondialdehyde (from 2.8+/-0.5 to 2.2+/-0.4 micromol/L, p<0.01). CONCLUSIONS: 1. Investigated vitamins were decreased in hemodialysis patients and after supplementation increased to normal range. 2. Increased plasma malondialdehyde, as a product of lipid peroxidation, significantly decreased during the use of vitamin E-coated dialyzer. 3. Adequate supplementation of above mentioned vitamins led to increased quality of life in hemodialysis patients from some clinical points of view. PMID- 18446747 TI - Is survival enough for quality of life in Sagliker Syndrome-uglifying human face appearances in chronic kidney disease? AB - BACKGROUND: It is known that secondary hyperparathyroidism (SH) and particularly skeletal changes is a severe condition in chronic kidney disease (CKD). Sagliker syndrome (SS) is a very prominent feature in CKD including uglifying human face appearances, short stature, extremely severe maxillary and mandibulary changes, soft tissues in the mouth, teeth-dental abnormalities, finger tip changes and severe psychological problems. METHODS: In the last 8 years we have confronted 36 extremely incredible SS cases in CKD by performing an international study in Turkey, India, Malaysia, Romania and Egypt. RESULTS: In addition to the uglifying human face appearance, we found extremely severe X-ray and tomographical, pantomographical, histo-pathological changes in the head and whole body. Finally, we compared previous face pictures with recent ones. Just a few years earlier they had been pretty and good-looking young boys and girls. By investigating their history, we understood they had not received proper therapy and were in the late-irreversible period. CONCLUSION: SS is a serious and severe complication of CKD. Late and improper treatment leads to abnormalities throughout skeleton particularly in the skull and face. Changes particularly in children and teens become irreversible-disastrous for appearance and psychological health. Appropriate treatment must begin as early as possible in specialized centers. It is possible that SS patients may survive long-term with dialysis, but with all those particular changes could anyone claim this type of life would continue in an acceptable way without extending their height, correcting all the changes in the skull and face, remodeling new faces and most particularly convincing the patients to deal with all those tragi-dramatic psychological problems? PMID- 18446748 TI - Neurobiological model and quality of life in discovering personality of the uremic patient. AB - The Short Form-36 Health Survey (SF-36) questionnaire is designed to measure the patient's functional capacity and well-being. It was created to reach a compromise between lengthy investigation methods and one dimensional, overly simple tools for measuring quality of life (QoL). In 1987, the psychiatrist Robert Cloninger proposed a psycho-biological model hinged upon three principal and independent dimensions of the human personality: novelty seeking (NS), harm avoidance (HA) and reward dependence (RD), linked with dopaminergic, serotoninergic and noradrenergic activity, respectively. According to Cloninger, each dimension is the expression of the integration of a hereditary condition, characterized by biologic substrates, in response to specific environmental stimuli. We furthermore searched for any interference between the SF-36 scores and plasmatic dopamine, serotonin and noradrenaline concentrations, in an attempt to identify eventual correlations between the condition of the patients, their subjective QoL evaluation and neurohormonal plasmatic equilibrium. We compared results obtained from healthy subjects with populations of patients in different periods of their clinical existence: patients on hemodialysis; with a functioning transplantation; with renal graft function loss; returning to dialysis after graft loss and two years after restarting hemodialysis. PMID- 18446749 TI - Is it necessary to check outcomes to improve quality of care? The example of anemia management. AB - The aim of this study was to verify the importance of continuously monitoring the level of adherence to the anemia guideline recommendations in order to improve not only quality of care but also patient safety. Data presented in this investigation were gained through the FME database EuCliD which contains the clinical data of over 24,000 prevalent patients under treatment at the time of the analysis in 344 dialysis centres in 15 countries. Patient data from 4 countries (United Kingdom, Turkey, Italy, Portugal) was used for this study. The parameter selected was anemia control. The level of hemoglobin (Hb) was considered as the quality indicator for anemia, the target being an Hb level >11 g/dL, for UK centres the target was >10 g/dL. All new patients commencing hemodialysis between October 2003 and September 30, 2004 with the previous follow up of less than one month and without previous blood transfusion were considered. A total of 902 patients were enrolled. The study showed that 4 to 6% of the Italian, Portuguese and British patients treated in FME clinics received a blood transfusion during the first year of follow-up. This is consistent with reports by USRDS that only 3.3% of ESRD patients received at least 1 transfusion per quarter in 1992 after erythropoietin became available and was prescribed to 88% of patients. About 18% Turkish patients, required blood transfusions during the first year of follow-up on hemodialysis, which is more comparable with USRDS data reported in 1989, when 16% of patients needed at least 1 transfusion quarterly. In conclusion, the practice of blood transfusion for hemodialysis patients is still frequent especially in elderly patients. PMID- 18446750 TI - Palliative care in nephrology. AB - The goal of palliative care is to achieve good quality of life for patients with chronic life-limiting illnesses, and their families, through assessment and management of physical, psychosocial and spiritual problems and needs. Patients with kidney diseases present a particular target of such care from the time of diagnosis to the time of family bereavement family. End-stage renal disease is associated with limited life expectancy, high morbidity and considerable burden of symptoms especially in elderly patients. Nephrologists who are not prepared for the holistic aspects of care of such patients, frequently encounter high mortality rates. Pain and other physical, psychosocial and spiritual symptom management appear to be an important issue in nephrology. Withdrawal from dialysis is another problem that may require special attention in the form of legal and ethical guidance. PMID- 18446752 TI - Reflections on 'Survival is not enough--quality of life in CKD'. PMID- 18446751 TI - Burn-out in the dialysis unit. AB - The management of human resources is definitely one of the most important chapters in managerial activities. So, the involved participation of personnel is one of fundamental importance for all systems of quality management. The aim of this study is to analyse satisfaction of personnel in dialysis units. We administered a questionnaire subdivided into 6 basic sections with 34 items regarding the work environment, the material, the environmental climate, the objectives, the quality, and justifications and suggestions. We received 298 replies to the questionnaire, of which 72 from doctors (D) (24.2%) and 226 from nurses (N) (75.8%). From a possible maximum score of 170, the scores reached were 115 points for the D and 113 for the N. It is obvious that N considered the environmental climate, the objectives and the quality of the services to be inferior compared to D. Thirty-nine percent of D and 27% of N were very critical of the items analyzed. A second step was dedicated to the administration of the questionnaire to the dialysis patients to verify if there was agreement. One hundred and twenty-five patients (5.7%) (randomized in a single dialysis unit for age and sex), of a total of 2170 patients responded. Their answers were then compared with those of the personnel. The data of our study showed that most of the personnel did not receive counseling about uncertainties, expectations did not correspond to reality and there was distrust and scarcity of involvement. These elements appeared to cause irritation and dissatisfaction and if not resolved are responsible, together with technical and environmental factors, for the serious burn-out syndrome in the personnel of dialysis units. PMID- 18446753 TI - Large old trees influence patterns of delta13C and delta15N in forests. AB - Large old trees are the dominant primary producers of native pine forest, but their influence on spatial patterns of soil properties and potential feedback to tree regeneration in their neighbourhood is poorly understood. We measured stable isotopes of carbon (delta(13)C) and nitrogen (delta(15)N) in soil and litter taken from three zones of influence (inner, middle and outer zone) around the trunk of freestanding old Scots pine (Pinus sylvestris L.) trees, to determine the trees' influence on below-ground properties. We also measured delta(15)N and delta(13)C in wood cores extracted from the old trees and from regenerating trees growing within their three zones of influence. We found a significant and positive gradient in soil delta(15)N from the inner zone, nearest to the tree centre, to the outer zone beyond the tree crown. This was probably caused by the higher input of (15)N-depleted litter below the tree crown. In contrast, the soil delta(13)C did not change along the gradient of tree influence. Distance-related trends, although weak, were visible in the wood delta(15)N and delta(13)C of regenerating trees. Moreover, the wood delta(15)N of small trees showed a weak negative relationship with soil N content in the relevant zone of influence. Our results indicate that large old trees control below-ground conditions in their immediate surroundings, and that stable isotopes might act as markers for the spatial and temporal extent of these below-ground effects. PMID- 18446754 TI - Enhancing the understanding of earthworm feeding behaviour via the use of fatty acid delta13C values determined by gas chromatography-combustion-isotope ratio mass spectrometry. AB - Litter-dwelling (epigeic) Lumbricus rubellus and soil-dwelling (endogeic) Allolobophora chlorotica earthworms were observed aggregating under C(3) (delta(13)C = -31.3 per thousand; delta(15)N = 10.7 per thousand) and C(4) (delta(13)C = -12.6 per thousand; delta(15)N = 7.5 per thousand) synthetic dung pats applied to a temperate grassland (delta(13)C = -30.3 per thousand; delta(15)N = 5.7 per thousand) in an experiment carried out for 372 days. Bulk delta(13)C values of earthworms collected from beneath either C(3) or C(4) dung after 28, 56, 112 and 372 days demonstrated that (i) L. rubellus beneath C(4) dung were significantly (13)C-enriched after 56 days (delta(13)C = -23.8 per thousand) and 112 days (delta(13)C = -22.4 per thousand) compared with those from C(3) dung treatments (56 days, delta(13)C = -26.5 per thousand; 112 days, delta(13)C = -27.0 per thousand), and (ii) A. chlorotica were 2.1 per thousand (13)C-enriched (delta(13)C = -24.2 per thousand) relative to those from C(3) dung (delta(13)C = -26.3 per thousand) treatments after 372 days. Bulk delta(15)N values did not suggest significant uptake of dung N by either species beneath C(3) or C(4) dung, but showed that the endogeic species (total mean delta(15)N = 3.3 per thousand) had higher delta(15)N values than the epigeic species (total mean delta(15)N = 5.4 per thousand). Although the two species exhibited similar fatty acid profiles, individual fatty acid delta(13)C values revealed extensive routing of dietary C into body tissue of L. rubellus, but minor incorporation into A. chlorotica. In particular, the direct incorporation of microbial biomarker fatty acids (iC(17:0), aC(17:0)) from (13)C-labelled dung in situ, the routing of dung C into de novo synthesised compounds (iC(20:4)(omega)(6),C(20:5)(omega)(3), and the assimilation of essential fatty acids ((C(18:1)(omega)(9), C(18:1)(omega(7), C(18:2)(omega(6), C(18:3)(omega)(3)) derived from dung, were determined. PMID- 18446755 TI - Memento of the post-mortem. AB - When the Department of Pathology of the Radboud University Nijmegen Medical Centre in The Netherlands moved from its old to its new premises, the demolition of the marble post-mortem tables was impending, taking with it the Department's (physical) memory. To keep the importance of this memory and of the post-mortem itself on everyone's minds in the new building, the artist Piet Hein Eek was invited to incorporate these post-mortem tables into a work of art. This became a triptych: the three post-mortem tables were stood upright against the wall behind a mounted double sheet of glass, containing screen prints of enlarged microscopic images. The two emblems of pathology-post-mortem tables and double glass slides containing specimens-were thus united into a fascinating work of art: a true memento of the post-mortem, re-embedded in the contemporary world by its design. PMID- 18446756 TI - Randomized clinical trial evaluating elective laparoscopic appendicectomy for chronic right lower-quadrant pain (Br J Surg 2008; 95 169-174). PMID- 18446757 TI - Influence of recent vegetation on labile and recalcitrant carbon soil pools in central Queensland, Australia: evidence from thermal analysis-quadrupole mass spectrometry-isotope ratio mass spectrometry. AB - The effect of a recent vegetation change (<100 years) from C(4) grassland to C(3) woodland in central Queensland, Australia, on soil organic matter (SOM) composition and SOM dynamics has been investigated using a novel coupled thermogravimetry-differential scanning calorimetry-quadrupole.mass spectrometry isotope ratio mass spectrometry (TG-DSC-QMS-IRMS) system. TG-DSC-QMS-IRMS distinguishes the C isotope composition of discrete SOM pools, showing changes in labile, recalcitrant and refractory carbon in the bulk soil and particle size fractions which track the vegetation changes. Analysis of evolved gases (by QMS) from thermal decomposition, rather than observed weight loss, proved essential in determining the temperature at which SOM decomposes, because smectite and kaolinite clays contribute to observed weight losses. The delta(13)C analyses of the CO(2) evolved at different temperatures for bulk soil and particle size separates showed that most of the labile SOM under the more recent woody vegetation was C(3)-derived carbon whereas the delta(13)C values in the recalcitrant SOM showed greater C(4) contributions. This indicated a shift from grass (C(4))- to tree (C(3))-derived carbon in the woodland, which was also supported by the two-phase (13)C enrichment with depth, i.e. C(3) vegetation dominated the top soil (0-10 cm), but the C(4) contribution increased with depth (more gradual). This is perturbed by the inclusion of charcoal from forest fires ((14)C age incursions) and by the deep incorporation of C(3) carbon due to root penetration. PMID- 18446759 TI - Randomized clinical trial of laparoscopic total (Nissen) versus posterior partial (Toupet) fundoplication for gastro-oesophageal reflux disease based on preoperative oesophageal manometry (Br J Surg 2008; 95: 57-63). PMID- 18446761 TI - The incidence of lateral pelvic side-wall nodal involvement in low rectal cancer may be similar in Japan and the West (Br J Surg 2008; 95: 33-49). PMID- 18446763 TI - Off-line pyrolysis and compound-specific stable carbon isotope analysis of lignin moieties: a new method for determining the fate of lignin residues in soil. AB - Off-line pyrolysis was used to liberate lignin moieties from dung and soil and, after trimethylsilylation, the delta(13)C values of these derivatives were determined by gas chromatography-combustion-isotope ratio mass spectrometry. Initial delta(13)C values determined for 4-vinylphenol, syringol, 4 vinylguaiacol, 4-acetylsyringol, 4-vinylsyringol, 4-(2-Z-propenyl)syringol, 4-(2 E-propenyl)syringol and 4-(2-propenone)syringol pyrolysis products of the lignin polyphenol structure from C(4) (delta(13)C(bulk) = -12.6%) and C(3) (delta(13)C(bulk) = -30.1 per thousand) dung confirmed the robust and reproducible nature of the off-line preparation technique. C(4) dung was used as a treatment in a randomised field experiment to assess the short-term sequestration of dung carbon in managed grasslands. Since lignin was on average 3.5 per thousand depleted in (13)C compared with bulk dung delta(13)C values, this may have resulted in an under-estimation of dung C incorporation based on bulk delta(13)C values. Therefore, an investigation of the compound-specific delta(13)C values of dung-derived lignin moieties extracted from soils sampled up to 372 days was undertaken. Delta(13)C values between lignin moieties extracted from treated and untreated soils showed that dung-derived lignin was not especially resistant to degradation and suggested that individual moieties of the lignin macromolecule must: (i) move into soil, (ii) be degraded, or (iii) be transformed diagenetically at different rates. This adds to a gathering body of evidence that lignin is not particularly stable in soils, which has considerable significance for the perceived role of different biochemical components in the cycling of C in soils. PMID- 18446765 TI - Changing trends in surgery for acute appendicitis (Br J Surg 2008; 95: 363-368). PMID- 18446766 TI - Rapid TLC/GC-MS identification of acetylcholinesterase inhibitors in alkaloid extracts. AB - Alkaloid extracts from 12 plant species of the families Amaryllidaceae, Fumariacae and Papaveraceae were studied with respect to their acetylcholinesterase inhibitory activity and alkaloid patterns. Fifty-three alkaloids were identified by GC-MS, including known acetylcholinesterase (AChE) inhibitors such as galanthamine, epigalanthamine, sanguinine and epinorgalanthamine in extracts of Amaryllidaceae plants and protopine in extracts of Fumariaceae and Papaveraceae plants. The galanthamine-containing extracts of the amaryllidaceous plants were found to be the most active while the extract of Corydalis bulbosa was the most active among the extracts of the tested plants from the Fumariaceae and Papaveraceae plants. TLC bioautographic assay, preparative TLC and GC-MS analysis were combined to identify the active compounds in the studied extracts. Galanthamine was isolated from the known AChE inhibitors in the extracts of Amaryllidaceae plants. Corydaline, bulbocapnine and stylopine were found to be active in the extracts of plant species of the families Fumariaceae and Papaveraceae. Available standards of deshydrocorydaline--a precursor of corydaline, corydaline and stylopine--were tested for AChE inhibitory activity. Deshydrocorydaline and corydaline showed potent inhibitory activity comparable with that of the positive control galanthamine. PMID- 18446768 TI - Late gastrointestinal disorders after rectal cancer surgery with and without preoperative radiation therapy (Br J Surg 2008; 95: 206-213). PMID- 18446769 TI - Organic oxygen and hydrogen isotopes in a porcine controlled dietary study. AB - Controlled feeding studies have been useful in assessing the relationship between isotope values from dietary sources and consumer tissues. We report the organic oxygen and hydrogen values of animal tissue from a porcine controlled dietary study. A complex mixture of fractionation and incorporation is revealed. In both deltaD and delta(18)O, differences in the absolute values and the amount of variation between and within consumer tissue are documented. Significant differences in deltaD and delta(18)O are observed between protein sources such as keratin and collagen. PMID- 18446770 TI - Influence of dietary composition on the carbon, nitrogen, oxygen and hydrogen stable isotope ratios of milk. AB - The stable isotope ratios ((13)C/(12)C, (15)N/(14)N, (18)O/(16)O, D/H) of animal feed and milk were investigated, considering cows stabled in two farms and fed with diets made up of different kinds of C(3) plants and different amounts of maize. Maize was characterised by delta(13)C, delta(18)O and deltaD values significantly higher than those of the C(3) plants, while, for the C(3) plants, Festuca arudinacea had significantly higher content of (13)C and (15)N. The delta(13)C and delta(18)O values of the overall diet and the delta(13)C of milk casein and lipids were shown to be significantly correlated with the percentage of maize in the animal diet. On the other hand, the delta(18)O values of milk water and the delta(18)O, deltaD and delta(15)N values of casein were shown to be only slightly influenced by the amount of maize in the feed, being probably more closely correlated with the geo-climatic and pedological characteristics of the area of origin and with the presence of fresh plant or silage in the ration. The delta(13)C value of casein was shown to be a suitable parameter for evaluating the amount of maize in the diet: each 10% increase in the maize content corresponded to a shift of 0.7 per thousand to 1.0 per thousand in the delta(13)C of casein. A threshold value of -23.5 per thousand for delta(13)C in milk casein, above which it is not possible to exclude the presence of maize in the diet, was suggested. The results obtained could be useful for determining mislabelling of dairy products declared to have been produced by pastured animals or of PDO cheeses with an established amount of maize in the diet and for verifying the unpermitted addition of exogenous components to milk. PMID- 18446771 TI - Simultaneous determination of eight bioactive alkaloids in Corydalis saxicola by high-performance liquid chromatography coupled with diode array detection. AB - Corydalis saxicola Bunting (Papaveraceae), a traditional folk medicine, has been used to treat hepatic diseases for a long time. Owing to its signicant clinical effectiveness against hepatitis, cirrhosis and hepatoma, C. saxicola and its preparation are widely applied. In this study, eight alkaloids, namely isocorydine, scoulerine, dehydrocheilanthifoline, dehydrodiscretamine, dehydroisoapocavidine, dehydrocavidine, palmatine and berberine, which have been previously proven to possess potential antitumour activity, were selected as the chemical markers of C. saxicola. To evaluate the quality of C. saxicola, a simple, accurate and reliable HPLC-DAD method was developed for the simultaneous determination of the above eight compounds. Separation was achieved on a Gemini C(18) column (5 microm, 250 x 4.6 mm i.d., Phenomenex Inc., CA, USA) with a gradient solvent system of 20 mM aqueous ammonium acetate-acetonitrile, at a flow rate of 1.0 mL/min and detected at 270 and 280 nm. All eight calibration curves showed good linearity (R(2) > 0.9992). The method was reproducible with intra- and inter-day variations of less than 5%. The recovery was in the range of 96.09 102.80%. This assay was successfully utilised to quantify the eight alkaloids in C. saxicola from different locations. The results demonstrated that this method is simple, reliable and suitable for the quality control of this medicinal herb. PMID- 18446772 TI - Fingerprint of Hedyotis diffusa Willd. by HPLC-MS. AB - A HPLC-MS fingerprint method has been developed based on the consistent chromatographic features of the major chemical constituents among 10 batches of Hedyotis diffusa Willd. Chromatographic separation was conducted on a Hypersil Keystone Hypurity C(18) column using methanol:water:acetic acid as the mobile phase. Major compounds, including oleanolic acid, ursolic acid and ferulic acid, were analysed by HPLC-MS. Their analysis was ascertained by comparison with data derived from the standard compounds. The HPLC-MS fingerprint was successfully applied to analyse and differentiate samples from different geographical origins, or processing methods. H. diffusa was well distinguished from Hedyotis chrysotricha by HPLC-MS. Therefore the establishment of fingerprint of H. diffusa is critical in assessing and controlling its overall quality. PMID- 18446773 TI - Aggressive vascular surgery in asymptomatic patients is a bad idea. PMID- 18446774 TI - A meta-analysis of 21,178 patients undergoing open or endovascular repair of abdominal aortic aneurysm. AB - BACKGROUND: Several studies have compared outcomes after elective open and endovascular approaches to abdominal aortic aneurysm (AAA) surgery, with varying results. METHODS: A random-effects meta-analysis was undertaken to compare operative outcomes, postoperative complications, 30-day mortality and long-term patient survival after surgery. Endpoints were compared using odds ratios (ORs), weighted mean differences (WMDs) or log hazard ratios (HRs) as appropriate. RESULTS: Forty-two studies comprising 21,178 patients (10,855 open; 10,323 endovascular) were included. In the elective setting (20,715 patients), the endovascular method was associated with a shorter stay in intensive care (WMD--36 h; P < 0.001) and a shorter total postoperative stay (WMD--5.4 days; P < 0.001). Cardiac (OR 1.76; P = 0.002) and respiratory (OR 4.01; P < 0.001) complications were more common after open surgery. In the endovascular group, 30-day mortality was lower (OR 0.46; P < 0.001). Endovascular surgery was also associated with an improved long-term aneurysm-related mortality (HR 0.39; P < 0.001). For ruptured AAA (463 patients), the less invasive operation was associated with a reduced stay in intensive care (WMD--100.4 h; P = 0.005) and a significantly lower 30-day mortality (OR 0.45; P = 0.005). CONCLUSIONS: The endovascular repair of AAA offers a clear benefit in terms of reduction in postoperative adverse events and 30-day mortality. In the longer term, it is also associated with a reduction in aneurysm-related mortality, but not in all-cause mortality. PMID- 18446775 TI - Chemoprevention of gastrointestinal cancer. PMID- 18446776 TI - Wholly endovascular repair of thoracoabdominal aneurysm. AB - BACKGROUND: The aim was to evaluate a wholly endovascular approach to the repair of thoracoabdominal aortic aneurysm (TAAA). METHODS: Six patients (median age 71 years) underwent wholly endovascular repair of TAAA (maximum diameter 56-85 mm) employing individually customized endografts. Procedures were performed under general anaesthesia, with spinal drainage in five patients. Patients were followed by serial computed tomography, plain radiography and duplex imaging for a median of 17 (range 8-44) months. RESULTS: All grafts were deployed as intended, with preservation of all target vessels. There were no postoperative deaths, strokes or paraplegia. One patient suffered a silent myocardial infarction. In two patients a persistent paraostial endoleak was treated by further balloon dilatation of the stent within the endograft fenestration. Imaging before discharge confirmed aneurysm exclusion in all patients. Two patients required late secondary intervention to abolish endoleaks due to side branch disconnection. One patient suffered late occlusion of the coeliac axis without clinical sequelae, and late occlusion of a solitary renal artery in another resulted in dependence on dialysis. There have been no late deaths and all aneurysms remain excluded. CONCLUSION: Wholly endovascular TAAA repair is relatively safe, but long-term follow-up is required to establish its durability. PMID- 18446777 TI - A systematic review of topical negative pressure therapy for acute and chronic wounds. AB - BACKGROUND: Topical negative pressure (TNP) therapy is becoming increasingly popular for all kinds of wounds. Its clinical and cost effectiveness is unclear. METHODS: A search of randomized controlled trials (RCTs) on TNP in adult patients with all kinds of wounds in all settings was undertaken in Medline, Embase, Cinahl (to October 2007) and the Cochrane Library (to issue 4, 2007). Information was also sought from manufacturer of the VAC device. Selection of trials for analysis, quality assessment, data abstraction and data synthesis were conducted by two authors independently. The primary endpoint was any measure of wound healing. Secondary endpoints were infection, pain, quality of life, oedema, microcirculation, bacterial load, adverse events, duration of hospital stay and cost. RESULTS: The search identified 15 publications on 13 RCTs. These reported on patients with chronic wounds, diabetic wounds, pressure ulcers, skin grafts and acute wounds. In chronic and diabetic wounds, TNP did not allow earlier complete wound healing. It was, however, associated with a 1-10 day reduction in the time needed to prepare the wound for secondary closure surgery. In one trial on acute wounds, 17 (95 per cent confidence interval (c.i.) 0.02 to 0.32) per cent more wounds appeared to heal with TNP; the number needed to treat was six. This was, however, at the cost of an 11 (95 per cent c.i. 0.01 to 0.21) per cent higher complication rate; the number needed to harm was nine. CONCLUSION: There is little evidence to support the use of TNP in the treatment of wounds. PMID- 18446778 TI - Pubertal maturation modifies the regulation of insulin-like growth factor-I receptor signaling by estradiol in the rat prefrontal cortex. AB - The transition from adolescence to adulthood is accompanied by substantial plastic modifications in the cerebral cortex, including changes in the growth and retraction of neuronal processes and in the rate of synaptic formation and neuronal loss. Some of these plastic changes are prevented in female rats by prepubertal ovariectomy. The ovarian hormone estradiol modulates neuronal differentiation and survival and these effects are in part mediated by the interaction with insulin-like growth factor-I (IGF-I). In this study, we have explored whether the activation by estradiol of some components of IGF-I receptor signaling is altered in the prefrontal cortex during puberty. Estradiol administration to rats ovariectomized after puberty resulted, 24 h after the hormonal administration, in a sustained phosphorylation of Akt and glycogen synthase kinase 3 beta in the prefrontal cortex. However, this hormonal effect was not observed in animals ovariectomized before puberty. These findings suggest that during pubertal maturation there is a programming by ovarian hormones of the future regulatory actions of estradiol on IGF-I receptor signaling in the prefrontal cortex. The modification in the regulation of IGF-I receptor signaling by estradiol during pubertal maturation may have implications for the developmental changes occurring in the prefrontal cortex in the transition from adolescence to adulthood. PMID- 18446779 TI - Adaptation of microglomerular complexes in the honeybee mushroom body lip to manipulations of behavioral maturation and sensory experience. AB - Worker honeybees proceed through a sequence of tasks, passing from hive and guard duties to foraging activities. The underlying neuronal changes accompanying and possibly mediating these behavioral transitions are not well understood. We studied changes in the microglomerular organization of the mushroom bodies, a brain region involved in sensory integration, learning, and memory, during adult maturation. We visualized the MB lips' microglomerular organization by applying double labeling of presynaptic projection neuron boutons and postsynaptic Kenyon cell spines, which form microglomerular complexes. Their number and density, as well as the bouton volume, were measured using 3D-based techniques. Our results show that the number of microglomerular complexes and the bouton volumes increased during maturation, independent of environmental conditions. In contrast, manipulations of behavior and sensory experience caused a decrease in the number of microglomerular complexes, but an increase in bouton volume. This may indicate an outgrowth of synaptic connections within the MB lips during honeybee maturation. Moreover, manipulations of behavioral and sensory experience led to adaptive changes, which indicate that the microglomerular organization of the MB lips is not static and determined by maturation, but rather that their organization is plastic, enabling the brain to retain its synaptic efficacy. PMID- 18446781 TI - Randomized clinical trial of early versus delayed temporary stoma closure after proctectomy. AB - BACKGROUND: Temporary faecal diversion is recommended with a low colorectal, coloanal or ileoanal anastomosis (LA). This randomized study evaluated early (EC; 8 days) versus late (LC; 2 months) closure of the temporary stoma. METHODS: Patients undergoing rectal resection with LA were eligible to participate. If there was no radiological sign of anastomotic leakage after 7 days, patients were randomized to EC or LC. The primary endpoints were postoperative morbidity and mortality 90 days after the initial resection. RESULTS: Some 186 patients were analysed. There were no deaths within 90 days and overall morbidity rates were similar in the EC and LC groups (31 versus 38 per cent respectively; P = 0.254). Overall surgical complication (both 15 per cent; P = 1.000) and reoperation (both 8 per cent; P = 1.000) rates were similar, but wound complications were more frequent after EC (19 versus 5 per cent; P = 0.007). Small bowel obstruction (3 versus 16 per cent; P = 0.002) and medical complications (5 versus 15 per cent; P = 0.021) were more common with LC. Median (range) hospital stay was reduced by EC (16 (6-59) versus 18 (9-262) days; P = 0.013). CONCLUSION: Early stoma closure is feasible in selected patients, with reduced hospital stay, bowel obstruction and medical complications, but a higher wound complication rate. REGISTRATION NUMBER: NCT00428636 (http://www.clinicaltrials.gov). PMID- 18446782 TI - Radiation exposure during endovascular aneurysm repair. AB - BACKGROUND: Endovascular stent-grafting is an established option for the repair of abdominal aortic aneurysm (AAA) that can involve prolonged manipulation under radiological control. The aim was to determine the average radiation exposure sustained during endovascular aneurysm repair (EVAR) and the first year of postoperative surveillance. METHODS: Prospective radiation dose data were recorded and used to calculate dose area product (DAP) values for 96 patients undergoing EVAR. The DAP data were then used to determine the entrance skin dose (ESD), an indicator of potential skin damage, and the effective dose, an indicator of long-term cancer risk, for each patient. RESULTS: The median ESD during EVAR was 0.85 (interquartile range 0.51-3.74) Gy. The threshold for possible radiation-induced skin damage of 2 Gy was exceeded in 29 per cent of procedures. The effective dose of radiation in the first year following EVAR was 79 mSv. CONCLUSION: Radiation doses administered during EVAR were higher than previously thought, with a potential risk of radiation-induced skin damage and later malignancy. PMID- 18446783 TI - The L1-CAM, Neuroglian, functions in glial cells for Drosophila antennal lobe development. AB - Although considerable progress has been made in understanding the roles of olfactory receptor neurons (ORNs) and projection neurons (PNs) in Drosophila antennal lobe (AL) development, the roles of glia have remained largely mysterious. Here, we show that during Drosophila metamorphosis, a population of midline glial cells in the brain undergoes extensive cellular remodeling and is closely associated with the collateral branches of ORN axons. These glial cells are required for ORN axons to project across the midline and establish the contralateral wiring in the ALs. We find that Neuroglian (Nrg), the Drosophila homolog of the vertebrate cell adhesion molecule, L1, is expressed and functions in the midline glial cells to regulate their proper development. Loss of Nrg causes the disruption in glial morphology and the agenesis of the antennal commissural tract. Our genetic analysis further demonstrates that the functions of Nrg in the midline glia require its ankyrin-binding motif. We propose that Nrg is an important regulator of glial morphogenesis and axon guidance in AL development. PMID- 18446784 TI - Locomotor control by the central complex in Drosophila-An analysis of the tay bridge mutant. AB - Several aspects of locomotor control have been ascribed to the central complex of the insect brain; however, the role of distinct substructures of this complex is not well known. The tay bridge1 (tay1) mutant of Drosophila melanogaster was originally isolated on the basis of reduced walking speed and activity. In addition, tay1 is defective in the compensation of rotatory stimuli during walking and histologically, tay1 causes a mid-sagittal constriction of the protocerebral bridge, a constituent of the central complex. Cloning of the tay gene revealed that it encodes a novel protein with no significant homology to any known protein. To associate the behavioral phenotypes with the anatomical defect in the protocerebral bridge, we used different driver lines to express the tay cDNA in various neuronal subpopulations of the central brain in tay1-mutant flies. These experiments showed an association of the aberrant walking speed and activity with the structural defect in the protocerebral bridge. In contrast, the compensation of rotatory stimuli during walking was rescued without a restoration of the protocerebral bridge. The results of our differential rescue approach are supported by neuronal silencing experiments using conditional tetanus toxin expression in the same subset of neurons. These findings show for the first time that the walking speed and activity is controlled by different substructures of the central brain than the compensatory locomotion for rotatory stimuli. PMID- 18446785 TI - Exendin-4 induction of Egr-1 expression in INS-1 beta-cells: interaction of SRF, not YY1, with SRE site of rat Egr-1 promoter. AB - Glucagon-like peptide-1 (GLP-1) induces several immediate early response genes such as c-fos, c-jun, and early growth response-1 (Egr-1), which are involved in cell proliferation and differentiation. We recently reported that exendin-4 (EX 4), a potent GLP-1 agonist, upregulated Egr-1 expression via phosphorylation of CREB, a transcription factor in INS-1 beta-cells. This study was designed to investigate the role of another transcription factors, serum response factor (SRF) and Yin Yang-1 (YY1), in EX-4-induced Egr-1 expression. EX-4 significantly increased Egr-1 mRNA and subsequently its protein level. EX-4-induced Egr-1 expression was inhibited by pretreatment with a PKA inhibitor, H-89, and an MEK inhibitor, PD 98059. The siRNA-mediated inhibition of PKA and ERK1 resulted in significant reduction of EX-4-induced Egr-1 expression. Promoter analyses showed that SRE clusters were essential for Egr-1 transcription, and YY1 overexpression did not affect Egr-1 promoter activity. EMSA results demonstrated that EX-4 induced transient increase in DNA-protein complex on SRE site, and that both SRF and phospho-SRF were bound to this site. Treatment of either YY1 consensus oligonucleotide or YY1 antibody did not effect the change of density or migration of the DNA-protein complex. Collectively, EX-4-induced Egr-1 expression is largely dependent on cAMP-mediated extracellular signal-regulated kinase activation, and EX-4 induces Egr-1 transcription via the interaction of SRF and phospho-SRF to SRE sites. PMID- 18446786 TI - Resveratrol causes COX-2- and p53-dependent apoptosis in head and neck squamous cell cancer cells. AB - Cyclooxygenase-2 (COX-2) content is increased in many types of tumor cells. We have investigated the mechanism by which resveratrol, a stilbene that is pro apoptotic in many tumor cell lines, causes apoptosis in human head and neck squamous cell carcinoma UMSCC-22B cells by a mechanism involving cellular COX-2. UMSCC-22B cells treated with resveratrol for 24 h, with or without selected inhibitors, were examined: (1) for the presence of nuclear activated ERK1/2, p53 and COX-2, (2) for evidence of apoptosis, and (3) by chromatin immunoprecipitation to demonstrate p53 binding to the p21 promoter. Stilbene induced apoptosis was concentration-dependent, and associated with ERK1/2 activation, serine-15 p53 phosphorylation and nuclear accumulation of these proteins. These effects were blocked by inhibition of either ERK1/2 or p53 activation. Resveratrol also caused p53 binding to the p21 promoter and increased abundance of COX-2 protein in UMSCC-22B cell nuclei. Resveratrol-induced nuclear COX-2 accumulation was dependent upon ERK1/2 activation, but not p53 activation. Activation of p53 and p53-dependent apoptosis were blocked by the COX-2 inhibitor, NS398, and by transfection of cells with COX-2-siRNA. In UMSCC-22B cells, resveratrol-induced apoptosis and induction of nuclear COX-2 accumulation share dependence on the ERK1/2 signal transduction pathway. Resveratrol-inducible nuclear accumulation of COX-2 is essential for p53 activation and p53-dependent apoptosis in these cancer cells. PMID- 18446787 TI - Differential intracellular transport and binding of verotoxin 1 and verotoxin 2 to globotriaosylceramide-containing lipid assemblies. AB - Although verotoxin-1 (VT1) and verotoxin-2 (VT2) share a common receptor, globotriaosyl ceramide (Gb(3)), VT2 induces distinct animal pathology and is preferentially associated with human disease. Moreover VT2 cytotoxicity in vitro is less than VT1. We therefore investigated whether these toxins similarly traffic within cells via similar Gb(3) assemblies. At 4 degrees C, fluorescent VT1 and VT2 bound both coincident and distinct punctate surface Gb(3) microdomains. After 10 min at 37 degrees C, similar distinct/coincident micropunctate intracellular localization was observed. Most internalized VT2, but not VT1, colocalized with transferrin. After 1 h, VT1 and VT2 coalesced during retrograde transport to the Golgi. During prolonged incubation (3-6 h), VT1, and VT2 (more slowly), exited the Golgi to reach the ER/nuclear envelope. At this time, VT2 induced a previously unreported, retrograde transport-dependent vacuolation. Cell surface and intracellular VT1 showed greater detergent resistance than VT2, suggesting differential 'raft' association. >90% (125)I-VT1 cell surface bound, or added to detergent-resistant cell membrane extracts (DRM), was in the Gb(3)-containing sucrose gradient 'insoluble' fraction, whereas only 30% (125)I-VT2 was similarly DRM-associated. VT1 bound more efficiently to Gb(3)/cholesterol DRMs generated in vitro. Only VT1 binding was inhibited by high cholesterol/Gb(3) ratios. VT2 competed less effectively for (125)I-VT1/Gb(3) DRM binding but only VT2-Gb(3)/cholesterol DRM-binding was augmented by sphingomyelin. Differential VT1/VT2 Gb(3) raft-binding may mediate differential cell binding/intracellular trafficking and cytopathology. PMID- 18446788 TI - Palmitate increases superoxide production through mitochondrial electron transport chain and NADPH oxidase activity in skeletal muscle cells. AB - The effect of unbound palmitic acid (PA) at plasma physiological concentration range on reactive oxygen species (ROS) production by cultured rat skeletal muscle cells was investigated. The participation of the main sites of ROS production was also examined. Production of ROS was evaluated by cytochrome c reduction and dihydroethidium oxidation assays. PA increased ROS production after 1 h incubation. A xanthine oxidase inhibitor did not change PA-induced ROS production. However, the treatment with a mitochondrial uncoupler and mitochondrial complex III inhibitor decreased superoxide production induced by PA. The importance of mitochondria was also evaluated in 1 h incubated rat soleus and extensor digitorum longus (EDL) muscles. Soleus muscle, which has a greater number of mitochondria than EDL, showed a higher superoxide production induced by PA. These results indicate that mitochondrial electron transport chain is an important contributor for superoxide formation induced by PA in skeletal muscle. Results obtained with etomoxir and bromopalmitate treatment indicate that PA has to be oxidized to raise ROS production. A partial inhibition of superoxide formation induced by PA was observed by treatment with diphenylene iodonium, an inhibitor of NADPH oxidase. The participation of this enzyme complex was confirmed through an increase of p47(phox) phosphorylation after treatment with PA. PMID- 18446789 TI - Hepatitis C virus infection: molecular pathways to metabolic syndrome. AB - Chronic infection with hepatitis C virus (HCV) can induce insulin resistance (IR) in a genotype-dependent fashion, thus contributing to steatosis, progression of fibrosis and resistance to interferon therapy. The molecular mechanisms in genotype 1 patients that lead to metabolic syndrome are still ambiguous. Based on our current understanding, HCV proteins associate with mitochondria and endoplasmic reticulum and promote oxidative stress. The latter mediates signals involving the p38 mitogen-activated protein kinase and activates nuclear factor kappa B. This transcription factor plays a key role in the expression of cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin 6, interleukin 8, tumor growth factor beta, and Fas ligand. TNF-alpha inhibits the function of insulin receptor substrates and decreases the expression of the glucose transporter and lipoprotein lipase in peripheral tissues, which is responsible for the promotion of insulin resistance. Furthermore, reduced adiponectin levels, loss of adiponectin receptors, and decreased anti-inflammatory peroxisome proliferator-activated receptor alpha in the liver of HCV patients may contribute to reduced fatty acid oxidation, inflammation, and eventually lipotoxicity. This chain of events may be initiated by HCV-associated IR and provides a direction for future research in the areas of therapeutic intervention. PMID- 18446792 TI - Features of TAP-independent MHC class I ligands revealed by quantitative mass spectrometry. AB - TAP is responsible for transferring cytosolic peptides into the ER, where they can be loaded onto MHC molecules. Deletion of TAP results in a drastic reduction of MHC class I surface expression and alters the presented peptide pattern. This key molecule in antigen processing is tackled by several viruses and lost in some tumors, rendering the altered cells less vulnerable to T cell-based immune surveillance. Using the TAP-deficient cell line LCL721.174 and its TAP-expressing progenitor cell line LCL721.45, we identified and quantified more than 160 HLA ligands, 50 of which were presented TAP-independently. Peptides which were predominantly presented on the TAP-deficient LCL721.174 cell line had a decreased MHC binding affinity according to their SYFPEITHI and BIMAS score. About half of the identified TAP-independently presented peptides were not derived from signal sequences and may partly be generated by the proteasome. Furthermore, we have excluded the possibility that differences in HLA ligand presentation between LCL721.45 and LCL721.174 were due to varying expression of the source proteins or due to changes in the antigen loading complex. Features of peptides presented independently of TAP as well as proteasomal contribution to their generation provide an insight into basic immunological mechanisms. PMID- 18446790 TI - Targeting TARP, a novel breast and prostate tumor-associated antigen, with T cell receptor-like human recombinant antibodies. AB - MHC class I molecules are important components of immune surveillance. There are no available methods to directly visualize and determine the quantity and distribution of MHC/peptide complexes on individual cells or to detect such complexes on antigen-presenting cells in tissues. MHC-restricted recombinant antibodies with the same specificity of T cell receptors (TCR) may become a valuable tool to address these questions. They may also serve as valuable targeting molecules that mimic the specificity of cytotoxic T cells. We isolated by phage display a panel of human recombinant Fab antibodies with peptide specific, MHC-restricted TCR-like reactivity directed toward HLA-A2-restricted T cell epitopes derived from a novel antigen termed TCRgamma alternative reading frame protein (TARP) which is expressed on prostate and breast cancer cells. We have characterized one of these recombinant antibodies and demonstrated its capacity to directly detect specific HLA-A2/TARP T cell epitopes on antigen presenting cells that have complexes formed by naturally occurring active intracellular processing of the antigen, as well as on the surface of tumor cells. Moreover, by genetic fusion we armed the TCR-like antibody with a potent toxin and demonstrated that it can serve as a targeting moiety killing tumor cells in a peptide-specific, MHC-restricted manner similar to cytotoxic T lymphocytes. PMID- 18446795 TI - Laser-fabricated porous alumina membranes for the preparation of metal nanodot arrays. PMID- 18446796 TI - Magnificent sea-anemone-like magnetic silica capsules reinforced with carbon nanotubes. PMID- 18446791 TI - Selective expansion of memory CD4(+) T cells by mitogenic human CD28 generates inflammatory cytokines and regulatory T cells. AB - Costimulatory signals are important for development of effector and regulatory T cells. In this case, CD28 signaling is usually considered inert in the absence of signaling through the TCR. By contrast, mitogenic rat CD28 mAb reportedly expand regulatory T cells without TCR stimulation. We found that a commercially available human CD28 mAb (ANC28) stimulated PBMC without TCR co-ligation or cross linking; ANC28 selectively expanded CD4(+)CD25(+)FOXP3(-) (Teff) and CD4(+)CD25(+)FOXP3(+) (Treg) cells. ANC28 stimulated the CD45RO(+) CD4(+) (memory) population, whereas CD45RA(+)CD4(+) (naive) cells did not respond. ANC28 also induced inflammatory cytokines. Treg induced by ANC28 retain the Treg phenotype longer than costimulated Treg. Treg induced by ANC28 suppressed CD25(-) T cells through a contact-dependent mechanism. Purity influenced the response of CD4(+)CD25(+ )cells because bead-purified CD4(+)CD25(+ )cells (85-90% pure) responded strongly to ANC28, whereas 98% pure FACS-sorted CD4(+)CD25(bright) (Treg) did not respond. Purified CD4(+)CD25(int) cells responded similarly to the bead-purified CD4(+)CD25(+) cells. Thus, pre-activated CD4(+) T cells (CD25(int)) respond to ANC28 rather than Treg (CD25(bright)). The ability of ANC28 to expand both effectors producing inflammatory cytokines as well as suppressive regulatory T cells might be useful for ex vivo expansion of therapeutic T cells. PMID- 18446797 TI - Self-assembly of single-stranded RNA on carbon nanotube: polyadenylic acid to form a duplex structure. AB - All messenger-RNA (mRNA) molecules in eukaryotic cells have a polyadenylic acid [poly(rA)] tail at the 3'-end and human poly(rA) polymerase (PAP) has been considered as a tumor-specific target. A ligand that is capable of recognizing and binding to the poly(rA) tail of mRNA might interfere with the full processing of mRNA by PAP and can be a potential therapeutic agent. We report here for the first time that single-walled carbon nanotubes (SWNTs) can cause single-stranded poly(rA) to self-structure and form a duplex structure, which is studied by UV melting, atomic force microscopy, circular dichroism spectroscopy, and NMR spectrometry. SWNTs have shown potential applications that range from nanodevices, gene therapy, and drug delivery to membrane separations. Our studies may provide new insights into the application of SWNTs under physiological conditions, possibly being used as probes that target specific gene sequences. PMID- 18446798 TI - Creating a uniform distribution of fullerene C60 nanorods in a polymer matrix and its photovoltaic applications. PMID- 18446799 TI - Identification of peptidases in Nicotiana tabacum leaf intercellular fluid. AB - Peptidases in the extracellular space might affect the integrity of recombinant proteins expressed in, and secreted from, plant cells. To identify extracellular peptidases, we recovered the leaf intercellular fluid from Nicotiana tabacum plants by an infiltration-centrifugation method. The activity of various peptidases was detected by an in vitro assay in the presence of specific inhibitors, using BSA and human serum gamma-globulin as substrates. Peptidases were detected by 1- and 2-D zymography in a polyacrylamide gel containing gelatin as substrate. Proteolytic activity was observed over a wide range of molecular masses equal to, or higher than, 45 kDa. To identify the peptidases, the extracellular proteins were digested with trypsin and analyzed by LC and MS. Seventeen peptides showing identity or similarity to predicted plant aspartic, cysteine, and serine peptidases have been identified. The extracellular localization of a cysteine peptidase aleurain homolog was also shown. PMID- 18446800 TI - The up-regulation of 14-3-3 proteins in Smad4 deficient epidermis and hair follicles at catagen. AB - Each postnatal hair follicle (HF) perpetually goes through three phases: anagen, catagen, and telogen. The molecular signals that orchestrate the follicular transition between phases are still largely unknown. Our previous study shows that the keratinocyte specific Smad4 knockout mice exhibit progressive alopecia due to the mutant HFs failure to undergo programmed regression. To investigate the detailed molecular events controlling this process, the protein profiles of Smad4 mutant and control epidermal and HF keratinocytes were compared using 2-D difference gel electrophoresis (2-D DIGE) proteomic analysis. Eighty-six differentially expressed protein spots were identified by MALDI-TOF/TOF MS or ESI MS/MS as 72 proteins, of which 29 proteins were found to be changed during the anagen-catagen transition of HFs in Smad4 mutants compared with the controls. The differentially expressed proteins represent a wide spectrum of functional classes such as keratin, the cytoskeleton, cellular growth and differentiation, ion combination and transfer, protein enzymes. Notably, we found that the 14-3-3sigma protein together with the 14-3-3zeta and 14-3-3beta proteins were significantly down-regulated only in wild-type keratinocytes but not in Smad4 mutant keratinocytes during the catagen phase, suggesting that increased expression of 14-3-3 proteins might contribute to the blockade of catagen initiation in Smad4 deficient HFs. PMID- 18446801 TI - Novel approaches to predict the retention of histidine-containing peptides in immobilized metal-affinity chromatography. AB - The new method lazy learning method-local lazy regression (LLR) was first used to model the quantitative structure-retention relationship (QSRR) for predicting and explaining the retention behaviors of peptides in the nickel column in immobilized metal-affinity chromatography (IMAC). The best multilinear regression (BMLR) method implemented in the CODESSA was used to select the most appropriate molecular descriptors from a large set and build a linear regression model. Based on the selected five descriptors, another two approaches, projection pursuit regression (PPR) and LLR were used to build more accurate QSRR models. The coefficients of determination (R(2)) of the best model developed based on LLR were 0.9446 and 0.9252 for the training set and the test set, respectively. By comparison, it was proved that the novel local learning method LLR was a very promising tool for QSRR modeling with excellent predictive capability for the prediction of imidazole concentration (IMC) values of histidine-containing peptides in IMAC. It could be used in other chromatography research fields and that should facilitate the design and purification of peptides and proteins. PMID- 18446802 TI - Microchip analysis of plant glucosinolates. AB - We describe a new and selective analytical method for the separation and quantitation of plant glucosinolates. The new method, which utilizes microchip CE (micro-CE) with fluorescence detection, circumvents the multistep procedures characteristic of conventional methods. Glucosinolates form charge transfer complexes with the xanthene dyes phloxine-B and eosin-B. The glucosinolates phloxine-B complex cannot be excited at 470 nm. Thus, the decrease in peak intensity of phloxine-B after complex formation is used to quantitatively measure total glucosinolates in Arabidopsis thaliana seeds. For qualitative analysis, complex formation with eosin-B is used. The sensitivity of eosin-B detection at excitation/emission 470 nm/540 nm was low. However, sensitivity increased following complex formation with sinigrin (> or =3 microg/mL). A batch-learning, self-organizing map was applied to visualize and organize analytical data into 2 D matrix with similar and related data clustered together or near each other. This organized matrix was used to optimize electrophoretic conditions for the analysis. This study suggests potential applications of micro-CE in plant metabolomics analyses without use of labeling fluorophores. PMID- 18446803 TI - Comprehensive proteome analysis of mouse liver by ampholyte-free liquid-phase isoelectric focusing. AB - In this study, ampholyte-free liquid-phase IEF (LIEF) was combined with narrow pH range 2-DE and SDS-PAGE RP-HPLC for comprehensive analysis of mouse liver proteome. Because LIEF prefractionation was able to reduce the complexity of the sample and enhance the loading capacity of IEF strips, the number of visible protein spots on subsequent 2-DE gels was significantly increased. A total of 6271 protein spots were detected after integrating five narrow pH range 2-DE gels following LIEF prefractionation into a single virtual 2-DE gel. Furthermore, the pH 3-5 LIEF fraction and the unfractionated sample were separated by pH 3-6 2-DE and identified by MALDI-TOF/TOF MS, respectively. In parallel, the pH 3-5 LIEF fraction was also analyzed by SDS-PAGE RP-HPLC MS/MS. LIEF-2-DE and LIEF-HPLC could obviously improve the separation efficiency and the confidence of protein identification, which identified a higher number of low-abundance proteins and proteins with extreme physicochemical characteristics or post-translational modifications compared to conventional 2-DE method. Furthermore, there were 207 proteins newly identified in mouse liver in comparison with previously reported large-scale datasets. It was observed that the combination of LIEF-2-DE and LIEF HPLC was effective in promoting MS-based liver proteome profiling and could be applied on similar complex tissue samples. PMID- 18446804 TI - A novel strategy for avian species identification by cytochrome b gene. AB - We report a DNA-based test that can be applied to any avian species so that the amplicon can be used in species identification. The need for the test arose from the requirement to enforce the Wildlife Conservation Act in Taiwan where over 150 avian species are protected. It is difficult to enforce the law if no gross morphology is present and hence there is a requirement to develop a DNA test. This study uses a novel strategy for avian species identification by the cytochrome b gene where a series of primer pairs producing amplicons of decreasing size was designed. The test is designed to produce the largest possible amplicon based upon the quality of the DNA in the sample. A total of 331 avian samples were tested representing 40 species. Sequencing of the amplicons revealed limited intraspecies variation and that no DNA sequence was shared by samples from two different avian species. The closest genetic distance among the 40 species was 0.059 which was between Lonchura punctulata and Estrilda melpoda based upon data from the smallest amplicon. A DNA databank including 138 sequence types from 331 samples tested, representing 40 different species, was constructed in this study. A blind test was used to determine the value for this system for forensic applications that successfully identified the species. PMID- 18446805 TI - Fabrication and integration of planar electrodes for contactless conductivity detection on polyester-toner electrophoresis microchips. AB - In this report, we describe the microfabrication and integration of planar electrodes for contactless conductivity detection on polyester-toner (PT) electrophoresis microchips using toner masks. Planar electrodes were fabricated by three simple steps: (i) drawing and laser-printing the electrode geometry on polyester films, (ii) sputtering deposition onto substrates, and (iii) removal of toner layer by a lift-off process. The polyester film with anchored electrodes was integrated to PT electrophoresis microchannels by lamination at 120 degrees C in less than 1 min. The electrodes were designed in an antiparallel configuration with 750 microm width and 750 microm gap between them. The best results were recorded with a frequency of 400 kHz and 10 Vpp using a sinusoidal wave. The analytical performance of the proposed microchip was evaluated by electrophoretic separation of potassium, sodium and lithium in 150 microm wide x 6 microm deep microchannels. Under an electric field of 250 V/cm the analytes were successfully separated in less than 90 s with efficiencies ranging from 7000 to 13,000 plates. The detection limits (S/N = 3) found for K+, Na+, and Li+ were 3.1, 4.3, and 7.2 micromol/L, respectively. Besides the low-cost and instrumental simplicity, the integrated PT chip eliminates the problem of manual alignment and gluing of the electrodes, permitting more robustness and better reproducibility, therefore, more suitable for mass production of electrophoresis microchips. PMID- 18446806 TI - Macrocyclic polyamine-modified poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith for capillary electrochromatography. AB - 1,4,10,13,16-Pentaazatricycloheneicosane-9,17-dione (macrocyclic polyamine) modified polymer-based monolithic column for CEC was prepared by ring opening reaction of epoxide groups from poly(glycidyl methacrylate-co-ethylene dimethacrylate) (GMA-co-EDMA) monolith with macrocyclic polyamine. Conditions such as reaction time and concentration of macrocyclic polyamine for the modification reaction were optimized to generate substantial EOF and enough chromatographic interactions. Anodic EOF was observed in the pH range of 2.0-8.0 studied due to the protonation of macrcyclic polyamine at the surface of the monolith. Morphology of the monolithic column was examined by SEM and the incorporation of macrocyclic polyamine to the poly(GMA-co-EDMA) monolith was characterized by infrared (IR) spectra. Successful separation of inorganic anions, isomeric benzenediols, and benzoic acid derivatives on the monolithic column was achieved for CEC. In addition to hydrophobic interaction, hydrogen bonding and electrostatic interaction played a significant role in the separation process. PMID- 18446807 TI - Structural characterization of mesquite (Prosopis velutina) gum and its fractions. AB - Structural and physicochemical characteristics of mesquite gum (from Prosopis velutina) were investigated using FT-IR spectroscopic, mass spectrometric and chromatographic methods. Four fractions (F-I, F-IIa, F-IIb and F-III) were isolated by hydrophobic interaction chromatography. The samples were characterized and analyzed for their monosaccharide and oligomers composition by high performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). L-Arabinose (L-Ara) and D-galactose (D-Gal) were found as the main carbohydrate constituent residues in the polysaccharides from mesquite gum and their ratio (L-Ara/D-Gal) varied within the range 2.54 to 3.06 among the various fractions. Small amounts of D-glucose (D-Glc), D-mannose (D-Man) and D-xylose (D Xyl) were also detected, particularly in Fractions IIa, IIb and III. Infrared spectroscopy identified polysaccharides and protein in all the samples. Data from mass spectrometry (MALDI-TOF MS) was consistent with the idea that the structure corresponding to the periphereal chains of Fraction I is predominantly a chain of pentoses attached to uronic acid. PMID- 18446808 TI - Monodisperse gelatin microspheres as a drug delivery vehicle: release profile and effect of crosslinking density. AB - Uniform gelatin microspheres (GMS) of a wet size of 100 microm in diameter were fabricated by the electric field assisted precision particle fabrication (E-PPF) method and crosslinked with different glutaraldehyde (GA) concentrations to study the effect of the crosslinking density on drug release. The drug release profiles of the crosslinked GMS were studied along with the intraparticle drug distribution and the particle degradation characteristics. Due to the concentration gradient of GA along the diffusion path into the GMS, the crosslinking density is higher on the GMS surface, making it less susceptible to degradation. As a result, the GMS with higher GA concentrations (0.375-0.875%) exhibited a highly resistant surface toward enzymatic degradation. On the other hand, the amount of drug complexation at the surface decreases as the GA concentration increases, which can be attributed to the lowered basicity of gelatin caused by the increased crosslinking density. These factors collectively affect the drug release kinetics and give rise to similar release profiles for GMS above a GA concentration of 0.375%. PMID- 18446809 TI - Investigation of interaction between human hemoglobin A0 and platinum anticancer drugs by capillary isoelectric focusing with whole column imaging detection. AB - CIEF with whole column imaging detection (WCID) was used to investigate the interaction of platinum-based anticancer drugs, cis-platinum(II) diamine dichloride (cisplatin) and [SP-4-2-{1R-trans)]-(1,2-cyclohexanediamine N,N')[ethanedioata(2-)-O,O']platinum (oxaliplatin), with human hemoglobin A(0) (Hb). This technique facilitates the investigation and characterization of the formation of adducts between drugs and proteins. Cisplatin and oxaliplatin were mixed with the target protein at different concentrations (0:1, 1:1, 1:10, 1:50, and 1:100), and the reaction mixtures were incubated for 0, 0.5, 1, 12, 24, 48, and 72 h at 37 degrees C in a water-bath. The focused Hb-drug adduct profiles were imaged by WCID. At higher drug to protein molar ratios (for both oxaliplatin and cisplatin), the results exhibit significant changes in the peak shapes and heights, which may indicate the destabilization of the protein. However, the conformational change was less evident at lower molar ratios. In addition, a major pI shift was observed for the oxaliplatin reaction mixtures (for 1:10, 1:50, and 1:100 ratios). In comparison with previously reported findings obtained by other analytical methods, conclusions were drawn about the validity of CIEF as a simple and convenient method for the investigation of protein-drug interactions. These results may provide useful information for further understanding the activity and toxicity of these chemotherapeutic drugs and improving their clinical performance. PMID- 18446810 TI - Elevated fibroblast growth factor-2 increases tumor necrosis factor-alpha induced endothelial cell death in high glucose. AB - Glucose and tumor necrosis factor-alpha (TNFalpha) concentrations are elevated in diabetes. Both of these factors correlate with diabetic vasculopathy and endothelial cell apoptosis, yet their combined effects have not been measured. We have previously shown that the angiogenic growth factor fibroblast growth factor 2 (FGF-2), which is generally protective against endothelial cell death, is similarly elevated in high glucose conditions. We therefore investigated the effect of TNFalpha on endothelial cell death under normal and elevated glucose conditions, with a particular focus on FGF-2. Porcine aortic endothelial cells were cultured in 5 and 30 mM glucose and stimulated with TNFalpha, together with FGF-2 or a neutralizing FGF-2 antibody. Cell death was measured via cell counts or an annexin apoptotic assay, and cell cycle phase was determined by propidium iodide labeling. TNFalpha-induced endothelial cell death increased for cells in high glucose, and cell death was enhanced with increasing FGF-2 exposure and negated by a neutralizing FGF-2 antibody. Endothelial cells were most susceptible to TNFalpha-induced cell death when stimulated with FGF-2 18 h prior to TNFalpha, corresponding to cell entry into S phase of the proliferative cycle. The FGF-2 associated increase in TNFalpha-induced cell death was negated by blocking cell entry into S phase. Endothelial cell release of FGF-2 in high glucose leads to cell cycle progression, which makes cells more susceptible to TNFalpha-induced cell death. These data suggest that growth factor outcomes in high glucose depend on secondary mediators such as cytokines and stimulation cell cycle timing. PMID- 18446811 TI - Two distinct amplification events of the c-myc locus in a colorectal tumour. AB - Southern hybridisation of genomic DNA extracted from a human primary colorectal carcinoma revealed amplification of a fragment containing the wild-type c-myc locus. Two additional rearranged DNA fragments, lying upstream of c-myc, fused to distant non-contiguous sequences from the same chromosome, with an opposite configuration (head to head vs. head to tail), were also found to be amplified. Sequences analysis suggested that these rearrangements resulted from illegitimate recombination at two distinct points within the DNA sequence just upstream of the c-myc ORF and further that these events triggered two different amplification mechanisms, only one of which, involving a strand invasion event following DNA double strand breaks, increased the copy number of the c-myc ORF. PMID- 18446812 TI - Brachy-syndactyly caused by loss of Sfrp2 function. AB - Wnt signaling pathways are regulated both at the intracellular and extracellular levels. During embryogenesis, the in vivo effects of the secreted frizzled related protein (Sfrp) family of Wnt inhibitors are poorly understood. Here, we show that inactivation of Sfrp2 results in subtle limb defects in mice with mesomelic shortening and consistent shortening of all autopodal elements that is clinically manifested as brachydactyly. In addition, there is soft-tissue syndactyly of the hindlimb. The brachydactyly is caused by decreased chondrocyte proliferation and delayed differentiation in distal limb chondrogenic elements. These data suggest that Sfrp2 can regulate both chondrogenesis and regression of interdigital mesenchyme in distal limb. Sfrp2 can also repress canonical Wnt signaling by Wnt1, Wnt9a, and Wnt4 in vitro. Sfrp2-/- and TOPGAL/Sfrp2-/- mice have a mild increase in beta-catenin and beta-galactosidase staining, respectively, in some phalangeal elements. This however does not exclude a potential concurrent effect on non-canonical Wnt signaling in the growth plate. In combination with what is known about BMP and Wnt signaling in human brachydactylies, our data establish a critical role for Sfrp2 in proper distal limb formation and suggest SFPR2 could be a novel candidate gene for human brachy syndactyly defects. PMID- 18446814 TI - Study of pepsin phosphorylation using immobilized metal affinity chromatography. AB - The interactions of pepsin with immobilized trivalent metal ions and the participation of the enzyme phosphate group in this process were investigated using high performance immobilized metal affinity chromatography. Two different sorbents were used: the newly prepared one, consisting of Ga(3+ )chelate of (6 amino-1-hydroxyhexane-1,1-diyl) bis(phosphonic acid) covalently bound to a methacrylate support (BP-Ga(3+)), and the commercial one, containing immobilized Fe(3+ )ions (POROS MC20-Fe(3+)). The comparison of the behavior of porcine pepsin A and its partially dephosphorylated form on both sorbents showed that both forms of pepsin were adsorbed under the same conditions. To eliminate the participation of free carboxyl groups in pepsin adsorption, both enzyme forms were modified by amidation or esterification. Native enzyme and its partially dephosphorylated form both with modified carboxyl groups differed in their interaction with immobilized Ga(3+ )and Fe(3+). Phosphorylated pepsin molecules with esterified carboxyl groups were adsorbed on both sorbents while nonphosphorylated ones with esterified carboxyl groups were not adsorbed. PMID- 18446813 TI - BMP signaling dynamics in embryonic orofacial tissue. AB - The bone morphogenetic protein (BMP) family represents a class of signaling molecules, that plays key roles in morphogenesis, cell proliferation, survival and differentiation during normal development. Members of this family are essential for the development of the mammalian orofacial region where they regulate cell proliferation, extracellular matrix synthesis, and cellular differentiation. Perturbation of any of these processes results in orofacial clefting. Embryonic orofacial tissue expresses BMP mRNAs, their cognate proteins, and BMP-specific receptors in unique temporo-spatial patterns, suggesting functional roles in orofacial development. However, specific genes that function as downstream mediators of BMP action during orofacial ontogenesis have not been well defined. In the current study, elements of the Smad component of the BMP intracellular signaling system were identified and characterized in embryonic orofacial tissue and functional activation of the Smad pathway by BMP2 and BMP4 was demonstrated. BMP2 and BMP4-initiated Smad signaling in cells derived from embryonic orofacial tissue was found to result in: (1) phosphorylation of Smads 1 and 5; (2) nuclear translocation of Smads 1, 4, and 5; (3) binding of Smads 1, 4, and 5 to a consensus Smad binding element (SBE)-containing oligonucleotide; (4) transactivation of transfected reporter constructs, containing BMP-inducible Smad response elements; and (5) increased expression at transcriptional as well as translational levels of Id3 (endogenous gene containing BMP receptor-specific Smad response elements). Collectively, these data document the existence of a functional Smad-mediated BMP signaling system in cells of the developing murine orofacial region. PMID- 18446815 TI - Repeatability of monolithic HPLC columns while using a flow program. AB - Fast HPLC methods are becoming more and more important. Using monolithic HPLC columns for fast separations, a flow program can be applied for further decrease in the total run time. An interesting issue was whether the flow program affects repeatability. The investigated method was a generic assay for the oral antidiabetic drugs glibenclamide and glimepiride in the presence of two of their degradation products. A flow program ranging from 5.0 to 9.9 mL/min had been set up to decrease the run time to approximately 1.7 min. Within-day RSD% (n = 40) for both retention times and peak areas were less than 1%. At flow rates higher than 7 mL/min, repeatability was impaired to some extent. It became mainly noticeable through the day-to-day precision (n = 60) which showed RSD% up to 2%. However, further investigations indicated that this was rather related to pump inefficiency at high flow rates than to the flow program as such. Presuming the use of appropriate equipment, qualified for high flow rates, the application of a flow program for shortening the run time is absolutely reasonable and does not affect repeatability. PMID- 18446818 TI - Serum concentrations of laminin gamma2 fragments in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: The laminin (LN) gamma2 chain expression has been linked to tumor invasion and prognosis. To provide a convenient clinical use, procedures that analyze LNgamma2 expression by using the serum and/or urine of patients should be developed. METHODS: The serum concentrations of the N-terminal fragments of the LNgamma2 chain in 73 patients with head and neck squamous cell carcinomas were measured by immunoassay. RESULTS: The concentrations of the LNgamma2 fragments ranged between 14.5 and 324.2 ng/mL, and the normal upper limit was estimated to be 50 ng/mL. The LNgamma2 fragment concentrations increased according to the T classification. The amount of elevated LNgamma2 fragment concentrations decreased after the use of curative treatments. Three patients displayed a continuous increase of the concentrations and subsequently died of the diseases. CONCLUSIONS: The serum concentrations of the LNgamma2 fragments may prove useful in assessing the treatment results and clinical courses of patients with head and neck squamous cell carcinomas. PMID- 18446816 TI - Myocardial function improved by electromagnetic field induction of stress protein hsp70. AB - Studies on myocardial function have shown that hsp70, stimulated by an increase in temperature, leads to improved survival following ischemia-reperfusion (I-R). Low frequency electromagnetic fields (EMFs) also induce the stress protein hsp70, but without elevating temperature. We have examined the hemodynamic changes in concert with EMF pre-conditioning and the induction of hsp70 to determine whether improved myocardial function occurs following I-R injury in Sprague-Dawley rats. Animals were exposed to EMF (60 Hz, 8 microT) for 30 min prior to I-R. Ischemia was then induced by ligation of left anterior descending coronary artery (LAD) for 30 min, followed by 30 min of reperfusion. Blood and heart tissue levels for hsp70 were determined by Western blot and RNA transcription by rtPCR. Significant upregulation of the HSP70 gene and increased hsp70 levels were measured in response to EMF pre-exposures. Invasive hemodynamics, as measured using a volume conductance catheter, demonstrated significant recovery of systolic contractile function after 30 min of reperfusion following EMF exposure. Additionally, isovolemic relaxation, a measure of ventricular diastolic function, was markedly improved in EMF-treated animals. In conclusion, non-invasive EMF induction of hsp70 preserved myocardial function and has the potential to improve tolerance to ischemic injury. PMID- 18446819 TI - Is therapy with calcium and vitamin D and parathyroid autotransplantation useful in total thyroidectomy for preventing hypocalcemia? AB - BACKGROUND: Routine calcium and vitamin D administration and routine autotransplantation of parathyroid glands can prevent hypocalcemia after total thyroidectomy. METHODS: Routine autotransplantation of 1 or more parathyroid glands and oral calcium and vitamin D supplementation was used in 252 patients. RESULTS: One, 2, or 3 parathyroid glands were autotransplanted in 223, 27, and 2 patients, respectively. Routine oral calcium and vitamin D was administered in postoperative period in all patients. Postoperative hypocalcemia occurred in 17%, of whom 1.6% had minor symptoms related to hypocalcemia. No patient developed permanent hypocalcemia during the follow-up period. The postoperative stay was 1 day in 93.6% of the cases. The incidence of postoperative hypocalcemia and hospital stay was higher in patients who underwent autotransplantation of more than 1 parathyroid gland. CONCLUSIONS: Routine oral calcium and vitamin D supplementation and autotransplantation of at least 1 parathyroid gland effectively reduced symptomatic hypocalcemia and permanent hypoparathyroidism in total thyroidectomy. PMID- 18446820 TI - Characterization of alterations of Rb2/p130 tumor suppressor in all-trans retinoic acid resistant SK-OV3 ovarian carcinoma cells. AB - Rb2/p130 tumor suppressor protein regulates cell cycle progression primarily through interactions with members of the E2F family of transcription factors and repression of the transactivation of E2F target genes. In ATRA sensitive ovarian carcinoma CA-OV3 cells, a dramatic increase in Rb2/p130 protein mediates growth arrest at G0/G1. However, although Rb2/p130 is expressed at high levels in SK-OV3 cells, they fail to growth arrest in response to ATRA treatment. We show that the functional activity of Rb2/p130 in SK-OV3 cells is reduced when compared to CA OV3 cells. To determine the basis for the reduced functional activity, we characterized the Rb2/p130 protein in SK-OV3 cells and investigated the possible role of alterations to this molecule in mediating resistance to ATRA growth suppression. Direct sequencing of Rb2/p130 cDNA cloned from SK-OV3 cells revealed the presence of two homozygous missense mutations (T178C and C259G) which result in amino acid changes Ser60 to Pro60 and Pro87 to Ala87 respectively. Unfortunately the same missense mutations were observed in Rb2/p130 cDNA cloned from ATRA sensitive CA-OV3 cells. We next investigated differences in Rb2/p130 protein subcellular localization. While Rb2/p130 was localized in the nucleus in both cell lines, we observed regions of intense staining within the nucleus of SK OV3 cells. This is suggestive of aggregation and/or subnuclear sequestration of the Rb2/p130 protein. Finally, the PAGE migration pattern of Rb2/p130 suggested that a hyperphosphorylated form of Rb2/p130 accumulated in SK-OV3 cells but not in CA-OV3 cells. It is possible that this hyperphosphorylated form can be responsible for the decreased Rb2/p130 functional activity observed in SK-OV3 cells and may contribute to the resistance of these cells to ATRA mediated growth suppression. PMID- 18446821 TI - Oxygen isotope analysis of carbonates in the calcite-dolomite-magnesite solid solution by high-temperature pyrolysis: initial results. AB - Accurate and efficient measurement of the oxygen isotope composition of carbonates (delta(C) (18)O) based on the mass spectrometric analysis of CO(2) produced by reacting carbonate samples with H(3)PO(4) is compromised by: (1) uncertainties associated with fractionation factors (alpha(CO)(2)C) used to correct measured oxygen isotope values of CO(2)(delta(CO(2)(18)O) to delta(C) (18)O; and (2) the slow reaction rates of many carbonates of geological and environmental interest with H(3)PO(4). In contrast, determination of delta(C) (18)O from analysis of CO produced by high-temperature (>1400 degrees C) pyrolytic reduction, using an elemental analyser coupled to continuous-flow isotope-ratio mass spectrometry (TC/EA CF-IRMS), offers a potentially efficient alternative that measures the isotopic composition of total carbonate oxygen and should, therefore, theoretically be free of fractionation effects. The utility of the TC/EA CF-IRMS technique was tested by analysis of carbonates in the calcite dolomite-magnesite solid-solution and comparing the results with delta(C) (18)O measured by conventional thermal decomposition/fluorination (TDF) on the same materials. Initial results show that CO yields are dependent on both the chemical composition of the carbonate and the specific pyrolysis conditions. Low gas yields (<100% of predicted yield) are associated with positive (>+0.2 per thousand) deviations in delta(C(TC/EA) (18)O compared with delta(C(TDF) (18)O. At a pyrolysis temperature of 1420 degrees C the difference between delta(C) (18)O measured by TC/EA CF-IRMS and TDF (Delta(C(TC/EA,TDF) (18)O) was found to be negatively correlated with gas yield (r = -0.785) and this suggests that delta(C) (18)O values (with an estimated combined standard uncertainty of +/-0.38 per thousand) could be derived by applying a yield-dependent correction. Increasing the pyrolysis temperature to 1500 degrees C also resulted in a statistically significant correlation with gas yield (r = -0.601), indicating that delta(C) (18)O values (with an estimated uncertainty of +/-0.43 per thousand) could again be corrected using a yield-dependent procedure. Despite significant uncertainty associated with TC/EA CF-IRMS analysis, the magnitude of the uncertainty is similar to that associated with the application of poorly defined values of alpha(CO)(2), (C) used to derive delta(C) (18)O from delta(CO(2) (18)O measured by the H(3)PO(4) method for most common carbonate phases. Consequently, TC/EA CF IRMS could provide a rapid alternative for the analysis of these phases without any effective deterioration in relative accuracy, while analytical precision could be improved by increasing the number of replicate analyses for both calibration standards and samples. Although automated gas preparation techniques based on the H(3)PO(4) method (ISOCARB, Kiel device, Gas-Bench systems) have the potential to measure delta(CO)(2) (18)O efficiently for specific, slowly reacting phases (e.g. dolomite), problems associated with poorly defined alpha(CO)(2), (C) remain. The application of the Principle of Identical Treatment is not a solution to the analysis of these phases because it assumes that a single fractionation factor may be defined for each phase within a solid-solution regardless of its precise chemical composition. This assumption has yet to be tested adequately. PMID- 18446822 TI - Biomolecular characterization of human glioblastoma cells in primary cultures: differentiating and antiangiogenic effects of natural and synthetic PPARgamma agonists. AB - Gliomas are the most commonly diagnosed malignant brain primary tumors. Prognosis of patients with high-grade gliomas is poor and scarcely affected by radiotherapy and chemotherapy. Several studies have reported antiproliferative and/or differentiating activities of some lipophylic molecules on glioblastoma cells. Some of these activities in cell signaling are mediated by a class of transcriptional factors referred to as peroxisome proliferator-activated receptors (PPARs). PPARgamma has been identified in transformed neural cells of human origin and it has been demonstrated that PPARgamma agonists decrease cell proliferation, stimulate apoptosis and induce morphological changes and expression of markers typical of a more differentiated phenotype in glioblastoma and astrocytoma cell lines. These findings arise from studies mainly performed on long-term cultured transformed cell lines. Such experimental models do not exactly reproduce the in vivo environment since long-term culture often results in the accumulation of further molecular alterations in the cells. To be as close as possible to the in vivo condition, in the present work we investigated the effects of PPARgamma natural and synthetic ligands on the biomolecular features of primary cultures of human glioblastoma cells derived from surgical specimens. We provide evidence that PPARgamma agonists may interfere with glioblastoma growth and malignancy and might be taken in account as novel antitumoral drugs. PMID- 18446823 TI - Absence of systems consolidation of fear memories after dorsal, ventral, or complete hippocampal damage. AB - We examined the effects of dorsal, ventral, or complete damage to the hippocampus on long-term retention of a Pavlovian conditioned fear response to a tone and a context paired with foot shock. Rats received a fear conditioning episode, in which a tone and context or context-alone were paired with foot shock. Two days or 12 weeks later, they received sham, dorsal, ventral, or complete NMDA-induced damage of the hippocampus. During a retention test conducted 2 weeks after surgery, the sham control rats exhibited high levels of freezing in the context and in the presence of the tone. Rats with dorsal, ventral, or complete hippocampal damage displayed very little freezing in the context at either learning-surgery intervals. Partial hippocampal damage tended to cause a smaller but consistent deficit in conditioned responding to context at the shorter (2 day) learning-surgery interval. Rats with hippocampal damage did not display less severe retrograde amnesia for more remote (12 weeks) memories. A similar pattern of results was observed for freezing to the tone. We find that the severity of retrograde amnesia for fear conditioning is related to the extent of the damage and that there is consistent and severe retrograde amnesia for remote contextual and cued fear memories. These findings support the idea that the hippocampal formation plays an essential and possibly permanent role in fear memories. PMID- 18446825 TI - Effect of tooth loss on spatial memory and trkB-mRNA levels in rats. AB - The mechanism by which tooth loss accelerates spatial memory impairment is unknown. The purpose of this study was to test the hypothesis that tooth loss affects trkB-mRNA levels and leads to an accelerated decrease in the hippocampal cell density in rats. A radial maze was used to evaluate the spatial memory of male Wistar rats that were categorized based on the number of extracted molar teeth. Number of hippocampal pyramidal cells and the trkB-mRNA expressions in the amygdala, perirhinal cortex, thalamus, and the hippocampal CA1, CA3, and CA4 areas, were evaluated using molecular biological techniques. Seven weeks after tooth extraction, maze performance was significantly lower in each tooth loss group than in the control group, and the number of extracted teeth was inversely proportional to the induction of the trkB-mRNA and the hippocampal cell density. The average weight of rats increased by controlled feeding throughout the experiment without showing a significant difference between the control and experimental groups. The results indicated that, in rats, the spatial memory linked trkB-mRNA was reduced in association with the tooth loss; this supports the hypothesis and suggests that teeth have a role in the prevention of spatial memory impairment. PMID- 18446824 TI - Nicotinic acetylcholine receptor expression in the hippocampus of 27 mouse strains reveals novel inhibitory circuitry. AB - Mouse strains are well-characterized to exhibit differences in their physiological and behavioral responses to nicotine. This report examines the expression of the high-affinity nicotine binding receptor subunit, neuronal nicotinic receptor subunit alpha 4 (nAChR alpha 4), in the dorsal hippocampus of 27 inbred mouse strains. Multiple differences among mouse strains in the cellular expression of nAChR alpha 4 between subregions of the hippocampal field are evident. Differences that we describe in the expression of nAChR alpha 4 suggest mouse strains of diverse genetic origin could exhibit significant variation in how this receptor contributes to modulating intrahippocampal circuitry. These findings define a genetic frame-work in which the strain-specific responses to nicotine include underlying contributions by the varied anatomical context in which nAChRs are expressed. PMID- 18446826 TI - Hypoxic-ischemic brain injury activates early hippocampal stem/progenitor cells to replace vulnerable neuroblasts. AB - Although the phenomenon of ongoing neurogenesis in the hippocampus is well described, it remains unclear what relevance this has in terms of brain self repair following injury. In a highly regulated developmental program, new neurons are added to the inner granular cell layer of the dentate gyrus (DG) where slowly dividing radial glial-like type 1 neural stem/progenitors (NSPs) give rise to rapidly proliferating type 2 neural progenitors which undergo selection and maturation into functional neurons. The induction of these early hippocampal progenitors after injury may represent an endogenous mechanism for brain recovery and remodeling. To determine what role early hippocampal progenitors play in remodeling following injury, we utilized a model of hypoxic-ischemic injury on young transgenic mice that express green fluorescent protein (GFP) specifically in neural progenitors. We demonstrate that this injury selectively activates programmed cell death in committed but immature neuroblasts, which is followed by proliferation of both early type 1 and later type 2 progenitors. This subsequently leads to newly generated neurons becoming stably incorporated into the DG. PMID- 18446827 TI - Hippocampal and amygdala volumes in children and adults with childhood maltreatment-related posttraumatic stress disorder: a meta-analysis. AB - Little work has directly examined the course of hippocampal volume in children and adults with childhood maltreatment-related posttraumatic stress disorder (PTSD). Data from adults suggest that hippocampal volume deficits are associated with PTSD, whereas findings from children with PTSD generally show no hippocampal volume deficits in PTSD. Additionally, the role of the amygdala in emotional response makes it a possible region for investigation in children and adults with childhood maltreatment-related PTSD. The objectives of this study were 2-fold: (1) to meta-analytically determine whether hippocampal and amygdala volumes in children and adults with PTSD from childhood maltreatment differ from those in healthy controls, and (2) to use cross-sectional findings performed with meta analyses as a proxy for longitudinal studies to estimate the course of hippocampal and amygdala volumes in child and adult subjects with PTSD from childhood maltreatment. Using electronic databases, we identified articles containing hippocampal and amygdala data for children with PTSD and adults with PTSD from childhood maltreatment. Data were extracted and effect sizes were calculated using Comprehensive Meta-Analysis Version 2.0. Reduced bilateral hippocampal volume was found in adults with childhood maltreatment-related PTSD compared with healthy controls, but this deficit was not seen in children with maltreatment-related PTSD, suggesting hippocampal volume deficits from childhood maltreatment may not be apparent until adulthood. Greater left than right hippocampal volume was found in the adult healthy control group but not in the PTSD group. Amygdala volume in children with maltreatment-related PTSD did not differ from that in healthy controls. Hippocampal volume is normal in children with maltreatment-related PTSD but not in adults with PTSD from childhood maltreatment, suggesting an initially volumetrically normal hippocampus with subsequent abnormal volumetric development occurring after trauma exposure. However, longitudinal studies are needed to support these preliminary findings. PMID- 18446828 TI - Lesions of the mammillary body region severely disrupt the cortical head direction, but not place cell signal. AB - The rat limbic system contains a variety of location (place and grid) cells and directional (head direction; HD) cells, thought to be critical for navigation. The HD cells can be found throughout many portions of the hippocampal formation, as well as additional limbic cortical and subcortical regions. These HD containing regions are generally strongly interconnected anatomically. Earlier work, along with theoretical considerations, suggest that despite the ubiquitous presence of HD cells, there may be a single region which is critical for the initial formation of this HD signal. Specifically, it has been suggested that the critical HD cell network resides in a reciprocal loop formed by the interconnected lateral mammillary nucleus and dorsal tegmental nucleus of Gudden. Unlike the HD cells, place cells have not been observed in subcortical structures. They are, however, found in various forms throughout much of the hippocampal formation. Theoretical accounts of the place cells suggest that they are partly dependent on a path integration process which is, in turn, dependent on the HD cells. According to the above reasoning, lesions of the mammillary bodies should completely eliminate both HD and place/grid cells in the hippocampal formation. Here, we tested for both HD and place cell activity in various hippocampal formation sub regions following lesions of the mammillary bodies. We found that these lesions caused nearly complete elimination of the HD cell signal, but left the place cell signal largely intact. Our interpretation of these findings is somewhat limited by the fact that we did not provide a thorough test of the path integration abilities of the post lesion place cells. These findings pose a challenge for current theoretical accounts of place and grid cells. They also help to explain the role played by the mammillary bodies in spatial learning and memory. PMID- 18446829 TI - Aberrant dentate gyrus cytoarchitecture and fiber lamination in Lis1 mutant mice. AB - Mutant mice with a heterozygous deletion of LIS1, show varying degrees of hippocampal abnormality and enhanced excitability. To examine how LIS1 affects cytoarchitecture and fiber lamination in dentate gyrus (DG), we performed a series of immunohistochemistry studies. By using different neuronal- and glial specific antibodies, we found that the majority of hippocampal cell populations were affected by heterozygous mutation of LIS1; some reelin-positive Cajal Retzius cells were left undisturbed. Granule cell dispersion was significant in hippocampal sections from Lis1-deficient mice. However, the fiber termination of commissural/associational fibers and mossy fibers appeared relatively compact despite obvious granule cell dispersion and CA1-CA3 pyramidal cell disorganization. vGlut1-immunoreactive axon terminals were found aberrantly traversing the dispersed granule cell layer. Consistent with previous observations, we also found that immature granule cells in Lis1 mutants, here stained with antibodies to doublecortin (DCX) and Mash-1, are aberrantly located and bear an abnormal cellular morphology. Our findings suggest that LIS1 mutants exhibit abnormal cell positioning and aberrant hippocampal neurogenesis, but maintain relatively normal fiber termination patterns. The functional consequences of hippocampal granule cell dispersion could offer critical insight to the epileptic and cognitive disorder associated with LIS1 haploinsufficiency. PMID- 18446830 TI - High-resolution multi-voxel pattern analysis of category selectivity in the medial temporal lobes. AB - Although the parahippocampal cortex (PHc) is known to be critical for memory formation, little is known about what is encoded by this area. Using multi-voxel pattern analysis of high-resolution functional magnetic resonance imaging (MRI) data, we examined responses to blocks of categorically coherent stimuli and found that patterns of activity in PHc were selective for not only scenes, but also for other nonspatial object categories (e.g., faces and toys). This pattern of results was also found in the parahippocampal place area (PPA), indicating that this region is not sensitive exclusively to scenes. In contrast, neither the hippocampus nor perirhinal cortex (PRc) were found to be selective for category information. The results indicate that regions within the medial temporal lobe may support distinct functions, and that the PHc appears to be particularly sensitive to category-level information. PMID- 18446831 TI - Hippocampal atrophy is the critical brain change in patients with hypoxic amnesia. AB - Anoxia is considered a good model for studying amnesia. However, not all individuals who experience anoxic events develop memory problems. Moreover, the question still remains about whether, after anoxia, damage is limited to the hippocampus in patients with amnesia and without other significant cognitive deficits. Here we investigated brain damage in a selected sample of adults affected exclusively by an amnesic syndrome after an anoxic episode. The cerebral MR images of these patients were submitted to visual inspection, volumetric measurements of the mesial temporal structures following manual segmentation, and to Voxel-Based Morphometry of the whole brain. We studied five anoxic patients and thirty-three well-matched healthy subjects. Our aim was to: (a) quantify regional atrophic changes associated with chronic anoxic damage compared to control subjects (Group Comparison Analysis); (b) identify regions of common abnormality across all patients (Conjunction Analysis in the VBM); (c) investigate whether measures of regional volume reduction correlated with neuropsychological memory scores; (d) compare the results obtained with visual inspection and ROI analyses with those obtained with VBM. We found that anoxic patients presented a significant reduction of gray matter volume in the hippocampus bilaterally compared to healthy subjects. The only common atrophic region across all patients was the hippocampus bilaterally. Correlation analysis showed only a trend between the Prose immediate free recall test and the left hippocampus. Our findings confirm that the hippocampus is very sensitive to damage stemming from anoxia. Patients with hypoxic amnesia may present damage in other brain regions, but only hippocampal atrophy is common in all of them. PMID- 18446832 TI - A pilot case series using qualitative and quantitative methods: biological, psychological and social outcome in severe and enduring eating disorder (anorexia nervosa). AB - OBJECTIVE: We explore the level of disability and quality of life in participants with severe and enduring eating disorder (anorexia nervosa). METHOD: We use qualitative and quantitative methods to assess in detail eleven participants with a 10-year history of anorexia nervosa. Outcomes for quality of life are compared with those of a sample of primary care patients with moderate-severe depression. Outcomes for living skills are compared with a standardized community sample of patients with schizophrenia. RESULTS: Despite scoring highly for communication skills and levels of responsibility, participants were as impaired as the sample of patients with schizophrenia for self-care and social contact. Participants were severely depressed and scores for quality of life mirrored those of the primary care population. Qualitative data illustrate intrapersonal and interpersonal avoidance leading to self-neglect and social isolation despite social skills. CONCLUSION: Quality of life and living skills are as impaired as those of other severe and enduring mental illnesses. PMID- 18446833 TI - Heat reversal of activity-based anorexia: implications for the treatment of anorexia nervosa. AB - OBJECTIVE: Activity-based anorexia (ABA) provides an animal model of anorexia nervosa (AN). In this model, rats given restricted access to food but unrestricted access to activity wheels, run excessively while reducing food intake, lose a sizeable percentage of body weight, become hypothermic, and can fail to recover unless removed from these conditions. METHOD: Once rats had lost 20% of body weight under standard ABA conditions, they were assigned to one of two ambient temperature (AT) conditions. RESULTS: Increased AT reduced running rates and led to weight gain in active rats. The effect of increasing AT on food intake was dependent on whether the rats were sedentary or active. Although warming reduced food intake in the sedentary rats their body weight remained stable, whereas in active rats increased AT did not reduce food intake and weight gain gradually rose. CONCLUSION: From a translational perspective, these findings offer a fresh perspective to the disorder, and underscore the need for further studies to assess the effects of heat treatment in patients as an innovative adjunctive treatment for anorexia nervosa. PMID- 18446834 TI - Evaluation of body experience questionnaires in eating disorders in female patients (AN/BN) and nonclinical participants. AB - OBJECTIVE: Body image disturbance is an important factor in the development and the treatment of eating disorders. Therefore, evaluations of different instruments for measuring body image disturbances are necessary. METHOD: Four widely used questionnaires are evaluated: The Body Attitude Test, The Eating Disorder Inventory, The Body Shape Questionnaire, and the Body Attitude Questionnaire. Psychometric properties of these questionnaires are investigated in 228 patients with eating disorder and 389 female controls. Normative values for a Flemish population are provided. RESULTS: All questionnaires have good psychometric properties. To separate patients from controls all four questionnairescan be used. To differentiate between patients with anorexia nervosa and bulimia nervosa, the Body Attitude Test and the Body Dissatisfaction subscale of the Eating Disorder Inventory show good criterion-related validity. CONCLUSION: All these measures are useful as preliminary screening devices to identify populations with a high proportion or risk for developing eating disorders. More research is needed because there is still a great lack of clarity about what constitutes the normal range of attitudes towards the body. PMID- 18446835 TI - Small is beautiful: microRNAs and breast cancer-where are we now? AB - MicroRNAs are a recently discovered class of small regulatory RNAs that influence the stability and translational efficiency of target mRNAs. They have been implicated in an increasing number of biological processes, including neoplasia. Recent studies have shown an involvement for these regulatory molecules in breast cancer. For example, miRNA profiling studies have identified microRNAs that are deregulated in breast cancer. Furthermore, functional studies have uncovered their roles in breast cancer as both tumour suppressor genes (eg miR-335) and oncogenes (eg miR-21). miRNAs deregulated in breast cancer influence the translational regulation of well-established regulatory molecules, such as oestrogen receptor-alpha, which is regulated by miR-206, and novel cancer-related molecules whose functions are not yet fully understood.. Here we present an overview of our current understanding of miRNA in breast cancer. PMID- 18446836 TI - Discussion of research using propensity-score matching: comments on 'A critical appraisal of propensity-score matching in the medical literature between 1996 and 2003' by Peter Austin, Statistics in Medicine. PMID- 18446837 TI - Retroesophageal subclavian artery--esophageal fistula: a rare complication of a salivary bypass tube. AB - Salivary bypass tubes have been used with great success in preventing neck wound contamination from saliva and decreasing the risk of pharyngoesophageal stenosis. However, complications from esophageal tubes and risk factors for these complications should not be overlooked. Complications can be fatal, as demonstrated in this case of esophageal-subclavian artery fistulization. Retroesophageal subclavian artery (RRESA) is 1 of the most common anatomical variations of the aortic system. Typically producing no symptoms, its discovery is usually coincidental. However, under the right circumstances, this artery can form a fistulous tract. This occurrence has also been documented in cases of long term nasogastric tube placement and incorrect use of "esophageal" stents. This unique case describes a 62-year-old man who suffered an arterioesophageal fistula during use of a Montgomery salivary bypass tube (MSBT)--a frequently used and exceptionally safe management tool in patients with head and neck cancer. PMID- 18446838 TI - Hypopituitarism after radiotherapy for extracranial head and neck cancers. AB - BACKGROUND: The purpose of this study was to investigate the incidence of radiotherapy-induced primary and secondary hypopituitarism. METHODS: Three hundred twelve patients treated with radiotherapy for extracranial head and neck tumors between 1964 and 2000 were evaluated. Radiotherapy doses to the hypothalamus and pituitary were estimated by reconstructing treatment plans. RESULTS: Clinical hypopituitarism was observed in 44 (14.1%) patients after a median interval of 5.6 years. Hypothalamic dysfunction was reported in 14 patients after a median interval of 4.4 years. Neither fractionation nor adjuvant chemotherapy significantly impacted clinical hypopituitarism on multivariate analysis, but total dose to the pituitary was significant (p = .0228). Twenty three of 68 (33.8%) patients tested for hypopituitarism demonstrated subclinical hypopituitarism. The 5- and 10-year rates of freedom from clinical hypopituitarism were 93% and 72%. The 5- and 10-year rates of freedom from subclinical hypopituitarism were 85% and 65%. CONCLUSION: Clinical and subclinical manifestations of late radiation toxicity were observed in the hypothalamic-pituitary axis. PMID- 18446840 TI - Effect of nutrient mixture and black grapes on the pharmacokinetics of orally administered (-)epigallocatechin-3-gallate from green tea extract: a human study. AB - (-)Epigallocatechin-3-gallate (EGCG), a green tea component, has been attributed with anticarcinogenic and antioxidant activities. The extent and rate of absorption of EGCG by the small intestine depends on various factors such as molecular size, lipophilicity, solubility, pKa, gastric and intestinal transit time, lumen pH, membrane permeability and first pass metabolism. The bioavailability of EGCG can be increased by decreasing the presystemic elimination by stabilizing EGCG in the lumen, helping its transfer across the intestinal apical membrane and its accumulation and thus its availability by inhibiting phase I and II enzymes and phase III transporters. In a crossover study, five human volunteers were given a single oral dose of GTE (A), nutrient mixture (NM) containing GTE (B) and formulation B along with black grapes 250 g (C). Blood samples were drawn at 0, 2, 4, 6 and 8 h. The pharmacokinetic parameters were analysed by WinNonLin (Vs 5.0.1.) using a non-compartmental approach. Supplementation with nutrient mixture normally prescribed to cancer patients containing ascorbic acid, selenium, N-acetyl cysteine and other nutrients (formulation B) resulted in an increase of the systemic availability of EGCG by 14% and formulation C further increased it by 13%, thus leading to a total increase of 27%. PMID- 18446841 TI - A combined extract of Cinnamomi Ramulus, Anemarrhenae Rhizoma and Alpiniae Officinari Rhizoma suppresses production of nitric oxide by inhibiting NF-kappaB activation in RAW 264.7 cells. AB - An herbal mixture prepared with Cinnamomi Ramulus, Anemarrhenae Rhizoma and Alpiniae Officinari Rhizoma (CAA) is used in oriental medicine for treating several ailments. The purpose of this study was to determine the mechanisms by which CAA elicits an antiinflammatory effect on nitric oxide (NO) production in the mouse macrophage cell line RAW 264.7 cells. The results indicated that lipopolysaccharide (LPS)-induced NO production was inhibited by CAA in a dose dependent manner. Western blotting and RT-PCR analysis demonstrated that CAA decreased LPS-induced inducible nitric oxide synthase (iNOS) protein and gene expression in RAW 264.7 cells. Furthermore, CAA inhibited the LPS-induced DNA binding activity of nuclear factor-kappa B (NF-kappaB) and this effect was mediated through inhibiting the degradation of inhibitory factor-kappaBalpha (IkappaBalpha). Therefore, the results demonstrate that CAA inhibits LPS-induced production of NO and expression of iNOS by blocking NF-kappaB activation. CAA might be a potential therapeutic candidate for treating inflammatory diseases such as arthritis. PMID- 18446842 TI - Pharmacological studies on Indian black tea (leaf variety) in acute and chronic inflammatory conditions. AB - Infusions of Indian black tea (BTI), when administered orally, produced significant inhibition of rat paw oedema, induced with carrageenin (pre and post treatment) and arachidonic acid. BTI was also found to inhibit peritoneal capillary permeability and caused a marked reduction of lipopolysaccharide induced PGE(2) generation. In these models, the observed antioedema effect was similar to that of BW755C (a dual inhibitor of cyclooxygenase and 5-lipoxygenase enzymes). BTI was found to scavenge superoxide and hydroxyl radicals, and also protected rat erythrocytes from the damaging effects of hydrogen peroxide. In chronic studies, BTI inhibited granuloma formation along with the reduction of both lipid peroxidation and hydroxyproline content (in the granuloma tissue). Significant antiarthritic activity was observed with regular administration of BTI in the Freund's adjuvant induced model of arthritis. Chronic treatment with BTI (in arthritic rats) resulted in a decrease of paw diameter and tissue lipid peroxidation, along with a restoration of GSH, catalase and superoxide dismutase levels. PMID- 18446843 TI - Antiinflammatory and antioxidant activity of Hypericum rumeliacum Boiss. subsp. apollinis (Boiss. & Heldr.) Robson & Strid methanol extract. AB - Plants of the genus Hypericum are widely used in folk medicine for the treatment of gastric ailments (including pectic ulcers), burns, swelling, inflammation, anxiety, as well as for bacterial and viral infections. The aerial parts of Hypericum rumeliacum Boiss. subsp. apollinis (Boiss. & Heldr.) Robson & Strid (Guttiferae), a perennial herb growing wild in Greece, were subjected to biological and phytochemical studies. The H. rumeliacum methanol extract showed, on the DPPH test, antioxidant activity (IC(50) = 23.61 microg/mL). The antiinflammatory activity of the extract (70 mg/kg, i.p.), in the carrageenan induced paw oedema in rat, was studied. In this experimental model an inhibition of paw oedema, significant from the first to third hour, was observed. The histological examination confirmed resolution of the inflammatory process observed in vivo. Through HPLC analysis of the H. rumeliacum methanol extract, the naphthodianthrones hypericin, pseudohypericin and some polyphenol compounds, such as chlorogenic acid, rutin and isoquercitrin, were identified and quantified. The antioxidant activity of H. rumeliacum could be chiefly related to polyphenol compounds that are well known as the main contributors to the free radical-scavenging effects. The antiinflammatory effect of the methanol extract of the aerial parts could be due to the synergic action both of hypericin and polyphenol compounds. PMID- 18446844 TI - Experimental study on the hemostatic activity of the Tibetan medicinal herb Lamiophlomis rotata. AB - The blood hemostatic activity of the Tibetan medicinal herb Lamiophlomis rotata was evaluated in BALB/c mice and Wistar rats. L. rotata aqueous extract (LRAE) was given to mice at concentrations of 0.5, 1.0, 2.0 g/kg body weight and 0.75, 1.5, 3.0 g/kg to rats. The hemostatic activity of LRAE was estimated by changes in bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). At the same time hepatic function and blood fat indexes including AST, ALT, Alb, Chol and LDL-C were measured also. The results showed that an appropriate level of LRAE could shorten the BT and TT values and increase the Alb level paralleling that of FIB. However, the shortening of the PT was only possible by a high and long administration of LRAE, and no change in APTT was observed. On the other hand, LRAE showed some effects in improving the liver function and reducing blood lipids by decreasing the levels of AST, ALT, Chol and LDL-C. All these changes had a significant dose effect and time-effect relationship. These results confirm the hemostatic and thromboplastic effects of L. rotata and these effects might be implemented by improving the synthetic function of the liver. PMID- 18446845 TI - Induction of G2/M arrest and apoptosis by water extract of Strychni Semen in human gastric carcinoma AGS cells. AB - The seed of Strychnos nux-vomica (Loganiaceae) has been used in traditional Oriental medicine as a folk remedy for the treatment of cancer. However, the mechanism responsible for the anticancer effects of Strychni Semen is not clearly understood. The study tested whether and how the water extract of Strychni Semen (ESS) treatment would affect the growth of AGS human gastric carcinoma cells. ESS was found to inhibit the growth of AGS cells in a concentration-dependent manner. Cell cycle analysis showed G2/M phase arrest and apoptosis in AGS cells following ESS treatment. ESS-mediated G2/M arrest was found to be associated with up regulation of cyclin A, Cdc2, tumor suppressor p53 and cyclin dependent kinase (Cdk) inhibitor p21(WAF1/CIP1), whereas the expressions of other G2/M regulatory proteins, including cyclin B1 and Cdk2, were down-regulated compared with the control. The induction of apoptotic cell death by ESS was associated with down regulation of anti-apoptotic Bcl-2 and up-regulation of pro-apoptotic Bax expression. Further results indicate that caspase-3, caspase-8 and caspase-9 are all activated by ESS, together with cleavage of downstream caspase-3 target proteins. Taken together, the results of this study suggest the involvement of multiple signaling pathways targeted by ESS in mediating G2/M cell cycle arrest and apoptosis in AGS cells, and warrant further investigation. PMID- 18446846 TI - Antioxidant and prooxidant properties of a polyphenol-rich extract from Geranium sanguineum L. in vitro and in vivo. AB - A polyphenol-rich extract from Geranium sanguineum L. (PC) protected biological membranes due to its antioxidant capacity. PC caused a dose-dependent decrease of the osmotic hemolysis of human erythrocytes and increased their resistance against the toxic effect of H(2)O(2); no effect on catalase activity was observed. While PC reduced the accumulation of TBA-reactive products in rat liver microsomes in inducible lipid peroxidation (LPO), the non-induced LPO was not affected. Further the effect of PC on the products of LPO was investigated in the lungs, livers and sera of intact and influenza virus-infected mice (VIM). The infection enhanced LPO in the lungs and livers. In the group of PC-treated VIM, malondialdehyde (MDA) in the lungs and livers was brought to control levels. PC treatment caused a significant increase of MDA in the lungs of intact mice, a slight one in the livers and did not affect MDA in the sera. Thus the extract exhibited prooxidant characteristics in intact animals as well as antioxidant properties in VIM. The reducing ability of PC on LPO could be an alternative mechanism of its protective effect in experimental influenza infection. PMID- 18446839 TI - Nasopharyngeal carcinoma--review of the molecular mechanisms of tumorigenesis. AB - Nasopharyngeal carcinoma (NPC) is a head and neck cancer rare throughout most of the world but common in certain geographic areas, such as southern Asia. While environmental factors and genetic susceptibility play important roles in NPC pathogenesis, the Epstein-Barr virus in particular has been implicated in the molecular abnormalities leading to NPC. There is upregulation of cellular proliferation pathways such as the Akt pathway, mitogen-activated protein kinases, and the Wnt pathway. Cell adhesion is compromised due to abnormal E cadherin and beta-catenin function. Aberrations in cell cycle are due to dysregulation of factors such as p16, cyclin D1, and cyclin E. Anti-apoptotic mechanisms are also upregulated. There are multiple abnormalities unique to NPC that are potential targets for novel treatments. PMID- 18446847 TI - Ginkgo biloba extract improves coronary artery circulation in patients with coronary artery disease: contribution of plasma nitric oxide and endothelin-1. AB - In patients with coronary artery disease (CAD), coronary blood flow is usually impaired due to imbalanced vasoactive substances such as nitric oxide (NO) and endothelin-1 (ET-1). The study was designed to test the effects of Ginkgo biloba extract (GBE) on the distal left anterior descending coronary artery (LAD) blood flow and plasma NO and ET-1 levels. Eighty CAD patients were randomly assigned to GBE (n = 42) and control (n = 38) groups. The LAD blood flow was assessed non invasively using Doppler echocardiography at baseline and after 2 weeks. GBE treatment demonstrated a significant improvement in maximal diastolic peak velocity (MDPV), maximal systolic peak velocity (MSPV) and diastolic time velocity integral (DTVI) compared with controls (14.61 +/- 4.51% vs 0.67 +/- 2.66%, 9.03 +/- 4.81% vs 0.34 +/- 2.67% and 14.69 +/- 5.08% vs 0.68 +/- 3.00%, respectively, p < 0.01). NO was increased by 12.42% (p < 0.01), whereas ET-1 was decreased by 5.82% (p < 0.01). The NO/ET-1 ratio was increased by 19.47% (p < 0.01). A linear correlation was confirmed between the percentage change in LAD blood flow and in NO, ET-1 or NO/ET-1 ratio following GBE treatment. The results suggest that GBE treatment in CAD patients led to an increase of LAD blood flow, which might at least be related partly to the restoration of the delicate equilibrium between NO and ET-1. PMID- 18446848 TI - Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. AB - The roots and rhizomes of licorice (Glycyrrhiza) species have long been used worldwide as a herbal medicine and natural sweetener. Licorice root is a traditional medicine used mainly for the treatment of peptic ulcer, hepatitis C, and pulmonary and skin diseases, although clinical and experimental studies suggest that it has several other useful pharmacological properties such as antiinflammatory, antiviral, antimicrobial, antioxidative, anticancer activities, immunomodulatory, hepatoprotective and cardioprotective effects. A large number of components have been isolated from licorice, including triterpene saponins, flavonoids, isoflavonoids and chalcones, with glycyrrhizic acid normally being considered to be the main biologically active component. This review summarizes the phytochemical, pharmacological and pharmacokinetics data, together with the clinical and adverse effects of licorice and its bioactive components. PMID- 18446849 TI - Acanthopanax senticosus suppresses reactive oxygen species production by mouse peritoneal macrophages in vitro and in vivo. AB - Excess production of reactive oxygen species by macrophages has been implicated in many inflammatory diseases. The present study investigated the inhibitory effect of the stem bark extract of Acanthopanax senticosus on the production of superoxide anion and hydrogen peroxide in mouse peritoneal macrophages in vitro and in vivo. Exposure of mouse peritoneal macrophages to A. senticosus extract significantly suppressed superoxide anion production induced by zymosan in a dose dependent manner. Similarly, exposure of mouse peritoneal macrophages to A. senticosus extract significantly inhibited hydrogen peroxide production induced by phorbol 12-myristate 13-acetate (PMA) in a dose-dependent manner. Intraperitoneal administration of A. senticosus extract to KM mice reduced the ex vivo production of zymosan induced-superoxide anion and PMA-induced hydrogen peroxide by their peritoneal macrophages. Exposure to A. senticosus extract did not affect the cell viability or systemic toxicity. A. senticosus inhibited reactive oxygen species production by mouse peritoneal macrophages in vitro and in vivo and may be partly responsible for the antiinflammatory function. PMID- 18446850 TI - Korean red ginseng attenuates hypercholesterolemia-enhanced platelet aggregation through suppression of diacylglycerol liberation in high-cholesterol-diet-fed rabbits. AB - Intake of Korean red ginseng (KRG, ginseng Radix rubra), rich in glycosylated saponins (ginsenosides), has been known to inhibit platelet aggregation in the normocholesterolemic condition. However, it is unclear whether KRG can attenuate hypercholesterolemia-enhanced platelet aggregation. This study examined whether the daily consumption of a KRG-water extract (WE) could prevent the hypercholesterolemia-enhanced platelet aggregation and progression of hypercholesterolemic atherosclerosis. KRG-WE administration (200 mg/kg/day) for 8 weeks potently inhibited the platelet aggregation induced by low doses of agonists (0.5 microg/mL collagen and 0.025 unit/mL thrombin), whereas it weakly reduced the blood-cholesterol levels and formation of atheromatous lesions. In further investigation, KRG-WE significantly suppressed collagen-induced 1,2 diacylglycerol liberation, but had no significant effect on arachidonic acid liberation. Taken together, it can be suggested that the antiplatelet effect of KRG-WE may, at least partly, be due to the inhibition of 1,2-diacylglycerol generation rather than regulation of blood lipid levels. In conclusion, daily consumption of KRG-WE could be a useful alternative measure for the prevention of thrombus and atheroma formation in hypercholesterolemia. PMID- 18446852 TI - Retraction. Polyurethane hydrogel colored contact lens with gradient water content. PMID- 18446851 TI - Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. AB - Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity. PMID- 18446853 TI - Epidemiologic transition in an isolated indigenous community in the Valley of Oaxaca, Mexico. AB - The objective of the present study is to analyze age-specific mortality in a rural indigenous community in the throes of a secular increase in size in the Valley of Oaxaca, southern Mexico, over 30 years, 1970-1999. Variation in mortality by age group was analyzed over time for evidence of an epidemiological transition. The seasonal rain pattern in the Valley of Oaxaca (83% from May through September) was evaluated for its relationship with mortality in wet and dry months. Mortality and causes of death changed markedly over the 30-year interval. Infant and preschool mortality, overall mortality, and causes of death changed from the 1970s through the 1990s. Prereproductive deaths (<15 years) predominated in the 1970s and were largely due to gastrointestinal and respiratory diseases, with periodic outbreaks of measles. Deaths of adults 65+ years predominated in the 1990s and were largely due to degenerative diseases usually associated with aging. The marked changes in age and causes of death over the three decades (epidemiologic transition from Stage I to Stage II) occurred concurrently with significant secular increases in body size in children, adolescents, and young adults, highlighting improved health and nutritional conditions in the community which is in early Stage II of the demographic transition. The demographic transition to Stage II is a leading indicator (15-25 years lag) for the onset of the secular trend, while the epidemiologic transition to Stage II is a predictor that the secular increase is in process in the study community. PMID- 18446854 TI - Hair color measurement and variation. AB - Pigmentation of hair in humans has been investigated by medical scientists, anthropologists and, more recently, by forensic scientists. In every investigation, hair color must first be defined by the researchers. Subjective color assessment inhibits the reproducibility of experiments and the direct comparison of results. The aim of this study was to objectively measure human hair color and examine the variation found in a population with European ancestry, using the CIE L*a*b* color space. Observer-perceived hair colors were compared with self-reported hair colors and the color as measured by reflective spectrophotometry of 132 subjects of European ancestry. The presented data show that self-reported hair colors and observer-reported colors are similar; however, these categories are not necessarily the best way to categorize hair color for quantitative research. Using a two-step cluster analysis, hair color can be divided into categories or clusters based on spectrophotometric measurements in the CIE L*a*b* color space and these clusters can be well discriminated from each other. This separation is primarily based on the b* (yellow) color component and the clusters show agreement to observer-reported colors. This study illustrates the possibilities for and necessity of objectively defining the hair color phenotype for various downstream applications. PMID- 18446855 TI - Brief communication: Locomotor limb preferences in captive chimpanzees (Pan troglodytes): implications for morphological asymmetries in limb bones. AB - Understanding the evolutionary origins of hemispheric specialization remains a topic of considerable interest in a variety of scientific disciplines. Whether nonhuman primates exhibit population-level limb preferences continues to be a controversial topic. In this study, limb preferences for ascending and descending locomotion were assessed as a means of examining the hypothesis that asymmetries in forelimb bones might be attributed to asymmetries in posture. The results indicated that captive chimpanzees showed a population-level leftward asymmetry in descending locomotion but no group bias for ascending locomotion. The results are consistent with previous behavioral studies in captive chimpanzees as well as studies on skeletal asymmetries of the forelimbs of chimpanzees. PMID- 18446856 TI - Predictors of reproductive success in female white-faced capuchins (Cebus capucinus). AB - Early investigations into variable reproductive success in nonhuman primates tended to focus on the benefits conferred by high dominance rank. However, the effect of high rank on individual reproductive success has been found to vary both intra- and interspecifically, requiring researchers to expand their investigations to include additional factors. Here we examine the age and rank of the mother, sex of the infant, group size, number of close kin, replacement of group males, and resource availability as possible predictors of female reproductive success in white-faced capuchins (Cebus capucinus) in the Santa Rosa sector of the Area de Conservacion Guanacaste, Costa Rica. We examine the length of interbirth intervals (IBI) and infant survivorship as measures of individual reproductive success for the 31 adult females that resided in our three study groups between 1986 and 2007. The greatest predictor of IBI length was whether or not the first infant in the interval survived (number of matrilineal kin and resource availability were also significant predictors); while infant survivorship was most significantly predicted by the occurrence of a turnover in group males in the year following the birth of an infant (infant sex was also a significant factor). Based on these findings, we conclude that male and female reproductive strategies are at odds in this species, with male strategies strongly influencing female reproductive success. PMID- 18446857 TI - Cockayne syndrome type II in a Druze isolate in Northern Israel in association with an insertion mutation in ERCC6. AB - Cockayne syndrome (CS) (OMIM #133540) is a rare autosomal recessive disease characterized by severe growth and developmental retardation, progressive neurological dysfunction and symptoms of premature aging. The underlying cause of the disease is a defect in transcription-coupled DNA repair, specifically the nucleotide excision repair (NER) pathway. To date, about half of the reported CS cases have an altered cellular response to UV resulting from mutations in either the CSA or the CSB genes. We have identified a large, highly consanguineous, Druze kindred descended from a single ancestor, with six CS cases. All six of them presented with the congenital severe phenotype that includes severe failure to thrive, severe mental retardation, congenital cataracts, loss of adipose tissue, joint contractures, distinctive face with small, deep-set eyes and prominent nasal bridge, and kyphosis. They had no language skills, could not sit or walk independently, and died by the age of 5 years. Cellular studies of the fibroblasts from three patients showed a significant defect in transcription coupled DNA repair (TCR) and a marked correction of the abnormal cellular phenotype with a plasmid containing the cDNA of the ERCC6 gene. Molecular studies led to identification of a novel insertion mutation, c.1034-1035insT in exon 5 of the ERCC6 gene (p.Lys345Asnfs*24). This mutation was identified in 1:15 healthy individuals from the same village, indicating an extremely high carrier frequency. Identification of the causative mutation enables comprehensive genetic counseling among the population at risk from this village. PMID- 18446858 TI - Postnephrectomy fistula between the renal artery stump and inferior vena cava treated with Amplatzer vascular plug: gray-scale and Doppler sonographic findings. AB - Fistulous communication between the renal artery stump and the inferior vena cava is a rare complication of nephrectomy. We report a case of an adult male in whom a fistula was detected on investigation for persistent postoperative anemia. The fistula was initially identified with Doppler sonography and subsequently confirmed on a catheter angiogram. It was successfully occluded percutaneously with an Amplatzer vascular plug. The plug had a distinctive appearance on subsequent sonographic studies that was useful for follow-up evaluation. PMID- 18446859 TI - Sonographic findings of healthy volunteers infected with dengue virus. AB - PURPOSE: Sonography has historically been used in developing countries to help diagnose dengue infection during epidemics of dengue hemorrhagic fever in endemic areas and to predict the clinical course. In this article, we describe the sonographic findings in subjects infected with attenuated, monovalent strains of dengue virus. METHODS: As part of a major research protocol to validate challenge strains of dengue virus for use in vaccines, 12 subjects were infected with 1 of 4 strains of dengue virus, and 3 subjects received placebo. The challenge was followed by an observation period. During this time, they were imaged regardless of the development of symptoms. RESULTS: Seven of 12 subjects infected with dengue virus showed sonographic evidence of subclinical plasma leakage, including perihepatic and perisplenic ascites, pericardial effusion, and gallbladder wall thickening. None of the 3 placebo recipients developed effusions. CONCLUSION: Sonographic evidence of fluid collection was seen in over half of subjects infected with dengue virus who did not show any evidence of dengue hemorrhagic fever. These findings shed light on possible mechanisms of plasma leakage and its role in the pathogenesis of dengue fever and dengue hemorrhagic fever. PMID- 18446860 TI - Fine mapping of a locus for nonsyndromic mental retardation on chromosome 19p13. AB - Mental retardation (MR) occurs in approximately 3% of the population and therefore significantly impacts public health. Despite this relatively high prevalence, the specific causes of MR remain unknown in most cases, although both genetic and environmental factors are known to contribute. We describe a consanguineous family with autosomal recessive (AR) nonsyndromic MR (NSMR). Because the consanguinity of this family is complex, we explore alternative approaches for generating accurate estimates of the evidence for linkage in this family, and demonstrate evidence for linkage to chromosome 19p13 (lod score ranging from 1.2 to 3.5, depending on assumptions of allele frequencies). Fine mapping of the linked region defined a critical region of 3.6 Mb, which overlaps with a previously reported gene (CC2D1A) for MR. However, no mutations in the coding region of this gene are present in the family we describe. These results suggest that another gene causing autosomal recessive nonsyndromic MR (ARNSMR) is located within this genomic region. PMID- 18446862 TI - Sonographic diagnosis of fibromatosis. AB - PURPOSE: To investigate the value of sonography in the diagnosis of fibromatosis. METHOD: We retrospectively reviewed the sonographic findings, pathologic results, and other medical records of 42 patients with pathologically proven fibromatosis. The tumor's size and location were recorded. Echogenicity, margins, vascularity, and relationship with the adjacent tissue were analyzed. RESULTS: A total of 42 patients with 44 lesions were included in the study. In 21 patients, the tumor was a primary tumor. In 7 of these patients, a preoperative diagnosis of fibromatosis was obtained via sonographically guided biopsy or surgical biopsy. In another 21 patients, the tumor was a recurrence (including 1 case of malignant transformation). Well-defined and regular margins were demonstrated in 26 lesions (59%), whereas poorly defined and irregular borders were seen in the other 18 lesions. On Doppler imaging, vascularity was absent in 66% (29/44) lesions, moderate in 23% (10/44), and marked in 11% (5/44). Infiltration into the adjacent skeletal muscles, cortical bone, or encasement vessels, nerves, or tendons was found in 21 (48%) lesions. CONCLUSION: In patients with fibromatosis, sonography demonstrates a nonspecific hypoechoic solid mass and can guide the percutaneous needle biopsy. PMID- 18446861 TI - The biochemical structure and function of methylenetetrahydrofolate reductase provide the rationale to interpret the epidemiological results on the risk for infants with Down syndrome. AB - Studies on the structure of the methylenetetrahydrofolate reductase (MTHFR) gene and the mechanisms by which folate may reduce homocysteine levels in bacteria and in humans have provided a rationale to understand the conflicting epidemiological observations between the studies on the 677C-T and 1298A-C MTHFR polymorphic variants, and the risk of having an infant with Down syndrome (DS). However, three of the combined genotypes (CTCC, TTAC, and TTCC) are very infrequent in the human population. In fact, these three rare genotypes were only observed in two of the eight epidemiological studies that analyzed these genotype combinations and the risk of DS. In a study of the Indian population these three genotypes were identified in mothers of DS children but not in control mothers demonstrating a statistically significant increase in the risk of giving birth to DS infants. Conversely, the CTCC and TTAC genotypes were only observed in control mothers and not in mothers of DS infants in the Spanish study, while the TTCC genotype was not observed in any Spanish mother analyzed. These results were not related to the frequency of the T allele, since this was lower in the Indian population (21.4% among case mothers and 12.4% in control mothers) than in the Spanish population (33.9%). At present, several important biological aspects on the Hcy cycle are known, including: (a) the biochemical structure and function of the MTHFR enzyme, (b) the biological basis for the effect of the different 677C-T and 1298A-C MTHFR genotype combinations on Hcy levels, (c) that folate is not synthesized by the organism that obtained it from the diet, (d) that TT homozygotes will be at particular risk when their folate status is low because the mutant enzyme requires much higher levels of folate than the physiological one to stabilize the binding of flavin-adenosine-dinucleotide (FAD), (e) that the release of flavin is prevented by increasing the levels of folate, and (f) that the cystathionine-beta-synthase gene is located on chromosome 21. Together, these facts suggest that destabilization of the Hcy cycle in function of the levels of S-adenosylmethionine (SAM), may be modified by some embryonic and maternal genotypes, as well as by maternal nutritional status and life style. This may also influence the probability that some embryos survive to birth, but in different way for those with and without trisomy 21, as is discussed in this article. PMID- 18446863 TI - An unusual case of a glomus tumor developing in a subcutaneous vein of the wrist. AB - Glomus tumors are benign tumors that originate in a neuromyoarterial glomus body and most commonly occur in the subungual regions. We present an unusual case of a glomus tumor in a subcutaneous vein of the dorsum of the wrist in a 65-year-old man and describe its gray-scale and power Doppler sonographic appearance, with a brief discussion of the clinical and histologic findings. PMID- 18446864 TI - Sonographic appearances of the normal ulnar nerve in the cubital tunnel. AB - PURPOSE: To investigate the sonographic characteristics of the normal ulnar nerve in the cubital tunnel, as well as any differences related to age, sex, and dominant arm. METHOD: Two hundred twelve elbows in healthy volunteers were evaluated sonographically. The cross-sectional area (CSA) of the ulnar nerve within the cubital tunnel was measured with the elbow in extension and in flexion. The presence and number of fascicles was determined. The displacement of the ulnar nerve out of the cubital tunnel in full elbow flexion was also investigated. RESULTS: The mean +/- SD CSA of the ulnar nerve was 6.6 +/- 1.7 mm(2) (6.7 +/- 1.8 mm(2) in men and 6.5 +/- 1.7 mm(2) in women). The mean CSA of the ulnar nerve was highest for subjects aged 50-59 years, and lowest for subjects aged 30-39 years. Forty-two of 212 (19.8%) ulnar nerves had 2 fascicles, and 5 (2.4%) had 3 fascicles. The remaining 165 (77.8%) nerves had 1 fascicle. During elbow flexion, 49 of 212 (23.1%) ulnar nerves showed subluxation, and 18 (8.5%) were dislocated. CONCLUSION: There were differences in the CSA of the ulnar nerve between some age groups, but there was no variation with sex or handedness. Sonography can evaluate the morphologic changes of the nerve during flexion of the elbow. PMID- 18446865 TI - Bio-Vision 2016: the second national framework plan for biotechnology promotion in Korea. PMID- 18446866 TI - Mitochondrial pAL2-1 plasmid homologs are senescence factors in Podospora anserina independent of intrinsic senescence. AB - Since the first description of a linear mitochondrial plasmid in Podospora anserina, pAL2-1, and homologous plasmids have gone from being considered beneficial longevity plasmids, via neutral genetic elements, toward mutator plasmids causing senescence. The plasmid has an invertron structure, with terminal inverted repeats and encodes a DNA and a RNA polymerase. Here we test whether pAL2-1 homologs cause rapid aging independent of intrinsic and external conditions. We first analyzed a natural population of P. anserina and in 40% of the 112 isolates we detected pAL2-1 homologous plasmids. Though the lifespan varied considerably among the strains, plasmid-infected wild-type strains are on average shorter lived than plasmid-free strains and typically show a reduced lifespan extending effect of calorie restriction (CR). However, interesting exceptions were found, inviting further study. To further investigate the effect of pAL2-1 homologs under various conditions, we constructed and analyzed isogenic lines with and without the plasmid. We found that the presence of pAL2-1 homologs did not significantly affect growth rate as suggested by the population analysis, but reduced lifespan under all conditions. This effect was particularly clear for the lifespan extending conditions tested (CR, low temperature, antibiotics) supporting the idea that pAL2-1 homologs are additional senescence factors independent of the intrinsic senescence determinants. PMID- 18446867 TI - Mitochondria and ageing in Drosophila. AB - Studies in different organisms have revealed that ageing is a complex process involving a tight regulation of gene expression. Among other features, ageing organisms generally display an increased oxidative stress and a decreased mitochondrial function. The increase in oxidative stress can be attributable to reactive oxygen species, which are mainly produced by mitochondria as a by product of energy metabolism. Consistent with these data, mitochondria have been suggested to play a significant role in lifespan determination. The fruitfly Drosophila melanogaster is a well-suited organism to study ageing as it is relatively short-lived, mainly composed of post-mitotic cells, has sequenced nuclear and mitochondrial genomes, and multiple genetic tools are available. It has been used in genome-wide studies to unveil the molecular signature of ageing, in different feeding and dietary restriction protocols and in overexpression and down-regulation studies to examine the effect of specific compounds or genes/proteins on lifespan. Here we review the various features linking mitochondria and ageing in Drosophila melanogaster. PMID- 18446868 TI - Recent progress of microbial genome projects in Korea. PMID- 18446869 TI - Native-DIGE: a new look at the mitochondrial membrane proteome. AB - Respiratory chain proteins play a pivotal role in mitochondrial metabolism and thereby in the aging process. Differential display of the mitochondrial proteome reveals the abundance changes occurring in proteins as response to complex events such as senescence and aging. However, there is an absolute need to implement a detection technique that could potentially encompass the hydrophobic and very basic membrane proteins, along with the soluble ones. It is also important to assess protein-protein interactions, besides changes in abundance. Native difference gel electrophoresis (DIGE) is an approach that facilitates sensitive quantitative assessment of changes in membrane and soluble proteins. It stretches the boundaries of detecting abundance changes to protein-protein interactions for interpretation of a proteome in a more "meaningful" way. Here we evaluate the benefits of blue-native fluorescence DIGE as a method in differential quantitative proteomics with a focus on critical issues for application and experimental design. PMID- 18446870 TI - Mitochondrial protein quality control: implications in ageing. AB - Mitochondria represent both a major source for reactive oxygen species (ROS) production and a target for oxidative macromolecular damage. Increased production of ROS and accumulation of oxidized proteins have been associated with cellular ageing. Protein quality control, also referred as protein maintenance, is very important for the elimination of oxidized proteins through degradation and repair. Chaperone proteins have been implicated in refolding of misfolded proteins while oxidized protein repair is limited to the catalyzed reduction of certain oxidation products of the sulfur-containing amino acids, cysteine and methionine, by specific enzymatic systems. In the mitochondria, oxidation of methionine residues within proteins can be catalytically reversed by the methionine sulfoxide reductases, an ubiquitous enzymatic system that has been implicated both in ageing and protection against oxidative stress. Irreversibly oxidized proteins are targeted to degradation by mitochondrial matrix proteolytic systems such as the Lon protease. The ATP-stimulated Lon protease is believed to play a crucial role in the degradation of oxidized proteins within the mitochondria and age-related declines in the activity and/or expression of this proteolytic system have been previously reported. Age-related impairment of mitochondrial protein maintenance may therefore contribute to the age-associated build-up of oxidized proteins and impairment of mitochondrial redox homeostasis. PMID- 18446871 TI - High levels of stable phytase accumulate in the culture medium of transgenic Medicago truncatula cell suspension cultures. AB - The use of plants for production of recombinant proteins is becoming widely accepted. More recently, plant cell cultures have been proposed as valuable systems for producing a wide range of biologically active proteins. Such systems provide certain advantages over whole plants, but yields are still considered a limitation. In this study we established a Medicago truncatula cell suspension line expressing phytase from Aspergillus niger. Phytase is an N-glycosylated enzyme that breaks down indigestible phytate, resulting in an increased availability of phosphorus and other minerals in monogastric animals and reduced levels of phosphorus output in their manure. Various production systems have previously been used to express heterologous phytase, including several plant species. In this work, remarkable amounts of enzymatically active recombinant phytase were produced and secreted into the culture medium. Recombinant phytase accumulated to at least 25 mg/L and remained stable along the growth curve, and an enriched fraction with high enzymatic activity was easily obtained. We therefore propose M. truncatula cell suspension cultures as a potential system for the production of recombinant proteins. Most importantly, we have shown that, contrary to general belief, it is possible to achieve high levels of a functional recombinant protein in plant cell culture systems. PMID- 18446872 TI - [Pharmaceutical care of depressive patients. Compliance in focus]. PMID- 18446873 TI - [Clinical toxicology of tricyclic antidepressives. Modern antidepressives reduce suicide risk]. PMID- 18446879 TI - Monodentate, N-heterocyclic carbene-type coordination of 2,2'-bipyridine and 1,10 phenanthroline to iridium. PMID- 18446880 TI - Transformation of a 1-zirconacyclopent-3-yne, a five-membered cycloalkyne, into a 1-zirconacyclopent-3-ene and formal "1-zirconacyclopenta-2,3-dienes". PMID- 18446881 TI - Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG-CoA reductase. AB - This study presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized sequence. This approach was performed using the design of a competitive inhibitor for 3-hydroxy 3-methylglutaryl CoA reductase (HMGR). In a previous design for constrained peptides, a head-to-tail cyclic structure of peptide was used as a model of linear analog in searches for lead peptides with a structure close to an active conformation. Analysis of the conformational space occupied by the peptides suggests that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. Using the space obtained by an analysis of the bioactive conformations of statins, eight cyclic peptides were selected for a peptide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion ("V" parameter) applied for constrained peptides. Three cyclic peptides (FGYVAE, FPYVAE, and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC(50) = 0.4 microM) showed a 1200-fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC(50) = 484 microM) from soybean. Experimental analysis of the modeled peptide structures confirms the appropriateness of the proposed approach for the modeling of active conformations of peptides. PMID- 18446883 TI - An unusual paper about an important topic. Editorial. PMID- 18446882 TI - The six-minute walk test in outpatients with obesity: reproducibility and known group validity. AB - BACKGROUND AND PURPOSE: To assess the reproducibility and validity of the six minute walk test (6MWT) in men and women with obesity in order to facilitate evaluation of treatment outcome. METHOD: A test--retest design was used to test reproducibility and a comparative design to test known group validity. Forty three obese outpatients (16 male), mean age 47 (21-62) years, mean body mass index (BMI) 40 (3-62)kg-m(-2) performed the 6MWT twice within one week. Intraclass correlation (ICC1.1) and measurement error (S(w)) were calculated from the mean square values derived from a one-way repeated-measures ANOVA (fixed effect model). The reproducibility was also analysed by means of coefficient of variation (CV) and the Bland Altman method including 95% limits of agreement. The variance of the distance walked was analysed by means of regressions. The known group validity of the 6MWT (distance walked and the work of walking) in obese participants was shown by comparisons with 41 lean participants (18 male), mean age 47 (24-65) years, mean BMI 22.7 kg-m(-2) (19-25). RESULTS: The obese group walked 534 m (confidence interval [CI] 508-560 the first and 552 m (CI 523-580) the second walk (p < 0.001). S(w) was 25 m, CV 4.7%, ICC1.1 was 0.96. The limits of agreement were -46 m+80 m. The validity tests showed that they walked 162 m shorter (p < 0.001) and performed much heavier work (p < 0.001) than the lean group. In the obese group, BMI alone explained 38% of the variance of the distance walked. CONCLUSIONS: The 6MWT showed good reproducibility and known group validity and can be recommended for evaluating walking ability in subjects with obesity. For individual evaluation, however, an improved walking distance of at least 80 m was required to make the difference clinically significant. Despite shorter walking distance the obese participants performed heavier work than the lean. PMID- 18446884 TI - Immunization of rabbits with DNase I produces polyclonal antibodies with DNase and RNase activities. AB - Immunization of rabbits with DNase I leads to the production of antiidiotypic Abs with DNase activity. It is not known at present whether antiidiotypic Abs against DNA-hydrolyzing enzymes can possess RNase activity. Here we show that immunization of healthy rabbits with bovine DNase I produces IgGs with intrinsic DNase and RNase activities. Electrophoretically and immunologically homogeneous polyclonal IgGs were obtained by sequential chromatography of the immune sera on Protein A-Sepharose and gel filtration. Affinity chromatography on DNA cellulose using elution of Abs with different concentrations of NaCl and an acidic buffer separated catalytic IgGs into four Ab subfractions, three of which demonstrated only DNase activity while one subfraction hydrolyzed RNA faster than DNA. The serum of patients with many different autoimmune (AI) diseases contains small fractions of antibodies (Abs) interacting with immobilized DNA, which possess both DNase and RNase activities. Our data suggest that a fraction of abzymes from AI patients hydrolyzing both DNA and RNA can contain a subfraction of Abs against DNase I. PMID- 18446887 TI - High throughput screening and antioxidant assay of dibenzo[a,c]cyclooctadiene lignans in modified-ultrasonic and supercritical fluid extracts of Schisandra chinensis Baill by liquid chromatography--mass spectrometry and a free radical scavenging method. AB - Dibenzo[a,c]cyclooctadiene lignans of Schisandra chinensis Baill are well known because of their hepatoprotective activity, antioxidant activity, and anticancer effect. For the isolation of the dibenzo[a,c]cyclooctadiene lignans of Schisandra chinensis Baill two extraction methods were used: modified-ultrasonic extraction and supercritical fluid extraction. A specific and fast analytical method for structure identification is established for quality control because structure elucidation could be accomplished by means of liquid chromatography-mass spectrometry (LC-MS) technologies. The separation and identification of the compounds were completed by: (i) a water-acetonitrile gradient system using a C18 reversed-phase column; (ii) UV detection at 225 nm; (iii) MS/MS experiments with electrospray ionization interface (ESI) ion trap mass spectrometry in the positive mode. Normalized collision energy was used to obtain fragment ions of structural relevance in the LC-MS/MS. These results provided a reliable LC-MS/MS method for the determination of the dibenzo[a,c]cyclooctadiene lignans from Schisandra chinensis Baill. Finally, we also detected 1,1-diphenyl-2 picrylhydrazyl (DPPH) scavenging effects (%) of the modified-ultrasonic and supercritical fluid extracts of Schisandra chinensis Baill compared with 6 hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). The antioxidant activities of the modified-ultrasonic and supercritical fluid extracts were lower than that of trolox. PMID- 18446886 TI - Nucleic acid sensor for insecticide detection. AB - Nucleic acid sensor based on polyaniline (PANI) has been fabricated by covalently immobilizing double stranded calf thymus (dsCT) DNA onto perchlorate (ClO(-) (4)) doped PANI film deposited onto indium-tin-oxide (ITO) glass plate using 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) chemistry. These dsCT-DNA-PANI-ClO(4)/ITO and PANI-ClO(4)/ITO electrodes have been characterized using square wave voltammetry, electrochemical impedance, scanning electron microscopy (SEM) and Fourier-transform-infrared (FTIR) measurements. This disposable dsCT-DNA-PANI-ClO(4)/ITO bioelectrode, stable for about 4 months, can be used to detect cypermethrin (0.005 ppm) and trichlorfon (0.01 ppm) in 30 and 60 s, respectively. PMID- 18446885 TI - A comparative molecular force spectroscopy study of homophilic JAM-A interactions and JAM-A interactions with reovirus attachment protein sigma1. AB - JAM-A belongs to a family of immunoglobulin-like proteins called junctional adhesion molecules (JAMs) that localize at epithelial and endothelial intercellular tight junctions. JAM-A is also expressed on dendritic cells, neutrophils, and platelets. Homophilic JAM-A interactions play an important role in regulating paracellular permeability and leukocyte transmigration across epithelial monolayers and endothelial cell junctions, respectively. In addition, JAM-A is a receptor for the reovirus attachment protein, sigma1. In this study, we used single molecular force spectroscopy to compare the kinetics of JAM-A interactions with itself and sigma1. A chimeric murine JAM-A/Fc fusion protein and the purified sigma1 head domain were used to probe murine L929 cells, which express JAM-A and are susceptible to reovirus infection. The bond half-life (t(1/2)) of homophilic JAM-A interactions was found to be shorter (k(off)(o) = 0.688 +/- 0.349 s(-1)) than that of sigma1/JAM-A interactions (k(off)(o) = 0.067 +/- 0.041 s(-1)). These results are in accordance with the physiological functions of JAM-A and sigma1. A short bond lifetime imparts a highly dynamic nature to homophilic JAM-A interactions for regulating tight junction permeability while stable interactions between sigma1 and JAM-A likely anchor the virus to the cell surface and facilitate viral entry. PMID- 18446888 TI - Comparison of supercritical fluid and Soxhlet extractions for the isolation of nitro compounds from soils. AB - Supercritical fluid extraction (SFE) with CO(2), a clean and rapid alternative to conventional Soxhlet extraction, was investigated for the extraction of nitro compounds from soil samples. Quantitative extraction by SFE was accomplished at a pressure of 25 MPa and an extraction temperature of 60 degrees C, for 30 min in dynamic mode and using acetonitrile as modifier, and the results were comparable with those obtained by acetonitrile Soxhlet extraction (3 h) for all soil samples. Extracts from these two procedures were analyzed by gas chromatography coupled with mass spectrometry. Quantitative reproducibility for SFE extracts was acceptable (RSD 2-10%), and the quantity of solvent was reduced from 160 mL for Soxhlet extraction to 5 mL in the case of SFE. PMID- 18446891 TI - SFC and SFE in a historical perspective. PMID- 18446897 TI - [H5N1 with a special sense for sugar chains]. PMID- 18446898 TI - [GPCR--structure of the human beta-2 receptor clarified]. PMID- 18446900 TI - [Discovery of the tricyclic antidepressives]. PMID- 18446901 TI - [Mechanisms of action of the tri- and tetracyclic antidepressives. Adaptive change and reordering of transmitter systems]. PMID- 18446902 TI - [The medicinal chemistry of tricyclic antidepressives. Targets and stereochemistry]. PMID- 18446903 TI - [Treatment with tricyclic antidepressives. Before- and after tricyclic antidepressives]. PMID- 18446905 TI - [Tricyclics as co-analgesics. Therapeutic options for chronic pain]. PMID- 18446906 TI - [Tricyclic antidepressives as sleep aids. A medical treatment option for insomnia]. PMID- 18446907 TI - [Individualized treatment with tricyclic antidepressives. The pharmacogenetics of depression]. PMID- 18446908 TI - Torsional angular dependence of 1J(Se,Se) and Fermi contact control of 4J(Se,Se): analysis of nJ(Se,Se) (n=1-4) based on molecular orbital theory. AB - (n)J(Se,Se) (n=1-4) nuclear couplings between Se atoms were analyzed by using molecular orbital (MO) theory as the first step to investigating the nature of bonded and nonbonded (n)J(Se,Se) interactions between Se atoms. The values were calculated by employing Slater-type triple xi basis sets at the DFT level, which were applied to structures optimized with the Gaussian 03 program. The contribution from each occupied MO (psi(i)) and psi(i)-->psi(a) (psi(a)=unoccupied MO) transition was evaluated separately. 1J(Se,Se) was calculated for the MeSeSeMe model compound, which showed a typical dependence on the torsion angle (phi(C(Me)SeSeC(Me))). This dependence explains the small values (< or =64 Hz) of 1Jobsd(Se,Se) observed for RSeSeR' and large values (330 380 Hz) of 1Jobsd(Se,Se) observed for 4-substituted naphtho[1,8-c,d]-1,2 diselenoles, which correspond to synperiplanar diselenides. The HOMO-->LUMO and HOMO-1-->LUMO transitions contribute the most to 1J(Se,Se) at phi=0 and 180 degrees to give large values of 1J(Se,Se), whereas various transitions contribute and cancel each other out at phi=90 degrees to give small values of 1J(Se,Se). Large 4Jobsd(Se,Se) values were also observed in the nonbonded Se...Se, Se...Se=O, and O=Se...Se=O interactions at naphthalene 1,8-positions. The Fermi contact (FC) term contributes significantly to 4J(Se,Se), whereas the paramagnetic spin-orbit (PSO) term contributes significantly to 1J(Se,Se). 2J(Se,Se) and 3J(Se,Se) were analyzed in a similar manner and a torsional angular dependence was confirmed for 3J(Se,Se). Depending on the structure, the main contribution to (n)J(Se,Se) (n=2, 3) is from the FC term, with a lesser contribution from the PSO term. Analysis of each transition enabled us to identify and clearly visualize the origin and mechanism of the couplings. PMID- 18446909 TI - Supramolecular polymerization and polymorphs of oligo(p-phenylene vinylene) functionalized bis- and monoureas. AB - Bis- and monoureas hybridized with the oligo(p-phenylene vinylene) (OPV) pi electronic segment and 3,4,5-tridodecyloxyphenyl wedge were synthesized and their supramolecular polymerization in diluted solution, gel formation in concentrated solution, and liquid crystallinity in bulk state were investigated. Bisurea 1a featuring a hexamethylene linker showed the highest supramolecular polymerization ability and formed tapelike nanofibers that can gelate various organic solvents. On the other hand, bisurea 1b featuring a dodecamethylene linker and monourea 2 showed a lower degree of supramolecular polymerization, resulting in gel formations in a smaller variety of solvents. These results clearly reflect a high level of cooperativity between the two urea sites and the two OPV segments of 1a upon hydrogen-bonding and pi-pi stacking interactions, respectively. When the gels of 1a, 1b, and 2 were dried, all the compounds self-organized into multilamellar superstructures. Thermal treatment of these lamellae at high temperatures induces columnar liquid-crystalline mesophases as a result of microsegregation between the rigid OPV parts and the molten aliphatic wedges. These results demonstrate that the present molecular constituent is very useful for fabricating dye-based functional assemblies providing nanoscale pi-electronic fibers, and solvent-incorporated and bulk soft materials. PMID- 18446910 TI - Experimental and theoretical approaches toward anion-responsive tripod-lanthanide complexes: mixed-donor ligand effects on lanthanide complexation and luminescence sensing profiles. AB - A new series of tripods were designed to form anion-responsive, luminescent lanthanide complexes. These tripods contain pyridine, thiazole, pyrazine, or quinoline chromophores combined with amide carbonyl oxygen and tertiary nitrogen atoms. Crystallographic and EXAFS studies of the 10-coordinated tripod La(NO(3))(3) complexes revealed that each La(3+) cation was cooperatively coordinated by one tetradentate tripod and three bidentate NO(3)(-) anions in the crystal and in CH(3)CN. Quantum chemical calculations indicated that the aromatic nitrogen plays a significant role in lanthanide complexation. The experimentally determined stability constants of complexes of the tripod with La(NO(3))(3), Eu(NO(3))(3), and Tb(NO(3))(3) were in good agreement with the theoretically calculated interaction energies. Complexation of each tripod with lanthanide triflate gave a mixture of several lanthanide complex species. Interestingly, the addition of a coordinative NO(3)(-) or Cl(-) anion to the mixture significantly influenced the lanthanide complexation profiles. The particular combination of tripod and a luminescent Eu(3+) center gave anion-selective luminescence enhancements. Pyridine-containing tripods exhibited the highest NO(3)(-) anion selective luminescence and thus permit naked-eye detection of the NO(3)(-) anion. PMID- 18446911 TI - Clathrate formation from octaazaphthalocyanines possessing bulky phenoxyl substituents: a new cubic crystal containing solvent-filled, nanoscale voids. AB - The synthesis of octaazaphthalocyanine (AzaPc) derivatives, with bulky phenoxyl substituents placed at eight peripheral positions and containing either H(+), Ni(2+) or Zn(2+) ions in their central cavity, is described. The required precursors, derivatives of pyrazine-2,3-dicarbonitrile, were prepared using a nucleophilic aromatic substitution reaction between 2,6-diisopropylphenol or 2,6 diphenylphenol and 5,6-dichloropyrazine-2,3-dicarbonitrile. Analysis of the resulting AzaPcs by UV/Visible and (1)H NMR spectroscopy confirms that steric isolation of the AzaPc cores was enforced both in solution and in the solid state. X-ray diffraction studies of single crystals of the AzaPcs reveal that solvent inclusion takes place in each case. Of particular significance is the finding that the zinc derivative of 2,3,9,10,16,17,23,24-octa-(2,6 diisopropylphenoxy)octaazaphthalocyanine provides nanoporous cubic crystals, containing massive (8 nm(3)) solvent-filled voids, similar to those of the analogous phthalocyanine derivative. Exchange of the included solvent within the voids can be readily achieved by using a number of alternative solvents including water. Based on the observed loading of included water, the internal volume of this nanoporous cubic crystal appears to be more hydrophilic than its phthalocyanine counterpart. PMID- 18446912 TI - Diastereo- and enantiomerically pure allylboronates: their synthesis and scope. AB - Allylboronates are highly attractive reagents for allyl additions. Enantiomerically pure, stable reagents with a stereogenic centre in alpha position to boron are especially versatile, albeit often difficult to synthesize. Starting from boron-containing allyl alcohols 6 and 7, which are discussed in detail herein, a set of reagents were obtained via [3,3]-sigmatropic rearrangements and consecutive transformations in the side chain. The configurations could be established first by chemical correlation, but also by X ray crystallography (16, 18, 34, and 39). Allyl additions were performed resulting in the formation of predominantly (Z)-configured homoallylic alcohols (31, 43-45) with high enantiomeric excess. Detailed investigations on the matched mismatched interaction between the reagents 15/16 (and ent-15/ent-16, respectively) and isopropylidene glyceraldehyde 42d are presented. PMID- 18446913 TI - Organocatalytic multicomponent alpha-methylenation/Diels-Alder reactions: a versatile route to substituted cyclohexenecarbaldehyde derivatives. AB - This article describes the design and optimization of an effective organocatalytic three-component domino alpha-methylenation/Diels-Alder reaction to produce vinyl-substituted cyclohexenecarboxaldehydes in a highly regioselective fashion. In these one-pot transformations, 2-formyl-1,3-butadienes (4) were prepared in situ from alpha,beta-unsaturated aldehydes and formalin and were subsequently trapped with a variety of buta-1,3-dienes. The outcomes of the reactions were dependent on the electronic properties of the dienes. 1 Vinylcyclohexenecarbaldehydes 6 were formed by use of acyclic electron-rich dienes, while the initially formed cycloadducts of 4 with cyclopentadiene underwent Cope rearrangements, leading to the formation of tetrahydro-3H-indene-5 carbaldehyde compounds 7. The mechanisms involved in these reactions were deduced from experimental findings. Furthermore, the method was also extended to one-pot domino methylenation/Diels-Alder reactions of dihydrofurans and dihydropyrans to yield spirocyclic lactols 22. In these reactions, the unstable intermediate hydroxyethyl and hydroxypropyl acroleins behaved as dienophiles, undergoing cycloaddition reactions with dienes with good yields and selectivities. The wide variety of functionalized 1-vinylcyclohex-3-enecarbaldehydes 6, 4-vinylcyclohex-1 enecarbaldehydes 7, and spiro lactols 22 generated through the use of these organocatalytic domino processes as a diversity-oriented synthesis provided useful intermediates for the construction of novel odorants. PMID- 18446914 TI - The synthesis and isolation of a metal-substituted bis-silene. PMID- 18446915 TI - Long-wavelength fluorescence from 2-aminopurine-nucleobase dimers in DNA. AB - When 2-aminopurine (2AP) is substituted for adenine in DNA, it is widely accepted that its fluorescence spectrum is essentially unchanged from that of the free fluorophore. We show that 2AP in DNA exhibits long-wavelength emission and excitation bands, in addition to the familiar short-wavelength spectra, as a result of formation of a ground-state heterodimer with an adjacent, pi-stacked, natural base. The observation of dual emission from 2AP in a variety of oligodeoxynucleotide duplexes and single strands demonstrates the generality of this phenomenon. The photophysical and conformational properties of the long wavelength-emitting 2AP-nucleobase dimer are examined. Analogous long-wavelength fluorescence is seen when 2AP pi-stacks with aromatic amino acid sidechains in the active sites of methyltransferase enzymes during DNA nucleotide flipping. PMID- 18446916 TI - Monomer versus alcohol activation in the 4-dimethylaminopyridine-catalyzed ring opening polymerization of lactide and lactic O-carboxylic anhydride. AB - Model reactions for the 4-dimethylaminopyridine (DMAP)-catalyzed ring-opening polymerization of lactide and the corresponding lactic O-carboxylic anhydride (lacOCA) have been studied computationally at the B3LYP/6-31G(d) level of theory. The solvent effect of dichloromethane was taken into account through PCM/SCRF single-point calculations at the B3LYP/6-31G(d) level of theory. In marked contrast with that predicted for the reaction of alcohols with acetic anhydride, the mechanism in which nucleophilic activation of the monomer involving acylpyridinium intermediates was found to be energetically less favorable than the base activation of the alcohol through hydrogen bonding. The concerted pathway for the ring-opening of lactide and lacOCA was shown to compete with the traditional stepwise mechanism involving tetrahedral intermediates. Furthermore, DMAP is proposed to act as a bifunctional catalyst through its basic nitrogen center and an acidic ortho-hydrogen atom. PMID- 18446917 TI - Mononuclear biscarbene complexes by direct nucleophile addition to a CO ligand of Fischer arylcarbene complexes. PMID- 18446918 TI - Freeze-align and heat-fuse: microwires and networks from nanoparticle suspensions. PMID- 18446919 TI - Bio-inspired fabrication of lotus leaf like membranes as fluorescent sensing materials. AB - A fluorescent organic small molecule, hexaphenylsilole (HPS), has been used as a sensing material, while a HPS/polymethyl methacrylate composite film with a lotus leaf like structure is prepared by a simple electrospin method. The film shows high stability and excellent sensitivity for the metal ions Fe(3+) and Hg(2+), respectively. The special surface morphology containing micro-/nanocomposite structure is attributed to the exhibition of these unusual properties. PMID- 18446920 TI - Hybridization-sensitive on-off DNA probe: application of the exciton coupling effect to effective fluorescence quenching. AB - The design of dyes that emit fluorescence only when they recognize the target molecule, that is, chemistry for the effective quenching of free dyes, must play a significant role in the development of the next generation of functional fluorescent dyes. On the basis of this concept, we designed a doubly fluorescence labeled nucleoside. Two thiazole orange dyes were covalently linked to a single nucleotide in a DNA probe. An absorption band at approximately 480 nm appeared strongly when the probe was in a single-stranded state, whereas an absorption band at approximately 510 nm became predominant when the probe was hybridized with the complementary strand. The shift in the absorption bands shows the existence of an excitonic interaction caused by the formation of an H aggregate between dyes, and as a result, emission from the probe before hybridization was suppressed. Dissociation of aggregates by hybridization with the complementary strand resulted in the disruption of the excitonic interaction and strong emission from the hybrid. This clear change in fluorescence intensity that is dependent on hybridization is useful for visible gene analysis. PMID- 18446921 TI - Proceedings of the 12th International Conference on Ion Sources. Jeju, Korea. August 26-31, 2007. PMID- 18446922 TI - Proceedings of the 1st International Symposium on Green Technology and Ecosystem Health. Hangzhou, China. October 13-15, 2007. PMID- 18446923 TI - Proceedings of the 3rd Annual Perioperative Medicine Summit. September 10-12, 2007. Cleveland, Ohio, USA. PMID- 18446924 TI - Proceedings of two international symposia on urinary tract infection organised by the Commission for Urinary Tract Infection of the International Society of Chemotherapy for Infection and Cancer. June 23-24, 2006, Weimar, Germany and March 30-April 3, 2007, Munich, Germany. PMID- 18446925 TI - Drug subsidy could help Tanzania tackle malaria. PMID- 18446926 TI - Thomas Wakley, plagiarism, libel, and the founding of The Lancet. PMID- 18446927 TI - Communication skills of health-care professionals working in oncology--can they be improved? AB - Communication skills' training has been placed high on the agenda by the National Institute of Clinical Excellence guidelines and the National Health Service in the UK. The paper reviews the importance of good communication skills in cancer care for the patient and describes research that has identified ways in which health-care professionals (HCP) can improve their communication with patients. The evidence as to why there is a lack of facilitative skills is reviewed along with what skills are required in order to improve communication with patients. The paper describes evidence of increased facilitative skills post-training, discusses whether there is evidence of transfer of these skills into clinical practice and how this might be best achieved. To conclude, research evidence would support the fact that training in communication skills needs to provide the best possible outcomes for HCP and their patients. Patient concerns, needs and preferences need to be elicited and the impact of concerns identified, so that the HCP can appropriately tailor their information giving, advice, treatment and plan of care. PMID- 18446928 TI - Challenges inherent to t'ai chi research: part II-defining the intervention and optimal study design. AB - Although a growing body of clinical research has begun to evaluate the efficacy and safety of t'ai chi as a therapeutic tool for a variety of health conditions, little attention has been devoted to evaluating "how" t'ai chi is scientifically studied, and the advantages or limitations of different methodological approaches. In a companion to this paper (Part I), we argued that t'ai chi is a complex, multicomponent intervention, which poses unique challenges regarding the distinction of specific versus nonspecific effects and limitations regarding the use of reductionistic research frameworks. In this second, companion paper, we discuss additional obstacles inherent in precisely defining the t'ai chi intervention in an experimental paradigm. These challenges include t'ai chi's pluralism, the concept of t'ai chi dosage, and long- versus short-term evaluations of t'ai chi's efficacy and safety. To address these challenges, and with a goal to provide complete and unbiased evidence, we propose a pluralistic methodological approach to clinical research that includes controlled randomized trials of fixed protocols, community-based pragmatic trials, cross-sectional studies of long-term practitioners, and studies that integrate qualitative methods. PMID- 18446929 TI - Tamoxifen and the uterus and endometrium. PMID- 18446930 TI - Tamoxifen and the uterus and endometrium. PMID- 18446931 TI - Patient vs. "customer-owner". PMID- 18446933 TI - Beware this buzz. PMID- 18446932 TI - Evaluating the RUC. PMID- 18446934 TI - SSRI antidepressants don't actually do anything to improve depressed states. PMID- 18446935 TI - Chemical con trick? PMID- 18446936 TI - All the rage. PMID- 18446937 TI - See with your mind. PMID- 18446938 TI - We do everything. PMID- 18446939 TI - School's in. PMID- 18446940 TI - Efforts to deliver 'trauma therapy' in third world countries. PMID- 18446941 TI - The 2008/09 benefits year. PMID- 18446942 TI - Is it o.k. for me to come in--given that I have a psychiatric history? PMID- 18446943 TI - Test pilot for humanity. Interview by Catherine Jackson. PMID- 18446944 TI - Find a pathway back into work. AB - Intensive condition management programmes are key to helping people claiming long term sickness benefits get back into employment PMID- 18446945 TI - Changing roles and responsibilities. AB - The Mental Health Act 2007 introduces some important changes to the roles and responsibilities of key mental health practitioners and of their employers PMID- 18446946 TI - Walking talking therapy. AB - Given the links between mental health, obesity and exercise, could physical activity be incorporated into therapy sessions with young people? PMID- 18446947 TI - Customers care. PMID- 18446948 TI - Important safeguards may be lost when the Mental Health Act Commission goes. PMID- 18446949 TI - [Transient constrictive pericarditis]. PMID- 18446950 TI - [Central precocious puberty and hypothalamic hamartoma]. PMID- 18446951 TI - [Osteoporosis in children. A case report]. PMID- 18446952 TI - Census shows wide variation in numbers of clinical staff. PMID- 18446953 TI - NHS service providers can advertise under new code. PMID- 18446954 TI - DH admits target on health inequalities is hard to meet. PMID- 18446955 TI - Neediest areas worst off. PMID- 18446956 TI - Lift-off for air ambulances as government comes calling. PMID- 18446957 TI - On keeping change at bay. PMID- 18446958 TI - Managers should lend a listening ear to patients. PMID- 18446959 TI - Data briefing. Can fluoridation help the poorest? PMID- 18446960 TI - Doctors without borders? AB - *Irregular migrants' access to primary care is at GPs' discretion, but observers predict a ban on all but emergency care. *An analysis found patients only want basic GP services, which in turn reduce hospital admissions. *The DH and Home Office have completed a review of foreign nationals' access to NHS care, expected shortly. PMID- 18446962 TI - Huge variation in GP practice pay regardless of size of list. PMID- 18446961 TI - Fresh thinking on problem drinking. PMID- 18446963 TI - PCT threatened with court over fight for information. PMID- 18446964 TI - Most trusts off course for new target. PMID- 18446965 TI - 'Intelligent' measures to play bigger role in choice. PMID- 18446966 TI - Crime scene--and you're in the dock. PMID- 18446967 TI - On valuing all the front line. PMID- 18446968 TI - Who will stand for rare conditions? PMID- 18446969 TI - Data briefing. How GP practices are ignoring the evidence. PMID- 18446970 TI - Dose of realism. PMID- 18446971 TI - Good management. Partnerships. PMID- 18446972 TI - Rx for uncertainty. Does a popular cholesterol-lowering drug do what it's supposed to do? PMID- 18446973 TI - All about your kidneys. Keep them safe, and they will keep you going. PMID- 18446974 TI - Twisting without shouting. A gentle introduction to the joys of yoga. PMID- 18446975 TI - Healthy eating. An ancient culinary delight. Falling in love with tortillas. PMID- 18446976 TI - Could a dog save your life? No one knows for sure how they do it, but a growing number of canine companions are helping people with diabetes avoid dangerous hypoglycemia. PMID- 18446977 TI - Diabetes? POW! An interview with comic-book authors Kamaal and Malcolm Washington. Interview by Shelley Lowenstein. PMID- 18446978 TI - Symlin up close. How people are benefiting from this injected drug. PMID- 18446979 TI - When the moon hits your eye. PMID- 18446980 TI - Research profile. Choosing and losing. Why do some people skip their med? John D. Piette, Ph.D. PMID- 18446981 TI - Gene therapy in thoracic oncology. PMID- 18446982 TI - Anne Wilkinson (1910-61). PMID- 18446983 TI - Fund-raising for the Osler Library. PMID- 18446984 TI - The Open Arms revisited and renewed. PMID- 18446985 TI - Osler Society of McGill University: Report for the Academic Year 1982-83. PMID- 18446986 TI - The Open Arms -- the story of the plaque. PMID- 18446987 TI - Osler's 134th birthday party. PMID- 18446988 TI - Redpath Museum exhibit in the Osler Library. PMID- 18446989 TI - [Another view on physical education and sports in France before 1914: Georges Hebert and the success of the natural method]. PMID- 18446990 TI - Eating disorders among dietetics students: an educator's dilemma. PMID- 18446992 TI - [Homeboundness in the elderly]. PMID- 18446991 TI - The clinical effectiveness of hyaluronan products. PMID- 18446993 TI - [Aging and gerontological diseases in relation to age-related homeostasis and age dimension technology]. PMID- 18446994 TI - The less they know, the better: abstinence-only HIV/AIDS programs in Uganda. AB - Young people in Uganda have never known a world without HIV/AIDS. Ignorance and denial fuel HIV, leaving young people without the critical information that could help them prevent infection. As of 2002, according to government estimates, HIV prevalence among young people in Uganda stood at an estimated 4.9 percent, with rates of 6.5 percent in major towns and 4.1 percent in rural areas. This is the summary and excerpts from the recommendations of this publication. PMID- 18446995 TI - [Experimental study on etiological mechanism of convulsion--special reference to convulsions and epileptiform activity waves associated with physical maturity]. PMID- 18446996 TI - [Problems in forensic psychiatry--psychiatric evaluation of a criminal case with personality disorder]. PMID- 18446997 TI - The gender laws: federal legislation and the feminization of veterinary medicine. PMID- 18446998 TI - Forgotten veterinarians. 7. Louis A. Merillat. PMID- 18446999 TI - Animal therapy over the ages: 16. Disease concepts, spiritual domain, and the power of prayer. PMID- 18447000 TI - On the synergistic effect of doxorubicin and mitomycin C against breast cancer cells. AB - The combination of doxorubicin and mitomycin C has been shown previously to result in supra-additive tumor cell killing in vitro in both murine and human breast cancer cells and in vivo against murine breast cancer cells. Median effect analysis was used to determine the significance and degree of interaction. The origin of this synergy was sought by evaluating the contribution of membrane efflux pump modulation, formaldehyde production, reactive oxygen species, DNA cross-linking, and DNA double-strand breaks to this effect. The interaction of mitomycin C and doxorubicin in vitro was found to be a true synergy whose mechanism was efflux pump-independent. DNA cross-links were only found to increase additively with co-administration of the drugs; however, a supra additive increase in DNA double-strand breaks was observed. The results suggest that poisoning of topoisomerase IIalpha by doxorubicin may interact with drug induced DNA cross-links to enhance the formation of DNA double-strand breaks. This interaction, together with glutathione depletion and mitomycin C-derived formaldehyde, may be the underlying mechanism(s) of the synergy observed between mitomycin C and doxorubicin. PMID- 18447001 TI - The effect of chlorpyrifos-oxon and other xenobiotics on the human cytochrome P450-dependent metabolism of naphthalene and deet. AB - Chlorpyrifos-oxon (CPO), a metabolite of chlorpyrifos, is a potent inhibitor of acetylcholinesterase and, although the neurotoxicological impact of this organophosphorus compound has been broadly studied both in vitro and in vivo, there are few studies of metabolic interactions of CPO with other xenobiotics. CPO significantly activated the production of 1-naphthol (5-fold), 2-naphthol (10 fold), trans-1,2-dihydro-1,2-naphthalenediol (1.5-fold), and 1,4-naphthoquinone from naphthalene by human liver microsomes (HLM). It was further demonstrated that the production of naphthalene metabolites by CYP2C8, 2C9*(1), 2C19, 2D6*(1), 3A4, 3A5, and 3A7 was activated by CPO, while the production of naphthalene metabolites by CYP1A1, 1A2, 1B1, and 2B6 was inhibited by CPO. CPO inhibited CYP1A2 production of naphthalene metabolites, while activating their production by CYP3A4. Similarly, CPO inhibited the production of N,N-diethyl-m hydroxymethylbenzamide (BALC) from DEET by human liver microsomes, but activated the production of N-ethyl-m-toluamide (ET) from this substrate. CYP2B6, the most efficient isoform for BALC production, was inhibited by CPO, while CYP3A4, the most efficient isoform for ET production, was activated by CPO. CPO inhibited CYP2B6 production of both BALC and ET from DEET, but activated CYP3A4 production of ET, while inhibiting CYP3A4 BALC production. CPO appears to facilitate the binding of naphthalene to CYP3A4. This metabolic activation is independent of cytochrome b5, suggesting that activation of CYP3A4 by CPO is associated with a conformational change of the isoform rather than facilitating electron transfer. PMID- 18447002 TI - Rutin inhibits nitric oxide and tumor necrosis factor-alpha production in lipopolysaccharide and concanavalin-a stimulated macrophages. AB - The effect of rutin, a flavonoid present in onions, apples, tea and red wine, on the production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) was analyzed using in vitro as well as in vivo systems. The level of nitrite in lipopolysaccharide (LPS) stimulated BALB/c mice (88.21 microM) was significantly reduced in rutin treated animals (16.92 microM). The nitrite level in concanavalin-A (Con-A) treated control animals (77.15 microM) was also significantly reduced to 11.03 microM when the animals were pretreated with rutin. The drastically elevated levels of TNF-alpha in LPS stimulated animals (686.8 pg/ml) was lowered by pretreatment with rutin (182.4 pg/ml). Rutin also inhibited Con-A induced TNF-alpha production. Rutin inhibited nitrite production by activated macrophages in vitro (74.75 microM) to the normal level (16.13 microM) at a concentration of 5 microg/ml. In vitro L929 bioassay also showed inhibition of TNF-alpha production by rutin treatment. PMID- 18447003 TI - Hypothyroidism is a predisposing factor for fenofibrate-induced rhabdomyolysis- patient report and literature review. AB - A literature survey reveals that both lipid lowering drugs - statins and fibrates -and hypothyroidism are documented causes of muscle disorders including rhabdomyolysis leading to acute renal failure. We describe a case of fenofibrate monotherapy (Lipicard) induced dialysis dependent acute renal failure in an undiagnosed hypothyroid patient which is the first case to be reported from Sri Lanka. We strongly recommend that all patients who are receiving statins and/or fibrates should be screened for occult hypothyroidism which seems to aggravate the muscle damage due to the above drugs, with or without other risk factors. PMID- 18447004 TI - Sudden enlargement of the prostate in a patient taking Fansidar for malaria. PMID- 18447005 TI - Nanoalloys: from theory to application. Preface. PMID- 18447006 TI - Nanoalloys: tuning properties and characteristics through size and composition. AB - A brief sketch of the history of metals and alloys is followed by examples illustrating the current status of the field of nanoalloys and a discussion of our results on the characterization of structural and dynamical (thermal) properties of Ni-Al bimetallic clusters. PMID- 18447007 TI - A study of bimetallic Cu-Ag, Au-Ag and Pd-Ag clusters adsorbed on a double vacancy-defected MgO(100) terrace. AB - Binary M2Ag6, M2Ag7, M1Ag7 and M1Ag8 clusters (M = Cu, Au, Pd) adsorbed on an MgO(100) terrace presenting a double vacancy (DV) neutral defect are investigated through a combination of density-functional (DF) biased searches and global optimizations. Alloying allows one to probe the adsorption characteristics of the DV-defected surface. It is found that Au1Ag7 and Au2Ag6 are core-shell magic clusters, in analogy with the pure silver case. The magic character is reduced for Cu1Ag7 and Cu2Ag6, because the shortening of Cu-Ag distances is counteracted by a double-frustration effect due to the DV, and is practically absent for Pd1Ag7 and Pd2Ag6, because the requirements of the metallic bond conduction electron count are in conflict with the metal-surface interaction. However, fluxionality is enhanced for Pd-Ag clusters with respect to the pure silver case, which could influence their catalytic properties. PMID- 18447008 TI - Global optimisation and growth simulation of AuCu clusters. AB - Global optimisation techniques and Molecular Dynamics simulations are employed to investigate the structure and the chemical order of AuCu clusters, with composition Au0.75Cu0.25, Au0.5Cu0.5 and Au0.25Cu0.75. Global optimisations by Parallel Excitable Walkers algorithm have located the global minimum configurations of clusters at size N = 100, 160 and 200 atoms. Stable clusters do not exhibit any alloy-like ordering, and combine the tendency to surface segregation of the gold atoms with the icosahedral structural motif. As unique exception to the icosahedral trend, an almost perfect decahedron is located at size N = 100, exhibiting copper atoms in its outer shell. As regards to the dynamics, the paper deals with the growth of AuCu clusters, both depositing gold and copper atoms onto an heterogeneous seed, and depositing copper atoms onto an homogeneous gold seed. In agreement with the global optimisation results, the former growth process leads to the formation of Ih clusters, whose surface is enriched in gold atoms. The latter deposition process turns into the formation of decahedral clusters with a reversed Cu(shell)Au(core) chemical ordering. PMID- 18447009 TI - Mechanical properties of bimetallic crystalline and nanostructured nanowires. AB - Nanowires are basic components of interconnects at the nanoscale level in electronic as well as in electromechanical devices. Presently, there is a fast growing interest in their synthesis as well as in their mechanical testing. Focused ion beams now allow machining pillars with diameters as small as a few tens of nanometres and nanoindenter systems allow measuring strains at the atomic scale and compressive stresses up to the 10 GPa range. Such pillars typically contain less than millions of atoms, which makes their modelling and the modelling of their mechanical properties at the atomic scale realistic. A few Molecular Dynamics studies are presently available, discussing deformation mechanisms in thin narrow crystalline nanowires, but the literature about nanoalloy wires and nanostructured wires, as they can be synthesized from clusters, is almost non-existent. In the latter, the dislocation activity may be inhibited, leading to specific mechanical properties. By means of large scale computations, we use Ni3A1 to discuss the mechanical properties of crystalline and nanostructured nanowires. We also compare wires to their bulk counterparts. Both isothermal and isoenergetic whereby mechanical work converts into heat in the system-deformation mechanisms are considered. The comparison between pair correlation functions, stress distributions, configuration analysis and strain stress relations capture most of the stress-induced evolution mechanisms of nanowires with different diameters and structures, including elastic properties, dislocation activity, grain rotation and boundary motion, local melting, superplasticity and fracture. A structural transition which may be martensitic is predicted for the first time at the nanoscale level, suggesting possible shape memory properties of nanoalloy nanowires. PMID- 18447010 TI - Solid-solution precursor to melting in onion-ring Pd-Pt nanoclusters: a case of second-order-like phase change? AB - The thermodynamical behaviour of icosahedral, multilayer Pd-Pt clusters is addressed using a combination of simulation tools, mainly parallel tempering Monte Carlo. A preferential swapping trial move is introduced to increase the chance of successfully exchanging Pd and Pt atoms in the cluster. The 2-, 3- and 4-shell, Pd-rich clusters have been studied. We generally find that the clusters melt at a temperature significantly below the bulk melting point at the same corresponding composition. More interestingly, for the smaller clusters melting is initiated by a solid-solution intermediate phase in which the overall icosahedral frame remains, but the Pd and Pt atoms can swap sites. The transition to this solid-solution phase is seen to have a continuous, second-order like character, which is interpreted from the similarity between the present system with the ferromagnetic Ising model on the 3D cubic lattice. As the cluster grows, the onion-ring structure becomes thermodynamically unstable. The 4-layer cluster already exhibits a solid-solution in its core at temperatures as low as 100 K. The bulk behaviour is thus recovered at very small scales. PMID- 18447011 TI - Atomistic computer simulations on the generation of bimetallic nanoparticles. AB - Computer simulations on the generation of bimetallic nanoparticles are presented in this work. Two different generation mechanisms are simulated: (a) cluster cluster collision by means of atom dynamics simulations; and (b) nanoparticle growth from a previous seed through grand canonical Monte Carlo (gcMC) calculations. When two metal nanoparticles collide, different structures are found: core/shell, alloyed and three-shell (A-B-A). On the other hand, the growth mechanism at different chemical potentials by means of gcMC reveals the same results as atom dynamics collisions do. PMID- 18447012 TI - Dynamical equilibrium in nanoalloys. AB - Using Monte Carlo simulations on a lattice-gas model, we study the segregation isotherm of a cluster made of thousands of atoms for a system that tends to phase separate, e.g., Cu-Ag. We show that the Ag segregation involves the vertices first, then the edges and finally the (111) and (100) facets. In these facets, the segregation starts on the outer shells, leading to a heterogeneous chemical composition. When the nominal Ag concentration (or the chemical potential difference delta(mu)c between Ag and Cu), is increased a dynamical equilibrium replaces the progressive evolution of the segregation towards the core of the facets: the whole facet oscillates between one pseudo Ag-pure state and another one corresponding to a rather Cu-pure core surrounded by Ag-enriched outer shells. A remarkable consequence is that very different concentrations can be observed for facets of equivalent orientation. This dynamical equilibrium occurs in a delta(mu) range that is very close to the critical value delta(mu)c associated with the first-order phase transition of the Fowler-Guggenheim type that affects the surfaces of semi-infinite alloys. These results, which have been obtained in the grand-canonical ensemble, can also be derived in the canonical ensemble due to a sufficient number of facets that behave with each other as a reservoir. PMID- 18447013 TI - Optical properties and relaxation processes at femtosecond scale of bimetallic clusters. AB - The optical properties of Au-Ag and Ni-Ag clusters are measured by linear optical absorption spectroscopy and the time-resolved pump-probe femtosecond technique allowing a study of the influence of alloy or core-shell structure. PMID- 18447014 TI - Stability and dissociation pathways of doped Au(n)X+ clusters (X = Y, Er, Nb). AB - Size dependent stabilities, fragmentation pathways and dissociation energies of a series of gas phase cationic doped gold clusters, Au(n)X+ (3 < or = n < or = 20; X = Y, Er and Nb), and pure Au(n)+ clusters were investigated in photofragmentation experiments. Size dependent stability patterns were obtained and the branching between monomer and dimer evaporation was studied. For bare gold, the competing neutral monomer and dimer evaporation channels were found to be in agreement with earlier studies. For doped clusters, monomer evaporation is the most likely fragmentation channel with the exception of Au18Y+ and Au20Y+ for which gold dimer evaporation is also observed. Relations between the evaporative activation energies and both the experimental abundances and the fragment yield were derived based on unimolecular rate constants. The dissociation energies from this analysis show an odd-even staggering and enhanced stabilities for certain cluster sizes, in agreement with simple electronic shell model predictions. PMID- 18447015 TI - Laser synthesis of bimetallic nanoalloys in the vapor and liquid phases and the magnetic properties of PdM and PtM nanoparticles (M = Fe, Co and Ni). AB - In this work, we present several examples of the synthesis and characterization of bimetallic nanoparticle alloys using the Laser Vaporization Controlled Condensation (LVCC) method. In the first example, the vapor phase synthesis of Au Ag, Au-Pd, and Au-Pt nanoparticle alloys are presented. The formation of nanoalloys is concluded from the observation of one plasmon absorption band at a wavelength that varies linearly with the gold mole fraction in the nanoalloy. Both XRD data and HRTEM-EDX data confirm the formation of nanoparticle alloys and not simply mixtures of the two metal nanoparticles. Irradiation of a mixture of Au/Ag nanoparticles dispersed in water with the 532 nm unfocused laser results in efficient alloying while the 1064 nm laser radiation results only in evaporation and size reduction of the unalloyed nanoparticles. Selective absorption of the femtosecond 780 nm radiation by large Au aggregates results in the formation of smaller aggregates with fractal structures, and no evidence for the Au-Ag alloy formation. The synthesis of palladium and platinum nanoparticles alloyed with transition metals such as iron and nickel using the LVCC method is also presented. The alloyed nanoparticles (FePd, FePt, NiPd, NiPt, and FeNi) are found to be superparamagnetic. PMID- 18447016 TI - Magnetic properties of Co(N)RhM nanoparticles: experiment and theory? AB - The magnetism of Co-Rh nanoparticles is investigated experimentally and theoretically. The particles (approximately 2 nm) have been synthesized by decomposition of organometallic precursors in mild conditions of pressure and temperature, under hydrogen atmosphere and in the presence of a polymer matrix. The magnetic properties are determined by SQUID, Mossbauer spectroscopy, and X ray magnetic circular dichroism (XMCD). The structural and chemical properties are characterized by wide angle X-ray scattering, transmission electronic microscopy and X-ray absorption near edge spectroscopy. All the studied Co-Rh clusters are magnetic with an average spin moment per atom mu that is larger than the one of macroscopic crystals or alloys with similar concentrations. The experimental results and comparison with theory suggest that the most likely chemical arrangement is a Rh core, with a Co-rich outer shell showing significant Co-Rh mixing at the interface. Measured and calculated magnetic anisotropy energies (MAEs) are found to be higher than in pure Co clusters. Moreover, one observes that the MAEs can be tuned to some extent by varying the Rh concentration. These trends are well accounted for by theory, which in addition reveals important spin and orbital moments induced at the Rh atoms as well as significant orbital moments at the Co atoms. These play a central role in the interpretation of experimental data as a function of Co-Rh content. A more detailed analysis from a local perspective shows that the orbital and spin moments at the Co-Rh interface are largely responsible for the enhancement of the magnetic moments and magnetic anisotropy. PMID- 18447017 TI - Structure and chemical ordering in CoPt nanoalloys. AB - The structure and chemical ordering of CoPt nanoclusters in the size range of 1 to 3 nm are investigated by global optimization methods and Monte Carlo simulations using a many body potential derived from the tight binding model. For the smaller systems (number of atoms N < 100), the optimized clusters display a polyicosahedral-like atomic structure with a little core-shell chemical ordering characterized by a particular surface chemical configuration: some pentagonal or hexagonal Pt rings centered, respectively on a Co atom or a Co dimer. A transition to the decahedral symmetry occurs at about N = 100 atoms, with a pseudo L1(0) ordered phase in each tetrahedral unit. For larger cluster sizes, 201 < N < 1289, the L1(0)-ordered/disordered transition on the face centered cubic truncated octahedron is studied by canonical Monte Carlo simulations showing that the critical disordering temperature decreases with the cluster size. We also notice a Co surface segregation especially at edges and, possibly, (100) facets, depending on the cluster size, on both cubic and fivefold symmetry structures. PMID- 18447018 TI - Direct synthesis of hydrogen peroxide from H2 and O2 using supported Au-Pd catalysts. AB - The direct synthesis of H2O2 at low temperature (2 degrees C) from H2 and O2 using carbon-supported Au, Pd and Au-Pd catalysts is described and contrasted with data for TiO2, Al2O3 and Fe2O3 as supports. The Au-Pd catalysts all perform significantly better than the pure Pd/TiO2 and Au/ TiO2 materials. The Au Pd/carbon catalysts gave the highest rate of H2O2 production, and the order of reactivity observed is: carbon > TiO2 > Al2O3. Catalysts were prepared by co impregnation of the supports using incipient wetness with aqueous solutions of PdCl2 and HAuCl4, and following calcination at 400 degrees C the catalysts were stable and could be reused several time without loss of metal. The method of preparation is critical, however, to achieve stable catalysts. No promoters are required (e.g. halides) to achieve the high rates of hydrogen peroxide synthesis. The surface and bulk composition of the gold palladium nanoparticles was investigated by STEM-XEDS spectrum imaging. For TiO2 and Al2O3 as supports the Au Pd particles were found to exhibit a core-shell structure, Pd being concentrated on the surface. In contrast, the Au-Pd/carbon catalyst exhibited Au Pd nanoparticles which were homogeneous alloys and X-ray photoelectron studies were consistent with these observations. The origin of the enhanced activity for the carbon supported catalysts is a result of higher H2 selectivity for the formation of hydrogen peroxide which is due to the surface composition and size distribution of the nanoparticles. The key problem remaining is the sequential hydrogenation of hydrogen peroxide which limits the utilisation of the direct synthesis methodology and this is discussed in detail. PMID- 18447019 TI - Structures and associated catalytic properties of well-defined nanoparticles produced by laser vaporisation of alloy rods. AB - Bimetallic clusters, all containing gold, have been produced by laser vaporisation of bulk alloys followed by deposition of the formed clusters onto Al2O3 and TiO2 powders or flat silica supports. This technique allows a narrow size distribution of highly dispersed gold-based nanoparticles on powders and nanocrystalline structured thin films on 2D supports to be obtained. The catalytic performances of the as-obtained AuFe, AuNi, AuTi powdery catalysts have been studied in the PROX reaction and compared with those obtained in the oxidation of CO in the temperature range 25-300 degrees C. By comparing the activities of the different catalysts, it is concluded that the nature of the gold partner directly affects the activity of gold. The following tendency is observed: AuFe and AuNi have rather similar activities, significantly lower than that of AuTi. In this paper, we also present a first attempt to study reactivity of original self-supported systems. We show that significant CO oxidation reactivity can be obtained over unsupported nanoporous AuTi and PdAu thin films. By completely excluding the support effect, unsupported catalysts could provide a way of understanding the relevant catalytic mechanisms more easily. PMID- 18447020 TI - In situ investigation of Pt(100--x)Au(x) and Pt(100--y)Sn(y) nanoalloys. AB - Dispersed sols of 1-10 nm sized Pt(100--x)Au(x) and Pt(100--y)Sn(y) nanoalloys have been prepared separately at various x and y above and below the miscibility limit in the bulk metals. Pt(100--x)Au(x) was derived from trisodium citrate reduction of aqueous solutions of H2PtCl6 and HAuCl4. Pt(100--y)-Sn(y) was produced by (i) complexing Sn2+ with glucose at 323 K at pH > 7, (ii) neutralising this with H2PtC16 addition and (iii) reducing the bimetallic precursor with glucose on raising the temperature to 373 K. For Pt(100--x)Au(x (where both metals were zero-valent) as x increased the average size of nanoalloy particles increased. These particles adsorbed onto graphite, where the extent of hydrogen chemisorption at 298 K decreased by 67% at 9 at % Au. Pt/SnO2 nanoparticles (<3 nm in size) were adsorbed onto alumina. The Pt interacted with and catalysed the reduction of SnO2, with some Pt(100--y)Sn(y) nanoalloy formation at about 673 K which even in the bulk occurs over a wider range of compositions than Pt-Au) and enhanced H2 chemisorption at 17-33 at % Sn. Nevertheless some Sn must remain in a positive oxidation state on the alumina surface. The ratio of rates of 2MP/ 3MP formation from MCP and n-hexane may be informative in chemically fingerprinting (and revealing fundamental differences in) these nanoalloy surfaces. The reasons for this are seen in terms of the surface structures on these two types of nanoalloy particles (i.e. the availability of contiguous asymmetric pairs of active surface atoms *, which, as expected, is found to pass through a maximum or decrease beyond specific values of x and y). PMID- 18447021 TI - To alloy or not to alloy? Cr modified Pt/C cathode catalysts for PEM fuel cells. AB - The cathode electrocatalysts for proton exchange membrane (PEM) fuel cells are commonly platinum and platinum based alloy nanoparticles dispersed on a carbon support. Control over the particle size and composition has, historically, been attained empirically, making systematic studies of the effects of various structural parameters difficult. The controlled surface modification methodology used in this work has enabled the controlled modification of carbon supported Pt nanoparticles by Cr so as to yield nanoalloy particles with defined compositions. Subsequent heat treatment in 5% H2 in N2 resulted in the formation of a distinct Pt3Cr alloy phase which was either restricted to the surface of the particles or present throughout the bulk of the particle structure. Measurement of the oxygen reduction activity of the catalysts was accomplished using the rotating thin film electrode method and the activities obtained were related to the structure of the nanoalloy catalyst particles, largely determined using Cr K edge and Pt L3 edge XAS. PMID- 18447022 TI - Structure-performance relationships of Rh and RhPd alloy supported catalysts using combined EDE/DRIFTS/MS. AB - Energy dispersive extended X-ray absorption fine structure spectroscopy (ED XAFS), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and mass spectrometry (MS), have been combined for the structure-function study of Rh and RhPd supported catalysts for the reduction of NO by CO. The combined results show that although alloying of Rh with Pd prevents the dissociative oxidation of the Rh by NO, it does not prevent the extensive disruptive oxidation of Rh by CO. The influence of oxidative disruption by molecular CO in such systems may therefore be far more pervasive and catalytically important than has been previously observed. The overall metal particle size observed in the RhPd alloy system during the CO/NO reaction is significantly larger than for the Rh-only system for the entire temperature range employed. The catalytically active sites, however, are likely to be similar, with the overall activity of the alloy system to be reduced due to inactive RhPd alloy nanoparticles. PMID- 18447023 TI - Synthesis, characterization, electronic structure and catalytic performance of bimetallic and trimetallic nanoparticles containing tin. AB - When anchored on a high-area, siliceous supports, nanoparticle catalysts, consisting of two or three different metals, but totaling no more than twenty atoms in all, exhibit exceptional activities and selectivities in solvent-free, one-step hydrogenation reactions at low temperatures (< 420 K) and much lower pressures (e.g. 30 bar) than those required in current industrial manufacture. The two selective hydrogenations illustrated here are the conversion of (a) cyclododecatriene (CDT) to cyclododecene (CD) and (b) dimethyl terephthalate (DMT) to cyclohexane dimethanol (CHDM); each of these products is extensively used in the polymer industry. All our mixed-metal nanoparticles are derived from an appropriately chosen parent (precursor) mixed-metal carbonyl having phenyl containing tin ligands, e.g. Ru4(mu4-SnPh)2(CO)12. Various techniques are used to characterize the denuded, anchored cluster catalysts; and it is expected that aberration-corrected high-resolution electron microscopy (and other techniques, which are outlined) will be invaluable in such characterization. Density functional theory has provided important insights into the structures and electronic properties of our catalysts and their precursors. PMID- 18447024 TI - Energy dispersive X-ray spectroscopy of bimetallic nanoparticles in an aberration corrected scanning transmission electron microscope. AB - The technique of X-ray energy dispersive spectroscopy (XEDS) spectrum imaging in a dedicated scanning transmission electron microscope (STEM) is discussed in relation to its applicability to bimetallic nanoparticles. It is shown that the recent availability of aberration corrected microscopes and multivariate statistical analysis (MSA) techniques has allowed us to overcome many of the intrinsic limitations previously encountered when attempting STEM-XEDS spectrum imaging on nanoscopic volumes of material. We demonstrate through a variety of applications to Au-Ag and Au-Pd bimetallic nanoparticle systems, that STEM-XEDS can provide invaluable high spatial resolution compositional information on (i) alloy homogeneity and phase segregation effects within individual nanoparticles, (ii) particle size-alloy composition correlations, (iii) the detection of trace amounts of alloying element and (iv) metal component distribution in extremely highly dispersed catalyst systems. PMID- 18447025 TI - Highly size-controlled synthesis of Au/Pd nanoparticles by inert-gas condensation. AB - Gold/Palladium nanoparticles were fabricated by inert-gas condensation on a sputtering reactor. With this method, by controlling both the atmosphere on the condensation chamber and the magnetron power, it was possible to produce nanoparticles with a high degree of monodispersity in size. The structure and size of the Au/Pd nanoparticles were determined by mass spectroscopy, and confirmed by atomic force microscopy and electron transmission microscopy measurements. The chemical composition was analyzed by X-ray microanalysis. From these measurements we confirmed that with the sputtering technique we are able to produce particles of 1, 3, and 5 nm on size, depending on the choice of the synthesis conditions. From TEM measurements made both in the regular HREM, as well as in STEM-HAADF mode, we found that the particles are icosahedral in shape, and the micrographs show no evidence of a core-shell structure, in contrast to what is observed in the case of nanoparticles prepared by chemical synthesis. PMID- 18447026 TI - Structures and optical properties of 4-5 nm bimetallic AgAu nanoparticles. AB - Three types of bimetallic AgAu nanoparticles, with mean size of 4-5 nm, Ag(core)Au(shell), Au(core)Ag(shell) and alloyed AgAu, have been synthesized using an inverse micelle method. To image these small size nanoparticles, quantitative high angle annular dark field imaging using scanning transmission electron microscopy was successfully applied. Our results show that good control of nanoparticle size dispersion and composition modulation was achieved. Optical properties of the nanoparticles are correlated with direct internal structure analysis. The structural stability is discussed, based on thermodynamic considerations. PMID- 18447027 TI - Growth and structural properties of CuAg and CoPt bimetallic nanoparticles. AB - Core/shell CuAg and alloyed CoPt have been synthesized using two vapor phase deposition techniques. For CuAg prepared by Thermal Evaporation (TE), the size and the morphology of the Cu cores are the key parameters to promote the formation of the core/shell arrangement. For CoPt synthesized by Pulsed Laser Deposition (PLD), the growth kinetics of nanoparticles, depending on the deposition rate, the substrate nature and the temperature, controls the nanoparticle morphology. The competition between the growth and the ordering kinetics governs the nanoparticle structure. By reducing the growth kinetics, as grown L1(0) ordered nanoparticles are obtained according to the bulk phase diagram. PMID- 18447028 TI - Binding energy and preferred adsorption sites of CO on gold and silver-gold cluster cations: adsorption kinetics and quantum chemical calculations. AB - We revisit the reactivity of trapped pure gold (Au(n)+, n < 26) and silver gold alloy cluster cations (Ag(m)Au(n)+, m + n < 7) with carbon monoxide as studied in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The experimental results are discussed in terms of ab initio computations which provide a comprehensive picture of the chemical binding behaviour (like binding energy, adsorption sites, associated vibrational frequencies) of CO to the noble metal as a function of cluster size and composition. Starting from results for pure gold cluster cations for which an overall decrease of CO binding energy with increasing cluster size was experimentally observed--from about 1.09 +/- 0.1 eV (for n = 6) to below 0.65 +/- 0.1 eV (for n > 26) we demonstrate that metal--CO bond energies correlate with the total electron density and with the energy of the lowest unoccupied molecular orbital (LUMO) on the bare metal cluster cation as obtained by density functional theory (DFT) computations. This is a consequence of the predominantly sigma-donating character of the CO-M bond. Further support for this concept is found by contrasting the predictions of binding energies to the experimental results for small alloy cluster cations (Ag(m)Au(n)+, 4 < m + n < 7) as a function of composition. Here, binding energy drops with increasing silver content, while CO still binds always in a head-on fashion to a gold atom. Finally we show how the CO stretch frequency of Ag(m)Au(n)CO+ may be used to identify possible adsorption sites and pre-screen favorable isomers. PMID- 18447029 TI - Preparation of regular arrays of bimetallic clusters with independent control of size and chemical composition. AB - Regular arrays of bimetallic clusters have been prepared by atomic deposition, under UHV, on a nanostructured ultrathin alumina film. The alumina films are obtained by oxidation at 1000 K of a Ni3Al (111) surface. They present two regular hexagonal superstructures with lattice parameters of 2.4 and 4.1 nm. Pd clusters nucleate exclusively on the 4.1 nm superstructure forming regular arrays of clusters extending on the whole (1 cm2) substrate. Gold deposited on a previously formed Pd clusters array, condenses exclusively on the Pd clusters in forming a regular array of bimetallic AuPd clusters with a narrow size distribution. The size and the composition of the AuPd clusters can be controlled independently. Gold clusters nucleates also on the 4.1 nm superstructure but they can escape from the nucleation sites and coalesce with other gold clusters. By condensing Pd on the preformed Au clusters, PdAu clusters are formed together with pure Pd clusters nucleated on the free sites of the 4.1 nm superstructure of the alumina film. PMID- 18447030 TI - [Rabies in Tunisia during the 19th century: case increase or disease emergence?]. AB - At the end of the 19th century, a canine rabies epidemics started in Tunis and in several other cities of the Beylik. Archives' data trace the epidemics back to 1870 and at that time its rapid progression was ascribed to the increase of immigration from Europe. Whether the European "street rabies virus" was also imported with the settlers' pet dogs is controversial. The epidemics might rather be linked to other factors such as socio-cultural or ecological changes. The authors try to reconstruct the history of rabies in Tunisia during this period. Changes in canine ecology and increase of dog populations in urban and suburban areas might account for the emergence of rabies at the end of 19th century and its persistence in an endemo-epidemic state. PMID- 18447031 TI - [Research on self-initiation of cell death towards the end of the 19th century]. AB - At the end of the 19th century, research on cell Death in France and Germany was not simply forgotten by contemporary research but in this context it appears that the growing power of cell theory together with an ancient philosophical "superiority" of life over death hijacked more surely the attention of the discoverers--among whom Vogt--of self-initiation of cell Death than the contemporary forgetting of biologists of "programmed" cell Death along with their "incapacity" to read in German. So the work of the Pasteurian Metchnikoff on muscular phagocytosis anticipates on the one hand the equivocity of factors that are disclosed in the framework of recent research. But Metchnikoff did not take advantage of it for theoretical consequences of the duality--normal and pathological--of muscular phagocytosis because this was not his aim. The research by Noetzel in Halle on self-dismantling of tadpole tails during the development does not contradict this perspective. Self-initiation of cell Death towards the end of the 19th century deals with cellular and intracellular levels but it leads to observations done with the microscope and not to inferences at molecular level. The thinness of these older observations is not really contradicted or repeated by contemporary research. It designs a field of observations that has its autonomy in comparison with actual issues on cell Death. On the contrary, the Weismann-Goette debate is closer to today. Behind the opposition of organisms that would be immortals and organisms whose mortality would lie in the necessity to reproduce themselves with the intention to rejuvenate, appears a debate initiated at that time and which now comes to its maturity between Darwinians who support a secondary death and those who support a more equivocal conception where Life and Death associate in depth but still do not mix. PMID- 18447032 TI - [Through entomology to psychoanalysis]. AB - Vues analytiques sur la vie des abeilles et des termites (Analytical perspectives on the life of bees and termites) is a letter from L. R. Delves Broughton to Freud dated the 7th of August, 1927. The letter was translated into French by Marie Bonaparte (1882-1962) for the Revue Francaise de Psychanalyse (French Review of Psychoanalysis) in 1927. A German translation of the letter was done for the review Imago in 1928. In his letter Delves Broughton develops a captivating connection between Man's libidinal economy and that of certain social insects. His main argument is based on the readings of several works by Sigmund Freud (1856-1939) and Maurice Maeterlinck (1862-1949). He proposes, as in the bioanalysis project of Sandor Ferenczi (1873-1933), the application of psychoanalytic knowledge on a specific area of the natural sciences: entomology. PMID- 18447033 TI - [Violence in the early modern period: current status of research]. PMID- 18447034 TI - Risk factors for cardiovascular disease in a Portuguese university population. AB - OBJECTIVE: To characterize the distribution of risk factors for cardiovascular disease among university students, through calculating the prevalence of hypercholesterolemia, hyperhomocysteinemia, hyperglycemia, hypertension, overweight, and sedentarism, as well as nutrient intake. METHODS: Cross-sectional study in a random stratified sample of 378 students from Aveiro University in the 2005/2006 academic year. Lifestyle questionnaires were completed on dietary habits and physical activity. The following were assessed: anthropometric measures, blood pressure, lipids, glycemia and homocysteine. Homocysteine was measured in 32 (25.2%) males and 95 (74.8%) females. RESULTS: A high prevalence of sedentarism was found (0.55, 95% CI: 0.50 to 0.60). The prevalence of overweight was 12.2% (0.122, 95% CI: 0.09 to 0.16) and of obesity 3.2% (0.032, 95% CI: 0.02 to 0.06). Hypercholesterolemia was found in 17.7% (0.177, 95% CI, 0.14 to 0.2) of the students and hypertension in 13.7% of males and 3.5% of females (p<0.001). High levels of homocysteine were found in 15.6% of males. The prevalence of hypercholesterolemia among health sciences students was higher than in technical and natural sciences (20.2% vs. 13.7%). Human and social sciences was the area with the highest prevalence of risk factors for non-communicable diseases (NCDs) (38.1%). DISCUSSION AND CONCLUSIONS: The high prevalence of risk factors for NCDs in higher education highlights the need for nutritional and health promotion programs, emphasizing the harmful effects of sedentary behavior. Longitudinal study of this cohort will enable analysis of the impact of such behavior in early life on subsequent development of health problems. PMID- 18447035 TI - Health promoting universities. PMID- 18447036 TI - Inflammation, homocysteine and carotid intima-media thickness. AB - INTRODUCTION: Cardiovascular disease is the main cause of morbidity and mortality in chronic renal patients. Carotid intima-media thickness (CIMT) is one of the most accurate markers of atherosclerosis risk. In this study, the authors set out to evaluate a population of chronic renal patients to determine which factors are associated with an increase in intima-media thickness. METHODS: We included 56 patients (F=22, M=34), with a mean age of 68.6 years, and an estimated glomerular filtration rate of 15.8 ml/min (calculated by the MDRD equation). Various laboratory and inflammatory parameters (hsCRP, IL-6 and TNF-alpha) were evaluated. All subjects underwent measurement of internal carotid artery intima media thickness by high-resolution real-time B-mode ultrasonography using a 10 MHz linear transducer. RESULTS: Intima-media thickness was used as a dependent variable in a simple linear regression model, with the various laboratory parameters as independent variables. Only parameters showing a significant correlation with CIMT were evaluated in a multiple regression model: age (p=0.001), hemoglobin (p=00.3), logCRP (p=0.042), logIL-6 (p=0.004) and homocysteine (p=0.002). In the multiple regression model we found that age (p=0.001) and homocysteine (p=0.027) were independently correlated with CIMT. LogIL-6 did not reach statistical significance (p=0.057), probably due to the small population size. CONCLUSION: The authors conclude that age and homocysteine correlate with carotid intima-media thickness, and thus can be considered as markers/risk factors in chronic renal patients. PMID- 18447037 TI - Effects of different intensities of resistance exercise on hemodynamic variations in young adults. AB - INTRODUCTION: Prescription and monitoring of physical activity are usually based only on heart rate (HR). The objective of this study was to determine the hemodynamic variations induced by resistance exercise. METHODS: Healthy male volunteers aged between 18 and 28 (n=11) underwent anthropometric evaluation, measurement of HR and blood pressure and a 10 repetition maximum (RM) test. Subsequently they performed the same exercise on 3 non-consecutive days (>48 h interval) consisting of 3x10 repetitions with 50, 75 and 100% of 10 RM. HR and blood pressure were measured at each interval. These data were used to calculate double product (DP) and myocardial oxygen consumption (mVO2). RESULTS: HR increased significantly (p<0.05) in all measurements following exercise compared to resting values, but systolic blood pressure (SBP) showed no significant alterations. DP and mVO2 increased in the three series of exercises. DISCUSSION: The activity proposed for the study significantly altered HR, in contrast to other studies that show increases in SBP. CONCLUSION: The increased cardiac load in the conditions of this study did not involve unnecessary risk for the subjects. The results also help to confirm the theory that monitoring blood pressure together with HR is more effective than the methodology currently used (HR only), particularly for monitoring people at risk of CAD. PMID- 18447038 TI - Early flow propagation velocity for assessment of diastolic function in myocardial infarction treated with acute reperfusion. AB - INTRODUCTION: Acute myocardial infarction (MI) causes left ventricular (LV) diastolic dysfunction, which influences prognosis and clinical evolution. Early flow propagation velocity (FPV), evaluated by color M-mode Doppler, has been demonstrated to be a diastolic function parameter with excellent correlation with relaxation constant tau, and is relatively independent of pre- and afterload. OBJECTIVE: The aim of this study was to evaluate left ventricular relaxation in MI patients treated with acute reperfusion therapy. METHODS: Patients with ST elevation MI treated with reperfusion therapy were evaluated by echocardiagraphy in the first 48 hours and after one week. The parameters studied were: early peak filling velocity (E), late peak filling velocity (A), E/A ratio, E-wave deceleration time (EDT), isovolumic relaxation time (IVRT) and FPV. The values obtained at the first and second evaluation were compared; we evaluated the relation between pain-to-reperfusion time (PRT; < or =3 hours vs. >3 hours) and the presence of single-vessel or multivessel disease with the parameters previously mentioned. RESULTS: 40 patients were studied and 19 included, 15 (80%) male, mean age 57+/-14 The most prevalent risk factors were: hypertension (11 patients - 58%), smoking (14 - 74%), diabetes (6 - 30%), and dyslipidemia (12 - 63%). MI location was anterior in six patients (31%) and inferior in 13 (69%). Five patients (26%) underwent fibrinolysis and 14 (74%) direct percutaneous coronary intervention. Mean pain-to-reperfusion time was 3.7+/-2.8 hours. Four patients (21%) had single-vessel disease and 14 (74%) had multivessel disease. Near significance was found for the difference in the E/A ratio between the two evaluations and a significant difference in the FPV. A significant correlation was also found between PRT and E/A ratio at the two evaluations (p=0.003, p=0.05), and between PRT and IVRT after one week (p=0.011). E/A ratio, IVRT and FPV were normal at the two evaluations in patients who had undergone earlier reperfusion therapy. No significance was found between the number of diseased vessels and the parameters of diastolic function assessed. DISCUSSION AND CONCLUSIONS: In the early phase of M1 treated with acute reperfusion, a delayed relaxation pattern was observed, which evolved to a normal pattern by the second evaluation, as statistically confirmed by FPV. Earlier reperfusion therapy preserves diastolic function. FPV is a sensitive and independent parameter for assessment of diastolic function in MI patients treated with acute reperfusion therapy. PMID- 18447039 TI - Acute myocardial infarction in the puerperium. AB - The authors describe the case of a forty-two-year-old patient with acute myocardial infarction (MI) on the third day of puerperium, who underwent direct angioplasty. The authors review the main physiological cardiovascular and hemostatic changes in pregnancy, which are usually well tolerated but which increase the probability of cardiovascular events when risk factors or previous cardiac disease are associated. Blood volume and cardiac output increase by around 50% during pregnancy, hemoglobin concentration falls, and reduced peripheral vascular resistance leads to a fall in arterial blood pressure during the first half of pregnancy. End-diastolic pressure, stroke volume and cardiac output increase in the immediate puerperium, and cardiovascular risk is highest in the perinatal period. The incidence of MI during pregnancy and puerperium is low; however, it is on the increase due to the growing number of pregnancies in women close to the end of their reproductive age. PMID- 18447040 TI - Spontaneous acquired left descending coronary artery to left ventricle fistula in a patient with an apical saddle thrombus. AB - Coronary artery fistulas are a rare anomaly. The majority are congenital in origin, although they may be acquired due to invasive cardiac procedures or trauma. The most common course is between the right coronary artery and the right ventricle. The authors describe the case of an acquired left anterior descending coronary artery to left ventricle fistula, associated with a saddle thrombus, in a patient with a previously normal coronary angiogram and none of the predisposing factors mentioned above. Spontaneous formation of acquired coronary fistulas is reported as a very rare event in the literature. PMID- 18447041 TI - Heart failure and depression: an association with clinical importance. AB - Major depression is found in one fifth of heart failure patients, and clinically significant depressive symptoms in almost half. The association of depression and heart failure appears to be related both to the psychological aspects of severe heart disease, and to pathophysiological and psychosocial mechanisms. The presence of depression is associated with a worsening of the prognosis, and increased risk of death, rehospitalization, and functional decline. Detection and treatment of depression should be part of a comprehensive approach to heart failure patients by cardiologists and family doctors. Good quality cardiac care should include psychosocial assessment, strengthening of the doctor-patient relationship and of family and social bonds, and, when appropriate, antidepressants and psychotherapy. Selective serotonin reuptake inhibitors are effective and safe antidepressants in cardiac patients. They should be prescribed in therapeutic doses until sustained remission is obtained. Collaboration between psychiatrists and other specialists at primary and secondary care levels is recommended and contributes to better quality care. PMID- 18447042 TI - Patent ductus arteriosus studied by magnetic resonance imaging. PMID- 18447043 TI - Consensus meeting on erectile dysfunction: erectile dysfunction and cardiovascular disease. PMID- 18447044 TI - [The contemporary scientific context of A. Laveran's discovery]. AB - The history of Laveran's discovery of the malaria parasite is well known. The fact that it went unconfirmed for many years reflects poorly on medical research at the time. Pasteur's discoveries had spawned widespread interest in the field of bacteriology in the mid-nineteenth century, and most epidemiologists suspected that a bacterium was responsible for malaria. Laveran's claim to have detected a parasite was greeted with scepticism. Here the author recalls how the medical world finally came to recognize the importance of Laveran's discovery. PMID- 18447045 TI - [Morphology, biology and life-cycle of Plasmodium parasites]. AB - Laveran first discovered that an infectious agent was responsible for malaria by using a simple microscope, without the assistance of specific stains. Our knowledge of the Plasmodium life cycle and cellular biology has progressed with each technological advance, from Romanovsky staining and histology to electron microscopy, immunocytochemistry, molecular methods and modern imaging techniques. The use of bird, primate and rodent models also made a major contribution, notably in the development of antimalarial drugs that are still in use today. PMID- 18447047 TI - [Perspectives and challenges of malaria vaccine. Why we must do more]. AB - During the last 10 years the development of a malaria vaccine has attracted an increasing amount of attention both from the political sector and from financial investors. This has led to a number of major scientific and technological advances, but much remains to be done. Numerous potential target antigens are under investigation, and most research is focusing on a subunit vaccine. Irradiated attenuated sporozoites are also a promising approach, even if major technological and regulatory challenges remain to be overcome. Barriers to vaccine development include an inadequate understanding of certain aspects of host-parasite biology and protective immune responses. Other challenges are to increase the antigenicity of some antigens, and to optimize the quality of the immune response. However, research funding remains the main obstacle. PMID- 18447048 TI - [A new view of malaria provided by parasite imaging]. AB - Infection by Plasmodium, the causative agent of malaria, starts when the parasite, injected by a mosquito vector, reaches and invades the liver, where it transforms into a stage that is capable of infecting erythrocytes and that causes the symptoms and complications of the disease. This phase of the infection, called pre-erythrocytic stage, is the most elusive of the parasite's life cycle, yet it was identified more than fifty years ago as a primary target of vaccine strategies aimed at avoiding erythrocyte infection. Recently in vivo imaging in a rodent model revealed that the pre-erythrocytic phase is unexpectedly complex. In particular, it includes a component of lymphatic infection, thus altering our representation of how an immune response can be mounted against these parasite stages. PMID- 18447049 TI - [Current antimalarial drugs: resistance and new strategies]. AB - The development and spread of antimalarial drug resistance is hindering the control of Plasmodium falciparum malaria. Unfortunately, a vaccine will not be available for many years. Resistance to chloroquine, the most commonly used antimalarial drug, has been reported in practically all endemic countries. This resistance also affects most of the other antimalarial drugs, to different degrees. The problem is further aggravated by cross-resistance among drugs belonging to the same family. In recent years; failure of chloroquine prophylaxis and treatment of P. vivax infection has been reported in South-East Asia and South America. Antimalarial drug resistance leads to an increase in morbidity and mortality, especially among children. By analogy with tuberculosis and HIV infection, the accent is currently being placed on the use of antimalarial combinations in order to overcome the problem of multidrug resistance. Artemisinins are particularly good candidates for combination therapy. PMID- 18447050 TI - [Treatment of malaria: outlook]. AB - Prospects for new and effective antimalarial treatments have improved significantly in the past few years. There are more funds, new operational paradigms and actors, and more products in the pipeline. However, the limited novelty of the products currently in clinical development means that more emphasis therefore needs to be placed on the discovery of novel chemical entities to achieve effective, sustainable control. The development and deployment of new products is both lengthy and complex. PMID- 18447051 TI - [Current situation and future perspectives for malaria prophylaxis among travellers and military personnel]. AB - Malaria remains a major public health problem, both for travellers and for the 40,000 French soldiers deployed each year to endemic areas. Epidemiological data show that imported malaria (IM) is on the increase, and that migrants account for more than 60% of malaria cases notified each year in France. The increase in IM among French military personnel is explained by prematurely terminated chemoprophylaxis on return, repeated short missions, and more cases of P. vivax and P. ovale infection. The choice of chemoprophylaxis depends mainly on the level of chloroquine resistance in the country visited. The atovaquone-proguanil combination is well tolerated and only requires 7 days of intake on return from the endemic area. Doxycycline monohydrate is cheaper and better-tolerated than mefloquine, and is thus preferred for French military personnel. However, its short half-life necessitates very good compliance. Chemoprophylaxis should be combined with vector control measures and with personal protection (impregnated bednets, protective clothing, repellents, and indoor insecticide spraying). The need for these measures should be clearly explained before departure, during the stay, and after return. PMID- 18447052 TI - [Alphonse Laveran, a student of the Imperial Military Health Service School of Strasbourg]. PMID- 18447053 TI - [Alphonse Laveran Military Hospital No. 303 of Constantine. Evocation and testimony]. PMID- 18447054 TI - [Babinski's legacy]. AB - Joseph Babinski may be considered as a founder of modern neurology. Based upon a strict neurological examination, he was able to clarify a clinical distinction between hysterical and organic symptomatology. Besides his observation on the Sign, which made him world famous, his description of new concepts in cerebellar signs, his studies on reflexes constituted important landmarks in clinical neurology. But he was also a therapist, moving from palliative treatment to give a great impulse in the development of French Neurosurgery. PMID- 18447055 TI - [Babinski and hysteria]. AB - Babinski made important contributions to both psychiatry and neurology. He disagreed with Charcot's theatrical interpretation of hysteria and made a subtle distinction between Suggestion and Persuasion, thereby differentiating Hysteria from Pithiatism. This paper examines Charcot's concepts and the way in which Babinski refined and honed his master's theories. PMID- 18447056 TI - [Joseph Babinski: a complex personality]. AB - Joseph Babinski (1857-1932), a Paris hospital neurologist known for the discovery of his eponymous sign, was a highly complex personality. He was known as a handsome but silent "blue-eyed giant". His parents left Poland for Paris after the insurrection of 1848. Joseph and his elder brother Henri (1855-1931) were born in Paris and were therefore French, but they remained devoted to Poland. Joseph suffered from excruciating self-doubt and was meticulous. He was a reasoner and a righter of wrongs. Henri, who trained as a civil engineer at the French National School of Mines, prospected mineral, gold and diamond deposits in various countries. On his return to France at the end of the century, he wrote, under the pseudonym Ali-Bab, a monumental cookbook called "Gastronomie pratique", which was widely acclaimed Joseph and Henri, both unmarried, lived together and formed an inseparable couple. Joseph Babinski had no religious, political or ideological commitments. Some areas of his private life still remain rather shadowy. PMID- 18447057 TI - [Endoscopic management of gynecological malignancies: an update. 2007]. AB - All the different surgical procedures used to treat gynecologic cancers have already been performed with the endoscopic approach. However, the prospective randomized trials required to confirm the oncologic efficacy of this approach are still lacking in gynecology, whereas such studies are available for abdominal surgery. Animal studies suggest that the risk of tumor dissemination in the non traumatized peritoneum may be higher after pneumoperitoneum than after laparotomy, and they also show the importance of the surgeon's experience and technique. All the parameters of pneumoperitoneum can influence the risk of postoperative dissemination. By controlling these parameters we may, in future, be able to create a peritoneal environment suitable for oncologic indications and thereby prevent or minimize the risk of peritoneal dissemination and postoperative tumor growth. In endometrial cancer, the laparoscopic approach should be reserved for clinical stage I disease, if the volume of the uterus and local conditions are appropriate for vaginal extraction. In cervical cancer, the laparoscopic approach should be reserved for patients with favorable prognostic factors (stage IB, less than 2 cm in diameter). Laparoscopy is the gold standard for surgical diagnosis of adnexal masses, but puncture should be avoided whenever possible. Surgical treatment of invasive ovarian cancer should use laparotomy, whatever the stage. In contrast, restaging of early ovarian cancer initially managed as a benign mass is a good indication for the laparoscopic approach. Laparoscopic management of tumors with low malignant potential should include complete staging of the peritoneum. An excellent knowledge of the principles of endoscopy and of oncologic surgery is required. Training in endoscopic oncological techniques will be a major challenge in the field of gynecologic surgery in coming years. PMID- 18447058 TI - [Laparoscopic surgery in urologic oncology]. AB - Laparoscopic management of urological malignancies is a fast-growing field. From nephrectomy to prostatectomy, the laparoscopic approach has been tried for all forms of surgical ablation for urological cancers. It is associated with less blood loss, lower transfusion requirements, less post-operative pain and a shorter hospital stay. The rates of metastasis, pelvic carcinosis and tumoral on the trocar path appear to be no higher than after open surgery. Provided the general rules of oncologic surgery are respected, laparoscopy is safe and effective in the management of urological malignancies. PMID- 18447059 TI - [Laparoscopy and colorectal cancer]. AB - Laparoscopy is associated with better postoperative outcome than laparotomy in the treatment of colon cancer, and similar oncologic results. Thus, laparoscopy is now a validated approach to colon cancer management. In contrast, more studies are needed before endorsing the use of laparoscopy to treat rectal carcinoma. The initial oncologic results are encouraging, but the procedure is complex and the learning curve is long. PMID- 18447060 TI - [Boundary cap cells--a nest of neural stem cells in the peripheral nervous system]. AB - The peripheral nervous system (PNS) is formed by neural crest cells (NCC) that migrate out of the neural tube in early mid-gestation. NCC give rise to most components of the PNS, including sensory neurons, glial satellite cells and Schwann cells. Neural crest cells also give rise to another type of PNS cell population named boundary cap (BC) cells, that form clusters at the surface of the neural tube, at entry and exit points of peripheral nerve roots. Using various genetic tools we were able to trace BC cell progeny during development and to ablate them in vivo. This revealed a previously unsuspected function of BC cells: they are required to maintain the integrity of the spinal cord motor column as, in their absence, motor neurons translocate their cell bodies along their axons into the periphery. In addition, we found that trunk BC-derived cells migrated along peripheral axons and colonized spinal nerve roots and dorsal root ganglia (DRG). All Schwann cell precursors occupying the dorsal roots were derived from BC cells. In the DRG, BC-derived cells were the progenitors of both neurons (mainly nociceptive afferents) and satellite cells. These unexpected observations indicate that BC cells constitute a source of peripheral nervous system (PNS) components that, after the major neural crest ventrolateral migratory stream, feed a secondary wave of migration to the PNS. PMID- 18447061 TI - [Multifocal motor neuropathy: a retrospective study of the response to high-dose intravenous immunoglobulin (IVIg) and current perspectives for diagnosis and treatment]. AB - Multifocal motor neuropathy (MMN) was first distinguished from other motor neuropathies in 1986. It is characterised by slowly progressive predominantly distal and asymmetric limb weakness and wasting that predominates in the arms, with muscle cramps and fasciculations, within an anatomical distribution of individual motor nerves. Sensory involvement is minimal or absent. The electrodiagnostic hallmark is focal motor conduction block (CB), persisting for years at atypical sites. The most typical laboratory finding is increased serum IgM autoantibody titers to the ganglioside GM1. High-dose intravenous immunoglobulin (IVIg) is currently the gold-standard treatment for MMN. To document short-term and long-term responses to IVIg, we conducted a retrospective study of 40 patients with MMN defined using ENMC Workshop criteria and treated with periodic IVIg infusions (Tegeline) between 1995 and 2003. For the short-term analysis we compared the 22 patients who had never previously received IVIg with the 18 IVIg-experienced patients. For the long-term evaluation (> 6 months), the patients were classified into four groups according to their dependence on periodic IVIg. The MRC score improved significantly in 14 (70% ; 95% CI 0.46 to 0.88) of the 20 assessable treatment-naive patients (data were missing for two patients). This rate was significantly higher than at six months in a historical group of placebo-treated patients (20%; p < 0.0001). No criteria predictive of the response were identified. At the end of follow-up (mean 2.2 +/- 2.0 years) only 8 patients (22%) in the cohort remained in remission after a good initial response to IVIg, while 25 patients (68%) were dependent on periodic IVIg infusions. This study confirms the good short-term response of MMN to IVIg but indicates that the longer-term results are variable. New therapeutic strategies are required to increase the short-term and long-term efficacy of IVIg, and to reduce reliance on this treatment. PMID- 18447062 TI - [Jeune'disease (asphyxiating thoracic dystrophy) and respiratory failure: importance of early respiratory management with periodic hyperinsufflation]. AB - Asphyxiating thoracic dystrophy (ATD) is a rare autosomal recessive form of chondrodysplasia characterized by short ribs. Respiratory failure is due to the reduced volume and complete immobility of the thoracic cage. There is no consensus on the treatment of this restrictive pulmonary disease. Surgical attempts to enlarge the thoracic cage are disappointing. We report the cases of nine children with ATD treated by periodic respiratory hyperinsufflation. Their clinical outcome was related to the severity of their respiratory distress and their age at the beginning of this treatment. It is possible to use periodic hyperinsufflation very early after birth to prevent secondary respiratory failure. Periodic insufflation can also be used to treat older children with severe restrictive respiratory insufficiency requiring tracheostomy and endotracheal management. This treatment promotes alveolar multiplication and thoracic growth. Four children had laboratory and/or clinical evidence of hepatic dysfunction that improved on ursodeoxycholic acid therapy. Three children who had muscle weakness at birth improved during childhood. PMID- 18447063 TI - [Physiopathology of the acute adverse effects of angiotensin-converting-enzyme inhibitors]. AB - Angiotensin-I-converting-enzyme inhibitors are currently used to treat more than 40 million cardiovascular patients worldwide. These drugs have a variety of acute adverse effects, the nature of which depends on the clinical context, and which include angioedema, anaphylactoid reactions in hemodialysis patients, and severe hypotensive reactions during blood product transfusions. These adverse effects result from a combination of factors affecting the synthesis, metabolism and pharmacological activity of bradykinin and des-arginine9-bradykinin, two powerful vasodilatory and pro-inflammatory peptides. Experimental evidence obtained in our laboratory suggests that acquired, genetic and pharmacological factors can influence the risk of these rare but potentially life-threatening effects. PMID- 18447064 TI - Empowered patient or empowered physician: an analysis of the importance of the empowered patient in the health delivery system. AB - This paper develops a simple theoretical model which compares resource allocation in the health care system when physicians are empowered with the decisions taken when patients are empowered. We show that even when there is no asymmetry of information, the institutional arrangement (empowered patient or empowered physician) matter. Ceteris paribus, we find that patients demand more time with physicians when they are empowered (relative to the situation when physicians are empowered), whereas physicians want to spend more time developing their expertise when they are empowered. The reaction of physicians and patients to changes in policy instruments also differs across institutional arrangements. The analysis draws attention to the design of the compensation scheme for physicians, and shows that a non-linear scheme is generally optimal for access to resources if physicians are empowered. PMID- 18447065 TI - The modes of physician remuneration and their effect on direct patient contact. AB - Initiatives such as primary care reform have allocated millions of dollars towards the Canadian health care system. The way physicians are remunerated affects the supply of physician services and as such is essential to these initiatives to facilitate policy goals. However, there exists a gap in understanding how different modes of remuneration affect physician-patient contact. This paper examines if there is a significant difference between the average full-time-equivalent (FTE) of family physicians (FPs) remunerated through fee-for-service (FFS), salary, and blended arrangements. We used Nova Scotia physician billings dataset which tracks every services performed by both FFS and salaried physicians over the fiscal year 2003 to 2004. We estimated two semi logarithmic models to examine the relationship between (1) modes of remuneration and FTE, and (2) modes of remuneration and total services, using ordinary least squares method. The National Physician Survey shows a significant difference between the current modes of remuneration and the preferred modes of remuneration; thus ruling out the possibility of selectivity bias. The results show that compared to the FFS FPs, the salaried FPs and blended FPs produce on average 40.46% and 23.13% less FTE respectively. It also indicates that compared to the FFS FPs, the salaried FPs and blended FPs deliver 53.54% and 31.49% fewer services on average. PMID- 18447066 TI - The relationship between family physician density and health related outcomes: the Canadian evidence. AB - This paper analyzes if and to what extent the density of family physicians influences health related outcomes in Canada. The density of family physicians in a given region is assumed to serve as proxy for the access to and availability of desirable primary care services. We use self-reported general and mental health status as our overall health outcome measures. We also use several quality of care indicators reflecting whether or not an individual received influenza immunization, mammography, pap smear, and colorectal cancer screening if at high risk. The empirical results of this study suggest that an additional family physician per 10,000 population has a statistically significant impact in the order of 2% to 4% on self-reported general health status, as well as, other quality of care outcomes. We also find important socioeconomic and demographic factors, such as income, education and immigrant status, influencing health related outcomes considered in this study. Understanding the influence of physician density and socioeconomic factors on health related outcomes are important considerations for health policy and planning. PMID- 18447067 TI - Change of the guard in obstetrics and gynaecology: projected retirement to 2025. AB - The purpose of the paper is to forecast retirement of the specialist obstetricians and gynaecologists in Australia to 2025. The gender and hours of work of younger and older cohorts were compared to determine the likely impacts of the transition from older to younger cohorts. The paper used the Australian Institute of Health and Welfare's annual Medical Labour Force Surveys to examine trends in attrition of obstetricians and gynaecologists over the age of 45 years from the workforce and to predict their rate of retirement to 2025. The projection results show that between the years 2000 and 2025, 59% of the obstetricians and gynaecologists would retire. The rising proportion of women in obstetrics and gynaecology and shorter working hours of both men and women will have a compounding effect on physician retirement. The paper concludes that the changes in practice, increasing feminisation and retirement from the workforce coupled with higher female population growth in the childbearing years and slightly higher fertility mean that ensuring an adequate obstetricians and gynaecologists in Australia will be a significant challenge over the next 20 years. There is the potential for shortages in obstetric care with particular risks for rural areas. PMID- 18447068 TI - Comparison of the 1996 and 2001 census data for Aboriginal and non-Aboriginal workers in health care occupations. AB - To meet the unique health needs of Aboriginal peoples (First Nations, Inuit and Metis), it is important to increase and encourage Aboriginal representation in health care. One Federal initiative, the Aboriginal Health Human Resource Initiative (AHHRI) at Health Canada, focuses on: (1) increasing the number of Aboriginal people working in health careers; (2) adapting health care educational curricula to support the development of cultural competencies; and (3) improving the retention of health care workers in Aboriginal communities. A health care system that focuses on understanding the unique challenges, concerns, and needs of Aboriginal people can better respond to this specific population, which suffers disproportionately from ill health in comparison to their non-Aboriginal counterparts. This report examines the supply of Aboriginal health care providers in Canada, based on geographic region, area of residence, Aboriginal identity, and occupation. Findings are drawn from the 1996 and 2001 censuses from Statistics Canada. Quantitative results provide a greater understanding of labour force characteristics of First Nation, Inuit, Metis, and non-Aboriginal health providers. PMID- 18447069 TI - Effect of population ageing on future demand for physicians: a case study of Nova Scotia, Canada, 2000-2025. AB - The health care system has been under pressure for some time to keep pace with its health human resource (HHR) requirements. Future demographic trends, however, are magnifying these pressures. Because of the lengthy training period for physicians, closing the physician supply and demand gap requires time. This paper attempts to explore the future utilization of physicians in terms of full-time equivalent (FTE) in Nova Scotia to the year 2025 by four general types of medical disciplines: General Physicians, Medical Specialties, Surgical Specialties, and Diagnostic Specialties. Further, it makes projections by most responsible diagnosis, in- and out-hospital status, age and sex of the patients. The study shows that for paediatric patients, the incidence of all diseases would decline and for patients between age 15 and 54, the incidence of disease would either decline or increase marginally. Consistent with the baby boom ageing wave, the prevalence of disease would increase significantly for those above 54 years. This would result in requirements for all categories of physicians to decline for patients below age 54, in contrast with those 55 years of age and over where the demand would substantially increase. It is found that the growth in the requirements would be highest for diagnostic specialists, followed by surgical specialists, medical specialists, and the general practitioners. PMID- 18447070 TI - The influence of group discussion on performance judgments: rating accuracy, contrast effects, and halo. AB - The authors investigated the effect of group discussion, such as may occur formally in panel interview scenarios, assessment centers, or 360-degree feedback situations, on judgments of performance. Research on group polarization suggests that the effect of group discussion combined with raters' preexisting impressions of ratees or interviewees should result in an extremitization of impressions. Thus, the authors hypothesized that group discussion would (a) make ratings less accurate, (b) polarize impressions that were already good or poor as reflected by greater contrast effects, and (c) increase positive halo. Results indicated that group discussion resulted in less accurate ratings and greater contrast effects. Additional analyses suggested that group discussion increased positive halo. The authors discuss implications for research on group or panel judgments. PMID- 18447071 TI - Stability of harassment in children: analysis of the Canadian National Longitudinal Survey of Children and Youth data. AB - No longitudinal information about bullying and peer harassment among Canadian children currently exists. In the present study, the author examined the stability of bullying and harassment. The sample consisted of two cohorts of children aged 10-11 years (n=2798) and 12-13 years (n=1946) drawn from the Canadian National Longitudinal Survey of Children and Youth, which is a stratified random sample of households in Canada. The author analyzed children's reports of bullying and harassment from 1994 to 2001 using cross-sectional time series analyses. The results show that children who were not bullied or harassed in one cycle were unlikely to report being bullied or harassed at a subsequent cycle. About half of children who reported being bullied or harassed in a previous cycle also reported being bullied or harassed in a subsequent cycle. The author concludes that some children may be resilient, whereas others are vulnerable to ongoing bullying and harassment from their peers. PMID- 18447072 TI - Forgiveness: a China-Western Europe comparison. AB - The authors assessed forgiveness among Chinese (n=738) and Western European (n=810) participants using the Forgivingness Questionnaire (E. Mullet et al., 2003). They found that between the 2 samples, (a) the overall level of dispositional forgiveness was similar, (b) lasting resentment was higher among the Chinese than among the Western Europeans, and (c) sensitivity to the circumstances of the offense was higher among the Chinese than among the Western Europeans. These results contrast with what researchers have observed in previous studies in which forgiveness has been shown to be systematically higher in collectivistic cultures than in individualistic cultures. The authors suggest that there are possibly many other differences across cultures, namely in religion, that may impact views of forgiveness. PMID- 18447073 TI - Time perspective, depression, and substance misuse among the homeless. AB - Using the Zimbardo Time Perspective Inventory (ZTPI; P. G. Zimbardo & J. N. Boyd, 1999), the authors found that homeless people, in comparison with a control group, had a significantly more negative outlook concerning their past and present as evinced by high Past-Negative and Present-Fatalistic scores and low Past-Positive scores on the ZTPI. However, the homeless individuals were almost indistinguishable from control participants on measures of Present-Hedonism and Future thinking. The homeless individuals had significantly higher levels of depression, with 31 out of 50 (62%) reaching criteria for probable depression. However, this finding was unrelated to their atypical time perspective. There was no significant relation between substance misuse and time perspective. Despite their current difficulties, including depression and drug abuse, the homeless individuals maintained a propensity toward future thinking characterized by striving to achieve their goals. PMID- 18447074 TI - Partner effects of Mexican cultural values: the couple and parenting relationships. AB - In this investigation, the authors explored the impact of individuals' cultural values on their partners' relationship adjustment and perceptions of their parenting relationship. The authors examined Mexican cultural values of simpatia (i.e., harmonious interpersonal relationships) and respeto (i.e., respect for authority figures) using a sample of 50 Mexican-origin couples in southern Arizona. Congruent with their hypotheses, results supported the proposition that fathers' simpatia is positively associated with both relationship adjustment and the parenting relationship as reported by mothers, whereas fathers' respeto is negatively associated with both relationship adjustment and the parenting relationship as reported by mothers. However, the authors found little evidence of a contribution of mothers' cultural values to fathers' perceptions of either relationship adjustment or the parenting relationship. They interpret these findings to suggest that mothers' relationship adjustment and parenting relationship are more sensitive to and dependent on fathers' degree of traditional cultural values among Mexican-origin families. PMID- 18447075 TI - Exploring epistemological beliefs of bilingual Filipino preservice teachers in the Filipino and English languages. AB - In this study, the author investigated the epistemological beliefs of 864 bilingual Filipino preservice teachers using Filipino and English versions of the Schommer Epistemological Questionnaire (M. Schommer, 1998). The author conducted confirmatory factor analyses to determine the dimensions and structure of the epistemological beliefs. The results revealed two factors: Simple Learning and Structured Learning. The same factors were found using the Filipino and English versions of the questionnaire. The author discusses the results in terms of how they contribute to the growing evidence regarding the possible problems with particular multidimensional theories and quantitative measures of epistemological beliefs. The results also indicate how the specific epistemological beliefs of the Filipino preservice teachers may reflect features of the Philippine educational system and its tensions regarding pedagogy. PMID- 18447076 TI - How does culture influence the degree of romantic loneliness and closeness? AB - A culture promoting a strong desire for romantic relationships can greatly influence feelings of romantic loneliness and of closeness. In this study, the authors hypothesized that when not in a romantic relationship, U.S. young adults experience greater degrees of romantic loneliness because of a high desire for romantic relationships, compared with Korean young adults. The authors also predicted that when in a romantic relationship, U.S. young adults experience greater closeness to their romantic partner than do Korean young adults. Results revealed that in a sample of 227 U.S. and Korean students, U.S. students reported significantly higher levels of romantic loneliness than did Koreans when not in a romantic relationship and significantly lower levels of romantic loneliness when in a stable romantic relationship. U.S. students also reported a greater degree of closeness in romantic relationships than did Korean students. The results suggest that Western cultures' strong emphasis on the importance of romantic relationships may unduly amplify individuals' levels of loneliness. PMID- 18447077 TI - The problem of school bullies: what the research tells us. AB - This article includes an overview of the history of research on school bullying, its nature and prevalence, characteristics of bullies and victims, and teachers' knowledge of and attitudes toward bullying. Also, two model interventions designed to reduce this harmful behavior are examined. PMID- 18447078 TI - Internalization of values and self-esteem among Brazilian teenagers from authoritative, indulgent, authoritarian, and neglectful homes. AB - The relation between parenting styles and adolescent outcomes was analyzed in a sample of 1,198 15-18-year-old Brazilians. The adolescents were classified into 1 of 4 groups (Authoritative, Authoritarian, Indulgent, and Neglectful) on the basis of their own ratings of their parents on two dimensions: Acceptance/ Involvement and Strictness/Imposition. The adolescents were then contrasted along two different outcomes: (1) priority given to Schwartz Self-transcendence and Conservation values, and (2) level of Self-esteem (appraised in 5 domains: Academic, Social, Emotional, Family, and Physical). Results showed that Authoritative and Indulgent parenting is associated with the highest internalization of Self-Transcendence and Conservation values of teenagers, whereas Authoritarian parenting is associated with the lowest. On the other hand, adolescents with Indulgent parents have equal or higher levels of Self-esteem than adolescents with Authoritative parents, while adolescents raised in Authoritarian and Neglectful homes have the lowest scores in Self-Esteem. PMID- 18447079 TI - Acceptability of dating violence among late adolescents: the role of sports participation, competitive attitudes, and selected dynamics of relationship violence. AB - This study uses a vignette-based survey design to examine the relationship between both respondent-level and case-level characteristics and the acceptability of violence in dating relationships. Measures of sports participation, competitiveness, and the need to win (respondent characteristics) were administered to 661 male and female late adolescents. Participants also rated the acceptability of violence portrayed in a series of couple interaction vignettes varying along three dimensions: initiator act, recipient reaction, and initator-recipient gender combinations (case characteristics). Results from a multilevel analysis show that with regard to respondent characteristics, only the need to win is related (positively) to the acceptability of dating violence, not sports participation or competitiveness. With regard to case characteristics, recipient reaction has the strongest relationship, suggesting that how a victim of violence reacts may be a more important predictor (negative relationship) of the acceptability of dating violence than the initial act of violence. Overall, case characteristics explain three times more variation in the acceptability of dating violence than respondent characteristics (30% vs. 10%). PMID- 18447080 TI - Identity formation of United States American and Asian Indian adolescents. AB - The Extended Version of the Objective Measure of Ego Identity Status-II was completed by 434 high school students from the United States and India. Students were male and female between the ages of 13 and 18 years. Asian Indian adolescents were found to be more diffused, foreclosed, and in moratorium in identity formation than adolescents in the United States. Gender and age differences in identity status also were found. Adolescent males and females in India had higher moratorium scores than adolescent males and females in the United States. Younger adolescents had lower exploration scores than did older adolescents. Implications for research are discussed. PMID- 18447081 TI - Parental bond and life course transitions from adolescence to young adulthood. AB - In this study the effects of life course transitions in adolescence and young adulthood (leaving the parental home, living together with a partner,entering parenthood, and becoming financially independent) on the parent-child bond are investigated. Data are presented from a three-wave study of 1,064 adolescents and young adults (aged 12-24 years at Wave 1) over a six-year period. As the youth in this study proceeded through the life course, they tended to report a closer parental bond. However, this age-related effect was counterbalanced by a tendency toward a weakened bond with parents following departure from the parental home. Results are in line with individuation theory, which contends that parent-child relationships become less close as a result of transitions leading to more autonomy. PMID- 18447082 TI - Male and female development of delinquency during adolescence and early adulthood: a differential autoregressive model of delinquency using an overlapping cohort design. AB - Although it is well known that during adolescence the delinquent involvement of females is consistently less when compared to male involvement, it remains an important question whether the development of delinquency has a similar trajectory for both sexes. The main hypothesis tested is whether sex differences in delinquency, specifically growth, peak age, and decline, are constant. An autoregression model in continuous time, implemented as a structural equation model, is used for the description of the development of delinquency in males and females. The data are collected in an overlapping cohort design, and both within person and between-persons data are integrated into a single model. The result shows that the involvement with delinquency over time is different for males and females. The main difference increases up to the age of 16, and decreases thereafter. The model indicates that both sexes reach the maximum in delinquency at the same age. It is concluded that males and females differ both in their start level at age 12 and in the amount of change with age. PMID- 18447083 TI - Parenting and adolescent well-being in two European countries. AB - The main and interactive effects of parental behavioral control and parental support on adolescent adjustment were examined with students ages 15-19 in Italy (N = 391, 59.1% male) and The Netherlands (N = 373, 45.3% male). In general, parental support was associated with better adjustment and parental control was associated with worse adjustment. However, parental control as well as age and sex moderated the effects of parental support on psychological discomfort and expectations of future success. Positive self-perceptions were less well predicted. Further, there were more moderated effects in the Dutch sample than in the Italian sample. Generalizability of the contributions of parenting behavior to adolescent adjustment outside of a North American context is discussed. PMID- 18447084 TI - Hispanic versus African American girls: body image, nutrition, and puberty. AB - Public health research has been dominated by the biomedical model, which does not appear to be appropriate for studying public health variables across different populations. For example, when comparing the Hispanic American (HA) and African American (AA) population in the U.S., there are similarities on several demographic and public health variables. Despite these similarities, there is a public health paradox. HA with strong cultural ties engage in fewer high-risk behaviors and therefore have favorable health outcomes. The primary focus of this study however, is the health disparities between AA and HA girls in particular. Pediatric research indicates that HA girls are developing secondary sexual characteristics at a later age than AA girls. Researchers have acknowledged that growth trends are sensitive to life changes such as catastrophes, prosperity, and those which affect diet and lifestyle. Thus, this study investigated whether there are differences in food intake between HA and AA girls as a function of early sexual maturation and body image perceptions in the context of culture. Participating were 23 HA and 44 AA girls, aged 7 to 10 years, and 1 of their parent/guardians. PMID- 18447085 TI - College students' role models, learning style preferences, and academic achievement in collaborative teaching: absolute versus relativistic thinking. AB - Based on the perspective of postformal operations, this study investigated whether college students' role models (technical teachers vs. lecturing teachers) and preferred learning styles (experience-driven mode vs. theory-driven mode) in collaborative teaching courses would be moderated by their cognitive development (absolute thinking vs. relativistic thinking) and examine whether academic achievement of students would be contingent upon their preferred learning styles. Two hundred forty-four college students who have taken the technical courses with collaborative teaching participated in this study. The results showed that those participants with absolute thinking perceived the modeling advantage of technical teachers was greater than that of lecturing teachers, preferred the experience driven mode over the theory-driven mode, and displayed differential academic achievement between technical courses and general courses. On the other hand, the students with relativistic thinking revealed no difference in perceived modeling advantage of role models, learning styles preferences, and academic achievement between two categories of courses. In addition, this research indicates that college students' preferred learning styles would interact with course category (technical courses vs. general courses) to display differential academic achievement. Implications and future directions are discussed. PMID- 18447086 TI - Parenting styles and learned resourcefulness of Turkish adolescents. AB - This study investigated the differences among 834 high school students regarding learned resourcefulness in terms of perceived parenting style and gender. The data were gathered by administering the Parenting Style Inventory (PSI) and Rosenbaum's Self-Control Schedule (SCS). The results of ANOVA pertaining to the scores of learned resourcefulness yielded a significant main effect for parenting style groups. Neither the main effect for gender nor the gender and parenting style interaction effect was significant. The findings suggest that those who perceived their parents as authoritative had a relatively high level of learned resourcefulness as compared to those who perceived their parents as neglectful and authoritarian. Findings also indicated that those who perceived their parents as indulgent had a higher level of learned resourcefulness than those who perceived their parents as neglectful and authoritarian. PMID- 18447087 TI - Predictors of perceived satisfaction with parental control in Chinese adolescents: a 3-year longitudinal study. AB - Over three consecutive years, 2,559 Chinese adolescents (mean age = 12.65 years at Wave 1) responded to instruments assessing their trust of parents, perceived parental trust of the children, readiness to communicate with the parents, and satisfaction with parental control. Results showed that mutual trust between the parents and their adolescent children and the children's readiness to communicate with the parents were related to perceived satisfaction with parental control at Time 1, Time 2, and Time 3. Although readiness to communicate with the parents and mutual trust between the parents and their adolescent children predicted perceived satisfaction with parental behavioral control and its change over time, trust of the parent was the strongest predictor. While the influence of trust of the father on satisfaction with paternal control was stronger for adolescent girls than for adolescent boys, influence of paternal trust on satisfaction with paternal control was stronger for adolescent boys than for adolescent girls. PMID- 18447088 TI - Prediction of work efficiency in early adolescence under the effects of noise. AB - This is a short summary of research on how different stress factors in the work environment (climate, light, noise) affect work performance of early adolescents. Due to the complexity of the measurements, the research consisted of a small sample of male adolescents (N = 20); average age 13.5 years (SD = 0.25). Tasks were used which demanded average work attention from the adolescent boys and in this context applied the basic theory of the "rare" signal detection. The research was performed in an artificially created condition, a "climate chamber," which provided a wide variety of settings for various work conditions. We performed 360 measurements for each effect and all possible interactions. Of all three stress factors in the work environment, only noise was significant (p < .001). Its effect on the elements of work success is predictable on the basis of the introduced model under the defined marginal terms. PMID- 18447089 TI - The relationship between leisure satisfaction and life satisfaction of adolescents concerning online games. AB - Increasing evidence indicates adolescents are likely to occupy their leisure time with online games. This study investigates the influences of leisure satisfaction on life satisfaction among adolescent online gamers. The self-completed market survey questionnaire employed is comprised of two sections: the first is Internet usage frequency, while the second employs two measures-the Leisure Satisfaction Scale (LSS) and the Satisfaction with Life Scale (SWLS), Data were gathered in a medium-sized metropolitan section of north Taiwan and interviews took place at a Cyber Cafe. Youths (totaling 134) between the ages of 13 and 18 voluntarily participated in the research. Results revealed significant positive relationships between physiological and aesthetic dimensions of leisure satisfaction and life satisfaction. However, the educational dimension of leisure satisfaction has a significant negative influence on life satisfaction. Findings also reveal a significant negative relationship between web surfing frequency and life satisfaction in adolescents. This suggests possible explanations for these results and discusses the implications. PMID- 18447090 TI - [Embryology of developmental neuropathology: research on premature fetuses at the neonatal research laboratory of the Baudelocque Clinic in Paris between 1947 and 1967]. PMID- 18447091 TI - Impact of breathing awareness meditation on ambulatory blood pressure and sodium handling in prehypertensive African American adolescents. AB - OBJECTIVES: This study evaluated the impact of a breathing awareness meditation (BAM) program on ambulatory blood pressure and sodium handling in African American adolescents with high-normal systolic blood pressure (SBP) levels. DESIGN AND METHODS: Following three consecutive days of SBP screenings, 66 eligible ninth graders were randomly assigned by school to either BAM (n = 20) or health education control (n = 46) groups. The BAM group engaged in 10-minute BAM sessions at school and at home each day for three months. Teachers conducted sessions at school during health classes. Before and after the intervention, overnight urine samples were collected, and ambulatory SBP, diastolic blood pressure, and heart rate were recorded periodically for 24 hours. RESULTS: Significant changes before and after the intervention were observed between BAM and control groups for SBP during school hours (-4.7 vs .9 mm Hg, P < .05), SBP at night (-4.8 vs -.6 mm Hg, P < .01), and heart rate during school hours (-6.7 vs -2.3 bpm, P < .02), adjusted for their respective preintervention levels. The overnight urinary sodium excretion rate decreased in the BAM group but increased in the control group (-.3 +/- 4.9 vs 1.1 +/- 4.0 mEq/hour, P < .03). CONCLUSIONS: These findings demonstrate the potential beneficial impact of BAM taught by school health teachers on blood pressure control in the natural environment in African American youth at risk for development of hypertension. PMID- 18447092 TI - Rural African Americans' dietary knowledge, perceptions, and behavior in relation to cardiovascular disease. AB - OBJECTIVES: To determine the relationship of demographics to opinions and knowledge of cardiovascular disease, hypertension, obesity, and dietary intake and to evaluate the relationship of dietary knowledge and dietary behaviors in rural African American adults. METHODS: The cross-sectional study involved a sample of participants who attended one of three cardiovascular information seminars in rural Macon County, Alabama. A total of 127 African American men and women, aged 21-75 years, completed a self-administered 79-item questionnaire. Data analysis included Chi-square and Fisher's exact tests. OUTCOME MEASURES: Agreement or disagreement with current scientific opinion regarding coronary heart disease, obesity, and dietary intake; agreement with statements of personal knowledge of heart disease, hypertension, and dietary intake; assessment and beliefs about the health risks associated with overweight/ obesity; and congruence between dietary knowledge and dietary practices. RESULTS: Women and older respondents tended to agree more with current scientific knowledge about heart disease mortality than did men and younger respondents. Younger respondents reported knowledge but less personal concern about fat intake/heart disease and salt intake/hypertension associations than did other age groups. Participants generally believed that excess weight increased the risk of high blood pressure, diabetes, heart disease, and cancer "a lot." Knowledge of the salt content of processed foods was associated with decreased frequency of adding salt at the table, while those not concerned about salt consumption and hypertension were more likely to add salt and consume processed meats. Respondents with knowledge of the effects of fat intake on heart disease were more likely to consume low-fat dairy products. CONCLUSIONS: The findings suggest that sex and age, in particular, require consideration in the development of community cardiovascular disease intervention programs aimed at southern, rural African American adults. PMID- 18447093 TI - Differences in food intake and disparity in obesity rates between adult Jews and Bedouins in southern Israel. AB - OBJECTIVE: The goal of this study was to compare eating patterns of Jews and Muslim Bedouins and investigate possible dietary causes for discrepancy in obesity rates. METHODS: We pooled two surveys that included data from 793 Jews and 169 Bedouins aged 35-64years recruited from 1998 through 2003 in southern Israel. For the Jewish sample, we used a proportional geographic cluster random sample of persons aged > or = 35 years. For the Bedouins, a convenience sample of 519 participants was used. Participants were interviewed at home, using modified 24-hour food questionnaires with additional questions regarding health and eating habits. RESULTS: The Jewish group was older and better educated than were the Bedouins. The Bedouins had a higher age-adjusted body mass index than did the Jews (P = .03), and the rate of obesity was higher among Bedouins than Jews (27.9% vs 20.0%, respectively). Compared to Jewish men, Bedouin men reported lower intake of fat, cholesterol, total saturated fat, and protein and fat as a percentage of total energy, but they reported higher intake of carbohydrates, fiber, and carbohydrates as a percentage of total energy. Bedouin women reported lower intake of total saturated fat, percentage of protein and fat, and higher intake of carbohydrates and fiber than did Jewish women. CONCLUSION: The Bedouin population is adapting Western eating patterns that appear to be associated with increased obesity. To address this problem, culturally sensitive intervention programs will have to be developed. PMID- 18447094 TI - Self-reported heart disease among Arab and Chaldean American women residing in southeast Michigan. AB - OBJECTIVES: This study estimates the prevalence of heart disease among Arab and Chaldean American women and examines the association between Arab and Chaldean ethnicity and heart disease among a sample of women. METHODS: This was a cross sectional study of a convenience sample of 2084 Arab, Chaldean, and African American women aged > or = 18 years who completed a survey that was distributed at churches, mosques, and small businesses in southeast Michigans. Logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between ethnicity and self-reported heart disease before and after adjusting for demographic, socioeconomic status, health care, chronic conditions, and health behavior variables. PARTICIPANTS: A sample of 2084 Arab, Chaldean, and African American women 18 years of age and older. RESULTS: The overall prevalence of heart disease was 5.1%. Estimates were higher for Arabs (7.1%), lower for Chaldeans (6.6%), and lowest among African Americans (1.8%). In the unadjusted model, Chaldeans and Arabs were four times more likely to have heart disease than were African Americans. However, in the fully adjusted model, the association between Chaldean or Arab ethnicity and heart disease was no longer statistically significant. CONCLUSIONS: Arab or Chaldean ethnicity was not significantly associated with self-reported heart disease among women, which suggests that other factors account for this relationship. Future studies should collect more detailed socioeconomic status, acculturation, and health behavior information. PMID- 18447095 TI - Serum biochemistry in Nigerians with hyperglycemic emergencies. AB - BACKGROUND: Management of plasma biochemical changes plays an important role in determining the prognosis of patients with hyperglycemic emergencies. This biochemical aspect, which has not been examined in detail in Nigerians with hyperglycemic emergency was the focus of this study. PATIENTS AND METHODS: Patients who presented with hyperglycemic emergency over a one-year period were studied. Demographic data and clinical evaluation findings were documented in a protocol. Plasma levels of glucose, electrolytes, and urea as well as urine samples for glucose, ketones, and protein were determined before and after initiating treatment for hyperglycemic emergency. RESULTS: Thirteen (40.6%) patients presented with diabetic ketoacidosis (DKA), 11 (34.4%) with hyperglycemic hyperosmolar state (HHS), while 8 (25%) had normo-osmolar nonketotic hyperglycemic state (NNHS). The mean glucose level at presentation in HHS was statistically significantly higher than in DKA and NNHS. Seventeen (53.1%) patients had hyperosmolality and 11 (64.7%) of these were in the HHS group, while 6 (35.3%) were in the DKA category. Mean anion gap in DKA was significantly higher when compared to patients with NNHS. Plasma bicarbonate was significantly lower in DKA than in HHS and NNHS. CONCLUSION: Presenting plasma glucose in Nigerian patients with hyperglycemic emergency appear to be generally lower than values reported elsewhere. A group of patients with hyperglycemic emergency have biochemical features intermediate between DKA and HHS; this NNHS accounts for approximately 25% of all our hyperglycemic emergency patients. PMID- 18447096 TI - A comparison of anthropometric indices for predicting hypertension and type 2 diabetes in a male industrial population of Chennai, South India. AB - OBJECTIVES: To assess the association of four obesity-related indices--body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to stature ratio (WSR)--with hypertension and type 2 diabetes among a male industrial population in south India. DESIGN, SETTING, AND PARTICIPANTS: A cross sectional study of 2148 men aged 18-69 years in two purposely selected industrial units in Chennai, India, in 2003-2005. MAIN OUTCOME MEASURES: The examination included blood pressure and anthropometric measurements (height, weight, hip circumference, and WC) to calculate BMI, WHR, and WSR. Fasting blood samples were taken to assess plasma glucose. RESULTS: Prevalence of overweight was 43.4%; prevalences of central obesity using WC > or = 90.0 cm and WHR > 0.90 were 50.0% and 70%, respectively. The prevalences of hypertension and type 2 diabetes were 26.5% and 16.3%, respectively. There was a significant increase in the prevalence of type 2 diabetes and hypertension across the quintiles for the four anthropometric indices. In logistic regression analysis, BMI and WC showed a significant graded increase in the odds ratio for hypertension after adjusting for age. In case of type 2 diabetes, only WHR showed significant increase in odds ratio across quintiles after adjusting for age and BMI. CONCLUSIONS: WHR was the best predictor for type 2 diabetes in the study sample. BMI and WC were good predictors for hypertension. We recommend that WHR should be routinely used in this clinical setting in addition to BMI to detect persons at high risk in these industrial units. Prospective studies are needed to provide evidence of the predictive power of anthropometric indices for Asian Indians. PMID- 18447097 TI - Home blood pressure monitoring in an ethnically diverse inner-city cardiology practice. AB - OBJECTIVES: To evaluate home blood pressure monitoring (HBPM) in an inner city cardiology practice. DESIGN: Retrospective study. SETTING: Inner city cardiology practice. PATIENTS: Consecutive patients were evaluated for hypertension and had > or = 8 home blood pressure recordings during 2-4 weeks while clinically stable on a medical regimen. MAIN OUTCOME MEASURES: Blood pressure differences, blood pressure load, defined as %HBPM systolic blood pressure readings > 140 and/or diastolic blood pressure readings > 90 mm Hg. RESULTS: 55 patients, (33 female, age 62 +/- 12.5 years). Office systolic, diastolic and mean BPs were higher than HBPM values (147 +/- 19 mmHg vs 139 +/- 17 mmHg, P = < .0001), (86 +/- 10 mm Hg vs 79 +/- 10 mm Hg, P < .0001), and (106 +/- 11 mm Hg vs 99 +/- 10 mmHg, P < .0001) respectively. Office and home pulse pressure (PPs) were similar (61 +/- 17 mm Hg vs 60 +/- 17 mm Hg, P = .42). Office and home PPs were more strongly correlated (r = .78, P < .0001) than were systolic (r = .51, P < .0001), diastolic (r = .51, P < .0001). Blood pressure load increased in a step-wise manner with increasing office blood pressure, 7.5% for patients with office blood pressure < 120/80 mm Hg to 73.5% in patients with office blood pressure > 160/100 mm Hg (P = .02). Office BPs showed 10/55 patients were normal or controlled (blood pressure < 140/ 90 mmHg) and 45 were high or uncontrolled (blood pressure > or = 140/90 mmHg). HBPM reclassified 2/10 patients as high/uncontrolled whereas 17/45 patients became normal/controlled. CONCLUSIONS: Office systolic and diastolic BPs are 7-8 mm Hg higher than home recordings in ethnically diverse patients. Office and home PPs are more strongly correlated than systolic, diastolic or mean arterial BPs. Blood pressure load is related to office BPs. HBPM reclassified approximately one third of the patients. HBPM appears useful in managing minority populations with hypertension. PMID- 18447099 TI - Prevalence of mitral annulus calcification in African Americans: comparison with non-Hispanic whites and Hispanics. AB - BACKGROUND: The association of ethnic ancestry with coronary artery calcifications suggests that mitral annulus calcification may also vary with ethnicity. We sought to compare prevalence and clinical correlates of mitral annulus calcification in non-Hispanic Whites, Hispanics, and African Americans. DESIGN: This was a retrospective study of 857 patients age 40-75 years that included 217 (25%) African Americans, 349 (41%) Hispanics, and 291 (34%) non Hispanic Whites referred for echocardiography. Multiple logistic regression was used to determine the interrelationships between mitral annulus calcification, risk factors, and ethnicity. RESULTS: Mitral annulus calcification was detected in 181 (21.1%) patients including 35 (16.1%) African Americans, 80 (22.9%) Hispanics, and 66 (22.7%) non-Hispanic whites. In univariate analysis, patients with mitral annulus calcification were older and more likely to have hypertension, diabetes, dyslipidemia, smoking history, and two or more risk factors than were those without calcification. In multivariate analysis, age and smoking history were independent predictors of mitral annulus calcification; dyslipidemia and diabetes were borderline significant predictors; and after adjusting for the remaining variables in the model, ethnicity was not an independent significant predictor of mitral annulus calcification. CONCLUSION: In a retrospective study of middle-aged and elderly African Americans, non-Hispanic Whites, and Hispanics referred for echocardiography, mitral annulus calcification is common in all three major ethnic groups but not significantly associated with ethnic ancestry. PMID- 18447098 TI - Hypertension knowledge among patients from an urban clinic. AB - OBJECTIVE: To determine levels and correlates of hypertension knowledge. DESIGN: Cross-sectional telephone survey. SETTING: Urban, public hospital clinic. PARTICIPANTS: 296 adults with hypertension. MAIN OUTCOME MEASURE: Hypertension knowledge was assessed through a 10-item test; respondents received one point for each correct answer. RESULTS: Eighty-nine percent of respondents were Black, 79% were female, 75% had a monthly income < $1000, and 62% had completed high school. Items with the lowest percentage of correct responses included knowing that hypertension does not cause cancer (41.9% correct), a blood pressure of 130/80 mm Hg is normal (59.8% correct), hypertension lasts a lifetime (60.5% correct), and renal failure is a complication of hypertension (76.4% correct). Overall, 39% answered 9 or 10 questions correctly. Low hypertension knowledge (< or = 7 questions correct) was associated with age > or = 60 years, having less than a high school education, and reporting a first hypertension diagnosis within 9 years before being surveyed. CONCLUSIONS: Hypertension knowledge deficits in specific content areas and among certain subgroups were present in this urban population. Educational programs focusing on newly diagnosed hypertensive patients and aimed at filling targeted knowledge deficits may be a cost-effective approach to increase hypertension knowledge in similar populations. PMID- 18447100 TI - Ethnic and sex differences in disease burden in patients undergoing coronary angiography: the confounding influence of obesity. AB - BACKGROUND: Data from cohort studies, predominantly in Caucasians, have identified obesity as a major risk factor for coronary artery disease (CAD), irrespective of sex. In contrast, reports examining the effects of obesity on mortality in African Americans suggest a weak relationship between body mass index (BMI) and mortality, particularly among women. Data correlating body weight with angiographic severity of CAD is sparse in minority populations. We sought to investigate ethnic-sex differences in the influence of obesity on the extent and severity of CAD. METHODS: We studied 640 patients (66.9% African American) who underwent coronary angiography at a tertiary care center. Cardiovascular risk factor profiles and CAD burden, quantified by the Duke Myocardial Jeopardy scoring system, a validated prognostication tool, were compared across ethnic and sex groups. RESULTS: Clustering of major cardiovascular risk factors, a higher prevalence of obesity classes II and III, and a statistically significant inverse correlation between BMI and Duke scores were observed among the cohort of African American women. General linear model analysis and stepwise multiple linear regression analysis revealed Duke score to be negatively associated with BMI and higher classes of obesity after adjustment for age and other cardiovascular risk factors in African American women but not in other subgroups. CONCLUSIONS: The observed inverse relationship between BMI and angiographic severity of CAD in African American women is novel and appears to support prior data on the weak association between BMI and cardiovascular mortality in this subgroup. PMID- 18447101 TI - Smokers' response to combination bupropion, nicotine patch, and counseling treatment by race/ethnicity. AB - BACKGROUND: Evidence on how to tailor nicotine dependence treatment to specific race/ethnic groups is limited. The present study investigated responses to established smoking cessation treatments among African American, Hispanic, and White adults. METHODS: Participants were 559 smokers (126 African American, 73 Hispanic, and 360 White). All received treatment for eight weeks with open-label bupropion, the nicotine patch, and individual counseling. The dependent variable was tobacco abstinence during the last four weeks of treatment. The independent variables were race/ethnicity and other known predictors of abstinence, including sex, age, smoking history (nicotine dependence level, number of cigarettes smoked daily, serum cotinine level and expired carbon monoxide, number of past quit attempts, and age when daily smoking began), confidence in ability to stop smoking, body mass index, psychological status, and psychiatric history (past major depression and alcohol dependence). RESULTS: The total proportion of abstainers in the sample was 53%, with proportional differences by race/ethnicity (Whites 60%, African Americans 38%, Hispanics 41%). Compared to Whites, the odds ratios (OR) for quitting, adjusted for moderators of race/ ethnicity and other predictors of abstinence, were significantly lower among African Americans (OR .44, 95% confidence interval 195% CI] .27-.72) and Hispanics (OR .46, 95% CI .26 .81). CONCLUSION: Disparity in smoking cessation treatment outcome among African American and Hispanic smokers compared to Whites implies that the burden of tobacco-related illness will continue to fall disproportionately among minority racial/ethnic groups. Gaining knowledge on the effectiveness of nicotine dependence treatments and on the factors that facilitate or impede a successful response by minority smokers is a public health priority. PMID- 18447102 TI - Socioeconomic factors and women's use of complementary and alternative medicine in four racial/ethnic groups. AB - OBJECTIVE: Higher socioeconomic status (SES) is associated with using complementary and alternative medicine (CAM) in national surveys. Less is known about how socioeconomic factors affect CAM use in US subpopulations. We examined whether the relationship between SES and CAM use differs by racial/ethnic groups. METHODS: Using national survey data, we assessed education and income effects on women's CAM use in four racial/ethnic groups (Whites, Blacks, Mexican Americans, and Chinese Americans), controlling for age, health status, and geographic region. CAM use was defined as using any of 11 domains in the prior year. RESULTS: Adjusted effects of SES on CAM use were similar among Mexican American and non-Hispanic White women--education had a distinct gradient effect, with each increasing level of education significantly more likely to use CAM; household income > or = $60,000 was associated with CAM use compared to income < $20,000. For Chinese American women, socioeconomic factors were not associated with CAM use when controlling for confounders. Although income was not associated with CAM use among African American women, college graduates were three times more likely to use CAM than those with less than a high school education, adjusting for confounders. CONCLUSION: SES effects on CAM use are not uniform across racial/ethnic populations. Other factors, such as culture and social networks, may interact with SES to influence CAM use in minority populations. PMID- 18447103 TI - Asian and Pacific Islander childhood vaccination coverage: National Immunization Survey, 2002-2004. AB - OBJECTIVE: Public health data on Asian/Pacific Islanders are most often collected and reported as one aggregated group. This aggregation of data can mask potential differences among the many ethnic/national/cultural groups classified as Asian/Pacific Islanders. We used data from the National Immunization Survey (NIS) to examine immunization status for all US children and four mutually exclusive groups: Asian only, Native Hawaiian only, Pacific Islander only, and other. METHODS: We included information from 64,718 US children 19-35 months of age who had adequate vaccination histories from provider(s) for 2002 to 2004; among these, 2673 (4.3%) were Asian only, Native Hawaiian only, or Pacific Islander only. The sample sizes reported are unweighted, while results are based on weighted analyses. RESULTS: Vaccination coverage estimates for children in the Native Hawaiian only group were consistently higher than estimates for all US children, whereas those in the Asian only group were nearly the same. Children in the Pacific Islander only group had vaccination coverage estimates that were lower than estimates for all US children. CONCLUSION: The results of this study indicated that although overall the Asian/Pacific Islander group had similar childhood vaccination coverage to all US children, the group does not have homogeneous coverage, with Pacific Islanders having lower coverage. Public health researchers should, whenever possible, examine individual groups of Asian/Pacific Islanders to more accurately measure the health status of this growing population. PMID- 18447104 TI - Concept mapping as a tool to engage a community in health disparity identification. AB - OBJECTIVES: To engage a community to critically examine local health disparities. DESIGN: Concept mapping is a tool used to rapidly assess the variations in thinking of large stakeholder groups' about a particular topic. SETTING: Jackson, Mississippi. PARTICIPANTS: Community members. METHODS: Dialog groups and community meetings were held, and participants were asked to respond to the statement, "A specific thing that causes African Americans to get sicker and die sooner is..." Aggregate responses were rated for importance and feasibility and then sorted into related groups. Aggregate sorts and ratings were then processed by using multidimensional scaling and hierarchical cluster analysis. RESULTS: There were 132 (unduplicated) reported contributors to health disparities. These responses fell into eight general clusters: economic issues, government, contextual factors, cultural factors, HIV, stress, environment, and motivation. Factors respondents felt were the most important contributors to disparities (economic factors, contextual factors, stress) did not correlate with those that they thought were most likely to be changed in society (contextual factors, government, motivation). CONCLUSIONS: Concept mapping provided a mechanism for rapidly documenting community thinking about health disparities. This mechanism stimulated community dialog and was used as a first step toward the long-term goal of creating equal community, academic, and medical partnerships for addressing disparities. The concept mapping process stimulated critical thinking about contributors to health inequities and uncovered contextual factors previously unknown to researchers and public health planners. The process allowed for active engagement and exchange of knowledge between the community and researchers and allowed a mechanism for identifying and rectifying disconnects in knowledge within and between stakeholder groups. PMID- 18447105 TI - Educating and mobilizing youth to detect undiagnosed elevated blood pressure: searching for the silent killer. AB - BACKGROUND: Hispanic individuals with high blood pressure are less likely than other ethnic groups to be aware of their high blood pressure or to be on medication for the condition. We investigated the feasibility of using high school students in predominantly Hispanic neighborhoods to conduct a large-scale blood pressure screening and education outreach in their communities. METHODS: In 2005, 960 students from Los Angeles high schools in predominantly Hispanic communities were trained to conduct blood pressure screening and provide educational materials and referrals. A multivariable analysis using logistic regression was conducted to analyze the association between self-reported cardiovascular risk factors and elevated blood pressure. RESULTS: Students presented educational materials to 5395 persons and screened 5165 persons in their communities. Of 5395 individuals screened, 299 (6%) were found to have elevated blood pressure, of which only 77 (26%) were taking antihypertensive medication. Of those with elevated blood pressure on screening, 46% indicated they had a history of hypertension, and 3% of the entire screened community were identified as having elevated blood pressure for the first time. Older age, male sex, heavy alcohol consumption, and history of hypertension were all independently associated with elevated blood pressure. CONCLUSIONS: Training high school students to identify persons with elevated blood pressure is feasible and could reach large numbers of ethnic minorities unaware of their blood pressure status. PMID- 18447106 TI - Patient preferences: do they contribute to healthcare disparities? AB - OBJECTIVES: The purpose of this study was to examine the effect of race on whether or not a patient would accept an invasive cardiac procedure when referred by a physician. METHODS: A retrospective longitudinal review of medical records at a public health hospital in southeastern Louisiana was conducted to determine cardiovascular patient acceptance/ rejection differences. Patient charts were examined using specific indicators (type of pain, laboratory values, blood pressure, and radiographic tests) to determine which patients were eligible to be referred. In order to be selected, each medical record had to have documentation of a physician referral for an invasive cardiac procedure. Medical charts without this referral were deemed ineligible for the cohort. RESULTS: Patient preferences were similar for both minorities and Caucasians, despite the fact that the study controlled for disease severity, age, income, sex, race, social support, diagnosis, and family history. CONCLUSION: Race did not contribute to disparate acceptance and rejection rates among African Americans and Caucasians. A possible reason for this occurrence is that the site was a teaching hospital, which may indicate more physician oversight and better articulation of treatment options. Future studies should delve deeper into physician and institutional bias in non teaching facilities during patient/physician interactions. PMID- 18447107 TI - Language preference as a predictor of access to and use of healthcare services among Hispanics in the United States. AB - OBJECTIVES: The objective of this study was to determine if Spanish language preference was significantly associated with barriers to healthcare services among a nationally representative sample of Hispanic persons in the United States. DESIGN: Cross-sectional analysis of secondary data. Differences in outcomes between those responding in Spanish and those responding in English were tested using chi-square analyses and multiple logistic regression models. SETTING: Nationally representative sample of US adults responding to the 2005 Behavioral Risk Factor Surveillance System survey. PARTICIPANTS: Respondents identifying themselves as Hispanic (n = 20,400). MAIN OUTCOME MEASURES: Four health care outcomes including health insurance coverage, having a personal health care provider, forgoing care because of cost, and having a routine check up within the past five years. RESULTS: Those responding in Spanish were less likely to have healthcare coverage, less likely to have a personal healthcare provider, and less likely to have had a routine check-up within the past five years. No difference was found for indicating that cost was a barrier to receiving care in this model. CONCLUSIONS: Disparities in healthcare access exist between Hispanic persons in the United States whose language preference is Spanish and those whose language preference is English. In an effort to achieve Healthy People 2010 goals and to provide care to all persons in the United States, barriers to care, such as language preference, should be addressed more fully in our healthcare system. PMID- 18447108 TI - The prevalence and characteristics of childhood overweight in a multiethnic, school-based health setting. AB - OBJECTIVE: The prevalence and correlates of overweight and the risk of overweight in minority children attending urban school-based health centers remains poorly characterized. The purpose of our study was to examine the prevalence and characteristics of overweight and at risk for overweight in low socioeconomic status minority children enrolled in East Harlem school-based health centers in New York City. DESIGN: A retrospective cross-sectional study during the period of September 2002 to August 2003. SETTING: Four Pediatric School-based Health Centers in East Harlem. PARTICIPANTS: Children and adolescents, aged 5 to 18 years. MAIN OUTCOME MEASURES: We examined presence of overweight or the risk of overweight based on body mass index (BMI) percentile and other clinical characteristics. Bivariate and multivariate analyses were performed to assess the relationship between demographics and clinical characteristics with overweight and the risk of overweight. RESULTS: Of the 491 children enrolled, 45.8% were either overweight or at risk for overweight, with the highest risk observed in Hispanic/Latino children. This latter relation remained significant after adjusting for age, sex, and birthweight status. In addition, high screening office blood pressure was related to overweight status and higher BMI percentile. CONCLUSIONS: A large proportion of minorities, especially Hispanic/Latino children, attending school-based health centers in an urban community sample, are overweight or at risk for overweight. Elevated screening blood pressure was also a common co-morbidity. Further research should determine the predictors and correlates of overweight, and effective targeted school-based interventions should be tested in this high-risk population. PMID- 18447109 TI - Acromegaly presenting as cardiac failure. AB - BACKGROUND: In acromegaly, specific structural and functional changes in the heart appear to contribute to the increased mortality in this disease. This disease is uncommon in Nigeria, West Africa and little has been published about it; also rare is clinically evident heart failure. We are therefore highlighting a late presentation of acromegaly as heart failure. CASE REPORT: A 45-year-old woman presented with a 4-year history of progressive increase in body size, lactation and amenorrhoea, and a six-week history of worsening symptoms of heart failure. Physical examination showed coarse facial features, spade like hands and feet, pitting pedal edema, galactorrhoea, and features of congestive cardiac failure. Chest radiograph showed gross cardiomegaly. On skull radiograph, destruction of the floor of the pituitary fossa was noted, with erosion of the clinoid processes. She had hyperprolactinamia. Fasting and post-glucose growth hormones values were elevated. Echocardiography revealed features of both diastolic and systolic dysfunction with left ventricular hypertrophy and dilation. A diagnosis of acromegalic cardiomyopathy in severe congestive heart failure was made. She was managed with anti-heart failure drugs with good results and subsequently began on a dopamine agonist. She was lost to follow up. CONCLUSIONS: Acromegaly is uncommon in our practice. This patient presented late with complications. Management was very difficult because of the combination of severe complications and lack of resources. PMID- 18447110 TI - Smoking cessation treatments: measuring responses among ethnic groups. PMID- 18447111 TI - A lifesaving education. PMID- 18447112 TI - Do black and white patients accept and reject doctor recommendations for heart treatments at the same rate? PMID- 18447113 TI - Minority children in a low socioeconomic environment found to have increased rates of being overweight. PMID- 18447114 TI - [Prevalence of dental disorders in 483 horses and ponies]. AB - Prevalence of dental disorders in 483 horses and ponies Five equine veterinarians working at three equine referral hospitals examined the oral cavity of 483 horses and ponies prior to surgery, to gain information about the prevalence of common dental disorders in the horse. A thorough examination, using hands/fingers, a full-mouth speculum, a dental mirror and a good light source, is essential to detect such disorders. Many horses examined needed dental attention even though there were no problems with mastication or riding. The most detected abnormalities were sharp enamel points on the buccal side of the upper arcade and the lingual side of the lower arcade, and hooks at 106/206 and 311/411. Regular dental care would improve the condition and welfare of horses. PMID- 18447115 TI - [How do I export a horse?]. PMID- 18447116 TI - [Not listening]. PMID- 18447117 TI - [Horse Advisory Committee III--Infectious complications--nervous system]. PMID- 18447118 TI - [Instruments, books and other objects memorable to (almost) forgotten opinions, therapies, buildings, et cetera. Horse limb prosthesis]. PMID- 18447119 TI - [Results from the credit management survey]. PMID- 18447120 TI - [The animal in art: the kidnapping of Europa]. PMID- 18447121 TI - ['Mediation' also an option]. PMID- 18447122 TI - Screening for lung cancer with low-dose CT. AB - Lung cancer represents the leading cause of cancer-related mortality in the world. In the past, many attempts were made to detect the disease at an early stage and subsequently reduce its mortality. Chest X-ray was abandoned for this purpose. For several years low-dose computed tomography has been introduced as a potential tool for early screening in a high-risk population. As demonstrated in several papers, the task is not easy and researchers are faced with many difficulties. This paper reviews mainly the role of low-dose CT for early cancer screening. Results of past and current trials, controversies related to the high rate of lung nodules, cost-effectiveness, and delivered radiation dose to the patient are presented. Finally some limitations of low dose CT for lung cancer detection are explained. PMID- 18447123 TI - MRI of cartilage and subchondral bone injury. A pictorial review. AB - In this article, we present an overview of various cartilage and subchondral bone abnormalities seen on MRI. Injury of bone is often associated with cartilage damage and vice versa. A number of common conditions affecting joints typically show certain combinations of chondral and subchondral changes. PMID- 18447124 TI - Gorham-Stout disease of the humerus. AB - Gorham-Stout disease is characterized by local proliferation of small vascular or lymphatic channels resulting in progressive destruction and resorption of bone. The etiology and pathogenesis of the disease remains mostly unknown, despite some 175 reported cases. A case of Gorham-Stout disease of the humerus in a 14-year old boy is described. The patient presented with progressive pain and deformity of the right arm. Although the disease was described in different bones of the body its location in the humerus is rare. We report the natural history and clinical follow-up in a young patient. A fibular graft was performed but 10 months later, resorption and pathological fractures occurred again. This study presents the radiographic and MRI features of Gorham disease. PMID- 18447125 TI - Intradiploic epidermoid cyst. PMID- 18447126 TI - Fahr disease. PMID- 18447127 TI - Malignant right coronary artery. PMID- 18447128 TI - MR findings of dysplastic hips in Saldino-Mainzer syndrome. PMID- 18447129 TI - Acute colonic diverticular haemorrhage: MSCT diagnosis. PMID- 18447130 TI - Lemierre syndrome in a 19-year-old man with acute swollen neck. PMID- 18447131 TI - Three-dimensional demonstration of systemic blood supply to normal left basal segments. PMID- 18447132 TI - The galaxy sign in pulmonary sarcoidosis. PMID- 18447133 TI - Infant with subdural hemorrhages of different age: hallmark of non-accidental head injury (NAHI). PMID- 18447134 TI - Calcinosis associated with dermatomyositis. PMID- 18447135 TI - Expression of a recombinant protein immunochemically equivalent to the major Anisakis simplex allergen Ani s 1. AB - BACKGROUND: Anisakis simplex is a nematode which can parasitize humans, producing anisakiasis and can induce immunoglobulin-(Ig)-E-mediated allergic symptoms. Parasite recombinant proteins, such as the major allergen Ani s 1, may be useful tools to avoid misdiagnosis of A simplex allergy due to cross-reactivity when whole parasite extracts are used. OBJECTIVE: To obtain Ani s 1 allergen as a recombinant protein with IgE-binding properties similar to its natural counterpart. METHODS: Ani s 1-encoding cDNA was amplified by polymerase chain reaction and cloned. The allergen was expressed in Escherichia coli as a nonfusion protein. Natural and recombinant Ani s 1 were investigated by means of Western blotting, enzyme allergosorbent test, enzyme-linked immunosorbent assay (ELISA), and ELISA inhibition using sera from 53 patients with A simplex allergy. RESULTS: Residues of the amino acid sequence of the encoded protein were 99.4% identical to the reported one. Purified rAni s 1 was obtained with a yield of 2 mg/L of culture while the yield of the natural counterpart was only 50 micro/g of larvae. rAni s 1 reactivity was not significantly different from that of the natural allergen; the correlation was excellent (p = 0.92, P < .001). ELISA inhibition experiments showed that the dose-response inhibition curve obtained with rAni s 1 overlapped with that of nAni s 1. In an enzyme allergosorbent analysis, 86.8% of the A simplex-allergic patient sera reacted to rAni s 1. CONCLUSION: Recombinant Ani s 1 is immunochemically equivalent to its natural counterpart and therefore might be useful for the in vitro diagnosis of anisakiasis and A simplex-mediated allergy. PMID- 18447136 TI - Mite-specific immunotherapy using allergen and/or bacterial extracts in atopic patients in Brazil. AB - OBJECTIVE: This study aimed to evaluate the clinical efficacy and antibody response changes after specific immunotherapy (SIT) using Dermatophagoides pteronyssinus (Dpt) allergens with or without bacterial extracts in Brazilian mite-atopic patients. METHODS: One-hundred patients with allergic rhinitis were selected for a randomized double-blind, placebo-controlled trial and distributed into 4 groups: Dpt (Dpt allergen extract), Dpt+MRB (Dpt allergen plus mixed respiratory bacterial extracts), MRB (MRB extract only) and placebo. Rhinitis symptom and medication scores; skin prick test (SPT) to Dpt extract; and serum immunoglobulin (Ig) E, IgG4, and IgG1 levels to Dpt, Der p 1, and Der p 2 allergens were evaluated before and after a year of treatment. RESULTS: After 1 year, the SPT response was reduced in the Dpt group (P=.03), whereas IgE levels to Der p 2 decreased only in the Dpt (P = .048) and Dpt+MRB (P = .005) groups. IgG4 and IgG1 levels to Dpt and Der p 1 increased in the Dpt group (P < .05), whereas in the Dpt + MRB group the IgG1 level only increased to Dpt (P=.001) and the IgG4 only increased to Der p 1 (P=.049). IgE levels to Dpt decreased only in the MRB (P= .005) and Dpt + MRB (P= .001) groups. Rhinitis symptom and medication scores fell in all groups, including the placebo group (P<.001). CONCLUSIONS: SIT using Dpt extract alone was effective in reducing SPT response and IgE levels to Der p 2 allergen, while bacterial extracts induced decreases in IgE levels to whole Dpt extract. However, only groups receiving Dpt allergen had higher levels of IgG1 and IgG4 to Dpt and Der p 1 after a year of treatment. PMID- 18447137 TI - Predictive value of the sulfidoleukotriene release assay in oral allergy syndrome to celery, hazelnut, and carrot. AB - BACKGROUND: Patients sensitized to birch pollen frequently suffer from a food allergy to plant foods such as celery, carrots, or hazelnut. One of the main manifestations of birch pollen-related food allergy is the oral allergy syndrome. Skin tests and allergen-specific immunoglobulin (Ig) E determinations are poor predictors of such reactions when assessed by double-blind placebo-controlled food challenge (DBPCFC). OBJECTIVE: To investigate whether a cellular test based on leukotriene release from basophils, the cellular antigen stimulation test in combination with enzyme-linked immunosorbent assay (CAST-ELISA), is predictive of pollen-related food allergy. METHODS: Birch pollen-sensitized patients with positive DBPCFC to celery (n=21), hazelnut (n=15), and carrot (n=7) underwent skin tests along with determination of specific IgE and CAST-ELISA for the respective allergens. The results were compared with those of 24 birch pollen sensitized patients with negative open food challenge to celery, hazelnut, and carrot. RESULTS: While skin prick tests had a sensitivity of 85%, 80%, and 29% for commercial extracts of celery, hazelnut, and carrot, respectively, prick testing with self-prepared extracts yielded sensitivities of 100%, 80%, and 100%, respectively. For specific IgE determinations, sensitivities were 71%, 73%, and 57%, respectively, and the respective specificities were 67%, 73%, and 60%. For CAST-ELISA with various sources and doses of allergens, the sensitivity varied from 71% to 95% for celery, 73% to 80% for hazelnut, and 43% to 86% for carrot. The respective specificities were 67% to 92%, 75% to 88%, and 77% to 91%. Analysis of the predictive value of CAST-ELISA with receiver operating characteristic curves showed that the results of the tests were more predictive of pollen-related food allergy than quantitative allergen-specific IgE determinations. CONCLUSIONS: CAST-ELISA is more specific than routine diagnostic tests for the diagnosis of pollen-related food allergy to celery, hazelnut, and carrot. PMID- 18447139 TI - Gene expression profile of ovalbumin-induced lung inflammation in a murine model of asthma. AB - BACKGROUND: Asthma is a chronic inflammatory disease that is associated with airway hyperresponsiveness, tissue remodeling, and airway obstruction, and that involves coordinate expression of multiple inflammatory genes in the lungs. OBJECTIVE: To evaluate the gene expression pattern in a mouse model of asthma and assess the effect of a new drug, R142571, on the gene expression profile. METHODS: Lung tissue from ovalbumin-sensitized mice was used to examine gene expression on the CodeLink oligonucleotide mouse 20 K bioarray platform. Data were validated for some genes by semiquantitative reverse-transcriptase polymerase chain reaction. RESULTS: Of the 19,736 genes represented on the microarray, expression of 378 genes was differentially regulated (215 upregulated and 163 downregulated), with at least a 2-fold change in expression (P <.05). The differentially regulated transcripts included genes known to be involved in several different biological processes, including signaling, DNA-dependent transcriptional regulation, immune response, proteolysis, and peptidolysis. Cluster analysis of the differentially regulated genes showed that at least 16 were downregulated by R142571 treatment at both of the doses used (1 and 10 mg/kg). In addition, 46 and 29 genes were downregulated at doses of 10 mg/kg and 1 mg/kg, respectively, as compared to the animals treated with vehicle. CONCLUSION: The cytokine expression pattern in our data, suggests that the murine model exhibits a predominantlyT helper 2-type response, as observed in asthmatic human subjects. Based on this study, we suggest that this mouse model would be an appropriate system for screening new drug molecules for treatment of atopic asthma. PMID- 18447138 TI - Allergy to bee venom in beekeepers in Germany. AB - OBJECTIVE: The aim of this study was to determine the incidence of bee venom allergy in German beekeepers, to explore risk factors for bee venom allergy in this group, and to determine which factors best predicted severe reactions. METHODS: A questionnaire incorporating 2 instruments on beekeepers' physical and mental health and working practice was included in 3 German beekeeping journals. A reference group also completed the questionnaire. Simple descriptive methods, bivariate correlation, cross-tabulation, 1-way analysis of variance, and stepwise discriminant analysis were used to analyze data. RESULTS: Altogether, 1053 questionnaires were returned. No significant differences were seen between the 2 groups. The mean number of bee stings annually was 57.8 (median, 30; range, 0 1000). Overall, 46 (4.4%) beekeepers reported systemic reactions to bee stings, 797 (75.6%) had mild local reactions, and 196 (18.6%) had no reactions. The study confirmed several risk factors. These were, in descending order of importance, symptoms of upper respiratory allergy while working on the hive, presence of other allergies, time spent as a beekeeper, and more severe nonallergic reactions to bee stings in springtime. These factors identified beekeepers at risk of allergic reactions to bee venom in 85.2% of cases. Our results also showed an association between allergy and emotional instability. Risk management in allergic beekeepers was not good. CONCLUSION: The results of this study will help to identify beekeepers at risk of systemic reactions to bee stings and to inform them about the dangers of bee venom allergy. PMID- 18447140 TI - Effect of active tuberculosis on skin prick allergy tests and serum IgE levels. AB - OBJECTIVE: Mycobacterium tuberculosis has been shown to suppress allergic airway disease driven by type 2 helper T cells in animal models. In this study, we investigated the effect of active tuberculosis on skin prick test (SPT) positivity and serum immunoglobulin (Ig) E levels of atopic patients with and without tuberculosis infection. MATERIALS AND METHODS: Seventeen atopic HIV negative men with pulmonary tuberculosis and 18 atopic healthy male controls at our military hospital were studied prospectively between March 2005 and March 2006. The sums of all SPT positive tests and positivity to house dust mite alone were calculated before initiation of treatment and after 6 months. Measurement of total serum IgE levels was also performed at the same moments. RESULTS: The mean (SD) initial serum total IgE concentrations were significantly higher in the tuberculosis patients than in the healthy controls (324.1 [317.67] U/mL vs. 146.7 [75.29] U/mL, respectively; P < .05), The total serum IgE concentrations after 6 months of treatment were also higher in the patients than in the controls. The mean sum of SPT positivity was higher in the tuberculosis patients than in the controls at both testing times. CONCLUSION: Our study does not support the hypothesis that M tuberculosis suppresses atopy and atopic disorders, but large, prospective experimental studies are needed before excluding the possibility of a relationship. PMID- 18447141 TI - Acute generalized exanthematous pustulosis due to tetrazepam. AB - Tetrazepam is a benzodiazepine that is widely used in Spain as a muscle relaxant, with occasional cutaneous side effects. We report a patient who developed a generalized pruriginous cutaneous reaction compatible with acute generalized exanthematous pustulosis (AGEP) due to tetrazepam. Patch tests with bromazepam, diazepam, and tetrazepam were negative at 48 and 72 hours; however, the tetrazepam patch showed a positive reaction at 10 days. Immunohistochemical studies revealed a mononuclear infiltrate composed of CD4+ and CD8+ T lymphocytes. Analysis of interleukin (IL) 8 expression by quantitative polymerase chain reaction revealed increased IL-8 mRNA levels in patch test-positive skin. Lymphoblast transformation test (LTT) was positive with tetrazepam but not with diazepam. Positive patch test and LTT suggested that tetrazepam-specific lymphocytes might be responsible for a T cell-mediated reaction. These results support previous data suggesting an important role for IL-8 and drug-specific T cells in the pathogenesis ofAGEP and imply that the reaction was specific to tetrazepam with no cross-reactivity to other benzodiazepines. PMID- 18447143 TI - Acquired angioedema associated with hereditary angioedema due to C1 inhibitor deficiency. AB - Angioedema caused by C1 inhibitor deficiency is a rare disorder that may be either hereditary or acquired, the latter being mainly associated with lymphoproliferative disorders. A 51-year-old woman who had suffered from episodes of acute peripheral edema since she was 12 was diagnosed with hereditary angioedema at the age of 40 and remained stable with stanozolol. Due to a worsening of her symptoms she was reassessed and low levels of C1q and an abnormal lymphocyte count were detected. Immunophenotyping of peripheral blood revealed 9% monoclonal lambda B cells with a follicular center phenotype. The histopathology was consistent with a grade II follicular lymphoma stage IV-A.With chemotherapy, the hematologic disease was controlled and C1q levels returned to normal values. This represents a rare case of a patient with hereditary angioedema who developed acquired angioedema due to a lymphoma that was associated with a reduction in the levels of C1q as her symptoms worsened. PMID- 18447142 TI - Cold urticaria and celiac disease. AB - Cold urticaria can be associated with blood and thyroid disorders, drugs, or infections. Celiac disease is an autoimmune enteropathy caused by permanent gluten intolerance. It is often associated with other autoimmune diseases, such as chronic idiopathic urticaria. Nevertheless, association with cold urticaria has not yet been described. A boy aged 3 years 8 months presented local urticaria angioedema when exposed to cold temperatures. An ice cube test was positive and iron deficiency anemia was demonstrated. He later developed legume intolerance, rhinoconjunctivitis related to pollen sensitization, and asthma. Due to persistence of cold urticaria symptoms and refractory anemia, a test for immunoglobulin A autoantibodies to tissue transglutaminase and an intestinal biopsy were performed. Results of both tests were compatible with celiac disease.A study of human leukocyte antigen indicated a high risk phenotype (HLA, DR6/DR7; DQA 0501, 0201; DQB 0301, 0201). After 7 months of a gluten-free diet, the boy's anemia resolved and he is free of symptoms when exposed to cold. This is a first description of the possibility of an association between celiac disease and cold urticaria. A poor course of cold urticaria in the absence of evidence of another underlying condition should lead to suspicion of celiac disease. PMID- 18447144 TI - Hypereosinophilia, hyper-IgE syndrome, and atopic dermatitis in a toddler with food hypersensitivity. AB - We describe a 20-month-old girl with hypereosinophilia, hyper-immunoglobulin (Ig) E syndrome, and atopic dermatitis. Her peripheral eosinophil count and IgE plasma levels were 2.65 x 10(9)/L and 6702 IU/mL, respectively. Specific IgE levels for a variety of foods and inhalants were high and single-blind food challenges were positive for cow's milk, hen's egg, oat, wheat, and soy. When the patient received an extensively hydrolyzed milk formula, an exclusion diet, and 2 mg/kg of prednisone daily, the atopic dermatitis partially improved. Further improvement was observed with 1 mg/kg of azathioprine daily. Long-term clinical response was satisfactory. We suggest that food hypersensitivity should be ruled out in patients with hypereosinophilia, hyper-IgE syndrome, and atopic dermatitis. Azathioprine may be a good therapeutic alternative for treatment in such cases. PMID- 18447145 TI - Fatal intraoperative anaphylaxis after aprotinin administration. PMID- 18447146 TI - Use of the comet test to assess DNA damage in children with ataxia-telangiectasia and their relatives. PMID- 18447147 TI - Anaphylaxis due to metronidazole with positive skin prick test. PMID- 18447148 TI - Anaphylaxis to salbutamol. PMID- 18447149 TI - Allergy to proton pump inhibitors: diagnosis and assessment of cross-reactivity. PMID- 18447150 TI - Occupational asthma and rhinoconjunctivitis caused by cricket allergy. PMID- 18447151 TI - Should plans pay physicians to switch patients to generics? PMID- 18447152 TI - PBMs' rebate income threatened by lawsuits and move to generics. PMID- 18447153 TI - CMS hybrid payment system shows promise. PMID- 18447154 TI - What makes Harvard Pilgrim so good? PMID- 18447155 TI - The epilepsy battle in the war between brands and generics. PMID- 18447156 TI - Health plans come together for better outcomes research. PMID- 18447157 TI - Health plans embrace retail clinics. PMID- 18447158 TI - Aetna and Hannaford make a Singapore connection. PMID- 18447159 TI - Health 2.0. Will its promise be realized? PMID- 18447160 TI - PDP drug restrictions block comparison shopping. PMID- 18447161 TI - Humana's multi-year pacts could be attractive to customers. PMID- 18447162 TI - Recently-approved sapropterin reduces phenylalanine levels. PMID- 18447163 TI - Specialty drug spending to double by 2010. PMID- 18447164 TI - New pathogenesis of the cobalamin-deficient neuropathy. AB - Subacute combined degeneration (SCD) is considered the neurological counterpart of pernicious anaemia because it is the paradigmatic neurological manifestation of acquired vitamin B12 (cobalamin (Cbl)) deficiency in adulthood. Hitherto, the theories advanced to explain the pathogenesis of SCD have postulated a causal relationship between SCD lesions and the impairment of either or both of two Cbl dependent reactions. We have identified a new experimental model, the totally gastrectomised (TGX) rat, to reproduce the key morphological features of the disease, and found new mechanisms responsible for the pathogenesis of SCD. We have demonstrated that the neuropathological lesions in TGX rats are not only due to mere vitamin withdrawal but also to the overproduction of the myelinolytic tumour necrosis factor (TNF)-alpha, nerve growth factor, the soluble(s) CD40:sCD40 ligand dyad, and the reduced synthesis of the neurotrophic agents, epidermal growth factor and interleukin-6. Cbl replacement treatments normalised all of these abnormalities. PMID- 18447165 TI - [The black reaction: an ante litteram "cognitive" biotechnology]. AB - The black reaction, also known nowadays as "Golgi staining" or "Golgi impregnation", paved the way to the development of modern neuroscience at the end of XIX century. By this staining, the silhouette of the nerve cell appears in all its morphological complexity with all its ramifications, which could be followed and analyzed even at a great distance from the cell body. However the reaction has been fundamental for discoveries in several other areas of biomedical research: cytology, myology, bacteriology. With the aid of the black reaction, for example, it was possible to observe: the Golgi apparatus, the T system related to the function of the sarcoplasmatic reticulum, the Muller-Golgi canaliculi of the peptic glands and many more; this wide and various success is due to its character of morphological amplification of fine structures. In spite of its still controversial biochemical nature, the black reaction has been an unavoidable versatile tool in different areas of biology, so we propose to consider this method as an ante litteram "cognitive" biotechnology. PMID- 18447166 TI - The morpho-functional organization of secretory traffic. Here today, where tomorrow? AB - The morpho-functional principles of secretory traffic are still unclear, in stark contrast with our advanced knowledge of the underlying molecular machineries. Recently, the conceptual and technological hindrances that have delayed progress in this area have been disappearing, and new glimpses of the organization of traffic in intact cells are being revealed by a cluster of powerful morphological techniques. Here, we discuss the new advances in the light of the three main possible traffic principles: by anterograde vesicles, progression/maturation, and flow via continuities. PMID- 18447167 TI - [Camillo Golgi: historical profile of a Nobel Prize politically engaged]. AB - The article analyzes the role and activity of Camillo Golgi as Senator of the Italian Parliament in the light of the official acts which testify his modalities of political intervention, his style and his proposals, with the aim of verifying if and how his experience as scientific researcher and teacher at the University of Pavia shaped his political life. PMID- 18447168 TI - [Golgi, Cajal and neurophysiology]. AB - In developing neurohistology, neither Golgi nor Cajal paid much attention to the findings of the physiologists who at that time worked on the nervous system, possibly because they felt that the microscope alone could answer functional as well as structural questions. Cajal was personally acquainted with Sherrington but surprisingly did not use his findings on the role of synapses in reflex mechanisms to support the neuron theory. Golgi did not trust the physiologists' concepts in general and therefore did not pay attention to the physiological literature, an attitude rightly criticized by Luciani, a prominent neurophysiologist of those times. In recent years, attempts to resurrect Golgi's theory of the diffuse nerve net have been based on the evidence of extrasynaptic communications between neurons through tight junctions or the so-called volume transmission. Here are mentioned earlier efforts to reconcile the neuron theory with Golgi's theory by Antonio Pensa, a pupil of Golgi who influenced the scientific development of the great neurophysiologist Giuseppe Moruzzi. The article also argues that the known mechanisms of extrasynaptic communication by no means prove the existence of a neural net a la Golgi, that is of a net predicated on a fusion of neurites. The greatness of Golgi must be sought in his immortal contributions to various fields of biology and medicine, rather than in his only major scientific mistake: a stubborn defense of an indefensible theory. PMID- 18447169 TI - [Camillo Golgi and the "Accademia di Scienze Mediche e Naturali in Ferrara"]. AB - Drawing from sources and documents preserved in Ferrara, the Author proposes to add to the literature concerning Camillo Golgi some probably original data about the presence of Golgi within the Academy of Ferrara: honours, commemorations, scholarships, contributions of local scholars spurred by Golgi's researches accomplished in the field of histology, neurology and malariology. PMID- 18447170 TI - [Camillo Golgi and the contribution of the Italian scientists to the development of the malariology in the last quarter of the nineteenth century]. AB - Between 1885 and 1892--a period in which great advances have been made in techniques and practice of the young science of microbiology--Camillo Golgi provided a notable contribution to malariology. Continuing studies and researches of Roman malariologists Ettore Marchiafava (1847-1935) and Angelo Celli (1857 1914), on the malarial parasites--described by the French military physician Alphonse Laveran--he studied the reproduction cycles of the Plasmodium in human blood (Golgi cycles) and elucidated the temporal coincidence between the recurrent chills and fever with the rupture and release of merozoites into the blood stream (Golgi law). He also demonstrated that the so-called tertian and quartan intermittent fevers are due to the presence in the blood of two different protozoan organisms Plasmodium malariae and Plasmodium vivax (Alphonse Laveran believed that there was only one species, Oscillaria malariae). These observations made it possible to diagnose and treat the disease. He established that quinine, to varying degrees, was effective against the parasites at different stages of their development--those in the early stages were most affected. Moreover, excluding the etiological specificity of the famous Bacillus malariae, isolated by Klebs and Tommasi Crudeli before Laveran's discovery in the ground and water of the Pontin Marshes south of Rome, his studies determined the definitive disappearance from the scene of this bacterium; and opened a new phase of the research to which the Italian malariologists will give an important contribution, although the contrasts and scientific rivalries. This article follows the developments of the malariological research in Italy, plagued by the disease, on the contrary of other developed European countries (France and Great Britain) and examines the factors that influenced Italian scholars. PMID- 18447171 TI - [From cellular biology to molecular biology: Golgi apparatus from the discovery to nowadays]. AB - On April the 9th 1898 Golgi presented the discovery of the Apparato Reticolare Interno or internal reticular apparatus to the Societa Medico-Chirurgica in Pavia. The internal reticular apparatus was described as "a fine and elegant network within the cell body" of Purkinje cells. The discovery of this new intracellular structure can be considered a byproduct of Golgi studies devoted to the analysis of the nervous system histology. Golgi and his co-workers detected the internal reticular apparatus in many cell types and described the organelle pleiomorphism due to specific physiological or pathological conditions. However, the real existence of the apparatus was questioned until the organelle was finally identified by electron microscopy in 1954. At this point Golgi apparatus became an actual intracellular structure without any clear function. The involvement in cell secretion processes was verified by using biochemical and molecular investigations from the 1960s. Nowadays, Golgi apparatus is clearly known to be involved in different cell functions as growth, homeostasis and division. The correct execution of these functions lies on the ability to maintain an equilibrated balance between the proteins therein resident. Recently, Golgi apparatus has been involved also in human pathology as mutations in proteins localized in the organelle are linked to some hereditary disorders like the Lowe syndrome. Golgi apparatus has been debated since its discovery. From the Golgi milestones discussed here it is evident that controversies that have arisen were often resolved by information resulting from the application of new technical developments. Indeed the compound dynamic structure and the relevance in cell physiology and in human pathology render Golgi apparatus an open object for future studies. Overall, the history of the Golgi apparatus represents an excellent model not only to follow the transition of the study approaches from cellular biology to molecular cell biology but also to understand the current attention paid to integrate the molecular function and the organelle structure in order to explain what goes wrong in the context of human disease. PMID- 18447172 TI - [Angelo Maffucci and the experimental medicine]. AB - Maffucci had been interested in experimental pathology since 1879. His activity is documented by some experimental works mainly performed at the "Incurabili" Hospital of Neaples, Italy, where he first approached this discipline under the direction of the well-known German pathologist Otto von Schron. His publications between the years 1882 and 1887, when he was already director to Pisa, were concerned with the infectious embryo pathology, the absorption in the peritoneum and in the articulations, as well as with hypertrophic cirrhosis of the liver, which represented a perfect combination of experimentation and autopsy. His first work on infectious embryo pathology, published in 1887, strongly contributed to the understanding of the different infectious pathologies and asserted unequivocally the need for experimentation in the fields of medical and biological sciences. For this important contribution in the field of pathology and for his brilliant ideas, the National Academy of Lincei awarded the scientist a gold medal in 1903. PMID- 18447173 TI - [Pre-judices versus rational observations in infectious diseases]. AB - The article deals with the history of the concepts of epidemic diseases and contagion. The idea that illnesses could be transmitted from animals to humans and from humans to humans is totally absent in ancient medical theories, but present in the works of historicians, veterinaries, architects. Which is the idea that brings ancient medicine to the refusal of the idea of contagion? And can a supposed 'medical authority' still be a real obstacle toward the comprehension of the ethiology of infectious diseases? PMID- 18447174 TI - The historical evolution of some intrinsic dimensions of quarantine. AB - The word "Quarantine" makes its first recorded appearance in the English language in the seventeenth century. It was originally a thirty-to-forty day period in which subjects suspected of carrying a contagious disease were subjected to detention and segregation with selective restraint regulations regarding circulation. Five dimensions are implicit in this original use of the term: "time", "disease", "context", "restraint" and "segregation". These dimensions have undergone modification through time, and more recently the term has come to indicate a more variable time period, adopted with reference to the compulsory physical separation not only of groups of human beings potentially exposed to contagious disease, but also of animals, goods and various means of transportation. Currently, "new" pathologies such as SARS and avian influenza must also be considered, and the context dimension has become much more various than in the past, while the restraint dimension is now connected with personal liberty and autonomy and not only with medical-health risks. Finally, the original palliative, rather than curative, segregation dimension has left space to specialised therapeutic quarantine units, in this way completing the medical and figurative evolution of the concept of quarantine through time. PMID- 18447175 TI - [P. Minonzio's ideas about contagion]. AB - Paolo Minonzio was a physician working in a little country town near Varese in XIX century. He wrote a diary illustrating his medical experience which represents an interesting document of the spreading of bacteriological theories in a provincial context. PMID- 18447176 TI - [Documents and figures about the vaccine in Bologna at the beginning of the nineteenth century]. AB - An interesting documentation, related with the campaign for the diffusion of the vaccine in Italy at the beginning of the nineteenth century, is available at the Museum Luigi Cattaneo of Anatomical Waxes of the University of Bologna. In this collection there are two wax models reproducing a cow-udder with pocks and two girl arms with the pocks of a "true" and "false" vaccine rash. The waxes were moulded under the direction of the leading physician Pietro Moscati, and overlap with the engravings of the chief treatise about the cow-pox and vaccine published by Luigi Sacco in 1809. The presence of the same models also in the Museums of the University of Pavia, and the available documentation about these waxes, demonstrate the educational purpose of the preparations. According to Sacco, they would be an effective tool directed to physicians and midwiwes for the learning and the knowledge of the outcomes of vaccination. PMID- 18447177 TI - [The history of medical bibliography and the development of the idea of infectious disease between sixteenth and seventeenth century]. AB - The aim of this paper is to underline the importance of the main medical bibliographies printed during the Sixteenth and Seventeenth Century, as instrument of transmission and information of the most important medical ideas. The history of medical bibliography is like a mirror where it is possible to recognize the main features of the medical knowledge and of its development during the centuries. The paper analyzes how the idea of infectious disease is documented in the main medical bibliography of the Sixteenth and the Seventeenth centuries and how it developed in relationship with the structure of the medical bibliographies. The study offers a concrete example of the importance and usefulness of the history of medical bibliography to the historians of medicine in their research. PMID- 18447178 TI - [Reizungwelle or propagated disturbance? A neurophysiological debate in the late 19th and early 20th century]. AB - The article aims at illustrating the contribution of German and British scientists to the origin and the transmission of the nervous impulses. The debate originated at a time when physiologists tried to ascertain whether the stimulation wave is concomitant with the nervous impulse. PMID- 18447179 TI - [Atherosclerosis, an historical approach]. AB - The history of atherosclerosis represents a very interesting and intriguing charter of the history of medicine. Atherosclerosis was present even in the old age, as demonstrated by paleopathological studies. Starting from these observations, recent evidences highlighted the crucial role of inflammation in the genesis of atherosclerosis. PMID- 18447180 TI - [G. F. d'Acquapendente and Don Carlo Medici's gibbosity]. AB - Don Carlo dei Medici (1595-1666) is the son of Ferdinando I (1549-1609), Granduca of Tuscany, and becomes Cardinal of Catholic Roman Church in 1615. In 1604 Fabrizio d'Acquapendente is called in Florence to treat him, because of an aggravation of his health, and of his congenital neck's gibbosity. The recent paleopathological researches have diagnosed his congenital cervical gibbosity as effect of the Klippel-Feil's syndrome, and characteristic lesions of tubercolosis. PMID- 18447181 TI - [Historical outline of the Museum of Pathological Anatomy in Florence]. AB - The Museum of Pathological Anatomy, established in Florence in 1824, contains waxes of astounding beauty, almost photographic reproductions of the most common diseases in the 19th century. Work of eminent artists, such as L. Calamai (1796 1851) and E. Tortori (1829-1893), the wax models are extraordinary examples of the symbiosis between art and science, and served to instruct medical students in pathology without resorting to corpse dissection. The Museum also houses a vast collection of anatomical specimens, preserved in formalin and easy to investigate by means of modern molecular techniques for the study of the aetiology and pathomorphosis of diseases in relation to the profound modifications in the composition and socio-economic conditions of the resident Florentine population over the 19th and 20th centuries. PMID- 18447183 TI - [A modern example of anthropogenic mummification from Savoca]. AB - The Savoca mummies are probably the best known Sicilian collection of mummified human remains after those from Palermo. The 18th century subterranean chamber located in the Chiesa dei Cappuccini holds several preserved bodies, contained in either wall niches or coffins. A recent detailed inspection allowed the authors to determine that such corpses underwent spontaneous desiccation after being placed in the wall niches situated in the crypt beneath the Cathedral of Savoca. However, one unidentified specimen, belonging to an adult male and tentatively dated to the second half of the 19th century, shows clear signs of an artificial intervention aimed at preventing the decay of the cadaver. In addition, two skulls, located in the columbaria above the wall niches, show craniotomy, indicating that some of the remains were anthropogenically mummified. The case described seems to suggest that the traditional embalming techniques were still in use in the late Modern Era, despite the development of innovative methods of intra-arterial injection. PMID- 18447182 TI - [The 'dreams' of Cesare Augusto Levi: a pre-Freud interpretation]. AB - On 25th February, 1887 Cesare Augusto Levi, a poet and archaeologist born in Venice in 1856, held a conference on dreams at the "Ateneo di Venezia". The conference deals with the nature of dreams, with the unconscious, with hypnosis and magnetism. Levi advocates a socially oriented version of psychiatry and he may be considered as a forerunner of Freud's theories. PMID- 18447184 TI - [Gaetano Perusini (1879-1915): his contribution to the description of Alzheimer's disease]. AB - In 1906 Perusini began his scientific career publishing three papers. These articles were important for the understanding of degenerative dementia. Perusini studied the difference between Senile and Presenile Dementia. Emil Kraepelin distinguished its two forms, but Perusini didn't take a clear position because of his early heroic death on the slopes of Mount Sabotino on December in 1915. PMID- 18447185 TI - Some comparative perspectives on two early-Victorian registrars of births and deaths in rural Lincolnshire in the context of national legislation. PMID- 18447186 TI - Anthropometric measures of living standards and gender inequality in nineteenth century Britain. PMID- 18447187 TI - [Two hundred blood tests from Auschwitz. A notorious research project and the question about the contribution Adolf Butenandts]. AB - The 1939 Nobel Laureate in Chemistry and later President of the Max Planck Society Adolf Butenandt has been increasingly exposed to criticism in recent years. One far-reaching accusation against him is his postulated participation in the human experiments executed by the SS-physician Josef Mengele in the Auschwitz concentration camp. It concerns a project initiated by anthropologist Otmar von Verschuer in 1943. For this, Verschu-ER Obtained blood samples from his assistant Mengele in the Auschwitz concentration camp. When methodological problems occurred in the project Butenandt helped Verschuer. According to the reconstruction of geneticist Benno Muller-Hill the research project included lethal human experiments: Mengele had selectively infected concentration camp detainees with tuberculosis to observe their racially conditioned resistibility against that disease, he claims. This reconstruction, however, contradicts other sources. Therefore an alternative reconstruction is offered here. According to that, the project represented a large-scale attempt of serological race diagnosis in man. Human experiments are not plausible for this project. Yet it is clearly connected to race biological research and implementation. PMID- 18447188 TI - [Natural philosophy in medieval medicine]. AB - Medieval medicine is not much interested in natural philosophy. Nevertheless, it is based upon clear methodological and epistemological principles, where the word 'nature' is used in several ways. The natural 'virtues' of things--including magical ones--are most important for therapy. Human health is influenced by stars (planets, zodiac) and seasons, and the physician has to take into account such cosmic effects. The chances of healing depend on the patients' 'nature' in relation to the power of illness. A strong nature makes medicine superfluous, an overwhelming disease cannot be beaten. Thus, medicine is limited to 'neutral' situations when supporting the patient makes his 'nature' win. PMID- 18447189 TI - [Between research and genocide. The Nuremberg physician trials 1946/47: Raphael Lemkins point of view on human experimentation and genocide]. AB - While the significance of the new concept of genocide, as introduced by the Polish emigre jurist Raphael Lemkin, has been recognised, its importance for the Nuremberg Medical Trial has been overlooked. Lemkin commented extensively on the Trial, and his views are presented here. These comments help illuminate a neglected facet of the Trial, that of eugenics and racial extermination, taken at the time as amounting to genocide. Far from neglecting eugenics as some have suggested, the eugenic component of the Trial was extensive. PMID- 18447190 TI - [Agnes Bluhm, the woman scientist among the eugenics specialists, and the women's movement]. AB - The paper tries to assess the early female physician Agnes Bluhm (1862-1943) as one of the outstanding German female scientists of her time and draws up a connection from her achievements in early genetics to her commitments in eugenics and feminism. This leads to a more precise judgement on her position within the German racial hygiene and allows to correct misunderstandings that have assigned Bluhm to the right wing in the German women's movement. PMID- 18447191 TI - [The Watson-Crick model of the DNA doublehelix. The history of the discovery and the role of the protein paradigm]. AB - At the beginning, the two fundamental papers by Watson and Crick published in 1953 are presented. Subsequently, the main phases of protein and nucleic acids research, starting in the middle of the 19th century, are shortly reviewed. It is outlined, how the 'protein-paradigm' was gradually developed and ultimately became widely accepted. It is then described how Caspersson in 1936 newly raised the question what the chemical nature of genes was: proteins or nucleic acids ? In the main part of this report six lines of research are reviewed, the results of which led to the demise of the 'protein paradigm', the creation of the Watson Crick model of the DNA and the elaboration of the mechanism of DNA replication: (a) mutation experiments with UV and determination of the UV action spectrum, (b) determination of the chemical identity of the transforming agent in bacteria, (c) detailed chemical analysis of the DNA of different organisms, (d) molecular investigation of the infection of bacteria by bacteriophages, (e) X-ray analysis of DNA fibers, (f) model building and theoretical treatment of all data obtained. In this article, the factors promoting and inhibiting scientific progress in this field are described (and, above all, the relations between scientists with fixated concepts). The results from these lines of research led to the recognition of the decisive role of nucleic acids as the carriers of genetic information and, in this way, formally established the 'nucleic acid paradigm'. Finally the question is discussed why Watson and Crick found the right solution for the DNA structure (and not one of their competitors). PMID- 18447192 TI - [The establishment of psychiatric genetics in Germany, Great Britain and the USA, ca. 1910-1960. To the inseparable history of eugenics and human genetics]. AB - The article reconstructs the emergence of institutionalized research programs in the field of psychiatric genetics. It focuses on the first institutions in this field in Germany, the United Kingdom, and the United States: the Genealogisch Demographische Abteilung (GDA) at the Deutsche Forschungsanstalt fur Psychiatrie in Munich founded in 1917/18; the Program (later: Department) of Medical Genetics at the New York State Psychiatric Institute, associated with Columbia University, and founded in 1936; and the Psychiatric Genetics Unit at the Institute of Psychiatry in London, founded in 1959. The early protagonists which today are considered the founding-fathers of this field in Britain and the USA, Eliot Slater and Franz Kallmann, both had been research fellows at the Munich GDA in the mid-1930s which at that time was directed by Ernst Rudin. Rudin was perceived as the leading personality in the field internationally; at the same time, he was one of the protagonists of the German movement of eugenics and racial hygiene, and after the Nazi-takeover in 1933 closely co-operated with the regime in regard to health and racial policies. The contribution documents that not only Rudin, but also Kallmann and Slater throughout their career in medical genetics until the 1960s were motivated by eugenic ideas, and engaged in eugenic organisations, however, with different consequences, and in different political contexts. It is further argued that these eugenic motivations had repercussions on the topics and questions pursued in the protagonists' genetic research. PMID- 18447193 TI - [Without sense and understanding? Rudolf Virchow's strategy of collecting by the example of his pathological museum]. AB - The Berlin pathologist Rudolf Virchow (1821-1902) has been called a "m anic" collector in the most recent studies on the history of science and culture because of his collection of over 23,000 pathoanatomical wet and dry specimens. A closer look at Virchow's collecting efforts, however, reveal that there was system behind the relative abundance of objects. This contribution will attempt to reconstruct Virchow's collection concept as well as his ideas about a meaningful arrangement of the specimens in the museum he founded in 1899. The study follows a reference of Virchow's to the corresponding specimen collections in the English hospital schools, which Virchow had always seen as exemplary. In this connection, the strategies and concepts of the British pathologist Thomas Hodgkin (1798-1866) will be investigated more closely as they relate to the specimen collection he administered at Guy's Hospital in London. There, abnormally changed organ specimens were presented along the two axes of anatomy and nosology. Virchow encountered this practice under the Charite prosector, Robert Froriep (1804-1861), where he experienced his socialization as collector and presenter in pathology between 1844 and 1847. In his second Berlin phase between 1856 and 1902, he expanded his institute at the Charite to a worldwide renowned center for pathology. During this time, Virchow added a third dimension to his collection strategy under the heading "progression", in order to document whole series in the developmental process of all diseases in all primarily and secondarily affected organs. After the opening of his Pathological Museum on the grounds of the CharitY, he strove until his death to arrange his specimens in the form of a three-dimensional textbook. Various structural conditions, a dearth of exhibition cases, as well as his decreasing vitality limited the scope of Virchow's achievements. The most essential reason why Virchow realized only a small portion of his exhibition concept, however, lay in the sheer endlessness of diseases to be portrayed in their being and manifestation. PMID- 18447194 TI - No evidence for MMR-ASD link. PMID- 18447195 TI - Which patients with vaginal discharge should be referred? PMID- 18447197 TI - Managing women with pelvic organ prolapse. PMID- 18447198 TI - Diagnosis vital in ectopic pregnancy. PMID- 18447199 TI - Future lines of treatment. 1908. PMID- 18447200 TI - Hand problems. PMID- 18447202 TI - Exploring Scotland's influenza pandemic of 1918-19: lest we forget. AB - The 1918-1919 influenza pandemic resulted in more deaths than any other medical event in human history; the most recent scholarship puts the death toll worldwide at 100 million. Scotland suffered a proportionate loss of life but it was little reported at the time and has been little studied by social historians since. The Great War had been such a traumatic experience that the authorities, and the general public, could take no more tragic news and the result was an uncanny silence. There is little information on the way in which people were affected by the pandemic. Such information could now be valuable as we plan a response to a pandemic of avian flu. This article aims to initiate study of an important episode in healthcare in Scotland. PMID- 18447203 TI - Benjamin Franklin's place in the history of medicine. AB - Benjamin Franklin's seemingly endless curiosity and his prolific contributions in diplomacy, politics, literature, and science may well justify calling him the most eminent man in eighteenth-century American life. One portion of these contributions still striking for the insights and productivity it shows was in medicine. He saw the value in inoculation against smallpox. He was aware of the placebo effect. He, in effect, launched the first American medical school. He devised a flexible urethral catheter. He identified lead poisoning as a cause of abdominal pain and peripheral neuropathy. He accurately described psoriasis well before RobertWillan. These contributions in medicine of his time were not then notably influential, but they certainly illustrate the versatility of his intellect. PMID- 18447204 TI - [Diagnosis and treatment of pulmonary aspergillosis. Role of voriconazole (discussion)]. PMID- 18447205 TI - [Prediction on the efficacy of fluoroquinolones for anaerobic infections using Monte Carlo simulation]. AB - Various analysis based on PK-PD (pharmacokinetics-pharmacodynamics) theory were performed for prediction on the efficacy of antimicrobial agents for infectious diseases. However, there have been few reports when causative organisms would be anaerobic bacteria. Although the antimicrobial activity of fluoroquinolones against anaerobes has been weak, gatifloxacin (GFLX), moxifloxacin (MFLX), and garenoxacin (GRNX) are considered as anti-anaerobic quinolones in recent days. Therefore, we investigated prediction on the efficacy of fluoroquinolones for anaerobic infections using Monte Carlo Simulation. Although the target attainment of fluoroquinolones (levofloxacin, GFLX, and MFLX) on AUC/MIC value has not established yet, we have assumed 40 and 125 as the target attainment of AUC/MIC value. GFLX and MFLX would be effective against anaerobic infections caused by Prevotella intermedia, Fusobacterium nucleatum, Micromonas micros, which are the causative organisms for respiratory tract infections. From these results, GFLX and MFLX would be effective against anaerobic infections in respiratory tract as anti-anaerobic fluoroquinolones. PMID- 18447207 TI - [Antimicrobial activity of meropenem against main bacterial species isolated from patient blood in 2006]. AB - Using broth micro-dilution method, we studied the susceptibility of 180 clinical isolates of Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis to meropenem (MEPM) and reference agents. All strains were isolated from the blood of patients admitted to Keio University Hospital between January 2006 and November 2006. The results were as follows: 1. MEPM showed greater potency against Gram-negative bacteria than the other carbapenems including doripenem in particular. A metallo-beta-lactamase producing multi-drug resistant P. aeruginosa strain was detected. 2. A comparison of the antibacterial activity of MEPM with that in our previous studies 1997-1998, 1999, 2002-2003, and 2004 showed no marked increase in MEPM-resistant clinical isolates. These results suggest that MEPM retains its potency as the agent of choice in treating serious infections. PMID- 18447206 TI - [Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2006]. AB - The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 876 strains of Gram-positive bacteria, 1764 strains of Gram-negative bacteria, and 198 strains of anaerobic bacteria obtained from 30 medical institutions during 2006 was measured. The results were as follows; 1. MEPM was more active than the other carbapenem antibiotics tested against Gram negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MEPM was also active against most of the species tested in Gram positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus. 2. As for Pseudomonas aeruginosa, all of the MEPM-resistant strains were resistant to imipenem (IPM). MEPM showed low cross-resistant rate both againt IPM-resistant P. aeruginosa (41.8%) and ciprofloxacin-resistant P. aeruginosa (33.3%). 3. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 4.3% (6 strains) in Escherichia coli, 1.1% (1 strain) in Citrobacter freundii, 21.7% (5 strains) in Citrobacter koseri, 3.1% (4 strains) in Klebsiella pneumoniae, 3.3% (3 strains) in Enterobacter cloacae, 0.8% (1 strain) in Serratia marcescens, and 4.9% (2 strains) in Providencia spp. The proportion of metallo-beta-lactamase strains was 3.1% (10 strains) in P. aeruginosa. 4. Of all species tested, there were no species, which MIC90 of MEPM was more than 4-fold higher than those in our previous study. Therefore, there is almost no significant decrease in susceptibility of clinical isolates to meropenem. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem at present, 11 years after available for commercial use. PMID- 18447208 TI - [Investigation on optimal regimen of ceftazidime against infection caused by Pseudomonas aeruginosa using Monte Carlo simulation]. AB - An optimal regimen for the use of ceftazidime (CAZ) (one of injectable antimicrobial agents in cephem family) against Pseudomonas aeruginosa infection was explored, using Monte Carlo simulation. Pharmacokinetic parameters needed for Monte Carlo simulation were derived from the existing data for healthy adults, and the data on MIC distribution of CAZ against clinically isolated bacterial strains reported by Working Group of Forum on Microbial Resistance. When CAZ was used within the currently approved dosage and administration for adults (4 g/day at maximum), intravenous administration of CAZ, 1 g, t.i.d., per day was found to have the highest probability to achieve the target of maximum bactericidal activity for cephems, i.e., 60-70%T > MIC (time above MIC). The probability to achieve the same target was the second highest with two intravenous CAZ, 2 g, b.i.d., per day, and third with CAZ, 1 g, b.i.d., per day. These results suggest that when treating P. aeruginosa infection with CAZ, for which T > MIC serves as PK/PD parameter, increasing the frequency of dosing is effective method to reinforce its efficacy, and that CAZ, t.i.d., per day is an optimal dosage and administration within the range of the regimens described in its package insert. PMID- 18447209 TI - [Analysis on the effective dosage regimens for meropenem, biapenem and doripenem against P. aeruginosa infection based on pharmacokinetics and pharmacodynamics theory]. AB - Recently, PK/PD (pharmacokinetics/pharmacodynamics) analysis for the antimicrobial dosage method became one of the popular categories in chemotherapy and infectious disease societies world wide. Carbapenems are often used for empiric therapy because of its broad-spectrum and activities against microorganisms. PK/PD analysis is well studied in some antibiotics including carbapenems and it is necessary also from the point of view of prevention for emergence of resistant strains. We report the result of the analysis for the effective dosage regimens of meropenem, biapenem and doripenem against Pseudomonas aeruginosa infection based on PK/PD theory with the MIC distributions against the strains isolated from the patients blood at Keio University in 2004 and 2006. The highest target attainment rate for the free drug 40% time above the MIC (40%T > or = MIC) in traditional infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2004 was as follows: 90.89% in 500 mg every 6 hours regimen for meropenem, 83.25% in 300 mg every 6 hours regimen for biapenem, 81.73% in 250 mg every 6 hours regimen for doripenem in the approved maximum daily dose for each agent. The highest target attainment rate for the free drug 40%T > or = MIC in prolonged infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2004 was as follows: 100% in 500 mg every 6 hours regimen for meropenem, 83.97% in 300 mg every 8 hours regimen for biapenem, 99.98% in 500 mg every 8 hours regimen for doripenem in the maximum daily dose for each agents. The highest target attainment rate for the free drug 40%T > or = MIC in traditional infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2006 was as follows: 80.57% in 500 mg dose in every 6 hours regimen for meropenem, 56.70% in 300 mg every 6 hours regimen for biapenem, 69.44% in 250 mg every 6 hours regimen for doripenem in the maximum daily dose for each agent. The highest target attainment rate for the free drug 40%T > or = MIC in prolonged infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2006 was as follows: 89.35% in 500 mg every 6 hours regimen for meropenem, 60.84% in 300 mg every 6 hours regimen for biapenem, 82.78% in 500 mg every 8 hours regimen for doripenem in the maximum daily dose for each agent. The target attainment rates for the free drug Css/MIC > or = 1 with continuous infusion were lower than the target attainment rates for the free drug 40%T > or = MIC in the regimens of prolonged infusion intermittent dose regimens in all three agents using both of the MIC distributions against P. aeruginosa in 2004 and 2006. The result of the PK/PD analysis for meropenem, biapenem and doripenem indicated that intermittent dose with prolonged infusion was the best method to obtain higher target attainment rate. PMID- 18447210 TI - [Randomized controlled observation on head point-through-point therapy for treatment of insomnia]. AB - OBJECTIVE: To observe the therapeutic effect of head point-through-point therapy on insomnia and to probe the mechanism. METHODS: Seventy-one cases of insomnia were randomly divided into a head penetration needling group (n=36) and a routine acupuncture group (n=35). In the head penetration needling group, Shenting (GV 24)-through-anterior Shencong (EX-HN 1), bilateral Toulinqi (GB 15)-through bilateral Shencong (EX-HN 1), posterior Shencong-through-Qiangjian (GV 18) were selected; and in the routine acupuncture group, Baihui (CV 20), Yintang (EX-HN 3), Sishencong (EX-HN 1), Neiguan (PC 6), etc. were selected. After treatment of 30 days, their therapeutic effects, cumulative scores of Pittsburgh Sleep Quality Index (PSQI) and plasma serotonin contents before and after treatment were compared. Results The total effective rate of 91.7% in the head penetration needling group was better than 77.1% in the routine acupuncture group (P < 0.05), and the improvement of sleep quality, falling asleep time and the total cumulative score of PSQI in the head penetration needling group was superior to that in the routine acupuncture group (P < 0.05), and plasma serotonin was significantly increased in the head penetration needling group with a significant difference as compared with that in the routine acupuncture group (P < 0.05). CONCLUSION: The therapeutic effect of head penetration needling is better than that of the routine acupuncture, and the mechanism is related with regulation of serotonin metabolism. PMID- 18447211 TI - [Controlled study on needle-pricking therapy combined with spinal massage for treatment of ankylosing spondylitis]. AB - OBJECTIVE: To observe the therapeutic effect of needle-pricking therapy combined with spinal massage on ankylosing spondylitis and to probe into the mechanism. METHODS: Ninety-three cases who were definitely diagnosed as having ankylosing spondylitis at active stage were randomly divided into a medication group (n=46) and an observation group (n=47). The observation group were treated by needle pricking the main points, Neck No. 2 nerve, Neck No. 5 nerve point, etc., combined with spinal rotation massage, and the medication group were treated with Azulfidine. Changes of cumulative score of arthralgia and arthroncus, function of joint, Keitel test, and ESR and CRP before and after treatment were observed. RESULTS: The effective rate and the markedly effective rate were 95.8%0 and 68.1% in the observation group and 78.3% and 23.9% in the medication group, respectively, the former being significantly better than the latter (P < 0.01). CONCLUSION: Needle-pricking therapy combined with spinal massage has a significant therapeutic effect with a steady and long-term effect for treatment of ankylosing spondylitis at active stage. PMID- 18447212 TI - [Assessment of effectiveness of electroacupuncture and fluoxetine for treatment of depression with physical symptoms]. AB - OBJECTIVE: To study on clinical therapeutic effect and safety of electroacupuncture and Fluoxetine for treatment of mild or moderate depression with physical symptoms. METHODS: Seventy-five cases were randomly divided into a western medicine group (group A), an electroacupunctue group(group B) and an electroacupuncture plus medicine group (group C), 25 cases in each group. The group A were treated by oral Fluoxetine, 20 mg each day; the group B by electroacupuncture with Baihui (GV 20) and Yintang (EX-HN 3) selected as main points; the group C by oral administration of Fluoxetine plus electroacupunctue. HAMD depression scale was used for assessment of clinical therapeutic effect and TESS adverse reaction scale was used for adverse reactions. RESULTS: The clinical effective rate was 78.3% in the group A, 82.6% in the group B and 91.7% in the group C, with significant differences between group C and A, group C and B (P < 0.05). Groups B and C had significant therapeutic effects in improvement of physical symptoms, and the adverse reaction of Fluoxetine in the group C was less than that in the group A. CONCLUSION: Electroacupuncture can significantly improve physical symptoms and relieve adverse reactions of Fluoxetine. Electroacupuncture combined with Fluoxetine has a better therapeutic effect on depression with mild or moderate physical symptoms, with less adverse reactions. PMID- 18447213 TI - [Clinical observation on treatment of cerebral infarction-induced broca aphasia by Tiaoshen Fuyin acupuncture therapy combined with language training]. AB - OBJECTIVE: To observe therapeutic effect of Tiaoshen Fuyin acupuncture therapy on cerebral infarction-induced Broca aphasia. METHODS: Sixty cases were randomly divided into an observation group and a control group, 30 cases in each group. The observation group were treated with Tiaoshen Fuyin acupuncture therapy and language training, and the control group with simple language training. For the acupuncture treatment, Sishencong (EX-HN 1), Benshen (GB 13), Shenting (GV 24), Lianquan (CV 23), Xinshu (BL 15), Shentang (BL 44), Shendao (GV 11), Lingtao (HT 4) were selected and language training included training of phonatory organs in mouth, the mouth shape, sound, spoken language expression and practical exchange ability. They were treated for 5 therapeutic courses. Language examination was conducted once each before and after treatment with "Aphasia Battery of Chinese" (ABC method). RESULTS: The therapeutic effect of Tiaoshen Fuyin acupuncture therapy combined with language training was better than that of simple language training. CONCLUSION: Tiaoshen Fuyin acupuncture therapy combined with language training can significantly improve language function and increase life quality in the patient of cerebral infarction-induced Broca aphasia. PMID- 18447214 TI - [Effects of acupuncture on gastrointestinal responses after renal transplantation]. AB - OBJECTIVE: To observe the effect of acupuncture on gastrointestinal responses after renal transplantation. METHODS: Sixty cases with gastrointestinal responses after renal transplantation were randomly divided into an acupuncture group and a medication group, 30 cases in each group. The acupuncture group were treated with acupuncture at Neiguan (PC 6), Zusanli (ST 36), Sanyinjiao (SP 6), etc.; the medication group were treated with oral administration of Weilexin. The symptoms of abdominal pain, nausea, gastric distention, and other gastrointestinal responses were observed in the two groups. RESULTS: The effective rate was 93.3% in the acupuncture group and 76.7% in the medication group with a very significant difference between the two groups (P < 0.01), the acupuncture group being significantly better than the medication group. CONCLUSION: Acupuncture has a good effect of promoting recovery of gastrointestinal function after renal transplantation. PMID- 18447215 TI - [Observation on clinical therapeutic effect of point sticking therapy on hyperplasia of mammary glands]. AB - OBJECTIVE: To compare therapeutic effects of point sticking therapy and Chinese herbs on hyperplasia of mammary glands. Methods Sixty-three female patients with hyperplasia of mammary glands were randomly divided into an observation group (n=33) and a control group (n=30). The observation group were treated with point sticking therapy, i.e., Sanleng (Rhizoma Spargani), Ezhu (Rhizoma Zedoariae), Zhi Nanxing (Pedate Pinallia Jackinthepulpit Rhizome) and Bingpian (Borneolum) were made a plaster to apply Qihai (CV 6), Guanyuan (CV 4) and Ashi points on breast. The control group were treated with oral administration of Rupixiao. RESULTS: After treatment of 3 courses, the total effective rate was 97.0% in the observation group, and 83.3% in the control group, the former significantly being better than the latter (P < 0.05). The score of mastalgia improvement was (13.82 +/- 5.90) points in the observation group and (7.00 +/- 3.89) points in the control group with a very significant difference between the two groups (P < 0.01). CONCLUSION: ooint sticking therapy has a definite therapeutic effect n hyperplasia of mammary glands. PMID- 18447216 TI - [Electroacupuncture for treatment of simple obesity complicated with fatty liver]. AB - OBJECTIVE: To observe clinical therapeutic effect of electroacupuncture (EA) on simple obesity complicated with fatty liver. METHODS: Thirty cases of such disease were treated with EA at Zhongwan (CV 12), Tianshu (ST 25), Qimen (LR 14), Daimai (GB 26), Yanglingquan (GB 34), etc.. After treatment of 3 months, the therapeutic effect and changes of B-ultrasonography of liver, body weight (BW), body mass index (BMI), fat degree, visceral fatty (VFT) content in the cross region, subcutaneous fat (FAT), waist/hip ratio (WHR) were investigated. RESULTS: After treatment, the total effective rate for slimming was 80.0% and the total effective rate for fatty liver was 80.0%, and body weight, BMI, fat degree, VFA, FAT and WHR significantly decreased (P < 0.01). CONCLUSION: Electroacupuncture has good slimming action and it is one of effective methods for fatty liver. PMID- 18447217 TI - [Acupuncture at Siguan points for treatment of primary dysmenorrhea]. AB - OBJECTIVE: To observe the therapeutic effect of acupuncture at Siguan points with Qinglong Baizei method on primary dysmenorrhea (PD) and to study the mechanism. METHODS: One hundred and eighty cases of PD were zandomly divided into group A, group B and group C, 60 cases in each group. Group A were treated by acupuncture at Hegu (LI 4) and Taichong (LR 3) with Qinglong Baiwei method; group B were treated by routine acupuncture with Sanyinjiao (SP 6), Ciliao (BL 32) selected as main points; and group C were treated by oral administration of Yueyueshu Decoction. After treatment of 3 months, the therapeutic effects were analyzed, and changes of hemorrheological indexes and prostaglandin level were observed. RESULTS: The cured rate and the total effective rate were 75.0% and 100.0% in group A, 60.0% and 95.0% in group B, and 25.0% and 90.0% in group C, respec tively, group A and B being significantly better than group C (P < 0.01). And the analgesic effects within 30 min of treatment in both group A and group B were significantly better than that in group C (P < 0.01), and that in group A was significantly better than that in group B (P < 0.01). CONCLUSION: Acupuncture at Siguan points with Qinglong Baiwei method has a significant therapeutic effect on primary dysmenorrhea. The possible mechanism is to relieve pain by improving blood circulation and inhibiting production of prostaglandin. PMID- 18447218 TI - [Clinical observation on strong stimulation of acupoints around eyes for treatment of adolescent myopia]. AB - OBJECTIVE: To observe the therapeutic effect and influential factors of strong stimulation of acupoints around eyes by reducing method of twisting the needle for treatment of adolescent myopia, and to compare the different curative effects of both weak and strong stimulus intensities and wearing glasses in daytime. METHODS: According to the principle of knowing and permission, the patients were divided into a strong stimulation group (60 cases, 120 eyes), a weak stimulation group (60 cases, 120 eyes) and a wearing glasses group (60 cases, 120 eyes). Both the strong stimulation group and the weak stimulation group were treated by reducing method of twisting the needle, with Cuanzhu (BL 2), Yuyao (EX-HN 4), Sizhukong (TE 23), Sibai (ST 2) and Taiyang (EX-HN 5) selected. Each acupoint was twisted 360 and 90 times per min for the strong stimulation group, and 90 degrees and 60 times per min for the weak stimulation group; the wearing glasses group were not treated with acupuncture, but with wearing glasses in daytime. RESULTS: After treatment with the reducing method of twisting the needle, the vision improved (P < 0.01), with more obviously increased in the strong stimulation group than the weak stimulation group (P < 0.01), and there was no significant change of vision in the wearing glasses group. The age and the myopic degree of the patient before treatment were closely related with the change of vision after treatment (P < 0.01). CONCLUSION: The reducing method of twisting the needle has a definite clinical therapeutic effect on adolescent myopia; strong stimulation has a better effect than the weak one; the age and the myopic degree of the patient possibly influence the therapeutic effect. PMID- 18447219 TI - [Clinical observation on drug-separated moxibustion at Shenque (CV 8) for treatment of infantile autumn diarrhea]. AB - OBJECTIVE: To observe therapeutic effect of drug-separated moxibustion at Shenque (CV 8) for treatment of infantile autumn diarrhea. METHODS: One hundred and thirty-six cases were randomly divided into an obser vation group and a control group, 68 cases in each group. The observation group were treated with drug separated moxibustion at Shenque (CV 8) and the control group with oral administration of Smecta. The mean diarrhea-stopping time, the negative conversion rate of Human Rotavirus antigen in stool after treatment for 72 h, and the markedly-effective rate and the total effective rate were observed after treatment for 6 days in the twO groups. RESULTS: The markedly-effective rate and the total effective rate were 79.4% and 94.1% in the observation group and 35.3% and 75.0% in the control group, respectively, with very significantly or significantly difference between the two groups (P < 0.01 or P < 0.05); the mean diarrhea-stopping time in the observation group was shorter than that in the control group (P < 0.01); the negative conversion rate of Human Rotavirus antigen in stool after treatment for 72 h was 88.2%0 in the observation group and 69.1% in the control group with a very significantly difference between the two groups (P < 0.01). CONCLUSION: Drug-separated moxibustion at Shenque (CV 8) has a significant therapeutic effect on infantile autumn diarrhea, helps negative conversion of Human Rotavirus antigen in stool and shortens duration of disease. PMID- 18447220 TI - [Original relations of acupoints with channels-collaterals and acupuncture therapy]. AB - With analysis and systematization of ancient medical books being unearthed Mazoangdui tomb and other literatures, it is found that ancient names and meanings of moxibustion and acupuncture parts passed the courses from Mai to Maikou, the place and region above Mai, then to acupoints on the body surface showing channels, gi and blood. This change trace reveals original relationship acupoints with channels-collaterals, and acupuncture therapy. The acupoint is a point and channels-collaterals are lines, except a less acupoints which located by obvious anatomic markers, most of are special parts on the channels and collaterals, are not a isolated point. The acupoint is the gate of needle inserting the human body, proposal of this concept and increase of the number of acopoints are closely related with invention, popularity and spreading of acupuncture therapy. PMID- 18447221 TI - [Try to discuss manipulation of the "Feijing Zouqi" needling technique]. AB - Based on description of "Feijing Zouqi" needling methods in Jin Zhen Fu (Rhyme Prose of Golden Needle) written by Xu Feng, and explain and analyze the descriptions of "Feijing Zouqi" needling method in Zhenjiu Juying (A Collection of Gems in Acu-Moxibustion) written by Gao Wu, Zhenjiu Wendui written by Wang Ji, Zhenjiu Dacheng (Great Compendium on Acu-Moxibustion) written by Yang Ji-zhou, Yixue Rumen (Elementary Medicine) written by LI Chan and many other works, summarize the technique characteristics of all the "Feijing Zouqi" needling methods. The characteristic of "Qinglong Baiwei" needling method is " first toward the left, then toward the right, slowly move or adjust with the hand"; and "Baihu Yaotou" needling method emphasizes "Tuifang Jinyuan" and "Yaozhen "; key point of "Canggui Tanxue" needling method is "Zuanti Sifang"; Chifeng Yingyuan" needling method emphasizes "Siwei Feixuan". PMID- 18447222 TI - [Observation on therapeutic effect of three needling method on piriformis injury syndrome]. AB - OBJECTIVE: To search for an effective needling method for treatment of piriformis injury syndrome. METHODS: Eighty-two cases were randomly divided into a three needling group and a routine needling group, 41 cases in each group. The three needling group were treated by acupuncture at Huantiao (GB 30), Yanglingquan (GB 34) and Shenmai (BL 62), with needling shallow, middle and deep layers for Huantiao, Yanglingquan, and after acupuncture massage was given at the Foot Taiyang Channel and the Foot-Shaoyang Channel on lumbosacral region and the affected foot. The routine needling group were treated by routine needling at Huantiao (GB 30), Juliao (GB 29), Chengfu (BL 36), Yanglingquan (GB 34), massage was given also. Their therapeutic effects were compared. RESULTS: The cured rate was 87.8% in the three needling group and 63.4% in the routine needling group, with a significant difference between the two groups (P < 0.05). CONCLUSION: The therapeutic effect of three needling method on piriformis injury syndrome is better than that of routine needling. PMID- 18447223 TI - [The role of collagen fiber in "Zusanli" (ST 36) in acupuncture analgesia in the rat]. AB - OBJECTIVE: To probe into the mechanism of acupuncture analgesia. METHODS: Type-I collagenase was injected to destroy the structure of collagen fibers in the acupoint. Paw withdrawing latency and mast cell degranulation rate in the acute adjuvant arthritis rat were investigated. Effects of acupuncture at "Zusanli" (ST 36) with twirling or thrusting-lifting manipulation on acupuncture analgesia and mast cells were compared when the structures of collagen fibers in the acupoint were destroyed or not. RESULTS: When the structures of collagen fiber were destroyed, the analgesic effects of both acupuncture manipulations were attenuated and the degranulation rate of mast cells caused by acupuncture were significantly inhibited. CONCLUSION: Collagen fibers and mast cells in the acupoint play an important role in acupuncture analgesia. Collagen fibers participate in transmission and transform process of acupuncture signs from the acupoint to the target organ, and the degranulation of mast cells is positively correlated with acupuncture analgesia. PMID- 18447224 TI - [Effects of electroacupuncture on behavior, plasma COR and expressions of PKA and PKC in hippocampus of the depression model rat]. AB - OBJECTIVE: To probe into the mechanism of acupuncture for treatment of depression. METHODS: Thirty-two healthy SD male rats were randomly divided into a normal group, a model group, an electroacupuncture (EA) group and a Maprotiline group. The depression rat model was made in the latter three groups, and from the second day of the experiment EA was given at Baihui (GV 20), "Yintang" (EX-HN 1), "Zusanli" (ST 36) and "Fenglong" (ST 40) in the EA group, once every other day; the rats in the Maprotiline group were treated with oral administration of Maprotiline hydrochroride, once each day. After treatment of 3 weeks, changes of behaviors, plasma cortisol (COR) level and expressions of protein kinase A (PKA) and protein kinase C (PKC) in hippocampus were observed in the rats. RESULTS: In the depression model rats, the body weight increased slowly, and horizontal and vertical activities and consumption of sugar liquid significantly decreased; plasma cortisol content significantly increased; expressions of PKA and PKC in the hippocampus significantly reduced. In the rats of EA group, the score of behaviors, the consumption of sugar liquid and the increase of body weight were not significantly different to those in the model group, but the plasma cortisol level significantly decreased and closed to the normal level, and positive expressions of PKA and PKC in the hippocampus could be effectively reversed. In the Maprotiline group, the consumption of sugar liquid significantly increased and plasma cortisol level significantly decreased, and expressions of PKA and PKC in the hippocampus increased as compared with those in the model group. CONCLUSION: The depression model rat has dysfunction of the hypothalamus pituitary-adrenal axis (HPAA) and EA can regulate functions of HPAA. The mechanism is possibly carried out by regulating functions of relative enzymes in the signal transduction pathway in hippocampal cells. PMID- 18447225 TI - [Analgesic effect of transcutaneous electrical acupoint stimulation combined with target-controlled infusion in general anesthesia and effects on cardiovascular system]. AB - OBJECTIVE: To observe analgesic effect of transcutaneous electrical acupoint stimulation combined with target-controlled infusion (TCI) in general anesthesia and effects on cardiovascular system. METHODS: Sixty selective breast operation patients were randomly divided into a combined group and a TCI group, 30 cases in each group. The combined group received anesthesic induction for 30 min with transcutaneous electrical acupoint stimulation and then TCI into vein for general anesthesia, and the transcutaneous electrical acupoint stimulation was continued till the end of the operation. The TCI group only received TCI irito vein for general anesthesia. The target-controlled concentration of the general anesthesia drugs in plasma was monitored to evaluate the analgesic effect of transcutaneous electrical acupoint stimulation. Meanwhile, the effects of the transcutaneous electrical acupoint stimulation on cardiovascular system were investigated. RESULTS: The mean Propofol and Fentany dosages needed were 226.67 mg and 0.11 mg in the combined group, and 272.22 mg and 0.14 mg in the TCI group during the operation, respectively, with significant differences (P < 0.05 or P < 0.01). The changes of heart rate and blood pressure in the combined group during skin cutting were significantly less than those in the TCI group (P < 0.05). The awaking time in the combined group was significantly shortened. CONCLUSION: The transcutaneous electrical acupoint stimulation has a certain analgesic effect in the operation and can reduce 17% Propofol dosage and 14% Fentany dosage, and it can decrease the skin-cutting-induced stress reaction of the cardiovascular system and accelerate waking. PMID- 18447226 TI - [Talking about "moxibustion treatment for before sick" from "ischemic preconditioning"]. AB - "Treatment for before sick" is a theory of TCM, reflecting preventing thought of "prevention being better than cure" and "nipping in the bud", while "moxibustion treatment for before sick" is highly praised by doctors of past ages. Moxibustion can activate human vital-qi and increase immunologic function of the organism, playing a preventive role for before sick, which is similar to the essence of "ischemic preconditioning" raised in recent years. Because of convenient manipulation, no adverse effect, it has very important position in the field of preventive medicine. PMID- 18447227 TI - [Professor Wu Bing-huang's experiences in acupuncture treatment of facial paralysis]. AB - Professor WU Bing-huang's unique experiences in acupuncture treatment of facial paralysis are introduced. He excellently uses anatomical and pathological knowledge of facial nerves, selecting acupoints according to nervous distribution, selecting needling methods according to the nervous trend, selecting acupuncture stimulation amount according to pathological changes and judging prognosis according to affected position. PMID- 18447228 TI - [Present situation and thinking of traditional Chinese medicine and acupuncture in Australia]. AB - Victoria of Australia is the first state that legislated for TCM independently in western countries. The state as well as Australia have remarkable achievements in regular management of TCM and acupuncture practices, education and scientific researches in TCM, professional association, etc. after Chinese Medicine Registration Act 2000. The author of this paper introduces the characteristics in such aspects as TCM legislations, management of practical registration, professional education, professional association and medical insurance, etc. in Australia through the personal experiences as a Chinese acupuncturist practiced in Australia, and puts forward some impressions and suggestions. PMID- 18447229 TI - [Study on treatment of flaccidity from the Governor Vessel]. AB - The relationship of affected regions, cause of disease, pathogenesis of flaccidity with physiological functions of the Governor Vessel is expounded, indicating that "skin, muscle, tendon, vessel and joint" are basic structures of performing motor function of the organism, which depend on nourishing of qi, blood, body fluid, essence and marrow; "insufficiency of essence and marrow" and "deficiency of qi and blood" are keys of pathogenensis of flaccidity; "deficiency or obstruction of the Governor Vessel" and "yang of the Governor Vessel unable to function" are the basis of channels and collaterals for flaccidity attack. Clinically, regulation of the Governor Vessel can promote repair of morphosis and functions of the Governor Vessel (brain and spinal cord), and rebuilding of the regulative system of the brain-the Governor Vessel (spinal cord)-viscera channels, qi and blood functional activities, so as to restore the normal distribution and transduction of qi, blood, body liquid, essence and marrow to nourish skin, muscle, tendon, vessel and joint. PMID- 18447230 TI - [Probing into origination of the Governor Vessel from recording of Taisu]. AB - Based on the recording of the Governor Vessel in Taisu (Commentary on Huang di's Internal Classic), deeply analyze and probe cognition and feature of the Governor Vessel in Taisu, and compare with other related literatures in Huangdi's Internal Classic and Classic on 81 Medical Problems, discovering that cognition of the Governor Vessel in Taisu is more early than the theory of the Governor Vessel handed down from ancient times, infer that the Governor Vessel recorded in Taisu possibly is early model of the theory of the Governor Vessel handed down from ancient times. Further studies discover that cognition of the Governor Vessel in Taisu is related with clinical practice of "spinal cord method", which possibly is clinical basis of origination of the Governor Vessel. PMID- 18447231 TI - Study: wait times continue to lengthen--visits increase as EDS disappear. AB - Despite seemingly insurmountable odds, several ED managers have been able to reduce wait times--in many cases, quite dramatically. Here are some of the strategies they say will help you decrease those waiting times: Create a chest pain policy that focuses not only on getting patients back as quickly as possible, but also frontloads your work force. Encourage staff to bring EKG results to the ED doc as soon as they are obtained. When seeking important hospitalwide changes, remind your board of the political consequences of a poor ED image. PMID- 18447232 TI - Consultant, more staff lead to ED turnaround. AB - Process improvement changes can reduce wait times, length of stay, patients who left without being seen, and significantly boost your patient satisfaction scores. Here are some important lessons learned by the ED team at Cape Fear Valley Medical Center in Fayetteville, NC: If you are using an outside consultant, visit the facility of one of their clients to see if their approach has been successful. Divide your staff into teams, each of which is assigned a specific zone in your department. Employ informatics to organize and maintain control over your new processes. PMID- 18447233 TI - Streamlined process cuts time to triage in half. AB - The two EDs in the Children's Healthcare of Atlanta have reduced their time to triage by 50% by eliminating assessment steps they considered nonessential. An ED leadership team, including assistant managers, administrative resource nurses, educators, trauma coordinators, managers, and physicians, reviewed the existing process. Steps eliminated included obtaining vital signs, conducting a full neurological assessment, using the stethoscope, or initiating procedures such as pain control or fever meds. The process was piloted with a select group of staff. PMID- 18447234 TI - Mobile unit helps ED cut LWBS in half. AB - One viable option for reducing the stress on an overburdened ED is the leasing of a mobile unit. For a relatively modest cost, it can be used as a fast-track department, as the ED at Jefferson Memorial Hospital in Ranson, WV, is doing. The unit at Jefferson is staffed by a registered nurse, a nurse practitioner, and a technician who floats between the mobile unit and the main ED. The mobile care unit has four beds and also is equipped with computers, a medication dispensing system, and monitors to view digital X-rays. The triage nurse determines whether a patient goes to the mobile unit or the main ED. PMID- 18447235 TI - Process improvement helps PCP relations. AB - The ED at Doctors Hospital in Columbus, OH, has replaced a simple clipboard with a formal process for responding to calls from family physicians seeking to have their patients admitted. They have also instituted a 30-minute guarantee for those patients. Here are some of the strategies they used. An orange-colored sheet is filled out by the ED physician and copied to the other "pod" areas in the department. The bottom half of the sheet is attached to the grease board to alert other staff. ED docs must check off boxes indicating they have followed the required process steps. PMID- 18447236 TI - 'ED of the future' girded for disasters. AB - Optimizing your ED to deal with mass disasters can also help make your current patients comfortable. Here are some changes instituted at Washington (DC) Hospital Center as part of its "Bridge to ER One" initiative: Patient rooms are oversized so that in a disaster they will be able to accommodate two patients. "ER One" rooms each have a shower and toilet, to avoid the contamination spread of common facilities. Rubber floors reduce stress and fatigue for staff members and ambulatory patients. PMID- 18447237 TI - Is 'non-pay for non-performance' a wave of the future of health care? AB - Failing to follow proper safety procedures can cost you big bucks. Experts predict financial penalties for poor safety will become more common in the future. Hospital association supports the move, as long as new public health power is not abused. PMID- 18447239 TI - Docs, paramedics using new two-way video link. AB - Visuals of patients and accident scene help docs communicate with paramedics. Some paramedics are resentful of the 'big brother' aspects of the new system. City of Tucson matches federal grant in order to make program a reality. PMID- 18447238 TI - Six Sigma CAP initiative reduces mortalities. AB - Compliance Joint Commission CAP core measures improved by 70% to 90%. Methodology helps team identify critical processes and key stakeholders, and to track results. Early positive data, proactive education efforts help sway initially reluctant physicians. PMID- 18447240 TI - Majority of hospitals won't bill for 'never events'. AB - Policy also includes apologies, reporting events to agencies such as The Joint Commission. What are considered normal customer service practices in other industries are 'radical' in health care. Risk manager says 'doing the right thing' also can help reduce your hospital's liability exposure. PMID- 18447241 TI - Facility, insurer seek to create a 'healthy city'. AB - Citizens receive free exercise, smoking cessation, and stress prevention programs. Hospital shifting its focus from treating disease to preventing it. Patient outcomes--whether within or without hospital walls--should be part of your mission. PMID- 18447242 TI - Hospital associations put nix on billing for 'never events'. AB - Hospitals, associations agree that the policy is 'the right thing to do'. CMS announcement it would not reimburse for specified errors may have impacted timing of policies. Not paying for adverse events likely a trend to spread to other states. PMID- 18447243 TI - Joint Commission still sees room for improvement. AB - Discharge instructions for heart failure patients, pneumococcal screening, ACE inhibitor at discharge still areas of concern. Requiring a standard process for continual quality measurement, reporting, and improvement has contributed to improvement. Processes are not yet 'ingrained in facilities and systems and process redesign'; the right things don't happen in 'all encounters' all the time. PMID- 18447244 TI - AAN: technology may to be blame for nursing shortage. AB - Nurses spending much less of their time actually caring for patients. Technology must improve so that devices in different areas of treatment can 'talk' to each other. American Academy of Nursing making available a tool to measure work practices, technology being used. PMID- 18447245 TI - UPMC to develop organ donation program for ED. AB - Rapid response system includes equipment, administrative supervision, and QI. System approach includes planning ahead and rehearsing responses. It can take several years to develop protocols and pilot a new rapid response program. PMID- 18447246 TI - Two health care systems bring home Baldrige award. AB - Baldrige evaluators look for organizations where consistent, systematic processes are fully deployed. Standard order sets, education, and training are keys to system's quality improvement. New processes are driven down to the unit and department levels to ensure adaptation. PMID- 18447247 TI - OHRP action shuts down quality improvement research in Michigan. AB - Government agency indicates QI projects tracking results need to obtain informed consent. Experts say regulations provide exceptions which project in question meets. Checklist had already demonstrated effectiveness in earlier research. PMID- 18447248 TI - Magnet facility credits communication for success. AB - Task forces include ancillary departments, so key messages can be spread to the entire facility. Dashboards display performance information on system, facility, and unit levels. Multiple publications reinforce education on key quality improvement goals. PMID- 18447249 TI - Bidding systems address U.S. nursing shortage. AB - Allowing nurses to bid on shifts gives them greater control over their schedules, personal lives. Daunted by the high cost of 'canned' systems, facilities created their own programs internally. Bids can range from 1.1 to 1.5 times current salary; some nurses submit low bids to ensure getting the shift they want. PMID- 18447250 TI - VAP: just how good a benchmark is it really? AB - VAP shares symptoms with several conditions common to the ICU. Diagnosis is considered to be more reliable in the outpatient setting. New measures should reflect the totality of complications that can affect ventilated patients in addition to pneumonia. PMID- 18447251 TI - 'Modest' benefits seen with use of hospitalists. AB - Hospitalists shown to reduce LOS by half a day, with lower average costs as well. Weakness of model also noted, such as increased handoffs during admission and discharge. Quality managers should look to hospitalists as potential physician champions. PMID- 18447252 TI - Laser scanning cytometry (LSC) in pathology--a perspective tool for the future? AB - Cytometry is becoming a standard method of examination not only in biology but also in various fields of experimental and clinical medicine. While in flow cytometry suspensions of cells are measured, laser scanning cytometers enable both the measurement of cells in single-cell suspensions (after immobilising the cells on a conventional glass slide) and in frozen or paraffin-embedded tissue sections. We discuss the possible fields of utilisation and future perspectives of laser scanning cytometry in medicine with special reference to clinical pathology and cytology (Fig. 3, Ref. 49). Full Text (Free, PDF) www.bmj.sk. PMID- 18447253 TI - Serum bFGF concentrations in gastric cancer patients. AB - BACKGROUND: Angiogenetic factors play an important role in the formation of new blood vessels involved in the growth and metastatic spread of solid tumors, but there is limited information regarding the clinical significance of serum bFGF levels in gastric cancer patients. PATIENTS AND METHODS: Serum bFGF concentrations were measured by quantitative sandwich enzyme immunoassay technique in 30 controls and in 30 gastric cancer patients before surgery. The association between preoperative serum bFGF levels and clinical pathological features were evaluated. RESULTS: Preoperative serum bFGF levels in patients with gastric cancer were significantly higher than those in control patients (p=0.027). On the other hand; there is no relationship between serum bFGF levels and clinical-pathologic parameters in gastric cancer patients. CONCLUSION: Circulating bFGF might not be a marker suitable for assessing tumor progression (Tab. 1, Ref. 7). Full Text (Free, PDF) www.bmj.sk. PMID- 18447254 TI - Diagnosis and treatment of liver injury--the experience of the University Trauma Center. AB - BACKGROUND: The incidence of liver injury is increasing steadily because of serious injuries resulting mainly from traffic accidents. The aim of the study was to evaluate the results of the University Trauma Center, with consideration of the present diagnostic and therapeutic possibilities for liver injuries. METHODS: Between January 1st 2000 and April 1st 2006 a total of 132 patients with various degrees of liver injury were admitted to the Trauma Center, University Hospital in Pilsen. 76 injured patients (57.6%) were treated conservatively, and only 56 (42.4%) received surgical treatment, with a total of 87 operations performed. RESULTS: 10 patients with polytrauma (7.6%) died of hemorrhagic shock (group Moore IV-VI). Six injured patients (4.5%) had a complicated course during their hospitalization. The average period of hospitalization was 17 days (1-69 days). CONCLUSION: The mortality and morbidity of patients with liver injury are comparable in the group presented here with the results of other large trauma centers. If compared with previous years, there has been a considerable decrease in mortality from this serious injury. At present the basic diagnostic means in liver injury are as follows: "bed-side" ultrasonography, spiral computed tomography, and in more complicated injuries magnetic resonance, angiography, or endoscopic retrograde cholangiography. In terms of therapeutic tactics conservative methods prevail in haemodynamically stable patients, irrespective of the degree of liver injury. The surgical policy applies "damage control surgery", where during the initial surgery life-saving and non-time-demanding procedures are the target (e.g. liver tamponade), correcting hypothermia, haemocoagulation and metabolic acidosis. Only after stabilization of the injured patient other definitive procedures are possible (Tab. 2, Ref. 16). Full Text (Free, PDF) www.bmj.sk. PMID- 18447255 TI - Hepatocellular carcinoma--evaluation of a group of 74 patients treated at the surgical department. AB - The authors present their experience with treatment of 74 patients operated on for hepatocellular carcinoma. Resection could be performed only in 44 patients. In 19 cases, a catheter for regional chemotherapy was implanted. Tumor destruction with alcohol was performed 4 times and radiofrequency thermal ablation 5 times either as a single intervention or in addition to the resection. Liver cirrhosis was verified by histology in 29 operated patients. Hospital mortality: 2 operated patients. Median survival after the liver resection: 42 months, mean survival: 72 months. The importance of preoperative indocyanine green elimination test for the exact determination of functional capacity of the liver and the priority of radical resection as compared to the other treatment modalities are emphasized (Tab. 2, Ref. 12). Full Text (Free, PDF) www.bmj.sk. PMID- 18447256 TI - Screening for six Mediterranean mutations in 90 Egyptian patients with phenylketonuria. AB - OBJECTIVES: The aim of this study is to assess the prevalence of six common mutations in the Mediterranean basin and Turkey among a large group of Egyptian PKU cases BACKGROUND: Phenylketonuria (PKU) is one of the most common inborn errors of amino acid metabolism that is caused by deficiency of hepatic phenylalanine hydroxylase (PAH). This deficiency is attributed to more than 528 mutations in the PAH gene. METHODS: Ninety unrelated patients with PKU (180 alleles) were screened for six mutations (IVS10-11G>A, R261Q, R252W, Y277D, E221G and G272S) using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The IVS10-11G>A mutation was found in thirty alleles (17%), the R261Q in twelve (7%) and R252W in three (1.6%), while Y277D, E221G and G272S were not found in this patient group. CONCLUSION: Screening for six Mediterranean mutations identified a heterogeneous pattern among Egyptian PKU patients with a high frequency of IVS10-11 G>A (17%) (Tab. 2, Ref. 31). Full Text (Free, PDF) www.bmj.sk. PMID- 18447257 TI - Comparison of long-term care in European developed countries to possible implementation in Slovakia. AB - Long-term care within the public services system does not exist in Slovakia. Long term care is a relatively closed system of health care and social care services. Initially, long-term care policies were formulated as a response to ageing of the population, which brought about growing needs of elderly people for social care and health care, and was associated with relatively rapid increases of necessary costs. All industrial countries are facing similar problems when it comes to the integration of long-term care. In developed countries, current long-term care focuses on all age groups in need of assistance and support from others due to the limitations caused by their state of health (Ref. 34). Full Text (Free, PDF) www.bmj.sk. PMID- 18447258 TI - Preeclampsia or initial diagnosis of chronic renal disease during pregnancy. AB - An unusual case of early nephrotic syndrome without hypertension which slightly resolved after delivery is documented. Renal biopsy was performed postpartum and the diagnosis was focal and segmental glomerulosclerosis with moderate chronic renal changes. It is questioned whether the case was due to preeclampsia or was the initial diagnosis of chronic renal disease which was made during pregnancy. The role of renal biopsy in such cases is briefly discussed (Tab. 2, Ref. 15). Full Text (Free, PDF) www.bmj.sk. PMID- 18447259 TI - A variable origin of the vertebral artery. AB - This study presents and describes the variation of the vertebral artery arising from the aortic arch as a case report. This variation was found in one of the cadavers at the Institute of Anatomy of Medical Faculty of Comenius University in Bratislava. Anomalous arising was discovered during the student's dissection of thorax and abdomen. Non standard arising of the vertebral artery is compared to the standard arising in the anatomical literature and atlases. The variable arising was confronted to the possible variations of the vertebral artery reported in literature (Fig. 4, Ref. 9). Full Text (Free, PDF) www.bmj.sk. PMID- 18447260 TI - Anomalous styloid process and its clinical implications. AB - In literature, there is paucity of information on the different shapes of styloid processes of the temporal bone of the skull. Textbooks of anatomy describe the styloid process to be slender, approximately 2.5 cm in length and concave on the anterior aspect only. In the present case, we observed the styloid process to be much longer than usual, bearing a concavity on the anterior, as well as the posterior aspects as a consequence of which, the bone was constricted in its proximal part. The mastoid process which is usually conical, was found to be rounded in this case. The length of the styloid process measured 2.8 and 2.7 cm on left and right sides, respectively. The skiagram displayed the biconcave profile of the styloid process and the rounded appearance of the mastoid process, thus substantiated the findings on gross examination of the skull. The anatomical knowledge of the mastoid process is important for surgeons assessing the mastoid air cells. The elongated styloid process is often a feature of Eagle's syndrome. An enlarged and calcified styloid process is often asymptomatic, unless detected radiologically. An abnormally elongated styloid process or its calcification may cause recurrent throat pain, foreign body sensation, dysphagia, or facial pain. An enlarged styloid process may also compress upon the internal carotid artery, leading to transient ischemic attack and may pose a threat to anesthetists performing intubation procedures. Awareness of such variations may be of clinical importance to radiologists and surgeons (Fig. 2, Ref. 11). Full Text (Free, PDF) www.bmj.sk. PMID- 18447261 TI - Auditory evoked potentials (AEP)--an important help in early diagnosis of Schwannoma originating from vestibular nerve. AB - Early diagnosis of expansive formations enables efficient therapy and maximal reduction of remaining neurological damage. Schwannoma situated entirely within the inner auditory canal with free pontocerebellar angle is a rather rare event. Of significant diagnostical help are auditory evoked potentials (AEP), computerised tomography (CT) of the temporal bone pyramid with measuring the inner auditory canal diameter, and magnetic resonance (MRI). In this paper we present a case of a 56-year-old woman with gradually advancing noise in the right ear, weakening of hearing and occasional instability while walking. AEP register no evoked response at the right side, whereas at the left side the latencies and amplitudes of evoked acoustic responses are adequate. CT of the temporal bone pyramid shows a difference in the inner auditory canal diameters of 0.04 cm. MRI shows a Schwannoma tumorous formation in the inner auditory canal, situated entirely within the canal with free pontocerebellar angle (Fig. 3, Ref. 16). Full Text (Free, PDF) www.bmj.sk. PMID- 18447262 TI - Hemosuccus pancreaticus. AB - In this study, authors describe a rare case of a 40-year old patient with a history of chronic pancreatitis due to ethanol abuse, repeatedly hospitalized for intermittent bleeding into gastrointestinal tract (GIT). The sources of bleeding were pseudoaneurysms of the peripancreatic arteries (gastroduodenal artery, right hepatic artery) bleeding into GIT via pancreatic duct. This type of bleeding is referred as hemosuccus pancreaticus and belongs to a rare form of bleeding into upper GIT. Development of each pseudoaneurysm was monitored with a 6 month time interval. The diagnosis was established using endoscope, Doppler ultrasound and CT angiography. During the therapeutic process, while stopping bleeding, two different radiological interventions were used. In pseudoaneurysm of gastroduodenal artery, hemostasis was achieved using selective transcatheter arterial embolization (TAE) with steel coils. In the second intervention, a stent was inserted into vascular lesion. In the discussion, authors review the problems of hemosuccus pancreaticus, epidemiology, symptoms, diagnostic and possible therapeutic approaches (Fig. 3, Ref. 31). Full Text (Free, PDF) www.bmj.sk. PMID- 18447263 TI - Value of antibiotic therapy for bioptically proved chronic prostatitis. PMID- 18447264 TI - [Floor tile workers have it more frequently. Tumor of the knee of uncertain origin]. PMID- 18447265 TI - [Lucrative "lipolysis". The spring time diet consultation (interview by Dr. Jochen Aumiller)]. PMID- 18447266 TI - [Important banks agree: good future prospects for established physicians]. PMID- 18447267 TI - [Winter pause was too short--ticks are already becoming mobile]. PMID- 18447268 TI - [Difficult toe nail diagnosis in the diabetic patient. Is it a fungus--or not?]. PMID- 18447269 TI - [When you must convey difficult news to a patient. Are you a good Job's messenger?]. PMID- 18447270 TI - [Recognizing simple clinical signs. When is an asthma attack an emergency?]. PMID- 18447271 TI - [Gambler--porn addict--computer freak. Were is the borderline to illness?]. PMID- 18447272 TI - [Diagnosis "gambling addiction": phenomenology, classification and therapy]. PMID- 18447273 TI - [Can sex become addictive?]. PMID- 18447274 TI - [Addicted to computer games]. PMID- 18447275 TI - [Anorectal bleeding]. PMID- 18447276 TI - [Hypertension in adolescents]. PMID- 18447277 TI - [Otitis externa]. PMID- 18447278 TI - [Once daily mesalazine for long-term remission. Ulcerative colitis: maintenance therapy becomes easier]. PMID- 18447279 TI - [16-year-old patient with low blood pressure. Fingers and toes turn blue in cold weather]. PMID- 18447280 TI - [Is your physician assistant anxious and shy? References for self assured presentation]. PMID- 18447281 TI - [Headaches can be life threatening, therefore: attend to alarm signs]. PMID- 18447282 TI - [Diagnostic imaging in headache: when and how?]. PMID- 18447283 TI - [Study finds more fatalities than in lax blood glucose control. Is HbA(1c) of 6.5% too low for the type 2 diabetes patient? (interview by Maria Weiss)]. PMID- 18447284 TI - [Utilization of heart catheter in Germany. Used too often in stable coronary heart disease, too seldom in myocardial infarct]. PMID- 18447285 TI - [Ankle joint osteoarthritis. The best prevention: sport injuries must heal completely]. PMID- 18447286 TI - [Pathogenesis of upper ankle joint osteoarthritis]. PMID- 18447287 TI - [Clinical picture and diagnostics of upper ankle joint osteoarthritis]. PMID- 18447288 TI - [Conservative and surgical therapy of upper ankle joint osteoarthritis]. PMID- 18447289 TI - [Periumbilical dermatoses]. PMID- 18447291 TI - [Emergency checklist: fracture of the skaphoid bone]. PMID- 18447290 TI - [The incidental finding in the family practice]. PMID- 18447292 TI - Emergency department managers warned of 'catastrophic' crowding due to elderly. AB - While a new study indicates there may be twice as many elderly patients visiting your ED in 2013 as there were in 2003, there are steps to minimize the amount of time they spend in your department. Develop a list of outpatient links to home health agencies, visiting nurse organizations, care centers, nursing homes, and assisted living facilities. Negotiate a reimbursement arrangement that provides an incentive for administration to help move your patients upstairs more quickly. Make sure your staff are aware of the unique presentations seen in the elderly. This will help speed diagnosis and care. PMID- 18447293 TI - Having a patient advocate dedicated to the ED. AB - The ED at St. Mary's Hospital in Tucson, AZ, has its own departmental patient advocate. This new staff position saves a lot of time for the rest of the team members. Here are some of the functions a patient advocate can perform in your ED: proactively prevent problems and satisfy delivery of care needs in a timelier manner to avoid complaints; train the ED staff in customer service and communication techniques; communicate with outside clinics to support uninsured or underinsured patients who don't have primary care physicians. PMID- 18447294 TI - Award-winning ED treats its patients like family. AB - Patients appreciate ED staff who make extra efforts to ensure their needs are met. One way to ensure this level of service is to treat all patients as if they were friends or family. Here are some strategies you can use: Encourage staff, when possible, to call a cab for discharged patients to make sure they have transportation home. If you hire temporary staff on a seasonal basis, make an effort to hire the same staff each time, to ensure familiarity with the patient population. Communicate results of patient satisfaction surveys--the good and the bad--with your staff on a regular basis. PMID- 18447295 TI - Are curtained dividers a setup for a lawsuit? PMID- 18447296 TI - Interview questions are dangerous territory. PMID- 18447297 TI - Joint commission adds outpatient measures, 5 will have a direct impact on ED managers. AB - The new outpatient performance measures added by The Joint Commission carry implications for reimbursement, accreditations, and new business (as they will be publicly reported), and they also provide ED managers with new opportunities to justify additional resources. To optimize your responses: Actively monitor your department data to identify opportunities to improve processes. A standardized approach (i.e., protocols, order sets) will go long way toward ensuring optimal performance. You may be able to justify additional equipment by demonstrating that it is needed to meet Joint Commission requirements for timely service. PMID- 18447298 TI - Meds reconciliation summit promises more clarification. AB - The Joint Commission has responded to feedback concerning medication reconciliation with a summit designed to hear complaints from medical organizations and to come up with a list of possible modifications to its guidelines. Here are some areas where relief may be on the way: While survey consistency has improved, and The Joint Commission has specifically stressed medication reconciliation at its most recent surveyor training session. The Joint Commission is considering amending its requirement for medication reconciliation to be done for all patients under all conditions. The Joint Commission also will address potential changes in the information that must be included in the medication reconciliation list. PMID- 18447299 TI - History of veterinary medicine in Zimbabwe. Part II. Creating awareness, strengthening extension and looking into the future. AB - Livestock farming was going on in the then Southern Rhodesia, before the advent of colonization in 1890. However, history of conventional veterinary medicine dates back only to the arrival of the Pioneer Column, 115 years ago. At that time, veterinary infrastructure and staffing was poor relative to size of the country, in terms of livestock census. Despite that, few veterinarians on the ground managed to eradicate rinderpest (RD), rabies for 37 years, contagious bovine pleuropneumonia (CBPP), glanders, epizootic lymphangitis, East coast fever (ECF) and contagious epivaginitis. However, the 1964-1979 war of liberation (WOL), also dubbed Second Chimurenga, disrupted, among other things, gains that had been made in veterinary medicine thus far. After independence, this drawback was addressed head-on. The 1980-1990 era was approached on a note of optimism and enthusiasm to uphold high standard set by professional predecessors. The aim was to learn from previous mistakes, shift emphasis from primary animal health care to herd health and production management. By necessity the livestock policy, and indeed, the Animal Health Act, should be reviewed in the wake of the fast-track land acquisition and resettlement drive, "War on Land" also referred to as Third Chimurenga. This paper traces the history of veterinary medicine in Zimbabwe from the 1950s. PMID- 18447300 TI - History of veterinary medicine in Southern Rhodesia (Zimbabwe). Part III. Rippling effects of the 1896 rinderpest outbreak. AB - This paper looks at the rippling effects of the first and last 1896 rinderpest outbreak that occurred in Zimbabwe. Following the devastating effects of this outbreak, the Department of Veterinary Services remains on full alert. We conclude that since there has been no outbreak of this pandemic, it is logical to assert that the veterinary services of this country are doing a sterling job, given that there are countries in Africa today where the disease is smoldering. PMID- 18447301 TI - Antonin Klobouk, Biography. PMID- 18447302 TI - Jan Kolda, Biography. PMID- 18447303 TI - Jaroslav Nejezchleba, Biography. PMID- 18447304 TI - Hernquist's Animal Pharmacy--can any of the drugs sold there in the eighteenth century be of use to day? AB - Carl von Linne's 300th birthday is celebrated this year (2007) in Sweden. One of his pupils, Peter Hernquist, has also been acknowledged and an exhibition on his Veterinary Pharmacy has been presented in Skara, Sweden. Some of the drugs sold in this pharmacy are discussed. Thus chamomile prescribed by Hernquist for external use for wounds and light inflammatory processes in the skin could most likely have been effective as it is considered to be to day. Also for indigestion and flatulence Hernquist might have had therapeutic success using chamomile teas. Willow bark, which Hernquist recommended for "fevers" most likely could have been effective for mild fevers due to its contents of salicin, which is transformed to salicylic acid. Although many drugs were ineffective Hernquist was known as a successful veterinary surgeon. Placebo effects and natural healing could be part of his success. PMID- 18447305 TI - 'Shotgun therapy': the understanding and use of thyroid organotherapy in Britain, 1890-1925. PMID- 18447306 TI - The Countess's Ointment. PMID- 18447307 TI - Institutional responses to communicable diseases at Victoria College, University of Toronto, 1900-1940. AB - Between 1900 and 1940 students and staff risked their lives to attend, and teach at, Victoria College. Not only did Victoria experience three major epidemics- diphtheria in 1911, influenza from 1918 to 1920, and smallpox in 1927--but almost yearly one or two students contracted diseases such as scarlet fever, measles, and mumps. Yet at a time when there was no health insurance and few hospital facilities, how did the university cope with the problem? This paper examines the care provided to Victoria's residential students. In the process the paper illustrates not only the upheaval endured by individual students but also the enormous financial and emotional toll paid by the institution, especially by members of its female staff. PMID- 18447308 TI - Physique as destiny: William H. Sheldon, Barbara Honeyman Heath and the struggle for hegemony in the science of somatotyping. AB - When Ron Rosenbaum unveiled his explosive journalistic report on the "Great Ivy League Nude Posture Photo Scandal" in 1995 it was a story that revealed the uneven evolution of attitudes toward body, race, and gender in the last half century. His intention was to highlight how easily ideas about the body have been taken up by scientists and sustained in elite institutions of higher education well beyond the bounds of common sense. The villain of his story was William H. Sheldon, a constitutional psychologist who appropriated the ritual of taking posture photos for his scientific study of somatotypes, a system built upon the relationship of body type to character. Sheldon's toxic eugenic views and equation of physique with destiny in the years following World War II made him increasingly unpopular. And while Rosenbaum concluded that Sheldon's downfall was due to the anger of women students over the taking of nude photos, the deathknell of his career was dealt by his former female assistant, Barbara Honeyman Heath. Publicly denouncing his methods as fraudulent and his somatotypes inaccurate she went on to build a successful career modifying somatotyping techniques and participating in projects all over the world. PMID- 18447309 TI - Baptism of fire: New Brunswick's public health movement and the 1918 influenza epidemic. AB - In the fall of 1918 when war-weary New Brunswickers were hit by the influenza pandemic, theirs was the only Canadian province with a Minister of Health, the first to be appointed anywhere in the British Empire. But it was a new position and a controversial one. This paper traces the growth of a public health movement in New Brunswick in the late 19th and early 20th centuries, the campaign for the establishment of a provincial Department of Health, and the role played by the 1918 influenza epidemic in legitimizing and consolidating the newly minted Department, masthead of the public health movement. PMID- 18447310 TI - A contagious journey within a culture of complacency: the smallpox scare of 1962 in New York and Toronto. AB - In 1962 smallpox was perceived to be an ancient disease that was no longer a threat to public health in North America. This state of complacency was shattered, however, by the journey of a 14-year-old boy who entered the United States on a flight from Brazil and who then continued on into his native Canada. This trip led to an investigation and re-examination of immigration health procedures as well as a discovery of the general population's low level of smallpox immunity. The smallpox incursion was fought by the use of a thorough but troubling system of ring vaccination that left a good deal to pure luck. Many of the issues that grew out of this 1962 experience were subsequently resuscitated during the 21st century's fears concerning the use of biological weapons by potential terrorist groups. PMID- 18447311 TI - "Liberation sticks" or "coffin nails"? Representations of the working woman and cigarette smoking in Canada, 1919-1939. AB - When Canadian women first took up public smoking in the 1920s, the attraction was a complex one, both for them and for advertisers. Newly enfranchised and moving into the workforce in ever greater numbers, the (usually) young and single waged or salaried woman sought a ready symbol for her liberation as well as the pleasures resulting from the product itself to encapsulate the presumed freedom of the era. Commercial interests both responded to women's personal and cultural goals and furthered them by reconceptualizing smoking in the public mind as a behaviour associated with respectable, middle-class women in public spaces. Despite this representation, the archetypal woman smoker in the 1920s was a waged or salaried woman, not a middle-class one. Working women defined the image of the female smoker. PMID- 18447312 TI - Clinically correct? AIDS education in Ontario in the 1980s and 1990s. AB - This paper reviews AIDS prevention initiatives in Canada and the United States in the 1980s and 1990s, and presents a content analysis of print materials used in Ontario during this period. Problems in public health publications included biased approaches, inaccessible or clinical language, anti-sex messages, and imprecise or ambiguous information. Community AIDS groups pioneered creative and effective pedagogical approaches that merit the careful attention of health educators. The Toronto case study showed how public health departments and schools collaborated successfully with community groups, most notably the AIDS Committee of Toronto. PMID- 18447313 TI - Advice concerning pregnancy and health in late medieval Europe: peasant women's wisdom in The Distaff Gospels. AB - This paper explores an area which has proven difficult for scholars to penetrate: women's popular wisdom concerning medical matters in the later medieval period. Contextualized within an examination of medieval medical texts both by and about women, our discussion focuses on a later 15th-century French work, The Distaff Gospels. This text, published recently in English for the first time since 1510, consists of more than 200 pieces of advice or "gospels," ostensibly conveyed to one another by a group of women who met together during the long winter evenings to spin. A significant portion of the advice might be considered "medical" in nature; it is grouped into two broad categories: pregnancy and health. We conclude that although our text is male mediated, it provides a reliable and valuable guide to peasant women's medical lore during this period. PMID- 18447314 TI - [Influenza, an eternal problem]. AB - Influenza remains a serious disease in humans and animals (primarily poultry). Since influenza is caused by a virus that both undergoes continuous antigenic change and possesses an animal reservoir, it will be quite difficult to avoid any future pandemics and an eradication of the disease is likely to be impossible. It is now clear, for instance, that the avian viruses may jump into the human population. Are we heading towards another influenza pandemic? One cannot discount that eventuality and one should be cautious while trying to produce new specific drugs as well as efficient vaccines that eventually cannot be discounted, and various precautions must be taken in the production of new specific drugs and vaccines. PMID- 18447315 TI - A locator list of some medieval ophthalmological texts. AB - At the turn of the last century, there was a flurry of interest in medieval ophthalmological texts. Many of these were edited by practising ophthalmologists, interested in learning and applying the techniques of their distant predecessors. The editions are often difficult to find, and I have listed them along with at least one library location. PMID- 18447316 TI - The body environmental. PMID- 18447317 TI - Cigarettes, alcohol, and the question of corporate responsibility. PMID- 18447318 TI - ['The spirit has left the bottle': the medieval Arabic physician 'Abd al-Latif ibn Yusuf al-Baghdadi: his medical work and his bizarre affiliation with twentieth-century spiritualism]. AB - The Arabic physician 'Abd al-Latif ibn Yusuf al-Baghdadi, lived at the crossroads of the twelfth and the thirteenth century. His unbridled curiosity and his unquenchable thirst for knowledge of any kind brought him to far-away countries and regions and put him in contact with all sorts and conditions of people. The great Egyptian famine of the years 1200-1202 enabled him to study and examine thousands of human cadavers and skeletons at first hand. This led to a new understanding of the anatomical structure of the human body, and rejected the more or less antiquated ideas of the Greek doctor Galen of Pergamum. However, 'Abd al-Latif's vision was granted only a short life. After his death, his discovery sank into oblivion and as a consequence it was never again mentioned in Arabic medical manuals. From then on the Arabic physicians once more referred to the anatomical data which were developed and taught by Galen. Relatively few specimens of his remaining medical work were preserved for posterity. However, his Book of the two advices (or: K. al-Nasihatain) is of the utmost importance as a source for the medical thinking and the medical treatment in the late twelfth and the early thirteenth century A.D. During the years following World War I, 'Abd al-Latif's name reappeared within the spiritualistic movement in England. He became known as Abduhl Latif the great Persian physician and acted as a control of mediums. Until the late sixties, he practised the art of healing as the head of a medical mission somewhere in the Spheres. PMID- 18447319 TI - Same-single-cell analysis for the study of drug efflux modulation of multidrug resistant cells using a microfluidic chip. AB - Since multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy, we report a microfluidic approach combined with the same-single cell analysis to investigate the modulation of MDR, manifested as the inhibition of drug efflux. A microfluidic chip that was capable of selecting and retaining a single multidrug-resistant cancer cell was used to investigate drug efflux inhibition in leukemia cell lines. Three advantages of the microfluidic-based same-single-cell analysis (dubbed as SASCA) method have been revealed. First, it readily detects the modulation of drug efflux of anticancer compounds (e.g., daunorubicin) by MDR modulators (e.g., verapamil) among cellular variations. Second, SASCA is able to compare the different cellular abilities in response to drug efflux modulation based on the drug transport kinetics of single cells. Third, SASCA requires only a small number of cells, which may be beneficial for investigating drug resistance in minor cell subpopulations (e.g., cancer "stem" cells). PMID- 18447320 TI - Protein quantification by isotope dilution mass spectrometry of proteolytic fragments: cleavage rate and accuracy. AB - The practice of quantifying proteins by peptide fragments from enzymatic proteolysis (digestion) was assessed regarding accuracy, reliability, and uncertainty of the results attainable. Purified recombinant growth hormone (rhGH, 22 kDa isoform) was used as a model analyte. Two tryptic peptides from hGH, T6 and T12, were chosen to determine the amount of the protein in the original sample. Reference solutions of T6 and T12 (isotopically labeled forms), value assigned by quantitative amino acid analysis (AAA) after complete hydrolysis, were used as internal standards. The accuracy of protein quantification by fragments T6 and T12 was evaluated by comparison of peptide results to those obtained for the same rhGH sample by AAA. The rate of cleavage (and thus the experimental protocol used) turned out to be crucial to the quality of results in protein quantification using enzymatic fragments. Applying a protocol customarily found in (qualitative) bottom-up proteomics gave results significantly higher than the target value from AAA (+11% with T6 and +6% with T12). In contrast, using a modified protocol optimized for fast and complete hydrolysis, results were unbiased within the limits of uncertainty, while the time needed for completion of proteolysis was considerably reduced (30 min as compared to 1080 1200 min). The method assessed highlighted three important criteria deemed necessary for successful protein quantification using proteolysis-based mass spectrometry methods. These are the following: the requirement for both the selected peptides and labeled internal standard to be stable throughout digestion; the correct purity assignment to the selected peptide standards; the proof of equimolar release of the selected peptides. The combined (overall) uncertainty for protein quantification was established by combination of estimates obtained for individual components and found to be U = 4% for this example. This uncertainty is of the same order as that typically attainable in quantification of "small" organic molecules using liquid chromatography/isotope dilution mass spectrometry. PMID- 18447321 TI - Attomole detection of hemagglutinin molecule of influenza virus by combining an electrochemiluminescence sensor with an immunoliposome that encapsulates a Ru complex. AB - An immunoliposome (80 nm in diameter) encapsulating a Ru complex with two aminobutyl moieties was prepared to detect the presence of hemagglutinin molecules, which play an important role in influenza virus infection. The highly sensitive detection was accomplished by electrochemiluminescence (ECL) from the Ru complex adsorbed onto Au electrodes after competitive immunoreactions. This method clarified that the adsorption of the Ru complex onto the electrode was an important factor in obtaining high sensitivity. Optimization of the analytical conditions enabled determination of the hemagglutinin molecules of the influenza virus in the concentration range of 3 x 10(-14) (6 x 10(-19) mol/50 microL sample) to 2 x 10(-12) g/mL. The sensitivity was far superior to that obtained by conventional ELISA as well as to that obtained by biosensors and reported thus far. PMID- 18447322 TI - Terbutaline enantiomer separation and quantification by complexation and field asymmetric ion mobility spectrometry-tandem mass spectrometry. AB - Recently, we introduced a new approach to chiral separation and analysis of amino acids by chiral complexation and electrospray high-field asymmetric waveform ion mobility spectrometry coupled to mass spectrometry (ESI-FAIMS-MS). In the present work, we extended this approach to the separation of the drug compound terbutaline. Terbutaline enantiomers were complexed with metal ions and an amino acid to form diastereomeric complexes of the type [M(II)(L-Ref)2((+)/(-)-A) H](+), where M(II) is a divalent metal ion, L-Ref is an amino acid in its L-form, and A is the terbutaline analyte. When metal and reference compound were suitably chosen, these complexes were separable by FAIMS. We also detected and characterized larger clusters that were transmitted at distinct FAIMS compensation voltages (CV), disturbing data analysis by disintegrating after the FAIMS separation and forming complexes of the same composition [M(II)(L Ref)2((+)/(-)-A)-H](+), thus giving rise to additional peaks in the FAIMS CV spectra. This undesired phenomenon could be largely avoided by adjusting the mass spectrometer skimmer voltages in such a way that said larger clusters remained intact. In the quantitative part of the present work, we achieved a limit of detection of 0.10% (-)-terbutaline in a sample of (+)-terbutaline. The limit of detection and analysis time per sample compared favorably to literature values for chiral terbutaline separation by HPLC and CE. PMID- 18447323 TI - Screening of oxygen evolution electrocatalysts by scanning electrochemical microscopy using a shielded tip approach. AB - Oxygen evolution electrocatalysts in acidic media were studied by scanning electrochemical microscopy (SECM) in the substrate generation-tip collection (SG TC) imaging mode with a 100 microm diam tip. Pure IrO2 and Sn(1-x)Ir(x)O2 combinatorial mixtures were prepared by a sol-gel route to form arrays of electrocatalyst spots. The experimental setup has been developed to optimize screening of electrocatalyst libraries under conditions where the entire array is capable of the oxygen evolution reaction (OER). The activity of individual spots was determined by reducing the interference from the reaction products of neighboring spots diffusing to the tip over the spot of interest. A gold layer deposited on the external wall of the SECM tip was used as a tip shield. In this study the shield was kept at a constant potential to reduce oxygen under mass transfer controlled conditions. The tip shield consumes oxygen coming from the neighbor spots in the array and enables the tip to correctly detect the activity of the spot below the tip. Simulations and experimental results are shown, demonstrating the effectiveness of the tip shield with the SG-TC setup in determining the properties of the composite materials and imaging arrays. PMID- 18447324 TI - Direct electrochemistry and electrocatalytic activity of cytochrome c covalently immobilized on a boron-doped nanocrystalline diamond electrode. AB - Cytochrome c (Cyt c) was covalently immobilized on a boron-doped nanocrystalline diamond (BDND) electrode via surface functionalization with undecylenic acid methyl ester and subsequent removal of the protecting ester groups to produce a carboxyl-terminated surface. Cyt c-modified BDND electrode exhibited a pair of quasi-reversible and well-defined redox peaks with a formal potential (E(0)) of 0.061 V (vs Ag/AgCl) in 0.1 M phosphate buffer solution (pH 7.0) and a surface controlled process with a high electron transfer constant (ks) of 5.2 +/- 0.6 s( 1). The electrochemical properties of as-deposited and Cyt c-modified boron-doped microcrystalline diamond (BDMD) electrodes were also studied for comparison. Investigation of the electrocatalytic activity of the Cyt c-modified BDND electrode toward hydrogen peroxide (H2O2) revealed a rapid amperometric response (5 s). The linear range of response to H2O2 concentration was from 1 to 450 microM, and the detection limit was 0.7 microM at a signal-to-noise ratio of 3. The stability of the Cyt c-modified BDND electrode, in comparison with that of the BDMD and glassy carbon counterpart electrodes, was also evaluated. PMID- 18447325 TI - Thermal analysis. PMID- 18447326 TI - NMR and X-ray structural characterization of a cisplatin analogue able to slow down the Pt-N7 rotation of a coordinated guanine base by a billion-fold times: 2,2'-bipiperidine(dimethylmalonato)platinum(II) complex. AB - The synthesis and the NMR and X-ray structural characterization of a cisplatin analogue designed to reduce the Pt-N7 rotation of a coordinated guanine base by a billion times are reported. The [Pt(dmm){(+/-)-bip}] (dmm=dimethylmalonato; bip=2,2'-bipiperidine) complex crystallizes in the C2/m space group, which contemplates a mirror plane bisecting the bip and dmm ligands. Because the bip moiety (R, R or S, S configuration at the 2,2'-carbon atoms) does not have planes of symmetry, the requirements of the crystal symmetry are satisfied by a statistical disorder made of bip molecules of R, R or S, S configurations alternating at the same crystallographic site. Such an unexpected arrangement has been permitted by a "quasi planarity" of the bip ligand [maximum deviation from the mean plane through the C and N atoms of 0.2927(9) A], which allows bip molecules of different chiralities to fit in the same space. The bip array of heavy atoms is overlaid, from both sides, by a layer of "quasi axial" (C)H and (N)H atoms (six per side). Those on one side are hydrogen-bonded to the dmm oxygen atoms of another complex molecule joined in a pair. The distance between the average platinum coordination planes is as short as 3.498(1) A, comparable to those found in crystals of the [PtCl 2(bipy)] complex (bipy=2,2'-bipyridine) and of graphite, in which, however, all atoms of each unit are rigorously coplanar and there are no out-of-plane hydrogen atoms. The NMR data show a net chemical shift separation between geminal methylene protons, with the "quasi axial" protons being always at higher field with respect to the "quasi equatorial" ones. This is in accordance with a rigid bip ligand frame and the inability of the bip methylene protons adjacent to the coordinated nitrogen to rotate away from a cis G base (G=guanine) during G rotation around the Pt-N7 bond. PMID- 18447328 TI - K3(U3O6)(Si2O7) and Rb3(U3O6)(Ge2O7): a pentavalent-uranium silicate and germanate. AB - A new uranium(V) silicate, K3(U3O6)(Si2O7), and the germanate analogue, Rb3(U3O6)(Ge2O7), have been synthesized under high-temperature, high-pressure hydrothermal conditions and characterized by single-crystal X-ray diffraction. Their structures contain uranate columns formed of triple octahedral chains of the alpha-UF5 type linked by disilicate (or digermanate) units to form a 3-D framework structure. The valence state of uranium is confirmed by X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and magnetic susceptibility. PMID- 18447327 TI - Preparation and structural characterization of the Ih and the D5h isomers of the endohedral fullerenes Tm3N@C80: icosahedral C80 cage encapsulation of a trimetallic nitride magnetic cluster with three uncoupled Tm3+ ions. AB - We report an efficient method for the preparation and purification of the Ih and the D5h isomers of Tm3N@C80. Following preparation in a Kratschmer-Huffman electric-arc generator, the Tm3N@C80 isomers were obtained by a chemical separation process followed by a one-stage isomer selective chromatographic high performance liquid chromatography (HPLC) separation (pyrenyl, 5PYE column). The HPLC chromatographic retention behavior on a pentabromobenzyl (5PBB) column suggests a charge transfer of approximately 6 electrons; [M3N] 6+@C80(6-) and the chromatographic retention mechanisms of the Ih and the D5h isomers of Tm3N@C80 on both 5PBB and 5PYE columns are discussed. Single-crystal X-ray diffraction data demonstrate that the Tm3N cluster has a planar structure but represents a tight fit for trapping the Tm3N cluster inside the I h - and the D 5h -C 80 cages. Specifically, the Tm atoms punch out the cage carbon atoms adjacent to them. The "punched out" effect can be demonstrated by cage radii and pyramidal angles at cage carbon atoms near the Tm atoms. The magnetic susceptibility (chiT) for Tm3N@ Ih -C80 was found to exhibit Curie-Weiss behavior with C = 23.4 emu.K/mol, which is consistent with the calculated value for three uncoupled Tm3+ ions by considering the spin and orbital contributions with no quenching of the orbital angular momentum ( L = 5, S = 1, and J = 6; Ccalcd = 23.3 emu.K/mol). The electrochemical measurements demonstrate that both the Ih and the D5h isomers of Tm3N@C80 have a large electrochemical gap. PMID- 18447329 TI - Palladium(II) and platinum(II) organometallic complexes with 4,7-dihydro-5-methyl 7-oxo[1,2,4]triazolo[1,5-a]pyrimidine. Antitumor activity of the platinum compounds. AB - Palladium and platinum complexes with HmtpO (where HmtpO=4,7-dihydro-5-methyl-7 oxo[1,2,4]triazolo[1,5-a]pyrimidine, an analogue of the natural occurring nucleobase hypoxanthine) of the types [M(dmba)(PPh3)(HmtpO)]ClO4[dmba=N,C chelating 2-(dimethylaminomethyl)phenyl; M=Pd or Pt], [Pd(N N)(C6F5)(HmtpO)]ClO4[N-N=2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (Me2bpy), or N, N, N', N'-tetramethylethylenediamine (tmeda)] and cis [M(C6F5)2(HmtpO)2] (M=Pd or Pt) (head-to-head atropisomer in the solid state) have been obtained. Pd(II) and Pt(II) complexes with the anion of HmtpO of the types [Pd(tmeda)(C6F5)(mtpO)], [Pd(dmba)(micro-mtpO)] 2, and [NBu4]2[M(C6F5)2(micro-mtpO)]2(M=Pd or Pt) have been prepared starting from the corresponding hydroxometal complexes. Complexes containing simultaneously both the neutral HmtpO ligand and the anionic mtpO of the type [NBu4][M(C6F5)2(HmtpO)(mtpO)] (M=Pd or Pt) have been also obtained. In these mtpO HmtpO metal complexes, for the first time, prototropic exchange is observed between the two heterocyclic ligands. The crystal structures of [Pd(dmba)(PPh 3)(HmtpO)]+, cis-[Pt(C6F5)2(HmtpO)2].acetone, [Pd(C6F5)(tmeda)(mtpO)].2H2O, [Pd(dmba)(micro-mtpO)]2, [NBu4]2[Pd(C6F5)2(micro-mtpO)]2.CH2Cl2.toluene, [NBu4]2[Pt(C6F5)2(micro-mtpO)](2).0.5(toluene), and [NBu4][Pt(C6F5)2(mtpO)(HmtpO)] have been established by X-ray diffraction. Values of IC50 were calculated for the new platinum complexes cis-[Pt(C6F5)2(HmtpO)2] and [Pt(dmba)(PPh3)(HmtpO)]ClO4 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780 cisR), lung (NCI-H460), and breast cancers (T47D). At 48 h incubation time, both complexes were about 8-fold more active than cisplatin in T47D and show very low resistance factors against an A2780 cell line, which has acquired resistance to cisplatin. The DNA adduct formation of cis-[Pt(C6F5)2(HmtpO)2] and [Pt(dmba)(PPh3)(HmtpO)]ClO4 was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by these platinum complexes on plasmid DNA pB R322 were also obtained. PMID- 18447330 TI - Preparation, structures, and photocatalytic properties of three new uranyl organic assembly compounds. AB - Three new uranyl-organic coordination polymers (UO2)8(NDC)12(4,4'-bipyH2)3(4,4' bipyH)3 (1), (UO2)3O[Ag(2,2'-bipy)2]2(NDC)3 (2), and (UO2)2(NDC)2(2,2'-bipy)2 (3), where NDC=1,4-naphthalenedicarboxylate and bipy=bipyridine, have been prepared in hydrothermal conditions. Both 1 and 2 possess a 2D structure while 3 is composed of 1D zigzag chains. In 1 there are mononuclear pentagonal bipyramidal U-O polyhedra and 1D channels filled with 4,4'-bipy molecules, whereas in 2 there are mononuclear hexagonal-bipyramidal U-O polyhedra and tetranuclear pentagonal-bipyramidal U-O clusters which form 2D channels with occluded [Ag(2,2'-bipy)2]+ counterions. In 3 both the NDC and the bipy ligands coordinate to uranyl centers, leading to hexagonal-bipyramidal polyhedra which are connected to form 1D zigzag chains. Under UV or visible irradiation, 1 and 2 degrade rhodamine B with similar efficiency. The correlation between photocatalytic reaction rate and oxygen concentration for 1 and 2 has also been elucidated. Crystal data: 1, triclinic, space group P1, a=11.037(2) A, b=15.126(3) A, c=15.660(3) A, alpha=62.05(3) degrees, beta=72.26(3) degrees, gamma=82.05(3) degrees, and Z=2; 2, triclinic, space group P1, a=14.161(3) A, b=15.122(3) A, c=18.212(4) A, alpha=85.73(3) degrees, beta=76.99(3) degrees, gamma=67.32(3) degrees, and Z=2; 3, monoclinic, space group P2(1)/n, a=10.7976(18) A, b=31.501(6) A, c=11.590(2) A, beta=97.609(4) degrees, and Z=4. PMID- 18447331 TI - Evaluation of CO coordination energies from spectroscopic data: on the use of vibrational isotopic effects. AB - For molecules containing a linearly coordinated carbonyl group, relationships linking 13C and 18O isotopic effects on the CO stretching vibration to the force constant of the M-C coordination bond are proposed. These relationships are rationalized by simple considerations involving the mechanical coupling of the CO and M-C oscillators, tested on model triatomic molecules, and generalized to larger systems. Previous theoretical considerations and several examples presented here show that the long-accepted relation between the shift in the stretching frequency of the coordinated CO with respect to that of isolated CO and the coordination strength has no general predictive power. In contrast, the force constant of the coordination bond can be correlated with the coordination binding energy, and a method for empirically estimating this important parameter from spectroscopic observations of the strongly absorbing CO stretching vibrations of molecular systems or adsorbates is proposed. PMID- 18447332 TI - Versatile scorpionates and new developments in the denticity changes of NNCp hybrid scorpionate/cyclopentadienyl ligands in Sc and Y compounds: from kappa1 Neta5-Cp to kappa2-NNeta5-Cp. AB - Reaction of hybrid scorpionate/cyclopentadienyl ligands in the form of the lithium derivatives [Li(bpzcp)(THF)] [bpzcp=2,2-bis(3,5-dimethylpyrazol-1-yl)-1,1 diphenylethylcyclopentadienyl], [Li(bpztcp)(THF)] [bpztcp=2,2-bis(3,5 dimethylpyrazol-1-yl)-1-tert-butylethylcyclopentadienyl], and the in situ generated "Li(bpzpcp)" [bpzpcp=2,2-bis(3,5-dimethylpyrazol-1-yl)-1 phenylethylcyclopentadienyl] with MCl3(THF)3 afforded the group 3 halide compounds [MCl2(bpzcp)(THF)] (M=Sc, 1; Y, 2), [MCl2(bpztcp)(THF)] (M=Sc, 3; Y, 4), and [MCl2(bpzpcp)(THF)] (M=Sc, 5; Y, 6). The H2O adduct of 4, [YCl2(bpztcp)(H2O)] (7), was formed when a solution of 4 was allowed to stand at room temperature in the presence of moisture. Complexes 1-7 adopt a pseudo octahedral structure with heteroscorpionate ligands kappa2-NNeta5-Cp coordinated to the metal through the cyclopentadienyl group and two imino nitrogens of pyrazole rings. The alkyl heteroscorpionate scandium and yttrium complexes recently reported by our group, [M(CH2SiMe3)2(bpzcp)], react with 2,6 dimethylphenol and 3,5-dimethylphenol to give the bis(aryloxide) derivatives [M(OAr)2(bpzcp)] (M=Sc, OAr=2,6-dimethylphenoxide, 8; M=Y, OAr=2,6 dimethylphenoxide, 9; M=Y, OAr=3,5-dimethylphenoxide, 10). Complex 9 underwent an interesting hydrolysis process to give the tetranuclear complex [{Y(bpzcp)}(micro OH)2(micro3-OH){Y(OAr)2}]2 (11). Variable-temperature 1H NMR experiments on 9 and 10 revealed a rapid fluxional exchange between coordinated and noncoordinated pyrazolyl rings, producing interconversion between the two enantiomers in which the scorpionate ligand can be coordinated in a kappa1-Neta5-Cp form. The structures of the complexes were determined by spectroscopic methods and the X ray crystal structures of 2, 7, and 11 were also established. Complexes 1 and 2 are active olefin polymerization catalysts after activation with methylaluminoxane. These compounds gave atactic polystyrenes with narrow molecular weight distribution (Mn/Mw 1.26-1.91) and with low molecular weights. PMID- 18447333 TI - Squarato-metal(II) complexes. 2. unusual bonding mode for a squarato-bridged trinuclear copper(II) complex. AB - Herein, we report the structural characterization and magnetic properties of the unique squarato-bridged-tricopper(II) complex, [Cu3(pmap)3(micro1,2,3 C4O4)](ClO4)(4).2H 2O (1), based on the tripod tripyridylamine ligand bis[2-(2 pyridyl)ethyl]-(2-pyridyl)methylamine (pmap). Each of the three copper centers is penta-coordinated by four N atoms of a pmap ligand and one bridging O atom of the central squarato dianion. This complex is the first example of a non-polymeric X ray structurally characterized trimeric transition metal complex with the three metal cations being bridged by a single squarato ligand in a micro1,2,3 coordination mode. The magnetic properties of the complex were measured over the temperature range 2-300 K. The complex exhibits moderate bulk antiferromagnetic interaction. The three magnetic exchange pathways have J values of -27.8, -20.8, and -31.9 cm(-1). The DFT calculations corroborate the relatively strong antiferromagnetic couplings obtained from the fitting of the experimental magnetic susceptibility data and allow an assignment of the fitted J values. Several geometrical parameters have been analyzed using theoretical calculations to establish magnetostructural correlations for complex 1. PMID- 18447334 TI - Synthesis, characterization, and in vitro cytotoxicity of some gold(I) and trans platinum(II) thionate complexes containing water-soluble PTA and DAPTA ligands. X ray crystal structures of [Au(SC4H3N2)(PTA)], trans-[Pt(SC4H3N2)2(PTA)2], trans [Pt(SC5H4N)2(PTA)2], and trans-[Pt(SC5H4N)2(DAPTA)2]. AB - A series of gold(I) and platinum(II) complexes of the type [Au(SR)(P)] and trans [Pt(SR) 2(P) 2] [SR = 2-thiopyridine (SPy), 2-thiopyrimidine (SPyrim); P = 1,3,5 triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5 phosphabicyclo[3.3.1]nonane (DAPTA)] were prepared and characterized, and their in vitro cytotoxicities against a panel of seven human cancer cell lines were evaluated. The highly water soluble gold(I) complexes [Au(SR)(P)] [P = PTA and SR = SPy ( 1), SPyrim ( 2); P = DAPTA and SR = SPy ( 3), SPyrim ( 4)] showed low cytotoxicity, while the platinum(II) complexes trans-[Pt(SR) 2(P) 2] [P = PTA and SR = SPyrim ( 5), SPy ( 6); P = DAPTA and SR = SPyrim ( 7), SPy ( 8)] demonstrated potent cytotoxicity for ovarian, colon, renal, and melanoma cancer cell lines on the basis of a comparison with ID 50 values for some established cytotoxic drugs. Single crystals of 2, 5, 6, and 8 suitable for X-ray structural characterization were obtained, and the study revealed the trans configuration for 5, 6, and 8 in their solid states. PMID- 18447335 TI - Alignment of ethyl halide molecules (C2H5X, X= I, Br, Cl) induced by strong ps laser irradiation. AB - The alignment of polyatomic molecules under strong 35 ps laser irradiation is investigated for a broad range of laser intensities (10(13)-10(15) W/cm(2)) using time-of-flight mass spectrometry. The dynamic alignment of the molecules under study (C2H5X, X = I, Br, Cl) is verified in single-pulse experiments by recording the fragments' angular distributions, their dependence on the laser intensity, and also the comparison of the ionic signal of the various fragments recorded for linear and circular polarization. For all cases, the angular distributions of the Coulomb explosion fragments are found to be independent of the laser peak intensity, implying that the molecular alignment is taking place during the rise time of the laser pulses at relatively low intensities (approximately 10(13) W/cm(2)). Moreover, the same result implies that the alignment mechanism is close to the adiabatic limit, albeit the laser pulse duration is much shorter than the characteristic rotational times (1/2B) of the molecules under study. Finally, by comparing the angular distributions of the different molecules, we conclude that the degree of alignment is only weakly dependent on the molecular mass and the moment of inertia under the irradiation conditions applied. PMID- 18447336 TI - Assessment of scaffold hopping efficiency by use of molecular interaction fingerprints. AB - A novel scoring algorithm based on molecular interaction fingerprints (IFPs) was comparatively evaluated in its scaffold hopping efficiency against four virtual screening standards (GlideXP, Gold, ROCS, and a Bayesian classifier). Decoy databases for the two targets under examination, adenosine deaminase and retinoid X receptor alpha, were obtained from the Directory of Useful Decoys and were further enriched with approximately 5% of active ligands. Structure and ligand based methods were used to generate the ligand poses, and a Tanimoto metric was chosen for the calculation of the similarity interaction fingerprint between the reference ligand and the screening database. Database enrichments were found to strongly depend on the pose generator algorithm. In spite of these dependencies, enrichments using molecular IFPs were comparable to those obtained with GlideXP, Gold, ROCS, and the Bayesian classifier. More interestingly, the molecular IFP scoring algorithm outperformed these methods at scaffold hopping enrichment, regardless of the pose generator algorithm. PMID- 18447337 TI - Polynuclear cobalt(II/III) sulfites: synthesis, structure, and magnetic properties of the octanuclear cluster (NH4)11(Li subset[Co4IICo4III(SO3)16(NH3)8]).10H2O encapsulating a lithium cation. AB - Partial oxidation of an aqueous solution of CoIICl(2).6H2O with (NH4)6[Mo7VIO24].4H2O in the presence of (NH4)2SO3.H2O and LiCl, at pH approximately 5.3, leads to isolation of the octanuclear cluster (NH4)11(Li subset[Co4IICo4III(SO3)16(NH3)8].10H2O), 1. The structure of the anion of 1 consists of a central [Co4II], almost ideal square planar unit, and a pair of symmetry-related CoIII dimers above and below the Co4II plane grafting onto the tetramer by 16 bridging sulfite groups. The [Co8(SO3)16(NH3)8]12- cluster encapsulates a lithium cation which lies at the center of the Co4II square. PMID- 18447338 TI - Formation of superoxide anion on aerial oxidation of Cu(II)-porphyrinogen in the synthesis of tetrakis(cyclohexyl)porphyrinogenCu(III) anion. AB - Tetraethylammonium-tetrakis(cyclohexyl)porphyrinogenCu(II) (1) is spontaneously oxidized by aerial oxygen to the corresponding Cu(III) (2) species, producing 1 equiv of O2(-). Steric crowding of the peripheral hydrogens in 1 prevented any direct Cu-O2 bond formation in the oxidation process, which suggests an outer sphere electron transfer reaction. PMID- 18447339 TI - Preparation of CdSe quantum dots with full color emission based on a room temperature injection technique. AB - High quality CdSe quantum dots are synthesized through a room temperature injection technique by using CdAc2 and Na2SeSO3 as precursors. In this synthesis approach, small CdSe clusters are formed after the injection at room temperature. Thereafter, CdSe quantum dots with emissions from the green to the red region can be obtained by transferring these clusters to different temperatures (40-150 degrees C) for particle growth. Meanwhile, CdSe quantum dots with emission in the blue-violet region (500-430 nm) are gained by an oxidation etching approach using H2O2 as oxidant. The advantage of this method is the natural separation of the nucleation and the growth process, which can provide a longer time for the preparation of the nuclei in simple operations and a well controlled fluorescence of the products, as the evolution of the fluorescence is slow at this low particle growth temperature. PMID- 18447340 TI - Tetranuclear clusters containing a CrIII-doped MnIII4O2 core: syntheses, structures, and magnetic properties. AB - The oxidation of MnII carboxylates by (NBu4)Cr2O7 in the presence of different phosphonic acids and chelating ligands results in six CrIII-doped tetranuclear manganese clusters formulated [Mn3CrO2(O2CCH3)4(O3PC5H4N)2(bpy)2] (1), [Mn3CrO2(O2CCH3)4(O3PC5H4N)2(phen)2] (2), [Mn3CrO2(O2CPh)4(O3PC5H4NO)2(phen)2] (3), [Mn3CrO2(O2CPh)4(O3PC6H11)2(bpy)2] (4), [Mn 3CrO2(O2CPh)4(O3PC6H11)2(phen) 2] (5), and [Mn3CrO2(O2CCH3)4(O3PC6H11)2(bpy)2] (6). Single-crystal X-ray analyses reveal that all the compounds contain similar [M4O2]8+ cores with the four metal sites arranged in planar topologies. The metal ions within the core are bridged by both carboxylate and phosphonate ligands. Temperature-dependent magnetic measurements show that in all cases dominant antiferromagnetic interactions are propagated between the metal centers. The ac magnetic measurements on compounds 5 and 6 reveal that both the in-phase and the out-of phase signals are frequency dependent, characteristic of single-molecule magnet behaviors. PMID- 18447341 TI - Understanding selectivity in the oxidative addition of the carbon-sulfur bonds of 2-cyanothiophene to Pt(0). AB - The reaction of 2-cyanothiophene with a zerovalent platinum bisalkylphosphine fragment yields two thiaplatinacycles derived from the cleavage of the substituted and unsubstituted C-S bonds. While cleavage away from the cyano group is preferred kinetically, cleavage adjacent to the cyano group is preferred thermodynamically. Density functional theory using B3LYP level of theory on a model of this system is consistent with experimental results in that the transition state energy leading to the formation of the kinetically favored C-S bond cleavage product is lower by 5.3 kcal mol(-1) than the barrier leading to the thermodynamically favored product. There is a 6.7 kcal mol(-1) difference between these two products. The cyano substituent at the 2- position of thiophene did not substantially change the mechanism involved in the C-S bond cleavage of thiophene previously reported. PMID- 18447342 TI - Interplay of supramolecular organization, metallophilic interactions, phase changes, and luminescence in four polymorphs of IrI(CO)2(OC(CH3)CHC(CH3)N(p tol)). AB - Four polymorphs of IrI(CO)2(OC(CH3)CHC(CH3)N(p-tol)) have been characterized by single crystal X-ray crystallography. While all contain the same molecular unit with no significant structural variations within the molecules, all show different degrees of metallophilic interactions between the planar molecules. Three of these (the amber, the pale yellow, and the orange forms) are stable at room temperature, while the fourth, the L. T. orange form, is only obtained by cooling the orange polymorph. At 77 K, the amber, pale yellow, and L. T. orange polymorphs show intense luminescence. The variations in the luminescence among the polymorphs are considered in the context of the structural differences between them and the nature of the metallophilic interactions between the iridium centers. These results demonstrate how subtle variations in molecular organization can affect the physical properties of planar d8 transition metal compounds, which are an important class of lumiphores. PMID- 18447343 TI - Relationship between viscosity coefficients and volumetric properties using a scaling concept for molecular and ionic liquids. AB - In this work, a scaling concept based on relaxation theories of the liquid state was combined with a relation previously proposed by the authors to provide a general framework describing the dependency of viscosity on pressure and temperature. Namely, the viscosity-pressure coefficient (partial differentialeta/partial differentialp)T was expressed in terms of a state independent scaling exponent, gamma. This scaling factor was determined empirically from viscosity versus Tvgamma curves. New equations for the pressure- and temperature-viscosity coefficients were derived, which are of considerable technological interest when searching for appropriate lubricants for elastohydrodynamic lubrication. These relations can be applied over a broad range of thermodynamic conditions. The fluids considered in the present study are linear alkanes, pentaerythritol ester lubricants, polar liquids, associated fluids, and several ionic liquids, compounds selected to represent molecules of different sizes and with diverse intermolecular interactions. The values of the gamma exponent determined for the fluids analyzed in this work range from 1.45 for ethanol to 13 for n-hexane. In general, the pressure-viscosity derivative is well-reproduced with the values obtained for the scaling coefficient. Furthermore, the effects of volume and temperature on viscosity can be quantified from the ratio of the isochoric activation energy to the isobaric activation energy, Ev/Ep. The values of gamma and of the ratio Ev/Ep allow a classification of the compounds according to the effects of density and temperature on the behavior of the viscosity. PMID- 18447344 TI - Molecular dynamics simulations of electroosmosis in perfluorosulfonic acid polymer. AB - An atomistic MD simulation method has been developed to study the electroosmotic drag in the hydrated perfluorosulfonic acid polymer. The transport characteristics of the hydroniums and water molecules are evaluated from their velocity distribution functions with an electric field applied. It is shown that the microstructure of the hydrated perfluorosulfonic acid polymer is not perturbed significantly by the electric field up to 2 V/microm, and the velocity distribution functions obey the peak shifted Maxwell velocity distribution functions. The evaluated peak shifting velocities are only about 1% of the average thermal motion. The hydronium flow and water flow are evaluated from the average transport velocities or the peak shifting velocities. The electroosmotic drag coefficients from the MD simulations are in good correspondence with the experimental values. It is also shown that the electroosmotic drag coefficient has no or weak temperature dependence. PMID- 18447345 TI - Solubilization of an organic solute in aqueous solutions of unimeric block copolymers and their mixtures with monomeric surfactant: volume, surface tension, differential scanning calorimetry, viscosity, and fluorescence spectroscopy studies. AB - The ability of aqueous systems, formed by unimeric copolymers and their mixtures with a monomeric surfactant, in solubilizing large quantities of 1-nitropropane (PrNO2) was explored. The copolymers are F68 and L64, which differ for the hydrophilicity, and the surfactant is sodium dodecanoate. For a better understanding of the mechanism of solubilization, thermodynamic (volume and differential scanning calorimetry), spectroscopy (steady-state fluorescence), viscosity, and interfacial investigations were carried out. PrNO2 causes the micellization of the unimeric copolymer, and the required amount of PrNO2 depends on the composition, the copolymer nature, and the temperature. Large quantities of PrNO2 form mixed micelles where PrNO2 experiences an environment similar to its pure liquid state. The presence of the additive allows a decrease of the critical micellar temperature, evidence of which is quantitatively explained through a novel thermodynamic approach. A synergistic effect in solubilizing PrNO2 was observed when surfactant monomers were added to the unimeric copolymer solutions. The increased amount of PrNO2 leads to the complete self-assembling of both the copolymer and the surfactant; a process favored by temperature increase. For all of the investigated systems, the presence of PrNO2 generates a viscosity increase. PMID- 18447346 TI - Enthalpy-entropy contributions to salt and osmolyte effects on molecular-scale hydrophobic hydration and interactions. AB - Salts and additives can significantly affect the strength of water-mediated interactions in solution. We present results from molecular dynamics simulations focused on the thermodynamics of hydrophobic hydration, association, and the folding-unfolding of a hydrophobic polymer in water and in aqueous solutions of NaCl and of an osmolyte trimethylamine oxide (TMAO). It is known that addition of NaCl makes the hydration of hydrophobic solutes unfavorable and, correspondingly, strengthens their association at the pair as well as the many-body level (Ghosh, T.; Kalra, A.; Garde, S. J. Phys. Chem. B 2005, 109, 642), whereas the osmolyte TMAO has an almost negligible effect on the hydrophobic hydration and association (Athawale, M. V.; Dordick, J. S.; Garde, S. Biophys. J. 2005, 89, 858). Whether these effects are enthalpic or entropic in origin is not fully known. Here we perform temperature-dependent simulations to resolve the free energy into entropy and enthalpy contributions. We find that in TMAO solutions, there is an almost precise entropy-enthalpy compensation leading to the negligible effect of TMAO on hydrophobic phenomena. In contrast, in NaCl solutions, changes in enthalpy dominate, making the salt-induced strengthening of hydrophobic interactions enthalpic in origin. The resolution of total enthalpy into solute-solvent and solvent-solvent terms further shows that enthalpy changes originate primarily from solvent-solvent energy terms. Our results are consistent with experimental data on the hydration of small hydrophobic solutes by Ben-Naim and Yaacobi (Ben Naim, A.; Yaacobi, M. J. Phys. Chem. 1974, 78, 170). In combination with recent work by Zangi, Hagen, and Berne (Zangi, R.; Hagen, M.; Berne, B. J. J. Am. Chem. Soc. 2007, 129, 4678) and the experimental data on surface tensions of salt solutions by Matubayasi et al. (Matubayasi, N.; Matsuo, H.; Yamamoto, K.; Yamaguchi, S.; Matuzawa, A. J. Colloid Interface Sci. 1999, 209, 398), our results highlight interesting length scale dependences of salt effects on hydrophobic phenomena. Although NaCl strengthens hydrophobic interactions at both small and large length scales, that effect is enthalpy-dominated at small length scales and entropy-dominated for large solutes and interfaces. Our results have implications for understanding of additive effects on water-mediated interactions, as well as on biocompatibility of osmolyte molecules in aqueous solutions. PMID- 18447347 TI - Solubility of solids in near-critical conditions: effect of a third component. AB - The effect of cosolvents on the solubility equilibria near the critical end-point of binary mixtures is analyzed. The problem has received recent attention for the particular case of ionic cosolvents (Mazo, R. M. J. Phys. Chem. B 2007, 111, 7288 7290), where a pronounced salting-out effect was predicted. Here we make a thermodynamic analysis to view the problem from a different perspective. Our conclusions are that, at the critical end-point, the Setchenov constant, which reflects the effect of cosolvents on solubility equilibria, diverges following the behavior of the osmotic susceptibility and that the sign of this divergence is encoded in the critical end-line of the ternary system. PMID- 18447348 TI - Ab initio and QM/MM study of electron addition on the disulfide bond in thioredoxin. AB - Thioredoxin controls the intracellular redox potential through a disulfide/dithiol couple. Under conditions of oxidative stress, this protein functions via one-electron exchange, in which formation of the disulfide radical anion occurs. Combined quantum mechanical (QM) and molecular mechanical (MM) calculations using two- and three-level ONIOM schemes were performed on the thioredoxin (Trx) protein of Chlamydomonas reinhardtii in its oxidized-disulfide and one-electron-reduced forms. In both cases, the active site disulfide moiety was described at the MP2(fc)/6-31+G(d) level, and larger regions of varying sizes around the active site were described at the B3LYP/6-31+G(d) level. The remainder of the 112 residues and 33 water molecules of the crystal structure (PDB entry 1EP7) were described by the AMBER force field. Adiabatic electron affinities were calculated for the disulfide bond in all systems. Separate QM or QM/QM calculations were performed on the QM regions to establish the role of the remainder of the protein on the active site properties. The radical anion species becomes more stable as the number of amide groups in the vicinity increases. One electron reduction potentials were calculated for the small molecule models, and approximated for the protein for which the values are similar to the experimental one (approximately 0 V). This high reduction potential is due to interaction with the charged end of Lys40, as indicated by mutation in silico to norleucine. The inclusion of the protonated Asp30 side chain and a water molecule in the QM region leads to an increase in the electron affinity. Proton transfer from the Asp30 side chain to the Cys39 sulfur in the radical anion species is strongly disfavored. The radical anion is more stable than the protonated form, which is consistent with experimental results. PMID- 18447349 TI - Exploring structure and dynamics of the diaquotriamminezinc(II) complex by QM/MM MD simulation. AB - The structural and dynamical properties of the cis-(O-Zn-O angle approximately 90 degrees) and trans-(O-Zn-O angle approximately 180 degrees) isomers of the model diaquotriamminezinc(II) complex in aqueous solution have been evaluated using the hybrid quantum mechanical/molecular mechanical molecular dynamics simulation approach at ab initio Hartree-Fock level. In both complexes, the first hydration shell contains five ligands (two water and three ammonia molecules) arranged in a trigonal bipyramidal geometry. In the metastable cis-isomer two different bond lengths of 2.34 and 2.13 A are observed for the Zn-Oax and Zn-Oeq bonds, respectively. The trans-isomer shows the maximum of the Zn-O distance at 2.26 A. The Zn-N bond distances in both cases are approximately 2.12 A. A geometrical transformation of the cis-isomer into the trans-isomer was observed after 11.5 ps of simulation, and the trans-isomer then remained stable throughout the whole simulation time of 30 ps. A comparative study for both isomers has been performed in terms of radial distribution functions, coordination number distributions, angular distribution functions, tilt and theta angle distributions, ligands' mean residence time, ion-ligand stretching frequencies, and the vibrational and librational motions of water ligands. The results are compared with the data for the previously studied zinc-monoamine and -diamine complexes. PMID- 18447350 TI - Dependence of glycine CH2 stretching frequencies on conformation, ionization state, and hydrogen bonding. AB - We experimentally and theoretically examined the conformation, pH, and temperature dependence of the CH2 stretching frequencies of glycine (gly) in solution and in the crystalline state. To separate the effects of the amine and carboxyl groups on the CH2 stretching frequencies we examined the Raman spectra of 2,2,2-d3-ethylamine (CD3-CH2-NH2) and 3,3,3-d3-propionic acid (CD3-CH2-COOH) in D2O. The symmetric (nusCH2) and asymmetric (nuasCH2) stretching frequencies show a significant dependence on gly conformation. We quantified the relation between the frequency splitting (Delta = nuasCH2-nusCH2) and the xi angle which determines the gly conformational geometry. This relation allows us to determine the conformation of gly directly from the Raman spectral frequencies. We observe a large dependence of the nusCH2 and nuasCH2 frequencies on the ionization state of the amine group, which we demonstrate theoretically results from a negative hyperconjugation between the nitrogen lone pair and the C-H antibonding orbitals. The magnitude of this effect is maximized for C-H bonds trans to the nitrogen lone pair. In contrast, a small dependence of the CH2 stretching frequencies on the carboxyl group ionization state arises from delocalization of electron density from carboxyl oxygen to C-H bonding orbitals. According to our experimental observations and theoretical calculations the temperature dependence of the nusCH2 and nuasCH2 of gly is due to the change in the hydrogen-bonding strength of the amine/carboxyl groups to water. PMID- 18447352 TI - Inhibitors of UDP-galactopyranose mutase thwart mycobacterial growth. AB - Galactofuranose (Galf) residues are fundamental components of the cell wall of mycobacteria. A key enzyme, UDP-galactopyranose mutase (UGM), that participates in Galf incorporation mediates isomerization of UDP-Galf from UDP-galactopyranose (UDP-Galp). UGM is of special interest as a therapeutic target because the gene encoding it is essential for mycobacterial viability and there is no comparable enzyme in humans. We used structure-activity relationships and molecular design to devise UGM inhibitors. From a focused library of synthetic aminothiazoles, several compounds that block the UGM from Klebsiella pneumoniae or Mycobacterium tuberculosis were identified. These inhibitors block the growth of M. smegmatis. PMID- 18447353 TI - Toward long-distance mechanical communication: studies on a ternary complex interconnected by a bridging rotary module. AB - A heterotropic ternary complex was obtained from a photochromic dithienylethene derivative bearing pyridyl groups (1), a chiral tetrasubstituted ferrocene as a scissoring component bearing two pyridyl and free-base porphyrin groups (3*), and a biaryl derivative as an intermediately bridging component bearing four zinc porphyrin handles (2). The three components are connected together via bidentate coordination bonds and mechanically interconnected. Exposure of the ternary complex to UV or visible light allowed for the isomerization of 1. This configurational change gave rise to an angular motion of 2, resulting in a scissoring motion of 3*. In the absence of 2, the isomerization of 1 does not lead to any defined motions of 3*. Thus, the heterotropic ternary complex may be regarded as a prototype of "molecular reacher" for remote manipulation of molecular events. PMID- 18447354 TI - Stabilization by extra-helical thymines of a DNA duplex with Hoogsteen base pairs. AB - We present the crystal structure of the DNA duplex formed by d(ATATATCT). The crystals contain seven stacked antiparallel duplexes in the asymmetric unit with A.T Hoogsteen base pairs. The terminal CT sequences bend over so that the thymines enter the minor groove and form a hydrogen bond with thymine 2 of the complementary strand in the Hoogsteen duplex. Cytosines occupy extra-helical positions; they contribute to the crystal lattice through various kinds of interactions, including a unique CAA triplet. The presence of thymine in the minor groove apparently contributes to the stability of the DNA duplex in the Hoogsteen conformation. These observations open the way toward finding under what conditions the Hoogsteen duplex may be stabilized in vivo. The present crystal structure also confirms the tendency of A.T-rich oligonucleotides to crystallize as long helical stacks of duplexes. PMID- 18447355 TI - Site-selective guest inclusion in molecular networks of butadiyne-bridged pyridino and benzeno square macrocycles on a surface. AB - We present here the formation of a modular 2D molecular network composed of two different types of square-shaped butadiyne-bridged macrocycles, having intrinsic molecular voids, aligned alternately at the solid-liquid interface. Site selective inclusion of a guest cation took place at every other molecular void in the molecular network with two different recognition sites. PMID- 18447356 TI - 6-Peroxo-6-zirconium crown and its hafnium analogue embedded in a triangular polyanion: [M6(O2)6(OH)6(gamma-SiW10O36)3]18- (M = Zr, Hf). AB - We have synthesized and structurally characterized the unprecedented peroxo zirconium(IV) containing [Zr6(O2)6(OH)6(gamma-SiW10O36)3]18- (1). Polyanion 1 comprises a cyclic 6-peroxo-6-zirconium core stabilized by three decatungstosilicate units. We have also prepared the isostructural hafnium(IV) analogue [Hf6(O2)6(OH)6(gamma-SiW10O36)3]18- (2). We investigated the acid/base and redox properties of 1 by UV-vis spectroscopy and electrochemistry studies. Polyanion 1 represents the first structurally characterized Zr-peroxo POM with side-on, bridging peroxo units. The simple, one-pot synthesis of 1 and 2 involving dropwise addition of aqueous hydrogen peroxide could represent a general procedure for incorporating peroxo groups into a large variety of transition metal and lanthanide containing POMs. PMID- 18447357 TI - Enantioselective alkyl-alkyl Suzuki cross-couplings of unactivated homobenzylic halides. AB - The first effective method for asymmetric cross-couplings of unactivated alkyl electrophiles has been developed, specifically, a nickel-based catalyst for stereoconvergent Suzuki reactions of homobenzylic bromides with alkylboranes. To the best of our knowledge, there are no previous examples of enantioselective Suzuki couplings of alkyl electrophiles (activated or unactivated). Both of the catalyst components are commercially available. PMID- 18447358 TI - Effect of O6-methylguanine on the stability of G-quadruplex DNA. AB - The effects of substitution of O6-methylguanine on the structure and stability of a human telomere quadruplex was studied by circular dichroism, thermal denaturation, analytical ultracentrifugation, and molecular dynamics simulations. The results show that, while quadruplex structures can form containing the modified base, they are much less stable than the normal unmodified structure. The extent of destabilization is critically dependent on the exact position of the modified base within the quadruplex structure. PMID- 18447359 TI - Calculations predict rapid tunneling by carbon from the vibrational ground state in the ring opening of cyclopropylcarbinyl radical at cryogenic temperatures. AB - B3LYP/6-31G(d) calculations have been performed on the ring opening of cyclopropylcarbinyl radical 1 to 3-buten-1-yl radical 2. The dynamics of the reaction have been computed with canonical variational transition state theory (CVT), both with and without inclusion of small-curvature tunneling (SCT). The CVT + SCT calculations predict that 1 should undergo rapid and temperature independent ring opening to 2 at cryogenic temperatures, by tunneling from the lowest vibrational level of 1. PMID- 18447360 TI - A new class of easily activated palladium precatalysts for facile C-N cross coupling reactions and the low temperature oxidative addition of aryl chlorides. AB - A new class of one-component Pd precatalysts bearing biarylphosphine ligands is described. These precatalysts are air- and thermally stable, are easily activated under normal reaction conditions at or below room temperature, and ensure the formation of the highly active monoligated Pd(0) complex necessary for oxidative addition. The use of these precatalysts as a convenient source of LPd(0) in C-N cross-coupling reactions is explored. The reactivity that is demonstrated in this study is unprecedented in palladium chemistry. PMID- 18447361 TI - Effect of regulated deficit irrigation and crop load on the antioxidant compounds of peaches. AB - The use of regulated deficit irrigation (RDI) strategies is becoming a common practice in areas with low water availability. Little information is available about the effects of RDI on the antioxidant content of fruits. In this study, the influence of RDI on the content of vitamin C, phenolic compounds and carotenoids was investigated. Two irrigation strategies, fully irrigated (FI) and RDI, were compared at two levels of thinning, commercial and half of the commercial crop load. RDI strategies affected the content of vitamin C, phenolics and carotenoids of Flordastar peaches. RDI caused fruit peel stress lowering the content of vitamin C and carotenoids, while increasing the phenolic content, mainly anthocyanins and procyanidins. Fruit weight was the only quality index influenced by the crop load as it increased in FI fruits at low crop load. In general, fruits from commercial crop load had slightly higher content of antioxidants to fruits from low crop load, although these influences were only observed in the peel. Additionally, the influence of irrigation controlled by two sensors related to plant water level, maximum daily trunk shrinkage (MDS) and sap flow (SF) on the antioxidant constituents of peaches was evaluated. The response of the fruits to SF sensor was similar to that observed for RDI strategy. According to the tested water sensors, SF did not act as a good plant-based water indicator for use in irrigation scheduling, as it caused an increase in the content of phenolics, similar to that observed for fruits subjected to RDI. Therefore, selection of RDI strategies and plant water indicators should be taken into account as they affect the content of antioxidants of peaches. PMID- 18447362 TI - Application of the superarmed glycosyl donor to chemoselective oligosaccharide synthesis. AB - Recently, we discovered a novel method for "superarming" glycosyl donors. Herein, this concept has been exemplified in one-pot oligosaccharide syntheses, whereby the superarmed glycosyl donor was chemoselectively activated over traditional "armed" and disarmed glycosyl acceptors. Direct side-by-side comparison of the reactivities of the classic armed and superarmed glycosyl donors further validates the credibility of the novel concept. PMID- 18447363 TI - Superarming the S-benzoxazolyl glycosyl donors by simple 2-O-benzoyl-3,4,6-tri-O benzyl protection. AB - The strategic placement of common protecting groups led to the discovery of a new method for "superarming" glycosyl donors. Conceptualized from our previous studies on the O-2/O-5 Cooperative Effect, it was determined that S-benzoxazolyl glycosyl donors possessing both a participating moiety at C-2 and an electronically armed lone pair at O-5, such as the superarmed glycosyl donor shown above, were exceptionally reactive. PMID- 18447364 TI - Phosphonoxins II: diastereoselective synthesis of phosphonic acid analogues of polyoxins. AB - A diastereoselective synthesis of polyoxin analogues termed phosphonoxin B1 and B2 has been achieved. The key step was sulfinimine-mediated asymmetric formation of ( RS ,2S,3S,4S)-beta-aminophosphonate 3a or (SS ,2R,3S,4S)-beta aminophosphonate 7 as the major diastereoisomer. A double stereodifferentiation effect was not observed, and the diastereoselectivity is controlled by the absolute configuration of the sulfinyl group. PMID- 18447365 TI - Slow motion analysis of protein folding intermediates within wet silica gels. AB - Resolving the complete folding pathway of a protein is a major challenge to conventional experimental methods because of the rapidity and complexity of folding. Here, we show that entrapment of the protein cytochrome c in wet, optically transparent, porous silica gel matrices has enabled a dramatic expansion, to days or weeks, of the folding time, allowing direct observation of the entire folding pathway using a combination of three spectroscopic techniques, far-ultraviolet circular dichroism, tryptophan fluorescence, and Soret absorption spectroscopy. During refolding in silica gels, collapse and helix formation occur in a stepwise manner, as observed in aqueous solution. Analysis of kinetics and transient spectra indeed reveals a sequence of four distinct intermediates with progressively increasing degrees of folding, two of which closely resemble those previously characterized in solution, namely, the early collapsed and the molten globule intermediates. The other two are the precollapsed and pre-molten globule intermediates that may escape detection by conventional kinetic methods. Interestingly, varying the strength of the gel network has a dramatic effect on the folding time, but no significant effect on the structural features of each folding intermediate, indicating that the interaction between the protein and gel matrix has no measurable effect on the folding pathway. These results better define the major pathway of cytochrome c folding. In addition, in this paper we present the results of the application of this method to a simple, apparent two state folder ubiquitin, helping to interpret the results for cytochrome c. PMID- 18447366 TI - Noble metals on the nanoscale: optical and photothermal properties and some applications in imaging, sensing, biology, and medicine. AB - Noble metal nanostructures attract much interest because of their unique properties, including large optical field enhancements resulting in the strong scattering and absorption of light. The enhancement in the optical and photothermal properties of noble metal nanoparticles arises from resonant oscillation of their free electrons in the presence of light, also known as localized surface plasmon resonance (LSPR). The plasmon resonance can either radiate light (Mie scattering), a process that finds great utility in optical and imaging fields, or be rapidly converted to heat (absorption); the latter mechanism of dissipation has opened up applications in several new areas. The ability to integrate metal nanoparticles into biological systems has had greatest impact in biology and biomedicine. In this Account, we discuss the plasmonic properties of gold and silver nanostructures and present examples of how they are being utilized for biodiagnostics, biophysical studies, and medical therapy. For instance, taking advantage of the strong LSPR scattering of gold nanoparticles conjugated with specific targeting molecules allows the molecule-specific imaging and diagnosis of diseases such as cancer. We emphasize in particular how the unique tunability of the plasmon resonance properties of metal nanoparticles through variation of their size, shape, composition, and medium allows chemists to design nanostructures geared for specific bio-applications. We discuss some interesting nanostructure geometries, including nanorods, nanoshells, and nanoparticle pairs, that exhibit dramatically enhanced and tunable plasmon resonances, making them highly suitable for bio-applications. Tuning the nanostructure shape (e.g., nanoprisms, nanorods, or nanoshells) is another means of enhancing the sensitivity of the LSPR to the nanoparticle environment and, thereby, designing effective biosensing agents. Metal nanoparticle pairs or assemblies display distance-dependent plasmon resonances as a result of field coupling. A universal scaling model, relating the plasmon resonance frequency to the interparticle distance in terms of the particle size, becomes potentially useful for measuring nanoscale distances (and their changes) in biological systems. The strong plasmon absorption and photothermal conversion of gold nanoparticles has been exploited in cancer therapy through the selective localized photothermal heating of cancer cells. For nanorods or nanoshells, the LSPR can be tuned to the near-infrared region, making it possible to perform in vivo imaging and therapy. The examples of the applications of noble metal nanostructures provided herein can be readily generalized to other areas of biology and medicine because plasmonic nanomaterials exhibit great range, versatility, and systematic tunability of their optical attributes. PMID- 18447367 TI - Protein conjugation with amphiphilic block copolymers for enhanced cellular delivery. AB - Modification of a model protein, horseradish peroxidase (HRP), with amphiphilic block copolymer poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (Pluronic), was previously shown to enhance the transport of this protein across the blood-brain barrier in vivo and brain microvessel endothelial cells in vitro. This work develops procedures for synthesis and characterization of HRP with Pluronic copolymers, having different lengths of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) blocks. Four monoamine Pluronic derivatives (L81, P85, L121, P123) were synthesized and successfully conjugated to a model protein, HRP, via biodegradable or nondegradable linkers (dithiobis(succinimidyl propionate) (DSP), dimethyl 3,3'-dithiobispropionimidate (DTBP), and disuccinimidyl propionate (DSS)). The conjugation was confirmed by HRP amino group titration, matrix-assisted laser desorption/ionization-time of flight spectroscopy, and cation-exchange chromatography. HRP conjugates containing an average of one to two Pluronic moieties and retaining in most cases over 70% of the activity were synthesized. Increased cellular uptake of these conjugates was demonstrated using the Mardin-Derby canine kidney cell line and primary bovine brain microvessel endothelial cells. The optimal modifications included Pluronic L81 and P85. These copolymers have shorter PPO chains compared to Pluronic P123 and L121, which were less efficient. There was little if any dependence of the uptake on the length of the hydrophilic PEO block for the optimal modifications. The proposed modifications may be used to increase cellular uptake of other proteins. PMID- 18447371 TI - Compressibility of liquids. Rule of noncrossing V-P curvatures. AB - Weight analysis of the liquid introduced into the stainless steel bomb under pressures up to 1 kbar in the temperature range of 20-50 degrees C at the interval of 10 degrees C was performed for 1,4-dioxane, acetonitrile, toluene, ethyl acetate, chlorobenzene, and n-hexane. The coefficients of the Tait equation were determined for all of the solvents at each temperature. There was a clear linear relation between the tangent bulk modulus (1/beta T) at atmospheric pressure (1 bar) and the secant bulk modulus at 1 kbar; 1/betaT=0.9865 x (1000 V0/DeltaV(1kbar))-4559 was found at a wide range of temperatures for different liquids, including glycerol and even mercury. This represents the rule of noncrossing P-V curvatures for the liquids. Using the correlation, it is possible to predict the coefficients (C, B) of the Tait equation from the experimental data of betaT at 1 bar or, on the other hand, to calculate the value of betaT from experimental compression at high pressures. PMID- 18447369 TI - End modification of a linear DNA duplex enhances NER-mediated excision of an internal Pt(II)-lesion. AB - The study of DNA repair has been facilitated by the development of extract-based in vitro assay systems and the use of synthetic DNA duplexes that contain site specific lesions as repair substrates. Unfortunately, exposed DNA termini can be a liability when working in crude cell extracts because they are targets for DNA end-modifying enzymes and binding sites for proteins that recognize DNA termini. In particular, the double-strand break repair protein Ku is an abundant DNA end binding protein that has been shown to interfere with nucleotide excision repair (NER) in vitro. To facilitate the investigation of NER in whole-cell extracts, we explored ways of modifying the exposed ends of synthetic repair substrates to prevent Ku binding and improve in vitro NER efficiency. Replacement of six contiguous phosphodiester linkages at the 3'-ends of the duplex repair substrate with nuclease-resistant nonionic methylphosphonate linkages resulted in a 280 fold decrease in binding affinity between Ku and the modified duplex. These results are consistent with the published crystal structure of a Ku/DNA complex [Walker et al. (2001) Nature 412, 607-614] and show that the 3'-terminal phosphodiester linkages of linear DNA duplexes are important determinants in DNA end-binding by Ku. Using HeLa whole-cell extracts and a 149-base pair DNA duplex repair substrate, we tested the effects of modification of exposed DNA termini on NER-mediated in vitro excision of a 1,3-GTG-Pt(II) intrastrand cross-link. Methylphosphonate modification at the 3'-ends of the repair substrate resulted in a 1.6-fold increase in excision. Derivatization of the 5'-ends of the duplex with biotin and subsequent conjugation with streptavidin to block Ku binding resulted in a 2.3-fold increase excision. By combining these modifications, we were able to effectively reduce Ku-derived interference of NER excision in vitro and observed a 4.4-fold increase in platinum lesion excision. These modifications are easy to incorporate into synthetic oligonucleotides and may find general utility whenever synthetic linear duplex DNAs are used as substrates to investigate DNA repair in whole-cell extracts. PMID- 18447372 TI - Physicochemical characterization and tube-like structure formation of a novel amino acid-based zwitterionic amphiphile N-(2-hydroxydodecyl)-L-valine in water. AB - Surface activity and aggregation behavior of an amino acid-based zwitterionic amphiphile N-(2-hydroxydodecyl)-L-valine were studied in aqueous solutions (pH 13). The self-assembly formation was investigated by use of a number of techniques including surface tension, conductivity, viscosity, fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy. The amphiphile exhibits two breaks in the surface tension vs concentration plot indicating stepwise aggregate formation and thus results in two values of critical aggregation concentration. The amphiphile was found to be very surface active compared to fatty acid soaps. The average hydrodynamic diameter and size distribution of the aggregates were obtained from DLS measurements. Conductivity measurements suggested formation of vesicles or closed tubules. TEM pictures revealed the existence of spherical vesicles, separated tubules, and tubules with multiple Y-type junctions in going from dilute to moderately concentrated solution. However, in concentrated solution, the junctions break to form separate tubular structures which upon further increase of concentration are converted to rod-like micelles. The mechanism of branched tubule formation is discussed in light of the experimental observations. PMID- 18447373 TI - Kinetics and mechanism of the sonolytic conversion of the aqueous perfluorinated surfactants, perfluorooctanoate (PFOA), and perfluorooctane sulfonate (PFOS) into inorganic products. AB - The perfluorinated surfactants perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are recognized as widespread in the environment as well as recalcitrant toward most conventional water treatment technologies. In this study, acoustic cavitation as driven by high-frequency ultrasound is shown to be effective in the degradation of aqueous solutions of PFOS and PFOA and effective over a wide range of concentrations from 10 nM to 10 muM for a given compound. Sulfur, fluorine, and carbon mass balances indicate that mineralization occurs immediately following the degradation of the initial perfluorinated surfactant. Near complete conversion of PFOS and PFOA to CO, CO2, F-, and SO42- occurs due to pyrolytic reactions at the surface and vapor phase of transiently collapsing cavitation bubbles. The initial PFOS or PFOA pyrolytic degradation occurs at the bubble-water interface and involves the loss of the ionic functional group leading to the formation of the corresponding 1H-fluoroalkane or perfluoroolefin. The fluorochemical intermediates undergo a series of pyrolytic reactions in the bubble vapor leading to C1 fluoro-radicals. Secondary vapor-phase bimolecular reactions coupled with concomitant hydrolysis converts the C1 fluoro-radicals to carbon monoxide, carbon dioxide, and HF, forming a proton and fluoride upon dissolution. Sonochemical half-lives, which are calculated from high-temperature gas-phase kinetics, are consistent with kinetic observations and suggest that mineralization occurs shortly after initial perfluorinated surfactant interfacial pyrolysis. PMID- 18447374 TI - Oscillations in the concentration of fluoride ions induced by a pH oscillator. AB - Sustained oscillations in the concentration of free fluoride ions can be generated when the BrO3--SO32--Mn(II) oscillator is coupled either to Al3+-F- complex formation or to the Ca2+-F- precipitation process in a flow reactor. By careful analysis of the relevant equilibria and optimization of the reactant concentrations, one can obtain [F-] oscillations of several orders of magnitude as measured with an ion-selective electrode. The BrO3--SO32--Mn(II)-Al(NO3)3-NaF system also exhibits bistability, that is, simultaneously stable steady states of high and low [F-]. PMID- 18447375 TI - Conformational stability of 1-butene: an electron momentum spectroscopy investigation. AB - The valence-shell electron momentum distributions for 1-butene are measured by electron momentum spectroscopy (EMS) employing non-coplanar symmetric geometry. The experimental electron momentum distributions are compared with the density functional theory (DFT) calculations using different-sized basis sets. Although the two conformers of 1-butene in the gas phase, namely the skew and syn, have very close ionization potentials, the electron momentum distributions, especially in the low momentum region, can show prominent differences for some of the valence orbitals. By comparing the experimental electron momentum profiles with the theoretical ones, the skew conformer is found to be more stable than the syn and their relative abundances at room temperature are estimated to be (69 +/- 6)% and (31 +/- 6)%, respectively. It demonstrates that EMS has the latent potential to study the relative stability of conformers. PMID- 18447376 TI - Neurobiology with caged calcium. PMID- 18447377 TI - Genetically encoded calcium indicators. PMID- 18447378 TI - Cys-loop neuroreceptors: structure to the rescue? PMID- 18447379 TI - Discovery of aryl aminoquinazoline pyridones as potent, selective, and orally efficacious inhibitors of receptor tyrosine kinase c-Kit. AB - Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation. PMID- 18447380 TI - Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. AB - The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients. PMID- 18447381 TI - Activity-based probe for specific photoaffinity labeling gamma-aminobutyric acid B (GABAB) receptors on living cells: design, synthesis, and biological evaluation. AB - A trimodular activity-based probe was designed, synthesized, characterized, and applied to photoaffinity label the GABA(B) receptors transiently expressed in Chinese hamster ovary (CHO) cells. The probe exhibits specific binding activity at the ligand-binding pocket of GB1 subunits and high specificity of photoaffinity labeling, which makes the probe valuable for studying the localization and function of GABA(B) receptors on living cells. PMID- 18447382 TI - A highly specific BODIPY-based fluorescent probe for the detection of hypochlorous acid. AB - A fluorescent probe, HKOCl-1, has been successfully developed for the detection of hypochlorous acid on the basis of a specific reaction with p-methoxyphenol. The formation of HOCl has been successfully detected not only in an abiotic system but also in an enzymatic system (myeloperoxidase/H2O2/Cl(-) system) and in living macrophage cells upon stimulation. This new probe might be used as an efficient tool for probing the roles HOCl plays in biological systems. PMID- 18447383 TI - An RCM strategy to stereodiverse delta-sultam scaffolds. AB - An asymmetric approach for the synthesis of substituted delta-sultams with multiple synthetic handles is described. This study demonstrates the facile construction of a stereochemically diverse array of substituted delta-sultams, more specifically substituted 3,4,5,6-dihydro 1,2-thiazine 1,1-dioxides. A pivotal Mitsunobu alkylation/RCM sequence is used to assemble key allyl sultam building blocks possessing a C3 stereogenic handle. All subsequent reactions are achieved with high levels of diastereoselectivity to afford enantiopure delta sultams in good yields. PMID- 18447384 TI - (Iso)-quinoline alkaloids from fungal fruiting bodies of Cortinarius subtortus. AB - Chemical analysis of the fruiting bodies of the agaricoid fungus Cortinarius subtortus yielded three new natural products, two quinoline and one isocarbostyryl alkaloid. The structures of compounds 1- 3 were determined by analysis of NMR and MS data. Compound 1 exhibited inhibitory effects against the phytopathogenic fungus Colletotrichum coccodes. All three compounds displayed moderate antioxidant activity in a DPPH free radical scavenging bioassay. PMID- 18447385 TI - A C-3 methylated isocembranoid and 10-oxocembranoids from a formosan soft coral, Sinularia grandilobata. AB - Five new cembranoids, designated grandilobatins A-E (1- 5), were isolated from the soft coral Sinularia grandilobata. Grandilobatin C (3) was found to have a novel skeleton with the C-4 methyl group of the normal cembranoid rearranged to C 3, while the other metabolites were identified as new 10-oxocembranoids. Metabolite 4 has weak cytotoxicity toward MDA-MB-23 human breast tumor cells. Also, 4 significantly inhibited the accumulation of the pro-inflammatory iNOS protein of LPS-stimulated RAW264.7 macrophage cells at 50 microM. PMID- 18447386 TI - Synthesis of hydrophobic derivatives of the G/?C base for rosette nanotube self assembly in apolar media. AB - Eleven self-complementary G/?C derivatives bearing hydrophobic moieties were synthesized and characterized. One representative derivative from this family was shown to self-assemble into rosette nanotubes in hexane and form Langmuir Blodgett films at the air-water interface. PMID- 18447387 TI - Enantioselective Baeyer-Villiger oxidation catalyzed by palladium(II) complexes with chiral P,N-ligands. AB - Asymmetric Baeyer-Villiger reaction of symmetrical cyclobutanones 1a-j with urea hydrogen peroxide (UHP) can be catalyzed by a complex of Pd(II) and the new terpene-derived P, N-ligand 7. The resulting lactones 2a-j were obtained in high yields and with good enantioselectivity (< or =81% ee). PMID- 18447388 TI - Stereoselective synthesis of 3,3-diarylacrylonitriles as tubulin polymerization inhibitors. AB - A series of 3,3-diarylacrylonitriles were synthesized stereoselectively as tubulin polymerization inhibitors for potential use in cancer chemotherapy. This synthetic route features stannylcupration and palladium-catalyzed Stille cross coupling chemistry, allowing both E and Z isomers of 3,3-diarylacrylonitriles to be prepared in a very short sequence of reactions. PMID- 18447389 TI - Improved procedure for the bimolecular oxidative amidation of phenols. AB - Trifluoroacetic acid (TFA) is an effective promoter of the bimolecular Ritter like oxidative amidation of 4-substituted phenols induced by PhI(OAc) 2 in MeCN. This suppresses the need for fluoroalcohol cosolvents, increases the yields, and facilitates isolation/purification procedures. PMID- 18447390 TI - Propargylic oxidations catalyzed by dirhodium caprolactamate in water: efficient access to alpha,beta-acetylenic ketones. AB - Dirhodium(II) caprolactamate (1, Rh 2(cap) 4) with 70% w/w aqueous tert-butyl hydroperoxide (T-HYDRO ) is a highly effective catalytic oxidation protocol for the selective C-H oxidation of alkynes to propargylic ketones. The oxidation occurs readily in aqueous solvent under mild conditions with an inexpensive and easily handled oxidant. Alpha,beta-acetylenic carbonyl compounds are formed in up to 80% isolated yield. PMID- 18447391 TI - Bronsted acid TfOH-mediated [3 + 2] cycloaddition reactions of diarylvinylidenecyclopropanes with nitriles. AB - Diarylvinylidenecyclopropanes undergo a [3 + 2] cycloaddition reaction with MeCN in the presence of Bronsted acid TfOH to give the corresponding 3,4-dihydro-2 H pyrrole derivatives 2 in moderate to excellent yields under reflux within a short time. As for the diarylvinylidenecyclopropane substrate containing a strongly electron-donating methoxy group on the benzene ring, the reaction leads to the formation of a different type of 3,4-dihydro-2 H-pyrrole derivatives 4 under the same conditions. PMID- 18447393 TI - Increased mitochondrial thioredoxin 2 potentiates N-ethylmaleimide-induced cytotoxicity. AB - Thioredoxin 2 (Trx2) is a mitochondrially localized antioxidant and antiapoptotic protein, whose functions are mainly dependent on the conserved cysteines at its redox active center. In the current study, we showed by mass spectrometry that a thiol alkylating agent, N-ethylmaleimide (NEM), alkylated a single cysteine residue in the active center of Trx2. The interaction between NEM and Trx2 in intact cells was confirmed by redox Western analysis. Overexpression of Trx2 in cultured 143B osteosarcoma cells caused increased sensitivity to NEM. Covalent modification by NEM resulted in a dominant-negative effect and increased the interaction between Trx2 and peroxiredoxin 3 (Prx3). Our data suggest that the alkylation of the essential thiol(s) of Trx2 has profound impact on the mitochondrial redox circuitry and that such effects are distinct from the responses to agents causing reversible disulfide bond formation between the vicinal dithiols in the active center. PMID- 18447392 TI - Highly enantioselective borane reduction of heteroaryl and heterocyclic ketoxime ethers catalyzed by novel spiroborate ester derived from diphenylvalinol: application to the synthesis of nicotine analogues. AB - An asymmetric synthesis for the preparation of nonracemic amines bearing heterocyclic and heteroaromatic rings is described. A variety of important enantiopure thionyl and arylalkyl primary amines were afforded by the borane mediated enantioselective reduction of O-benzyl ketoximes using 10% of catalyst 10 derived from ( S)-diphenylvalinol and ethylene glycol with excellent enantioselectivity, in up to 99% ee. The optimal condition for the first asymmetric reduction of 3- and 4-pyridyl-derived O-benzyl ketoxime ethers was achieved using 30% of catalytic loading in dioxane at 10 degrees C. ( S)- N ethylnornicotine ( 3) was also successfully synthesized from the TIPS-protected ( S)-2-amino-2-pyridylethanol in 97% ee. PMID- 18447394 TI - Oxidative DNA damage in XPC-knockout and its wild mice treated with equine estrogen. AB - Long-term hormone replacement therapy with equine estrogens is associated with a higher risk of breast, ovarian, and endometrial cancers. Reactive oxygen species generated through redox cycling of equine estrogen metabolites may damage cellular DNA. Such oxidative stress may be linked to the development of cancers in reproductive organs. Xeroderma pigmentosa complementation group C-knockout ( Xpc-KO) and wild-type mice were treated with equilenin (EN), and the formation of 7,8-dihydro-8-oxodeoxyguanosine (8-oxodG) was determined as a marker of typical oxidative DNA damage, using liquid chromatography electrospray tandem mass spectrometry. The level of hepatic 8-oxodG in wild-type mice treated with EN (5 or 50 mg/kg/day) was significantly increased by approximately 220% after 1 week, as compared with mice treated with vehicle. In the uterus also, the level of 8 oxodG was significantly increased by more than 150% after 2 weeks. Similar results were observed with Xpc-KO mice, indicating that Xpc does not significantly contribute to the repair of oxidative damage. Oxidative DNA damage generated by equine estrogens may be involved in equine estrogen carcinogenesis. PMID- 18447395 TI - hERG potassium channels and the structural basis of drug-induced arrhythmias. AB - hERG potassium channels have a critical role in the normal electrical activity of the heart. The block of hERG channels can cause the drug-induced form of long QT syndrome, a cardiac disorder that carries an increased risk of cardiac arrhythmias and sudden death. hERG channels are extraordinarily sensitive to block by large numbers of structurally diverse drugs. In previous years, the risk of compounds causing this cardiotoxic side effect has been a common reason for the failure of compounds in preclinical safety trials. Pharmaceutical companies have successfully utilized and developed higher throughput techniques for the early detection of compounds that block hERG, and this has helped reduce the number of compounds that fail in the late stages of development. Nevertheless, this screening-based approach is expensive, consumes chemistry resources, and bypasses the problem rather than shedding light on it. Crystal structures of potassium channels have facilitated studies into the structural basis for the gating and block of hERG channels. Most drugs bind within the inner cavity, and the individual amino acids that form the drug binding site have been identified by site-directed mutagenesis approaches. Gating processes have an important influence on the drug-binding site. Recent advances in our understanding of channel activation and inactivation are providing insight into why hERG channels are more susceptible to block than other K (+) channels. Knowledge of the structure of the drug-binding site and precise nature of interactions with drug molecules should assist efforts to develop drugs without the propensity to cause cardiac arrhythmias. PMID- 18447396 TI - Molecular structure and dynamic properties of a sulfonamide derivative of glutathione that is produced under conditions of oxidative stress by hypochlorous acid. AB - Reduced glutathione (GSH) is a cornerstone of the antioxidant stratagem for eukaryotes and some prokaryotes. Hypochlorous acid (HOCl), which is produced by neutrophilic myeloperoxidase, reacts rapidly with excess GSH to yield mainly oxidized glutathione (GSSG). GSSG can be further oxidized to give first N-chloro derivatives and, later, higher oxidation states at the S centers. Under certain conditions, another major species that is observed during the oxidation of GSH by HOCl (and a minor species for other oxidants) exhibits a molecular mass that is 30 mass units heavier than GSH. This GSH+2O-2H species, which has been employed as a biomarker for oxidative stress, has been previously proposed to be a sulfonamide. Employing NMR spectroscopy and mass spectrometry, we demonstrate that the GSH+2O-2H species is indeed a nine-membered cyclic sulfonamide. Alternative formulations, including six-membered 1,2,5-oxathiazine heterocycles, have been ruled out. Remarkably, the sulfonamide exists as a 2:1 equilibrium mixture of two diastereomers. Isotope tracer studies have demonstrated that it is the Glu C alpha center that has undergone racemization. It is proposed that the racemization takes place via an acyclic imine-sulfinic acid intermediate. The glutathione sulfonamides are stable products of GSH that have been detected in physiological systems. Elucidation of the structures of the glutathione sulfonamides provides further impetus to explore their potential as biomarkers of hypochlorous acid formation. PMID- 18447398 TI - Probing the dynamics of protein-protein interactions at neuronal contacts by optical imaging. PMID- 18447399 TI - Photocontrol of neural activity: biophysical mechanisms and performance in vivo. PMID- 18447400 TI - Space charge limited current measurements on conjugated polymer films using conductive atomic force microscopy. AB - We describe local (~150 nm resolution), quantitative measurements of charge carrier mobility in conjugated polymer films that are commonly used in thin-film transistors and nanostructured solar cells. We measure space charge limited currents (SCLC) through these films using conductive atomic force microscopy (c AFM) and in macroscopic diodes. The current densities we measure with c-AFM are substantially higher than those observed in planar devices at the same bias. This leads to an overestimation of carrier mobility by up to 3 orders of magnitude when using the standard Mott-Gurney law to fit the c-AFM data. We reconcile this apparent discrepancy between c-AFM and planar device measurements by accounting for the proper tip-sample geometry using finite element simulations of tip-sample currents. We show that a semiempirical scaling factor based on the ratio of the tip contact area diameter to the sample thickness can be used to correct c-AFM current-voltage curves and thus extract mobilities that are in good agreement with values measured in the conventional planar device geometry. PMID- 18447397 TI - Neurobiological applications of small molecule screening. PMID- 18447402 TI - Asymptomatic hyperthyroidism in older adults: is it a distinct clinical and laboratory entity? AB - Hyperthyroidism is the result of increased serum free thyroid hormone levels and is associated with a well recognized set of clinical signs and symptoms. However, older patients who develop hyperthyroidism tend to have fewer hyperadrenergic signs and an increased incidence of weight loss, cardiac arrhythmias and, occasionally, apathetic mood. This article highlights the paucity of clinical signs and symptoms of hyperthyroidism in older people and reviews the potential biochemical changes in thyroid hormone physiology that may account for an altered clinical presentation in older people with hyperthyroidism. First, a brief vignette from our own clinical practice is described to highlight an unusual presentation of hyperthyroidism in an older woman. The subject is then reviewed on the basis of relevant articles identified through a MEDLINE search of the English literature, using the key words 'hyperthyroidism' and 'aging'. The available evidence indicates that the clinical syndrome of asymptomatic hyperthyroidism in older adults appears to be distinct from the more widely recognized syndromes of apathetic hyperthyroidism or thyroid hormone resistance. Age-related changes in thyroid hormone economy and reduced cellular uptake of thyroid hormone as well as changes in thyroid hormone regulation of gene expression may account for reduced manifestations of hyperthyroidism in older adults. Thus, in addition to the well known changes in thyroid gland anatomy and function with aging, there may be an age-related resistance to thyroid hormone action. Asymptomatic hyperthyroidism may well be a syndrome that is currently under-diagnosed. PMID- 18447401 TI - Androgen deficiency as a predictor of metabolic syndrome in aging men: an opportunity for intervention? AB - The prevalence of metabolic syndrome is increasing globally and is an important risk factor for the development of cardiovascular disease. Longitudinal population studies have found that low testosterone status in men is a risk factor for the later development of metabolic syndrome. Men with metabolic syndrome and type 2 diabetes mellitus have a higher incidence of hypotestosteronaemia. Furthermore, in men, testosterone levels are inversely associated with the degree of carotid and aortic atherosclerosis. Early interventional, short-term studies have shown that testosterone replacement therapy has a beneficial effect on visceral obesity, insulin sensitivity, glycaemic control and lipid profiles in men with diagnosed hypogonadism with and without diabetes. The effect of testosterone therapy on atherogenesis in men is unknown; however, animal studies have shown that testosterone is atheroprotective and can ameliorate the degree of atherosclerosis. Testosterone is an arterial vasodilator and has been shown to improve myocardial ischaemia in men with coronary artery disease. This review discusses the role that testosterone may play in the pathogenesis of metabolic syndrome in men and also examines the potential role of testosterone replacement therapy in this condition. PMID- 18447403 TI - Alternatives to atypical antipsychotics for the management of dementia-related agitation. AB - Numerous recent studies have challenged the widely held belief that atypical antipsychotics are safe and effective options for the treatment of behavioural problems such as agitation in patients with dementia. Accordingly, there is a need to reconsider the place of atypical antipsychotics in the treatment of patients with dementia. The present article is intended to assist clinicians with the assessment and pharmacological management of agitation in patients with dementia. We review the risk-benefit evidence for the use of atypical antipsychotics in patients with dementia-related agitation (DRA). Emerging evidence indicates that, for patients with dementia, the risks associated with atypical antipsychotics may outweigh the benefits except for patients with severe agitation who require short-term chemical restraint. We then discuss the importance of a careful assessment to rule out potentially reversible factors contributing to DRA. Finally, we summarize the evidence supporting the use of medications other than antipsychotics to treat DRA. There is wide variability in the levels of evidence supporting the use of non-antipsychotic medication for the treatment of DRA. The best evidence currently exists for cholinesterase inhibitors and serotonin-specific reuptake inhibitor antidepressants. Emerging reports suggest that numerous other medications, for example, antiepileptics, lithium, anxiolytics, analgesics, beta-adrenoceptor antagonists, cannabinoid receptor agonists and hormonal agents, may prove to be viable alternatives to antipsychotics for the treatment of severe DRA and more research is urgently needed to help assess the effectiveness of these agents. A comprehensive biopsychosocial assessment and treatment plan is likely the most effective way to manage DRA. PMID- 18447406 TI - Big three of future geriatrics: prevention, maintenance, palliation. PMID- 18447407 TI - Dysphagia: causes, assessment, treatment, and management. AB - Dysphagia, or difficulty in swallowing, is a condition with a strong age-related bias. Rates of dysphagia vary due to differences in method between studies; eg, clinical history of "swallowing difficulty," evidence of aspiration, or dysphagia confirmed by swallowing investigations. In general, the rate is lower in the community than in nursing home facilities. The management and treatment of dysphagia among geriatric patients is complicated by cognitive decline, lowered immunity, malnutrition, and end-of-life decisions. This article reviews the current assessment, treatment, and management techniques for dysphagia; covers new developments in research and pilot studies; and reviews the ethical issues related to treatment when prognosis is poor. PMID- 18447404 TI - Surgical site infections in older adults: epidemiology and management strategies. AB - Surgical site infections (SSIs) represent a major source of morbidity and mortality among older adults. In this review we discuss the epidemiology and risk factors for SSIs among older adults. We also offer an overview of current treatment and management strategies for several common SSIs. Our comments focus on the following areas in order to illustrate issues of clinical importance in the older patient: (i) cardiac surgery; (ii) vascular grafts; (iii) total joint arthroplasty; (iv) breast surgery; and (v) spinal surgeries. Besides being common and relatively specific to older adults, several of these surgical procedures require the use of prosthetic materials or devices, which present unique treatment challenges in the context of infection. When an older adult does develop an SSI, it is critical for clinicians to establish an overall treatment goal for each patient. In the majority of patients, this will be either complete cure or remission followed by suppressive therapy. However, clinicians caring for older adults must consider not only the possibility of microbiological cure, but also balance the need to preserve functional status and overall quality of life. Infections associated with devices and prosthetic material can present unique treatment challenges. Treatment of significant infections often requires prolonged courses of parenteral and/or oral antimicrobial therapy, which can raise issues related to the safety and tolerability of antimicrobial agents, including higher rates of nephrotoxicity. Issues concerning overall functional status, nutritional reserve and medical co-morbidities must be taken into consideration when approaching SSIs in an older adult. PMID- 18447408 TI - Management for motor and non-motor complications in late Parkinson's disease. AB - The prevalence of neurodegenerative diseases such as Parkinson's disease (PD) increases with age. In an aging population, an understanding of the management of late complications of PD is becoming ever more important. Drug treatment for Parkinson's disease is largely symptomatic and relies primarily on levodopa (L dopa) and adjuvant therapies including dopamine agonists and catechol-O methyltransferase (COMT) inhibitors. Rehabilitation and allied health input also constitutes a core part of successful management. Most subjects who are symptomatic for more than 5 years are prone to late complications of PD. Some of these are related to the treatment, such as motor fluctuations, including the "on off" phenomenon and levodopa-related peak dose dyskinesia. Others, such as postural hypotension, falls, psychosis, and dementia, although well-recognized problems in the elderly, often require different treatment strategies if occurring in the context of PD. The practical evidence-based management of motor and non-motor complications in late PD is discussed. PMID- 18447409 TI - Delirium: the ADVISE approach and tips from the frontlines. AB - Delirium is very common among the elderly. For patients, their families, and the healthcare system, it is emotionally, functionally, and financially costly. This article takes the available guidelines for treatment and management of delirium one step further by providing practical tips from the perspective of a consultant geriatric psychiatrist working with these patients every day. PMID- 18447410 TI - Ulcerated papule on vertex of the scalp. PMID- 18447412 TI - Residual multiparticle entropy does not generally change sign near freezing. AB - The residual multiparticle entropy (RMPE) of two- and three-dimensional fluids changes sign near the freezing line, providing a quasiuniversal "one-phase" rule for the location of the liquid-solid transition. We present new simulation results for d-dimensional hard-sphere fluids (d=1-5) which show, however, that this freezing criterion fails in other spatial dimensions. The results also call into question the idea that a change in sign of the RMPE implies the emergence of a new kind of local structural order in the fluid. PMID- 18447413 TI - Glasslike behavior in aqueous electrolyte solutions. AB - When salts are added to water, generally the viscosity increases, suggesting that the ions increase the strength of the water's hydrogen-bond network. However, infrared pump-probe measurements on electrolyte solutions have found that ions have no influence on the rotational dynamics of water molecules, implying no enhancement or breakdown of the hydrogen-bond network. Here, we report optical Kerr effect and dielectric relaxation spectroscopic measurements, which have enabled us to separate the effects of rotational and transitional motions of the water molecules. These data show that electrolyte solutions behave like a supercooled liquid approaching a glass transition in which rotational and translational molecular motions are decoupled. It is now possible to understand previously conflicting viscosity data, nuclear magnetic resonance relaxation, and ultrafast infrared spectroscopy in a single unified picture. PMID- 18447414 TI - Distribution function in quantal cumulant dynamics. AB - We have derived a quantum distribution function in terms of cumulants that are expectation values of a (anti)symmetric-ordered product of position and momentum fluctuation operators. A second-order approximation leads a Gaussian distribution function, which is positive definite and has proper marginals so that the Shannon entropy can be evaluated. PMID- 18447415 TI - Frozen natural orbital coupled-cluster theory: forces and application to decomposition of nitroethane. AB - The frozen natural orbital (FNO) coupled-cluster method increases the speed of coupled-cluster (CC) calculations by an order of magnitude with no consequential error along a potential energy surface. This method allows the virtual space of a correlated calculation to be reduced by about half, significantly reducing the time spent performing the coupled-cluster (CC) calculation. This paper reports the derivation and implementation of analytical gradients for FNO-CC, including all orbital relaxation for both noncanonical and semicanonical perturbed orbitals. These derivatives introduce several new orbital relaxation contributions to the CC density matrices. FNO-CCSD(T) and FNO-LambdaCCSD(T) are applied to a test set of equilibrium structures, verifying that these methods are capable of reproducing geometries and vibrational frequencies accurately, as well as energies. Several decomposition pathways of nitroethane are investigated using CCSD(T) and LambdaCCSD(T) with 60% of the FNO virtual orbitals in a cc-pVTZ basis, and find differences on the order of 5 kcalmol with reordering of the transition state energies when compared to B3LYP 6-311 + G(3df, 2p). PMID- 18447405 TI - Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing. AB - Asthma and chronic obstructive pulmonary disease (COPD) are common disorders that are associated with increasing morbidity and mortality in older people. Bronchodilators are used widely in patients with these conditions, but even when used in inhaled form can have systemic as well as local effects. Older people experience more adverse drug effects because of pharmacodynamic and pharmacokinetic changes and particularly drug-drug and drug-disease interactions. Cardiovascular disease is common in older people and beta-adrenoceptor agonists (beta-agonists) have inotropic and chronotropic effects that can increase arrhythmias and cardiomyopathy. They can also worsen or induce myocardial ischaemia and cause electrolyte disturbances that contribute to arrhythmias. Tremor is a well known distressing adverse effect of beta-agonist administration. Long-term beta-agonist use can be associated with tolerance, poor disease control, sudden life-threatening exacerbations and asthma-related deaths. Functional beta2-adrenoceptors are present in osteoblasts, and chronic use of beta-agonists has been implicated in osteoporosis. Inhaled anticholinergics are usually well tolerated but may cause dry mouth, which can be troublesome in older people. Pupillary dilatation, blurred vision and acute glaucoma can occur from escape of droplets from loosely fitting nebulizer masks. Although ECG changes have not been seen in randomized controlled trials of long-acting inhaled anticholinergics, supraventricular tachycardias have been observed in a 5-year randomized controlled trial of ipratropium bromide. Paradoxical bronchoconstriction can occur with inhaled anticholinergics as well as with beta agonists, but tolerance has not been reported with anticholinergics. Anticholinergic drugs also cause central effects, most notably impairment of cognitive function, and these effects have been noted with inhaled agents. Use of theophylline is limited by its adverse effects, which range from commonly occurring gastrointestinal symptoms to palpitations, arrhythmias and reports of myocardial infarction. Seizures have been reported, but are rare. Theophylline is metabolized primarily by the liver, and commonly interacts with other medications. Its concentration in plasma should be monitored closely, especially in older people. Although many clinical trials have been conducted on bronchodilators in obstructive airways disease, the results of these clinical trials need to be interpreted with caution as older people are often under represented and subjects with co-morbidities actively excluded from these trials. PMID- 18447416 TI - Importance sampling for quantum Monte Carlo in manifolds: addressing the time scale problem in simulations of molecular aggregates. AB - Several importance sampling strategies are developed and tested for stereographic projection diffusion Monte Carlo in manifolds. We test a family of one parameter trial wavefunctions for variational Monte Carlo in stereographically projected manifolds which can be used to produce importance sampling. We use the double well potential in one dimensional Euclidean space to study systematically sampling issues for diffusion Monte Carlo. We find that diffusion Monte Carlo with importance sampling in manifolds is orders of magnitude more efficient compared to unguided diffusion Monte Carlo. Additionally, diffusion Monte Carlo with importance sampling in manifolds can overcome problems with nonconfining potentials and can suppress quasiergodicity effectively. We obtain the ground state energy and the wavefunction for the Stokmayer trimer. PMID- 18447417 TI - Algebraic approach to electronic spectroscopy and dynamics. AB - Lie algebra, Zassenhaus, and parameter differentiation techniques are utilized to break up the exponential of a bilinear Hamiltonian operator into a product of noncommuting exponential operators by the virtue of the theory of Wei and Norman [J. Math. Phys. 4, 575 (1963); Proc. Am. Math. Soc., 15, 327 (1964)]. There are about three different ways to find the Zassenhaus exponents, namely, binomial expansion, Suzuki formula, and q-exponential transformation. A fourth, and most reliable method, is provided. Since linearly displaced and distorted (curvature change upon excitation/emission) Hamiltonian and spin-boson Hamiltonian may be classified as bilinear Hamiltonians, the presented algebraic algorithm (exponential operator disentanglement exploiting six-dimensional Lie algebra case) should be useful in spin-boson problems. The linearly displaced and distorted Hamiltonian exponential is only treated here. While the spin-boson model is used here only as a demonstration of the idea, the herein approach is more general and powerful than the specific example treated. The optical linear dipole moment correlation function is algebraically derived using the above mentioned methods and coherent states. Coherent states are eigenvectors of the bosonic lowering operator a and not of the raising operator a(+). While exp(a(+)) translates coherent states, exp(a(+)a(+)) operation on coherent states has always been a challenge, as a(+) has no eigenvectors. Three approaches, and the results, of that operation are provided. Linear absorption spectra are derived, calculated, and discussed. The linear dipole moment correlation function for the pure quadratic coupling case is expressed in terms of Legendre polynomials to better show the even vibronic transitions in the absorption spectrum. Comparison of the present line shapes to those calculated by other methods is provided. Franck-Condon factors for both linear and quadratic couplings are exactly accounted for by the herein calculated linear absorption spectra. This new methodology should easily pave the way to calculating the four-point correlation function, F(tau(1),tau(2),tau(3),tau(4)), of which the optical nonlinear response function may be procured, as evaluating F(tau(1),tau(2),tau(3),tau(4)) is only evaluating the optical linear dipole moment correlation function iteratively over different time intervals, which should allow calculating various optical nonlinear temporal/spectral signals. PMID- 18447418 TI - Comments on the Hartree-Fock description of Hooke's atom and suggestion for an accurate closed-form orbital. AB - The ground-state Hartree-Fock (HF) wavefunction of Hooke's atom is not known in closed form, contrary to the exact solution. The single HF orbital involved has thus far been studied using expansion techniques only, leading to slightly disparate energies. Therefore, the present letter aims at proposing alternative definitions of the HF wavefunction. First, the HF limit is ascertained using a simple expansion, which makes it possible to formulate explicit expressions of HF properties. The resulting energy, 2.038 438 871 8 E(h), is found stable at the tenth digit. Second and more instructive, an analysis of the Hartree equation makes it possible to infer a remarkably simple and accurate HF orbital, i.e., phi (HF) (r) = n(HF) e (-alphar(2)) r(2) + beta(2), leading to an energy exceeding by 5.76 x 10(-7) E(h) only the above HF limit. This orbital makes it possible to obtain (near) Hartree-Fock properties in closed form, which in turn enables handy comparisons with exact quantities. PMID- 18447419 TI - Quasiparticle virtual orbitals in electron propagator calculations. AB - The computational limits of accurate electron propagator methods for the calculation of electron binding energies of large molecules are usually determined by the rank of the virtual orbital space. Electron density difference matrices that correspond to these transition energies in the second-order quasiparticle approximation may be used to obtain a virtual orbital space of reduced rank that introduces only minor deviations with respect to the results produced with the full, original set of virtual orbitals. Numerical tests show the superior accuracy and efficiency of this approach compared to the usual practice of omission of virtual orbitals with the highest energies. PMID- 18447420 TI - Quasidegenerate scaled opposite spin second order perturbation corrections to single excitation configuration interaction. AB - Scaled opposite spin (SOS) second order perturbative corrections to single excitation configuration interaction (CIS) are extended to correctly treat quasidegeneracies between excited states. Two viable methods, termed as SOS CIS(D(0)) and SOS-CIS(D(1)), are defined, implemented, and tested. Each involves one empirical parameter (plus a second for the SOS-MP2 ground state), has computational cost that scales with the fourth power of molecule size, and has storage requirements that are cubic, with only quantities of the rank of single excitations produced and stored during iterations. Tests on a set of low-lying adiabatic valence excitation energies and vertical Rydberg excitations of organic and inorganic molecules show that the empirical parameter can be acceptably transferred from the corresponding nondegenerate perturbation theories without any further fitting. Further tests on higher excited states show that the new methods correctly perform for surface crossings for which nondegenerate approaches fail. Numerical results show that SOS-CIS(D(0)) appears to treat Rydberg excitations in a more balanced way than SOS-CIS(D(1)) and is, therefore, likely to be the preferred approach. It should be useful for exploring excited state geometries, transition structures, and conical intersections for states of medium to large organic molecules that are dominated by single excitations. PMID- 18447421 TI - Electronic structure of copper phthalocyanine: a comparative density functional theory study. AB - We present a systematic density functional theory study of the electronic structure of copper phthalocyanine (CuPc) using several different (semi)local and hybrid functionals and compare the results to experimental photoemission data. We show that semilocal functionals fail qualitatively for CuPc primarily because of underbinding of localized orbitals due to self-interaction errors. We discuss an appropriate choice of functional for studies of CuPc/metal interfaces and suggest the Heyd-Scuseria-Ernzerhof screened hybrid functional as a suitable compromise functional. PMID- 18447422 TI - Monge-Ampere grids and the multidimensional mapped Fourier method. AB - The efficiency of a numerical method can be greatly improved by combining it with coordinate transformations tailored to a given problem. This is the basis for the mapped Fourier methods. However, obtaining "good" coordinate transformations is a major obstacle for this approach in multidimensions. Here, we calculate coordinate transformations based on solving the Monge-Ampere equation. These transformations are combined in the mapped Fourier method and applied to Schrodinger's equation in multidimensions. Dramatic improvements in accuracy compared to the standard Fourier method were observed in eigenvalue calculations for two-dimensional systems. This work indicates that the Monge-Ampere equation may serve as a useful tool for constructing efficient representations for problems in computational quantum mechanics and other fields. PMID- 18447423 TI - Atomic complexity measures in position and momentum spaces. AB - Fisher-Shannon (FS) and Lopez-Ruiz, Mancini, and Calbet (LMC) complexity measures, detecting not only randomness but also structure, are computed by using near Hartree-Fock wave functions for neutral atoms with nuclear charge Z=1-103 in position, momentum, and product spaces. It is shown that FS and LMC complexities are qualitatively and numerically equivalent for these systems. New complexity candidates are defined, computed, and compared by using the following information theoretic magnitudes: Shannon entropy, Fisher information, disequilibrium, and variance. Localization-delocalization planes are constructed for each complexity measure, where the subshell pattern of the periodic table is clearly shown. The complementary use of r and p spaces provides a compact and more complete understanding of the information content of these planes. PMID- 18447424 TI - Surface-hopping dynamics and decoherence with quantum equilibrium structure. AB - In open quantum systems, decoherence occurs through interaction of a quantum subsystem with its environment. The computation of expectation values requires a knowledge of the quantum dynamics of operators and sampling from initial states of the density matrix describing the subsystem and bath. We consider situations where the quantum evolution can be approximated by quantum-classical Liouville dynamics and examine the circumstances under which the evolution can be reduced to surface-hopping dynamics, where the evolution consists of trajectory segments exclusively evolving on single adiabatic surfaces, with probabilistic hops between these surfaces. The justification for the reduction depends on the validity of a Markovian approximation on a bath averaged memory kernel that accounts for quantum coherence in the system. We show that such a reduction is often possible when initial sampling is from either the quantum or classical bath initial distributions. If the average is taken only over the quantum dispersion that broadens the classical distribution, then such a reduction is not always possible. PMID- 18447425 TI - Self-consistent polarization neglect of diatomic differential overlap: application to water clusters. AB - Semiempirical self-consistent field (SCF) methods based on the neglect of diatomic differential overlap (NDDO) formalism have the ability to treat the formation and breaking of chemical bonds but have been found to poorly describe hydrogen bonding and weak electrostatic complexes. In contrast, most empirical potentials are not able to describe bond breaking and formation but have the ability to add missing elements of hydrogen bonding by using classical electrostatic interactions. We present a new method which combines aspects of both NDDO-based SCF techniques and classical descriptions of polarization to describe the diffuse nature of the electronic wavefunction in a self-consistent manner. We develop the "self-consistent polarization neglect of diatomic differential overlap" (SCP-NDDO) theory with the additional description of molecular dispersion developed as a second-order perturbation theory expression. The current study seeks to model water-water interactions as a test case. To this end, we have parametrized the method to accurate ab initio complete basis set limit estimates of small water cluster binding energies of Xantheas and co workers [J. Chem. Phys. 116, 1493 (2002); 120, 823 (2004)]. Overall agreement with the ab initio binding energies (n=2-6, and 8) is achieved with a rms error of 0.19 kcal/mol. We achieve noticeable improvements in the structure, vibrational frequencies, and energetic predictions of water clusters (n< or =21) relative to standard NDDO-based methods. PMID- 18447426 TI - Analyzing NMR shielding tensors calculated with two-component relativistic methods using spin-free localized molecular orbitals. AB - A recently developed analysis method [J. Chem. Phys. 127, 124106 (2007)] for NMR spin-spin coupling constants employing two-component (spin-orbit) relativistic density functional theory along with scalar relativistic natural localized molecular orbitals (NLMOs) and natural bond orbitals (NBOs) has been extended for analyzing NMR shielding tensors. Contributions from a field-dependent basis set (gauge-including atomic orbitals) have been included in the formalism. The spin orbit NLMO/NBO nuclear magnetic shielding analysis has been applied to methane, plumbane, hydrogen iodide, tetracholoplatinate(II), and hexachloroplatinate(IV). PMID- 18447427 TI - Variational calculation of second-order reduced density matrices by strong N representability conditions and an accurate semidefinite programming solver. AB - The reduced density matrix (RDM) method, which is a variational calculation based on the second-order reduced density matrix, is applied to the ground state energies and the dipole moments for 57 different states of atoms, molecules, and to the ground state energies and the elements of 2-RDM for the Hubbard model. We explore the well-known N-representability conditions (P, Q, and G) together with the more recent and much stronger T1 and T2(') conditions. T2(') condition was recently rederived and it implies T2 condition. Using these N-representability conditions, we can usually calculate correlation energies in percentage ranging from 100% to 101%, whose accuracy is similar to CCSD(T) and even better for high spin states or anion systems where CCSD(T) fails. Highly accurate calculations are carried out by handling equality constraints and/or developing multiple precision arithmetic in the semidefinite programming (SDP) solver. Results show that handling equality constraints correctly improves the accuracy from 0.1 to 0.6 mhartree. Additionally, improvements by replacing T2 condition with T2(') condition are typically of 0.1-0.5 mhartree. The newly developed multiple precision arithmetic version of SDP solver calculates extraordinary accurate energies for the one dimensional Hubbard model and Be atom. It gives at least 16 significant digits for energies, where double precision calculations gives only two to eight digits. It also provides physically meaningful results for the Hubbard model in the high correlation limit. PMID- 18447428 TI - Complex trajectory method in time-dependent WKB. AB - We present a significant improvement to a complex time-dependent WKB (CWKB) formulation developed by Boiron and Lombardi [J. Chem. Phys. 108, 3431 (1998)] in which the time-dependent WKB equations are solved along classical trajectories that propagate in complex space. Boiron and Lombardi showed that the method gives very good agreement with the exact quantum mechanical result as long as the wavefunction does not exhibit interference effects such as oscillations and nodes. In this paper, we show that this limitation can be overcome by superposing the contributions of crossing trajectories. Secondly, we demonstrate that the approximation improves when incorporating higher order terms in the expansion. Thirdly, equations of motion for caustics and Stokes lines are implemented to help overcome Stokes discontinuities. These improvements could make the CWKB formulation a competitive alternative to current time-dependent semiclassical methods. PMID- 18447429 TI - Reconciling semiclassical and Bohmian mechanics. V. Wavepacket dynamics. AB - In previous articles [B. Poirier J. Chem. Phys. 121, 4501 (2004); C. Trahan and B. Poirier, ibid. 124, 034115 (2006); 124, 034116 (2006); B. Poirier and G. Parlant, J. Phys. Chem. A 111, 10400 (2007)] a bipolar counterpropagating wave decomposition, psi = psi(+) + psi(-), was presented for stationary states psi of the one-dimensional Schrodinger equation, such that the components psi(+/-) approach their semiclassical Wentzel-Kramers-Brillouin analogs in the large action limit. The corresponding bipolar quantum trajectories are classical-like and well behaved, even when psi has many nodes, or is wildly oscillatory. In this paper, the method is generalized for time-dependent wavepacket dynamics applications and applied to several benchmark problems, including multisurface systems with nonadiabatic coupling. PMID- 18447430 TI - A multilayer multiconfigurational time-dependent Hartree approach for quantum dynamics on general potential energy surfaces. AB - The multiconfigurational time-dependent Hartree (MCTDH) approach facilitates multidimensional quantum dynamics calculations by representing the wavepacket in an optimal set of time-dependent basis functions, called single-particle functions. Choosing these single-particle functions to be themselves multidimensional wavefunctions which are represented using a MCTDH representation, a multilayer MCTDH scheme has been constructed and used for quantum dynamics calculations treating up to 1000 degrees of freedom rigorously [Wang and Thoss, J. Chem. Phys. 199, 1289 (2003)]. The present work gives a practical scheme which facilitates the application of the multilayer MCTDH approach, which previously has only been employed to study systems described by model-type Hamiltonians, to molecular systems described by more complicated Hamiltonians and general potential energy surfaces. A multilayer extension of the correlation discrete variable representation (CDVR) scheme employed in MCTDH calculations studying quantum dynamics on general potential energy surfaces is developed and tested in a simple numerical application. The resulting multilayer MCTDH/CDVR approach might offer a perspective to rigorously describe the quantum dynamics of larger polyatomic systems. PMID- 18447431 TI - Bichromatically driven double well: parametric perspective of the strong field control landscape reveals the influence of chaotic states. AB - The aim of this work is to understand the influence of chaotic states in control problems involving strong fields. Towards this end, we numerically construct and study the strong field control landscape of a bichromatically driven double well. A novel measure based on correlating the overlap intensities between Floquet states and an initial phase space coherent state with the parametric motion of the quasienergies is used to construct and interpret the landscape features. "Walls" of no control, which are robust under variations of the relative phase between the fields, are seen on the control landscape and associated with multilevel interactions involving chaotic Floquet states. PMID- 18447432 TI - Simultaneous analytical optimization of variational parameters in Gaussian-type functions with full configuration interaction of multicomponent molecular orbital method by elimination of translational and rotational motions: application to isotopomers of the hydrogen molecule. AB - We have extended the multicomponent molecular orbital (MCMO) method to the full configuration interaction (full-CI) fully variational molecular orbital method by elimination of translational and rotational motion components from total Hamiltonian. In the MCMO scheme, the quantum effects of protons and deuterons as well as electrons can be directly taken into account. All variational parameters in the full-CI scheme, i.e., exponents and centers (alpha and R) in the Gaussian type function (GTF) basis set as well as the CI coefficients, are simultaneously optimized by using their analytical gradients. The total energy of the H(2) molecule calculated using the electronic [6s3p2d1f] and nuclear [1s1p1d1f] GTFs is -1.161 726 hartree, which can be compared to the energy of -1.164 025 hartree reported using a 512 term-explicitly correlated GTF calculation. Although the d- and f-type nuclear GTFs contribute to the improvement of energy convergence, the convergence of electron-nucleus correlation energy is slower than that of electron-electron one. The nuclear wave functions are delocalized due to the electron-nucleus correlation effect compared to the result of Hartree-Fock level of MCMO method. In addition, the average internuclear distances of all diatomic molecules are within 0.001 A of the previously reported experimental results. The dipole moment of the HD molecule estimated by our method is 8.4 x 10(-4) D, which is in excellent agreement with the experimental result of (8-10) x 10(-4) D. PMID- 18447433 TI - Resonant 2-photon ionization study of the conformation and the binding of water molecules to 2-phenylethanethiol (PhCH2CH2SH). AB - The structures of 2-phenylethanethiol (PET, PhCH(2)CH(2)SH) and its 1:1 water clusters have been studied using resonant two-photon ionization spectroscopy including band contour analysis and UV-UV holeburning, combined with extensive ab initio calculations on ground and excited states. The most populated conformer, labeled Ggpi, has a gauche arrangement about the SCCC and HSCC bonds that permits a stabilizing SH...dpi type of hydrogen bond. The other observed conformer, Ag, is anti with respect to the SCCC bond. In the dominant 1:1 water cluster, a water molecule binds to the Ggpi conformer via an OH...S hydrogen bond and two significant CH...O interactions. There is also evidence for water binding to conformer Ag with a similar arrangement, and for a second Ggpi cluster where water inserts between the SH and the aromatic ring. The additional interactions to the water molecules result in net D(e) binding energies approximately double those resulting from a single thiol-water hydrogen bond. The (1)(pi,pi(*)) excited state lifetimes in the bare molecules are very short because of internal conversion to a dissociative (1)(n,pi(*)) state related to the thiol. In the dominant Gw(1) cluster, the lifetime is significantly increased from <1 to approximately 4 ns. Hydrogen bonding to the thiol, which raises the energy of the dissociative (1)(n,pi(*)) state, accounts for this behavior. PMID- 18447434 TI - Mechanisms of photoinduced Calpha[Single Bond]Cbeta bond breakage in protonated aromatic amino acids. AB - Photoexcitation of protonated aromatic amino acids leads to C(alpha)[Single Bond]C(beta) bond breakage among other channels. There are two pathways for the C(alpha)[Single Bond]C(beta) bond breakage, one is a slow process (microseconds) that occurs after hydrogen loss from the electronically excited ion, whereas the other is a fast process (nanoseconds). In this paper, a comparative study of the fragmentation of four molecules shows that the presence of the carboxylic acid group is necessary for this fast fragmentation channel to occur. We suggest a mechanism based on light-induced electron transfer from the aromatic ring to the carboxylic acid, followed by a fast internal proton transfer from the ammonium group to the negatively charged carboxylic acid group. The ion formed is a biradical since the aromatic ring is ionized and the carbon of the COOH group has an unpaired electron. Breakage of the weak C(alpha)[Single Bond]C(beta) bond gives two even-electron fragments and is expected to quickly occur. The present experimental results together with the ab initio calculations support the interpretation previously proposed. PMID- 18447435 TI - Ab initio spectroscopy and photoinduced cooling of the trans-stilbene molecule. AB - We present a theoretical study of the S(0)-->S(1) and S(0)<--S(1) vibronic spectra for trans-stilbene. Franck-Condon spectra in the harmonic approximation are generated for the complete system with 72 degrees of freedom by means of an analytic time-dependent approach accounting for Dushinsky rotations and thermal effects. The force fields are computed by means of density functional theory (DFT) and time-dependent DFT, on the one hand, and ab initio complete active space self-consistent field theory, on the other hand. The B3LYP functional shows that almost planar potential energy surface minima are found for the S(0) and S(1) state. Imposing C(2h) symmetry constraints, we obtain low-temperature high resolution Franck-Condon spectra for both absorption and emission which are in reasonably good agreement with the experimental spectra measured by Syage et al. [J. Chem. Phys. 81, 4685 (1984)] in supersonic jets. Due to thermal population of low-energy modes, the room temperature absorption spectrum is very broad. An almost structureless band which extends over several thousand cm(-1) is obtained from the present theory and agrees with the experimental absorption band shape. Finally, within the harmonic model, we study the effect of photoexcitation on the energy distribution in the excited S(1) state. We find noticeable cooling of approximately 20 K within a frequency interval spanning from -400 to 200 cm(-1) around the 0-0 transition. This indicates that photoinduced cooling must be taken into account when considering the dynamics of the photoinduced isomerization of trans-stilbene. Moreover, this is not the final word, as anharmonicity of the low frequency modes must be taken into account to obtain a full picture which would explain both the energy dependence of the isomerization rates as well as the dependence on the pressure of an external buffer gas. PMID- 18447436 TI - The C3N- anion: first detection of its electronic luminescence in rare gas solids. AB - The 193 nm laser irradiation of cyanoacetylene (HCCCN) that was isolated in rare gas solids led to a long-lived luminescence (origin at 3.58 eV), which was assigned to the a (3)Sigma(+)-X (1)Sigma(+) system of cyanoacetylide (CCCN(-)). The identification, which involved (15)N and (2)H isotopic substitution studies, is based on vibronic spacings in the phosphorescence spectrum (compared to previous infrared absorption measurements and to theoretical results regarding CCCN(-) vibrational frequencies), as well as on a BD(T)/cc-pVTZ prediction for the singlet-triplet energy gap in this anion (3.61 eV). The same emission was also generated from KrHC(3)N mixtures subjected to a glow electric discharge immediately before the solidification (cold-window-radial-discharge technique). PMID- 18447437 TI - Structures and heats of formation of the neutral and ionic PNO, NOP, and NPO systems from electronic structure calculations. AB - High level ab initio electronic structure calculations using the coupled cluster CCSD(T) method with augmented correlation-consistent basis sets extrapolated to the complete basis set limit have been performed on the PNO, NOP, and NPO isomers and their corresponding anions and cations. Geometries for all species were optimized up through the aug-cc-pV(Q+d)Z level and vibrational frequencies were calculated with the aug-cc-pV(T+d)Z basis set. The most stable of the three isomers is NPO and it is predicted to have a heat of formation of 23.3 kcal/mol. PNO is predicted to be only 1.7 kcal/mol higher in energy. The calculated adiabatic ionization potential of NPO is 12.07 eV and the calculated adiabatic electron affinity is 2.34 eV. The calculated adiabatic ionization potential of PNO is 10.27 eV and the calculated adiabatic electron affinity is only 0.24 eV. NOP is predicted to be much higher in energy by 29.9 kcal/mol. The calculated rotational constants for PNO and NPO should allow for these species to be spectroscopically distinguished. The adiabatic bond dissociation energies for the P[Single Bond]N, P[Single Bond]O, and N[Single Bond]O bonds in NPO and PNO are the same within approximately 10 kcal/mol and fall in the range of 72-83 kcal/mol. PMID- 18447438 TI - New, unexpected, and dominant mechanisms in the hydrogen exchange reaction. AB - A quasiclassical trajectory study of the state specific H+D(2)(upsilon = 0,j = 0) --> HD(upsilon' = 0,j' = 0) + D reaction at a collision energy of 1.85 eV (total energy of 2.04 eV) found that the scattering is governed by two unexpected and dominant new mechanisms, and not by direct recoil as is generally assumed. The new mechanisms involve strong interaction with the sloping potential around the conical intersection, an area of the potential energy surface not previously considered to have much effect upon reactive scattering. Initial investigations indicate that more than 50% of reactive scattering could be the result of these new mechanisms at this collision energy. Features in the corresponding quantum mechanical results can be attributed to these new (classical) reaction mechanisms. PMID- 18447439 TI - A quasiclassical trajectory study of the time-delayed forward scattering in the hydrogen exchange reaction. AB - The time-delayed forward scattering mechanism recently identified by Althorpe et al. [Nature (London) 416, 67 (2002)] for the H+D(2)(v=0,j=0)- >HD(v(')=3,j(')=0)+D reaction was analyzed by using quasiclassical trajectory (QCT) methodology. The QCT results were found to match the quantum wavepacket snapshots of Althorpe et al., albeit without the quantum scattering effects. Trajectories were analyzed on the fly to investigate the dynamics of the atoms during the reaction. The dominant reaction mechanism progresses from hard collinear impacts, leading to direct recoil, toward glancing impacts. The increased time required for forward scattered trajectories is due to the rotation of the transient HDD complex. Forward scattered trajectories display symmetric stretch vibrations of the transient HDD complex, a signature of the presence of a resonance, or a quantum bottleneck state. PMID- 18447440 TI - The [1+1] two-photon dissociation spectra of CO2 + via A 2Pi u,12(upsilon1upsilon20)<--X 2Pi g,12(000) transitions. AB - In the wavelength range of 235-354 nm, we have obtained the mass-resolved [1+1] two-photon dissociation spectra of CO(2) (+) via A (2)Pi(u,12)(upsilon(1)upsilon(2)0)<--X (2)Pi(g,12)(000) transitions by preparing CO(2) (+) ions in the X (2)Pi(g,12)(000) state via [3+1] multiphoton ionization of CO(2) molecules at 333.06 nm. The vibronic bands of (upsilon(1)20;upsilon(1)=0 11)micro (2)Pi(12) and (upsilon(1)20;upsilon(1)=0-6)kappa (2)Pi(12) involving the bending mode of CO(2) (+)(A (2)Pi(u,12)) were assigned. The spectroscopic constants of T(e)=27 908.9+/-1.1 cm(-1) [above CO(2) (+)(X (2)Pi(g,12))], nu(1)=1126.00+/-0.36 cm(-1), chi(11)=-1.602+/-0.005 cm(-1), nu(2)(micro (2)Pi(12))=402.5+/-13.3 cm(-1), and nu(2)(kappa (2)Pi(12))=493.1+/-23.6 cm(-1) for CO(2) (+)(A (2)Pi(u,12)) are deduced from the data of the A (2)Pi(u,12)(upsilon(1)upsilon(2)0)<--X (2)Pi(g,12)(000) transitions. The observed intensity reversal between (500) (2)Pi(12) and (420)micro (2)Pi(12) can be attributed to the conformational variation of CO(2) (+)(A (2)Pi(u,12)) from linear to bent, then the conversion potential barrier is estimated to be 5209 cm( 1) above CO(2) (+)(A (2)Pi(u,12)(000)). The wavelength and level dependence of the photofragment branching ratios have been measured and the dissociation dynamics of CO(2) (+) via A (2)Pi(u,12) state is discussed. PMID- 18447441 TI - Application of mean-field and surface-hopping approaches for interrogation of the Xe3+ molecular ion photoexcitation dynamics. AB - The dissociation dynamics of the excited Xe(3) (+) molecular ion through the Pi(12)(u) and Pi(12)(g) conical intersection was interrogated by computational simulation in which no adjustable parameters were used. The electronic ground and excited state potential energy surfaces were generated by the diatomics-in molecules method, and the Ehrenfest mean-field and Tully surface-hopping approaches treated the nonadiabatic interactions. Reproduction of the experimental spectrum of the symmetric photofragmentation as a function of excitation energy was obtained within the region of interest (2.5-3.75 eV), with the exception of a 0.25 eV width on the red side of the spectral apex. Good agreement was obtained with the experimental dissociated photofragment kinetic energy spectra. It was determined that the greatest contribution to the nonadiabatic coupling between the two states originated from the bending vibrational mode of the molecule in the Sigma(12)(u), ground electronic state before excitation. PMID- 18447442 TI - Pulsed-field-ionization zero-kinetic-energy photoelectron spectroscopy of metastable He2: Ionization potential and rovibrational structure of He2+. AB - A supersonic beam of metastable He(*) atoms and He(2) (*) a (3)Sigma(u) (+) molecules has been generated using a pulsed discharge at the exit of a pulsed valve prior to the gas expansion into vacuum. Pulsed-field-ionization zero kinetic-energy photoelectron spectra of the He(2) (+) X(+) (2)Sigma(u) (+) (v(+)=0-2)<--He(2) (*) a (3)Sigma(u) (+) (v(")=0-2) transitions and photoionization spectra of He(2) (*) in the vicinity of the lowest ionization thresholds have been recorded. The energy level structures of (4)He(2) (+) X(+) (2)Sigma(u) (+) (v(+)< or =2,N(+)< or =23) and (3)He(2) (+) X(+) (2)Sigma(u) (+) (v(+)=0,N(+)< or =11) have been determined, and an accurate set of molecular constants for all isotopomers of He(2) (+) has been derived in a global analysis of all spectroscopic data reported to date on the low vibrational levels of He(2) (+). The analysis of the photoionization spectrum by multichannel quantum defect theory has provided a set of parameters describing the threshold photoionization dynamics. PMID- 18447443 TI - Vibrational and photoionization spectroscopy of biomolecules: aliphatic amino acid structures. AB - The aliphatic amino acids glycine, valine, leucine, and isoleucine are thermally placed into the gas phase and expanded into a vacuum system for access by time of flight mass spectroscopy and infrared (IR) spectroscopy in the energy range of 2500-4000 cm(-1) (CH, NH, OH, and stretching vibrations). The isolated neutral amino acids are ionized by a single photon of 10.5 eV energy (118 nm), which exceeds by less than 2 eV their reported ionization thresholds. As has been reported for many hydrogen bonded acid-base systems (e.g., water, ammonia, alcohol, acid clusters, and acid molecules), the amino acids undergo a structural rearrangement in the ion state (e.g., in simplest form, a proton transfer) that imparts sufficient excess vibrational energy to the ion to completely fragment it. No parent ions are observed. If the neutral ground state amino acids are exposed to IR radiation prior to ionization, an IR spectrum of the individual isomers for each amino acid can be determined by observation of the ion intensity of the different fragment mass channels. Both the IR spectrum and fragmentation patterns for individual isomers can be qualitatively identified and related to a particular isomer in each instance. Thus, each fragment ion detected presents an IR spectrum of its particular parent amino acid isomer. In some instances, the absorption of IR radiation by the neutral amino acid parent isomer increases a particular fragmentation mass channel intensity, while other fragmentation mass channel intensities decrease. This phenomenon can be rationalized by considering that with added energy in the molecule, the fragmentation channel populations can be modulated by the added vibrational energy in the rearranged ions. This observation also suggests that the IR absorption does not induce isomerization in the ground electronic state of these amino acids. These data are consistent with theoretical predictions for isolated amino acid secondary structures and can be related to previous IR spectra of amino acid conformers. PMID- 18447444 TI - Ab initio study of the one- and two-photon circular dichroism of R-(+)-3-methyl cyclopentanone. AB - One- and two-photon circular dichroism spectra of R-(+)-3-methyl-cyclopentanone, a system that has been the subject of recent experimental studies of (2+1) resonance-enhanced multiphoton ionization circular dichroism, have been calculated with an origin-invariant density functional theory approximation in the region of the lowest electronic excited states, both for the gas phase and for a selection of solvents. A polarizable continuum model is used in the calculations performed on the solvated system. Two low-lying conformers are analyzed, and a comparison of the intensities and characteristic features is made with the corresponding two-photon absorption for each species, also for the Boltzmann-averaged spectra. The effect of the choice of geometry, basis set, and exchange-correlation functional is carefully analyzed. It is found that a density functional theory approach using the Coulomb attenuating method variant of Becke's three-parameter exchange and the Lee-Yang-Parr correlation functionals with correlation-consistent basis sets of double-zeta quality can reproduce the experimental electronic circular dichroism spectra very well. The features appearing in experiment are characterized in terms of molecular excitations, and the differences in the response of each state in the one- and two-photon processes are highlighted. PMID- 18447445 TI - Exact, Born-Oppenheimer, and quantum-chemistry-like calculations in helium clusters doped with light molecules: The He2N2(X) system. AB - Helium clusters doped with diatomic molecules, He(N)-BC, have been recently studied by means of a quantum-chemistry-like approach. The model treats He atoms as "electrons" and dopants as "nuclei" in standard electronic structure calculations. Due to the large mass difference between He atoms and electrons, and to the replacement of Coulomb interactions by intermolecular potentials, it is worth assessing up to what extent are the approximations involved in this model, i.e., decoupling of the BC rotation from the He-atom orbital angular momenta and Born-Oppenheimer separation of the BC stretch versus the He motions, accurate enough. These issues have been previously tackled elsewhere for the (4)He(2)-Br(2)(X) system, which contains a heavy dopant [Roncero et al., Int. J. Quantum Chem. 107, 2756 (2007)]. Here, we consider a similar cluster but with a much lighter dopant such as N(2)(X). Although the model does not provide the correct energy levels for the cluster, positions and intensities of the main detectable lines of the vibrotational Raman spectrum at low temperature are accurately reproduced. PMID- 18447446 TI - Ultrafast nonradiative dynamics in electronically excited hexafluorobenzene by femtosecond time-resolved mass spectrometry. AB - The fast nonradiative decay dynamics of the lowest two excited pipi(*) electronic states (S(2) and S(3)) of hexafluorobenzene have been investigated by using femtosecond time-resolved time-of-flight mass spectrometry. The molecules were excited at wavelengths between 265 nm > or = lambda(pump) > or = 217 nm and probed by four- and three-photon ionization at lambda(probe)=775 nm. The observed temporal profiles exhibit two exponential decay times (tau(1)=0.54-0.1 ps and tau(2)=493-4.67 ps, depending on the excitation wavelength) and a superimposed coherent oscillation with vibrational frequency nu(osc)=97 cm(-1) and damping time tau(D) that is two to three times longer than the respective tau(1). The first decay component (tau(1)) is assigned to rapid radiationless transfer from the excited optically bright pipi(*) electronic state (S(2) or S(3), respectively) through a conical intersection (CI) to the lower-lying optically dark pisigma(*) state (S(1)) of the molecule; the second component (tau(2)) is attributed to the subsequent slower relaxation from the S(1) state back to the electronic ground state (S(0)). tau(2) dramatically decreases with increasing vibronic excitation energy up to the CI connecting the pisigma(*) with the S(0) state. The coherent oscillation is identified as nuclear motion along the out-of plane vibration nu(16a) (notation as for benzene), which has e(2u) symmetry and acts as coupling mode between the pipi(*) and pisigma(*) states. PMID- 18447447 TI - A theoretical study of the excited states of AmO2n+, n=1,2,3. AB - The ground and excited states of the AmO(2) (+), AmO(2) (2+), and AmO(2) (3+) ions have been studied using the four-component configuration interaction singles doubles, spin-orbit complete active space self-consistent field, and spin-orbit complete active space-order perturbation theory methods. The roles of scalar relativistic effects and spin-orbit coupling are analyzed; results with different methods are carefully compared by a precise analysis of the wave functions. A molecular spinor diagram is used in relation to the four-component calculations while a ligand field model is used for the two-step method. States with the same number of electrons in the four nonbonding orbitals are in very good agreement with the two methods while ligand field and charge transfer states do not have the same excitation energies. PMID- 18447448 TI - Energy transfer of highly vibrationally excited naphthalene. III. Rotational effects. AB - The rotational effects in the energy transfer between Kr atoms and highly vibrationally excited naphthalene in the triplet state were investigated using crossed-beam/time-sliced velocity map ion imaging at various translational collision energies. As the initial rotational temperature changes from less than 10 to approximately 350 K, the ratio of vibrational to translational (V-->T) energy transfer cross section to translational to vibrational/rotational (T-->VR) energy transfer cross section increases, but the probability of forming a complex during the collisions decreases. Significant increases in the large V-->T energy transfer probabilities, termed supercollisions, at high initial rotational temperature were observed. PMID- 18447449 TI - Is the trend of the polarizability per atom for all small 3d transition metal clusters the same? The case of Nin (n< or =5) clusters. AB - The first theoretical study on static polarizability and polarizability anisotropy of small nickel clusters up to the pentamer is presented. All-electron type calculations were performed using a finite field approach as implemented in the density functional program deMon2K. A newly developed first-order field induced basis set for density functional calculations was employed. For the static polarizability per atom of these clusters, a different trend to the one reported in the literature for other transition metal cluster systems of similar size, is observed. PMID- 18447450 TI - Time-dependent photoionization of azulene: competition between ionization and relaxation in highly excited states. AB - Pump-probe photoionization has been used to map the relaxation processes taking place from highly vibrationally excited levels of the S(2) state of azulene, populated directly or via internal conversion from the S(4) state. Photoelectron spectra obtained by 1+2(') two-color time-resolved photoelectron imaging are invariant (apart from in intensity) to the pump-probe time delay and to the pump wavelength. This reveals a photoionization process which is driven by an unstable electronic state (e.g., doubly excited state) lying below the ionization potential. This state is postulated to be populated by a probe transition from S(2) and to rapidly relax via an Auger-like process onto highly vibrationally excited Rydberg states. This accounts for the time invariance of the photoelectron spectrum. The intensity of the photoelectron spectrum is proportional to the population in S(2). An exponential energy gap law is used to describe the internal conversion rate from S(2) to S(0). The vibronic coupling strength is found to be larger than 60+/-5 microeV. PMID- 18447451 TI - Ion core structure in (C(2)n+ and (CS2)n- (n=3-10) studied by infrared photodissociation spectroscopy. AB - Infrared photodissociation spectra of (CS(2))(n) (+) and (CS(2))(n) (-) with n=3 10 are measured in the 1100-2000 cm(-1) region. All the (CS(2))(n) (+) clusters exhibit three bands at approximately 1410, approximately 1490, and approximately 1540 cm(-1). The intensity of the 1540 cm(-1) band relative to those of the other bands increases with increasing the cluster size, indicating that the band at 1540 cm(-1) is assignable to the antisymmetric CS stretching vibration of solvent CS(2) molecules in the clusters. On the basis of density functional theory calculations, the 1410 and 1490 cm(-1) bands of (CS(2))(n) (+) are assigned to CS stretching vibrations of the C(2)S(4) (+) cation core with a C(2) form. The (CS(2))(n) (-) clusters show two bands at around 1215 and 1530 cm(-1). Similar to the case of cation clusters, the latter band is ascribed to the antisymmetric CS stretching vibration of solvent CS(2) molecules. Vibrational frequency analysis of CS(2) (-) and C(2)S(4) (-) suggests that the 1215 cm(-1) band is attributed to the antisymmetric CS stretching vibration of the CS(2) (-) anion core with a C(2v) structure. PMID- 18447452 TI - UV emission of I2 from the ion-pair state following amplified spontaneous emission. AB - This paper reports the results of processes resulting in D0(u) (+)-X (1)Sigma(g) (+) emission when a single rovibrational level of the E0(g) (+) state is prepared. Our study reveals that two kinds of processes populate the D0(u) (+) state; which one occurs depends on the experimental conditions. One process involves amplified spontaneous emission from the E0(g) (+) state. The other is collision-induced energy transfer in self-quenching. We distinguish these two processes from the time profiles of fluorescence signals. These processes give completely different vibrational distributions in the D0(u) (+) state from a given rovibrational level of the E0(g) (+) state. The discrepancy between our results and previous results for the E0(g) (+)-->D0(u) (+) relaxation is briefly discussed. PMID- 18447453 TI - Exploring a free energy landscape by means of multidimensional infrared and terahertz spectroscopies. AB - A model for the dipolar crystal system is employed to explore a role of free energy landscape (FEL), in which dipolar molecules are posted on two-dimensional lattice sites with two-state libratinal dynamics. All dipole-dipole interactions are included to have frustrated interactions among the dipoles. For the regular and distorted lattice cases, the FEL is calculated from the interaction energies and the total polarizations for all possible dipolar states at various temperatures. At high temperatures, the shape of the calculated FEL is smooth and parabolic, while it becomes bumpy at low temperatures exhibiting multiple local minima. To study dynamical aspects of the system, the single flip dynamics and the single-double mixed flips dynamics of dipoles are examined from a master equation approach. As the observables of linear absorption and two-dimensional (2D) infrared, far infrared, and terahertz spectroscopies, the first- and third order response functions of polarization are calculated for different physical conditions characterized by the FEL. While the linear absorption signals decay in time in a similar manner regardless of the FEL profiles, the 2D signals exhibit prominent differences for those profiles. This indicates that we may differentiate the FEL profiles by changing two-time valuables in 2D spectroscopy. As illustrated in the single-double flips case, the FEL study by means of 2D spectroscopy, however, relies on the dynamics which is set independently from the FEL. The Smoluchowski equation is applied to examine the description of the collective dynamics on the microscopically calculated FEL. We found that the one dimensional and 2D signals calculated from the Smoluchowski equation agree with those from master equation only at temperatures where the FEL becomes parabolic shape. PMID- 18447454 TI - Modeling equilibrium concentrations of Bjerrum and molecular point defects and their complexes in ice Ih. AB - We present a model for the determination of the thermal equilibrium concentrations of Bjerrum defects, molecular point defects, and their aggregates in ice I(h). First, using a procedure which minimizes the free energy of an ice crystal with respect to the numbers of defect species, we derive a set of equations for the equilibrium concentrations of free Bjerrum and point defects, as well their complexes. Using density-functional-theory calculations, we then evaluate the binding energies of Bjerrum-defect/vacancy and Bjerrum defect/interstitial complexes. In contrast to the complexes which involve the molecular vacancy, the results suggest that the molecular interstitial binds preferentially to the D-type Bjerrum defect. Using both theoretical binding and formation free energies as well as the available experimental data, we find that the preferential binding and the substantial presence of the interstitial as the predominant point defect in ice I(h) may lead to conditions in which the number of free D defects becomes considerably smaller than that of free L defects. Such a scenario could possibly be involved in the experimentally observed inactivity of D-type Bjerrum defects in the electrical properties of ice I(h). PMID- 18447455 TI - Relaxation time dispersions in glass forming metallic liquids and glasses. AB - Relaxation time dispersions in glass forming metallic liquids of diverse fragility characters were reviewed mainly based on mechanical relaxations. The compilation of the stretching exponents revealed the common nonexponential dynamic features among the metallic liquids. The time-temperature-superposition law of the relaxation profiles was identified with an average stretching exponent around 0.5 at low frequency regions near the glass transitions. No notable correlation of the stretching parameter with alloy composition was discerned. The construction of the frequency dependence of the stretching exponent across the whole range of liquid dynamics revealed a striking similarity of the nonexponential dynamics between metallic and fragile molecular liquids. PMID- 18447456 TI - Study of percolation and clustering in supercritical water-CO2 mixtures. AB - The microscopic structure of supercritical water-CO(2) mixture is investigated by neutron diffraction experiments exploiting the isotopic HD substitution. The investigated water reach mixtures are in the liquidlike region of the phase diagram, according to the behavior of the radial distribution functions, yet a reduction of the average number of hydrogen bonds, compared to equivalent states of pure water, is found. As a consequence, the average dimension of water clusters is reduced and the system stays below the percolation threshold. These results, along with the shift of the main peaks of the site-site radial distribution functions, suggest that the excess volume in these supercritical mixtures is likely associated with the CO(2) solvation shell. PMID- 18447457 TI - Ultrafast photoinduced electron transfer in the micelle and the gel phase of a PEO-PPO-PEO triblock copolymer. AB - Ultrafast photoinduced electron transfer (PET) from N,N-dimethylaniline (DMA) to coumarin dyes is studied in the micelle and the gel phase of a triblock copolymer, (PEO)(20)-(PPO)(70)-(PEO)(20) (Pluronic P123) by picosecond and femtosecond emission spectroscopies. The rate of PET in a P123 micelle and gel is found to be nonexponential and faster than the slow components of solvation dynamics. In a P123 micelle and gel, PET occurs on multiple time scales ranging from a subpicosecond time scale to a few nanoseconds. In the gel phase, the highest rate constant (9.3 x 10(9) M(-1) s(-1)) of ET for C152 is about two times higher than that (3.8 x 10(9) M(-1) s(-1)) observed in micelle phase. The ultrafast components of electron transfer (ET) exhibits a bell shaped dependence with the free energy change which is similar to the Marcus inversion. Possible reasons for slower PET in P123 micelle compared to other micelles and relative to P123 gel are discussed. PMID- 18447458 TI - Theoretical and spectroscopic study of infrared spectra of hydrogen-bonded 1 methyluracil crystal and its deuterated derivative. AB - Theoretical simulation of the band shape and fine structure of the N-H(D) stretching band is presented for 1-methyluracil and its deuterated derivative taking into account anharmonic coupling between the high-frequency N-H(D) stretching and the low-frequency N...O stretching vibrations, resonance interaction between two equivalent hydrogen bonds in the dimer, anharmonicity of the potentials for the low-frequency vibrations in the ground and excited state of the N-H(D) stretching mode, Fermi resonance between the N-H(D) stretching and the first overtone of the N-H(D) bending vibrations, and electrical anharmonicity. The effect of deuteration has been successfully reproduced by our model calculations. Infrared, far-infrared, Raman, and low-frequency Raman spectra of the polycrystalline 1-methyluracil have been recorded. The geometry and experimental frequencies are compared with the results of harmonic and anharmonic B3LYP6-311++G(**) calculations. PMID- 18447459 TI - One-dimensional model for water and aqueous solutions. III. Solvation of hard rods in aqueous mixtures. AB - A simple one-dimensional model for aqueous solution is applied to study the solvation thermodynamics of a simple solute (here, a hard-rod particle) in mixtures of waterlike particles and a cosolvent. Two kinds of cosolvents are considered, one that stabilizes and one that destabilizes the "structure of water." The results obtained for the Gibbs energy, entropy, enthalpy, and heat capacity of solvation are in qualitative agreement with experimental data on the solvation of argon and methane in mixtures of water and ethanol and of water and p-dioxane. PMID- 18447460 TI - Concentrating colloids with electric field gradients. I. Particle transport and growth mechanism of hard-sphere-like crystals in an electric bottle. AB - This work concerns the use of electric field gradients to manipulate the local particle concentration in a hard-sphere-like suspension. Inside a specially designed "electric bottle," we observed our colloids to collect in the regions of lowest field strength ("negative dielectrophoresis"). This allows for the use of larger field gradients and stronger dielectrophoretic forces than in the original electric bottle design, which was based on positive dielectrophoresis [M. T. Sullivan et al., Phys. Rev. Lett. 96, 015703 (2006)]. We used confocal scanning laser microscopy to quantitatively follow the time-dependent change in the particle density and the suspension structure. Within a few days, the dielectrophoretic compression was seen to initiate a heterogeneouslike growth of large single crystals, which took place far out-of-equilibrium. The crystals had a random hexagonal close-packed structure and displayed an intriguing growth mechanism, during which the entire crystal was continuously transported, while growing both on the "high-field" and the "low-field" sides, although at different rates. After switching off the electric field, the compressed crystals were found to relax to a lower packing fraction and melt, at a much slower rate than the crystal growth. Besides revealing the particular (far out-of-equilibrium) crystal growth mechanism in these electric bottles, our observations also shed light on the role of the different particle transport processes in the cell and some of the relevant tuning parameters. This is useful for different types of experiments, for instance, focusing more on melting, homogeneous crystallization, or the glass transition. PMID- 18447461 TI - Concentrating colloids with electric field gradients. II. Phase transitions and crystal buckling of long-ranged repulsive charged spheres in an electric bottle. AB - We explored the usefulness of electric field gradients for the manipulation of the particle concentration in suspensions of charged colloids, which have long ranged repulsive interactions. In particular, we studied the compression obtained by "negative" dielectrophoresis, which drives the particles to the regions of lowest field strength, thus preventing unwanted structural changes by induced dipole-dipole interactions. We used several sample cell layouts and suspension compositions, with a different range of the interparticle repulsions. For these systems, we obtained sufficient compression to observe a transition from the initial fluid phase to a random hexagonal close-packed crystal, as well as a body centered cubic crystal. The heterogeneous dielectrophoretic crystallization mechanism involved an intriguing "pluglike" motion of the crystal, similar to what we have previously reported for hard-sphere suspensions. In this way, remarkably large single crystals were formed of several millimeters wide and a couple of centimeters long. Moreover, we found that these crystals could be compressed to such an extent that it led to an anisotropic deformation ("buckling") and, upon subsequent relaxation, a reorientation of the lattice, while stacking errors disappeared. These striking differences with the compressed hard-sphere crystals that we studied before [M. E. Leunissen et al., J. Chem. Phys. 128, 164508 (2008).] are likely due to the smaller elastic moduli of the present lower-density soft-sphere crystals. PMID- 18447462 TI - Homogeneous nucleation in supersaturated vapors of methane, ethane, and carbon dioxide predicted by brute force molecular dynamics. AB - Molecular dynamics (MD) simulation is applied to the condensation process of supersaturated vapors of methane, ethane, and carbon dioxide. Simulations of systems with up to a 10(6) particles were conducted with a massively parallel MD program. This leads to reliable statistics and makes nucleation rates down to the order of 10(30) m(-3) s(-1) accessible to the direct simulation approach. Simulation results are compared to the classical nucleation theory (CNT) as well as the modification of Laaksonen, Ford, and Kulmala (LFK) which introduces a size dependence of the specific surface energy. CNT describes the nucleation of ethane and carbon dioxide excellently over the entire studied temperature range, whereas LFK provides a better approach to methane at low temperatures. PMID- 18447463 TI - Localization and coherent dynamics of excitons in the two-dimensional optical spectrum of molecular J-aggregates. AB - Two-dimensional optical spectra of J-aggregates at low temperature provide a large amount of information about the nature and dynamics of exciton states that is hidden in conventional broad band pump-probe spectra. By using numerical simulations, we study the two-dimensional absorption spectrum and find that it is dominated by a V-shaped negative peak and a blueshifted elliptic positive peak. We demonstrate a simple method to derive the energy dependence of the exciton localization size from the distance between these two features in the zero waiting time experiment. When the waiting time is turned on, the V peak is filled with an extra positive peak resulting from population relaxation. From the time evolution of this peak, energy dependent relaxation rates can be obtained. The oscillations of coherent contributions to the two-dimensional spectrum are not damped by inhomogeneous mechanisms and can be seen clearly. PMID- 18447464 TI - The low-lying pisigma* state and its role in the intramolecular charge transfer of aminobenzonitriles and aminobenzethyne. AB - Electronic absorption spectra of the low-lying pipi(*) and pisigma(*) states of several aminobenzonitriles and 4-dimethylaminobenzethyne have been studied by time-resolved transient absorption and time-dependent density functional theory calculation. In acetonitrile, the lifetime of the pisigma(*)-state absorption is very short (picoseconds or subpicosecond) for molecules that exhibit intramolecular charge transfer (ICT), and very long (nanoseconds) for those that do not. Where direct comparison of the temporal characteristics of the pisigma(*) state and the ICT-state transients could be made, the formation rate of the ICT state is identical to the decay rate of the pisigma(*) state within the experimental uncertainty. These results are consistent with the pisigma(*) mediated ICT mechanism, L(a) (pipi(*))-->pisigma(*)-->ICT, in which the decay rate of the pisigma(*) state is determined by the rate of the solvent-controlled pisigma(*)-->ICT charge-shift reaction. The pipi(*)-->pisigma(*) state crossing does not occur in 3-dimethylaminobenzonitrile or 2-dimethylaminobenzonitrile, as predicted by the calculation, and 4-aminobenzonitrile and 4 dimethylaminobenzethyne does not exhibit the ICT reaction, consistent with the higher energy of the ICT state relative to the pisigma(*) state. PMID- 18447466 TI - Study of the translational diffusion of the benzophenone ketyl radical in comparison with stable molecules in room temperature ionic liquids by transient grating spectroscopy. AB - Transient grating (TG) spectroscopy has been applied to the photoinduced hydrogen abstraction reaction of benzophenone (BP) in various kinds of room temperature ionic liquids (RTILs). After the photoexcitation of BP in RTILs, the formation of a benzophenone ketyl radical (BPK) was confirmed by the transient absorption method, and the TG signal was analyzed to determine the diffusion coefficients of BPK and BP. For comparison, diffusion coefficients of carbon monoxide (CO), diphenylacetylene (DPA), and diphenylcyclopropenone (DPCP) in various RTILs were determined by the TG method using the photodissociation reaction of DPCP. While the diffusion coefficients of the stable molecules BP, DPA, and DPCP were always larger than those predicted by the Stokes-Einstein (SE) relation in RTILs, that of BPK was much smaller than those of the stable molecules and relatively close to that predicted by the SE relation in all solvents. For the smallest molecule CO, the deviation from the SE relation was evident. The diffusion coefficients of stable molecules are better represented by a power law of the inverse of the viscosity when the exponent was less than unity. The ratios of the diffusion coefficient of BP to that of BPK were larger in RTILs (2.7-4.0) than those (1.4 2.3) in conventional organic solvents. The slow diffusion of BPK in RTILs was discussed in terms of the fluctuation of the local electric field produced by the surrounding solvent ions. PMID- 18447465 TI - The effects of molecular diffusion in ultrafast two-dimensional nuclear magnetic resonance. AB - The so-called "ultrafast" nuclear magnetic resonance (NMR) methods enable the collection of multidimensional spectra within a single scan. These experiments operate by replacing traditional t(1) time increments, with a series of combined radiofrequency-irradiation/magnetic-field-gradient manipulations that spatially encode the effects of the indirect-domain spin interactions. Barring the presence of sizable displacements, the spatial patterns thus imparted can be read out following a mixing period with the aid of oscillating acquisition gradients, leading to a train of t(2)-modulated echoes carrying in their positions and phases the indirect- and the direct-domain spin interactions. Both the initial spatial encoding as well as the subsequent spatial decoding procedures underlying ultrafast NMR were designed under the assumption that spins remain static within the sample during their execution. Most often this is not the case, and motion related effects can be expected to affect the outcome of these experiments. The present paper focuses on analyzing the effects of diffusion in ultrafast two dimensional (2D) NMR. Toward this end both analytical and numerical formalisms are derived, capable of dealing with the nonuniform spin manipulations, macroscopic sample sizes, and microscopic displacements involved in this kind of sequences. After experimentally validating the correctness of these formalisms these were used to analyze the effects of diffusion for a variety of cases, including ultrafast experiments on both rapidly and slowly diffusing molecules. A series of prototypical schemes were considered including discrete and continuous encoding modes, constant- and real-time manipulations, homo- and heteronuclear acquisitions, and single versus multiple quantum modalities. The effects of molecular diffusion were also compared against typical relaxation-driven losses as they happen in these various prototypical situations; from all these situations, general guidelines for choosing the optimal ultrafast 2D NMR scheme for a particular sample and condition could be deduced. PMID- 18447467 TI - Temporal asymmetry of fluctuations in nonequilibrium steady states: links with correlation functions and nonlinear response. AB - The presence of temporal asymmetries in fluctuation paths of nonequilibrium systems has recently been confirmed numerically in nonequilibrium molecular dynamics simulations of particular deterministic systems. Here we show that this is a common feature of homogeneously driven and thermostatted, reversible, deterministic, chaotic, nonequilibrium systems of interacting particles. This is done by expressing fluctuation paths as correlation functions. The theoretical arguments look rather general, and we expect them to easily extend to other forms of driving and thermostats. The emergence of asymmetry is also justified using the transient time correlation function expression of nonlinear response theory. Numerical simulations are used to verify our arguments. PMID- 18447468 TI - Semiquantal analysis of adiabatic hydrogen transfer rate. AB - The reaction rate of adiabatic proton/hydrogen/hydride (H) transfers in condensed phase is examined by combining the semiquantal time-dependent Hartree theory and the multidimensional transition state theory, which takes into account the zero point effect and the dynamical modulation of the wavepacket width in the adiabatic transfer regime. By applying the theory to a model potential consisting of a quartic double well coupled linearly and quadratically (symmetrically) to external degrees of freedom, a set of compact analytical formulas was derived for the adiabatic H transfer rate. The analysis suggests that the kinetic isotope effect on the H transfer rate may exhibit a maximum as a function of the coupling strength to the external degrees of freedom measured by the reorganization energy. PMID- 18447469 TI - Critical dynamics of ballistic and Brownian particles in a heterogeneous environment. AB - The dynamic properties of a classical tracer particle in a random, disordered medium are investigated close to the localization transition. For Lorentz models obeying Newtonian and diffusive motion at the microscale, we have performed large scale computer simulations, demonstrating that universality holds at long times in the immediate vicinity of the transition. The scaling function describing the crossover from anomalous transport to diffusive motion is found to vary extremely slowly and spans at least five decades in time. To extract the scaling function, one has to allow for the leading universal corrections to scaling. Our findings suggest that apparent power laws with varying exponents generically occur and dominate experimentally accessible time windows as soon as the heterogeneities cover a decade in length scale. We extract the divergent length scales, quantify the spatial heterogeneities in terms of the non-Gaussian parameter, and corroborate our results by a thorough finite-size analysis. PMID- 18447470 TI - Design of chemically propelled nanodimer motors. AB - The self-propelled motion of nanodimers fueled by a chemical reaction taking place under nonequilibrium steady state conditions is investigated. The nanodimer consists of a pair of catalytic and chemically inactive spheres, in general with different sizes, with a fixed internuclear separation. The solvent in which the dimer moves is treated at a particle-based mesoscopic level using multiparticle collision dynamics. The directed motion of the dimer can be controlled by adjusting the interaction potentials between the solvent molecules and the dimer spheres, the internuclear separation, and sphere sizes. Dimers can be designed so that the directed motion along the internuclear axis occurs in either direction and is much larger than the thermal velocity fluctuations, a condition needed for such nanodimers to perform tasks involving targeted dynamics. PMID- 18447471 TI - A stochastic simulation of nonisothermal nucleation. AB - The results of stochastic simulations of growth and evaporation of small clusters in vapor are reported. Energy dependent growth rates are determined from the monomer-cluster collision rate and decay rates are found from a detailed balance, with the equilibrium size and energy distribution of clusters calculated using the capillarity approximation and the equilibrium vapor pressure. These rates are used in simulations of two-dimensional random walks in size and energy space to determine the fraction of clusters in supersaturated vapor of size (i(min)+1) that reach a size i(max). By assuming that clusters of size i(min) are in equilibrium, this fraction can be related to the nonisothermal nucleation rate. The simulated rates show good agreement with the previously published analytical results. In the absence of an inert carrier gas, the nonisothermal nucleation rates are typically between 1% and 5% of the isothermal rates. PMID- 18447472 TI - Quantum-classical Liouville dynamics of proton and deuteron transfer rates in a solvated hydrogen-bonded complex. AB - Proton and deuteron transfer reactions in a hydrogen-bonded complex dissolved in a polar solution are studied using quantum-classical Liouville dynamics. Reactive flux correlation functions that involve quantum-classical Liouville dynamics for species operators and quantum equilibrium sampling are used to calculate the rate constants. Adiabatic and nonadiabatic reaction rates are computed, compared, and analyzed. Large variations of the kinetic isotope effect (KIE) for this reaction have been observed in the literature, which depend on the nature of the approximate calculation used to estimate the proton and deuteron transfer rates. Our estimate of the KIE lies at the low end of the range of previously observed values, suggesting a rather small KIE for this reaction. PMID- 18447473 TI - A first principles study on organic molecule encapsulated boron nitride nanotubes. AB - The electronic structures of boron nitride nanotubes (BNNTs) doped with organic molecules are investigated using density functional theory. An electrophilic molecule introduces acceptor states in the wide gap of BNNT close to the valence band edge, which makes the doped system a p-type semiconductor. However, with typical nucleophilic organic molecules encapsulation, only deep occupied molecular states but no shallow donor states are observed. There is a significant electron transfer from a BNNT to an electrophilic molecule, while the charge transfer between a nucleophilic molecule and a BNNT is negligible. When both electrophilic and nucleophilic molecules are encapsulated in the same BNNT, a large charge transfer between the two kinds of molecules occurs. The resulting small energy gap can strongly modify the transport and optical properties of the system. PMID- 18447474 TI - Coherent phonon excitation and linear thermal expansion in structural dynamics and ultrafast electron diffraction of laser-heated metals. AB - In this study, we examine the ultrafast structural dynamics of metals induced by a femtosecond laser-heating pulse as probed by time-resolved electron diffraction. Using the two-temperature model and the Gruneisen relationship we calculate the electron temperature, phonon temperature, and impulsive force at each atomic site in the slab. Together with the Fermi-Pasta-Ulam anharmonic chain model we calculate changes of bond distance and the peak shift of Bragg spots or Laue rings. A laser-heated thin slab is shown to exhibit "breathing" standing wave behavior, with a period equal to the round-trip time for sound wave and a wavelength twice the slab thickness. The peak delay time first increases linearly with the thickness (<70 nm for aluminum and <200 nm for gold), but becomes less dependent if further thickness increases. Coherent phonon excitation and propagation from the stressed bulk atoms due to impulsive forces as well as the linear thermal expansion due to lattice temperature jump are shown to contribute to the overall structural changes. Differences between these two mechanisms and their dependence on film thickness and other factors are discussed. PMID- 18447475 TI - Thermodynamics and kinetics of oxygen-induced segregation of 3d metals in Pt-3d Pt(111) and Pt-3d-Pt(100) bimetallic structures. AB - The stability of subsurface 3d transition metals (3d represents Ni, Co, Fe, Mn, Cr, V, and Ti) in Pt(111) and Pt(100) was examined in vacuum and with 0.5 ML atomic oxygen by a combined experimental and density functional theory (DFT) approach. DFT was used to predict the trends in the binding energy of oxygen and in the stability of 3d metals to remain in the subsurface layer. DFT calculations predicted that for both (111) and (100) crystal planes the subsurface Pt-3d-Pt configurations were thermodynamically preferred in vacuum and that the surface 3d Pt-Pt configurations were preferred with the adsorption of 0.5 ML atomic oxygen. Experimentally, the DFT predictions were verified by using Auger electron spectroscopy to monitor the segregation of Ni and Co in Pt-3d-Pt structures on polycrystalline Pt foil, composed of mainly (111) and (100) facets. The activation barrier for the oxygen-induced segregation of Ni was found to be 17+/ 1 kcal/mol attributed to the Pt(111) areas and 27+/-1 kcal/mol attributed to the Pt(100) areas of the Pt foil. For Pt-Co-Pt, the activation barrier was found to be 10+/-1 kcal/mol and was attributed to the Pt(111) areas of the Pt foil. The Bronsted-Evans-Polanyi relationship was utilized to predict the activation barriers for segregation of the other Pt-3d-Pt(111) and Pt-3d-Pt(100) systems. These results are further discussed in connection to the activity and stability for cathode bimetallic electrocatalysts for proton exchange membrane fuel cells. PMID- 18447476 TI - Beyond the dynamic density functional theory for steady currents: application to driven colloidal particles in a channel. AB - Motivated by recent studies on the dynamics of colloidal solutions in narrow channels, we consider the steady state properties of an assembly of noninteracting particles subject to the action of a traveling potential moving at a constant speed, while the solvent is modeled by a heat bath at rest in the laboratory frame. Here, since the description we propose takes into account the inertia of the colloidal particles, it is necessary to consider the evolution of both positions and momenta and study the governing equation for the one-particle phase-space distribution. First, we derive the asymptotic form of its solutions as an expansion in Hermite polynomials and their generic properties, such as the force and energy balance, and then we particularize our study to the case of an inverted parabolic potential barrier. We numerically obtain the steady state density and temperature profile and show that the expansion is rapidly convergent for large values of the friction constant and small drifting velocities. On the one hand, the present results confirm the previous studies based on the dynamic density functional theory (DDFT): On the other hand, when the friction constant is large, it display effects such as the presence of a wake behind the barrier and a strong inhomogeneity in the temperature field which are beyond the DDFT description. PMID- 18447477 TI - The adsorption of O2 on Pb films and the effect of quantum modulation: a first principles prediction. AB - Using first-principles calculations based on density-functional theory, we systematically study the adsorption of O(2) molecules on ultrathin Pb(111) films ranging from 3 to 11 monolayers (MLs). It is found that no matter how thick the film is, the O(2) molecule prefers to adsorb at the threefold hcp hollow site where it lies parallel to the surface. The adsorption mechanism is discussed from the hybridization of p orbitals of O(2) and Pb. The adsorption energy of O(2) on the Pb(111) film, about several hundred meV, shows a 2 ML oscillation with the thickness. This study well confirms the modulation of the surface reactivity of Pb films induced by the quantum well states, which is compatible with the previous experimental observation. PMID- 18447478 TI - Bias-driven local density of states alterations and transport in ballistic molecular devices. AB - We study dynamic nonequilibrium electron charging phenomena in ballistic molecular devices at room temperature that compromise their response to bias and whose nature is evidently distinguishable from static Schottky-type potential barriers. Using various metallic/semiconducting carbon nanotubes and alkane dithiol molecules as active parts of a molecular bridge, we perform self consistent quantum transport calculations under the nonequilibrium Green's function formalism coupled to a three-dimensional Poisson solver for a mutual description of chemistry and electrostatics. Our results sketch a particular tracking relationship between the device's local density of states and the contact electrochemical potentials that can effectively condition the conduction process by altering the electronic structure of the molecular system. Such change is unassociated to electronic/phononic scattering effects while its extent is highly correlated to the conducting character of the system, giving rise to an increase of the intrinsic resistance of molecules with a semiconducting character and a symmetric mass-center disposition. PMID- 18447479 TI - Tuning the work function of ultrathin oxide films on metals by adsorption of alkali atoms. AB - We report a theoretical investigation of the adsorption of alkali metal atoms deposited on ultrathin oxide films. The properties of Li, Na, and K atoms adsorbed on SiO(2)/Mo(112) and of K on MgO / Ag(100) and TiO(2)/Pt(111) have been analyzed with particular attention to the induced changes in the work function of the system, Phi. On the nonreducible SiO(2) and MgO oxide films there is a net transfer of the outer ns electron of the alkali atom to the metal substrate conduction band; the resulting surface dipole substantially lowers Phi. The change in Phi depends (a) on the adsorption site (above the oxide film or at the interface) and (b) on the alkali metal coverage. Deposition of K on reducible TiO(2) oxide films results in adsorbed K(+) ions and in the formation of Ti(3+) ions. No charge transfer to the metal substrate is observed but also in this case the surface dipole resulting from the K-TiO(2) charge transfer has the effect to considerably reduce the work function of the system. PMID- 18447480 TI - Molecular dynamics simulations of carbon nanotube/silicon interfacial thermal conductance. AB - Using molecular dynamics simulations with Tersoff reactive many-body potential for Si-Si, Si-C, and C-C interactions, we have calculated the thermal conductance at the interfaces between carbon nanotube (CNT) and silicon at different applied pressures. The interfaces are formed by axially compressing and indenting capped or uncapped CNTs against 2 x 1 reconstructed Si surfaces. The results show an increase in the interfacial thermal conductance with applied pressure for interfaces with both capped and uncapped CNTs. At low applied pressure, the thermal conductance at interface with uncapped CNTs is found to be much higher than that at interface with capped CNTs. Our results demonstrate that the contact area or the number of bonds formed between the CNT and Si substrate is key to the interfacial thermal conductance, which can be increased by either applying pressure or by opening the CNT caps that usually form in the synthesis process. The temperature and size dependences of interfacial thermal conductance are also simulated. These findings have important technological implications for the application of vertically aligned CNTs as thermal interface materials. PMID- 18447481 TI - Measuring the deformation of a ferrogel sphere in a homogeneous magnetic field. AB - A sphere of a ferrogel is exposed to a homogeneous magnetic field. In accordance to theoretical predictions, it gets elongated along the field lines. The time dependence of the elastic shear modulus causes the elongation to increase with time, similar to mechanic creep experiments, and the rapid excitation causes the sphere to vibrate. Both phenomena can be well described by a damped harmonic oscillator model. By comparing the elongation along the field to the contraction perpendicular to it, we can calculate Poisson's ratio of the gel. The magnitude of the elongation is compared to the theoretical predictions for elastic spheres in homogeneous fields. PMID- 18447482 TI - A molecular simulation study of an organosilane self-assembled monolayer/SiO2 substrate interface. AB - The bonding network of an alkylsilane self-assembled monolayer (SAM)SiO(2) substrate interface is investigated by means of canonical Monte Carlo (MC) simulations. SAMSiO(2) systems with different interfacial bonding topologies are sampled by the Metropolis MC method, and the AMBER potential with a newly developed organosilicon parameters are used to obtain an optimized structure with a given bonding topology. The underlying substrates are modeled as hydroxy terminated (100) or (111) cristobalites. The SAMSiO(2) interface is characterized by a polysiloxane bonding network which comprises anchoring bonds and cross linking bonds, namely, molecule-substrate and molecule-molecule Si-O-Si bonds, respectively. We show that at thermal equilibrium, the ratio of the number of anchoring bonds to cross-linking bonds decreases as a total Si-O-Si bond density increases, and that nevertheless, number of anchoring bonds always dominate over that of cross-linking bonds. Moreover we show that the total Si-O-Si bond density strongly affects the lateral ordering of the alkylsilane molecules, and that increase in the Si-O-Si bond density disorders the molecular packing. Our results imply that a lab-to-lab variation in the experimentally prepared SAMs can be attributed to different Si-O-Si bond densities at the SAMSiO(2) interface. PMID- 18447483 TI - Molecular dynamics simulation of nanocolloidal amorphous silica particles: Part II. AB - Explicit molecular dynamics simulations were applied to a pair of amorphous silica nanoparticles with diameter of 3.2 nm immersed in a background electrolyte. Mean forces acting between the pair of silica nanoparticles were extracted at four different background electrolyte concentrations. The dependence of the interparticle potential of mean force on the separation and the silicon to sodium ratio, as well as on the background electrolyte concentration, are demonstrated. The pH was indirectly accounted for via the ratio of silicon to sodium used in the simulations. The nature of the interaction of the counterions with charged silica surface sites (deprotonated silanols) was also investigated. The effect of the sodium double layer on the water ordering was investigated for three Si : Na(+) ratios. The number of water molecules trapped inside the nanoparticles was investigated as the Si : Na(+) ratio was varied. Differences in this number between the two nanoparticles in the simulations are attributed to differences in the calculated electric dipole moment. The implications of the form of the potentials for aggregation are also discussed. PMID- 18447484 TI - Inhomogeneous decomposition of ultrathin oxide films on Si(100): application of Avrami kinetics to thermal desorption spectra. AB - Thermal decomposition of ultrathin oxide layers on silicon surface was investigated with temperature programed desorption. Oxide layers were formed on Si(100) at 400 degrees C by exposure to O(2) molecular beam. Desorption spectrum for oxygen coverages between 1.7 and 2.6 ML exhibits a single dominant peak with an additional broad peak at lower temperatures. The former peak corresponds to stable binding states of O atoms at dimer bridge sites and dimer backbond sites. The high peak intensity indicates that most O atoms are at stable states. The latter peak corresponds to an unstable binding state, where O atoms are presumably trapped at dangling bonds. The SiO desorption rate from the stable binding states is well described by Avrami kinetics, suggesting that the decomposition process is spatially inhomogeneous with void formation and growth. The rate-determining step is the reaction at void perimeter even if the overlap between voids becomes quite large. The Avrami exponents determined from our experiment indicate that the increase in the initial coverage makes the oxide layer more stable and suppresses the rate of void formation at the potential nucleation sites. PMID- 18447485 TI - Properties of Coulomb crystals: rigorous results. AB - Rigorous equalities and bounds for several properties of Coulomb crystals are presented. The energy e(N) per particle pair is shown to be a nondecreasing function of the particle number N for all clusters described by double-power-law pairwise-additive potentials epsilon(r) that are unbound at both r-->0 and r- >infinity. A lower bound for the ratio of the mean reciprocal crystal radius and e(N) is derived. The leading term in the asymptotic expression for the shell capacity that appears in the recently introduced approximate model of Coulomb crystals is obtained, providing in turn explicit large-N asymptotics for e(N) and the mean crystal radius. In addition, properties of the harmonic vibrational spectra are investigated, producing an upper bound for the zero-point energy. PMID- 18447486 TI - Modeling the sorption dynamics of NaH using a reactive force field. AB - We have parametrized a reactive force field for NaH, ReaxFF(NaH), against a training set of ab initio derived data. To ascertain that ReaxFF(NaH) is properly parametrized, a comparison between ab initio heats of formation of small representative NaH clusters with ReaxFF(NaH) was done. The results and trend of ReaxFF(NaH) are found to be consistent with ab initio values. Further validation includes comparing the equations of state of condensed phases of Na and NaH as calculated from ab initio and ReaxFF(NaH). There is a good match between the two results, showing that ReaxFF(NaH) is correctly parametrized by the ab initio training set. ReaxFF(NaH) has been used to study the dynamics of hydrogen desorption in NaH particles. We find that ReaxFF(NaH) properly describes the surface molecular hydrogen charge transfer during the abstraction process. Results on heat of desorption versus cluster size shows that there is a strong dependence on the heat of desorption on the particle size, which implies that nanostructuring enhances desorption process. To gain more insight into the structural transformations of NaH during thermal decomposition, we performed a heating run in a molecular dynamics simulation. These runs exhibit a series of drops in potential energy, associated with cluster fragmentation and desorption of molecular hydrogen. This is consistent with experimental evidence that NaH dissociates at its melting point into smaller fragments. PMID- 18447487 TI - The effect of fullerene derivative on polaronic charge transfer in poly(3 hexylthiophene)/fullerene compound. AB - The effect of a structure of a fullerene derivative on electronic properties of poly(3-hexylthiophene)/fullerene composite was studied at 3 cm wave band EPR in wide (77-320 K) temperature region. All the systems with different fullerene derivatives demonstrate sum spectrum of small polarons with different mobilities and contributions depending on the structure of the fullerene derivative. Both the spin-lattice and spin-spin relaxation times were determined separately by using the steady-state saturation method. The treatment of polymer matrix by fullerene derivative changes its dimensionality and conformation. This leads to the change in the spin relaxation and susceptibility as well as in the rate of polaron diffusion along polymer chain. PMID- 18447488 TI - Multiscale theory of collective and quasiparticle modes in quantum nanosystems. AB - A quantum nanosystem (such as a quantum dot, nanowire, superconducting nanoparticle, or superfluid nanodroplet) involves widely separated characteristic lengths. These lengths range from the average nearest-neighbor distance between the constituent fermions or bosons, or the lattice spacing for a conducting metal, to the overall size of the quantum nanosystem (QN). This suggests the wave function has related distinct dependencies on the positions of the constituent fermions and bosons. We show how the separation of scales can be used to generate a multiscale perturbation scheme for solving the wave equation. Results for electrons or other fermions show that, to lowest order, the wave function factorizes into an antisymmetric (fermion) part and a symmetric (bosonlike) part. The former manifests the short-range/exclusion-principle behavior, while the latter corresponds to collective behaviors, such as plasmons, which have a boson character. When the constituents are bosons, multiscale analysis shows that, to lowest order, the wave function can also factorize into short- and long-scale parts. However, to ensure that the product wave function has overall symmetric particle label exchange behavior, there could, in principle, be states of the boson nanosystem where both the short- and long-scale factors are either boson- or fermionlike; the latter "dual fermion" states are, due to their exclusion principle-like character, of high energy (i.e., single particle states cannot be multiply occupied). The multiscale perturbation analysis is used to argue for the existence of a coarse-grained wave equation for bosonlike collective behaviors. Quasiparticles, with effective mass and interactions, emerge naturally as consequences of the long-scale dynamics of the constituent particles. The multiscale framework holds promise for facilitating QN computer simulations and novel approximation schemes. PMID- 18447489 TI - Electrostatic depletion forces between planar surfaces. AB - The interaction between two dielectric plates immersed in an electrolyte solution is examined by using a variational perturbation approximation for the grand partition function. This approach differs from previous treatments in that the screening length between the plates is treated as a variational parameter. A key finding is that adjacent to each plate is a layer of ion depletion with thickness given by about one-half of a Bjerrum length. Consequently, for plate-plate separations less than the Bjerrum length, nearly all the electrolyte is excluded from between the plates, and the interaction is given by the sum of a van der Waals interaction and an attractive osmotic depletion force. In contrast to the predictions of previous theories, the interaction between the plates at short range increases with increasing electrolyte concentration and may provide an important contribution to the salt-induced attraction, commonly referred to as salting out. Because the range of the osmotic depletion force is roughly equal to the Bjerrum length, it increases with the square of the valency of the electrolyte. At larger plate-plate separations, the van der Waals interaction is screened as electrolyte enters the space between the plates, leading to an exponential decay of the interactions, as has been previously observed. However, this interaction is slightly stronger than that previously predicted, due to ion depletion from the surface of the interface, also this effect increases with increasing electrolyte concentration. PMID- 18447490 TI - First-principles local density approximation (generalized gradient approximation) +U study of catalytic CenOm clusters: U value differs from bulk. AB - Ceria possesses strong catalytic properties for CONO(x) removal and H(2) production. Clusters often show more intriguing functionalities than their bulk counterparts. Here, the geometric and electronic structures of Ce(n)O(m) (n=1 4,m=2n-1,2n) clusters are studied for the first time using the projected augmented wave method in density functional theory with detailed assessment of the exchange-correlation functional and the Hubbard parameter U. We note that the U value strongly affects the electronic structures of the oxygen-deficient Ce(n)O(2n-1) clusters, though less so on the stoichiometric Ce(n)O(2n). Furthermore, the local density approximation (LDA)+U method is more accurate than the generalized gradient approximation+U in describing the localization of the 4f electrons of the Ce(n)O(m) clusters. The calculated vibration frequency of the CeO molecule with the LDA+U (U=4 eV) is 818.4 cm(-1), in close agreement with experimental values of 820-825 cm(-1) for the low lying states. Different optimal U values were noted for the ceria cluster (4 eV) and its bulk (6 eV), due to quantum-size and geometric effects. The largely reduced formation energy of an oxygen vacancy indicates that the catalytic effect of the Ce(n)O(m) clusters are far greater than bulk CeO(2). PMID- 18447491 TI - Mobius and twisted graphene nanoribbons: stability, geometry, and electronic properties. AB - Results of classical force field geometry optimizations for twisted graphene nanoribbons with a number of twists N(t) varying from 0 to 7 (the case N(t)=1 corresponds to a half-twist Mobius nanoribbon) are presented in this work. Their structural stability was investigated using the Brenner reactive force field. The best classical molecular geometries were used as input for semiempirical calculations, from which the electronic properties (energy levels, HOMO, LUMO orbitals) were computed for each structure. CI wavefunctions were also calculated in the complete active space framework taking into account eigenstates from HOMO 4 to LUMO+4, as well as the oscillator strengths corresponding to the first optical transitions in the UV-VIS range. The lowest energy molecules were found less symmetric than initial configurations, and the HOMO-LUMO energy gaps are larger than the value found for the nanographene used to build them due to electronic localization effects created by the twisting. A high number of twists leads to a sharp increase of the HOMO-->LUMO transition energy. We suggest that some twisted nanoribbons could form crystals stabilized by dipolar interactions. PMID- 18447492 TI - Excited-state relaxation in PbSe quantum dots. AB - In solids the phonon-assisted, nonradiative decay from high-energy electronic excited states to low-energy electronic excited states is picosecond fast. It was hoped that electron and hole relaxation could be slowed down in quantum dots, due to the unavailability of phonons energy matched to the large energy-level spacings ("phonon-bottleneck"). However, excited-state relaxation was observed to be rather fast (< or =1 ps) in InP, CdSe, and ZnO dots, and explained by an efficient Auger mechanism, whereby the excess energy of electrons is nonradiatively transferred to holes, which can then rapidly decay by phonon emission, by virtue of the densely spaced valence-band levels. The recent emergence of PbSe as a novel quantum-dot material has rekindled the hope for a slow down of excited-state relaxation because hole relaxation was deemed to be ineffective on account of the widely spaced hole levels. The assumption of sparse hole energy levels in PbSe was based on an effective-mass argument based on the light effective mass of the hole. Surprisingly, fast intraband relaxation times of 1-7 ps were observed in PbSe quantum dots and have been considered contradictory with the Auger cooling mechanism because of the assumed sparsity of the hole energy levels. Our pseudopotential calculations, however, do not support the scenario of sparse hole levels in PbSe: Because of the existence of three valence-band maxima in the bulk PbSe band structure, hole energy levels are densely spaced, in contradiction with simple effective-mass models. The remaining question is whether the Auger decay channel is sufficiently fast to account for the fast intraband relaxation. Using the atomistic pseudopotential wave functions of Pb(2046)Se(2117) and Pb(260)Se(249) quantum dots, we explicitly calculated the electron-hole Coulomb integrals and the P-->S electron Auger relaxation rate. We find that the Auger mechanism can explain the experimentally observed P-->S intraband decay time scale without the need to invoke any exotic relaxation mechanisms. PMID- 18447493 TI - Magnetic structure and orbital ordering in tetragonal and monoclinic KCrF(3) from first-principles calculations. AB - KCrF(3) has been systematically investigated by using the full-potential linearized augmented plane wave plus local orbital method within the generalized gradient approximation and the local spin density approximation plus the on-site Coulomb repulsion approach. The total energies for ferromagnetic and three different antiferromagnetic configurations are calculated in the high-temperature tetragonal and low-temperature monoclinic phases, respectively. It reveals that the ground state is the A-type antiferromagnetic in both phases. Furthermore, the ground states of the two phases are found to be Mott-Hubbard insulators with the G-type orbital ordering pattern. In addition, our calculations show the staggered orbital ordering of the 3d(x(2) ) and 3d(y(2) ) orbitals for the tetragonal phase and the 3d(z(2) ) and 3d(x(2) ) orbitals for the monoclinic phase, which is in agreement with the available data. More importantly, the relationship between magnetic structure and orbital ordering as well as the origin of the orbital ordering are analyzed in detail. PMID- 18447494 TI - Mechanisms of solute orientational order in nematic liquid crystals. AB - The order parameters of a number of different solutes dissolved in a number of different nematic liquid-crystal solvents are measured and compared. It is shown that the order parameters can all be rationalized with the ansatz that there exist two independent ordering mechanisms operating in the liquid crystals employed. With this ansatz it is possible to fit the experimental order parameters to better than 5%. This opens the possibility of the accurate prediction of order parameters in ordered liquids. PMID- 18447495 TI - Specifics of solvation of sulfonated polyelectrolytes in water, dimethylmethylphosphonate, and their mixture: a molecular simulation study. AB - Sulfonated polyelectrolyte membranes (PEMs), such as Nafion and styrene-olefin block copolymers, are explored as permselective membranes for fuel cells as well as suitable barrier materials against chemical agents. The permselective properties of PEM are determined by their microphase segregation into hydrophilic and hydrophobic domains. We performed classical molecular dynamics simulations of solvation of the hydrophilic fragments of PEM exemplified on sulfonated polystyrene (sPS) with potassium, calcium, and aluminum as counterions, in water, phosphor-organic nerve agent simulant dimethylmethylphosphonate (DMMP), and their binary mixture. The force field for the sulfonate group has been developed by optimizing the potential parameters to fit the benzenesulfonate conformations obtained from the density functional theory. For a comparison, we considered perfluorosulfonate oligomers representing fragments of Nafion polymer. We found a noticeable difference between the geometries of the polymer backbone in different solvents. The polymer backbone is stiffer in DMMP for both sPS and Nafion. An anisotropic structuring of the solvent around the phenylsulfonate group is substantially stronger than around the Nafion sidechain due to the rigidity and the anisotropy of the phenylsulfonate group. The counterion significantly affects the conformations of solvated sPS: the rigidity of the backbone increases when potassium or calcium ions are replaced by trivalent aluminum ions. PMID- 18447496 TI - Self-assembled ordered polymer nanocomposites directed by attractive particles. AB - We theoretically investigate general conditions under which an inorganic phase can direct the self-assembly of an ordered polymer nanocomposite. For this purpose, we consider a solution of triblock copolymers forming a hexagonal phase of micelles and investigate the effect of adding attractive particles. We show that if the triblock is functionalized at its ends by attaching groups with specific affinity for the particles, thus effectively becoming a pentablock, the particles direct the self-assembly of the system into phases where both the polymers and the particles exhibit mesoscopic order. Different lamellar and gyroid phases (both with Ia3d and I4(1)32 space symmetries) are presented in detail. Our results show that functionalization is a very powerful route for directing self-assembly of polymer nanocomposites. We briefly discuss the connections with recent theoretical and experimental results in diblock melts with nanoparticles as well as for problems where polymers are used to template the growth of an inorganic phase in solution. PMID- 18447497 TI - Structure and assembly of dense solutions and melts of single tethered nanoparticles. AB - The microscopic polymer reference interaction site model theory is generalized and applied to study intermolecular pair correlation functions and collective structure factors of dense solutions and melts of spherical nanoparticles carrying a single tethered chain. The complex interplay of entropy (translational, conformational, and packing) and enthalpy (particle-particle attraction) leads to different structural arrangements with distinctive small and wide angle scattering signatures. Strong concentration fluctuations, indicative of aggregate formation and/or a tendency for microphase separation, occur as the total packing fraction and/or particle-particle attraction strength increase. In analogy with block copolymers, the microphase spinodal curve is estimated by extrapolation of the inverse of the amplitude of the small angle scattering peak. For nanoparticles that are twice the diameter of monomers, the microphase separation boundary spinodal occurs at higher particle-particle attraction strength (or lower temperature) as compared to the macrophase demixing curve for nanoparticles with no tethers when the packing fraction is below 0.45, while the opposite trend is observed above 0.45. Increasing nanoparticle diameter results in a reduction in the microphase spinodal temperature and a qualitative change in its packing fraction dependence. PMID- 18447498 TI - Haloing, flocculation, and bridging in colloid-nanoparticle suspensions. AB - Integral equation theory with a hybrid closure approximation is employed to study the equilibrium structure of highly size asymmetric mixtures of spherical colloids and nanoparticles. Nonequilibrium contact aggregation and bridging gel formation is also qualitatively discussed. The effect of size asymmetry, nanoparticle volume fraction and charge, and the spatial range, strength, and functional form of colloid-nanoparticle and colloid-colloid attractions in determining the potential-of-mean force (PMF) between the large spheres is systematically explored. For hard, neutral particles with weak colloid nanoparticle attraction qualitatively distinct forms of the PMF are predicted: (i) a contact depletion attraction, (ii) a repulsive form associated with thermodynamically stable "nanoparticle haloing," and (iii) repulsive at contact but with a strong and tight bridging minimum. As the interfacial cohesion strengthens and becomes shorter range the PMF acquires a deep and tight bridging minimum. At sufficiently high nanoparticle volume fractions, a repulsive barrier then emerges which can provide kinetic stabilization. The charging of nanoparticles can greatly reduce the volume fractions where significant changes of the PMF occur. For direct and interfacial van der Waals attractions, the large qualitative consequences of changing the absolute magnitude of nanoparticle and colloid diameters at fixed size asymmetry ratio are also studied. The theoretical results are compared with recent experimental and simulation studies. Calculations of the real and Fourier space mixture structure at nonzero colloid volume fractions reveal complex spatial reorganization of the nanoparticles due to many body correlations. PMID- 18447499 TI - Phase behavior and structure formation in linear multiblock copolymer solutions by Monte Carlo simulation. AB - The solution phase behavior of short, strictly alternating multiblock copolymers of type (A(n)B(n))(m) was studied using lattice Monte Carlo simulations. The polymer molecules were modeled as flexible chains in a monomeric solvent selective for block type A. The degree of block polymerization n and the number of diblock units per chain m were treated as variables. We show that within the regime of parameters accessible to our study, the thermodynamic phase transition type is dependent on the ratio of m / n. The simulations show microscopic phase separation into roughly spherical aggregates for m / n ratios less than a critical value and first-order macroscopic precipitation otherwise. In general, increasing m at fixed n, or n at fixed m, promotes the tendency toward macroscopic phase precipitation. The enthalpic driving force of phase change is found to universally scale with chain length for all multiblock systems considered and is independent of the existence of a true phase transition. For aggregate forming systems at low amphiphile concentrations, multiblock chains are shown to self-assemble into intramolecular, multichain clusters. Predictions for microstructural dimensions, including critical micelle concentration, equilibrium size, shape, aggregation parameters, and density distributions, are provided. At increasing amphiphile density, interaggregate bridging is shown to result in the formation of networked structures, leading to an eventual solution-gel transition. The gel is swollen and consists of highly interconnected aggregates of approximately spherical morphology. Qualitative agreement is found between experimentally observed physical property changes and phase transitions predicted by simulations. Thus, a potential application of the simulations is the design of multiblock copolymer systems which can be optimized with regard to solution phase behavior and ultimately physical and mechanical properties. PMID- 18447500 TI - Brownian dynamics simulations of polyelectrolyte adsorption in shear flow: effects of solvent quality and charge patterning. AB - We probe the effects of solvent quality and charge patterning on polyelectrolyte adsorption in shear flow using Brownian dynamics simulations with hydrodynamic interaction (HI). The polyelectrolyte is modeled as a freely jointed bead-rod chain, and electrostatic and non-electrostatic interactions are accounted for by using screened Coulombic and Lennard-Jones potentials, respectively. In the absence of flow, the conformation of a polyelectrolyte molecule adsorbed onto a uniformly charged surface changes from flat to globular with an increase in bead bead attraction (hydrophobicity), consistent with prior experimental observations. In the presence of flow, migration due to bead-wall HI and, as a consequence, desorption decrease with an increase in bead-bead attraction, implying that flow-induced desorption is more difficult under poor-solvent conditions. When bead-bead non-electrostatic attraction is strong, desorption can be enhanced by increasing bead-bead electrostatic repulsion. Analogous to the effect of bead-surface electrostatic attraction, an increase in the strength of bead-surface non-electrostatic attraction reduces desorption. We also study the effect of shear flow on the adsorption of a polyelectrolyte molecule onto surfaces decorated with periodic arrays of charged patches. An increase in patch periodicity increases desorption even when the effective surface charge density is kept the same. The results of this work suggest mechanisms for controlling the desorption of polyelectrolyte molecules in shear flows. PMID- 18447501 TI - Adsorption of random copolymers by a selective layer: Monte Carlo studies. AB - We use scaling arguments and computer simulations to investigate the adsorption of symmetric AB-random copolymers (RC) from a diluted solution onto a selective ABA layer. Depending on the ratio between the layer thickness and the size of excess blobs, d/xi, three regimes of RC adsorption are predicted. For large values of the layer thickness RC adsorption can be understood as adsorption on two selective interfaces where sequences of RC chains form bridges. When the layer thickness is of the order of xi, excess blobs are trapped in the layer and localize the copolymer chain strongly. If the layer thickness is very small a weak adsorption scenario is predicted where large loops are formed outside the layer. Our simulations using the bond fluctuation model are in good agreement with the scaling predictions. We show that chain properties display non monotonous behavior with respect to the layer thickness with optimal values for d approximately xi. In particular, we discuss simulation results for density profiles, statistics of bridges, loops and tails formed by the adsorbed chains, as well as for the adsorption order parameter and free energy. PMID- 18447502 TI - Coarse-grained molecular dynamics simulation on the placement of nanoparticles within symmetric diblock copolymers under shear flow. AB - We present molecular dynamics simulations coupled with a dissipative particle dynamics thermostat to model and simulate the behavior of symmetric diblock copolymer/nanoparticle systems under simple shear flow. We consider two categories of nanoparticles, one with selective interactions toward one of the blocks of a model diblock copolymer and the other with nonselective interactions with both blocks. For the selective nanoparticles, we consider additional variants by changing the particle diameter and the particle-polymer interaction potential. The aim of our present study is to understand how the nanoparticles disperse in a block copolymer system under shear flow and how the presence of nanoparticles affects the rheology, structure, and flow behavior of block copolymer systems. We keep the volume fraction of nanoparticles low (0.1) to preserve lamellar morphology in the nanocomposite. Our results show that shear can have a pronounced effect on the location of nanoparticles in block copolymers and can therefore be used as another parameter to control nanocomposite self assembly. In addition, we investigate the effect of nanoparticles on shear induced lamellar transition from parallel to perpendicular orientation to further elucidate nanocomposite behavior under shear, which is an important tool to induce long-range order in self-assembling materials such as block copolymers. PMID- 18447503 TI - Microstructure and depletion forces in polymer-colloid mixtures from an interfacial statistical associating fluid theory. AB - By using a classical density functional theory (interfacial statistical associating fluid theory), we investigate the structure and effective forces in nonadsorbing polymer-colloid mixtures. The theory is tested under a wide range of conditions and performs very well in comparison to simulation data. A comprehensive study is conducted characterizing the role of polymer concentration, particle/polymer-segment size ratio, and polymer chain length on the structure, polymer induced depletion forces, and the colloid-colloid osmotic second virial coefficient. The theory correctly captures a depletion layer on two different length scales, one on the order of the segment diameter (semidilute regime) and the other on the order of the polymer radius of gyration (dilute regime). The particle/polymer-segment size ratio is demonstrated to play a significant role on the polymer structure near the particle surface at low polymer concentrations, but this effect diminishes at higher polymer concentrations. Results for the polymer-mediated mean force between colloidal particles show that increasing the concentration of the polymer solution encourages particle-particle attraction, while decreasing the range of depletion attraction. At intermediate to high concentrations, depletion attraction can be coupled to a midrange repulsion, especially for colloids in solutions of short chains. Colloid-colloid second virial coefficient calculations indicate that the net repulsion between colloids at low polymer densities gives way to net attraction at higher densities, in agreement with available simulation data. Furthermore, the results indicate a higher tendency toward colloidal aggregation for larger colloids in solutions of longer chains. PMID- 18447504 TI - Shear small-angle light scattering studies of shear-induced concentration fluctuations and steady state viscoelastic properties. AB - We aimed at elucidating the influence of shear-induced structures (shear-enhanced concentration fluctuations and/or shear-induced phase separation), as observed by rheo-optical methods with small-angle light scattering under shear flow (shear SALS) and shear-microscopy, on viscoelastic properties in semidilute polystyrene (PS) solutions of 6.0 wt % concentration using dioctyl phthalate (DOP) as a Theta solvent and tricresyl phosphate (TCP) as a good solvent. In order to quantify the effects of the shear-induced structures, we conducted a numerical analysis of rheological properties in a homogeneous solution based on the constitutive equation developed by Kaye-Bernstein, Kearsley, and Zapas (K-BKZ). In the low-to intermediate shear rate gamma region between tau(w) (-1) and tau(e) (-1), where tau(w) and tau(e) are, respectively, terminal relaxation time and the relaxation time for chain stretching, the steady state rheological properties, such as shear stress sigma and the first normal stress difference N(1), for the PS/DOP and PS/TCP solutions are found to be almost same and also well predicted by the K-BKZ equation, in spite of the fact that there is a significant difference in the shear-induced structures as observed by shear-SALS and shear-microscopy. This implies that the contribution of the concentration fluctuations built up by shear flow to the rheological properties seems very small in this gamma region. On the other hand, once gamma exceeds tau(e) (-1), sigma and N(1) for both PS/DOP and PS/TCP start to deviate from the predicted values. Moreover, when gamma further increases and becomes higher than gamma(a,DOP) (sufficiently higher than tau(e) ( 1)), above which rheological and scattering anomalies are observed for PS/DOP, sigma and N(1) for PS/DOP and PS/TCP are significantly larger than those predicted by K-BKZ. Particularly, a steep increase of sigma and N(1) for PS/DOP above gamma(a,DOP) is attributed to an excess free energy stored in the system via the deformation of interface of well-defined domains, which are aligned into the stringlike structure developed parallel to the flow axis, and stretching of the chains connecting the domains in the stringlike structures. Thus, we advocate that the effect of shear-induced structures should be well considered on the behavior of sigma and N(1) at the high gamma region above tau(e) (-1) in semidilute polymer solutions. PMID- 18447505 TI - Pathways of polaron and bipolaron transport in DNA double strands. AB - We investigate the pathways of polaron and bipolaron transports in DNA double strands with an extended Su-Schrieffer-Heeger model involving the effects of solvent polarization. We find that the long-range transport of polaron/bipolaron under high electric field at low temperature is the field-facilitated sequential tunneling through spatial-disordered potential barriers via multiple intrastrand and interstrand pathways. Although the interstrand pathways may be very active and effective in some DNA sequences, the intrastrand ones always dominate the charge transfer when the excess charge moves close to the final acceptor. PMID- 18447507 TI - Theoretical study of the potential energy surface for the interaction of cisplatin and their aquated species with water. AB - In this work, a systematic study of the interaction of neutral cisplatin ([Pt(NH(3))(2)Cl(2)]) and their charged aquated species ([Pt(NH(3))(2)Cl(H(2)O)](+) and [Pt(NH(3))(2)(H(2)O)(2)](2+)) with water was carried out. The potential energy surface (PES) was analyzed by considering 35 spatial orientations for the interacting species. The calculations were performed at various levels of theory including Moller-Plesset fourth order perturbation theory and density functional theory (DFT-B3LYP) using extended basis sets. Lennard-Jones (12-6) plus Coulomb classical potential was also used to assess the repulsion-dispersion and electrostatic contributions. The effect of atomic charges on the interaction energies is discussed using Mulliken, charges from electrostatic potential grid method and natural bond orbital schemes. The outcomes show that the electrostatic term plays a primary role on the calculation of interaction energies, with the absolute values of atomic charges from different approaches significantly affecting the overall interaction. Unusual results were revealed by basis set superposition error calculations for the structures located on the platinum-water PES. PMID- 18447506 TI - The Alzheimer's beta amyloid (Abeta1-39) monomer in an implicit solvent. AB - Results from replica-exchange and regular room temperature molecular dynamics simulations of the Alzheimer's beta amyloid (Abeta(1-39)) monomer in an implicit solvent are reported. Our data indicate that at room temperature, the monomer assumes random-coil and soluble conformations. No beta content is observed which therefore seems to be a product of oligomerization and aggregation of monomers. PMID- 18447508 TI - Additivity of noise propagation in a protein cascade. AB - Stochastic fluctuations in a protein synthetic cascade are investigated using standard Omega-expansion technique. For the steady-state sensitivity, we show the conditions that result in the ultrasensitive "all-or-none" behavior, and for the noise propagation, we show clearly that (i) for any one given protein species in this cascade, the contributions of fluctuations in upstream proteins to its noise should be additive; and (ii) the output noise levels can vary as a function of the input concentrations and cascade length. Our results provide a possible theoretical explanation for the previous experimental studies. PMID- 18447509 TI - On the number of significant mode-mode anharmonic couplings in vibrational calculations: Correlation-corrected vibrational self-consistent field treatment of di-, tri-, and tetrapeptides. AB - A computational study is made of the number of important anharmonic mode-mode couplings in the context of vibrational calculations for di-, tri-, and tetrapeptides. The method employed is the correlation-corrected vibrational self consistent field (CC-VSCF) algorithm, which includes correlation effects between different vibrational modes. It is found that results of good accuracy can be obtained in calculations that include only N log N mode-mode coupling terms, where N is the number of modes. This simplification significantly accelerates CC VSCF calculations for large molecules. A criterion based on the characteristics of the normal-mode displacements is employed to predict a priori unimportant coupling terms. The criterion is tested statistically using Spearman's rank correlation coefficient. The results are illustrated by calculations for several di-, tri-, and tetrapeptides using semiempirical PM3 potential surfaces. These results are analyzed and a statistical model for error estimation is given. The decrease in the number of included coupling from N(2) to N log N opens possibilities of anharmonic vibrational calculations for large peptides. PMID- 18447510 TI - Simulating electron spin resonance spectra of nitroxide spin labels from molecular dynamics and stochastic trajectories. AB - Simulating electron spin resonance spectra of nitroxide spin labels from motional models is necessary for the quantitative analysis of experimental spectra. We present a framework for modeling the spin label dynamics by using trajectories such as those from molecular dynamics (MD) simulations combined with stochastic treatment of the global protein tumbling. This is achieved in the time domain after two efficient numerical integrators are developed: One for the quantal dynamics of the spins and the other for the classical rotational diffusion. For the quantal dynamics, we propagate the relevant part of the spin density matrix in Hilbert space. For the diffusional tumbling, we work with quaternions, which enables the treatment of anisotropic diffusion in a potential expanded as a sum of spherical harmonics. Time-averaging arguments are invoked to bridge the gap between the smaller time step of the MD trajectories and the larger time steps appropriate for the rotational diffusion and/or quantal spin dynamics. PMID- 18447511 TI - Comment on "anharmonic properties of the vibrational quantum computer" [J. Chem. Phys. 126, 204102 (2007)]. AB - Suitable molecules for quantum computing cannot be discussed in terms of anharmonicity and CNOT gates alone. The validity of the approximate approach [M. Zhao and D. Babikov, J. Chem. Phys.126, 204102 (2007)] is limited. Frequencies and anharmonicities cannot be used independent from the molecule. Hermite polynomials with the linear approximation for the dipole moment lead to oversimplified gates with potentially low intensities. PMID- 18447515 TI - Perspective: Local ferromagnetic resonance measurement techniques: "Invited Review Article: Microwave spectroscopy based on scanning thermal microscopy: resolution in the nanometer range" [Rev. Sci. Instrum. 79, 041101 (2008)]. PMID- 18447516 TI - Invited Review Article: Microwave spectroscopy based on scanning thermal microscopy: resolution in the nanometer range. AB - Scanning thermal microscope-detected ferromagnetic resonance (SThM-FMR) combines a thermal near-field microscope with a FMR spectrometer and detects the thermal response due to resonant microwave absorption by measuring the resistivity change in the thermal nanoprobe. The advantage of this technique is to provide imaging capabilities at fixed resonance conditions as well as local microwave spectroscopy at the nanoscale. A technique that uses the same setup but detects the thermoelastic response of the sample is the scanning thermoelastic microscope detected FMR (SThEM-FMR). This latter technique is advantageous when FMR spectra of single nanostructures have to be recorded at a fixed position. The experimental setups and the signal generation processes of SThM/SThEM-FMR are described in detail. With the SThM-FMR setups a temperature resolution of 1 mK and a local resolution of 30 nm are actually achieved. With SThEM-FMR the obtained local resolution is 10 nm. The detection limits of both techniques can be as low as 10(6) spins. To demonstrate the potential of these new techniques SThM/SThEM-FMR investigations of local magnetic anisotropies, magnetization dynamics of single nanodots and inhomogeneous FMR excitations due to finite size effects are presented. Simultaneously, information on the magnetic parameters, the topography, and the thermal properties is provided. To describe the further potential of this recently developed SThM-FMR technique, combined magnetoresistance and FMR investigations are presented and an outlook on possible future applications is given. PMID- 18447517 TI - Precise measurements of the total concentration of atmospheric CO2 and 13CO2/12CO2 isotopic ratio using a lead-salt laser diode spectrometer. AB - We have developed a tunable diode laser spectrometer, called SIMCO (spectrometer for isotopic measurements of CO(2)), for determining the concentrations of (12)CO(2) and (13)CO(2) in atmospheric air, from which the total concentration of CO(2) and the isotopic composition (expressed in delta units) delta(13)CO(2) are calculated. The two concentrations are measured using a pair of lines around 2290.1 cm(-1), by fitting a line profile model, taking into account the confinement narrowing effect to achieve a better accuracy. Using the Allan variance, we have demonstrated (for an integration time of 25 s) a precision of 0.1 ppmv for the total CO(2) concentration and of 0.3[per thousand] for delta(13)CO(2). The performances on atmospheric air have been tested during a 3 days campaign by comparing the SIMCO instrument with a gas chromatograph (GC) for the measurement of the total CO(2) concentration and with an isotopic ratio mass spectrometer (MS) for the isotopic composition. The CO(2) concentration measurements of SIMCO are in very good agreement with the GC data with a mean difference of Delta(CO(2))=0.16+/-1.20 ppmv for a comparison period of 45 h and the linearity of the concentration between the two instruments is also very good (slope of correlation: 0.9996+/-0.0003) over the range between 380 and 415 ppmv. For delta(13)CO(2), the comparison with the MS data shows a larger mean difference of Delta(delta(13)CO(2))=(-1.9+/-1.2)[per thousand], which could be partly related to small residual fluctuations of the overall SIMCO instrument response. PMID- 18447518 TI - Simple active method for reducing magnetic interference in a thermoelectrically cooled photomultiplier tube. AB - We present a simple modification for thermoelectrically cooled photomultiplier tube (PMT) assemblies that eliminates the magnetic interference between the peltier element and the PMT. An active compensation is accomplished by forming current loops of the wires of the peltier element and placing them in such a way that they eliminate the interfering magnetic field. It is demonstrated that the improved system reduces measurement errors of the order of 1% to statistical noise at the level of 0.07%. PMID- 18447519 TI - Twin optical traps for two-particle cross-correlation measurements: eliminating cross-talk. AB - The correlated motions of two micron-sized particles reflect the (micro-) rheological properties of a fluid and can be conveniently detected using two optical traps in combination with interferometric displacement detection. When the correlations become small, cross-talk between the two beams becomes important. We have used dual optical traps created by either two orthogonally polarized laser beams derived from one laser source, or by two independent lasers of different wavelengths for microrheology experiments. High numerical aperture lenses (objective and condenser) in the optical path can introduce depolarization, and polarizing beam splitters are not perfect, both of which can lead to optical cross-talk. We have characterized the cross-talk in our setup and demonstrate that the use of two independent laser eliminates cross-talk entirely. PMID- 18447520 TI - Background removal in scanning tunneling spectroscopy of single atoms and molecules on metal surfaces. AB - Scanning tunneling spectroscopy has developed into a powerful spectroscopic technique that has found wide application in the atomic scale characterization of the electronic properties of clean surfaces as well as adsorbates and defects at surfaces. However, it still lacks the standard methods for data treatment and removal of artifacts in spectra as they are, e.g., common in photoemission spectroscopy. The properties of the atomic scale tip apex--the probe of the instrument--tend to introduce spurious background signals into tunneling spectra. We present and discuss two methods which permit to extract tip-independent information from low temperature tunneling spectra acquired on single atoms and molecules on single crystal surfaces by background subtraction. The methods rely on a characterization of the tip on the clean metal surface. The performance of both methods is demonstrated and compared for simulated and experimental tunneling spectra. PMID- 18447521 TI - Angle-resolving time-of-flight electron spectrometer for near-threshold precision measurements of differential cross sections of electron-impact excitation of atoms and molecules. AB - This article presents a new type of low-energy crossed-beam electron spectrometer for measuring angular differential cross sections of electron-impact excitation of atomic and molecular targets. Designed for investigations at energies close to excitation thresholds, the spectrometer combines a pulsed electron beam with the time-of-flight technique to distinguish between scattering channels. A large area, position-sensitive detector is used to offset the low average scattering rate resulting from the pulsing duty cycle, without sacrificing angular resolution. A total energy resolution better than 150 meV (full width at half maximum) at scattered energies of 0.5-3 eV is achieved by monochromating the electron beam prior to pulsing it. The results of a precision measurement of the differential cross section for electron-impact excitation of helium, at an energy of 22 eV, are used to assess the sensitivity and resolution of the spectrometer. PMID- 18447522 TI - Time-of-flight spectroscopy of the energy distribution of laser-ablated atoms and ions. AB - The growth of ultrathin films, deposited by laser ablation, crucially depends on the energy of the ablated species. Therefore, a time-of-flight (TOF) spectrometer has been constructed and measurements have been carried out in order to determine the energy distribution of laser-ablated Fe and Pt atoms and ions in the plasma created by nanosecond pulses of a frequency-doubled neodymium doped yttrium aluminum garnet laser. The experiments have been performed in ultrahigh vacuum at relatively low laser power. For measuring the spectra of the neutrals, a cross beam electron source for postionization and electric as well as magnetic fields for repelling the ions are employed. Nevertheless, measurements of neutral particles are restricted to low plasma densities due to electrostatic shielding within the plasma, leading to an inefficient deflection of charged particles by electrostatic and magnetic fields. Test measurements have been performed by utilizing the TOF spectrometer as a pressure gauge and also by chopping the electron beam, running the TOF spectrometer as a residual gas mass spectrometer. The spectra of the laser-ablated plasmas have shown plasma conditions with a Debye length of approximately 10(-4) m, densities of 10(15)-10(16) m(-3) and ion energies up to 150 eV. Neutral spectra have shown an unexpectedly low fraction of neutrals (10(-3)-10(-4)) and hyperthermal energies up to several 10 eV, possibly contributed by recombination of ions and electrons in the plasma. Even though gas spectra had demonstrated the expected sensitivity of the TOF spectrometer for low energy neutrals, no thermally evaporated neutral atoms could be found. PMID- 18447523 TI - An accelerator based fusion-product source for development of inertial confinement fusion nuclear diagnostics. AB - A fusion-product source, utilizing a 150 kV Cockraft-Walton linear accelerator, has been refurbished to provide a reliable nuclear diagnostic development tool to the national inertial confinement fusion (ICF) research program. The accelerator is capable of routinely generating DD reaction rates at approximately 10(7)/s when using a 150 kV, 150 microA deuterium (D) beam onto an erbium (Er) or titanium (Ti) target doped with D, and D(3)He reaction rates at approximately 5 x 10(5)/s when using a using a 120 kV, approximately 100 microA D beam onto a Er or Ti target doped with (3)He. The new accelerator is currently being used in a number of projects related to the national ICF program at the OMEGA Laser Fusion Facility [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)], which includes the wedge range filter charged-particle spectrometry program [F. H. Seguin et al., Rev. Sci Instrum. 75, 3520 (2004)] and the magnetic recoil neutron spectrometer [J. A. Frenje et al., Rev. Sci. Instrum. 72, 854 (2001)]. PMID- 18447524 TI - Measurement of incident position of hypervelocity particles on piezoelectric lead zirconate titanate detector. AB - A cosmic dust detector for use onboard a satellite is currently being developed by using piezoelectric lead zirconate titanate (PZT). The characteristics of the PZT detector have been studied by bombarding it with hypervelocity iron (Fe) particles supplied by a Van de Graaff accelerator. One central electrode and four peripheral electrodes were placed on the front surface of the PZT detector to measure the impact positions of the incident Fe particles. It was demonstrated that the point of impact on the PZT detector could be identified by using information on the time at which the first peak of the output signal obtained from each electrode appeared. PMID- 18447525 TI - Simulating ion beam extraction from a single aperture triode acceleration column: a comparison of the beam transport codes IGUN and PBGUNS with test stand data. AB - Ion beam extraction from two different ion sources with single aperture triode extraction columns was simulated with the particle beam transport codes PBGUNS and IGUN. For each ion source, the simulation results are compared to experimental data generated on well-equipped test stands. Both codes reproduced the qualitative behavior of the extracted ion beams to incremental and scaled changes to the extraction electrode geometry observed on the test stands. Numerical values of optimum beam currents and beam emittance generated by the simulations also agree well with test stand data. PMID- 18447526 TI - Direct coupling of pulsed radio frequency and pulsed high power in novel pulsed power system for plasma immersion ion implantation. AB - A novel power supply system that directly couples pulsed high voltage (HV) pulses and pulsed 13.56 MHz radio frequency (rf) has been developed for plasma processes. In this system, the sample holder is connected to both the rf generator and HV modulator. The coupling circuit in the hybrid system is composed of individual matching units, low pass filters, and voltage clamping units. This ensures the safe operation of the rf system even when the HV is on. The PSPICE software is utilized to optimize the design of circuits. The system can be operated in two modes. The pulsed rf discharge may serve as either the seed plasma source for glow discharge or high-density plasma source for plasma immersion ion implantation (PIII). The pulsed high-voltage glow discharge is induced when a rf pulse with a short duration or a larger time interval between the rf and HV pulses is used. Conventional PIII can also be achieved. Experiments conducted on the new system confirm steady and safe operation. PMID- 18447527 TI - New surface forces apparatus using two-beam interferometry. AB - We designed a new surface forces apparatus for measuring the interactions between two nontransparent substrates and/or in nontransparent liquids. The small displacement of a surface, the bottom one in this study, was measured by the two beam (twin path) interferometry technique using the phase difference between the laser light reflected by the fixed mirror and that by the mirror on the back of the bottom surface unit. It is possible to determine the distance with a resolution of 1 nm in the working range of 5 microm. This apparatus was successfully applied to measure the forces between mica surfaces in pure water and aqueous KBr solutions. PMID- 18447529 TI - A new advanced experimental setup for in-depth study of the interfacial reaction during reactive wetting. AB - Reactive wetting plays a crucial role in many technical processes, from soldering in microelectronics, production of metal/ceramic composites, to hot dip galvanizing in mass production of zinc coated steel sheet. In all these cases the wetting behavior of metal melts on different surfaces plays a crucial role in material joining and coating. In all these processes the formation of the interfacial reaction layer has to occur within as short a time as possible in order to ensure a fast overall production speed. As the interfacial layer determines the stability of the formed composites, detailed knowledge of its growth mechanisms is required for a directed process optimization. However, the investigation of the processes occurring at the buried interface between substrate and wetting phase is difficult, especially for the case of liquid metal wetting metallic or ceramic solid substrates at high temperatures. Here, a novel advanced technique for the investigation of high temperature wetting processes up to a temperature of 1100 K is presented. It is based on the sessile drop technique but, in addition, allows spinning off the droplet at any chosen wetting time, thus providing direct access to the interfacial reaction layer. Since the experimental setup is integrated into a UHV compatible reaction chamber, not only excellent control of the composition of the atmosphere is ensured, but also direct transfer to surface analytical tools such as scanning electron microscope or electron spectroscopy for chemical analysis without intermediate exposure to air is realized. As will be shown for the case of hot dip galvanising of steel, this is an outstanding advance compared to existing methods. PMID- 18447528 TI - A charge coupled device camera with electron decelerator for intermediate voltage electron microscopy. AB - Electron microscopists are increasingly turning to intermediate voltage electron microscopes (IVEMs) operating at 300-400 kV for a wide range of studies. They are also increasingly taking advantage of slow-scan charge coupled device (CCD) cameras, which have become widely used on electron microscopes. Under some conditions, CCDs provide an improvement in data quality over photographic film, as well as the many advantages of direct digital readout. However, CCD performance is seriously degraded on IVEMs compared to the more conventional 100 kV microscopes. In order to increase the efficiency and quality of data recording on IVEMs, we have developed a CCD camera system in which the electrons are decelerated to below 100 kV before impacting the camera, resulting in greatly improved performance in both signal quality and resolution compared to other CCDs used in electron microscopy. These improvements will allow high-quality image and diffraction data to be collected directly with the CCD, enabling improvements in data collection for applications including high-resolution electron crystallography, single particle reconstruction of protein structures, tomographic studies of cell ultrastructure, and remote microscope operation. This approach will enable us to use even larger format CCD chips that are being developed with smaller pixels. PMID- 18447530 TI - Laser powered heating stage in a scanning electron microscope for microstructural investigations at elevated temperatures. AB - A laser powered heating stage designed for application in high vacuum environment of a scanning electron microscope (SEM) is presented. It was developed to observe and characterize microstructural changes in crystalline materials at elevated temperatures up to 1000 degrees C. The approach utilizes the power output of a commercial infrared diode laser in order to heat up specimens without interference with the electronic system of the SEM. The heating stage can be used in combination with any standard characterization technique applicable for SEMs- electron backscatter diffraction, orientation contrast imaging, x-ray energy dispersive spectrometry, etc. The results of test measurements are presented. PMID- 18447531 TI - Vacuum ellipsometry as a method for probing glass transition in thin polymer films. AB - A vacuum ellipsometer has been designed for probing the glass transition in thin supported polymer films. The device is based on the optics of a commercial spectroscopic phase-modulated ellipsometer. A custom-made vacuum chamber evacuated by oil-free pumps, variable temperature optical table, and computer based data acquisition system was described. The performance of the tool has been demonstrated using 20-200 nm thick poly(methyl methacrylate) and polystyrene films coated on silicon substrates at 10(-6)-10(-8) torr residual gas pressure. Both polymers show pronounced glass transitions. The difficulties in assigning in the glass transition temperature are discussed with respect to the experimental challenges of the measurements in thin polymer films. It is found that the experimental curves can be significantly affected by a residual gas. This effect manifests itself at lower temperatures as a decreased or even negative apparent thermal coefficient of expansion, and is related to the uptake and desorption of water by the samples during temperature scans. It is also found that an ionization gauge--the standard accessory of any high vacuum system--can cause a number of spurious phenomena including drift in the experimental data, roughening of the polymer surface, and film dewetting. PMID- 18447532 TI - Rapid qualitative phase analysis in highly textured thin films by x-ray diffraction. AB - Phase analysis of highly out-of-plane textured specimens using x-ray diffraction is usually complicated due to the disappearance of most of the x-ray peaks in a common theta/2 theta diffraction geometry. In this paper, we propose a technique, where powderlike spectra of textured samples are obtained by multiaxial x-ray diffraction scans. This technique is a simple, yet powerful method which allows for significant improvement in thin film characterization and provides several types of information about the samples, such as the rapid qualitative identification of phases using common powder x-ray diffraction spectra databases, texture distribution, and quantitative residual stress analysis. PMID- 18447533 TI - Novel in situ setup to study the formation of nanoparticles in the gas phase by small angle x-ray scattering. AB - An in-house built aerosol generator setup for in situ gas phase studies of aerosol and nanoparticles is described. The aerosol generator with an ultrasonic ceramic disk mist maker provides high enough particle concentrations for structural gas phase analysis by synchrotron small angle x-ray scattering (for water approximately 4 x 10(8) droplets/s with a droplet size of approximately 2.5 microm). The working principle was proved by scattering of gold nanoparticles. For evaporation induced self-assembly studies of nanostructured particles, an additional thermal treatment chamber was included in the setup. The first on-line gas phase data with our setup for mesostructured silica particles are presented for different thermal treatments. Scanning electron microscope imaging revealed the average particle size to be approximately 1 microm. Furthermore, to quantify their internal nanostructure, diffraction experiments of deposited silica aerosols were carried out and the corresponding electron density map indicates a silica wall thickness of about 1 nm. PMID- 18447534 TI - A fast ramp rate thermally stimulated current technique to quantify electronic charge dynamics in thin films. AB - Thermally stimulated current (TSC) techniques have been applied to study thermally activated events in many materials. However, the temperature ramp rates in traditional TSC are typically too slow (few degrees per minute) to monitor materials whose properties are strongly time dependent. A fast ramp rate TSC (FR TSC) technique was developed with ramp rates of 1-5 K/s. This is up to 100 times faster than traditional TSC, so that material changes can be appropriately quantified in the time scale at which they take place. In this paper, the experimental design and challenges to achieve fast and stable ramp rates and to measure the low-level currents are discussed. The fast ramps were attained using a thermoelectric cooler, controlled by a proportional-integral-derivative feedback loop, for both heating and cooling. FR-TSC measurements (1 K/s and 20 100 degrees C) on poly(vinylidene fluoride-trifluoroethylene) ferroelectric thin films are discussed as an example material. From these measurements, thermally activated currents as well as irreversible and reversible charge dynamics were readily distinguished with multiple thermal cycles. These measurements suggest that this technique holds substantial promise in quantifying charge dynamics in fast response materials. PMID- 18447535 TI - Kilovolt Blumlein pulse generator with variable pulse duration and polarity. AB - A Blumlein pulse generator which utilizes the superposition of electrical pulses launched from two individually switched pulse forming lines has been designed and tested. By using a power metal-oxide-semiconductor field-effect transistor as a switch on each end of the Blumlein line, we were able to generate pulses with amplitudes of 1 kV across a 100 Omega load. Pulse duration and polarity can be controlled by the temporal delay in the triggering of the two switches. Using this technique, we have demonstrated the generation of pulses with durations between 8 and 60 ns. The lower limit in pulse duration was determined by the switch closing time and the upper limit by the length of the pulse forming line. A further advantage of the concept is that pulse distortions caused by the non negligible on-resistance of a line with a single switch can be eliminated by using switches with identical characteristics. PMID- 18447537 TI - A new stereolithography experimental porous flow device. AB - A new method for constructing laboratory-scale porous media with increased pore level variabilities for two-phase flow experiments is presented here. These devices have been created with stereolithography directly on glass, thus improving the stability of the model created with this precision rapid construction technique. The method of construction and improved parameters are discussed in detail, followed by a brief comparison of two-phase drainage results for air invasion into the water-saturated porous medium. Flow through the model porous medium is shown to substantiate theoretical fractal predictions. PMID- 18447536 TI - Magnetic microposts for mechanical stimulation of biological cells: fabrication, characterization, and analysis. AB - Cells use force as a mechanical signal to sense and respond to their microenvironment. Understanding how mechanical forces affect living cells requires the development of tool sets that can apply nanoscale forces and also measure cellular traction forces. However, there has been a lack of techniques that integrate actuation and sensing components to study force as a mechanical signal. Here, we describe a system that uses an array of elastomeric microposts to apply external forces to cells through cobalt nanowires embedded inside the microposts. We first biochemically treat the posts' surfaces to restrict cell adhesion to the posts' tips. Then by applying a uniform magnetic field (B<0.3 T), we induce magnetic torque on the nanowires that is transmitted to a cell's adhesion site as an external force. We have achieved external forces of up to 45 nN, which is in the upper range of current nanoscale force-probing techniques. Nonmagnetic microposts, similarly prepared but without nanowires, surround the magnetic microposts and are used to measure the traction forces and changes in cell mechanics. We record the magnitude and direction of the external force and the traction forces by optically measuring the deflection of the microposts, which linearly deflect as cantilever springs. With this approach, we can measure traction forces before and after force stimulation in order to monitor cellular response to forces. We present the fabrication methods, magnetic force characterization, and image analysis techniques used to achieve the measurements. PMID- 18447538 TI - A switched supply tunable red-green-blue light emitting diode driver. AB - This paper presents a new switched supply tunable red-green-blue (RGB) light emitting diode (LED) driver. The RGB LEDs act not only as light emitting devices but also as rectifying diodes in the presented driver circuit. The RGB LED color control is realized by controlling the switched supply voltage amplitude, frequency, and duty cycle. The driver efficiency is high since the only loss in the driver circuit is the switch and can be further reduced by direct alternate current supply. PMID- 18447539 TI - Precisely tunable continuous-wave terahertz source with interferometric frequency control. AB - We realized a tunable continuous-wave terahertz source with megahertz frequency resolution. The system is based on optical heterodyning of two near-infrared distributed feedback diode lasers, each laser being stabilized by electronic feedback from a low-finesse quadrature interferometer. The control loop permits precisely linear laser frequency scans over >1200 GHz, and a beat signal linewidth of 1 MHz at 80 ms time scale. Using GaAs photomixers and log-periodic antennae, we achieve a signal-to-noise ratio of the terahertz power of >70 dB at 100 GHz and 100 ms integration time, and still approximately 30 dB at 1 THz. As an example for high-resolution terahertz spectroscopy, we characterize the transmission properties of a subwavelength metal grating. PMID- 18447540 TI - Four point bending setup for characterization of semiconductor piezoresistance. AB - We present a four point bending setup suitable for high precision characterization of piezoresistance in semiconductors. The compact setup has a total size of 635 cm(3). Thermal stability is ensured by an aluminum housing wherein the actual four point bending fixture is located. The four point bending fixture is manufactured in polyetheretherketon and a dedicated silicon chip with embedded piezoresistors fits in the fixture. The fixture is actuated by a microstepper actuator and a high sensitivity force sensor measures the applied force on the fixture and chip. The setup includes heaters embedded in the housing and controlled by a thermocouple feedback loop to ensure characterization at different temperature settings. We present three-dimensional finite element modeling simulations of the fixture and discuss the possible contributions to the uncertainty of the piezoresistance characterization. As a proof of concept, we show measurements of the piezocoefficient pi(44) in p-type silicon at three different doping concentrations in the temperature range from T=30 degrees C to T=80 degrees C. The extracted piezocoefficients are determined with an uncertainty of 1.8%. PMID- 18447541 TI - Precision sampling measurements using ac programmable Josephson voltage standards. AB - We have performed a variety of precision measurements by comparing ac and dc waveforms generated by two independent ac programmable Josephson voltage standard (ACPJVS) systems. The objective of these experiments was to demonstrate the effectiveness of using a sampling digital voltmeter to measure small differences between Josephson waveforms for frequencies up to 3.6 kHz. The low uncertainties that we obtained confirm the feasibility of using this differential sampling method for high accuracy comparisons between ACPJVS waveforms and signals from other sources. PMID- 18447543 TI - Development of a magic-angle spinning nuclear magnetic resonance probe with a cryogenic detection system for sensitivity enhancement. AB - A novel nuclear magnetic resonance (NMR) probe for high-resolution solid-state NMR has been developed. In this probe, temperature of the detection coil is kept at cryogenic temperature (approximately 12 K) for sensitivity enhancement, which is achieved not only by suppression of thermal noise but also by increment of a Q factor of the coil. A marked feature of this probe is that a sample rotating at magic angle is thermally isolated from the cryogenic system in order to realize high-resolution solid-state NMR measurement at various sample temperatures. We call this system as cryocoil magic-angle spinning (cryocoil MAS). (1)H MAS NMR with the coil temperature of approximately 20 K was successfully observed for solid adamantane rotating at room temperature, and signal-to-noise increment due to this cryocoil approach was confirmed. PMID- 18447542 TI - Development of a control system for pulsed-electron spin resonance spectrometers. AB - A pulse control and data acquisition system with high time resolution of 300 ps and data-averaging rate of 100 kHz for a pulsed-ESR spectrometer was constructed. The system consists of two sets of 3.34 GHz data timing generator and a dual channel analog-to-digital converter with 1 GHz samples, both of which are commercially available. We developed a scheme and software to control these equipments with high efficiency in pulsing design, data acquisition, and accurate synchronization of the devices. The system was developed at Ku band (17.5 GHz) and demonstrated some examples of electron spin echo and double quantum measurements. PMID- 18447544 TI - Wide band resonant ultrasound spectroscopy of spheroidal modes for high accuracy estimation of Poisson coefficient of balls. AB - An original inversion method specifically adapted to the estimation of Poisson coefficient of balls by using their resonance spectra is described. From the study of their elastic vibrations, it is possible to accurately characterize the balls. The proposed methodology can create both spheroidal modes in the balls and detect such vibrations over a large frequency range. Experimentally, by using both an ultrasonic probe for the emission (piezoelectric transducer) and a heterodyne optic probe for the reception (interferometer), it was possible to take spectroscopic measurements of spheroidal vibrations over a large frequency range (100 kHz-45 MHz) in a continuous regime. This method, which uses ratios between wave resonance frequencies, allows the Poisson coefficient to be determined independently of Young's modulus and the ball's radius and density. This has the advantage of providing highly accurate estimations of Poisson coefficient (+/-4.3 x 10(-4)) over a wide frequency range. PMID- 18447545 TI - The numerical mirage method for photothermal characterization of materials. AB - Noncontact thermal measurement techniques offer rapid thermal characterization without modification or destruction of the sample being studied. A simple and versatile method has been developed, termed the "numerical mirage method," that utilizes the transient photothermal deflection of a laser beam traversing a modulated temperature gradient. This method expands the range and simplifies the experimental procedure of traditional mirage methods. A numerical solver is used to create accurate deflection profile models and a linear curve fitting routine is developed, from which the thermal diffusivity of a material may be determined. This method allows for rapid modification of sample and heating configurations. Verification of the method is performed on bismuth and fused quartz reference samples, and good agreement with literature is obtained. PMID- 18447546 TI - A microfabricated sensor for thin dielectric layers. AB - We describe a sensor for the measurement of thin dielectric layers capable of operation in a variety of environments. The sensor is obtained by microfabricating a capacitor with interleaved aluminum fingers, exposed to the dielectric to be measured. In particular, the device can measure thin layers of solid frozen from a liquid or gaseous medium. Sensitivity to single atomic layers is achievable in many configurations and, by utilizing fast, high sensitivity capacitance readout in a feedback system onto environmental parameters; coatings of few layers can be dynamically maintained. We discuss the design, readout, and calibration of several versions of the device optimized in different ways. We specifically dwell on the case in which atomically thin solid xenon layers are grown and stabilized, in cryogenic conditions, from a liquid xenon bath. PMID- 18447547 TI - A novel surface shear viscometer. AB - A novel rotary viscometer--developed for the determination of rheologic properties of liquid/air interface layers--is presented. The instrument can be used to measure the shear viscosity and the shear elasticity of liquid surfaces. It contains a rotor floating on the liquid surface which is rotated by means of an electromagnetic torque. A torsion filament is used to calibrate the applied torque. The viscosity data are obtained on the basis of the Navier-Stokes equation solved for the rotation of a cylinder touching the surface of water and submerged into the water. The time behavior of the surface viscosity of films gradually formed from solutions of some proteins as well as their activation energy is presented. PMID- 18447548 TI - High frequency pressure oscillator for microcryocoolers. AB - Microminiature pulse tube cryocoolers should operate at a frequency of an order higher than the conventional macro ones because the pulse tube cryocooler operating frequency scales inversely with the square of the pulse tube diameter. In this paper, the design and experiments of a high frequency pressure oscillator is presented with the aim to power a micropulse tube cryocooler operating between 300 and 80 K, delivering a cooling power of 10 mW. Piezoelectric actuators operate efficiently at high frequencies and have high power density making them good candidates as drivers for high frequency pressure oscillator. The pressure oscillator described in this work consists of a membrane driven by a piezoelectric actuator. A pressure ratio of about 1.11 was achieved with a filling pressure of 2.5 MPa and compression volume of about 22.6 mm(3) when operating the actuator with a peak-to-peak sinusoidal voltage of 100 V at a frequency of 1 kHz. The electrical power input was 2.73 W. The high pressure ratio and low electrical input power at high frequencies would herald development of microminiature cryocoolers. PMID- 18447549 TI - A design approach for systems based on magnetic pulse compression. AB - A design approach giving the optimum number of stages in a magnetic pulse compression circuit and gain per stage is given. The limitation on the maximum gain per stage is discussed. The total system volume minimization is done by considering the energy storage capacitor volume and magnetic core volume at each stage. At the end of this paper, the design of a magnetic pulse compression based linear induction accelerator of 200 kV, 5 kA, and 100 ns with a repetition rate of 100 Hz is discussed with its experimental results. PMID- 18447550 TI - A cryostat and temperature control system optimized for measuring relaxations of glass-forming liquids. AB - An experimental setup, including a cryostat and a temperature control system, has been constructed to meet the demands of measuring linear and nonlinear macroscopic relaxation properties of glass-forming liquids in the extremely viscous state approaching the glass transition. In order to be able to measure such frequency-dependent response functions accurately (including dielectric permittivity, specific heat, thermal expansivity, and shear and bulk moduli), as well as nonlinear relaxations following a temperature jump, one must have the ability to hold temperatures of liquids steady over the span of several days or even several weeks. To maximize temperature stability, special care is taken to thermally isolate the sample chamber of the cryostat. The main temperature control system is capable of maintaining temperatures within a few millikelvins. If liquid is deposited into a special transducer assembly that includes a subcryostat unit, the temperature of liquids can be maintained even more precisely, within a few tenths of a millikelvin. This subcryostat unit is more responsive to temperature changes because (i) it is equipped with a Peltier element that provides secondary heating and cooling, (ii) the transducer contains a layer of liquid that is only 50 micfom thick, and (iii) feedback proportional integral-derivative temperature control is implemented by a fully analog circuit. The subcryostat permits us to change and stabilize temperatures quickly; it takes only 10 s to stabilize the temperature within tenths of a millikelvin after a jump of 1 K, for example, a capability that is highly advantageous for accurately observing relaxation processes following a temperature step. PMID- 18447551 TI - An impedance-measurement setup optimized for measuring relaxations of glass forming liquids. AB - An electronics system has been assembled to measure frequency-dependent response functions of glass-forming liquids in the extremely viscous state approaching the glass transition. We determine response functions such as dielectric permittivity and shear and bulk moduli by measuring electrical impedances of liquid-filled transducers, and this technique requires frequency generators capable of producing signals that are reproducible over the span of several days or even several weeks. To this end, we have constructed a frequency generator that produces low-frequency (1 mHz-100 Hz) sinusoidal signals with voltages that are reproducible within 10 ppm. Two factors that partly account for this precision are that signals originate from voltages stored in a look-up table and that only coil-less filters are used in this unit, which significantly reduces fluctuations of output caused by changes of temperatures of circuits. This generator also includes a special triggering facility that makes it possible to measure up to 512 voltages per cycle that are spaced apart at uniform phase intervals. Fourier transformations of such data yield precise determinations of complex amplitudes of voltages and currents applied to a transducer, which ultimately allows us to determine electrical impedances of transducers with a reproducibility error that is only a few parts per hundred thousand. This equipment is used in tandem with a commercial LCR meter and/or impedance analyzer that give(s) impedance measurements at higher frequencies, up to 1 MHz. The experimental setup allows measurements of the transducer impedance over nine decades of frequency within a single run. PMID- 18447552 TI - Ultra-high-precision time control system over any long time delay for laser pump and synchrotron x-ray probe experiment. AB - An ultra-high-precision clock system for long time delay has been developed for picosecond time-resolved x-ray diffraction measurements using synchrotron radiation (SR) pulses and synchronized femtosecond laser pulses. The time delay control between pump laser pulse and the probe SR pulse was achieved by combining an in-phase quadrature modulator and a synchronous counter. This method allowed us to change the delay time by a nearly infinite amount while maintaining the precision of +/-8.40 ps. Time-resolved diffraction measurements using the delay control system were demonstrated for precise measurement of an acoustic velocity in a single crystal of gallium arsenide. PMID- 18447553 TI - An ultrahigh vacuum system for in situ studies of thin films and nanostructures by nuclear resonance scattering of synchrotron radiation. AB - A multifunctional ultrahigh vacuum (UHV) system has been set up at the nuclear resonance beamline ID18 of the European Synchrotron Radiation Facility (ESRF). Thin and ultrathin films, nanoislands and -wires, multilayers, and stoichiometric oxides can be prepared by molecular beam epitaxy and characterized by low-energy electron diffraction, Auger electron spectroscopy, and reflection high-energy electron diffraction. Upon characterization the sample is transferred under UHV conditions to the chamber for experiments with the synchrotron beam. Electronic and magnetic properties, vibrational dynamics, and diffusion phenomena can be investigated by several synchrotron radiation based techniques, such as nuclear forward scattering, nuclear inelastic and quasielastic scattering, synchrotron radiation based perturbed angular correlations, and nuclear and electronic reflectivity. In addition, two portable UHV chambers serve to transfer the sample to other beamlines profiting from the available experimental techniques at the ESRF. PMID- 18447554 TI - Design and control of a nanoprecision XY Theta scanner. AB - This paper describes the design and control of a nanoprecision XY Theta scanner consisting of voice coil motors and air bearing guides. The proposed scanner can be installed on a conventional XY stage with long strokes to improve the positioning accuracy and settling performance. Major design considerations in developing a high precision scanner are sensor accuracy, actuator properties, structural stability, guide friction, and thermal expansion. Considering these factors, the proposed scanner is made of invar, which has a small thermal expansion coefficient and good structural stiffness. Four voice coil motors drive the scanner, which is suspended by four air bearing pads, in the x, y, and theta directions. The scanner's position is measured by three laser interferometers which decouple the scanner from the conventional stage. The mirror blocks reflecting the laser beams are fixed using viscoelastic sheets, ensuring that the scanner has a well-damped structural mode. A time delay control algorithm is implemented on the real-time controller to control the scanner. The effectiveness of the proposed scanner is verified experimentally. PMID- 18447555 TI - A novel gas-loading system for mechanically closing of various types of diamond anvil cells. AB - Loading of gases in diamond anvil cells is a complicated but necessary task to obtain hydrostatic conditions for high-pressure measurements. A simple in operation, safe, and universal gas-loading system has been designed and constructed. Innovations were introduced to simplify the loading procedure up to the "three-button" mode. PMID- 18447556 TI - Optical diagnostics of mercury jet for an intense proton target. AB - An optical diagnostic system is designed and constructed for imaging a free mercury jet interacting with a high intensity proton beam in a pulsed high-field solenoid magnet. The optical imaging system employs a backilluminated, laser shadow photography technique. Object illumination and image capture are transmitted through radiation-hard multimode optical fibers and flexible coherent imaging fibers. A retroreflected illumination design allows the entire passive imaging system to fit inside the bore of the solenoid magnet. A sequence of synchronized short laser light pulses are used to freeze the transient events, and the images are recorded by several high speed charge coupled devices. Quantitative and qualitative data analysis using image processing based on probability approach is described. The characteristics of free mercury jet as a high power target for beam-jet interaction at various levels of the magnetic induction field is reported in this paper. PMID- 18447557 TI - High-throughput analysis of thin-film stresses using arrays of micromachined cantilever beams. AB - We report on a technique for making high-throughput residual stress measurements on thin films by means of micromachined cantilever beams and an array of parallel laser beams. In this technique, the film of interest is deposited onto a silicon substrate with micromachined cantilever beams. The residual stress in the film causes the beams to bend. The curvature of the beams, which is proportional to the residual stress in the film, is measured by scanning an array of parallel laser beams generated with a diffraction grating along the length of the beams. The reflections of the laser beams are captured using a digital camera. A heating stage enables measurement of the residual stress as a function of temperature. As the curvature of each beam is determined by the local stress in the film, the film stress can be mapped across the substrate. This feature makes the technique a useful tool for the combinatorial analysis of phase transformations in thin films, especially when combined with the use of films with lateral composition gradients. As an illustration, we apply the technique to evaluate the thermomechanical behavior of Fe-Pd binary alloys as a function of composition. PMID- 18447558 TI - Improved frequency/voltage converters for fast quartz crystal microbalance applications. AB - The monitoring of frequency changes in fast quartz crystal microbalance (QCM) applications is a real challenge in today's instrumentation. In these applications, such as ac electrogravimetry, small frequency shifts, in the order of tens of hertz, around the resonance of the sensor can occur up to a frequency modulation of 1 kHz. These frequency changes have to be monitored very accurately both in magnitude and phase. Phase-locked loop techniques can be used for obtaining a high performance frequency/voltage converter which can provide reliable measurements. Sensitivity higher than 10 mVHz, for a frequency shift resolution of 0.1 Hz, with very low distortion in tracking both the magnitude and phase of the frequency variations around the resonance frequency of the sensor are required specifications. Moreover, the resonance frequency can vary in a broad frequency range from 5 to 10 MHz in typical QCM sensors, which introduces an additional difficulty. A new frequency-voltage conversion system based on a double tuning analog-digital phase-locked loop is proposed. The reported electronic characterization and experimental results obtained with conducting polymers prove its reliability for ac-electrogravimetry measurements and, in general, for fast QCM applications. PMID- 18447559 TI - Broadband electron spin resonance at low frequency without resonant cavity. AB - We have developed a nonconventional broadband electron spin resonance (ESR) spectrometer operating continuously in the frequency range from 0.5 to 9 GHz. Dual antenna structure and the microwave absorbing environment differentiate the setup from the conventional one and enable broadband operation with any combination of frequency or magnetic field modulation and frequency or magnetic field sweeping. Its performance has been tested with the measurements on a 1,1 diphenyl-2-picrylhydrazyl (DPPH) sample and with the measurements on the single molecular magnet, V6, in solid state at low temperature. PMID- 18447560 TI - Extended tuning of an injection-locked diode laser. AB - We have investigated the application of an electronic feedback technique recently reported by Repasky et al. [Appl. Opt. 45, 9013 (2006)] to an injection-locked semiconductor diode laser. We find that without electronic feedback, the injection-locked slave laser will only follow the master for less than 1 GHz, but once the electronic feedback is applied, the slave laser is capable of following for more than 20 GHz, corresponding to the full scan range of the master laser. PMID- 18447561 TI - A fluid handling system with finger-tightened connectors for biological studies at kiloatmosphere pressures. AB - We present a high-pressure fluid handling system based around a simple-to construct seal for applications in the biologically relevant kiloatmosphere range. Connectors are compact and finger tightened, as compared to the wrench tightening required of cone-type seals commonly used. The seal relies on an O ring compression, and the system has been tested up to 2000 atm. While the system was designed for biological studies, it should be versatile enough for a wide range of applications, thus contributing finger-tightened convenience to the kiloatmosphere range. PMID- 18447562 TI - Three-dimensional hydrodynamic focusing in a microfluidic Coulter counter. AB - Electrical impedance-based particle detection or Coulter counting, offers a lab on-chip compatible method for flow cytometry. Developments in this area will produce devices with greater portability, lower cost, and lower power requirements than fluorescence-based flow cytometry. Because conventional Coulter apertures are prone to clogging, hydrodynamic focusing improves the device by creating fluid-walled channels with variable width to increase sensitivity without the associated risk of blocking the channel. We describe a device that focuses the sample in three dimensions, creating a narrow sample stream on the floor of the channel for close interaction with sensing electrodes. The key to this design is a stepped outlet channel fabricated in a single layer with soft lithography. In contrast to previous impedance-based designs, the new design requires minimal alignment with the substrate. Three-dimensional focusing maximizes the sensitivity of the device to cell-size particles within much larger channels. Impedance-based particle sensing experiments within this device show an increase in percentage conductivity change by a factor of 2.5 over devices that only focus the sample in the horizontal direction. PMID- 18447563 TI - Dual-reflector configuration in varied line-space grating displacement sensor. AB - A method to improve the accuracy of the wavelength encoding varied line-space grating displacement sensor is presented. Based on the detailed analysis of the measured displacement errors from the single-mirror configuration sensor, a dual reflector configuration is used to replace the previous configuration, and greatly decreases its errors. Experiments are conducted in order to make comparison of the two configurations. The results show that the measured displacement error of the sensor with dual-reflector configuration is lower than 0.03 mm in full scale (0 to 50 mm), only about 10% of the sensor with single mirror configuration. PMID- 18447564 TI - Thermographic measurement of the emittance plot of a single positive ion beamlet. AB - Measurements have been made of the emittance plot of a partly neutralized positive ion beamlet, using a slit, a polymer target, and an infrared camera. This thermographic approach is intrinsically linear and absolute (since the properties of the target are known and approximately independent of temperature). It is sufficiently sensitive that only one short pulse is required to capture the entire range of the angular coordinate y('). Ions and neutral atoms are both detected with equal sensitivity. The measurement is unaffected by secondary electrons emitted by the target and by electrons traveling with the positive ion beam, as both types of electron carry very little energy. No specialized electronics or beam deflection devices are required. Providing the region downstream of the mask is free of fields, the target can be several meters away from the mask, allowing good resolution in the y(') axis. The target can be as large as required. PMID- 18447565 TI - A modification of the commercial ESR900 cryostat to enable three-dimensional electron-paramagnetic-resonance studies of crystals. AB - Complete orientation studies of X-band electron-paramagnetic-resonance spectra of crystals largely benefit from the possibility to measure the spectrum for any orientation of the magnetic field with respect to the crystal without the need to remount the crystal. We report on a modification of a commercial cryostat to allow such experiments down to liquid helium temperatures and demonstrate its performance. PMID- 18447566 TI - Thermal effect on piezoelectric stick-slip actuator systems. AB - The piezoelectric stick-slip (PZT-SS) actuator is known to achieve motion with a theoretically unlimited range yet high resolution (several nanometers). In this type of actuator, friction plays an active role in producing a meaningful stick slip motion. However, friction is a source of heat which may cause significant temperature rise, affecting the dynamic performance of the actuator. Our study aimed to measure temperature rise in the stick-slip motion and to understand whether such a rise could significantly affect the displacement of the stick-slip motion. In this study, a temperature measurement system was developed using the off-the-shelf components, with which the temperature rise up to 0.436 degrees C was successfully measured on a proprietary PZT-SS actuator. The experiment further shows that the temperature rise affects the displacement of the actuator when operating voltage is at the low end (approximately 6 V). Therefore, one of the design recommendations for such an actuator system is that the operating voltage should be at the high end (approximately 30 V). The study also measured the temperature rise (approximately 0.263 degrees C after the system worked for 6300 s) at the friction interface due to the piezoelectric element which is a part of the whole PZT-SS actuator. This means that temperature rise is due to both the friction at two interacting surface and the operation of the piezoelectric element. PMID- 18447567 TI - Measurements of NOx, acyl peroxynitrates, and NOy with automatic interference corrections using a NO2 analyzer and gas phase titration. AB - NO(2) analyzers are much more valuable if they can also measure NO since the two (NO+NO(2)=NO(x)) are often found together. NO can be quantitatively converted to NO(2) by reaction with ozone and subsequent thermal decomposition of the N(2)O(5) that may form from further oxidation. The conversion of NO, along with decomposition of N(2)O(5) and removal of the remaining unreacted ozone with a heated chamber, allows for quantitative determination of NO(x) using a NO(2) analyzer and the determination of decomposed acyl peroxynitrates. Ambient tests are performed to demonstrate these methods. PMID- 18447568 TI - Dual chopped photoreflectance spectroscopy for nondestructive characterization of semiconductors and semiconductor nanostructures. AB - Photoreflectance (PR) spectroscopy unaffected by photoluminescence and light scattering has been developed for performing precise characterization of the electronic band structure of semiconductors and semiconductor nanostructures. Dual chopping of both the pump and probe lights eliminates the unexpected components included in the signal when detecting the sum frequency or difference frequency component by using a lock-in detection system. The obtained PR signal contains no background and is considered to be an ideal electromodulated reflectance. PMID- 18447569 TI - Secondary electron emission from distributed ion scattering off surfaces for space instrumentation. AB - We present an alternative method for generating start electrons for time of flight (TOF) space plasma analyzers. The technique presented here takes advantage of the processes occurring during the scattering of the particles off a surface, i.e., kinetic electron emission. The use of a thin microchannel plate as a scattering surface allows us to distribute this surface along a single plane normal to the particle velocity. The uncertainty on the TOF distance is thus minimized, allowing a greater mass resolution. The first tests carried out showed that a mass resolution of 10 for a beam energy of 10 keV is easily reachable. PMID- 18447570 TI - Precise measurement of the resolution in light microscopy using Fourier transform. AB - The resolution power of light microscope has been accurately measured (+/-5%) by Fourier transform of various object images and further evaluation of the highest spatial frequency in Fourier spectrum. Any unknown shape plane object with a shape feature's size smaller than the resolution to be measured was shown to provide a reliable resolution test. This simple method gives a direct measurement of the resolution power as defined by Abbe [Archiv. F. Mikroskopische Anat. 9, 413 (1873)]. The results have been justified by comparison to a standard resolution measurement by using calibrated periodic line patterns. Notably, the approach is applicable in super-resolution light microscopy (transmission, reflection, and fluorescence), where calibrated resolution targets do not occur. It was conveniently implemented by using a compact disk as a test object and free IMAGEJ imaging software. PMID- 18447571 TI - Epistemological development and collaborative learning: a hermeneutic analysis of music therapy students' experience. AB - Undergraduate education must address student's developmental needs, as well as their learning needs. Yet, there has been little discussion regarding music therapy students' epistemological development, how that influences their education and clinical training, and how that understanding can inform educators and clinical supervisors. As part of an introductory music therapy course that was taught using collaborative learning consensus groups, students provided written and verbal comments about their experience and some students agreed to a series of interviews (Luce, 2002). This hermeneutic analysis of that data was based upon Perry's Scheme and Women's Ways of Knowing suggested that (a) the students' comments reflected the various perspectives or positions within the models, (b) the collaborative learning consensus groups facilitated transitions and movement within the models, and (c) there was a need for more research to understand music therapy students' developmental needs, to enhance teaching methods and pedagogy, and to address students' developmental needs as they prepare to enter the profession. PMID- 18447572 TI - A comparison of music education and music therapy majors: personality types as described by the Myers-Briggs Type Indicator and demographic profiles. AB - The purpose of this study was to develop both personality and demographic profiles for students who are interested in majoring in music education or music therapy. Two primary questions were addressed in the study: (a) Are there similarities and differences in the personality types of music education and music therapy majors as measured by the Myers Briggs Type Indicator (MBTI )? (b) Are there similarities and differences in demographic characteristics of music education and music therapy majors in regard to (i) principal instrument studied in college, (ii) grade point average, (iii) scholarship awards, (iv) high school participation in private study and (v) ensembles, (vi) church/community participation, and (vii) volunteerism in high school? PMID- 18447573 TI - Supervising music therapy interns: a survey of AMTA national roster internship directors. AB - Music therapy internship directors provide supervision to interns during a critical phase in their educational process. Although the American Music Therapy Association provides guidelines for this role, little is known about the supervision practices currently being employed. In order to investigate these practices, a mailed survey was sent to all current national roster internship directors. This descriptive research project gathered information related to demographics, education and training, techniques, roles, challenges, and rewards. Results suggest that internship directors represent diverse demographics, clinical populations, and experience levels. They have advanced levels of education and experience but desire further training in supervision. A wide variety of supervisory techniques are employed, with coleading, live observation, and reviewing assignments being the most frequently utilized. Internship directors feel they hold many responsibilities and report high levels of enjoyment in their roles. Results are compared to previous studies and implications of providing further training to internship directors are explored. Recommendations for future research include the addition of university-affiliated internship programs. PMID- 18447574 TI - Music therapy internship supervisors and preinternship students: a comparative analysis of questionnaires. AB - The purpose of this study was to compare perceptions of professional competency between preinternship music therapy students and internship supervisors. Preinternship music therapy students and internship supervisors were asked to fill out the Internship Concerns Questionnaire (ICQ-ST, student; ICQ-SU, supervisor). Participants (N = 106) included 85 students at 16 AMTA-approved universities (n = 85), and 21 internship supervisors at active AMTA national roster internship sites (n = 21). Twenty items on the ICQ were rated on a Likert type scale, and 1 item (Part B) asked the participant to indicate any other concerns not addressed in the ICQ. Music therapy interns and supervisors differed significantly in their mean ratings on 2 of the 20 items: "Communicating with facility staff" (p = .025) and "Maintaining client confidence" (p = .016). In both cases the student interns reported a significantly lower mean level of concern about getting assistance in these areas than did their supervisors. The present study suggests that music therapy educators may better prepare music therapy students for a successful internship by evaluating the perceptual gaps in professional training expectations between students and supervisors prior to the internship. Internship supervisors may also benefit from student's own perceptions of their knowledge and skills upon beginning the internship. Ultimately, the student is responsible for being prepared to begin the process from intern to beginning professional at the start of the internship, and to commit to gaining as much as possible from the combination of academic and clinical experiences available to them. PMID- 18447575 TI - Awareness of music therapy practices and factors influencing specific theoretical approaches. AB - The investigator identified music therapists' theoretical awareness of their practices and analyzed factors influencing their specific theoretical orientations and models. A 2-page survey was mailed to 500 board-certified music therapists in the United States; 272 returned surveys were analyzed. Data analysis revealed that respondents': (a) adoption of current theoretical approaches is contingent on the attended college, area of practice, and their age groups; (b) work satisfaction is not a function of involvement with theoretical orientations but rather of their area of practice and attendance at national music therapy conferences; (c) involvement in music making is not a function of theoretical orientations but of academic degrees; (d) emphasis on client's musical growth and aesthetic quality of music was not a function of theoretical orientations or any other investigated factor; (e) satisfaction with past education was not a function of involvement with theoretical orientations but of the area of practice; (f) desire to expand their theoretical knowledge was not a function of theoretical orientations but of academic degrees. PMID- 18447576 TI - MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression. METHODS AND FINDINGS: We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins-MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A-that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%-100%) and specificity of 98.1% (95% CI 89.9%-100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%-100%) and specificity of 87.2% (95% CI 72.6%-95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DLCO%). CONCLUSIONS: Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression. PMID- 18447577 TI - A systematic review of studies that aim to determine which outcomes to measure in clinical trials in children. AB - BACKGROUND: In clinical trials the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. Selection of inappropriate outcomes can compromise the utility of a trial. However, the process of selecting the most suitable outcomes to include can be complex. Our aim was to systematically review studies that address the process of selecting outcomes or outcome domains to measure in clinical trials in children. METHODS AND FINDINGS: We searched Cochrane databases (no date restrictions) in December 2006; and MEDLINE (1950 to 2006), CINAHL (1982 to 2006), and SCOPUS (1966 to 2006) in January 2007 for studies of the selection of outcomes for use in clinical trials in children. We also asked a group of experts in paediatric clinical research to refer us to any other relevant studies. From these articles we extracted data on the clinical condition of interest, description of the method used to select outcomes, the people involved in the selection process, the outcomes selected, and limitations of the method as defined by the authors. The literature search identified 8,889 potentially relevant abstracts. Of these, 70 were retrieved, and 25 were included in the review. These studies described the work of 13 collaborations representing various paediatric specialties including critical care, gastroenterology, haematology, psychiatry, neurology, respiratory paediatrics, rheumatology, neonatal medicine, and dentistry. Two groups utilised the Delphi technique, one used the nominal group technique, and one used both methods to reach a consensus about which outcomes should be measured in clinical trials. Other groups used semistructured discussion, and one group used a questionnaire-based survey. The collaborations involved clinical experts, research experts, and industry representatives. Three groups involved parents of children affected by the particular condition. CONCLUSIONS: Very few studies address the appropriate choice of outcomes for clinical research with children, and in most paediatric specialties no research has been undertaken. Among the studies we did assess, very few involved parents or children in selecting outcomes that should be measured, and none directly involved children. Research should be undertaken to identify the best way to involve parents and children in assessing which outcomes should be measured in clinical trials. PMID- 18447578 TI - A blood test for lung fibrosis. PMID- 18447579 TI - Better reporting, better research: guidelines and guidance in PLoS Medicine. PMID- 18447580 TI - Posttranscriptional gene regulation by spatial rearrangement of the 3' untranslated region. AB - Translation termination at premature termination codons (PTCs) triggers degradation of the aberrant mRNA, but the mechanism by which a termination event is defined as premature is still unclear. Here we show that the physical distance between the termination codon and the poly(A)-binding protein PABPC1 is a crucial determinant for PTC recognition in human cells. "Normal" termination codons can trigger nonsense-mediated mRNA decay (NMD) when this distance is extended; and vice versa, NMD can be suppressed by folding the poly(A) tail into proximity of a PTC or by tethering of PABPC1 nearby a PTC, indicating an evolutionarily conserved function of PABPC1 in promoting correct translation termination and antagonizing activation of NMD. Most importantly, our results demonstrate that spatial rearrangements of the 3' untranslated region can modulate the NMD pathway and thereby provide a novel mechanism for posttranscriptional gene regulation. PMID- 18447581 TI - High-throughput SHAPE analysis reveals structures in HIV-1 genomic RNA strongly conserved across distinct biological states. AB - Replication and pathogenesis of the human immunodeficiency virus (HIV) is tightly linked to the structure of its RNA genome, but genome structure in infectious virions is poorly understood. We invent high-throughput SHAPE (selective 2' hydroxyl acylation analyzed by primer extension) technology, which uses many of the same tools as DNA sequencing, to quantify RNA backbone flexibility at single nucleotide resolution and from which robust structural information can be immediately derived. We analyze the structure of HIV-1 genomic RNA in four biologically instructive states, including the authentic viral genome inside native particles. Remarkably, given the large number of plausible local structures, the first 10% of the HIV-1 genome exists in a single, predominant conformation in all four states. We also discover that noncoding regions functioning in a regulatory role have significantly lower (p-value < 0.0001) SHAPE reactivities, and hence more structure, than do viral coding regions that function as the template for protein synthesis. By directly monitoring protein binding inside virions, we identify the RNA recognition motif for the viral nucleocapsid protein. Seven structurally homologous binding sites occur in a well defined domain in the genome, consistent with a role in directing specific packaging of genomic RNA into nascent virions. In addition, we identify two distinct motifs that are targets for the duplex destabilizing activity of this same protein. The nucleocapsid protein destabilizes local HIV-1 RNA structure in ways likely to facilitate initial movement both of the retroviral reverse transcriptase from its tRNA primer and of the ribosome in coding regions. Each of the three nucleocapsid interaction motifs falls in a specific genome domain, indicating that local protein interactions can be organized by the long-range architecture of an RNA. High-throughput SHAPE reveals a comprehensive view of HIV 1 RNA genome structure, and further application of this technology will make possible newly informative analysis of any RNA in a cellular transcriptome. PMID- 18447582 TI - Compilation and network analyses of cambrian food webs. AB - A rich body of empirically grounded theory has developed about food webs--the networks of feeding relationships among species within habitats. However, detailed food-web data and analyses are lacking for ancient ecosystems, largely because of the low resolution of taxa coupled with uncertain and incomplete information about feeding interactions. These impediments appear insurmountable for most fossil assemblages; however, a few assemblages with excellent soft-body preservation across trophic levels are candidates for food-web data compilation and topological analysis. Here we present plausible, detailed food webs for the Chengjiang and Burgess Shale assemblages from the Cambrian Period. Analyses of degree distributions and other structural network properties, including sensitivity analyses of the effects of uncertainty associated with Cambrian diet designations, suggest that these early Paleozoic communities share remarkably similar topology with modern food webs. Observed regularities reflect a systematic dependence of structure on the numbers of taxa and links in a web. Most aspects of Cambrian food-web structure are well-characterized by a simple "niche model," which was developed for modern food webs and takes into account this scale dependence. However, a few aspects of topology differ between the ancient and recent webs: longer path lengths between species and more species in feeding loops in the earlier Chengjiang web, and higher variability in the number of links per species for both Cambrian webs. Our results are relatively insensitive to the exclusion of low-certainty or random links. The many similarities between Cambrian and recent food webs point toward surprisingly strong and enduring constraints on the organization of complex feeding interactions among metazoan species. The few differences could reflect a transition to more strongly integrated and constrained trophic organization within ecosystems following the rapid diversification of species, body plans, and trophic roles during the Cambrian radiation. More research is needed to explore the generality of food-web structure through deep time and across habitats, especially to investigate potential mechanisms that could give rise to similar structure, as well as any differences. PMID- 18447583 TI - Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites. AB - The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG) fibers. The L1 family immunoglobulin protein Close Homologue of L1 (CHL1) is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation. PMID- 18447584 TI - Why we sleep: the temporal organization of recovery. PMID- 18447585 TI - A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay. AB - The nonsense-mediated decay (NMD) pathway subjects mRNAs with premature termination codons (PTCs) to rapid decay. The conserved Upf1-3 complex interacts with the eukaryotic translation release factors, eRF3 and eRF1, and triggers NMD when translation termination takes place at a PTC. Contrasting models postulate central roles in PTC-recognition for the exon junction complex in mammals versus the cytoplasmic poly(A)-binding protein (PABP) in other eukaryotes. Here we present evidence for a unified model for NMD, in which PTC recognition in human cells is mediated by a competition between 3' UTR-associated factors that stimulate or antagonize recruitment of the Upf complex to the terminating ribosome. We identify cytoplasmic PABP as a human NMD antagonizing factor, which inhibits the interaction between eRF3 and Upf1 in vitro and prevents NMD in cells when positioned in proximity to the termination codon. Surprisingly, only when an extended 3' UTR places cytoplasmic PABP distally to the termination codon does a downstream exon junction complex enhance NMD, likely through increasing the affinity of Upf proteins for the 3' UTR. Interestingly, while an artificial 3' UTR of >420 nucleotides triggers NMD, a large subset of human mRNAs contain longer 3' UTRs but evade NMD. We speculate that these have evolved to concentrate NMD-inhibiting factors, such as PABP, in spatial proximity of the termination codon. PMID- 18447586 TI - Cellular conductors: glial cells as guideposts during neural circuit development. PMID- 18447587 TI - Polycomb group genes: keeping stem cell activity in balance. PMID- 18447588 TI - One rhodopsin per photoreceptor: Iro-C genes break the rule. PMID- 18447589 TI - Selective thyromimetics for atherosclerosis and dyslipidaemia: another old target making progress. AB - BACKGROUND: Whereas many new targets for drug discovery have been identified from new biology, such as that from the Human Genome Project, some targets have been known for decades but have not been exploited. OBJECTIVE: One such target, selective thyromimetics, is reviewed from a historical perspective and in the light of recent developments. METHODS: The history of thyromimetics in atherosclerosis and dyslipidaemia is reviewed as the background to the recent publication of the first human data on a new selective thyromimetic, KB-2115 (eprotirome). CONCLUSION: The published data provide proof of concept/mechanism, opening the way to larger studies in a wider range of subjects and in combination with statins. PMID- 18447590 TI - Osteoarthritic pain: a review of current, theoretical and emerging therapeutics. AB - BACKGROUND: Despite exciting progress and growth in the understanding of molecular and cellular mechanisms of chronic pain, osteoarthritis (OA) pain remains a challenging clinical entity to treat. There is an emerging diversity of algogenic mechanisms suggesting heterogeneity in pain aetiology in the OA patient population. OBJECTIVE/METHODS: This review article summarises key issues in existing therapies for OA pain and highlights the emerging compounds in early and late development. It also highlights where tolerability may be a concern, especially in the older populations in which treatment interactions for co-morbid conditions may further narrow therapeutic index. Importantly, the authors also examine the diversity of biology that underpins OA pain and highlight the opportunities for the future. RESULTS/CONCLUSIONS: Many emerging therapies are presently in proof-of-concept clinical testing for treatment of OA. A growing understanding of the heterogeneity in the OA patient population, will challenge the ability to accurately understand observed efficacy or safety signals in these relatively small trials and how they may titrate to a broader patient population. We may need to wait several more years to understand whether the need for a differentiated therapy demanded by patients, payors and physicians alike, will be met. PMID- 18447591 TI - Spleen tyrosine kinase: a novel target for therapeutic intervention of rheumatoid arthritis. AB - BACKGROUND: In the last few years, significant progress has been made in understanding the pathogenic mechanisms and in defining the role of relevant cells and molecules in the pathophysiology of rheumatoid arthritis (RA). Various therapies, both biological (anti-TNF, anti-interleukins [e.g., IL-1]) and small molecule inhibitors have been explored for the treatment of RA. OBJECTIVE: To date, no single signaling pathway inhibitor as wide acting as the corticosteroids, is known. However, treatment with corticosteroids is also associated with allied side effects. Despite a lot of efforts in the category of small molecule inhibitors, no inhibitor is available to deal with RA at both fronts (inflammation and tissue damage), without causing immense side effects. METHOD: This present review explores the role of spleen tyrosine kinase (Syk) in the pathogenesis of RA and also discusses how it may meet the present day therapeutic requirements for the treatment of RA. This review gives an in-depth discussion on the role of Syk signaling in RA, the possibilities of using Syk as a target and also discusses the possible side effects that could be associated with its inhibition. CONCLUSION: We propose Syk inhibition as a potential therapeutic approach for the treatment of RA. PMID- 18447592 TI - Polymyxin B: a new strategy for multidrug-resistant Gram-negative organisms. AB - BACKGROUND: There has been a renewed interest in using polymyxin B as a last resort therapeutic option, due to emergence of multidrug-resistant Gram-negative bacteria. Despite being available for clinical use for decades, there is still a very limited understanding on many aspects of this agent. OBJECTIVE: To review what is known about polymyxin B and to identify missing information or gaps for future investigations. METHODS: Pertinent information was reviewed from published literature in English. RESULTS/CONCLUSION: For optimal use of polymyxin B, a more thorough understanding is needed on standardized susceptibility testing, serum and tissue concentrations achieved, antibacterial activity when polymyxin B is combined with other agents, and mechanisms of resistance. A more precise characterization of the relationship between drug concentration and toxicity is also required. PMID- 18447593 TI - Pituitary-targeted medical therapy of Cushing's disease. AB - BACKGROUND: The goals of ideal medical therapy for Cushing's disease should be to target the aetiology of the disorder, as is the case for surgery, which is the current 'gold standard' treatment. However, no effective drug that directly and reliably targets the adrenocorticotropin-secreting pituitary adenoma has yet been found. OBJECTIVE: To summarise pituitary-targeted medical treatment of Cushing's disease. METHODS: Compounds with neuromodulatory properties and ligands of different nuclear hormone receptors involved in hypothalamo-pituitary regulation have been investigated. RESULTS: The somatostatin analogue pasireotide and the dopamine agonist cabergoline, as well as their combination, show some therapeutic promise in the medical therapy of Cushing's disease. Other treatments such as retinoic acid analogues look promising and may be a possible option for further investigation. No other medical therapies seem to be reliably effective currently. CONCLUSION: Since a percentage of patients treated with surgery are not cured, or improve and subsequently relapse, there is an urgent need for effective medical therapies for this disorder. At present, only cabergoline and pasireotide are under active investigation. PMID- 18447594 TI - Pharmacotherapy for erectile dysfunction. AB - OBJECTIVE: To review advances in the pharmacological treatment of erectile dysfunction (ED) highlighting potential neuro-endocrine and molecular targets. METHODS: A comprehensive MEDLINE and PUBMED search was utilized to investigate current novel mechanistic approaches in treating erectile dysfunction. Search criteria included, but were not limited to, erectile dysfunction (ED), cGMP, nitric oxide, Rho-kinase, phosphodiesterase, gene therapy, apomorphine, melanocortin and corpora cavernosa. Articles relating to in vitro, animal and in vivo experimental therapy were evaluated and included in this review and future directions are described. RESULTS: Current first-line ED treatment often involves the use of phosphodiesterase inhibitors. However, many novel pharmacotherapeutic approaches under development including the use of melanocortins and Rho-kinase inhibitors as well as the introduction of gene therapy have demonstrated efficacy in animal as well as early human trials. CONCLUSIONS: The success of oral pharmacotherapy for ED has been accompanied by renewed interest into the ED pathophysiology and signal transduction pathways. This has led to the identification of new therapeutic targets, which are poised to change the dynamic of ED management by broadening treatment alternatives to include other oral and genetic therapies. PMID- 18447595 TI - Anti-nicotine abuse vaccines in the pipeline: an update. AB - Three different companies have completed Phase II clinical studies of their anti nicotine vaccines and are rushing to obtain regulatory approval and to bring their vaccine candidates to the market. The vaccines are composed of the nicotine molecule linked to a carrier protein and an adjuvant. The results in all three clinical studies are encouraging. Preliminary results seem to indicate that subjects with high anti-nicotine antibody levels demonstrate high quit rates and that the vaccines appear to be compatible with and complementary to approved forms of smoking cessation therapies. The data available do not yet allow us to give definitive results for long-term quit rates. We expect the vaccines to appear on the market during a time window between 2009 and 2011. PMID- 18447596 TI - New promise and hope for treating hereditary angioedema. AB - BACKGROUND: While there is no approved effective therapy for the treatment of acute attacks of hereditary angioedema in the USA, four different drugs are completing or have recently completed Phase III clinical trials. OBJECTIVE: To review the clinical status and future prospects of the new therapies under development for the treatment of hereditary angioedema. METHODS: A review was carried out of the literature and presentations at meetings on the efficacy and safety of plasma-derived C1 inhibitor, recombinant human C1 inhibitor, the kallikrein inhibitor DX-88, and the B2 bradykinin receptor antagonist HOE-140. RESULTS/CONCLUSION: Each of these drugs has been shown to be effective and safe for the treatment of hereditary angioedema; however, subtle differences in their mechanisms of action and delivery may influence how physicians and patients utilize the different drugs. The availability of effective therapy is expected to reshape the management of hereditary angioedema. PMID- 18447597 TI - New tubulin targeting agents currently in clinical development. AB - BACKGROUND: The first tubulin targeting agents were approved as cancer chemotherapeutics over 40 years ago and tubulin as an antitumor target continues to attract significant drug discovery and development attention. Mechanism of action as defined by tubulin binding sites and effect on microtubules distinguishes these agents, but the end result is equivalent in that microtubule disruption leads to cell cycle arrest at G2/M phase of the cell cycle and subsequent apoptotic cell death. OBJECTIVES: The goal of this review is to describe the state of clinical development of tubulin targeting agents as of early 2008, with descriptions of clinical experience slanted toward the most advanced trials for each agent. METHOD: Objective information in this review was obtained exclusively from public sources that included journals, scientific meeting abstracts, posters and oral presentations, websites and public presentations from companies. Opinions expressed in this review are exclusively from the author. RESULTS/CONCLUSIONS: A large number of tubulin targeting agents are currently in clinical development, including microtubule stabilizing and destabilizing compounds acting through all three of the characterized tubulin binding sites. With the approval of ixabepilone for refractory breast cancer, the epothilones appear best positioned to make an impact among the new microtubule stabilizing compounds. There are 17 microtubule destabilizing agents under clinical assessment, with many only in Phase I and results to date include at best modest efficacy signals with no obvious indication trend. PMID- 18447598 TI - Indications and limitations of third-generation aromatase inhibitors. AB - BACKGROUND: Use of aromatase inhibitors in postmenopausal breast cancer, initially in advanced disease but recently also for adjuvant therapy, represents a major advance. OBJECTIVE: To summarize research leading to this success and to review clinical data from large Phase III trials revealing efficacy of novel third-generation aromatase inhibitors in metastatic and early breast cancer. METHODS: Literature on PubMed and on ISI Web of Science for the last 10 years was searched using the word 'aromatase'. Recent key presentations and abstracts are also included. RESULTS/CONCLUSION: Third-generation aromatase inhibitors improve relapse-free survival compared to tamoxifen, and some trials reveal a survival advantage in early breast cancer. Although substantial data now confirm the safety of these potent compounds with respect to bone metabolism and cardiovascular risk, there is a need for continuous long-term follow-up, in particular into potential vascular effects. The mechanisms and optimal treatment of musculoskeletal and joint pain remain to be addressed. Ongoing studies evaluate sequential treatment versus monotherapy, potential differences between individual compounds and optimal duration of treatment, as well as combining aromatase inhibitors with novel targeting agents. PMID- 18447599 TI - Axitinib for renal cell carcinoma. AB - BACKGROUND: The approval of sunitinib, sorafenib and temsirolimus has dramatically altered the management of renal cell carcinoma (RCC). Bevacizumab plus IFN may also be added to the therapeutic armamentarium. Axitinib (AG-013736) is an oral and selective tyrosine kinase inhibitor. OBJECTIVE: Data supporting the development of axitinib for RCC are reviewed. METHODS: Preclinical and clinical data available for axitinib for RCC are presented. RESULTS: Axitinib inhibits VEGFR-1, VEGFR-2 and VEGFR-3 with picomolar potencies, and PDGFR-alpha, PDGFR-beta and c-kit with nanomolar potencies. Phase II clinical trials of axitinib in pretreated RCC following sorafenib or cytokine treatment have demonstrated promising activity accompanied by a favorable toxicity profile. Further development of axitinib for RCC is warranted. PMID- 18447600 TI - Doripenem: an expected arrival in the treatment of infections caused by multidrug resistant Gram-negative pathogens. AB - BACKGROUND: Potent new drugs against multidrug-resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter spp. and pan-drug-resistant Klebsiella pneumoniae, which constitute an increasing medical threat, are almost absent from the future pharmaceutical pipeline. OBJECTIVE: This drug evaluation focuses on the position of doripenem, a novel forthcoming carbapenem. Mechanisms of resistance and new drugs with anti-Gram-negative activity are also briefly reviewed. METHODS: Literature search was performed for new carbapenems, new antibiotics, doripenem, metallo-beta-lactamase inhibitors, multidrug-resistant pathogens, antipseudomonal antibiotics and multidrug-resistant epidemiology. RESULTS: Doripenem possesses a broad spectrum of activity against Gram-negative bacteria, similar to that of meropenem, while retaining the spectrum of imipenem against Gram-positive pathogens. Against P. aeruginosa, doripenem exhibits rapid bactericidal activity with 2 - 4-fold lower MIC values, compared to meropenem. Exploitation of pharmacokinetic/pharmacodynamic applications could offer a treatment opportunity against strains exhibiting borderline resistance to doripenem. Stability against numerous beta-lactamases, low adverse event potential and more potent in vitro antibacterial activity against P. aeruginosa and A. baumanni compared to the existing carbapenems, are its principal features. PMID- 18447601 TI - Idraparinux: review of its clinical efficacy and safety for prevention and treatment of thromboembolic disorders. AB - BACKGROUND: Idraparinux is a synthetic pentasaccharide that binds to antithrombin with high affinity. In view of its long half-life, it is suitable for once-a-week administration. OBJECTIVE: To review the evidence favoring the use of idraparinux for the acute and long-term treatment of patients with venous thromboembolism (VTE) and for the prevention of thromboembolic events in patients with atrial fibrillation (AF). METHODS: All preclinical and clinical studies carried out with the use of idraparinux were sought through electronic searches of MEDLINE from January 1, 1999 up to December 31, 2007. RESULTS: The administration of idraparinux in subcutaneous fixed doses of 2.5 mg once weekly was found to be as effective and safe as conventional antithrombotic therapy in the initial treatment of patients with deep vein thrombosis, but less effective than standard therapy in the initial treatment of patients with primary pulmonary embolism. During a 6-month extension of thromboprophylaxis, idraparinux was effective in preventing recurrent VTE but was associated with an increased risk of bleeding versus placebo. Finally, in patients with AF the long-term treatment with idraparinux was as effective as vitamin K antagonists, but caused more bleeding. CONCLUSIONS: In its current formulation, idraparinux can be recommended only for the initial treatment of patients with deep vein thrombosis. The bioequipotency of a biotinylated version of idraparinux (idrabiotaparinux), whose effects can be reversed by a neutralizing agent (avidin), is under investigation in the treatment of VTE at present, as is the use of lower doses in patients with AF. PMID- 18447603 TI - Paromomycin in the treatment of leishmaniasis. AB - BACKGROUND: The treatment options for leishmaniasis are limited. Most of the drugs available need parenteral administration, are toxic, require monitoring and have a prolonged treatment duration. All these factors increase the cost of the treatment. The development of resistance to pentavalent antimonials in patients with visceral leishmaniasis in North Bihar, India, has added another dimension to the problem. OBJECTIVE: To summarise the pharmacological and clinical data on antileishmanial activity of paromomycin and discuss the impact this agent may have on present treatment regimens. METHODS: A literature search on paromomycin and leishmaniasis was done on PubMed and through Google. RESULTS: Paromomycin, with its excellent efficacy, low cost, shorter duration of administration and good safety profile, has the potential to be used as a first-line drug. PMID- 18447602 TI - Gemifloxacin for community-acquired pneumonia. AB - BACKGROUND: Newer fluoroquinolones have become an important therapeutic choice in the treatment of community-acquired pneumonia (CAP). Gemifloxacin is one of the newest members of this class of antibiotics and has performed favourably in this indication. OBJECTIVE: To analyse the microbiological activity, pharmacokinetic/pharmacodynamic properties and clinical activity of gemifloxacin in CAP, as well as the safety reported in controlled clinical studies. METHODS: Literature research of English publications in the last 10 years addressing all aspects of gemifloxacin in CAP. RESULTS/CONCLUSIONS: Gemifloxacin is microbiologically the most active fluoroquinolone against Streptococcus pneumoniae--the leading pathogen of CAP. In several comparative studies gemifloxacin was highly effective and well tolerated in the treatment of mild-to moderate severe CAP. PMID- 18447604 TI - Betahistine: what's new on the agenda? AB - BACKGROUND: Betahistine is an orally administered, centrally acting histamine H(1) receptor agonist with partial H(3) antagonistic activity and no H(2)-binding effects. In the past betahistine was clinically studied mainly as a vasodilator for conditions such as cluster headaches, vascular dementia and Meniere's disease, for which it is still used. In recent years, histamine was found to be a key neurotransmitter in the regulation of feeding behavior. OBJECTIVE: To provide a review of the developmental history and current research interests of betahistine. METHODS: All reports of betahistine use in animals and humans were retrieved and reviewed. RESULTS/CONCLUSION: The unique pharmacologic properties of betahistine point to its potential future use as an antiobesity agent. PMID- 18447605 TI - Vernakalant--a promising therapy for conversion of recent-onset atrial fibrillation. AB - BACKGROUND: This paper reviews the pharmacology, electrophysiology, efficacy and safety of intravenous and oral vernakalant hydrochloride (RSD-1235), a novel antiarrhythmic drug that has relative atrial selectivity by blocking potassium channels that are present in the atria and not the ventricle. In addition, this drug has important rate-dependent sodium channel blocking properties. METHODS: Currently, there few commercially approved intravenous antiarrhythmic agents for the conversion of atrial fibrillation. Intravenously, vernakalant has been demonstrated to be useful in terminating over 50% of recent-onset atrial fibrillation (< 7 days duration) with minimal ventricular proarrhythmic effects. Intravenous vernakalant is not effective in terminating atrial flutter. Oral vernakalant is currently undergoing study and appears to be effective in suppressing atrial fibrillation recurrences after cardioversion of persistent atrial fibrillation. RESULTS/CONCLUSION: Intravenous vernakalant has the potential to be an important agent in the conversion of atrial fibrillation and oral vernakalant may be a useful drug for the suppression of atrial fibrillation recurrences. PMID- 18447606 TI - Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma. AB - BACKGROUND: Roflumilast is a selective phosphodiesterase-4 inhibitor with a broad range of anti-inflammatory actions. Studies in asthma and chronic obstructive pulmonary disease (COPD) have demonstrated that it can improve lung function and reduce inflammation. OBJECTIVE: To review the clinical data on roflumilast in COPD and asthma. METHODS: A PubMed search using the term roflumilast was used to identify articles, and the bibliographies of the identified articles were reviewed to identify other relevant reports. All roflumilast abstracts from the 2006 and 2007 International Meetings of the American College of Chest Physicians, American Thoracic Society and European Respiratory Society were also reviewed. RESULTS/CONCLUSION: The preliminary studies of roflumilast in COPD and asthma have only shown modest clinical benefits and may be associated with gastrointestinal side effects. Further studies are required to clarify the role of roflumilast in the management of COPD and asthma. PMID- 18447607 TI - Elocalcitol (BXL-628): a novel, investigational therapy for the therapeutic management of benign prostatic hyperplasia. PMID- 18447610 TI - Significant challenges facing HIV practitioners. PMID- 18447611 TI - Initiating therapy: when to start, what to use. AB - Decisions regarding whether to start combination antiretroviral therapy (cART) during primary infection and when to initiate treatment during chronic infection continue to evolve. Although current data suggest that there may be a benefit to therapy during primary infection, results are inconclusive. Once begun, treatment probably should be continued indefinitely, since its potential advantages disappear over time if treatment is stopped. Recent studies suggest that cART may be useful at higher CD4 cell count thresholds than are currently recommended in several guidelines. Several regimens are acceptable as initial therapy, with tenofovir/emtricitabine/efavirenz favored by many because of potency and ease of administration. Other favored regimens include combinations of 2 nucleoside (or nucleotide) reverse-transcriptase inhibitors and a ritonavir-boosted protease inhibitor. Some new antiretroviral drugs under study, particularly integrase inhibitors, may prove useful in treatment-naive patients. PMID- 18447612 TI - Managing antiretroviral therapy: changing regimens, resistance testing, and the risks from structured treatment interruptions. AB - The management of patients receiving therapy for human immunodeficiency virus infection has improved in recent years owing to factors such as new classes of antiretroviral drugs, new agents in existing classes, and reduced resistance rates when chronically infected patients begin treatment with preferred regimens. Transmitted resistance variants in approximately 10% of treatment-naive patients underline the need for pretreatment resistance testing, to improve rates of virologic efficacy. Structured treatment interruptions to reduce drug exposure and toxicity should not be used outside well-controlled research studies, since this practice has been associated with increased rates of death and disease progression. PMID- 18447613 TI - Preventing HIV antiretroviral resistance through better monitoring of treatment adherence. AB - Suboptimal adherence to antiretroviral therapy (ART) is the most common cause of viral rebound. Accurate and reliable measures of ART adherence will be needed in the transition from reactive response to proactive prevention of viral rebound in the era of chronic human immunodeficiency virus (HIV) disease management. Such tools could define individual "signature adherence patterns," which could inform regimen choice and guide behavioral intervention. Upcoming advances in adherence monitoring present opportunities to better match HIV-disease treatment strategies with individual adherence behavior. PMID- 18447614 TI - Management of hepatic complications in HIV-infected persons. AB - In the era of effective antiretroviral therapy (ART), liver disease is the second most common cause of death among persons with human immunodeficiency virus (HIV) infection. Liver disease-related deaths mostly result from chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). In addition, recent reports suggest that HCV infection may be transmitted sexually between HIV infected men who have sex with men. Management of these conditions in HIV infected persons requires careful consideration, balancing the potential benefits of therapy with the potential for significant treatment-related adverse effects (HCV infection) and viral resistance and/or hepatitis flares (HBV infection). Furthermore, several antiretroviral agents are active against HBV infection, including lamivudine, emtricitabine, tenofovir, and, more recently, entecavir. Despite the complexity and potential for antiretroviral-associated hepatotoxicity, ART usually is safe for patients with viral hepatitis coinfection, and, in some cases, treatment for HIV infection may be beneficial for the liver. PMID- 18447619 TI - No evidence of deer mouse involvement in plague (Yersinia pestis) epizootics in prairie dogs. AB - Plague, the disease caused by the bacterium Yersinia pestis, can have devastating impacts on black-tailed prairie dog (Cynomys ludovicianus) colonies. One suggested mechanism behind sporadic prairie dog die-offs involves an alternative mammal host, such as the deer mouse (Peromyscus maniculatus), which often inhabits prairie dog colonies. We examined the flea populations of deer mice to investigate the potential of flea-borne transmission of plague between deer mice and prairie dogs in northern Colorado, where plague is active in prairie dog colonies. Deer mice were predominantly infested with the flea Aetheca wagneri, and were rarely infested with prairie dog fleas, Oropsylla hirsuta. Likelihood of flea infestation increased with average monthly temperature, and flea loads were higher in reproductive animals. These results suggest that the deer mouse is an unlikely maintenance host of plague in this region. PMID- 18447620 TI - Seroprevalence against Sin Nombre virus in resident and dispersing deer mice. AB - Through dispersal, deer mice (Peromyscus maniculatus) enter peridomestic settings (e.g., outbuildings, barns, cabins) and expose humans and other deer mouse populations to Sin Nombre virus (SNV). In June 2004, research on deer mouse dispersal was initiated at 2 locations in Montana. During the course of the study, over 6000 deer mouse movements were recorded, and more than 1000 of these movements were classified as dispersal movements. More than 1700 individual deer mice were captured and tested for SNV, revealing an average SNV antibody prevalence of approximately 11%. Most of the dispersing and antibody-positive individuals were adult males. Among the few subadult dispersing mice discovered during the study, none were seropositive for SNV. Our results suggest that dispersal rates are higher in high abundance populations of deer mice and that during peak times of dispersal, human exposure to SNV, which commonly occurs in peridomestic settings, could increase. PMID- 18447615 TI - Antiretroviral therapy and central nervous system HIV type 1 infection. AB - Central nervous system (CNS) human immunodeficiency virus type 1 (HIV-1) infection begins during primary viremia and continues throughout the course of untreated systemic infection. Although frequently accompanied by local inflammatory reactions detectable in cerebrospinal fluid (CSF), CNS HIV-1 infection usually is not clinically apparent. In a minority of patients, CNS HIV 1 infection evolves into encephalitis during the late stages of systemic infection, which compromises brain function and presents clinically as acquired immunodeficiency syndrome dementia complex (ADC). Combination antiretroviral therapy (ART) has had a major impact on all aspects of CNS HIV-1 infection and disease. In those with asymptomatic infection, ART usually effectively suppresses HIV-1 in CSF and markedly reduces the incidence of symptomatic ADC. In those presenting with ADC, ART characteristically prevents neurological progression and leads to variable, and at times substantial, recovery. Similarly, treatment has reduced CNS opportunistic infections. With better control of these severe disorders, attention has turned to the possible consequences of chronic silent infection and the issue of whether indolent, low-grade brain injury might require earlier treatment intervention. PMID- 18447621 TI - Evaluation of cotton rats as a model for severe acute respiratory syndrome. AB - Experimental studies were conducted to evaluate two species of cotton rats, Sigmodon hispidus and Sigmodon fulviventer, as a model for severe acute respiratory syndrome (SARS). Blood and turbinate wash samples, and lung tissue were collected from each animal at different time points after SARS coronavirus (CoV) infection for determining the growth curve of virus, if any, by the standard infectivity assay in Vero E6 cells. In addition, sections of the lung, liver, spleen, and kidney were taken and used for histology analysis. All animals were observed daily for signs of illness, and in some experiments, animals were weighed on the day when they were sacrificed. The results indicated that the cotton rat species, S. hispidus and S. fulviventer, were not a useful model for either SARS-CoV infection or disease. This observation was supported by the absence of any signs of illness, the failure to consistently demonstrate virus in the blood and tissues, and the absent of any notable histopathology. However, infected animals were capable of producing neutralizing antibodies against SARS CoV, suggesting the seroconversion did occur. Further studies are warranted to consider other animal species in efforts to find better animal models for the evaluation of SARS-CoV vaccines and antiviral drugs. PMID- 18447622 TI - Tick-borne diseases in North Carolina: is "Rickettsia amblyommii" a possible cause of rickettsiosis reported as Rocky Mountain spotted fever? AB - Cases of Rocky Mountain spotted fever (RMSF) in North Carolina have escalated markedly since 2000. In 2005, we identified a county in the Piedmont region with high case numbers of RMSF. We collected ticks and examined them for bacterial pathogens using molecular methods to determine if a novel tick vector or spotted fever group rickettsiae (SFGR) might be emerging. Amblyomma americanum, the lone star tick, comprised 99.6% of 6,502 specimens collected in suburban landscapes. In contrast, Dermacentor variabilis, the American dog tick, a principal vector of Rickettsia rickettsii, comprised < 1% of the ticks collected. Eleven of 25 lone star tick pools tested were infected with "Rickettsia amblyommii," an informally named SFGR. Sera from patients from the same county who were presumptively diagnosed by local physicians with a tick-borne illness were tested by an indirect immunofluorescence antibody (IFA) assay to confirm clinical diagnoses. Three of six patients classified as probable RMSF cases demonstrated a fourfold or greater rise in IgG class antibody titers between paired acute and convalescent sera to "R. amblyommii" antigens, but not to R. rickettsii antigens. White-tailed deer, Odocoileus virginianus, are preferred hosts of lone star ticks. Blood samples collected from hunter-killed deer from the same county were tested by IFA test for antibodies to Ehrlichia chaffeensis and "R. amblyommii." Twenty-eight (87%) of 32 deer were positive for antibodies to E. chaffeensis, but only 1 (3%) of the deer exhibited antibodies to "R. amblyommii," suggesting that deer are not the source of "R. amblyommii" infection for lone star ticks. We propose that some cases of rickettsiosis reported as RMSF may have been caused by "R. amblyommii" transmitted through the bite of A. americanum. PMID- 18447623 TI - Vector competence of some French Culex and Aedes mosquitoes for West Nile virus. AB - To identify the mosquito species able to sustain the transmission of West Nile Virus (WNV) in the Camargue region (the main WNV focus of southern France), we assessed the vector competence of Culex modestus and Culex pipiens, the most abundant bird-feeders, and Aedes caspius, the most abundant mammophilic species occasionally found engorged with avian blood. Female mosquitoes were exposed to the infectious meal (10(10.3) plaque forming units (PFU)/mL) by membrane feeding, and hold at 26 degrees C. After the incubation period, disseminated infection was assessed by WNV detection using an indirect fluorescent antibody assay (IFA) on head squashes, and the transmission rate was assessed by the presence of WNV RNA in salivary secretions with a real-time reverse transcriptase-polymerase chain reaction (RT-PCR). After 14 incubation days, the disseminated infection and the transmission rates were 89.2% and 54.5% for Cx. modestus, 38.5% and 15.8% for Cx. pipiens, and 0.8% and 0 for Ae. caspius. Culex modestus was found to be an extremely efficient laboratory WNV vector and could thus be considered the main WNV vector in wetlands of the Camargue. Culex pipiens was a moderately efficient laboratory WNV vector, but in dry areas of the region it could play the main role in WNV transmission between birds and from birds to mammals. Aedes caspius was an inefficient vector of WNV in the laboratory, and despite its high densities, its role in WNV transmission may be minor in southern France. PMID- 18447624 TI - First detection of Rickettsia helvetica in Ixodes ricinus ticks in Austria. AB - A total of 853 Ixodes ricinus ticks collected from the nine federal states of Austria were examined by molecular methods for possible infections with Rickettsia spp. It was shown that roughly one-third of the ticks were infected with Rickettsia spp. Moreover, Rickettsia helvetica was detected in Austria for the first time. PMID- 18447625 TI - Underrecognition of leptospirosis during a dengue fever outbreak in Hawaii, 2001 2002. AB - During the 10-year period from 1997 through 2006, the reported mean annual incidence rate of leptospirosis in the state of Hawaii was 3.3/100,000 with a range of 22-60 infections reported each year. Because the clinical presentation is highly variable, however, leptospirosis illness is challenging to recognize and may be underdiagnosed. To assess whether the incidence may be substantially higher than reported figures indicate, we retrospectively studied the prevalence of anti-Leptospira IgM antibodies among specimens obtained over a 12-month period (May 2001 to April 2002) from patients presenting with febrile illness during a dengue fever outbreak in Hawaii. Of 1206 patients testing negative or indeterminate for dengue, 54 (4.5%; 95% confidence interval: 3.3%-5.7%) were positive for anti-Leptospira IgM antibodies using a commercially available dipstick enzyme-linked immunosorbent assay (ELISA). The most common clinical symptoms reported by laboratory-positive leptospirosis patients were fever (92%), headache (88%), and myalgia (83%). Three clinical symptoms were significantly less common among persons laboratory positive for leptospirosis when compared with the 122 patients who had been diagnosed with dengue fever during the outbreak: rash (p < 0.0001), chills (p = 0.05), and petechiae (p = 0.0005). Laboratory-positive leptospirosis infections were identified in persons exposed on each of the 5 most populous islands and illness onsets spanned a 10-month period, reflecting an endemic pattern of disease. If added to the figures obtained via routine passive surveillance, the number of leptospirosis infections identified through this study would more than double the annual incidence rate for Hawaii during 2001. These findings indicate that many leptospiral infections in Hawaii go undiagnosed. Physicians should maintain a high index of suspicion for leptospirosis when assessing patients presenting with acute febrile illness among residents and visitors to Hawaii. PMID- 18447627 TI - Blast-induced brain injury and posttraumatic hypotension and hypoxemia. AB - Explosive munitions account for more than 50% of all wounds sustained in military combat, and the proportion of civilian casualties due to explosives is increasing as well. But there has been only limited research on the pathophysiology of blast induced brain injury, and the contributions of alterations in cerebral blood flow (CBF) or cerebral vascular reactivity to blast-induced brain injury have not been investigated. Although secondary hypotension and hypoxemia are associated with increased mortality and morbidity after closed head injury, the effects of secondary insults on outcome after blast injury are unknown. Hemorrhage accounted for approximately 50% of combat deaths, and the lungs are one of the primary organs damaged by blast overpressure. Thus, it is likely that blast-induced lung injury and/or hemorrhage leads to hypotensive and hypoxemic secondary injury in a significant number of combatants exposed to blast overpressure injury. Although the effects of blast injury on CBF and cerebral vascular reactivity are unknown, blast injury may be associated with impaired cerebral vascular function. Reactive oxygen species (ROS) such as the superoxide anion radical and other ROS, likely major contributors to traumatic cerebral vascular injury, are produced by traumatic brain injury (TBI). Superoxide radicals combine with nitric oxide (NO), another ROS produced by blast injury as well as other types of TBI, to form peroxynitrite, a powerful oxidant that impairs cerebral vascular responses to reduced intravascular pressure and other cerebral vascular responses. While current research suggests that blast injury impairs cerebral vascular compensatory responses, thereby leaving the brain vulnerable to secondary insults, the effects of blast injury on the cerebral vascular reactivity have not been investigated. It is clear that further research is necessary to address these critical concerns. PMID- 18447626 TI - Targeting cell death in vivo in experimental traumatic brain injury by a novel molecular probe. AB - Traumatic brain injury (TBI) remains a frequent and major challenge in neurological and neurosurgical practice. Apoptosis may play a role in cerebral tissue damage induced by the traumatic insult, and thus its detection and inhibition may advance patient care. DDC (N,N'-didansyl-L-cystine) is a novel fluorescent probe for detection of apoptotic cells. We now report on the performance of DDC in experimental TBI. Closed head injury was induced in mice by weight-drop. DDC was administered intravenously in vivo. Two hours later, animals were sacrificed, and brain tissue was subjected to fluorescent microcopy, for assessment of DDC uptake, in correlation with histopathological assessment of apoptosis by TUNEL and caspase substrates, and also in correlation with the neurological deficits, as assessed by Neurological Severity Score (NSS). Selective uptake of DDC was observed at the primary site of injury, and also at remote sites. Uptake was at the cellular level, with accumulation of DDC in the cytoplasm. Cells manifesting DDC uptake were confirmed as apoptotic cells by detection of the characteristic apoptotic DNA fragmentation (positive TUNEL staining) and detection of activated caspases. The damaged region stained by DDC fluorescence correlated with the severity of neuronal deficits. Our study confirms the role of apoptosis in TBI, and proposes DDC as a useful tool for its selective targeting and detection in vivo. Such imaging of apoptosis, following future radiolabeling of DDC, may advance care for patients with head injury, by allowing real-time evaluation of the extent of tissue damage, assessment of novel therapeutic strategies, and optimization of treatment for the individual patient. PMID- 18447628 TI - Overall survival in women with breast cancer: the influence of pepsinogen C gene polymorphism. AB - We aimed to study the role of an insertion/deletion polymorphism in the Pepsinogen C (PGC) gene in the clinical outcome of 172 breast cancer patients. The six polymorphic alleles were amplified using PCR. Our results indicate that patients carrying the allele 6 present a higher 5-year survival mean (83.4% of 6 allele carriers were alive at 5 years vs. only 68.6% of noncarriers, p=0.001), suggesting a role for this polymorphism in the outcome of breast cancer patients. We hypothesize that PGC polymorphism can be a predictive biomarker in breast cancer, contributing to an individual profile of great interest in clinical oncology. PMID- 18447629 TI - Intercessory prayer: a delicate celestial orchestration between spiritual and physical worlds. PMID- 18447630 TI - Research scholars program: a faculty development initiative at the Oregon College of Oriental Medicine. AB - BACKGROUND: The Research Scholars Program (RSP) was created at the Oregon College of Oriental Medicine (OCOM) to provide faculty development in research literacy, research-informed clinical practice, and research participation skills. The RSP is part of a broad effort, funded by a National Institutes of Health/National Center for Complementary and Alternative Medicine R25 education grant, to infuse an evidence-based perspective into the curriculum at schools of complementary and alternative medicine. The RSP arose from the realization that this curriculum reform would first necessitate faculty training in both research appreciation and pedagogy. OCOM's grant, Acupuncture Practitioner Research Education Enhancement, is a partnership with the Oregon Health & Science University School of Nursing (OHSU SON). DESIGN: The RSP was developed initially as a collaborative effort among the OCOM Dean of Research (R.H.), OCOM Director of Research Education (S.F.), and an OHSU SON education specialist (K.L.). The 9-month, 8 hours per month seminar-style RSP provides the opportunity for a cohort of OCOM faculty and staff to explore research-related concepts and content as well as pedagogical practices that emphasize interactive, learner-centered teaching. The RSP adheres to a competency-based approach as developed by the Education Committee of the grant. As a tangible outcome, each Research Scholar designs a sustainable learning activity that infuses a research perspective into their courses, clinic supervision, or other sphere of influence at the college. In this paper, we describe the creative process and the lessons learned during the planning and initial implementation of the RSP. CONCLUSIONS: We view the early successes of the RSP as encouraging signs that research literacy and an evidence-based perspective are becoming increasingly accepted as needed skill sets for present day practitioners of acupuncture and Oriental medicine. PMID- 18447631 TI - A randomized, double-blind, placebo-controlled, clinical study of the general effects of a standardized Lycium barbarum (Goji) Juice, GoChi. AB - BACKGROUND: This randomized, double-blind, placebo-controlled clinical trial is the first study reported from outside China that has examined the general effects of the orally consumed goji berry, Lycium barbarum, as a standardized juice (GoChi; FreeLife International LLC, Phoenix, AZ) to healthy adults for 14 days. METHODS: Based upon the medicinal properties of Lycium barbarum in traditional Asian medicine, we examined by questionnaire subjective ratings (0-5) of general feelings of well-being, neurologic/psychologic traits, gastrointestinal, musculoskeletal, and cardiovascular complaints as well as any adverse effects. Also, measures of body weight, body-mass index, blood pressure, pulse rate, and visual acuity were assessed before and after consuming 120 mL of GoChi/day or placebo control solution. Data were statistically analyzed for changes between day 1 and day 15. RESULTS: Significant differences between day 1 and day 15 were found in the GoChi group (N = 16) in increased ratings for energy level, athletic performance, quality of sleep, ease of awakening, ability to focus on activities, mental acuity, calmness, and feelings of health, contentment, and happiness. GoChi also significantly reduced fatigue and stress, and improved regularity of gastrointestinal function. In contrast, the placebo group (N = 18) showed only two significant changes (heartburn and happiness). No significant changes in musculoskeletal or cardiovascular complaints were observed in either group. All parametric data (body weight, etc.) were not significantly different between groups or between day 1 and day 15 for either group. CONCLUSIONS: These results clearly indicate that daily consumption of GoChi for 14 days increases subjective feelings of general well-being, and improves neurologic/psychologic performance and gastrointestinal functions. The data strongly suggest that further research is indicated to confirm and extend knowledge of the potential effects of Lycium barbarum upon human health. PMID- 18447632 TI - On the impossibility of trigger point-acupoint equivalence: a commentary on Peter Dorsher's analysis. PMID- 18447633 TI - Interaction of systemically delivered adenovirus vectors with Kupffer cells in mouse liver. AB - When adenovirus (Ad) vectors are injected intravenously they are rapidly taken up by Kupffer cells (KCs) in the liver. This results in massive KC necrosis within minutes, followed by a more gradual disappearance of KCs from the liver. It is not known how KCs recognize Ad, or why Ad kills KCs. We used a variety of mutated and fiber-pseudotyped Ad vectors to evaluate how capsid proteins influence Ad uptake by KCs and to define the viral proteins that are involved in the destruction of KCs. We found that depletion of KCs from the liver was partially dependent on interactions between Ad and integrins, but was independent of the coxsackievirus and Ad receptor. The Ad5 fiber shaft was proven to be a particularly important contributory factor, because vectors with the shorter Ad35 shaft were not as effective at depleting KCs. In contrast, the fiber head played no discernible role. Variations in the ability of Ad vectors to deplete KCs could not be explained by differences in the amount of Ad that reached KCs, because all mutant Ads were accumulated by KCs at similar levels. Interestingly, we found that the Ad mutant ts1 did not cause KC death; this virus is known to bind and enter cells normally, but the capsid is unable to disassemble or lyse membranes. We conclude that Ad vectors kill KCs at a postbinding step and that this cell death can be mitigated if downstream events in viral entry are blocked. PMID- 18447634 TI - The first RSBI (ISA-TAB) workshop: "can a simple format work for complex studies?". AB - This article summarizes the motivation for, and the proceedings of, the first ISA TAB workshop held December 6-8, 2007, at the EBI, Cambridge, UK. This exploratory workshop, organized by members of the Microarray Gene Expression Data (MGED) Society's Reporting Structure for Biological Investigations (RSBI) working group, brought together a group of developers of a range of collaborative systems to discuss the use of a common format to address the pressing need of reporting and communicating data and metadata from biological, biomedical, and environmental studies employing combinations of genomics, transcriptomics, proteomics, and metabolomics technologies along with more conventional methodologies. The expertise of the participants comprised database development, data management, and hands-on experience in the development of data communication standards. The workshop's outcomes are set to help formalize the proposed Investigation, Study, Assay (ISA)-TAB tab-delimited format for representing and communicating experimental metadata. This article is part of the special issue of OMICS on the activities of the Genomics Standards Consortium (GSC). PMID- 18447635 TI - Use of PLGA 90:10 scaffolds enriched with in vitro-differentiated neural cells for repairing rat sciatic nerve defects. AB - Poly(lactic-co-glycolic acid) (PLGA) nerve tube guides, made of a novel proportion (90:10) of the two polymers, poly(L-lactide): poly(glycolide) and covered with a neural cell line differentiated in vitro, were tested in vivo for promoting nerve regeneration across a 10-mm gap of the rat sciatic nerve. Before in vivo testing, the PLGA 90:10 tubes were tested in vitro for water uptake and mass loss and compared with collagen sheets. The water uptake of the PLGA tubes was lower, and the mass loss was more rapid and higher than those of the collagen sheets when immersed in phosphate-buffered saline (PBS) solution. The pH values of immersing PBS did not change after soaking the collagen sheets and showed to be around 7.4. On the other hand, the pH values of PBS after soaking PLGA tubes decreased gradually during 10 days reaching values around 3.5. For the in vivo testing, 22 Sasco Sprague adult rats were divided into four groups--group 1: gap not reconstructed; group 2: gap reconstructed using an autologous nerve graft; group 3: gap reconstructed with PLGA 90:10 tube guides; group 4: gap reconstructed with PLGA 90:10 tube guides covered with neural cells differentiated in vitro. Motor and sensory functional recovery was evaluated throughout a healing period of 20 weeks using sciatic functional index, static sciatic index, extensor postural thrust, withdrawal reflex latency, and ankle kinematics. Stereological analysis was carried out on regenerated nerve fibers. Both motor and sensory functions improved significantly in the three experimental nerve repair groups, although the rate and extent of recovery was significantly higher in the group where the gap was reconstructed using the autologous graft. The presence of neural cells covering the inside of the PLGA tube guides did not make any difference in the functional recovery. By contrast, morphometric analysis showed that the introduction of N1E-115 cells inside PLGA 90:10 tube guides led to a significant lower number and size of regenerated nerve fibers, suggesting thus that this approach is not adequate for promoting peripheral nerve repair. Further studies are warranted to assess the role of other cellular systems as a foreseeable therapeutic strategy in peripheral nerve regeneration. PMID- 18447636 TI - Prevalence and molecular characterization of alpha-thalassemia syndromes among Indians. AB - OBJECTIVE: This study was undertaken to determine the prevalence and molecular basis of alpha-thalassemia in the Indian population and its implications in genetic counseling and prenatal diagnosis. METHODS: 1253 random samples were screened for hemoglobinopathies. Red cell indices were measured on the Sysmex K 1000 cell counter; HbA2 and HbF levels were quantitated using high performance liquid chromotography (HPLC). Cellulose acetate electrophoresis and isoelectric focusing (IEF) was done to detect the presence of Hb Bart's in cord blood samples. alpha-Globin gene mapping was done using Southern blot hybridization of BamHI and BglII digests. RESULTS: Of the 1253 subjects, 132 had a single alpha gene deletion (10.5%) while 29 had two alpha-gene deletions (2.31%). Fifteen cases showed the presence of alpha-gene triplication (1.1%). A single case showed the presence of one alpha-gene deletion as well as alpha-gene triplication ( alpha/alphaalphaalpha). Overall, the prevalence of alpha-thalassemia was 12.9%. Region-wise and caste-wise analysis showed the highest prevalence of alpha thalassemia among the Punjabi population originating from the northern region of India. CONCLUSION: alpha-Thalassemia is by far the commonest hemoglobinopathy in India, but it is not a cause of serious genetic risk is the milder form ( alpha/alphaalpha) of alpha-thalassemia, which is predominant. Knowing the alpha genotype is useful for genetic counseling for prenatal diagnosis in couples where one of the parents may have reduced indices coupled with a raised RBC count and normal HbA2 levels. PMID- 18447637 TI - Conversion potential of marrow cells into lung cells fluctuates with cytokine induced cell cycle. AB - Green fluorescent protein (GFP)-labeled marrow cells transplanted into lethally irradiated mice can be detected in the lungs of transplanted mice and have been shown to express lung-specific proteins while lacking the expression of hematopoietic markers. We have studied marrow cells induced to transit the cell cycle by exposure to interleukin-3 (IL-3), IL-6, IL-11, and Steel factor at different times of culture corresponding to different phases of cell cycle. We have found that marrow cells at the G(1)/S interface of the cell cycle have a three-fold increase in cells that assume a nonhematopoietic or pulmonary epithelial cell phenotype and that this increase is no longer seen in late S/G(2). These cells have been characterized as GFP(+) CD45(-) and GFP(+) cytokeratin(+). Thus, marrow cells with the capacity to convert into cells with a lung phenotype after transplantation show a reversible increase with cytokine induced cell cycle transit. Previous studies have shown that the phenotype of bone marrow stem cells fluctuates reversibly as these cells traverse the cell cycle, leading to a continuum model of stem cell regulation. The present study indicates that marrow stem cell production of nonhematopoietic cells also fluctuates on a continuum. PMID- 18447638 TI - Unrestricted somatic stem cells from human umbilical cord blood can be differentiated into neurons with a dopaminergic phenotype. AB - Recently, it has been shown that human unrestricted somatic stem cells (USSCs) from umbilical cord blood represent pluripotent, neonatal, nonhematopoietic stem cells with the potential to differentiate into the neural lineage. However, molecular and functional characterization of the neural phenotype and evaluation of the degree of maturity of the resulting cells are still lacking. In this study, we addressed the question of neuronal differentiation and maturation induced by a defined composition of growth and differentiation factors (XXL medium). We demonstrated the expression of different neuronal markers and their enrichment in USSC cultures during XXL medium incubation. Furthermore, we showed enrichment of USSCs expressing tyrosine hydroxylase (TH), an enzyme specific for dopaminergic neurons and other catecholamine-producing neurons, accompanied by induction of Nurr1, a factor regulating dopaminergic neurogenesis. The functionality of USSCs has been analyzed by patch-clamp recordings and high performance liquid chromatography (HPLC). Voltage-gated sodium-channels could be identified in laminin-predifferentiated USSCs. In addition, HPLC analysis revealed synthesis and release of the neurotransmitter dopamine by USSC-derived cells, thus correlating well with the detection of TH transcripts and protein. This study provides novel insight into the potential of unrestricted somatic stem cells from human umbilical cord blood to acquire a neuronal phenotype and function. PMID- 18447639 TI - Mouse embryonic stem cell-derived spheres with distinct neurogenic potentials. AB - Mouse embryonic stem (ES) cells grown in feeder-free suspension cultures in the presence of leukemia inhibitory factor (LIF) and basic fibroblast growth factor (bFGF) form spheres that retain pluripotency after multiple passages. ES cell derived spheres of any passage acquired increased competence to differentiate into neurons over time in culture. Eight-day-old spheres produced many neurons upon plating in differentiation conditions whereas 3-day-old spheres produce none, even after monolayer expansion or treatment with blockers of inhibitory signals, indicating the acquisition of a reversible, proto-neurogenic state during sphere development. Gene expression profiling with oligonucleotide microarrays was used to identify the transcriptional changes accompanying this process. Sphere growth was characterized by down-regulation of a subset of ES cell-expressed genes during the first few days of sphere formation, and progressive up-regulation of novel genes over the course of 1 week in culture. Differential gene expression between 3-day-old and 8 day-old spheres was verified by quantitative real-time PCR experiments. Gene Set Enrichment Analysis (GSEA) of microarray data indicated that neurogenic potential in the late stages of sphere development correlated predominantly with up-regulation of pathways related to mitochondrial function, cell metabolism, oxidative stress, hypoxia, and down regulation of RNA transcription and proteasome machineries, as well as pathways induced by myc and repressed by retinoic acid. We propose that differences in cellular metabolic state brought about by cell-cell contact and paracrine interactions in the sphere niche may play crucial roles in biasing the early stages of ES cell differentiation toward a neuronal phenotype. PMID- 18447640 TI - Characterization of a mesenchymal-like stem cell population from osteophyte tissue. AB - Osteophytes are a distinct feature of osteoarthritis (OA). Their formation may be related to pluripotential cells in the periosteum responding to stimulus during OA. This study aimed to isolate stem cells from osteophyte tissues and to characterize their phenotype, proliferation, and differentiation potential, as well as their immunomodulatory properties. Osteophyte-derived cells were isolated from osteophyte tissue samples collected during knee replacement surgery. These cells were characterized by the expression of cell-surface antigens, differentiation potential into mesenchymal lineages, growth kinetics, and modulation of alloimmune responses. Multipotential stem cells were identified from all osteophyte samples, namely osteophyte-derived mesenchymal stem cells (oMSCs). The surface antigen expression of oMSCs was consistent with that of MSCs; they lacked the hematopoietic and common leukocyte markers (CD34, CD45) while expressing those related to adhesion (CD29, CD166, CD44) and stem cells (CD90, CD105, CD73). The proliferation capacity of oMSCs in culture was superior to that of bone marrow-derived MSCs (bMSCs), and these cells readily differentiated into tissues of the mesenchymal lineages. oMSCs also demonstrated the ability to suppress allogeneic T cell proliferation, which was associated with the expression of the tryptophan-degrading enzyme indoleamine 2,3 dioxygenase (IDO). Our results showed that osteophyte-derived cells had similar properties to MSCs in the expression of antigen phenotype, differential potential, and suppression of alloimmune response. Furthermore, when compared to bMSCs, oMSCs maintained a higher proliferative capacity, which may offer new insights of the tissue formation and potentially an alternative source for therapeutic stem cell-based tissue regeneration. PMID- 18447641 TI - Whole-blastocyst culture followed by laser drilling technology enhances the efficiency of inner cell mass isolation and embryonic stem cell derivation from good- and poor-quality mouse embryos: new insights for derivation of human embryonic stem cell lines. AB - The optimization of human embryonic stem (hES) cell line derivation methods is challenging because many worldwide laboratories have neither access to spare human embryos nor ethical approval for using supernumerary human embryos for hES cell derivation purposes. Additionally, studies performed directly on human embryos imply a waste of precious human biological material. In this study, we developed a new strategy based on the combination of whole-blastocyst culture followed by laser drilling destruction of the trophoectoderm for improving the efficiency of inner cell mass (ICM) isolation and ES cell derivation using murine embryos. Embryos were divided into good- and poor-quality embryos. We demonstrate that the efficiency of both ICM isolation and ES cell derivation using this strategy is significantly superior to whole-blastocyst culture or laser drilling technology itself. Regardless of the ICM isolation method, the ES cell establishment depends on a feeder cell growth surface. Importantly, this combined methodology can be successfully applied to poor-quality blastocysts that otherwise would not be suitable for laser drilling itself nor immunosurgery in an attempt to derive ES cell lines due to the inability to distinguish the ICM. The ES cell lines derived by this combined method were characterized and shown to maintain a typical morphology, undifferentiated phenotype, and in vitro and in vivo three germ layer differentiation potential. Finally, all ES cell lines established using either technology acquired an aneuploid karyotype after extended culture periods, suggesting that the method used for ES cell derivation does not seem to influence the karyotype of the ES cells after extended culture. This methodology may open up new avenues for further improvements for the derivation of hES cells, the majority of which are derived from frozen, poor quality human embryos. PMID- 18447642 TI - Regulation of Sox2 by STAT3 initiates commitment to the neural precursor cell fate. AB - STAT3, a member of the signal transducer and activator or transcription (STAT) family of proteins, plays a major role in gliogenesis; however, its functions during differentiation of neural precursor cells (NPCs) are unclear. Our data demonstrate that STAT3 is present and active in the developing mouse central nervous system (CNS) as early as E7.5, several days prior to gliogenesis. We hypothesize that STAT3 is functioning very early in neural development to regulate NPC differentiation. To test this hypothesis, STAT3 dominant negative embryonic stem (ES) cells were generated and subjected to neural differentiation. The loss of STAT3 resulted in production of significantly fewer NPCs along with decreased expression of the neural stem cell marker nestin. Further investigation revealed the existence of a novel signaling pathway during early neural development in which STAT3 directly regulates the Sox2 promoter leading to Sox2 expression and subsequent nestin expression and commitment to the NPC fate. PMID- 18447643 TI - Promoter-dependent EGFP expression during embryonic stem cell propagation and differentiation. AB - Genetic modification is an important tool in embryonic stem (ES) cell research and requires efficient promoter systems. Here, we have compared the transcriptional activities of three ubiquitous promoters, elongation factor 1alpha (EF1alpha), phosphoglycerate kinase-1 (PGK), and cytomegalovirus (CMV), during propagation and differentiation of mouse (m) ES cells by using stable mES cell lines expressing enhanced green fluorescent protein (EGFP) under each of these promoters. In undifferentiated ES cells, the EGFP expression driven by the EF1alpha was most stable, followed by the PGK, whereas the down-regulation of EGFP expression driven by the CMV promoter was most significant during propagation up to passage 35. A similar pattern for the activities of these promoters was observed in embryoid bodies (EBs) during 14 days of differentiation, with brighter EGFP signals driven by the EF1alpha promoter versus the other two. Moreover, the EF1alpha and PGK promoters, but not CMV, were effective in almost all mES cell-differentiated neuronal cells, cardiomyocytes, and visceral endoderm cells, with the fluorescent signal intensity higher for EF1alpha and even for PGK. The CMV promoter yielded a weak fluorescent signal in about 60-80% of these differentiated cells, while a few differentiated cells with the CMV promoter showed bright EGFP expression like that with the EF1alpha promoter. These results extend previous observations for the activities of these promoters in mES cells and provide new information for choosing appropriate promoters to facilitate genetic modification of mES cells. PMID- 18447644 TI - Long-term maintenance of donor-derived hematopoiesis by intra-bone marrow-bone marrow transplantation. AB - The long-term maintenance of hematopoietic stem cells (HSCs) is assessed by serial bone marrow transplantation (BMT), in which HSCs are injected intravenously. Recently, we have found that intra-bone marrow (IBM)-BMT can efficiently reconstitute the hematopoietic system with cells of donor origin, in contrast to conventional intravenous (i.v.) BMT. In the present study, we have compared the long-term maintenance of HSCs using multiple rounds of serial i.v. BMT and IBM-BMT. The frequencies of donor-derived progenitor cells (Lin(-)/c kit(+) cells) and more primitive progenitors (Lin(-)/c-kit(+)/CD34(+)/Sca-1(+) cells) were higher in the tertiary recipients by serial IBM-BMT than in those that had received bone marrow cells by serial i.v.-BMT. Furthermore, neither donor-derived progenitor cells nor mature hematolymphoid cells were detected in approximately 25% of the tertiary recipients after serial i.v.-BMT, indicating that progenitor cells can be efficiently maintained by IBM-BMT but not by i.v. BMT. Finally, we confirmed that the recipients treated with the primary IBM-BMT (without carrying out serial BMT) showed a significantly higher survival rate than those treated with i.v.-BMT. These findings clearly show that IBM-BMT efficiently promotes the longterm maintenance of donor-derived hematopoiesis. PMID- 18447645 TI - Distribution of murine adipose-derived mesenchymal stem cells in vivo following transplantation in developing mice. AB - Systemic delivery of mesenchymal stem cells (MSCs) or stromal cells in vivo is attractive because it offers means of disseminating therapeutic cells to various tissues and organs in vivo. In the present study, we investigated the distribution and engraftment of the murine adipose-derived mesenchymal stem cells (ADSCs) without exposure to or exposed to bone microenvironment or transforming growth factor-beta1 (TGF-beta1) prior to transplantation into developing mice. The ADSCs harvested from the murine inguinal fat pad exhibited potential for differentiation toward osteogenic and adipogenic cell lineages in vitro. Fourteen days after systemic transplantation of the ADSCs marked with enhanced green fluorescent protein (EGFP) into developing mice, minimal donor GFP(+) cells were detected in the skeletal tissues in a limited number of the recipient mice. Exposure of the ADSCs to bone microenvironment for 7 or 14 days prior to transplantation into developing mice enhanced their migration and survival in the bones of the recipient mice. Exposure of ADSCs to TGF-beta1 prior to systemic transplantation exerted similar effects on cell migration and engraftment in various tissues, including the bones of the recipient developing mice. At 28 days following systemic transplantation, the ADSCs exposed to bone microenvironment were restricted mostly to the skeletal tissues of the recipient mice. Donor cells retrieved from the bones of the recipient mice at 28 days following cell transplantation expressed the differentiation markers Runx2 and Osterix (Osx). These data suggest that exposure of ADSCs to bone microenvironment or to TGF beta1 prior to transplantation enhances their survival in the skeletal tissues following transplantation. PMID- 18447646 TI - An inducible transgene expression system for regulated phenotypic modification of human embryonic stem cells. AB - Self-renewing pluripotent human embryonic stem (hES) cells are capable of regenerating such non-dividing cells as neurons and cardiomyocytes for therapies and can serve as an excellent experimental model for studying early human development. Both the spatial and temporal relationships of gene expression play a crucial role in determining differentiation; to obtain a better understanding of hES cell differentiation, it will be necessary to establish an inducible system in hES cells that enables specific transgene(s) to reversibly and conditionally express (1) at specific levels and (2) at particular time points during development. Using lentivirus (LV)-mediated gene transfer and a tetracycline-controlled trans-repressor (TR), we first established in hES cells a doxycycline (DOX)-inducible expression system of green fluorescent protein (GFP) to probe its reversibility and kinetics. Upon the addition of DOX, the percentage of GFP(+) hES cells increased time dependently: The time at which 50% of all green cells appeared (T(50)(on)) was 119.5+/-3.2 h; upon DOX removal, GFP expression declined with a half-time (T(50)(off)) of 127.7+/-3.9 h and became completely silenced at day 8. Both the proportion and total mean fluorescence intensity (MFI) were dose-dependent (EC(50)=24.5+/-2.2 ng/ml). The same system when incorporated into murine (m) ES cells similarly exhibited reversible dose dependent responses with a similar sensitivity (EC(50)=49.5+/-8.5 ng/ml), but the much faster kinetics (T(50)(on)=35.5+/-5.5 h, T(50)(off) = 71.5+/-2.4 hours). DOX induced expression of the Kir2.1 channels in mES and hES cells led to robust expression of the inwardly rectifying potassium (K(+)) current and thereby hyperpolarized the resting membrane potential (RMP). We conclude that the LV inducible system established presents a unique tool for probing differentiation. PMID- 18447647 TI - Selective POTE paralogs on chromosome 2 are expressed in human embryonic stem cells. AB - POTE is a primate-specific gene family that encodes cancer testis antigens that contain three domains, although the proteins vary greatly in size. The amino terminal domain is novel and has three cysteine-rich domains of 37 amino acids. The second and third domains are rich in ankyrin repeats and spectrin-like helices respectively. In humans, 13 highly homologous paralogs are dispersed among eight chromosomes. Some members of the POTE gene family have an actin insertion at the carboxyl end of the protein. The expression of the POTE gene in normal adult tissues is restricted, but several POTE paralogs are frequently expressed in many cancers including breast, prostate, and lung cancers. We show here that POTE is expressed in several human embryonic stem (ES) cell lines. We found that UC06, WA01 and ES03 cell lines express mainly a POTE-2gamma transcript but ES02 and ES04 cell lines predominantly express POTE-2alpha. The WA09 cell line expressed both POTE-2gamma and POTE-2alpha. There is no detectable POTE gene expression in fetal tissues (ages 16-36 weeks). The POTE paralogs that are expressed in ES cells may have a specific function during lineage-specific differentiation of ES cells. PMID- 18447648 TI - Phenotypic and morphological characterization of in vitro oligodendrogliogenesis. AB - The neurosphere assay has been used to maintain neural progenitor cells (NPCs) in the undifferentiated state. These cells are multipotent and gave rise to neurons and glial cells. Here we show that within 10 days of culture, neurospheres contained precursors and differentiated progeny of all three major central nervous system (CNS) cell lineages and these occupied distinct zones. The microenvironment of the inner zone supported cell differentiation. Cells of oligodendroglial lineage generated within the neurosphere were frequently observed. Of these cells, A2B5(+) cells were homogeneously distributed in the neurospheres, NG2(+) cells preferentially occupied the outer zone and O4(+) cells were localized at the inner zone of 10 day-old neurospheres. We prevented a massive cell death of dissociated neurosphere cells seen after differentiation triggered with adhesion and fetal calf serum by adding epidermal growth factor and basic fibroblast growth factor to the culture medium. Under these conditions, less than one third of cells did not express cell specific markers, glial fibrillary acidic protein-positive astroglia represented 43.4%, NG2(+) and/or O4(+) oligodendroglia represented 24.3%, and betaIII-tubulin(+) neurons 3.1% of cells recovered after neurosphere differentiation. We present evidence that oligodendroglial cells differentiate in a stepwise process as a result of their distribution in subsets that represent distinct developmental stages according to antigenic and morphological criteria. These include oligodendrocyte progenitors, preoligodendrocytes, and oligodendrocytes. The highly complex morphology of mature oligodendrocytes was compatible with functional cells. PMID- 18447650 TI - Haploinsufficiency of senescence evasion factor causes defects of hematopoietic stem cells functions. AB - The quality of hematopoietic stem cells (HSCs) is essentially defined by two characteristics, i.e., multilineage differentiation and self-renewal capacity. Thus, it is of high priority to clarify mechanisms that regulate these functions and to understand them at the molecular level. In the present study, we investigated the role of senescence evasion factor (synonymously hPrp19,hPSO4,hNMP200: SNEV), a multifunctional protein involved in pre-mRNA splicing, regulation of replicative life span, and DNA repair. Here we report that murine SNEV mRNA expression is high in lineage-depleted (Lin(-)) precursor cells of the bone marrow immediately after isolation as compared to fully differentiated peripheral blood lymphocytes (PBLs). Furthermore, the progenitor cell subset with highest colony-forming ability and self-renewal capacity (Lin( ), Sca-1(+)) showed also the highest SNEV expression. To test if the observed differences in SNEV mRNA levels cause stem cell defects, Lin(-) cells derived from heterozygous SNEV knockout mice were tested for primary as well as secondary colony-forming potential as a measure of self-renewal capacity. Interestingly, both, primary and secondary colonies were significantly less formed from SNEV(+/ ) cells, a defect that was rescued by ectopic SNEV expression. Similarly, bone marrow cells derived from the short-lived Senescence-Accelerated-Mouse-Prone (SAMP8) model showed similar differences in comparison to the aging-resistant (SAMR1) control strain. These data suggest that the expression of SNEV is closely associated with the growth of murine HSCs and determines the proliferative and repopulating capacity of phenotypically defined HSC subsets. PMID- 18447649 TI - Murine hematopoietic stem cells and multipotent progenitors express truncated intracellular form of c-kit receptor. AB - The c-kit receptor plays a vital role in self-renewal and differentiation of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). We have discovered that besides c-kit, the murine multipotent HSC/MPP-like cell line EML expresses the transcript and protein for a truncated intracellular form of c-kit receptor, called tr-kit. Notably, the tr-kit transcript and protein levels were down-regulated during cytokine-induced differentiation of the HSC/MPP-like cell line EML into myeloerythroid lineages. These findings prompted us to analyze tr kit expression in purified murine fetal liver and bone marrow cell populations containing long-term repopulating (LTR) HSCs, short-term repopulating (STR) HSCs, MPPs, lineage-committed progenitors, and immature blood cells. Remarkably, these studies have revealed that in contrast to more widespread expression of c-kit, tr kit is transcribed solely in cell populations enriched for LTR-HSCs, STR-HSCs, and MPPs. On the other hand, cell populations in which HSCs and MPPs are either present at a much lower frequency or are absent altogether, cells representing more advanced stages of differentiation into lymphoid and myeloid lineages do not express tr-kit. The observation that tr-kit is co-expressed with c-kit only in more primitive HSC- and MPP-enriched cell populations raises an exciting possibility that tr-kit functions either as a new component of the stem cell factor (SCF)/c-kit pathway or is involved in a novel signaling pathway, present exclusively in HSC and MPPs. Taken together, these findings necessitate functional characterization of tr-kit and analysis of its potential role in the self-renewal, proliferation, and/or differentiation of HSC and multipotent progenitors. PMID- 18447651 TI - Sustained macroscopic engraftment of cynomolgus embryonic stem cells in xenogeneic large animals after in utero transplantation. AB - Because embryonic stem (ES) cells are able to proliferate indefinitely and differentiate into any type of cell, they have the potential for providing an inexhaustible supply of transplantable cells or tissues. However, methods for the in vitro differentiation of human ES cells are still quite limited. One possible strategy would be to generate differentiated cells in vivo. In view of future clinical application, we investigated the possibility of using xenogeneic large animals for this purpose. We transplanted nonhuman primate cynomolgus ES cells into fetal sheep at 43-67 gestational days (full term 147 days, n=15). After birth, cynomolgus tissues, which were mature teratomas, had been engrafted in sheep when more than 1 x 10(6) ES cells were transplanted at <50 gestational days. Despite the sustained engraftment, both cellular and humoral immune responses against the ES cells were detected, and additional transplantation was not successful in the animals. At 2 weeks post-transplantation, the ES cell progeny proliferated when transplanted at 48 (<50) gestational days, whereas they were cleared away when transplanted at 60 (>50) gestational days. These results support the rapid development of the xenogeneic immunological barrier in fetal sheep after 50 gestational days. Notably, a large number of Foxp3(+) regulatory T cells were present around the ES cell progeny, but macrophages were absent when the transplant was conducted at <50 gestational days, implying that regulatory T cells and premature innate immunity might have contributed to the sustained engraftment. In conclusion, long-term macroscopic engraftment of primate ES cells in sheep is feasible despite the xenogeneic immunological barrier. PMID- 18447652 TI - Rapid single-step separation of pluripotent mouse embryonic stem cells from mouse feeder fibroblasts. AB - Highly enriched, pure populations of pluripotent mouse embryonic stem (mES) cells are a prerequisite to downstream experimental manipulations. However, the existing preplating method does not allow complete removal of co-cultured mouse embryonic fibroblast (MEF) feeder cells. The primary objective of the current investigation was to develop and validate a rapid, single-step separation technique for the complete removal of MEF feeder cells from mES cells. A discontinuous density gradient was prepared using Histopaque 1119 at incremental percentages from the top to bottom of a test tube (20, 40, 60, and 100% in culture medium). A suspension of mES cells and MEF feeder cells was layered on top of the gradient. After centrifugation at 400 x g, ES cells and MEF feeder cells were segregated discretely in separate layers at the 40/20% and 100/60% density interfaces, respectively. The mES cells were enriched to a purity of greater than 99% with a recovery rate of greater than 90%. The separation did not alter the viability or the differentiation potential of mES cells. This study validates a simple technique that enables the preparation of highly enriched mES cells that are essentially free of contaminating MEF feeder cells. The discontinuous density gradient separation method is inexpensive, efficient, rapid, and reproducible. The method can be readily scaled-up to accommodate large batch preparations, enabling a broad range of processing needs. Overall, this simple technique significantly expedites the recovery and enrichment of mES cells from MEFs. PMID- 18447653 TI - Switching statin therapy using a pharmacist-managed therapeutic conversion program versus usual care conversion among indigent patients. AB - STUDY OBJECTIVE. To evaluate the effectiveness of switching statin therapy using a therapeutic conversion program versus usual care conversion among patients enrolled in the Colorado Indigent Care Program when atorvastatin was removed from the formulary. DESIGN: Prospective cohort study. SETTING: Family medicine center and other ambulatory care clinics of a university-based health care system. PATIENTS: One hundred seventeen ambulatory care patients with dyslipidemia who were treated with atorvastatin. INTERVENTION: Clinical pharmacists in the family medicine center implemented a therapeutic conversion program (30 patients), switching atorvastatin to a new formulary regimen of simvastatin, rosuvastatin, or ezetimibe-simvastatin, using an algorithm designed to achieve patient-specific goals for low-density lipoprotein cholesterol (LDL). Usual care occurred in the other ambulatory care clinics without clinical pharmacists (87 patients), where medical providers switched atorvastatin to a formulary regimen based on a suggested (but optional) equipotency conversion algorithm. MEASUREMENTS AND MAIN RESULTS: Primary end points were LDL concentration and LDL goal attainment before and after conversion. Before and after conversion, respectively, mean LDL concentrations were 86.7 and 82.3 mg/dl in the therapeutic conversion group (p=0.44) versus 78.3 and 85.2 mg/dl in the usual care group (p=0.01). Percentages of patients attaining LDL goal were 80% before and 97% after conversion in the therapeutic conversion group (p=0.04) compared with 90% before and 75% after conversion in the usual care group (p=0.01). CONCLUSION: Use of a prospective, therapeutic statin conversion program was associated with increased control of dyslipidemia, whereas usual care statin conversion was associated with decreased control. These data suggest that proactive involvement of clinical pharmacists in converting lipid-lowering drugs results in superior patient care outcomes compared with a less aggressive approach. PMID- 18447654 TI - Dyslipidemia control in indigent patients receiving medication assistance compared with insured patients. AB - STUDY OBJECTIVES: To compare dyslipidemia management with statin-based therapy in insured patients versus indigent patients receiving medication assistance, and to determine drug therapy adherence rates in the two groups. DESIGN: Retrospective medical record review. Setting. University-based health care system. PATIENTS: Two hundred forty patients with dyslipidemia who received statin-based therapy from the outpatient pharmacies and clinical care at an affiliated clinic. MEASUREMENTS AND MAIN RESULTS: Prescription records identified 665 patients between October 1, 2004, and September 30, 2005. Forty of these patients had insurance (with a single carrier), and the remaining 625 patients received health care subsidies from the Colorado Indigent Care Program (CICP). Using a block scheme, 200 patients from the CICP were randomly extracted. The primary objective was measured by assessment of low-density lipoprotein cholesterol (LDL) goal attainment and use of a moderate-potency, lipid-lowering regimen capable of achieving an LDL level reduction of least 30%. Of a total of 240 patients who met study criteria, 26 were excluded whose records lacked LDL measurements while receiving therapy. The LDL goal was achieved in 122 (68.9%) of the 177 patients in the CICP group versus 29 (78.4%) of the 37 patients in the insured group (p=0.34). A moderate-potency, LDL-lowering regimen was used by 90.5% of 200 patients in the CICP group and 85% of 40 patients in the insured group (p=0.45). In patients classified as having moderately high, high, or very high cardiovascular risk, LDL goals were attained in 103 (67.3%) of 153 patients in the CICP group versus 16 (69.6%) of 23 patients in the insured group (p=0.83). In this higher-risk subgroup, a moderate-potency regimen was used in 162 (92.6%) of 175 patients in the CICP group versus 23 (92%) of 25 patients in the insured group (p=0.92). Among the very high-risk patients from the two groups combined, 30 (52.6%) of 57 patients achieved LDL concentrations below 70 mg/dl, and 58 (95.1%) of 61 patients were administered a moderate-potency, LDL-lowering regimen. The secondary objective, overall adherence, as assessed by the medication possession ratio, was better in the CICP group than in the insured group. CONCLUSION: Our data suggest that quality of dyslipidemia management is similar for indigent and insured populations. Overall LDL goal attainment rates were higher than those reported in the literature. Most patients with significant cardiovascular risk, including those at very high risk, were treated according to established guidelines. Adherence rates were greater for indigent patients. PMID- 18447655 TI - Effectiveness of a fenofibrate 145-mg nanoparticle tablet formulation compared with the standard 160-mg tablet in patients with coronary heart disease and dyslipidemia. AB - STUDY OBJECTIVE: To compare the effectiveness of a fenofibrate 145-mg nanoparticle tablet formulation with the standard 160-mg tablet in patients with dyslipidemia and coronary heart disease. DESIGN: Retrospective medical record review. SETTING: Outpatient university-affiliated cardiology clinic. PATIENTS: One hundred thirty patients with dyslipidemia and coronary heart disease treated for a minimum of 6 months with fenofibrate 160 mg/day (with or without 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor [statin] therapy) who were then switched to a minimum of 3 months of treatment with fenofibrate 145 mg/day. MEASUREMENTS AND MAIN RESULTS: Low-density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and triglyceride levels were compared during treatment with each formulation. In patients not taking statins, statistically significant reductions of 4.6% and 2.3%, respectively, were noted in mean triglyceride and LDL levels after the switch to fenofibrate 145 mg/day. In patients taking statins, statistically significant reductions of 5.1% and 2.8%, respectively, were observed in mean triglyceride and LDL levels. In total, a larger proportion of patients had 10% or greater improvement in LDL (14/130 [11%]) and triglyceride (32/130 [25%]) levels compared with the proportion of patients who had 10% or greater worsening in LDL (3/130 [2%]) and triglyceride (9/130 [7%]) levels, and a net additional 14 patients (11%) achieved National Cholesterol Education Program (NCEP) lipid panel targets after the switch to fenofibrate 145 mg/day. Mean HDL level was not significantly different after the switch to fenofibrate 145 mg/day. Safety parameters of fenofibrate 145-mg/day therapy were not examined, although fenofibrate 160 mg/day is generally well tolerated. CONCLUSION: Eleven percent of the patients in our study had improvements in their lipid profiles that resulted in achievement of NCEP lipid panel targets after treatment with the 145-mg nanoparticle formulation of fenofibrate. This improvement in lipid levels may have been related to increased bioavailability of the 145-mg formulation. However, the exact mechanism of the improvement in lipid levels is unknown. PMID- 18447656 TI - Comparison of scales for evaluating premenstrual symptoms in women using oral contraceptives. AB - STUDY OBJECTIVE: To compare two scales used in research to evaluate daily premenstrual mood symptoms during use of a monophasic oral contraceptive. DESIGN: Subanalysis of data from a prospective study. SETTING: University-affiliated medical center. SUBJECTS; One hundred two reproductive-aged (18-48 yrs) women taking a monophasic oral contraceptive containing ethinyl estradiol and drospirenone in the standard 21-7 fashion (21 days of hormones followed by 7 days of placebo), and who had self-identified premenstrual symptoms of headache, mood changes, or pelvic pain. INTERVENTION: Subjects completed a single-item questionnaire, the Scott & White Daily Diary of Symptoms, and a multiple-item questionnaire, the Penn State Daily Symptom Report (DSR), to assess their premenstrual symptoms. The Scott & White diary used a visual analog scale of 0-10 to assess pelvic pain, headache, and mood (a composite of anxiety, depression, and irritability). The Penn State DSR contained 17 items: 10 behavioral and seven physical components, each rated on a scale of 0-4, with one item that specifically rated mood swings. MEASUREMENTS AND MAIN RESULTS: Scores from the two scales were compared by using Spearman correlation coefficients, the Kendall W for concordance, and linear regression of ranked sums for study cycles. The Scott & White mood score significantly correlated with the total of the 17 items on the Penn State DSR, as well as the 10 behavioral items, the seven physical items, and the single mood-swing item (p<0.0001); specific coefficients of concordance were 0.44, 0.23, 0.10, and 0.28, respectively, and R2 values were 0.39, 0.39, 0.30, and 0.34, respectively. The daily Scott & White mood score was positively correlated with all 17 elements of the Penn State DSR (0.25-0.57). The greatest correlation was seen with the mood-swing element. Both instruments demonstrated the same patterns during the 21-7 oral contraceptive cycle, with symptoms increasing immediately before and peaking during the 7-day hormone-free interval. CONCLUSION: A single-item daily mood score using a rating scale of 0-10 was concordant with a relatively complex 17-element symptom index and demonstrated the same pattern of change during cycles of oral contraception. The simple scoring system offers an advantage, especially in clinical studies of long duration. PMID- 18447657 TI - Research publication by pharmacist authors in major medical journals: changes over a 10-year interval. AB - STUDY OBJECTIVE: To determine the degree to which pharmacists were involved in major clinical research publications in 1993 and 2003, and to compare the difference in publication rates by pharmacists between these 2 years. DESIGN: Retrospective analysis. DATA SOURCE: Thirty-seven medical journals that had high readership, had a focus on original research, were clinically oriented, and were highly regarded by the research community. MEASUREMENTS AND MAIN RESULTS: Selection of the medical journals was first determined by those having the highest impact factors. Then journals with regular publication of original clinical research and listings of authors' degrees or licensure were included. All original research articles in these journals were reviewed for both 1993 and 2003. The primary outcome was the presence of a pharmacist as an author of one of their research articles in each of those 2 years. For those articles, the following data were collected: study subjects, study design, authors' affiliations, source of research funding, and position of author (first and/or corresponding). The primary outcome was analyzed by using multivariate logistic regression analysis. Other outcomes were compared between 1993 and 2003 by using a chi(2) test. The number of clinical research articles identified was 8127 in 1993 and 8793 in 2003. The median (mean, interquartile range) number of authors/article increased from 5 (5.3, 3-7) in 1993 to 6 (6.6, 4-8) in 2003 (p<0.01). There were 191 pharmacist-authored papers (2.4%) in 1993, compared with 271 (3.1%) in 2003, for a relative increase of 29.2%. Adjusting for the increase seen in the number of authors during that period, the odds ratio that a pharmacist was an author in 2003 compared with 1993 was 1.26 (95% confidence interval 1.04-1.53). Most (94.2%) pharmacist-authored papers described studies involving human subjects. The proportion of clinical pharmacists (but not the number) serving as the primary author declined over time, from 36.6% (70/191) in 1993 to 27.3% (74/271) in 2003 (p=0.041). The most frequent funding sources were industry (from 38.2% in 1993 to 39.5% in 2003) and federal (from 25.1% in 1993 to 31.4% in 2003); however, the differences were not statistically significant. CONCLUSIONS: An increase was noted in the proportion of publications involving pharmacists as an author in major medical journals in 2003 compared with 1993. Pharmacists must continue to be active in clinical research, with adequate training and funding remaining significant obstacles. PMID- 18447658 TI - Lack of an effect of body mass on the hemodynamic response to arginine vasopressin during septic shock. AB - STUDY OBJECTIVE: To determine whether body mass alters the effectiveness of a fixed-dose infusion of arginine vasopressin. DESIGN: Retrospective medical record review. SETTING: All intensive care units of a tertiary medical center. PATIENTS: Sixty-six mechanically ventilated patients who received a fixed-dose intravenous infusion of arginine vasopressin at 0.04 U/minute as the sole agent for hemodynamic support during septic shock. MEASUREMENTS AND MAIN RESULTS: Patients were divided into four groups on the basis of body mass index. Effectiveness was measured as hemodynamic stability, which was defined as the proportion of patients achieving a mean arterial pressure (MAP) of 65 mm Hg or higher, the magnitude of the change in MAP at 1 hour, and the need for additional rescue vasopressors. Secondary outcomes included mortality and length of stay. Baseline characteristics of all four groups were comparable for age, sex, and severity of illness determined by using Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology II (SAPS II), and Sequential Organ Failure Assessment (SOFA) scores. The only significant differences in baseline characteristics among the groups were in their central venous pressures. The four groups similarly achieved hemodynamic stability at 1 hour after the administration of arginine vasopressin (p=0.41). We observed no significant differences among groups in the magnitude of MAP change (p=0.62), need for rescue catecholamine vasopressors (p=0.17), 28-day mortality rates (p=0.31), or length of stay in the intensive care unit (p=0.43). CONCLUSION: Body mass index did not alter the effects of arginine vasopressin on hemodynamic stability or changes in MAP when the drug was administered as a fixed-dose infusion of 0.04 U/minute. Our results do not support weight-based dosing of vasopressin, unlike the dosing for catecholamine vasopressors. PMID- 18447659 TI - Amino Acid requirements in critically ill patients with acute kidney injury treated with continuous renal replacement therapy. AB - Acute kidney injury in critically ill patients is often a complication of an underlying condition such as organ failure, sepsis, or drug therapy. In these patients, stress-induced hypercatabolism results in loss of body cell mass. Unless nutrition support is provided, malnutrition and negative nitrogen balance may ensue. Because of metabolic, fluid, and electrolyte abnormalities, optimization of nutrition to patients with acute kidney injury presents a challenge to the clinician. In patients treated with conventional intermittent hemodialysis, achieving adequate amino acid intake can be limited by azotemia and fluid restriction. With the use of continuous renal replacement therapy (CRRT), however, better control of azotemia and liberalization of fluid intake allow amino acid intake to be maximized to support the patient's metabolic needs. High amino acid doses up to 2.5 g/kg/day in patients treated with CRRT improved nitrogen balance. However, to our knowledge, no studies have correlated increased amino acid intake with improved outcomes in critically ill patients with acute kidney injury. Data from large, prospective, randomized, controlled trials are needed to optimize the dosing of amino acids in critically ill patients with acute kidney injury who are treated with CRRT and to study the safety of high doses and their effects on patient morbidity and survival. PMID- 18447660 TI - Current options in antifungal pharmacotherapy. AB - Infections caused by yeasts and molds continue to be associated with high rates of morbidity and mortality in both immunocompromised and immunocompetent patients. Many antifungal drugs have been developed over the past 15 years to aid in the management of these infections. However, treatment is still not optimal, as the epidemiology of the fungal infections continues to change and the available antifungal agents have varying toxicities and drug-interaction potential. Several investigational antifungal drugs, as well as nonantifungal drugs, show promise for the management of these infections. PMID- 18447661 TI - Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. AB - Diabetic neuropathy is one of the most common long-term complications in patients with diabetes mellitus, with a prevalence of 60-70% in the United States. Treatment options include antidepressants, anticonvulsants, tramadol, and capsaicin. These agents are modestly effective for symptomatic relief, but they do not affect the underlying pathology nor do they slow progression of the disease. Epalrestat is an aldose reductase inhibitor that is approved in Japan for the improvement of subjective neuropathy symptoms, abnormality of vibration sense, and abnormal changes in heart beat associated with diabetic peripheral neuropathy. Unlike the current treatment options for diabetic neuropathy, epalrestat may affect or delay progression of the underlying disease process. Data from experimental studies indicate that epalrestat reduces sorbitol accumulation in the sciatic nerve, erythrocytes, and ocular tissues in animals, and in erythrocytes in humans. Data from six clinical trials were evaluated, and it was determined that epalrestat 50 mg 3 times/day may improve motor and sensory nerve conduction velocity and subjective neuropathy symptoms as compared with baseline and placebo. Epalrestat is well tolerated, and the most frequently reported adverse effects include elevations in liver enzyme levels and gastrointestinal-related events such as nausea and vomiting. Epalrestat may serve as a new therapeutic option to prevent or slow the progression of diabetic neuropathy. Long-term, comparative studies in diverse patient populations are needed for clinical application. PMID- 18447662 TI - Prazosin for the treatment of posttraumatic stress disorder sleep disturbances. AB - An estimated 70-87% of patients who suffer from posttraumatic stress disorder (PTSD) experience sleep disruption. These patients have distressing dreams or nightmares in which the traumatic event is reexperienced, and they also have difficulty in falling or staying asleep. Selective serotonin reuptake inhibitors are the treatment of choice for PTSD, but with the exception of fluvoxamine, they are often ineffective or only partially effective for sleep problems. Sedative hypnotics may be helpful in the short term but are associated with tolerance and addiction potential. In the central nervous system, alpha(1)-adrenergic receptors are known to be important in both the startle and sleep responses. Stimulation of these receptors may contribute to PTSD-related trauma-content nightmares. Prazosin, a highly lipophilic alpha(1)-adrenergic receptor blocker that is traditionally used to treat hypertension and benign prostatic hyperplasia, has been shown to decrease the occurrence of trauma nightmares in both combat veterans and patients with non-combat-related PTSD. The available data, although mostly from open-label trials, suggest that this agent also improves sleep quality and patients' sense of wellbeing and ability to function in daily activities. The optimum dose is unknown; however, a dose-related response appears to be evident. Clinicians should monitor for orthostatic hypotension, usually seen early in therapy, when prazosin is started in patients with PTSD. PMID- 18447663 TI - Osteonecrosis of the jaw in patients receiving intravenous or oral bisphosphonates. AB - To identify potential risk factors for the development of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates, we conducted a MEDLINE search. We identified 44 English-language published case reports and case series describing 481 patients with bisphosphonate-related ONJ. Our review of these reports indicated that ONJ occurs more frequently in patients receiving intravenous bisphosphonates (453 patients [94.2%]) than in patients receiving oral bisphosphonates (28 patients [5.8%]). Most patients who developed ONJ had cancer (451 patients [93.8%]), with multiple myeloma being the most common diagnosis, followed by breast, prostate, and lung cancers. Nearly one third of patients had a history of glucocorticoid use. The inciting event (reported in 449 patients) preceding the diagnosis of ONJ was a tooth extraction or other surgical or invasive dental procedure in 309 patients (68.8%), whereas 93 patients (20.7%) developed ONJ spontaneously. Guidelines for the prevention and treatment of bisphosphonate-associated ONJ have been developed but are largely based on anecdotal evidence. Patients receiving bisphosphonates must be counseled on the risks and benefits of therapy. Further studies will help to elucidate the pathophysiology, frequency, and risk factors for development of bisphosphonate associated ONJ. PMID- 18447664 TI - Nonbloody, red stools from coadministration of cefdinir and iron-supplemented infant formulas. AB - Cefdinir is an extended-spectrum, third-generation cephalosporin that may be used for treatment of acute otitis media in patients allergic to penicillin. When administered with iron-containing products, including infant formulas, cefdinir or one of its metabolites may bind to ferric ions, forming a nonabsorbable complex that imparts a reddish color to the stool. We describe a 9-month-old infant with failure to thrive and acute otitis media who developed an erythematous maculopapular rash during treatment with amoxicillin-clavulanate. His antibiotic therapy was changed to cefdinir. Five days into a 10-day course of therapy, the infant's mother brought him to the pediatric clinic and reported the appearance of red stools. He had no associated gastrointestinal symptoms (vomiting, abdominal pain, or diarrhea). His hematocrit and hemoglobin level were normal, and Clostridium difficile antigen studies and tests for species of Shigella, Salmonella, and Camphylobacter as well as ova and parasites were all negative. Cefdinir was discontinued, and his stools returned to normal within 48 hours. Three weeks later, he again received cefdinir for recurrent otitis media. Red stools reappeared 48 hours later, were determined to be guaiac negative, and resolved within hours of drug discontinuation. During both occurrences of red stools, the infant had been breastfed and was receiving supplemental feedings with an iron-containing infant formula. In the product labeling of cefdinir, this adverse event is described as a consequence of the drug-drug interaction; however, it is not listed in the adverse drug reaction section of the labeling. As such, one may miss the association between cefdinir and reddish stools when investigating this event as a potential adverse reaction to cefdinir. When using the Naranjo adverse drug reaction probability scale to assess causality in our patient's case, this adverse drug reaction was determined as highly probable. As this infant had been breastfed, the use of a supplemental iron-containing infant formula was not identified as a potential contributing factor until the second occurrence of red stools. Health care professionals should review the entire product labeling, including the drug-drug interaction section, when investigating a potential adverse drug reaction. With the recent approval of generic formulations of cefdinir, clinicians should be aware of this drug-drug interaction with iron-containing products to prevent unnecessary alarm by parents and caregivers, as well as costly medical evaluations for gastrointestinal bleeding. PMID- 18447665 TI - Severe hypoglycemia from clarithromycin-repaglinide drug interaction. AB - Many drugs have been reported to interact with repaglinide in patients with type 2 diabetes mellitus, resulting in hypoglycemia. However, to our knowledge, an interaction between clarithromycin and repaglinide in these patients has not been previously reported. We describe an 80-year-old man with end-stage renal disease and well-controlled type 2 diabetes (hemoglobin A1c < 7%) who was hospitalized for treatment of severe hypoglycemia. He had been receiving repaglinide 0.5 mg 3 times/day for the previous 2 years. Clarithromycin 500 mg twice/day had been started for Helicobacter pylori infection several days before admission. Within 48 hours of starting the drug, he developed severe hypoglycemia, which resolved with intravenous glucose administration. However, 48 hours later, the patient again experienced hypoglycemia and was unresponsive. Intravenous glucose administration again resolved the problem. Repaglinide was discontinued, and no further hypoglycemic episodes occurred. Clinicians should be aware of this possible clarithromycin-repaglinide interaction; in particular, in elderly patients with type 2 diabetes who are taking repaglinide and begin clarithromycin therapy, blood glucose levels should be monitored closely for potential dosage adjustment of repaglinide. PMID- 18447666 TI - Demographics of abusive head trauma. PMID- 18447667 TI - Demographics of abusive head trauma in the Commonwealth of Pennsylvania. AB - OBJECT: The aim of this study was to characterize the prevalence and demographic features of abusive head trauma (AHT) among infants and children < 36 months of age in Pennsylvania. METHODS: The authors included all cases of substantiated AHT involving children < 36 months of age in Pennsylvania between 1996 and 2002 that had been reported to a statewide registry. Demographic information was derived from child abuse reports and birth certificates; the study cohort was contrasted with all infants born in Pennsylvania during the same period. RESULTS: The study identified 327 cases. The incidence was 14.7 cases (95% confidence interval 13.1 16.5) per 100,000 person-years for the first 2 years of life with a higher incidence during the 1st year (26.0 cases per 100,000 person-years) than the 2nd year (3.4 cases per 100,000 person-years). The incidence was similar among metropolitan, non-metropolitan, and rural counties. Significantly more cases occurred during the holiday months (October-December). The median age of victims was 4.1 months. Both victims and perpetrators were more commonly male (58.4% of victims, and 70% of identified perpetrators). Compared with the entire population of Pennsylvania parents, the parents of the study cohort were more likely to be younger, less educated, and unmarried. Both mothers and fathers were more often African-American and fathers more often Hispanic. Finally, mothers more often smoked during pregnancy, sought prenatal care later in the pregnancy, and delivered low birth weight infants. CONCLUSIONS: This population-based study of abusive head injuries throughout an entire state adds significantly to the growing knowledge about this condition. The results suggests that families of infants with abusive head injuries have significantly different demographic features compared with the general population, although which of these variables is independently significant cannot be ascertained from this study and require further investigation. PMID- 18447668 TI - Management of lumbar shunt site swelling in children. AB - OBJECT: The aim of this study was to define the origin and management of lumbar shunt site swelling/cerebrospinal fluid (CSF) leak seen in children who underwent placement of a percutaneous lumbar shunt due to recurrent problems with a ventricular shunt. METHODS: Fifty-seven children with a lumbar shunt were analyzed. Episodes of swelling along the lumbar shunt site, presenting symptoms, origin of the CSF leak, and surgical outcome were recorded. RESULTS: Twenty patients had 30 episodes of CSF leak/swelling at a mean interval of 92 +/- 233 days (+/- standard deviation) after placement or revision. There were 7 episodes of an external CSF leak; 5 of marked swelling; and 18 episodes of headache, dizziness, and swelling. In 4 patients, the cause of CSF leakage was a fracture/disconnection or dislocation of the proximal catheter. In the remaining patients, CSF leakage was from around the proximal catheter entry point into the spinal dura (with a rate of 16.9% for placement and 15.7% for revision/reinsertion). Interlaminar removal of the existing catheter, microsurgical repair of the leak, and replacement through an opening made with the stylet of a 14-gauge Tuohy needle (Medtronic Neurosurgery) was most effective compared with percutaneous blood patch, pericatheter fascial suture, and percutaneous repositioning of the proximal catheter or downgrading valve pressure. CONCLUSIONS: Lumbar shunt site swelling is predominantly a consequence of pericatheter CSF leakage from the mismatch in the dural opening, which corresponds to the outer diameter of the 14-gauge Tuohy needle and the smaller proximal lumbar catheter. It is best managed by direct repair of the defect through a microsurgical interlaminar approach and recannulation of the dura by using only the stylet of a 14-gauge Tuohy needle. PMID- 18447669 TI - Toward reducing shunt placement rates in patients with myelomeningocele. AB - OBJECT: The prevalence of shunt-dependent hydrocephalus in patients with myelomeningocele has been reported to be in the region of 85%, and shunt-related complications are a significant cause of morbidity and mortality in these patients. Since 1997 the authors have adopted a stringent policy with respect to shunt placement in patients with myelomeningocele, reserving this treatment for those with symptomatic hydrocephalus, severe ventricular dilation at the time of presentation, and/or unequivocal progressive ventriculomegaly after primary closure. They report their experience. METHODS: The authors reviewed all cases of myelomeningocele involving patients who presented to their institution over a 10 year period. They excluded cases in which the primary closure was carried out at another institution or in which there was not at least 12 months of clinical and imaging follow-up. Data regarding shunt insertion shunt-related complications, and clinical outcome were obtained from a review of the clinical records and analyzed. RESULTS: Fifty-four cases satisfied the inclusion criteria for this study. Shunt insertion was performed in 28 of these cases (51.9%). CONCLUSIONS: Applying more stringent guidelines for shunt placement, permitting moderate ventricular dilation, and accepting some mild increase in ventricular size after myelomeningocele closure has resulted in a reduced rate of shunt placement compared with previous series. The rate is comparable to that reported following in utero closure of myelomeningocele. PMID- 18447670 TI - Cerebrospinal fluid shunt infections in children over a 13-year period: anaerobic cultures and comparison of clinical signs of infection with Propionibacterium acnes and with other bacteria. AB - OBJECT: Shunt infections represent a major problem with risk for sequelae and even death. The aim in this retrospective study was to analyze the incidence, origin, and clinical presentation of shunt infections, with special reference to the results of cultures for anaerobic organisms performed in addition to the usual tests, to prolonged incubation times, and to infections caused by Propionibacterium acnes. METHODS: The medical records of 237 hydrocephalic children (age range 0-15 years) in whom operations were performed by a pediatric surgeon at Uppsala University Hospital during a 13-year period were reviewed. RESULTS: Thirty-four verified or suspected intraventricular shunt infections and 5 distal catheter infections occurred after 474 operations. Skin bacteria, such as coagulase-negative staphylococci ([CoNS], 19 patients), Staphylococcus aureus (7 patients), and P. acnes (6 patients) predominated. The addition of anaerobic cultures and prolonged incubation times increased the verification of shunt infection by more than one third. Children with P. acnes infection were significantly older, had a lower body temperature, fewer cerebrospinal fluid (CSF) leukocytes, a higher CSF/blood glucose ratio, more distal catheter infections, and other sources of infection. Four had an abdominal pseudocyst. Children < 1 year of age and infected with CoNS were more affected than older children with systemic and local symptoms. In children with distal catheter infection and growth of propionibacteria at the time of the distal catheter and valve replacement, no follow-up antibiotic treatment was necessary. CONCLUSIONS: Addition of anaerobic cultures and prolonged incubation times led to an increase in the detection of shunt infections. Infections caused by propionibacteria often result in mild symptoms that may be overlooked if adequate anaerobic cultures are not obtained. PMID- 18447671 TI - Chemotherapy administration directly into the fourth ventricle in a new piglet model. Laboratory Investigation. AB - OBJECT: The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets. METHODS: A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion. RESULTS: All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (> 0.1 microg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation. CONCLUSIONS: Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined. PMID- 18447672 TI - Brainstem tumors. PMID- 18447673 TI - Diffuse intrinsic brainstem tumors in neonates. Report of two cases. AB - The authors report on 2 newborn infants with the unusual presentation of intrinsic brainstem tumors. Both nondysmorphic, full-term neonates had cranial nerve palsies and hypotonia. Diagnoses of diffuse intrinsic brainstem gliomas were made on the basis of magnetic resonance imaging, which showed large expansive, nonenhancing intrinsic pontine masses. Intrinsic pontine tumors, characteristically seen in school-age children, are most often high-grade gliomas that are almost invariably fatal. However, the microanatomy and natural history of pontine tumors in neonates are unknown. With parental consent, both newborns were treated expectantly with supportive care but died of progressive disease by 2 weeks of age. In one child, postmortem examination revealed a primary brainstem primitive neuroectodermal tumor. The authors conclude that, as in older children, neonatal intrinsic brainstem tumors may be of a highly malignant nature. The rapid tumor progression in both cases indicates that where a diagnostic procedure may pose significant risks, supportive observation can aid in distinguishing malignant from benign tumor growth. PMID- 18447674 TI - Combination of myxopapillary ependymoma and fatty filum in a child with tethered cord syndrome. Case report. AB - The authors present a case of a child with a tethered spinal cord associated with a myxopapillary ependymoma. This 16-month-old boy presented to the authors' institution with developmental delays in standing and walking. Magnetic resonance (MR) imaging demonstrated a fatty terminal filum and tethered cord. The child underwent surgical exploration of the spine with resection of the fatty filum tissue and release of the cord. Histological analysis of the fatty filum suggested the presence of a coexisting myxopapillary ependymoma. The child made a good recovery with no evidence of tumor recurrence after 4-years of follow-up with serial MR imaging. This unusual combination has not previously been reported in children, and to the authors' knowledge there is only one reported case in an adult. The likelihood of a common pathophysiological process in these conditions is also discussed. PMID- 18447675 TI - Intraorbital and intracranial soft-tissue glomus tumor in an 8-year-old child. Case report. AB - Soft-tissue glomus tumors (or glomangiomas) are unrelated to neuroendocrine paragangliomas (glomus tympanicum, jugulare, and vagale). The authors present the first reported case of an orbital soft-tissue glomus tumor in a child. An 8-year old girl developed rapidly progressive right-eye blindness, proptosis, and a sixth cranial nerve palsy. Magnetic resonance imaging demonstrated a homogeneously enhancing lesion extending from the right orbit through the superior orbital fissure to the cavernous sinus and middle cranial fossa. A biopsy specimen demonstrated the lesion to be a soft-tissue glomus tumor. Following angiography and embolization, a gross-total resection of the tumor was achieved. The patient was treated with adjuvant proton-beam radiotherapy. At 24 months follow-up her proptosis and sixth cranial nerve palsy had resolved and there was no evidence of tumor recurrence. PMID- 18447676 TI - Chiari malformation presenting as a focal motor deficit. Report of two cases. AB - Chiari malformations may present with a wide range of symptoms and signs. Nevertheless, focal foot weakness as a presentation of a Chiari malformation has not been described in the pediatric neurosurgical literature. Two children with Chiari malformations and holocord syringomyelia presented with manifestations of a supposed isolated lumbar radiculopathy. Neurological deficits completely resolved after decompressive suboccipital craniectomy and cervical laminectomy. These cases emphasize the importance of imaging the entire craniospinal axis and avoidance of therapeutic intervention specifically aimed at a radiculopathic process when initial imaging fails to show a structural abnormality at the spinal level of deficit. The possible pathophysiological origins for this unusual presentation are discussed. Based on the experience gained with these patients, recommendations are made regarding the diagnostic workup and management of this entity in children presenting with focal deficits that are not supported by imaging of the affected root levels. Chiari malformations may rarely masquerade as lower motor and sensory deficits, and appropriate treatment may result in excellent recovery of function. PMID- 18447677 TI - Significant clinical and radiological resolution of a spinal cord syrinx following the release of a tethered cord in a patient with an anatomically normal conus medullaris. Case report. AB - The authors describe a case of progressive neurological deficit caused by syringomyelia in a 7-year-old boy with a normally positioned conus medullaris. This deficit responded favorably to surgical untethering of the filum terminale, with subsequent clinical and radiological improvement. The authors discuss the implications of their findings in the context of the current understanding of the pathophysiology of tethered cord syndrome, particularly in relation to the ongoing debate in the neurosurgical literature. PMID- 18447678 TI - Giant true dorsal thoracic meningocele in a school-age child. Case report. AB - A meningocele is a common form of spinal dysraphic lesions, but it is extremely uncommon in children in the upper thoracic region. The authors describe a rare case in which they found a giant true dorsal meningocele in the upper thoracic region in a symptomatic child, which, to their knowledge, is the first such reported case. A school-age child, who harbored a giant dorsal mass, complained of restriction of function. He underwent successful surgery in which the meningocele sac was totally removed. PMID- 18447679 TI - Delayed presentation and conservative management of an odontoid basilar synchondrosis fracture in a child. Case report. AB - The authors report the case of a 3-year-old boy who presented with neck pain after falling from a low height and who was discharged from the emergency department after imaging studies were noted to be normal. He presented again 2 months later with continued neck pain, and repeated imaging demonstrated a fracture of the odontoid basilar synchondrosis that had not been shown on the initial studies. Based on the normal alignment of his spine and evidence of early bone fusion at the time of his second presentation, he underwent cervical orthosis therapy only. To the authors' knowledge, this is the first reported case of an odontoid synchondrosis fracture in which computed tomography scans were normal at presentation. PMID- 18447680 TI - Gastric bypass: a risk factor for neural tube defects? Case report. AB - Gastric bypass surgery has become a safe and acceptable surgical weight loss treatment for individuals who suffer from morbid obesity. Patients who undergo this procedure are subject to vitamin deficiencies due to an iatrogenic malabsorptive state. Folate, a vitamin known for its role in the prevention of neural tube defects (NTDs), can be part of the deficiency spectrum resulting from this procedure. The authors describe the case of a woman who was nonadherent to multivitamin treatment after undergoing gastric bypass surgery. Her lack of understanding and appreciation of the relationship between gastric bypass surgery, folate deficiency, and NTDs may have contributed to her noncompliance with daily multivitamin consumption. As a result, her potential problems with folate absorption could have contributed to her subsequently giving birth to a child with a myelomeningocele. Thus, patient awareness and counseling along with aggressive vitamin supplementation among this particular population may help prevent the occurrence of NTDs after gastric bypass surgery. PMID- 18447681 TI - Fetus-in-fetu in the cranium of a 4-month-old boy: histopathology and short tandem repeat polymorphism-based genotyping. Case report. AB - Fetus-in-fetu is a very rare condition in which one fetus is contained within another. About 100 cases have been reported, and in most of these the fetus was located in the retroperitoneum. The authors describe an extremely rare case of an intracranial fetus-in-fetu in an extraaxial location. This is the eighth intracranial fetus-in-fetu to be reported, the first intracranial extraaxial case, and involves the oldest documented patient with this condition. Histopathological analysis of the mass revealed a degenerated amnionic membranelike tissue, well-differentiated extremities (including fingerlike structures), skin, matured lungs, well-formed intestines, cerebellar and cerebral tissue, and a notochord with ganglion cells. DNA analysis using short tandem repeat polymorphisms confirmed that the fetus-in-fetu mass and the host infant had heterozygous alleles and were of identical sex and genotype. PMID- 18447682 TI - Traumatic dissecting aneurysm at the vertebrobasilar junction in a 3-month-old infant: evaluation and treatment strategies. Case report. AB - Intracranial aneurysms in young infants are extremely rare, with few published reports on the etiology, evaluation, treatment strategies, and follow-up of this condition in this population. The authors report the case of a traumatic dissecting aneurysm at the vertebrobasilar junction (VBJ) in a 3-month-old infant caused by nonaccidental trauma. Therapeutic occlusion of the VBJ was contemplated, but coil embolization of the main aneurysm sac proved feasible, and anticoagulation and antiplatelet agents were initiated. The patient made a full neurological recovery, and follow-up studies demonstrated stable aneurysm occlusion. Management and follow-up strategies for this challenging condition are discussed. PMID- 18447683 TI - The Section on Neurological Surgery of theAmerican Academy of Pediatrics: annual report 2006 to 2007. PMID- 18447684 TI - Pontine tumors. PMID- 18447685 TI - Anterior debridement and fusion followed by posterior pedicle screw fixation in pyogenic spondylodiscitis: autologous iliac bone strut versus cage. AB - OBJECT: An anterior approach for debridement and fusion with autologous bone graft has been recommended as the gold standard for surgical treatment of pyogenic spondylodiscitis. The use of anterior foreign body implants at the site of active infection is still a challenging procedure for spine surgeons. Several authors have recently introduced anterior grafting with titanium mesh cages instead of autologous bone strut in the treatment of spondylodiscitis. The authors present their experience of anterior fusion with 3 types of cages followed by posterior pedicle screw fixation. They also compare their results with the use of autologous iliac bone strut. METHODS: The authors retrospectively reviewed the cases of 60 patients with pyogenic spondylodiscitis treated by anterior debridement between January 2003 and April 2005. Fusion using either cages or iliac bone struts was performed during the same course of anesthesia followed by posterior fixation. Twenty-three patients underwent fusion with autologous iliac bone strut, and 37 patients underwent fusion with 1 of the 3 types of cages. RESULTS: The infections resolved in all patients, as noted by normalization of their erythrocyte sedimentation rates and C-reactive protein levels. Patients in both groups were evaluated in terms of their preoperative and postoperative clinical and imaging findings. CONCLUSIONS: Single-stage anterior debridement and cage fusion followed by posterior pedicle screw fixation can be effective in the treatment of pyogenic spondylodiscitis. There was no difference in clinical and imaging outcomes between the strut group and cage group except for the subsidence rate. The subsidence rate was higher in the strut group than in the cage group. The duration until subsidence was also shorter in the strut group than in the cage group. PMID- 18447686 TI - Factors associated with cervical instability requiring fusion after cervical laminectomy for intradural tumor resection. AB - OBJECT: The indications remain unclear for fusion at the time of cervical laminectomy for intradural tumor resection. To identify patients who may benefit from initial fusion, the authors assessed clinical, radiological/imaging, and operative factors associated with subsequent symptomatic cervical instability requiring fusion after cervical laminectomy for intradural tumor resection. METHODS: The authors reviewed 10 years of data obtained in patients who underwent cervical laminectomy without fusion for intradural tumor resection and who had normal spinal stability and alignment preoperatively. The association of pre- and intraoperative variables with the subsequent need for fusion for progressive symptomatic cervical instability was assessed using logistic regression analysis, and percentages were compared using Fisher exact tests when appropriate. RESULTS: Thirty-two patients (mean age 41 +/- 17 years) underwent cervical laminectomy without fusion for resection of an intradural tumor (18 intramedullary and 14 extramedullary). Each increasing number of laminectomies performed was associated with a 3.1-fold increase in the likelihood of subsequent vertebral instability (odds ratio 3.114, 95% confidence interval 1.207-8.034, p = 0.02). At a mean follow-up interval of 25.2 months, 33% (4 of 12) of the patients who had undergone a >or= 3-level laminectomy required subsequent fusion compared with 5% (1 of 20) who had undergone a or= 3 level cervical laminectomy had an increased likelihood of developing subsequent symptomatic instability requiring fusion. A >or= 3-level laminectomy with myelopathic motor symptoms may herald patients most likely to benefit from cervical fusion at the time of tumor resection. PMID- 18447687 TI - Radiographic and clinical outcomes following single-level anterior cervical discectomy and allograft fusion without plate placement or cervical collar. AB - OBJECT: Although the clinical outcomes following anterior cervical discectomy and fusion (ACDF) surgery are generally good, 2 major complications are graft migration and nonunion. These complications have led some to advocate rigid internal fixation and/or cervical immobilization postoperatively. This paper examines a single-surgeon experience with single-level ACDF without use of plates or hard collars in patients with degenerative spondylosis in whom allograft was used as the fusion material. METHODS: The authors conducted a retrospective review of a prospective database of (Cloward-type) ACDF operations performed by the senior author (J.A.J.) between July 1996 and June 2005. Radiographic follow up included static and flexion/extension radiographs obtained to assess fusion, focal and segmental kyphosis, and change in disc space height. At most recent follow-up, the patients' condition was evaluated by an independent physician examiner. The Odom criteria and Neck Disability Index (NDI) were used to assess outcome. RESULTS: One hundred seventy patients underwent single-level ACDF for degenerative pathology during the study period. Their most common presenting symptoms were pain, weakness, and radiculopathy; 88% of patients noted >or= 2 neurological complaints. The mean hospital stay was 1.76 days (range 0-36 days), and 3 patients (2%) had major immediate postoperative complications requiring reoperation. The mean duration of follow-up was 22 months (range 12-124 months). Radiographic evidence of fusion was present in 160 patients (94%). Seven patients (4%) showed radiographic evidence of pseudarthrosis, and graft migration was seen in 3 patients (2%). All patients had increases in focal kyphosis at the operated level on postoperative radiographs (mean -7.4 degrees ), although segmental alignment was preserved in 133 patients (78%). Mean change in disc space height was 36.5% (range 28-53%). At most recent clinical follow-up, 122 patients (72%) had no complaints referable to cervical disease and were able to carry out their activities of daily living without impairment. The mean postoperative NDI score was 3.2 (median 3, range 0-31). CONCLUSIONS: Single-level ACDF without intraoperative plate placement or the use of a postoperative collar is an effective treatment for cervical spondylosis. Although there is evidence of focal kyphosis and loss of disc space height, radiographic evidence of fusion is comparable to that attained with plate fixation, and the rate of clinical improvement is high. PMID- 18447688 TI - Three-dimensional constructive interference in steady-state magnetic resonance imaging in syringomyelia: advantages over conventional imaging. AB - OBJECT: Neuroradiology has become indispensable in detecting the pathophysiology in syringomyelia. Constructive interference in steady-state (CISS) magnetic resonance (MR) imaging can provide superior contrast at the sub-arachnoid tissue borders. As this region is critical in preoperative evaluation, the authors hypothesized that CISS imaging would provide superior assessment of syrinx pathology and surgical planning. METHODS: Based on records collected from a database of 130 patients with syringomyelia treated at the authors' institution, 59 patients were prospectively evaluated with complete neuroradiological examinations. In addition to routine acquisitions with FLAIR, T1- and T2 weighted, and contrast-enhanced MR imaging series, the authors obtained sagittal cardiac-gated sequences to visualize cerebrospinal fluid (CSF) pulsations and axial 3D CISS MR sequences to detect focal arachnoid webs. Statistical qualitative and quantitative evaluations of spinal cord/CSF contrast, spinal cord/CSF delineation, motion artifacts, and artifacts induced by pulsatile CSF flow were performed. RESULTS: The 3D CISS MR sequences demonstrated a contrast-to noise ratio significantly better than any other routine imaging sequence (p < 0.001). Moreover, 3D CISS imaging can detect more subarachnoid webs and cavitations in the syrinx than T2-weighted MR imaging with less flow-void artifact. The limitation of 3D CISS imaging is a susceptibility to motion artifacts that can cause reduced spatial resolution. Lengthy acquisition times for axial segments can be reduced with multiplanar reconstruction of 3D CISS generated sagittal images. CONCLUSIONS: Constructive interference in steady-state imaging is the MR sequence of choice in the preoperative evaluation of syringomyelia, allowing significantly higher detection rates of focal subarachnoid webs, whereas standard T2-weighted MR imaging shows turbulent CSF flow voids. Constructive interference in steady-state MR imaging enables the neurosurgeon to accurately identify cases requiring decompression for obstructed CSF. Motion artifacts can be eliminated with technical variations. PMID- 18447689 TI - Biomechanical study of cervical flexion myelopathy using a three-dimensional finite element method. AB - OBJECT: The goal of this study was to perform a biomechanical study of cervical flexion myelopathy (CFM) using a finite element method. METHODS: A 3D finite element model of the spinal cord was established consisting of gray matter, white matter, and pia mater. After the application of semi-static compression, the model underwent anterior flexion to simulate CFM. The flexion angles used were 5 degrees and 10 degrees , and stress distributions inside the spinal cord were then evaluated. RESULTS: Stresses on the spinal cord were very low under semi static compression but increased after 5 degrees of flexion was applied. Stresses were concentrated in the gray matter, especially the anterior and posterior horns. The stresses became much higher after application of 10 degrees of flexion and were observed in the gray matter, posterior funiculus, and a portion of the lateral funiculus. CONCLUSIONS: The 5 degrees model was considered to represent the mild type of CFM. This type corresponds to the cases described in the original report by Hirayama and colleagues. The main symptom of this type of CFM is muscle atrophy and weakness caused by the lesion of the anterior horn. The 10 degrees model was considered to represent a severe type of CFM and was associated with lesions in the posterior fand lateral funiculi. This type of CFM corresponds to the more recently reported clinical cases with combined long tract signs and sensory disturbance. PMID- 18447690 TI - The biomechanical effectiveness of prophylactic vertebroplasty: a dynamic cadaveric study. AB - OBJECT: The purpose of the study was to investigate the segmental effects of prophylactic vertebroplasty under increasingly demanding loading conditions and to assess the effect of altered cement properties on the construct biomechanics. METHODS: Twelve human cadaveric 3-vertebral functional spinal units (T12-L2) were prepared such that the intact L-1 vertebra was prophylactically augmented with cements of differing elastic moduli (100, 50, 25, and 12.5% modulus of the base cement). These specimens were subjected to quasistatic subfailure compression pre and postaugmentation to 50% of the predicted failure strength and then cyclic loading in a fatigue rig (115,000 cycles) to characterize the high-stress, short cycle fatigue properties of the construct. Loading was increased incrementally in proportion to body weight to a maximum of 3.5 x body weight. Quantitative computed tomography assessment was conducted pre- and postaugmentation and following cyclic testing to assess vertebral condition, cement placement, and fracture classification. RESULTS: Adjacent and periaugmentation fractures were induced in the prophylactically augmented segments. However, it appeared that these fractures mainly occurred when the specimens were subjected to loads beyond those that may commonly occur during most normal physiological activities. CONCLUSIONS: Lowering the elastic modulus of the cement appeared to have no significant effect on the frequency or severity of the induced fracture within the vertebral segment. PMID- 18447691 TI - A porcine model of intervertebral disc degeneration induced by annular injury characterized with magnetic resonance imaging and histopathological findings. Laboratory investigation. AB - OBJECT: Appropriate animal models of disc degeneration are critical for the study of proposed interventions as well as to further delineate the degenerative process. The purpose of this study was to characterize a porcine model for disc degeneration confirmed on magnetic resonance (MR) imaging studies and histological analysis. METHODS: Twelve miniature pigs were used (weight 48-65 kg) to study degeneration in the lumbar spine. Under fluoroscopic guidance, the disc was percutaneously punctured with a 3.2-mm-diameter trephine to a 5-mm depth into the annulus fibrosus. Control and experimental levels were randomized among 6 levels in the lumbar spine. The unlesioned spinal levels were used as controls and were compared with lesioned levels. Magnetic resonance imaging grading and disc height were serially recorded preoperatively, and at 5, 8, 19, 32, and 39 weeks postoperatively. The animals were killed in groups of 3 at 7, 18, 32, and 41 weeks postinjury, and the discs were examined histopathologically. RESULTS: Consistent, sequential, and progressive degeneration of the annular injury was observed on MR imaging and histopathological studies from the time of injury to the final time point. The disc height and the disc height index also sequentially decreased from the time of the injury in a consistent manner. The uninjured control levels did not show any progressive degeneration and maintained their normal state. CONCLUSIONS: Based on MR imaging and histopathological findings, the authors demonstrated and characterized a reliable model of sequential disc degeneration in miniature pigs with percutaneous injury to the annulus fibrosus. In the early stages, as soon as 5 weeks after injury, significant disc degeneration was seen on MR imaging grading with decreases in disc height. This degeneration did not improve by the final time point of 39 weeks. PMID- 18447692 TI - Balloon kyphoplasty for painful C-7 vertebral hemangioma. AB - The authors report on the efficacy of balloon kyphoplasty applied to obliteration of symptomatic cervical hemangioma. This 49-year-old woman suffered from progressive neck pain, numbness of the upper extremities, and frequent headaches. Hemangioma of the C-7 vertebral body was diagnosed. Kyphoplasty was performed successfully through a right anterolateral approach. The patient became asymptomatic, and follow-up examinations confirmed complete recovery. To the authors' knowledge, this is the first description of cervical hemangioma treated by balloon kyphoplasty. PMID- 18447693 TI - Usefulness of three-dimensional digital subtraction angiography in endovascular treatment of a spinal dural arteriovenous fistula. AB - The use of 3D digital subtraction (DS) angiography provides a better understanding of spinal vascular lesion architecture. The authors report on 2 cases involving a spinal dural arteriovenous fistula (DAVF) and demonstrate the usefulness of 3D DS angiography for endovascular treatment of these spinal DAVFs. In both cases, middle-aged male patients suffered from bilateral leg hypesthesia, gait disturbance, and urinary dysfunction several months before treatment. Spinal angiography revealed DAVFs that were fed by a radicular artery branching from the intercostal artery and draining veins proceeding superiorly along the perimedullary veins. Endovascular embolization was performed in both cases. Selective 3D DS angiography of the intercostal artery clearly demonstrated the tortuous course of the feeder and the relationship among the feeding artery, fistula point, and draining veins in each case. This information was very useful in selecting a working angle for manipulating the microcatheter and for glue injection. In addition, the maximum intensity projection image from rotational DS angiography data clearly showed the fistula point at the dural sleeve and feeder entering the spinal canal via the intervertebral foramen and the relationship with the bone structure. Successful obliteration of the fistulae was achieved in both cases. Selective spinal 3D DS angiography was very useful in understanding the complex spinal vascular architecture and in choosing the best working angle and therapeutic strategy for endovascular treatment of spinal DAVFs. PMID- 18447694 TI - Lumbosacral reconstruction for intractable pyogenic spondylitis using a total leg flap with a vascularized tibia graft. AB - This report describes an effective technique of using a total leg flap for treating a 57-year-old male paraplegic patient with intractable sacral pyogenic spondylitis caused by methicillin-resistant Staphylococcus aureus. Spondylitis was accompanied by severe instability of the lumbosacral area, a large lumbosacral ulcer, and a large bone and muscle defect, which made it difficult for the patient to maintain a sitting position. A total leg flap procedure, a modification of the total thigh flap procedure, was performed as a 1-stage salvage surgery. The vascularized tibia and fibula were grafted between the lumbar and sacral vertebrae, and a musculocutaneous flap was used to cover the extensive ulceration in the lumbosacral skin defect. The intractable lesion of the lumbosacral spine, which had not been cured for more than 2 years despite repeated debridement, intravenous antibiotic injections, sugar treatment, pyoktanin treatment, and hyperbaric O(2) treatment, subsided and stabilized within 1 year of surgery. The patient returned to activities of daily living using a wheelchair, and was very satisfied with the results. Use of a total leg flap with a vascularized tibia graft is an effective treatment for intractable pyogenic spondylitis accompanied by a large bone defect and large lumbosacral ulcers. PMID- 18447695 TI - Multilevel bilateral calcified thoracic spinal synovial cysts. AB - Synovial cysts of the thoracic spine are quite rare. Bilateral presentation is even less frequent, and to the authors' knowledge multilevel occurrence and consistent calcification have not been reported so far. The pathogenesis of these cysts is unknown and their histological features have not been studied. They may be overlooked as the cause of myelopathy. The authors report a series of 4 cases of bilateral, multilevel, consistently calcified thoracic synovial cysts. The details of clinical, radiological, and histological findings are presented, along with a review of the literature, and a hypothesis on the pathogenesis of these lesions is formulated based on results of the clinical and pathological studies performed in these patients. PMID- 18447696 TI - Spontaneous thoracic spinal subdural hematoma associated with fibromuscular dysplasia. AB - Spontaneous spinal subdural hematoma (SDH) is an uncommon cause of acute spinal cord compression. When it does occur, however, it may have disastrous results and a poor prognosis. The nontraumatic acute spinal SDH usually results from a defect in a hemostatic mechanism (such as coagulopathy or the use of anticoagulant therapy) or from iatrogenic causes (such as spinal puncture). Fibromuscular dysplasia (FMD) is a nonatherosclerotic systemic arteriopathy of unknown cause that typically affects the small and medium arteries in young to middle-aged women. The authors report on their experience with a patient with an acute spontaneous spinal SDH that occurred in conjunction with FMD. PMID- 18447697 TI - Gas-filled intradural cyst with migration into the nerve root of the cauda equina. AB - Only 4 cases of gas-filled intradural cysts of the spine have been reported previously. All cysts were due to intradural herniation of a gas-containing disc. The authors report 2 additional patients with gas-filled intradural cysts that migrated into the nerve root of the cauda equina. After surgical treatment their severe leg pain completely resolved. PMID- 18447698 TI - Rectothecal fistula secondary to an anterior sacral meningocele. AB - A rectothecal fistula secondary to anterior sacral meningocele is an extremely rare disease. To the authors' knowledge, only 2 cases have been reported in the English-language literature. It can cause symptoms by compressing adjacent structures, causing urinary difficulties and constipation. The authors report an unusual case of a patient in whom this condition was diagnosed as an incidental finding. The patient had a sacral myelomeningocele with secondary meningitis to a rectothecal fistula. The authors will briefly review the diagnosis, the various treatments, and the surgical approach to treat this infrequent entity. PMID- 18447699 TI - Disseminated intraspinal hydatid disease. AB - Spinal echinococcosis is a rare entity, accounting for 1% of all cases of hydatid disease. The authors report the case of a 60-year-old man whom they treated for recurrent nerve root compression due to disseminated intraspinal echinococcosis (hydatid disease). Six years previously he had undergone surgery on an emergency basis at another institution after presenting with acute paraplegia due to a primary extradural hydatid cyst of the thoracic spine. Unfortunately, during surgical removal of the cysts, the echinococcosis disseminated into the spinal canal. This complication was documented by magnetic resonance (MR) imaging. In the 4 years before the authors treated him, he was hospitalized 4 times for 4 recurrences of nerve root compression. The authors treated the disseminated disease successfully with total T7-8 corpectomy, grafting with titanium cage and Texas Scottish Rite Hospital instrumentation, and long-term administration of albendazole (400 mg daily). Early diagnosis, proper utilization of MR imaging, and radical resection of diseased vertebrae and soft tissues followed by anthelmintic treatment are essential to control disseminated spinal hydatidosis and prevent recurrence. PMID- 18447700 TI - Cervical fusion. PMID- 18447701 TI - Thoracic outlet syndrome. PMID- 18447702 TI - Prognosis in spine surgery. PMID- 18447704 TI - Continued challenges with the use of erythropoiesis-stimulating agents in patients with cancer: perspectives and issues on policy-guided health care. AB - Erythropoiesis-stimulating agents (ESAs) are approved as an alternative to blood transfusions for treating anemia secondary to chemotherapy in patients with cancer. Recently, ESAs have been a source of controversy and confusion in the oncology community. This began when two European trials-the Breast Cancer Erythropoietin Survival Trial (BEST) and the Advanced Head-and-Neck Cancer Treated with Radiotherapy (ENHANCE) Study-raised safety concerns about decreased overall survival and increased venous thromboembolic events. In 2004, the United States Food and Drug Administration (FDA) convened its Oncologic Drugs Advisory Committee (ODAC) to review the data and reassess the risks and benefits of ESAs in patients with cancer. On May 10, 2007, ODAC reconvened when five trials (BEST, ENHANCE, AMG-20010103, AMG-20000161, and EPO-CAN-20) showed decreased overall survival. The briefing document noted that studies demonstrating detrimental effects on survival and/or tumor outcomes used an unapproved treatment regimen designed to maintain hemoglobin levels above 12 g/dl. On May 14, 2007, just days after the ODAC reconvened, the Centers for Medicare and Medicaid Services (CMS) released a proposed decision memo for a national coverage determination (NCD) imposing restrictions on ESAs. For health care providers, aspects of the proposed NCD were markedly inconsistent with FDA-approved ESA use and generally were considered ambiguous and unclear. Over objections of several professional associations and members of Congress, on July 30, 2007, CMS posted the final NCD and declared it effective immediately. When compared with FDA-approved labeling and professional society guidelines, the NCD revealed differences in ESA initiation, dosage escalation, dosage reduction, and definition of response. These discrepancies have generated confusion among health care providers, who are struggling over whether they can feasibly provide a dual system of care-one for Medicare patients and another for non-Medicare patients-that is evidence based. With this supplement, we hope to educate health care providers on the issues and challenges associated with policy-guided health care when discrepancies exist between the policy and evidence-based practice; offer guidance on implementing the NCD; and highlight the important role of pharmacists in the process. PMID- 18447705 TI - Pituitary apoplexy: correlation between magnetic resonance imaging and histopathological results. AB - OBJECT: The aim of this study was to correlate the magnetic resonance (MR) imaging findings in pituitary apoplexy with histopathological results and determine whether the histopathology influences clinical presentation and outcome. METHODS: The records of 36 patients with histologically confirmed pituitary apoplexy, who were treated surgically at the University of Virginia Health System between 1996 and 2006, were retrospectively reviewed. The MR images were divided into 3 groups: 1) infarction alone; 2) hemorrhage with or without infarction; and 3) tumor only with no evidence of apoplexy. The histological examination was divided into infarction alone or hemorrhagic infarction/hemorrhage. The MR imaging findings were then correlated with the histopathological results to assess how accurately the histopathology was predicted by the MR imaging. The clinical features and outcomes of the two histopathological groups were also compared. RESULTS: The MR imaging findings were able to predict the histopathology accurately in the majority of cases. The group of patients with infarction had less severe clinical features and a better outcome than those with hemorrhagic infarction/hemorrhage. CONCLUSIONS: Magnetic resonance imaging findings in the setting of pituitary apoplexy accurately predict the nature of the apoplectic process and help to guide the type and timing of therapy. PMID- 18447706 TI - Repeat posterior fossa exploration for patients with persistent or recurrent idiopathic trigeminal neuralgia. AB - OBJECT: Patients with trigeminal neuralgia (TN) and persistent or recurrent facial pain after microvascular decompression (MVD) typically undergo less invasive procedures in the hope of providing pain relief. The outcomes and risks of repeat posterior fossa exploration (PFE) for these patients are not clearly understood. METHODS: From September 2000 to November 2006, 29 patients (14 men, 15 women) underwent repeat PFE. The mean number of surgeries per patient at the time of repeat PFE was 3.2 (range 1-6). The mean follow-up duration after surgery was 33.7 months. RESULTS: Compression of the trigeminal nerve was noted in 24 patients (83%) by an artery (13 patients, 45%), vein (4 patients, 14%), or Teflon (7 patients, 24%). Four patients (14%) who underwent operations elsewhere had incorrect cranial nerves decompressed at their first surgery. Only MVD was performed in 18 patients (62%) and a partial nerve section (PNS) was performed in 11 patients (38%). An excellent facial pain outcome (no pain, no medications required) was achieved and maintained for 80% and 75% of patients at 1 and 3 years after surgery, respectively. Patients with Burchiel Type 1 TN were pain free without medications (91% at 1 year and 85% at 3 years) more frequently than patients with Burchiel Type 2 TN (27% at both 1 and 3 years; hazard ratio = 5.4, 95% confidence interval 1.4-21.1, p = 0.02). Fifteen patients (52%) had new or increased facial numbness. Two patients (7%) developed anesthesia dolorosa; both had undergone PNS. Two patients (7%) had hearing loss after surgery. CONCLUSIONS: Repeat PFE for patients with idiopathic TN has facial pain outcomes that are comparable with both percutaneous needle-based techniques and stereotactic radiosurgery. Patients with persistent or recurrent TN should be considered for repeat PFE, especially if other less invasive surgeries have not relieved their facial pain. PMID- 18447707 TI - Failure of long-term nerve root stimulation to improve neuropathic pain. AB - OBJECT: Stimulation of dorsal nerve roots or dorsal root ganglia was reported to alleviate neuropathic pain in selected patients during the early postoperative period. A prospective study was initiated to investigate long-term outcome in patients with neuropathic pain of the lower extremities or groin who were treated with selective nerve root stimulation. METHODS: The study included patients with dermatomally distributed neuropathic pain who were > 18 years of age and in whom the pain was refractory to medical treatment. The patients were prospectively evaluated using a visual analog scale (VAS) for pain and ratings for quality of life, activities of daily living, and depression preoperatively, and after defined intervals postoperatively. Implantation of electrodes was performed via foraminotomy or interlaminar fenestration in an awake procedure. An implantable pulse generator (IPG) was implanted in a second operation after successful test stimulation performed over several days. RESULTS: Three patients were included in the study before it was stopped. The mean maximum pain score preoperatively was 9.3. All patients had successful test stimulation with > 50% pain relief prior to implantation of the IPG (mean maximum VAS Score 3.6). The beneficial effect, however, was lost within the next few months despite adjustment of stimulation settings. With higher amplitudes, side effects such as pain attacks or motor phenomena occurred. They disappeared after stopping stimulation, but neuropathic pain recurred to its full extent. The study was stopped 18 months after the first implantation, when the third and last IPG of this series was explanted. Due to the overall short-term effect of stimulation, no relevant changes in ratings for quality of life, activities of daily living, or depression were detected. CONCLUSIONS: Spinal nerve root stimulation proved to be effective on short-term follow-up in 3 patients with neuropathic pain in a dermatomal distribution. Long term stimulation, however, was disappointing because of the loss of effectiveness and the occurrence of side effects. PMID- 18447708 TI - Normobaric oxygen therapy strategies in the treatment of postcraniotomy pneumocephalus. AB - OBJECT: Postsurgical pneumocephalus is an unavoidable sequela of craniotomy. Sufficiently large volumes of intracranial air can cause headaches, lethargy, and neurological deficits. Supplemental O(2) to increase the rate of absorption of intracranial air is a common but unsubstantiated neurosurgical practice. To the authors' knowledge, this is the first prospective study to examine the efficacy of this therapy and its effect on the rate of pneumocephalus absorption. METHODS: Thirteen patients with postoperative pneumocephalus that was estimated to be > or = 30 ml were alternately assigned to breathe 100% O(2) using a nonrebreather mask (treatment group) or to breathe room air (control group) for 24 hours. Head computed tomography (CT) scans without contrast enhancement were obtained at the beginning and end of treatment or control therapy. A neuroradiologist blinded to the type of treatment used software to calculate the 3D volume of the pneumocephalus from the CT scans. The percentage of pneumocephalus absorption was calculated for each study participant. RESULTS: There was no statistically significant difference between the treatment and control groups regarding the mean initial pneumocephalus volume or time interval between CT scans. There was a significant difference (p = 0.009) between the mean rate of pneumocephalus volume reduction in the treatment (65%) and control groups (31%) per 24 hours. No patient suffered adverse effects related to treatment. CONCLUSIONS: Administration of postsurgical supplemental O(2) through a nonrebreather mask significantly increases the absorption rate of postcraniotomy pneumocephalus as compared with breathing room air. PMID- 18447709 TI - Ventricular catheter trajectories from traditional shunt approaches: a morphometric study in adults with hydrocephalus. AB - OBJECT: The purpose of this study was to compare the margins of error of different shunt catheter approaches to the lateral ventricle and assess surface anatomical aiming landmarks for free-hand ventricular catheter insertion in adult patients with hydrocephalus. METHODS: Four adults who had undergone stereotactic brain magnetic resonance (MR) imaging and had normal ventricles, and 7 prospectively recruited adult patients with acute hydrocephalus were selected for inclusion in this study. Reconstructed MR images obtained prior to surgical intervention were geometrically analyzed with regard to frontal, parietal, and parietooccipital (occipital) approaches in both hemispheres. RESULTS: The ventricular target zones were as follows: the frontal horn for frontal and occipital approaches, and the atrium/posterior horn for parietal approaches. The range of possible angles for successful catheter insertion was smallest for the occipital approach (8 degrees in the sagittal plane and 11 degrees in the coronal plane), greater for parietal catheters (23 and 36 degrees ), and greatest for the frontal approach in models of hydrocephalic brains (42 and 30 degrees; p < 0.001 for all comparisons except frontal vs parietal, which did not reach statistical significance). There was no single landmark for aiming occipital or parietal catheters that achieved ventricular target cannulation in every case. Success was achieved in only 86% of procedures using occipital trajectories and in 66% of those using parietal trajectories. CONCLUSIONS: The occipital approach to ventricular catheter insertion provides the narrowest margin of error with regard to trajectory but has less aiming point variability than the parietal approach. The use of patient-specific stereotaxy rather than generic guides is required for totally reliable, first-pass ventricular catheterization via a posterior approach to shunt placement surgery in adults. PMID- 18447710 TI - Intracranial pressure monitoring with the Neurodur-P epidural sensor: a prospective study in patients with adult hydrocephalus or idiopathic intracranial hypertension. AB - OBJECT: Continuous intracranial pressure (ICP) monitoring using an epidural sensor is a common technique used in selected neurosurgical patients. The aim of this study was to assess the safety and accuracy of the Neurodur-P epidural sensor in the clinical setting. METHODS: The zero drift, as well as the medical and technical complications, of using the Neurodur-P sensor placed in the epidural space was evaluated in 106 patients with hydrocephalus of varying causes or with suspected intracranial hypertension. RESULTS: The median duration of ICP monitoring was 8 days (interquartile range [IQR] 6-12 days). In 78 (73.6%) of the 106 patients the pressure reading was recorded at sensor removal. No zero drift was observed in 28 sensors. The median drift was 0 mm Hg with an IQR of -1 to 1 mm Hg. No significant differences were found between patients monitored for < or = 5 days and those monitored for > 5 days (t = 535, p = 0.100). No correlation was found between zero drift and monitoring time (r = 0.153, p = 0.181). Of the 83 patients with a follow-up computed tomography scan, 3 showed a < 1 ml collection of blood at the catheter tip. No clinical infections could be attributed to the devices. Only 1 sensor malfunctioned. CONCLUSIONS: Continuous ICP monitoring using the Neurodur-P sensor is safe, reliable, and easy to perform. At present, using this device is the authors' standard method for the long-term monitoring of patients with alterations in complex cerebrospinal fluid dynamics or with implanted shunts. PMID- 18447711 TI - Cerebral oxygenation, vascular reactivity, and neurochemistry following decompressive craniectomy for severe traumatic brain injury. AB - OBJECT: This study addresses the changes in brain oxygenation, cerebrovascular reactivity, and cerebral neurochemistry in patients following decompressive craniectomy for the control of elevated intracranial pressure (ICP) after severe traumatic brain injury (TBI). METHODS: Sixteen consecutive patients with isolated TBI and elevated ICP, who were refractory to maximal medical therapy, underwent decompressive craniectomy over a 1-year period. Thirteen patients were male and 3 were female. The mean age of the patients was 38 years and the median Glasgow Coma Scale score on admission was 5. RESULTS Six months following TBI, 11 patients had a poor outcome (Group 1, Glasgow Outcome Scale [GOS] Score 1-3), whereas the remaining 5 patients had a favorable outcome (Group 2, GOS Score 4 or 5). Decompressive craniectomy resulted in a significant reduction (p < 0.001) in the mean ICP and cerebrovascular pressure reactivity index to autoregulatory values (< 0.3) in both groups of patients. There was a significant improvement in brain tissue oxygenation (PbtO(2)) in Group 2 patients from 3 to 17 mm Hg and an 85% reduction in episodes of cerebral ischemia. In addition, the durations of abnormal PbtO(2) and biochemical indices were significantly reduced in Group 2 patients after decompressive craniectomy, but there was no improvement in the biochemical indices in Group 1 patients despite surgery. CONCLUSIONS: Decompressive craniectomy, when used appropriately in protocol-driven intensive care regimens for the treatment of recalcitrant elevated ICP, is associated with a return of abnormal metabolic parameters to normal values in patients with eventually favorable outcomes. PMID- 18447712 TI - Traumatic brain injury during Operation Iraqi Freedom: findings from the United States Navy-Marine Corps Combat Trauma Registry. AB - OBJECT: The purpose of this study was to characterize traumatic brain injuries (TBIs) among military personnel (primarily Marines) during the second phase of Operation Iraqi Freedom from early in the medical care chain of evacuation through Landstuhl Regional Medical Center, a Level 4 American hospital in Germany. METHODS: Data were obtained from the Navy-Marine Corps Combat Trauma Registry (CTR) and included both battle and nonbattle injuries. Follow-up of patients with TBI was conducted to examine the short-term medical and personnel related effects of TBI among those surviving. RESULTS: Those injured in battle were more likely than those not injured in battle to have multiple TBI diagnoses, a greater number of all diagnoses, more severe TBIs, and to be medically evacuated. Intracranial injuries (for example, concussions) were the predominant type of TBI, although skull fractures and open head wounds were also seen. Improvised explosive devices were the most common cause of TBIs among battle injuries; blunt trauma and motor vehicle crashes were the most common causes among nonbattle injuries. Short-term follow-up of surviving patients with TBI indicated higher morbidity and medical utilization among the patients with more severe TBI, although mental conditions were higher among patients with milder TBI. CONCLUSIONS: Data from the Navy-Marine Corps CTR provide useful information about combatants' TBIs identified early in the combat casualty process. Results may improve clinical care for those affected and suggest strategies for primary prevention. The CTR staff plans to conduct additional follow-up studies of this group of patients with TBI. PMID- 18447713 TI - Chemokine detection in the cerebral tissue of patients with posttraumatic brain contusions. AB - OBJECT: The clinical outcome of patients with severe head injuries is still critically dependent on their secondary injuries. Although hypoxia and hypotension appear to mediate a substantial proportion of secondary injuries, many studies associate secondary brain injury with neuroinflammatory responses. Chemokines have been detected in the cerebrospinal fluid but not in the brain tissue of patients with head trauma. This study was performed to determine if chemokines were expressed in pericontusional brain tissue in patients with moderate or severe head trauma who underwent surgical evacuation of their brain contusions. METHODS: Twelve patients with posttraumatic cerebral contusion requiring a surgical evacuation were studied. A 20- to 40-mg sample of white matter was removed from the surgical cavity in the pericontusional area. Two patients undergoing elective surgery for clip ligation of an unruptured aneurysm were used as controls. The median interval from trauma to biopsy procedure was 44 hours (range 3-360 hours). Total RNA was isolated from these samples and a ribonuclease protection assay was performed to measure the mRNA levels of several chemokines: CCL2, CCL3, CCL4, CCL5, CXCL8, CXCL10, and XCL1. RESULTS: The CCL2, a monocyte chemoattractant produced by activated astrocytes, was the most strongly expressed chemokine, followed by CXCL8, CCL3, and CCL4. The chemokines CXCL10 and CCL5 were expressed at very low levels, and XCL1 was not detected. CONCLUSIONS: Chemokine activation occurs early after moderate or severe head trauma and is maintained for several days after trauma. This event may contribute to neuroinflammatory exacerbation of posttraumatic brain damage in the pericontusional brain tissue. PMID- 18447715 TI - Use of trans sodium crocetinate for sensitizing glioblastoma multiforme to radiation: laboratory investigation. AB - OBJECT: Adjuvant treatment with radiation (radiation therapy or radiosurgery) is a mainstay of treatment for patients harboring glioblastomas multiforme (GBM). Hypoxic regions within the tumor make cells less sensitive to radiation therapy. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion in the brain and elevate the partial brain oxygen level. The goal of this study was to evaluate the radiosensitizing effects of TSC on GBM tumors. METHODS: A rat C6 glioma model was used, in which C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Following creation of a right frontal tumor, animals were randomized into 1 of 4 groups: 1) TSC alone (animal treated with moderate-dose TSC only); 2) radiation (animals receiving 8 Gy of cranial radiation); 3) radiation and low-dose TSC (animals receiving 8 Gy of radiation and 50 microg/kg of TSC); or 4) radiation and moderate-dose TSC (animals receiving 8 Gy of radiation and 100 microg/kg of TSC). Animals were observed clinically for 60 days or until death. Magnetic resonance (MR) imaging was performed at 2-week intervals on each animal and quantitatively evaluated for tumor response. Immunohistochemical analysis was performed on all brain tumors. Survival differences were also evaluated using the Kaplan-Meier method. RESULTS: On MR imaging, a statistically significant reduction in tumor size was seen in the group receiving moderate-dose TSC and radiation treatment compared with the group receiving radiation treatment alone. The rate of tumor growth was significantly less for the combination of TSC and radiation treatment compared with either modality alone. Median survival times for the TSC-only and the radiation therapy-only groups were 15 and 30 days, respectively. The 60-day median survival times for the groups receiving a combination of either low- or moderate-dose TSC with radiation therapy were statistically improved compared with those for the other treatment groups. CONCLUSIONS: Use of TSC improves the extent of GBM tumor regression following radiation therapy and enhances survival. Radiosensitization of hypoxic tumors through increased oxygen diffusion may have clinical utility in patients with GBM tumors but must be explored in a clinical trial. PMID- 18447714 TI - Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. AB - OBJECT: The object of this study was to investigate the safety and clinical responses of immunotherapy targeting the WT1 (Wilms tumor 1) gene product in patients with recurrent glioblastoma multiforme (GBM). METHODS: Twenty-one patients with WT1/HLA-A*2402-positive recurrent GBM were included in a Phase II clinical study of WT1 vaccine therapy. In all patients, the tumors were resistant to standard therapy. Patients received intra-dermal injections of an HLA-A*2402 restricted, modified 9-mer WT1 peptide every week for 12 weeks. Tumor size, which was obtained by measuring the contrast-enhanced area on magnetic resonance images, was determined every 4 weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors (RECIST) 12 weeks after the initial vaccination. Patients who achieved an effective response continued to be vaccinated until tumor progression occurred. Progression-free survival and overall survival after initial WT1 treatment were estimated. RESULTS: The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The clinical responses were as follows: partial response in 2 patients, stable disease in 10 patients, and progressive disease in 9 patients. No patient had a complete response. The overall response rate (cases with complete or partial response) was 9.5%, and the disease control rate (cases with complete or partial response as well as those in which disease was stable) was 57.1%. The median progression-free survival (PFS) period was 20.0 weeks, and the 6-month (26-week) PFS rate was 33.3%. CONCLUSIONS: Although a small uncontrolled nonrandomized trial, this study showed that WT1 vaccine therapy for patients with WT1/HLA-A*2402-positive recurrent GBM was safe and produced a clinical response. Based on these results, further clinical studies of WT1 vaccine therapy in patients with malignant glioma are warranted. PMID- 18447717 TI - Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: laboratory investigation. AB - OBJECT: Many factors relating to the safety and efficacy of convection-enhanced delivery (CED) into intracranial tumors are poorly understood. To investigate these factors further and establish a more clinically relevant large animal model, with the potential to investigate CED in large, spontaneous tumors, the authors developed a magnetic resonance (MR) imaging-compatible system for CED of liposomal nanoparticles into the canine brain, incorporating real-time MR imaging. Additionally any possible toxicity of liposomes containing Gd and the chemotherapeutic agent irinotecan (CPT-11) was assessed following direct intraparenchymal delivery. METHODS: Four healthy laboratory dogs were infused with liposomes containing Gd, rhodamine, or CPT-11. Convection-enhanced delivery was monitored in real time by sequential MR imaging, and the volumes of distribution were calculated from MR images and histological sections. Assessment of any toxicity was based on clinical and histopathological evaluation. Convection-enhanced delivery resulted in robust volumes of distribution in both gray and white matter, and real-time MR imaging allowed accurate calculation of volumes and pathways of distribution. RESULTS: Infusion variability was greatest in the gray matter, and was associated with leakage into ventricular or subarachnoid spaces. Complications were minimal and included mild transient proprioceptive deficits, focal hemorrhage in 1 dog, and focal, mild perivascular, nonsuppurative encephalitis in 1 dog. CONCLUSIONS: Convection-enhanced delivery of liposomal Gd/CPT-11 is associated with minimal adverse effects in a large animal model, and further assessment for use in clinical patients is warranted. Future studies investigating real-time monitored CED in spontaneous gliomas in canines are feasible and will provide a unique, clinically relevant large animal translational model for testing this and other therapeutic strategies. PMID- 18447716 TI - Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor receptor-2: laboratory investigation. AB - OBJECT: Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice. METHODS: Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control. RESULTS: Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. CONCLUSIONS: These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM. PMID- 18447718 TI - Polymorphisms of methionine metabolism and susceptibility to meningioma formation: laboratory investigation. AB - OBJECT: Functionally relevant polymorphisms of methionine and folate metabolism have been shown to be associated with various human cancer entities including cerebral lymphoma and glioblastoma multiforme. The authors investigated the association of 7 functional polymorphisms of methionine metabolism with meningioma formation. METHODS: This case-controlled, monocenter association study included 290 patients of Caucasian origin undergoing surgical resection for intracranial meningioma (World Health Organization [WHO] Grade I, 190 cases; WHO Grade II, 82 cases; WHO Grade III, 18 cases) and 287 age- and sex-matched local controls. The authors analyzed the following genetic variants: dihydrofolate reductase c.594+59del19, 5,10-methylenetetrahydrofolate reductase c.677C > T and c.1298A > C, 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR) c.2756A > G, reduced folate carrier 1 c.80G > A, cystathionine beta-synthase (CBS) c.844_855ins68 and transcobalamin 2 c.776C > G. RESULTS: The variant CBS c.844_855ins68 -- that is, the allele carrying the insertion ("ins" or "i") as opposed to the wild-type allele designated as deletion ("del" or "d") -- was significantly overrepresented in meningioma patients (dd/ id/ii: 0.81/0.18/0.01) in comparison with the controls (dd/id/ii: 0.88/0.12/0; 2 df, chi-square 8.97, p = 0.011; multiple nominal regression with age and sex as covariables). In addition, explorative analyses revealed an association of the MTR c.2756A > G variant with meningioma WHO Grade III (AA/AG/GG: patients, 1.0/0/0; controls, 0.64/0.32/0.04; 2 df, chi-square 14.44, p = 0.001). CONCLUSIONS: The results of this study suggest that genetic variants of methionine metabolism are associated with meningioma formation. PMID- 18447719 TI - Lateral lakes of Trolard: anatomy, quantitation, and surgical landmarks. Laboratory investigation. AB - OBJECT: There is scant and conflicting information in the literature regarding the lateral lacunae, or lateral lakes of Trolard. As these venous structures can be encountered surgically, this study aimed at further elucidating their anatomy, identifying surgical landmarks, and associated quantitation. METHODS: Thirty-five adult cadavers were dissected of lateral lacunae. Following quantitation of the lacunae, these structures were measured, as were the distances from them to the coronal and sagittal sutures. RESULTS: A mean of 1.9 lacunae were identified on the right sides and 1.4 lacunae on the left sides. Although there tended to be slightly more lacunae on the right sides, this difference did not reach statistical significance (p > 0.05). The average lengths of the lacunae were 3.2 and 2.0 cm for the right and left sides, respectively. The mean widths of these venous lakes were 1.5 cm for the right sides and 0.8 cm for the left sides. Lacunae were variably positioned but tended to cluster near the vertex of the skull. None were identified posterior to the lambdoid sutures, and only 5 were found to lie anterior to the coronal suture, with 4 of these located on right sides (p < 0.05). When lacunae were identified anterior to the coronal suture, they were generally 5-6 cm from this structure. The majority of lacunae could be identified between the coronal and lambdoid sutures and within 3 cm of the midline. CONCLUSIONS: Although the situation varies, lateral lacunae are concentrated posterior to the coronal suture and anterior to the lambdoid sutures. They are most often found within 3 cm of the sagittal suture. These previously unreported data could be useful to the neurosurgeon in planning surgical procedures that traverse the calvaria. PMID- 18447720 TI - Neurosurgical implications of mannitol accumulation within a meningioma and its peritumoral region demonstrated by magnetic resonance spectroscopy: case report. AB - Mannitol is widely considered the hyperosmolar therapy of choice in routine neurosurgical practice for the reduction of intracranial pressure (ICP). The authors present a unique case of a patient with a large meningioma treated with mannitol, in which mannitol accumulation within the tumor and its surrounding parenchyma was shown using in vivo magnetic resonance spectroscopy (MRS). This rare appearance of mannitol on MRS was characterized by a wide-based peak at 3.8 ppm, which remained detectable several hours after the last dose. These findings provide the first in vivo evidence in support of the prevailing theory that mannitol leakage into the peritumoral edematous region may contribute to rebound increases in ICP and suggest that this phenomenon has the potential to occur in extraaxial tumors. Judicious use of mannitol in the setting of elevated ICP due to tumor may be indicated to avoid potentially deleterious side effects caused by its accumulation. PMID- 18447721 TI - Metastatic choriocarcinoma with multiple neoplastic intracranial microaneurysms: case report. AB - The authors report on a case of a metastatic choriocarcinoma that mimicked systemic necrotizing vasculitis on a cerebral angiogram. A 35-year-old woman presented with right hemiplegia and a drowsy mental state. A computed tomography (CT) scan revealed an intracerebral hemorrhage in the left frontal region. A cerebral angiogram showed multiple microaneurysms arising from the bilateral anterior cerebral arteries and middle cerebral arteries, and the renal angiogram showed multiple microaneurysms arising from the left distal renal artery. A chest CT scan revealed multiple metastatic lesions in the left lower lung field. The hematoma and microaneurysms were surgically removed. Choriocarcinoma was diagnosed after histological examination. Despite receiving postoperative chemotherapy, the patient died 1 month after the operation. PMID- 18447722 TI - Non-Hodgkin lymphoma of the cranial vault with retrobulbar metastasis mimicking a subacute subdural hematoma: case report. AB - Primary skeletal non-Hodgkin lymphoma is rare. The authors report a case of a small lymphocytic B-cell lymphoma of the skull occurring in a 53-year-old man who presented with right-hand apraxia. Initial computed tomography and magnetic resonance imaging revealed a hematoma-mimicking lesion in the left frontoparietal subdural area. A frontotemporoparietal craniectomy and biopsy procedure yielded a diagnosis of small lymphocytic B-cell lymphoma, with a metastatic nodule in the retrobulbar area. Three years after undergoing radiation therapy and surgery, the patient has shown neurological improvement without systemic dissemination of the malignancy. The lesion in this case was misdiagnosed as a subdural hematoma, and shows the importance of including lymphoma in the differential diagnosis of subdural mass lesions. PMID- 18447723 TI - Craniocerebral penetrating injury caused by a spear gun through the mouth: case report. AB - The authors report a case of a craniocerebral penetrating injury caused by the shaft of a spear gun. The entry point of the spear was located in the mouth without an obvious exit point. The authors first note the presentation of the patient, whose airway was obstructed by the shaft, and then discuss the surgical procedure, which was focused on removing the shaft in an anterograde direction because of an articulated wishbone located at the tip of the shaft. PMID- 18447724 TI - Nonvasculitic autoimmune inflammatory meningoencephalitis as a cause of potentially reversible dementia: report of 4 cases. AB - The aim of this study is to evaluate the presentation of unusual dementias in 4 patients and correlate these presentations with the histopathological findings after brain biopsy sampling to define a diagnostic entity. The authors detail the cases of 4 patients (2 women, 46 and 56 years of age; and 2 men, 67 and 74 years of age) who presented with acute and subsequently subacute encephalopathies. Their bizarre presenting symptom complexes and the results of neurological examinations, radiographic studies, electroencephalography (EEG) recordings, and serological marker tests are reviewed. The diagnostic surgical procedures and successful treatments in these patients are discussed. All 4 patients underwent craniotomy and excisional brain biopsy sampling as part of a comprehensive evaluation. Histopathological confirmation of nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM) by a neuropathologist was present in all 4 patients. All patients were successfully treated with a course of corticosteroid medication. Nonvasculitic autoimmune inflammatory meningoencephalitis is a potentially treatable form of dementia whose salient features include a younger average age at onset, rapid progression with significant cognitive and behavioral features, absence of family history, abnormal EEG findings, and elevated levels of inflammatory markers. Although it is an invasive procedure, brain biopsy sampling is safe and can offer histological confirmation of this condition. This procedure is important because NAIM can be treated successfully if it is distinguished from the nontreatable dementias that mimic it. PMID- 18447725 TI - Use of an inflatable balloon on a catheter to prevent subdural fluid collections after intraventricular tumor surgery: technical note. AB - Ventricular tumor surgeries pose significant challenges to the neurosurgeon. Apart from the operative challenges and typical complications of surgery, subdural fluid collection is common after these surgeries. Various methods have been used to prevent this complication. The authors' technique of implanting an inflatable balloon attached to a catheter after resection of a huge intraventricular tumor was highly effective in preventing the development of a subdural fluid collection. PMID- 18447726 TI - Carpal tunnel syndrome: matching minimally invasive surgical techniques. Technical note. AB - In the past few years, several different minimally invasive surgical techniques have been proposed to decompress the median nerve at the wrist. Use of these techniques has become widespread due to fewer local complications, faster functional recovery, and reduced surgical time. In this paper the authors compare 3 different minimally invasive surgical techniques used at their institution in the past 13 years. Between January 1994 and January 2007, 891 patients underwent 1272 surgeries at the authors' institution for carpal tunnel syndrome (CTS), for which a minimally invasive technique was used. In 473 cases (Group A), the transillumination technique with a single wrist incision and a "carpalotome" (a modified Paine retinaculotome) was used; in 216 cases (Group B), transillumination was abandoned and a single linear wrist incision for access with the carpalotome was performed; and in 583 cases (Group C), the techniques were further modified by making a second incision in the palm using the carpalotome. All 3 groups of patients were homogeneous for age, sex, and duration of the symptomatology. In 90% of the patients in Group A, in 88% of those in Group B, and 99.8% of patients in Group C, complete remission of symptoms was obtained. Due to persistence of symptoms, 44 patients in Group A, 24 in Group B, and only 1 in Group C underwent a repeated operation with the open technique. The only surgical complication requiring repeated operation of the 1272 operations was a lesion of the primitive median artery (1 patient in Group C). The technique of median nerve decompression at the wrist that was used for patients in Group C represents a valid alternative for treatment of CTS. PMID- 18447728 TI - Francois Magendie (1783-1855) and his contributions to the foundations of neuroscience and neurosurgery. AB - Francois Magendie lived during a tumultuous period in French history. Although this early medical pioneer made significant contributions to the fields of neuroanatomy, physiology, and pharmacology, little information is found in the non-French literature regarding this significant person in history. Based on this review, one could also consider this trained surgeon as an early pioneer of neurosurgery. For example, he is known to have used Galvanic current to treat various neuralgias, described a technique for extracting cerebrospinal fluid and quantitated and described its characteristics in normal and pathological specimens, and elucidated the functions of the the cranial nerves using vivisection. Additionally, he accurately described the functions of the dorsal and ventral rootlets using vivisection, and realized that the exposed meninges were susceptible to painful stimuli. Our current knowledge is based on the early contributions of scientists such as Francois Magendie. PMID- 18447727 TI - Acute third cranial nerve palsy from a third cranial nerve schwannoma presenting as a saccular aneurysm on three-dimensional computed tomography angiography: case illustration. PMID- 18447729 TI - The evolution of the endonasal approach for craniopharyngiomas. AB - Craniopharyngiomas have always been an extremely challenging type of tumor to treat. The transsphenoidal route has been used for resection of these lesions since its introduction. The authors present a historical review of the literature from the introduction of the endonasal route for resection of craniopharyngiomas until the present. Abandoned early due to technological limitations, this approach has been expanded both in its application and in its anatomical boundaries with subsequent progressive improvements in outcomes. This expansion has coincided with advances in visualization devices, imaging guidance techniques, and anatomical understanding. The progression from the use of headlights, to microscopy, to endoscopy and fluoroscopy, and finally to modern intraoperative magnetic resonance-guided techniques, combined with collaboration between otolaryngologists and neurosurgeons, has provided the framework for the development of current techniques for the resection of sellar and suprasellar craniopharyngiomas. PMID- 18447730 TI - In Memoriam: Henry D. Garretson, M.D., Ph.D. PMID- 18447733 TI - Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. AB - OBJECT: The authors conducted a study to investigate the long-term natural history of unruptured intracranial aneurysms and the predictive risk factors determining subsequent rupture in a patient population in which surgical selection of cases was not performed. METHODS: One hundred forty-two patients with 181 unruptured aneurysms were followed from the 1950s until death or the occurrence of subarachnoid hemorrhage or until the years 1997 to 1998. The annual and cumulative incidence of aneurysm rupture as well as several potential risk factors predictive of rupture were studied using life-table analyses and Cox's proportional hazards regression models including time-dependent covariates. The median follow-up time was 19.7 years (range 0.8-38.9 years). During 2575 person years of follow up, there were 33 first-time episodes of hemorrhage from previously unruptured aneurysms, for an average annual incidence of 1.3%. In 17 patients, hemorrhage led to death. The cumulative rate of bleeding was 10.5% at 10 years, 23% at 20 years, and 30.3% at 30 years after diagnosis. The diameter of the unruptured aneurysm (relative risk [RR] 1.11 per mm in diameter, 95% confidence interval [CI] 1-1.23, p = 0.05) and patient age at diagnosis inversely (RR 0.97 per year, 95% CI 0.93-1, p = 0.05) were significant independent predictors for a subsequent aneurysm rupture after adjustment for sex, hypertension, and aneurysm group. Active smoking status at the time of diagnosis was a significant risk factor for aneurysm rupture (RR 1.46, 95% CI 1.04-2.06, p = 0.033) after adjustment for size of the aneurysm, patient age, sex, presence of hypertension, and aneurysm group. Active smoking status as a time-dependent covariate was an even more significant risk factor for aneurysm rupture (adjusted RR 3.04, 95% CI 1.21-7.66, p = 0.02). CONCLUSIONS: Cigarette smoking, size of the unruptured intracranial aneurysm, and age, inversely, are important factors determining risk for subsequent aneurysm rupture. The authors conclude that such unruptured aneurysms should be surgically treated regardless of their size and of a patient's smoking status, especially in young and middle-aged adults, if this is technically possible and if the patient's concurrent diseases are not contraindications. Cessation of smoking may also be a good alternative to surgery in older patients with small-sized aneurysms. PMID- 18447734 TI - Embolization of hemangioblastomas. PMID- 18447735 TI - Superior petrosal vein. PMID- 18447738 TI - Radiation therapy: current and evolving strategies for nonmalignant intracranial tumors. PMID- 18447740 TI - The principles of skull base radiosurgery. AB - Stereotactic radiosurgery is commonly used for selected patients with benign cranial base tumors. The goal of radiosurgery is cessation of tumor growth and preservation of neurological function. Over the last 2 decades, the technique of radiosurgery has evolved due to improved imaging, better radiosurgical devices and software, and the continued analysis of results. In this report, the authors discuss technical concepts and dose selection in skull base radiosurgery. PMID- 18447739 TI - Effect of modern radiation techniques on the surgery of nonmalignant intracranial tumors. PMID- 18447741 TI - Surgery and radiotherapy: complementary tools in the management of benign intracranial tumors. AB - Historically, radiation therapy has been used extensively in the treatment of malignant and aggressive intracranial tumors, and the importance of its role has been repeatedly verified by prolonged patient survival rates and increased tumor control. As more modern capabilities are employed in surgery and radiotherapy, attention is being directed to the utility of radiation as either primary or secondary treatment of benign tumors. Specifically, primary treatment encompasses irradiation of small benign tumors without biopsy confirmation of tumor type; secondary treatment involves postoperative radiation therapy, with the possibility that less-aggressive tumor resection may be performed in areas that have a higher probability of resultant neurological deficit. Current literature suggests that this is not only a possible treatment strategy, but that it may be superior to more radical resection in some cases, for example, in vestibular schwannomas and meningiomas. This article provides an overview of factors to consider in the use of radiation therapy and reviews the relationships between radiation and surgery, notably the unique complementary role each plays in the treatment of benign intracranial tumors. PMID- 18447742 TI - Hitting a moving target: evolution of a treatment paradigm for atypical meningiomas amid changing diagnostic criteria. AB - OBJECT: The World Health Organization (WHO) reclassified atypical meningiomas in 2000, creating a more clear and broadly accepted definition. In this paper, the authors evaluated the pathological and clinical transition period for atypical meningiomas according to the implementation of the new WHO grading system at their institution. METHODS: A total of 471 meningiomas occurring in 440 patients between 1994 and 2006 were retrospectively reviewed to determine changes in diagnostic rates, postoperative treatment trends, and early outcomes. RESULTS: Between 1994 and 2000, the incidence of the atypical meningiomas ranged from 0 to 3/year, or 4.4% of the meningiomas detected during the entire period. After 2002, the annual percentage of atypical meningiomas rose over a 2-year period, leveling off at between 32.7 and 35.5% between 2004 and 2006. The authors also found a recent trend toward increased use of adjuvant radiation therapy for incompletely resected atypical meningiomas. Prior to 2003, 18.7% were treated with this therapy; after 2003, 34.4% of lesions received this treatment. Incompletely resected tumors were treated with some form of radiation 76% of the time. In cases of complete resection, most patients were not given adjuvant therapy but were expectantly managed by close monitoring using serial imaging and by receiving immediate treatment for tumor recurrence. The overall recurrence rate for expectantly managed tumors was 9% over 28.2 months, and 75% of recurrences responded to delayed radiation therapy. CONCLUSIONS: The authors documented a significant change in the proportion of meningiomas designated as atypical during a transition period from 2002 to 2004, and propose a conservative strategy for the use of radiation therapy in atypical meningiomas. PMID- 18447743 TI - Radiation therapy and CyberKnife radiosurgery in the management of craniopharyngiomas. AB - OBJECT: Many benign intracranial tumors are amenable to radiotherapy treatment including meningiomas, schwannomas, pituitary tumors, and craniopharyngiomas. The authors present their experience in the treatment of craniopharyngiomas in 16 patients using frameless CyberKnife stereotactic radiosurgery (SRS). The authors discuss the role of radiation therapy in the management of these tumors, and more specifically, the role of CyberKnife SRS. METHODS: Sixteen patients were treated for residual or recurrent craniopharyngioma between 2000 and 2007 with CyberKnife SRS at Stanford University Medical Center. All patients underwent magnetic resonance imaging and visual and neuroendocrine evaluations before and at regular intervals after SRS. A multisession treatment regimen and a nonisocentric treatment plan for each patient were used with a mean marginal dose of 21.6 Gy and a mean maximal dose of 29.9 Gy. RESULTS: There were adequate clinical data to assess outcomes in 11 of 16 patients. Evaluation of patients between 13 and 71 years of age (mean 34.5 years) with a mean follow-up period of 15.4 months revealed no deterioration in visual or neuroendocrine function. Tumor shrinkage was achieved in 7 of these 11 patients, and tumor control in another 3. One patient had cystic enlargement of the residual tumor. CONCLUSIONS: The authors' early experience with the application of CyberKnife SRS to residual or recurrent craniopharyngiomas has been positive; control or shrinkage of the tumor was achieved in 91% of patients, with no visual or neuroendocrine complications. Longer-term follow-up with a larger group of patients is required to fully evaluate the safety and effectiveness of this treatment modality. PMID- 18447744 TI - Evaluation of the role of Gamma Knife surgery in the treatment of craniopharyngiomas. AB - The management of craniopharyngioma involves balancing adequate reduction in tumor volume and prevention of recurrence while minimizing damage to delicate surrounding structures. Because of the lesion's proximity to the optic chiasm and its relationship to the hypothalamic-pituitary axis, morbidity rates following treatment can be high. Gamma Knife surgery (GKS) is now being considered as a viable method of providing tumor control while ensuring minimal side effects. The authors conducted a literature review of 10 studies in which GKS was used to treat craniopharyngioma; some lesions had been previously treated and some had not. The mean marginal dose ranged from 5 to 16.4 Gy (mean 12.3 Gy). Tumor control was achieved in 75% of cases overall and varied with tumor subtype (cystic, solid, mixed). Control was seen in 90% of solid, 80% of cystic, and 59% of mixed tumors. The overall morbidity rate resulting from radiosurgery was 4% and the overall mortality rate was 0.5%. These results suggest that GKS may provide a favorable benefit-to-risk profile for many patients with craniopharyngiomas. PMID- 18447745 TI - Radiation-induced meningiomas: the paradox of radiation treatment. PMID- 18447746 TI - Radiation-induced meningioma. AB - The long-term or delayed side effects of irradiation on neural tissue are now known to include the induction of new central nervous system neoplasms. However, during the first half of the 20th century, human neural tissue was generally considered relatively resistant to the carcinogenic and other ill effects of ionizing radiation. As a result, exposure to relatively high doses of x-rays from diagnostic examinations and therapeutic treatment was common. In the present article the authors review the literature relating to radiation-induced meningiomas (RIMs). Emphasis is placed on meningiomas resulting from childhood treatment for primary brain tumor or tinea capitis, exposure to dental x-rays, and exposure to atomic explosions in Hiroshima and Nagasaki. The incidence and natural history of RIMs following exposure to high- and low-dose radiation is presented, including latency, multiplicity, histopathological features, and recurrence rates. The authors review the typical presentation of patients with RIMs and discuss unique aspects of the surgical management of these tumors compared with sporadic meningioma, based on their clinical experience in treating these lesions. PMID- 18447747 TI - Radiation therapy in the treatment of pituitary tumors. AB - The treatment of pituitary tumors has progressed into a multidisciplinary approach that involves neurosurgeons, radiation oncologists, and endocrinologists. This has allowed improved outcomes in treatment of pituitary tumors due to a combination of surgical, medical, and radiation therapies. In this study, the authors review the role of radiation therapy in the treatment of pituitary adenomas. PMID- 18447748 TI - Radiosurgery for hypothalamic hamartomas. AB - Radiosurgery plays an important role in the treatment of refractory seizures induced by hypothalamic hamartomas (HHs). These lesions, deeply located and surrounded by a delicate vascular and neuronal network, are often associated with catastrophic epilepsy leading to progressive cognitive and behavioral deterioration. Surgical approaches include microsurgical resection, endoscopic resection or disconnection, radiofrequency lesioning, and interstitial brachytherapy. Radiosurgery is an emerging treatment modality for HHs, which provides excellent seizure outcomes and no lasting complications to date. PMID- 18447754 TI - Transfer RNA bindings to antitumor estradiol-platinum(II) hybrid and cisplatin. AB - The anticancer platinum (Pt) drugs exert their antitumor activity by direct or indirect Pt-DNA binding. It has been shown that Pt drugs can induce major DNA damage and minor RNA damage during cancer treatment. A recent report showed that a new anticancer estradiol-Pt(II) hybrid molecule (CD-37) binds DNA bases indirectly, while being more effective than cis-diaminedichloroplatinum(II) (cisplatin) against several types of cancer. In this report, we examine the bindings of CD-37 and cisplatin drugs with transfer RNA (tRNA) in vitro and compare the results to those of the corresponding Pt-DNA complexes. Solutions containing various CD-37 or cisplatin concentrations were reacted with tRNA at physiological pH. Using Fourier transform infrared (FTIR), UV-visible, and circular dichroism spectroscopic methods, the drug binding mode, the binding constant, and RNA structural variations are determined for Pt-tRNA complexes in aqueous solution. Structural analysis showed direct binding of cisplatin drug to guanine and adenine N7 sites, while both direct and indirect interactions of CD 37 with tRNA bases and the backbone phosphate group were observed. The overall binding constants estimated were K(CD-37) = 2.77 (+/-0.90) x 10(4) M(1) and K(cisplatin) = 1.72 (+/-0.50) x 10(4) M(1). Major aggregation of tRNA occurs at high CD-37 concentrations, while RNA remains in the A-family structure. PMID- 18447755 TI - The transactivation function of the Pea3 subfamily Ets transcription factors is regulated by sumoylation. AB - Pea3, an Ets transcriptional factor, comprises multiple regulatory domains that affect its DNA binding and transcriptional activation. The aim of this work is to uncover the mechanism of action of negative regulatory regions flanking the transactivation domain. Mutagenesis of amino acid residues in the C-terminal negative regulatory region for transactivation revealed critical residues, including a lysine residue, K96, required for its function. Corresponding mutations in the closely related Pea3 subfamily members, Erm and Er81, also dramatically increased the transactivation capacity of their activation domains. Interestingly, all three proteins are sumoylated at this conserved lysine residue. Pea3 contains four other lysines, K222, K256, K318, and K437, embedded in a perfect SUMO consensus motif. The contribution of these lysine residues to the regulation of Pea3 activity and their sumoylation pattern was explored using a GAL4-PEA3 chimera devoid of the ETS DNA-binding domain and by analyzing the native protein. All four candidate SUMO sites included in the GAL4-PEA3 chimera were modified by sumoylation, and their simultaneous mutation dramatically increased the transactivation potential of Pea3. Similar analysis of full-length Pea3 confirmed K96, K222, and K256 as major SUMO modification sites. Collectively, these observations suggest that the activity of Pea3 and its paralogs, Erm and Er81, is negatively regulated by sumoylation. PMID- 18447756 TI - Interaction of diazinon with DNA and the protective role of selenium in DNA damage. AB - The interaction of native calf thymus DNA with Diazinon, an organophophorus insecticide, in HEPES buffer at neutral pH, was monitored by UV absorption spectrophotometry, circular dichroism (CD), electrochemical technique, and fluorescence spectroscopy. UV spectra showed hyperchromicity and blue shift with the increase of Diazinon concentration. Fluorescence spectroscopy results indicated that the probable quenching mechanism of DNA-ethidium bromide (EB) fluorescence by Diazinon is a dynamic quenching procedure, because the Stern Volmer quenching constant (K(SV)) increased with the temperature rising. Unchanging of the CD signal around 280 nm with increasing ratio of Diazinon to DNA is an important evidence for non-intercalative-binding mode of Diazinon with DNA. Stoichiometry measurement of the DNA-nDiazinon indicated that a stable 1:2 complex of DNA-Diazinon was formed under the selected conditions. The electrochemical study of the Diazinon-DNA interaction was carried out by incubation of DNA with Diazinon in the presence of varying amounts of selenium (Se). This technique revealed that Se is able to diminish the DNA damage effect of Diazinon. PMID- 18447758 TI - The prevalence of depression in older U.S. women: 2006 behavioral risk factor surveillance system. AB - Depression, a type of mood disorder, is associated with psychological distress and suffering, and it can lead to impairments in physical, mental, and social functioning. The goal of this commentary is to provide an estimate of the prevalence of current depression and lifetime diagnosis for 14,425 community dwelling U.S. women aged 65 and older. Using information from the 2006 Behavioral Risk Factor Surveillance System (BRFSS), participants reported their lifetime diagnosis of depression and completed the Patient Health Questionnaire 8 to assess current depression and its severity. Our findings indicate that 5.9% of women 65 years old and older have current depression, 94.1% reported either no depressive symptoms or mild depressive symptoms, and 12.3% reported a lifetime diagnosis of depression. Mental health is integral to overall health and well being and should be treated in older women with the same urgency as physical health. Depression is a mental health issue of particular concern for women, given their increasing numbers, higher proportion in the US population, and role as caregivers. Continued surveillance from a system such as the BRFSS is needed to track changes in the mental health of older adults. PMID- 18447759 TI - The accuracy of women performing vaginal pH self-testing. AB - OBJECTIVE: To determine if women could measure their vaginal pH as accurately as could physicians. METHODS: Each participant measured her vaginal pH using a swab, completed a survey, and then was seen by her physician, who also performed a vaginal pH test. The physician did not have access to the patient's pH reading; only the study coordinator recorded patient results. Accuracy of patient measurements compared with physician results was analyzed by the kappa statistic. RESULTS: A total of 161 women were enrolled in the study. The average difference between the patients' pH readings and the physicians' readings was <0.5. Overall, 85% of the patients' readings were in agreement with the physicians' readings, and the kappa statistic was 0.6. CONCLUSIONS: Study participants could accurately measure vaginal pH through self-testing. Vaginal pH self-testing may be a convenient tool to help women determine whether they should use an over-the counter (OTC) antifungal medication or go to a physician for diagnostic workup. PMID- 18447760 TI - Predictors of mammography screening among ethnically diverse low-income women. AB - BACKGROUND AND PURPOSE: Breast cancer is the second leading cause of cancer deaths among women in the United States. Minority women are less likely to be screened and more likely to die from breast cancer than are Caucasian women. Although some studies have examined ethnic disparities in mammography screening, no study has examined whether there are ethnic disparities among low-income, ethnically diverse women. The present study was designed to determine whether there are ethnic disparities in mammography screening and predictors of screening among low-income African American, Mexican American, and Caucasian women, and to determine whether the disparities and predictors vary across ethnic groups. METHODS: The participants were 146 low-income women who were Mexican American (32%), African American (31%), or Caucasian (37%). Statistical analyses were performed to assess the relationships between mammography screening during the past 2 years and potential predictors of screening, both within ethnic groups and for the combined sample. RESULTS: The results varied depending on whether analyses combined ethnic groups or were performed within each of the three ethnic groups. CONCLUSIONS: It is, therefore, important to examine within-group differences when examining ethnic disparities in predictors of mammography. PMID- 18447761 TI - Domestic violence during pregnancy: survey of patients and healthcare providers. AB - BACKGROUND: Domestic violence is a major public health problem; surveys report that 3%-17% of pregnant women suffer from it during their pregnancy, endangering fetal and maternal health. First, we aim (1) to estimate the prevalence of domestic violence in women who had been admitted to the maternity department of a public hospital that provides healthcare to a multicultural population, (2) to identify risk factors for domestic violence, and (3) to evaluate obstetrical complications. Second, we aim (4) to evaluate the attitude of healthcare providers toward screening for domestic violence. METHODS: For six consecutive weeks, 200 women were systematically interviewed and screened for domestic violence in the early postpartum; 56 healthcare providers were interviewed. RESULTS: Twenty-two women [11%] were victims of violence during their recent pregnancy. These women have less family and social support than nonabused women, have fewer stable relationships, and suffer more frequently from affective disorders. There were no differences in terms of obstetrical complications. Most healthcare providers do not systematically screen for domestic violence during pregnancy because of language and cultural barriers, fear of shocking the patient, and lack of competence in how to manage the problem. CONCLUSIONS: Systematic screening for domestic violence should be recommended during pregnancy, considering its high prevalence. PMID- 18447762 TI - The effect of drug consultation center guidance on contraceptive use among women using isotretinoin: a randomized, controlled study. AB - BACKGROUND: Women of reproductive age treated with isotretinoin are required to use two forms of contraceptives, yet adherence to the recommendations is limited. Our objective was to determine if an active intervention by a drug consultation center (DCC) will increase contraceptive use among women taking isotretinoin. METHODS: In a randomized, controlled study, women of reproductive age who called the DCC seeking advice regarding isotretinoin were randomly assigned to an intervention group (information by phone during initial interview, by mailed written form, and by text messages sent to their cellular phones) and a control group (information given once). A follow-up call was made to all women 3 months after the first interview. RESULTS: One hundred eight women (50 in the intervention group and 58 control) were enrolled. Most women do not adhere to the recommended contraceptive use. After 3 months, 50% of the study group and 40% of the control group were using a contraceptive (p = 0.41), and only 2 women in each group used two methods of contraception. CONCLUSIONS: Strategies to increase adherence to contraceptive use among women treated with isotretinoin are needed. PMID- 18447763 TI - Disparities in child abuse victimization in lesbian, bisexual, and heterosexual women in the Nurses' Health Study II. AB - BACKGROUND: A growing body of research documents multiple health disparities by sexual orientation among women, yet little is known about the possible causes of these disparities. One underlying factor may be heightened risk for abuse victimization in childhood in lesbian and bisexual women. METHODS: Using survey data from 63,028 women participating in the Nurses' Health Study II, we investigated sexual orientation group differences in emotional, physical, and sexual abuse in childhood and adolescence. Multivariable log-binomial and linear regression models were used to examine orientation group differences in prevalence and severity of abuse, with heterosexual as the referent and controlling for sociodemographics. RESULTS: Results showed strong evidence of elevated frequency, severity, and persistence of abuse experienced by lesbian and bisexual women. Comparing physical abuse victimization occurring in both childhood and adolescence, lesbian (30%, prevalence ratio [PR] 1.61, 95% confidence interval [CI] 1.40, 1.84) and bisexual (24%, PR 1.26, 95% CI 1.00, 1.60) women were more likely to report victimization than were heterosexual women (19%). Similarly, comparing sexual abuse victimization occurring in both age periods, lesbian (19%, PR 2.16, 95% CI 1.80, 2.60) and bisexual (20%, PR 2.29, 95% CI 1.76, 2.98) women were more likely to report victimization than were heterosexual women (9%). CONCLUSIONS: This study documents prevalent and persistent abuse disproportionately experienced by lesbian and bisexual women. PMID- 18447764 TI - HIV testing practices among women living in public housing in Puerto Rico. AB - OBJECTIVE: The objective of our study was to examine HIV testing practices among a large sample of women living in public housing in Puerto Rico and the relationships among HIV testing, sociodemographic variables, and HIV-related behaviors. METHODS: A total of 1138 women were surveyed between April and August 2006 using a self-administered survey instrument. RESULTS: Eighty-two percent of the women in the sample group reported a history of HIV testing. Hierarchical logistic regression analyses revealed that those adults who were at least 25 years of age and those who perceived some risk of HIV were more likely to report previous HIV testing. Also, those who had attended an HIV/AIDS education workshop or discussion and those who reported knowing persons living with HIV/AIDS were more likely to report previous testing. CONCLUSIONS: A large percentage of the women in our study have been tested for HIV; it is imperative, however, that appropriate HIV education and prevention messages be given to them when they receive their results. Client-initiated HIV testing to learn HIV status provided through counseling and testing remains critical to the effectiveness of HIV prevention. It is unwise to underestimate the importance of being tested. One of the first steps in self-protection from HIV is to be informed of one's HIV status, which allows one to make appropriate and responsible sexual decisions. Future success in decreasing the number of new infections among women will result from targeting women who may be at high risk, although not because of sex work or drug use. Increasing knowledge of HIV serostatus and the implications of these results, especially among those who are infected, can serve as a gateway to sustained behavioral risk reduction intervention, as well as to care and treatment. Considering the fact that both the actual and estimated numbers of HIV/AIDS cases among women in Puerto Rico continue to increase, it is clear that effective, targeted, and aggressive strategies are urgently needed to prevent both primary and secondary HIV transmission. PMID- 18447766 TI - Jennifer fever in academic medicine: comment. PMID- 18447771 TI - Implementing a future national center concept in veterinary education for the dairy industry. PMID- 18447765 TI - Insulin sensitivity, food intake, and cravings with premenstrual syndrome: a pilot study. AB - OBJECTIVE: The objective of this pilot study was to evaluate possible differences in insulin sensitivity, food intake, and cravings between the follicular and luteal phases of the menstrual cycle in women with premenstrual syndrome (PMS). METHODS: Subjects were screened for PMS using the Penn Daily Symptom Rating (DSR) scale. Each subject had two overnight admissions (once in each cycle phase) to the Hospital of the University of Pennsylvania. They performed 3-day diet histories prior to each hospitalization. After admission, subjects received dinner and a snack, then were fasted until morning, when they underwent a frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity was determined by Minimal Model analysis. Blinded analysis of diet histories and inpatient food intake was performed by a registered dietitian. RESULTS: There was no difference found in insulin sensitivity between cycle phases (n = 7). There were also no differences in proportions of macronutrients or total kilocalories by cycle phase, despite a marked difference in food cravings between cycle phase, with increased food cravings noted in the luteal phase (p = 0.002). Total DSR symptom scores decreased from a mean of 186 (+/ 29.0) in the luteal phase to 16.6 (+/-14.2) in the follicular phase. Women in this study consumed relatively high proportions of carbohydrates (55%-64%) in both cycle phases measured. CONCLUSIONS: These findings reinforce the suggestion that although the symptom complaints of PMS are primarily confined to the luteal phase, the neuroendocrine background for this disorder may be consistent across menstrual cycle phases. PMID- 18447772 TI - What is your diagnosis? 1 month history of anorexia, weight loss, and 2 subcutaneous nodular swellings in the occipital area. PMID- 18447773 TI - Anesthesia case of the month. Development of the Cushing reflex secondary to a dangerous increase in intracranial pressure. PMID- 18447774 TI - Zoonosis update: West Nile virus. PMID- 18447775 TI - Acid-base and hormonal abnormalities in dogs with naturally occurring diabetes mellitus. AB - OBJECTIVE: To examine acid-base and hormonal abnormalities in dogs with diabetes mellitus. DESIGN: Cross-sectional study. ANIMALS: 48 dogs with diabetes mellitus and 17 healthy dogs. PROCEDURES: Blood was collected and serum ketone, glucose, lactate, electrolytes, insulin, glucagon, cortisol, epinephrine, norepinephrine, nonesterified fatty acid, and triglyceride concentrations were measured. Indicators of acid-base status were calculated and compared between groups. RESULTS: Serum ketone and glucose concentrations were significantly higher in diabetic than in healthy dogs, but there was no difference in venous blood pH or base excess between groups. Anion gap and strong ion difference were significantly higher and strong ion gap and serum bicarbonate concentration were significantly lower in the diabetic dogs. There were significant linear relationships between measures of acid-base status and serum ketone concentration, but not between measures of acid-base status and serum lactate concentration. Serum insulin concentration did not differ significantly between groups, but diabetic dogs had a wider range of values. All diabetic dogs with a serum ketone concentration > 1,000 micromol/L had a serum insulin concentration < 5 microU/mL. There were strong relationships between serum ketone concentration and serum glucagon-insulin ratio, serum cortisol concentration, and plasma norepinephrine concentration. Serum beta-hydroxybutyrate concentration, expressed as a percentage of serum ketone concentration, decreased as serum ketone concentration increased. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that ketosis in diabetic dogs was related to the glucagon-insulin ratio with only low concentrations of insulin required to prevent ketosis. Acidosis in ketotic dogs was attributable largely to high serum ketone concentrations. PMID- 18447776 TI - Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. AB - OBJECTIVE: To evaluate the effects of twice-daily oral administration of a low dose of trilostane treatment and assess the duration of effects after once-daily trilostane administration in dogs with naturally occurring hyperadrenocorticism (NOH). DESIGN: Prospective study. ANIMALS: 28 dogs with NOH. PROCEDURES: 22 dogs received 0.5 to 2.5 mg of trilostane/kg (0.23 to 1.14 mg/lb) orally every 12 hours initially. At intervals, dogs were reevaluated; owner assessment of treatment response was recorded. To assess drug effect duration, 16 of the 22 dogs and 6 additional dogs underwent 2 ACTH stimulation tests 3 to 4 hours and 8 to 9 hours after once-daily trilostane administration. RESULTS: After 1 to 2 weeks, mean trilostane dosage was 1.4 mg/kg (0.64 mg/lb) every 12 hours (n = 22 dogs; good response [resolution of signs], 8; poor response, 14). Four to 8 weeks later, mean dosage was 1.8 mg/kg (0.82 mg/lb) every 12 or 8 hours (n = 21 and 1 dogs, respectively; good response, 15; poor response, 5; 2 dogs were ill). Eight to 16 weeks after the second reevaluation, remaining dogs had good responses (mean dosages, 1.9 mg/kg [0.86 mg/lb], q 12 h [n = 13 dogs] and 1.3 mg/kg [0.59 mg/lb], q 8 h [3]). At 3 to 4 hours and 8 to 9 hours after once-daily dosing, mean post-ACTH stimulation serum cortisol concentrations were 2.60 and 8.09 Pg/dL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with NOH, administration of trilostane at low doses every 12 hours was effective, although 2 dogs became ill during treatment. Drug effects diminished within 8 to 9 hours. Because of potential adverse effects, lower doses should be evaluated. PMID- 18447777 TI - Clinical and clinicopathologic features of dogs that consumed foodborne hepatotoxic aflatoxins: 72 cases (2005-2006). AB - OBJECTIVE: To characterize clinical signs, clinicopathologic features, treatments, and survival in dogs with naturally acquired foodborne aflatoxicosis. DESIGN: Retrospective case series. ANIMALS: 72 dogs that consumed aflatoxin contaminated commercial dog food. PROCEDURES: Medical records of affected dogs were reviewed. Between December 2005 and March 2006, dogs were identified as having foodborne aflatoxin hepatotoxicosis on the basis of the history of consumption of contaminated food or characteristic histopathologic lesions (subject dog or a recently deceased dog in the same household or kennel). Recorded information included signalment, clinical features, clinicopathologic test results, treatments, and survival. Data were analyzed by survival status. RESULTS: Most dogs were of large breeds from breeding kennels. No significant differences were found in age or weight between 26 (36%) survivor dogs and 46 (64%) nonsurvivor dogs. Severity of clinical signs varied widely; 7 dogs died abruptly. In order of onset, clinical features included anorexia, lethargy, vomiting, jaundice, diarrhea (melena, hematochezia), abdominal effusion, peripheral edema, and terminal encephalopathy and hemorrhagic diathesis. Common clinicopathologic features included coagulopathic and electrolyte disturbances, hypoproteinemia, increased serum liver enzyme activities, hyperbilirubinemia, and hypocholesterolemia. Cytologic hepatocellular lipid vacuolation was confirmed in 11 dogs examined. In comparisons of clinicopathologic test results between survivor and nonsurvivor dogs, only granular cylindruria (7/21 dogs) consistently predicted death. Best early markers of aflatoxicosis were low plasma activities of anticoagulant proteins (protein C, antithrombin) and hypocholesterolemia. Despite aggressive treatment, many but not all severely affected dogs died. CONCLUSIONS AND CLINICAL RELEVANCE: Serum liver enzyme activities and bilirubin concentration were unreliable early markers of aflatoxin hepatotoxicosis in dogs. Hypocholesterolemia and decreased plasma protein C and antithrombin activities may function as exposure biomarkers. PMID- 18447778 TI - Long-term outcome of domestic ferrets treated surgically for hyperadrenocorticism: 130 cases (1995-2004). AB - OBJECTIVE: To determine the long-term survival rate and factors that affect survival time of domestic ferrets treated surgically for hyperadrenocorticism. STUDY DESIGN: Retrospective case series. ANIMALS: 130 ferrets with hyperadrenocorticism that were treated surgically. PROCEDURES: Medical records of ferrets surgically treated for hyperadrenocorticism were reviewed. Data recorded included signalment, duration of clinical signs prior to hospital admission, CBC values, serum biochemical analysis results, anesthetic time, surgical time, concurrent diseases, adrenal gland affected (right, left, or both [bilateral]), histopathologic diagnosis, surgical procedure, caudal vena caval involvement (yes or no), postoperative melena (yes or no), days in hospital after surgery, and whether clinical signs of hyperadrenocorticism developed after surgery. RESULTS: 130 ferrets were entered in the study (11 of 130 ferrets were admitted and underwent surgery twice). The 1- and 2-year survival rates were 98% and 88%, respectively. A 50% survival rate was never reached. Combined partial adrenal gland resection with cryosurgery had a significantly negative effect on survival time. No other risk factors were identified. Survival time was not significantly affected by either histopathologic diagnosis or specific affected adrenal gland (right, left, or bilateral). CONCLUSIONS AND CLINICAL RELEVANCE: Ferrets with adrenal gland masses that were treated surgically had a good prognosis. Survival time of ferrets with hyperadrenocorticism undergoing surgery was not affected by the histologic characteristic of the tumor, the adrenal glands affected (right, left, or bilateral), or complete versus partial adrenal gland resection. Debulking was a sufficient surgical technique to allow a favorable long-term outcome when complete excision was not possible. PMID- 18447780 TI - Periparturient hemorrhage in mares: 73 cases (1998-2005). AB - OBJECTIVE: To determine signalment, physical examination and clinicopathologic abnormalities, outcome, and subsequent fertility of mares with periparturient hemorrhage (PPH) and identify factors associated with outcome (ie, survival vs death). DESIGN: Retrospective case series. ANIMALS: 73 mares. PROCEDURES: Medical records were reviewed for information on age, breed, initial complaint, physical examination and clinicopathologic abnormalities, treatment, outcome, and subsequent fertility. RESULTS: Median age was 14.0 years (range, 5 to 24 years), and median number of foals produced prior to the diagnosis of PPH was 8 (range, 1 to 16). Ten (14%) mares had prepartum hemorrhage and 63 (86%) had postpartum hemorrhage. Treatment was aimed at restoring cardiovascular volume, enhancing coagulation, controlling pain, and reducing the effects of endotoxemia. Sixty-one (84%) mares survived and 12 (16%) died or were euthanized. Common complications included fever, leukopenia, retained fetal membranes, increased digital pulses, thrombophlebitis, and cardiac arrhythmias. Of the 53 surviving mares for which subsequent breeding information was available, 26 (49%) produced 1 or more foals after recovering from PPH. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that PPH can develop in mares of any age and parity. Treatment was associated with a good prognosis for survival and a reasonable prognosis for future fertility. PMID- 18447781 TI - Indications for and short- and long-term outcome of permanent tracheostomy performed in standing horses: 82 cases (1995-2005). AB - OBJECTIVE: To identify indications for and short- and long-term outcome of permanent tracheostomy performed in standing horses. DESIGN: Retrospective case series. ANIMALS: 82 horses undergoing permanent tracheostomy. PROCEDURES: Data obtained from medical records included signalment, diagnosis, surgical technique, complications, use of the horse before and after surgery, and owner satisfaction. Follow-up information was obtained through a telephone questionnaire administered to owners. RESULTS: Indications for permanent tracheostomy included nasopharyngeal cicatrix (n = 59), arytenoid chondropathy (55), and laryngeal hemiplegia (20); 54 horses had multiple indications for tracheostomy. Complications identified prior to discharge included partial dehiscence (n = 8), transient fever (10), and excessive swelling (13). Complications identified after discharge included partial dehiscence (n = 3), inversion of skin (2), and stenosis of the tracheostomy requiring repair (1). Long-term follow-up information was available for 64 horses. Fifty-seven of the 64 (89%) horses returned to their previous use, and owners of 63 (98%) horses reported being very satisfied with the results. The owner of 1 (2%) horse was unsatisfied with the results. The 1-year survival rate was 97% (95% confidence interval, 95% to 100%). Mean estimated truncated survival time (ie, failure-free period) was 9.7 years (95% confidence interval, 9.3 to 10.1 years). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that permanent tracheostomy can be safely performed in standing horses and was a viable treatment for horses with obstructive disease of the upper respiratory tract that was unresponsive to medical treatment or other surgical treatments. PMID- 18447782 TI - Collection and analysis of peritoneal fluid from healthy llamas and alpacas. AB - OBJECTIVE: To describe a technique for abdominocentesis in camelids and report peritoneal fluid biochemical and cytologic findings from healthy llamas and alpacas. DESIGN: Prospective study. Animals-17 adult llamas and 5 adult alpacas. PROCEDURES: Right paracostal abdominocentesis was performed. Peritoneal fluid was collected by gravity flow into tubes containing potassium-EDTA for cell count and cytologic evaluation and lithium heparin for biochemical analysis. Blood samples were collected via jugular venipuncture into heparinized tubes at the same time. Cytologic components were quantified. Fluid pH and concentrations of total carbon dioxide, sodium, potassium, chloride, lactate, and glucose were compared between peritoneal fluid and venous blood. RESULTS: All but 3 camelids had peritoneal fluid cell counts of < 3,000 nucleated cells/microL, with < 2,000 neutrophils/microL and < 1,040 large mononuclear cells/microL. All but 1 had peritoneal fluid protein concentrations of > or = 2.5 g/dL. Peritoneal fluid of camelids generally contained slightly less glucose, lactate, and sodium and roughly equal concentrations of potassium and chloride as venous blood. CONCLUSIONS AND CLINICAL RELEVANCE: Peritoneal fluid was collected safely from healthy camelids. Compared with blood, peritoneal fluid usually had a low cell count and protein concentration, but some individuals had higher values. Electrolyte concentrations resembled those found in blood. High cell counts and protein concentrations found in peritoneal fluid of some healthy camelids may overlap with values found in diseased camelids, complicating interpretation of peritoneal fluid values. PMID- 18447783 TI - Characterization of hypertriglyceridemia and response to treatment with insulin in llamas and alpacas: 31 cases (1995-2005). AB - OBJECTIVE: To evaluate camelids with hypertriglyceridemia with regard to signalment, clinical features of disease, and response to treatment with insulin. DESIGN: Retrospective case series. ANIMALS: 23 alpacas and 8 llamas with hypertriglyceridemia. PROCEDURES: For analysis of medical record data, 20 hypertriglyceridemic camelids with multiple recorded measurements of serum or plasma triglycerides concentration were classified as follows: those with an initial triglycerides concentration > 60 to > or = 500 mg/dL that were or were not treated with insulin (HT-I and HT-N camelids, respectively) and those with an initial triglycerides concentration > 500 mg/dL that were treated with insulin (lipemic [LIP-I] camelids). Only 1 recorded triglycerides concentration was available for an additional 11 hypertriglyceridemic camelids; data from those records were included in the characterization of signalment and clinical features of disease. RESULTS: Compared with the general population of hospitalized camelids, hypertriglyceridemic camelids did not differ significantly with respect to age or sex. Of 22 female camelids, only 7 were lactating or pregnant. Serum or plasma triglycerides concentrations in HT-N and HT-I camelids did not differ significantly at admission, but triglycerides concentrations in HT-I camelids decreased significantly after insulin treatment. Posttreatment triglycerides concentrations in HT-I camelids were significantly lower than those in HT-N camelids. During the period of hospitalization, triglycerides concentrations in HT-N camelids increased, whereas those in LIP-I camelids decreased significantly. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that hypertriglyceridemia affects llamas and alpacas of all ages and both sexes. Insulin treatment may reduce serum or plasma triglycerides concentrations in camelids with hypertriglyceridemia. PMID- 18447784 TI - Comments on pathophysiology of angle changes caused by iris bowing. PMID- 18447786 TI - Results of cytologic and microbiologic analysis of bronchoalveolar lavage fluid in New Zealand White rabbits. AB - OBJECTIVE: To determine cytologic and microbiologic findings in bronchoalveolar lavage (BAL) fluid and SpO(2) values obtained during BAL in healthy rabbits. ANIMALS: 9 rabbits. PROCEDURES: Bronchoscopic BAL of left and right caudal lobar bronchi (LB2 and RB4) was performed with 3 mL of sterile saline (0.9% NaCl) solution; SpO(2) was measured before, during, and after BAL. Percentage fluid recovered, total leukocyte counts, and differential cell counts were determined. Aerobic and anaerobic bacterial, mycoplasmal, and fungal cultures were performed from combined LB2 and RB4 samples. RESULTS: Mean +/- SD percentage fluid volumes recovered from LB2 and RB4 were 53 +/- 13% and 63 +/- 13%, respectively. Mean +/- SD total leukocyte counts from LB2 and RB4 were 422 +/- 199 cells/microL and 378 +/- 97 cells/microL, respectively. Macrophages were most frequently identified. There were no significant differences in volumes retrieved, total leukocyte counts, or differential cell percentages between LB2 and RB4. Microbial culture results were negative for 3 rabbits and positive for mixed aerobic and anaerobic bacterial growth in 6 and 2 rabbits, respectively. The SpO(2) was > or = 95% in 7 of 9 rabbits after anesthetic induction, < 95% in 5 of 6 rabbits 1 minute after BAL, and > or = 95% in 5 of 9 rabbits and > 90% in 4 of 9 rabbits 3 minutes after BAL. CONCLUSIONS AND CLINICAL RELEVANCE: Bronchoscopic BAL with 3 mL of saline solution provided adequate fluid recovery for microbiologic and cytologic examination from the caudal lung lobes. Transient low SpO(2) was detected immediately after BAL. PMID- 18447787 TI - Effect of acepromazine, butorphanol, or N-butylscopolammonium bromide on visceral and somatic nociception and duodenal motility in conscious horses. AB - OBJECTIVE: To evaluate effects of butorphanol, acepromazine, and N butylscopolammonium bromide (NBB) on visceral and somatic nociception and duodenal motility in conscious, healthy horses. ANIMALS: 6 adult horses. PROCEDURES: Visceral nociception was evaluated by use of colorectal distention (CRD) and duodenal distention (DD) threshold. Somatic nociception was evaluated via thermal threshold (TT). Nose-to-ground height, heart rate, and respiratory rate were also measured. Each horse received each treatment in randomized order; investigators were not aware of treatments. Butorphanol was administered IV as a bolus (18 microg/kg) followed by constant rate infusion at 13 microg/kg/h for 2 hours, whereas acepromazine (0.04 mg/kg), NBB (0.3 mg/kg), and saline (0.9% NaCl) solution (2 mL) were administered IV as a bolus followed by constant rate infusion with saline solution (10 mL/h) for 2 hours. Variables were measured before and for 3 hours after treatment. Data were analyzed by use of a 3-factor ANOVA followed by a Bonferroni t test for multiple comparisons. RESULTS: Nose-to ground height decreased after acepromazine. Respiratory rate decreased after acepromazine and increased after butorphanol. Heart rate increased briefly after NBB. Some horses had an increase in TT after butorphanol and acepromazine, but there was not a significant treatment effect over time. Drug effect on DD or motility was not evident. The CRD threshold increased significantly at 5, 65, 155, and 185 minutes after acepromazine and from 5 to 65 minutes after NBB. CONCLUSIONS AND CLINICAL RELEVANCE: Each drug caused predictable changes in sedation and vital signs, but consistent anti-nociceptive effects were not evident. PMID- 18447788 TI - Cardiopulmonary effects of anesthetic induction with thiopental, propofol, or a combination of ketamine hydrochloride and diazepam in dogs sedated with a combination of medetomidine and hydromorphone. AB - OBJECTIVE: To evaluate the cardiopulmonary effects of anesthetic induction with thiopental, propofol, or ketamine hydrochloride and diazepam in dogs sedated with medetomidine and hydromorphone. ANIMALS: 6 healthy adult dogs. PROCEDURES: Dogs received 3 induction regimens in a randomized crossover study. Twenty minutes after sedation with medetomidine (10 microg/kg, IV) and hydromorphone (0.05 mg/kg, IV), anesthesia was induced with ketamine-diazepam, propofol, or thiopental and then maintained with isoflurane in oxygen. Measurements were obtained prior to sedation (baseline), 10 minutes after administration of preanesthetic medications, after induction before receiving oxygen, and after the start of isoflurane-oxygen administration. RESULTS: Doses required for induction were 1.25 mg of ketamine/kg with 0.0625 mg of diazepam/kg, 1 mg of propofol/kg, and 2.5 mg of thiopental/kg. After administration of preanesthetic medications, heart rate (HR), cardiac index, and PaO(2) values were significantly lower and mean arterial blood pressure, central venous pressure, and PaCO(2) values were significantly higher than baseline values for all regimens. After induction of anesthesia, compared with postsedation values, HR was greater for ketamine diazepam and thiopental regimens, whereas PaCO(2) tension was greater and stroke index values were lower for all regimens. After induction, PaO(2) values were significantly lower and HR and cardiac index values significantly higher for the ketamine-diazepam regimen, compared with values for the propofol and thiopental regimens. CONCLUSIONS AND CLINICAL RELEVANCE: Medetomidine and hydromorphone caused dramatic hemodynamic alterations, and at the doses used, the 3 induction regimens did not induce important additional cardiovascular alterations. However, administration of supplemental oxygen is recommended. PMID- 18447789 TI - Pharmacokinetics of butorphanol tartrate in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus). AB - OBJECTIVE: To determine the pharmacokinetics of butorphanol tartrate after IV and IM single-dose administration in red-tailed hawks (RTHs) and great horned owls (GHOs). ANIMALS: 6 adult RTHs and 6 adult GHOs. PROCEDURES: Each bird received an injection of butorphanol (0.5 mg/kg) into either the right jugular vein (IVj) or the pectoral muscles in a crossover study (1-week interval between treatments). The GHOs also later received butorphanol (0.5 mg/kg) via injection into a medial metatarsal vein (IVm). During each 24-hour postinjection period, blood samples were collected from each bird; plasma butorphanol concentrations were determined via liquid chromatography-mass spectrometry. RESULTS: 2- and 1-compartment models best fit the IV and IM pharmacokinetic data, respectively, in both species. Terminal half-lives of butorphanol were 0.94 +/- 0.30 hours (IVj) and 0.94 +/- 0.26 hours (IM) for RTHs and 1.79 +/- 1.36 hours (IVj), 1.84 +/- 1.56 hours (IM), and 1.19 +/- 0.34 hours (IVm) for GHOs. In GHOs, area under the curve (0 to infinity) for butorphanol after IVj or IM administration exceeded values in RTHs; GHO values after IM and IVm administration were less than those after IVj administration. Plasma butorphanol clearance was significantly more rapid in the RTHs. Bioavailability of butorphanol administered IM was 97.6 +/- 33.2% (RTHs) and 88.8 +/- 4.8% (GHOs). CONCLUSIONS AND CLINICAL RELEVANCE: In RTHs and GHOs, butorphanol was rapidly absorbed and distributed via all routes of administration; the drug's rapid terminal half-life indicated that published dosing intervals for birds may be inadequate in RTHs and GHOs. PMID- 18447790 TI - Histologic and micro-computed tomographic evaluation of the osseointegration of a nonresorbable bone substitute in alveoli of ponies after tooth extraction. AB - OBJECTIVE: To evaluate the biological behavior of a nonresorbable bone substitute (NRBS) in the alveoli of ponies, compared with tissue quality in naturally healing alveoli, after cheek tooth extraction. ANIMALS: 5 clinically normal ponies. PROCEDURES: In each pony, both maxillary fourth premolars (Triadan 108/208) were repulsed bilaterally during anesthesia. One randomly chosen alveolus was filled with NRBS and isolated from the oral cavity by use of dental impression material and a spring-wire retention device. The other alveolus was occluded in its occlusal third portion with dental impression material. One year after surgery, cylindrical lateromedial biopsy specimens were collected from the apical, middle, and occlusal level of each alveolus. Biopsy samples were evaluated for bone mineral density and bone volume via micro-computed tomography; qualitative histologic characteristics were evaluated via light microscopy. RESULTS: Bone mineral density and bone volume were greater in control alveoli, compared with NRBS-treated alveoli. Control alveoli were characterized by the presence of few mature bone trabeculae and wide spaces containing fat tissue and mesenchymal stroma. In treated alveoli, biocompatibility and osteoconductive properties of the NRBS were excellent; continuous bone formation and bone remodeling were also evident. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the NRBS was integrated well in calcified alveolar tissues in ponies 1 year after maxillary cheek tooth extraction. Further research is necessary to establish the benefits of this NRBS in the development of a dental implant surgical technique in equids. PMID- 18447791 TI - Evaluation of the diffusion of corticosteroids between the distal interphalangeal joint and navicular bursa in horses. AB - OBJECTIVE: To determine whether clinically effective concentrations of methylprednisolone or triamcinolone can be achieved in the navicular bursa after injection of methylprednisolone acetate (MPA) or triamcinolone acetonide (TA) into the distal interphalangeal joint (DIPJ) and whether clinically effective concentrations of these drugs can be achieved in the DIPJ after injecting the navicular bursa with the same doses of MPA or TA. ANIMALS: 32 healthy horses. PROCEDURES: Horses in groups 1 through 4 received 40 mg of MPA in the DIPJ, 10 mg of TA in the DIPJ, 40 mg of MPA in the navicular bursa, and 10 mg of TA in the navicular bursa, respectively. Concentrations of corticosteroids that diffused into the adjacent synovial structure were determined. RESULTS: For group 1, injection of MPA into the DIPJ yielded a mean +/- SD concentration of 0.24 +/- 0.072 microg of methylprednisolone/mL in the navicular bursa. For group 2, injection of TA into the DIPJ yielded 0.124 +/- 0.075 microg of triamcinolone/mL in the navicular bursa. For group 3, injection of MPA into the navicular bursa yielded 0.05 +/- 0.012 microg of methylprednisolone/mL in the DIPJ. For group 4, injection of TA into the navicular bursa yielded 0.091 +/- 0.026 microg of triamcinolone/mL in the DIPJ. CONCLUSIONS AND CLINICAL RELEVANCE: A clinically effective concentration of methylprednisolone or triamcinolone diffused between the DIPJ and navicular bursa after intra-articular or intrabursal injection, which would justify injection of the DIPJ with MPA or TA to ameliorate inflammation of the navicular bursa. PMID- 18447792 TI - Effect of dietary nutrients on osteochondrosis lesions and cartilage properties in pigs. AB - OBJECTIVE: To evaluate dietary ingredients involved in cartilage and bone metabolism and their influence on osteochondrosis lesions in swine. ANIMALS: 80 crossbred gilts (mean initial weight, 39 kg). PROCEDURES: Pigs (10 pigs/treatment) were fed a corn-soybean meal basal (control) diet or the basal diet supplemented with additional minerals (copper and manganese or silicon), amino acids (proline and glycine; a combination of leucine, isoleucine, and valine; or methionine and threonine), or fatty acids (provided by fish oil) for 84 days. Pigs were then slaughtered and the distal portion of the left femur was collected for determination of osteochondrosis lesions at the femoral condyle. After evaluation of external joint surfaces, the distal portion of the femur was sectioned to evaluate lesions in the growth plate and articular cartilage. Additionally, a cartilage specimen was obtained from the patella for analysis. RESULTS: Pigs fed diets containing high amounts of methionine and threonine or the diet containing all additional ingredients had significantly lower total severity scores, compared with scores for pigs fed the control diet or a diet supplemented with fish oil. Pigs fed diets containing additional proline and glycine, copper and manganese, methionine and threonine, or all additional ingredients had significantly lower overall scores, compared with scores for pigs fed the control diet or a diet supplemented with fish oil. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary manipulation decreased the severity of osteochondrosis lesions, compared with results for pigs fed a control diet. However, additional research on optimal concentrations and combinations of dietary components is needed. PMID- 18447793 TI - Apoptosis of ligamentous cells of the cranial cruciate ligament from stable stifle joints of dogs with partial cranial cruciate ligament rupture. AB - OBJECTIVE: To describe the presence and amount of apoptotic ligamentous cells in different areas of partially ruptured canine cranial cruciate ligaments (prCCLs) and to compare these findings with apoptosis of ligamentous cells in totally ruptured cranial cruciate ligaments (trCCLs). ANIMALS: 20 dogs with prCCLs and 14 dogs with trCCLs. PROCEDURES: Dogs with prCCLs or trCCLs were admitted to the veterinary hospital for stifle joint treatment. Biopsy specimens of the intact area of prCCLs (group A) and the ruptured area of prCCLs (group B) as well as specimens from trCCLs (group C) were harvested during arthroscopy. Caspase-3 and poly (ADP-ribose) polymerase (PARP) detection were used to detect apoptotic ligamentous cells by immunohistochemistry. RESULTS: No difference was found in the degree of synovitis or osteophytosis between prCCLs and trCCLs. No difference was found in degenerative changes in ligaments between groups A and B. A substantial amount of apoptotic cells could be found in > 90% of all stained slides. A correlation (r(s) = 0.71) was found between the number of caspase-3-and PARP-positive cells. No significant difference was found in the amount of apoptotic cells among the 3 groups. No significant correlation could be detected between the degree of synovitis and apoptotic cells or osteophyte production and apoptotic cells. CONCLUSIONS AND CLINICAL RELEVANCE: The lack of difference between the 3 groups indicates that apoptosis could be a factor in the internal disease process leading to CCL rupture and is not primarily a consequence of the acute rupture of the ligament. PMID- 18447794 TI - Evaluation of computed tomographic anatomy of the equine metacarpophalangeal joint. AB - OBJECTIVE: To determine the detailed computed tomography (CT) anatomy of the metacarpophalangeal (MCP) joint in healthy horses. SAMPLE POPULATION: 10 cadaveric forelimbs from 10 adult horses without orthopedic disease. PROCEDURES: CT of the MCP joint was performed on 4 forelimbs. In 1 of the limbs, CT was also performed after intra-articular injection of 30 mL of contrast medium (40 mg of iodine/mL). Transverse slices 1-mm thick were obtained, and sagittal and dorsal planes were reformatted with a slice thickness of 2 mm. The CT images were matched with corresponding anatomic slices from 6 additional forelimbs. RESULTS: The third metacarpal bone, proximal sesamoid bones, and proximal phalanx could be clearly visualized. Common digital extensor tendon; accessory digital extensor tendon; lateral digital extensor tendon; superficial digital flexor tendon (including manica flexoria); deep digital flexor tendon; branches of the suspensory ligament (including its attachment); extensor branches of the suspensory ligament; collateral ligaments; straight, oblique, and cruciate distal sesamoidean ligaments; intersesamoidean ligament; annular ligament; and joint capsule could be seen. Collateral sesamoidean ligaments and short distal sesamoidean ligaments could be localized but not at all times clearly identified, whereas the metacarpointersesamoidean ligament could not be identified. The cartilage of the MCP joint could be assessed on the postcontrast sequence. CONCLUSIONS AND CLINICAL RELEVANCE: CT of the equine MCP joint can be of great value when results of radiography and ultrasonography are inconclusive. Images obtained in this study may serve as reference for CT of the equine MCP joint. PMID- 18447795 TI - Evaluation of technetium Tc 99m-labeled biotin for scintigraphic detection of soft tissue inflammation in horses. AB - OBJECTIVE: To evaluate the use of technetium Tc 99m-labeled EDTA-biotin monomer ((99m)Tc-EB1) as a scintigraphic imaging agent for soft tissue inflammatory lesions in horses. ANIMALS: 6 healthy adult horses. PROCEDURES: First (phase 1), the agent's safety and blood-tissue clearance and an appropriate imaging protocol were determined in 6 horses. Each horse was injected with (99m)Tc-EB1 (1.1 GBq, IV, once); images were acquired at intervals during the following 24-hour period. Subsequently (phase 2), inflammation was induced via injection of 200 mg (10 mL) of mepivacaine (0.4 mg/kg) into the right neck musculature and perineurally in the proximal palmar metacarpal region of the right forelimb of 2 horses. Six hours after mepivacaine injection, (99m)Tc-EB1 (2.2 GBq, IV, once) was administered; 8 hours after injection, comparative soft tissue images were acquired after administration of technetium (99m)Tc-hydroxymethylene diphosphonate ((99m)Tc-HDP; 7.4 GBq, IV, once). RESULTS: After injections of (99m)Tc-EB1, physical examinations, CBCs, and serum biochemical analyses revealed no abnormalities in any horse. Blood clearance of (99m)Tc-EB1 was rapid (A phase, 2.2 minutes; beta phase, 58 minutes). Soft tissue uptake of (99m)Tc-EB1 was immediate and persisted for as long as 4 hours after injection. At 6 hours after IM and perineural mepivacaine injections, mepivacaine-induced inflammation was detectable by use of (99m)Tc-EB1. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that (99m)Tc-EB1 is safe for use in horses and can identify soft tissue inflammation without concurrent uptake in bone. Compared with (99m)Tc-HDP administration, use of (99m)Tc-EB1 extended the duration of soft tissue scintigraphic image acquisition. PMID- 18447796 TI - Changes in gallbladder volume in healthy dogs after food was withheld for 12 hours followed by ingestion of a meal or a meal containing erythromycin. AB - OBJECTIVE: To assess the influence of meal ingestion and orally administered erythromycin on gallbladder volume in dogs. ANIMALS: 22 healthy dogs. PROCEDURES: Ultrasonographically determined gallbladder dimensions in unsedated dogs were used to calculate volume. Measurements were recorded after food was withheld for 12 hours (time 0) and 15, 30, 45, 60, 90, and 120 minutes after a 100-g meal without (n = 22) or with erythromycin (1.0 mg/kg [7], 2.5 mg/kg [7], and both dosages [8]). Gallbladder ejection fraction represented the percentage of volume change from time 0. Intraday and interday coefficients of variation determined operator repeatability and physiologic variation. RESULTS: We did not detect significant differences in gallbladder volume per unit of body weight between treatments at time 0 or in ejection fraction percentage within or between treatments. Median time 0 gallbladder volume was 0.6 mL/kg (range, 0.4 to 1.9) but was > 1.0 mL/kg in 3 of 22 (14%) dogs and or= 25% with at least 1 treatment, but 2 dogs with a gallbladder volume or= 25% were typical. No treatment consistently induced greater gallbladder contraction. Dogs with a gallbladder volume > 1.0 mL/kg and ejection fraction < 25% may require a combined meal and erythromycin protocol. PMID- 18447797 TI - Effects of temperature and handling conditions on lipid emulsion stability in veterinary parenteral nutrition admixtures during simulated intravenous administration. AB - OBJECTIVE: To determine whether lipid particle coalescence develops in veterinary parenteral nutrition (PN) admixture preparations that are kept at room temperature (23 degrees C) for > 48 hours and whether that coalescence is prevented by admixture filtration, refrigeration, or agitation. SAMPLE POPULATION: 15 bags of veterinary PN solutions. PROCEDURES: Bags of a PN admixture preparation containing a lipid emulsion were suspended and maintained under different experimental conditions (3 bags/group) for 96 hours while admixtures were dispensed to simulate IV fluid administration (rate, 16 mL/h). Bags were kept static at 4 degrees C (refrigeration); kept at 23 degrees C (room temperature) and continuously agitated; kept at room temperature and agitated for 5 minutes every 4 hours; kept static at room temperature and filtered during delivery; or kept static at room temperature (control conditions). Admixture samples were collected at 0, 24, 48, 72, and 96 hours and examined via transmission electron microscopy to determine lipid particle diameters. At 96 hours, 2 samples were collected at a location distal to the filter from each bag in that group for bacterial culture. RESULTS: Distribution of lipid particle size in the control preparations and experimentally treated preparations did not differ significantly. A visible oil layer developed in continuously agitated preparations by 72 hours. Bacterial cultures of filtered samples yielded no growth. CONCLUSIONS AND CLINICAL RELEVANCE: Data indicated that the veterinary PN admixtures kept static at 23 degrees C are suitable for use for at least 48 hours. Manipulations of PN admixtures appear unnecessary to prolong lipid particle stability, and continuous agitation may hasten lipid breakdown. PMID- 18447798 TI - Assessment of serum thyroid hormone concentrations in lambs with selenium deficiency myopathy. AB - OBJECTIVE: To assess changes in serum concentrations of thyroid hormones associated with selenium deficiency myopathy in lambs. ANIMALS: 35 lambs with selenium deficiency myopathy and 30 healthy lambs. PROCEDURES: Blood samples were collected via jugular venipuncture from lambs with selenium deficiency myopathy and healthy lambs. Activities of markers of selenium deficiency myopathy (erythrocyte glutathione peroxidase [GSH-Px] and plasma creatine kinase [CK]) and serum thyroid-stimulating hormone (TSH) and total thyroxine (tT(4)) and total triiodothyronine (tT(3)) concentrations were assessed; values in affected lambs were compared with those in healthy lambs. Correlations of erythrocyte GSH-Px and plasma CK activities with serum concentrations of TSH, tT(4), and tT(3) were investigated, and the tT(3):tT(4) concentration ratio was evaluated. RESULTS: Compared with findings in healthy lambs, erythrocyte GSH-Px activity, serum tT(3) concentration, and tT(3):tT(4) concentration ratio were significantly decreased and serum concentrations of tT(4) and TSH and the activity of plasma CK were significantly increased in affected lambs. Analysis revealed a significant negative correlation in the affected group between erythrocyte GSH-Px activity and each of the following: plasma CK activity (r = -0.443), serum TSH concentration (r = -0.599), serum tT(4) concentration (r = -0.577), and serum tT(3) concentration (r = -0.621). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that notable changes in circulating amounts of thyroid hormones develop in association with selenium deficiency in lambs. Such alterations in thyroid hormone metabolism may be involved in the high incidence of disorders, such as stillbirths and neonatal deaths, in selenium-deficient flocks. PMID- 18447799 TI - Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. AB - OBJECTIVE: To assess pharmacokinetics and pharmacodynamics of morphine and the effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. ANIMALS: 6 healthy Greyhounds, 3 male and 3 female. PROCEDURES: Morphine sulfate (0.5 mg/kg. IV) was administered to Greyhounds prior to and after 5 days of ketoconazole (12.7 +/- 0.6 mg/kg, PO) treatment. Plasma samples were obtained from blood samples that were collected at predetermined time points for measurement of morphine and ketoconazole concentrations by mass spectrometry. Pharmacokinetics of morphine were estimated by use of computer software. RESULTS: Pharmacodynamic effects of morphine in Greyhounds were similar to those of other studies in dogs and were similar between treatment groups. Morphine was rapidly eliminated with a half-life of 1.28 hours and a plasma clearance of 32.55 mL/min/kg. The volume of distribution was 3.6 L/kg. No significant differences in the pharmacokinetics of morphine were found after treatment with ketoconazole. Plasma concentrations of ketoconazole were high and persisted longer than expected in Greyhounds. CONCLUSIONS AND CLINICAL RELEVANCE: Ketoconazole had no significant effect on morphine pharmacokinetics, and the pharmacodynamics were similar between treatment groups. Plasma concentrations of ketoconazole were higher than expected and persisted longer than expected in Greyhounds. PMID- 18447800 TI - Pharmacokinetics of cetirizine in healthy cats. AB - OBJECTIVE: To develop a high-performance liquid chromatography (HPLC) assay for cetirizine in feline plasma and determine the pharmacokinetics of cetirizine in healthy cats after oral administration of a single dose (5 mg) of cetirizine dihydrochloride. ANIMALS: 9 healthy cats. PROCEDURES: Heparinized blood samples were collected prior to and 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after oral administration of 5 mg of cetirizine dihydrochloride to each cat (dosage range, 0.6 to 1.4 mg/kg). Plasma was harvested and analyzed by reverse-phase HPLC. Plasma concentrations of cetirizine were analyzed with a compartmental pharmacokinetic model. Protein binding was measured by ultrafiltration with a microcentrifugation system. RESULTS: No adverse effects were detected after drug administration in the cats. Mean +/- SD terminal half-life was 10.06 +/- 4.05 hours, and mean peak plasma concentration was 3.30 +/- 1.55 microg/mL. Mean volume of distribution and clearance (per fraction absorbed) were 0.24 +/- 0.09 L/kg and 0.30 +/- 0.09 mL/kg/min, respectively. Mean plasma concentrations were approximately 2.0 microg/mL or higher for 10 hours and were maintained at > 0.72 microg/mL for 24 hours. Protein binding was approximately 88%. CONCLUSIONS AND CLINICAL RELEVANCE: A single dose of cetirizine dihydrochloride (approx 1 mg/kg, which corresponded to approximately 0.87 mg of cetirizine base/kg) was administered orally to cats. It was tolerated well and maintained plasma concentrations higher than those considered effective in humans for 24 hours after dosing. The half-life of cetirizine in cats is compatible with once-daily dosing, and the extent of protein binding is high. PMID- 18447801 TI - Pharmacokinetics and effects of aminorex in horses. AB - OBJECTIVE: To investigate the pharmacokinetics and behavioral effects of aminorex administered IV and PO in horses. ANIMALS: 7 Thoroughbreds. PROCEDURES: In a cross-over design, aminorex (0.03 mg/kg) was administered IV or PO. Plasma and urinary aminorex concentrations were determined via liquid chromatography- mass spectrometry. RESULTS: Decrease of aminorex from plasma following IV administration was described by a 3-compartment pharmacokinetic model. Median (range) values of alpha, beta, and gamma half-lives were 0.04 (0.01 to 0.28), 2.30 (1.23 to 3.09), and 18.82 (8.13 to 46.64) hours, respectively. Total body and renal clearance, the area under the plasma time curve, and initial volume of distribution were 37.26 (28.61 to 56.24) mL x min/kg, 1.25 (0.85 to 2.05) mL x min/kg, 13.39 (8.82 to 17.37) ng x h/mL, and 1.44 (0.10 to 3.64) L/kg, respectively. Oral administration was described by a 2-compartment model with first-order absorption, elimination from the central compartment, and distribution into peripheral compartments. The absorption half-life was 0.29 (0.12 to 1.07) hours, whereas the beta and gamma elimination phases were 1.93 (1.01 to 3.17) and 23.57 (15.16 to 47.45) hours, respectively. The area under the curve for PO administration was 10.38 (4.85 to 13.40) ng.h/mL and the fractional absorption was 81.8% (33.8% to 86.9%). CONCLUSIONS AND CLINICAL RELEVANCE: Aminorex administered IV had a large volume of distribution, initial rapid decrease, and an extended terminal elimination. Following PO administration, there was rapid absorption, rapid initial decrease, and an extended terminal elimination. At a dose of 0.03 mg/kg, the only effects detected were transient and central in origin and were observed only following IV administration. PMID- 18447802 TI - Activity of selected rostral and caudal hyoid muscles in clinically normal horses during strenuous exercise. AB - OBJECTIVE: To determine the phase and quantitate the electromyographic (EMG) activity of the genioglossus, geniohyoideus, hyoepiglotticus, omohyoideus, sternohyoideus, sternothyroideus, and thyrohyoideus muscles of clinically normal horses during strenuous exercise. ANIMALS: 7 clinically normal adult horses (2 Thoroughbreds and 5 Standardbreds). PROCEDURES: Bipolar electrodes were surgically implanted in the aforementioned muscles, and horses were subjected to an incremental exercise test on a high-speed treadmill. The EMG, heart rate, respiratory rate, and static pharyngeal airway pressures were measured during exercise. The EMG was measured as mean electrical activity (MEA). The MEA values for maximal exercise intensity (13 or 14 m/s) were expressed as a percentage of the MEA measured at an exercise intensity of 6 m/s. RESULTS: MEA was detected during expiration in the genioglossus, geniohyoideus, sternohyoideus, and thyrohyoideus muscles and during inspiration in the hyoepiglotticus and sternothyroideus muscles. Intensity of the MEA increased significantly with exercise intensity in the genioglossus, geniohyoideus, and hyoepiglotticus muscles. Intensity of the MEA increased significantly in relation to expiratory pharyngeal pressure in the geniohyoideus and hyoepiglotticus muscles. CONCLUSIONS AND CLINICAL RELEVANCE: Once exercise intensity reached 6 m/s, no quantifiable additional increase in muscular activity was detected in the omohyoideus, sternohyoideus, sternothyroideus, and thyrohyoideus muscles. However, muscles that may affect the diameter of the oropharynx (genioglossus and geniohyoideus muscles) or rima glottis (hyoepiglotticus muscle) had activity correlated with the intensity of exercise or expiratory pharyngeal pressures. Activity of the muscles affecting the geometry of the oropharynx may be important in the pathophysiologic processes associated with nasopharyngeal patency. PMID- 18447803 TI - Effects of warm-up intensity on oxygen transport during supramaximal exercise in horses. AB - OBJECTIVE: To determine whether warm-up exercise at different intensities alters kinetics and total contribution of aerobic power to total metabolic power in subsequent supramaximal exercise in horses. ANIMALS: 11 horses. PROCEDURES: Horses ran at a sprint until fatigued at 115% of maximal oxygen consumption rate (VO(2max)), beginning at 10 minutes following each of 3 warm-up protocols: no warmup (NoWU), 1 minute at 70% VO(2max) (moderate-intensity warm-up [MoWU]), or 1 minute at 115% VO(2max) (high-intensity warm-up [HiWU]). Cardiopulmonary and blood gas variables were measured during exercise. RESULTS: The VO(2) was significantly higher in HiWU and MoWU than in NoWU throughout the sprint exercise period. Blood lactate accumulation rate in the first 60 seconds was significantly lower in MoWU and HiWU than in NoWU. Specific cardiac output after 60 seconds of sprint exercise was not significantly different among the 3 protocols; however, the arterial mixed-venous oxygen concentration difference was significantly higher in HiWU than in NoWU primarily because of decreased mixed-venous saturation and tension. Run time to fatigue following MoWU was significantly greater than that with NoWU, and there was no difference in time to fatigue between MoWU and HiWU. CONCLUSIONS AND CLINICAL RELEVANCE: HiWU and MoWU increased peak values for VO(2) and decreased blood lactate accumulation rate during the first minute of intense exercise, suggesting a greater use of aerobic than net anaerobic power during this period. PMID- 18447804 TI - The real business of health care. PMID- 18447805 TI - It's not the evidence, it's the way you use it: is clinical practice being tyrannised by evidence? My experience with the PBAC and evidence-based practice. PMID- 18447806 TI - Re: Care management for older people with mental health problems: from evidence to practice. PMID- 18447807 TI - Care management for older people with mental health problems: from evidence to practice. AB - AIM: To explore the implications of providing intensive care management in a typical old age mental health service in North West England. METHODS: The time spent by core groups of specialist mental health and social services staff on a range of activities deemed central to the provision of intensive care management was explored by means of a diary exercise. The difference between what is actually being done and what evidence suggests is needed was examined. RESULTS: More than 1500 hours of activity were appraised. Assessment and care management related tasks accounted for more than 40% and 30% of social work and nursing staff's time, respectively. However, several fundamental features of intensive care management were lacking, including health staff's adoption of the care manager role, arrangements to facilitate appropriate information sharing and sufficient time for practitioners to provide the necessary careful assessment of needs, liaison with other agencies, and close and regular contact with the elderly person and their care network. PMID- 18447808 TI - Re-visioning cultural competence in community health services in Victoria. AB - There are few studies exploring the need to develop and manage culturally competent health services for refugees and migrants from diverse backgrounds. Using data from 50 interviews with service providers from 26 agencies, and focus group discussion with nine different ethnic groups, this paper examines how the Victorian state government funding and service agreements negatively impact on the quest to achieve cultural competence. The study found that service providers have adopted "one approach fits all" models of service delivery. The pressure and competition for resources to address culturally and linguistically diverse communities' needs allows little opportunity for partnership and collaboration between providers, leading to insufficient sharing of information and duplication of services, poor referrals, incomplete assessment of needs, poor compliance with medical treatment, underutilisation of available services and poor continuity of care. This paper outlines a model for cultural consultation and developing needs led rather than service-led programs. PMID- 18447809 TI - A piece of the puzzle: the role of ethnic health staff in hospitals. AB - The role of ethnic health staff in hospitals has not been clearly articulated for managers and practitioners. This paper describes findings from a study based on ethnic and allied health staff interviews and observations of ethnic health staff interactions. Care was provided to language concordant patients directly and by assisting practitioners to work within the patient's cultural paradigms and family schema. The scope of practice involved: engaging patients in a therapeutic relationship, patient assessment, linking assessment with care options, facilitating communication between patients and practitioners, education, smoothing hospital experiences, referral and interpreting. Ethnic health staff displayed a range of specialised skills that managers need to harness within multidisciplinary teams to reach patients from diverse backgrounds. PMID- 18447810 TI - Rest during shift work in the emergency department. AB - The aim of this study was to pilot a program to encourage shift breaks for emergency department doctors and analyse the effects of breaks on tiredness and fatigue as well as possible effects on overall departmental performance. During Phase 1, medical staff were asked to fill out a survey regarding their working day at the end of every shift. A 30-minute uninterrupted break was promoted during Phase 2 by provision of a cover doctor on the roster as well as educational sessions and posters. There were 233 completed surveys received over the 4-week period. Only 33% of shifts worked included an uninterrupted break in Phase 1, which improved significantly to 60% during Phase 2. Subjective tiredness was significantly lower at the end of a shift when a break was taken (P < 0.001), while fatigue levels were also lower, but not significant (P = 0.060). There were significant improvements in some key performance indicators. PMID- 18447811 TI - Attitudes, beliefs and values of students in undergraduate medical, nursing and pharmacy programs. AB - First and final year students in medicine, nursing and pharmacy programs at the University of Auckland completed a questionnaire used in studies of professional subcultures. Before entering training, students differed in how they believed clinical work should be organised. The collectivist attitude of pharmacy students was greater among those completing their studies than it was among those commencing study. Doctors, nurses, pharmacists and other professional groups are expected to work in multidisciplinary teams to deliver high quality health services. This study suggests that the individualistic attitudes of medical students may need to be addressed during training if medical students are to graduate with a commitment to working in teams, an expectation of clinical governance. PMID- 18447812 TI - The working world of nursing unit managers: responsibility without power. AB - This paper seeks to explore the responsibility and power of the role of nursing unit managers (NUMs) in rural New South Wales using Kanter's theory of organisational power as a framework. Using in-depth individual interviews with twenty NUMs, data were analysed from four perspectives to gain a deep understanding of the NUMs' working world. The findings show that the NUMs' role is substantive, encompassing both clinical and managerial functions. Overall, the findings indicate that the participants lacked power commensurate with their role responsibilities. PMID- 18447813 TI - Evaluation of a hospital volunteer program in rural Australia. AB - A voluntary survey questionnaire that assessed experience with and perception of the volunteering program was mailed to 62 current and 9 former volunteers and 47 staff members of Latrobe Regional Hospital (LRH). Sixty-one completed questionnaires were returned. The nature of hospital work attracted volunteers (57%) and most volunteers felt oriented to the hospital, supervised and supported. The volunteers enjoyed working with patients and felt they contributed to better services and staff and patient support. There was a need felt that more training and development, recognition, orientation and supervision would be beneficial. Overall, most volunteers rated their experience as good (60%) to excellent (25%). Staff rated the contribution from volunteers as good (41%) to excellent (47%). Volunteers identified several areas of improvement, including opportunities for further training and supervision. Volunteers play a crucial role within the health care system. There is tremendous scope for further development of the volunteer role and increasing opportunities for training and development, recognition and encouragement. PMID- 18447814 TI - Predicting absenteeism and turnover intentions in the health professions. AB - OBJECTIVES: The study examined the mediating influence of individual psychological reactions to work on the relationship between organisational climate and job withdrawal behaviours (viz, intention to leave and absenteeism). METHODS: 1097 hospital employees were surveyed using the Queensland Public Agency Staff Survey (QPASS) to obtain measures of organisational climate, psychological reactions to work, job satisfaction, and self-reported levels of intention to leave. Group-level absenteeism data were provided from the Health Service District files. RESULTS: Two psychological states, quality of work life and job satisfaction, were found to fully mediate the relationship between the organisational climate variable, role clarity, and intention to leave, while individual distress was found to partially mediate the same relationship. However, the hypothesised mediation effect of psychological states on the relationship between organisational climate and absenteeism did not emerge. CONCLUSION: Skills shortages and increasing demands for health services make retention of staff in the health service industry vitally important. As a means of addressing this issue, this study presents an emergent mediating model defining relationships among individual psychological factors, aspects of organisational climate and intention to leave. Identification of the processes associated with staff withdrawal behaviours or intentions will assist in devising interventions to improve retention. PMID- 18447815 TI - Will the Australian nuclear medicine technologist workforce meet anticipated health care demands? AB - Determination of national nuclear medicine technologist workforce size was made from census data in 2001 and 1996 and from the professional body in 2004. A survey conducted by the authors in 2005 provided retention patterns in north eastern Australia and suggested causes. Utilisation of nuclear medicine diagnostic services was established through the Medicare Benefits Schedule group statistics. More than half the nuclear medicine technologist workforce is under 35 years of age. Attrition commences from age 30, with very few workers over 55 years. In 2005 there was a 12% attrition of the survey workforce. In the past decade, service provision increased while workforce size decreased and the nuclear medicine technologist workforce is at risk of failing to meet the anticipated rise in health service needs. PMID- 18447816 TI - Barriers to continuing medical education in Australian prevocational doctors. AB - To determine perceived barriers to continuing education for Australian hospital based prevocational doctors, a cross sectional cohort survey was distributed to medical administrators for secondary redistribution to 2607 prevocational doctors from August 2003 to October 2004. Four hundred and seventy valid questionnaires (18.1%) were returned. Only seven per cent (33/470) did not identify any barriers to continuing education. Barriers identified the most were lack of time (85% [371/437]), clinical commitment (65% [284/437]), resistance from registrars (13% [57/437]) and resistance from consultant staff (10% [44/437]). Other barriers included workload issues (27% [27/98]), teaching program inadequacies (26% [25/98]), lack of protected time for education (17% [17/98]), motivational issues (11% [10/98]) and geographic remoteness (10% [10/98]). Australian graduates (87%) identified lack of time more frequently than international medical graduates (77%) (P = 0.036). Perceived barriers did not differ significantly between doctors of differing postgraduate years. PMID- 18447817 TI - Health, health care and healing: Introduction to the Festschrift for Professor Ken Donald. PMID- 18447818 TI - Aboriginal and Torres Strait Islander Health: today's challenges, tomorrow's opportunities. PMID- 18447819 TI - Ken Donald and Muscular Christianity. PMID- 18447820 TI - Compensation and wellness: a conflict for veterans' health. AB - In Australia greater attention is being given to health determinants, and the dominance of treatment in health policy and budgets is giving away some ground to prevention, health promotion, rehabilitation and disability management. This creates a dilemma for compensation systems: should the inclusion criteria be broadened to match the new thinking or should a narrower definition of "disease, injury or death" be retained? This issue is explored in the context of war syndromes among veterans. While veterans experience symptoms more frequently and more severely than military and community controls, their patterns of symptoms are not unique. Current compensation and benefit programs can create iatrogenic effects. It is concluded that compensation systems should be kept as safety nets while resources are provided to improve the capacity of primary health care caregivers, community organisations and veterans with war syndromes and their families to better deal with these problems. Adapting compensation systems to promote wellness through self-management health partnerships is one way of directing resources to individuals and their families. Action research at the community level with veterans, their families, their organisations, primary health care organisations, policy makers and researchers would allow this sector to work out the best way to apply existing efficacious tools to these modern health problems. PMID- 18447821 TI - Looking after health care in the bush. PMID- 18447822 TI - Pathology in education and practice: a time for integration? AB - While there has been a strong history of pathology in understanding disease, in recent years we have seen less appreciation of the value of pathology in clinical practice. Divisions at the clinical level, with pathology delivered from isolated buildings at the periphery of hospitals rather than within the heart of it, confirms in the mind of the new graduate the lack of importance of the discipline, despite using the service daily. We argue that it is time for a reintegration of pathology services. PMID- 18447823 TI - The Australian health care system: reform, repair or replace? AB - A Festshrift gives us the opportunity to look both backwards and forwards. Ken Donald's career stretches back to his intern days in 1963 and has encompassed clinical and population health, academe, clinical settings and the bureaucracy, and playing sport at state and national levels. There has been considerable change in the health care system over the period of Ken's involvement in the sector with more change to come -- where have those changes left us? This paper discusses these changes in relation to performance criteria. PMID- 18447824 TI - Self-management support and training for patients with chronic and complex conditions improves health-related behaviour and health outcomes. AB - The Sharing Health Care SA chronic disease self-management (CDSM) project in rural South Australia was designed to assist patients with chronic and complex conditions (diabetes, cardiovascular disease and arthritis) to learn how to participate more effectively in the management of their condition and to improve their self-management skills. Participants with chronic and complex conditions were recruited into the Sharing Health Care SA program and offered a range of education and support options (including a 6-week peer-led chronic disease self management program) as part of the Enhanced Primary Care care planning process. Patient self-reported data were collected at baseline and subsequent 6-month intervals using the Partners in Health (PIH) scale to assess self-management skill and ability for 175 patients across four data collection points. Health providers also scored patient knowledge and self-management skills using the same scale over the same intervals. Patients also completed a modified Stanford 2000 Health Survey for the same time intervals to assess service utilisation and health-related lifestyle factors. Results show that both mean patient self reported PIH scores and mean health provider PIH scores for patients improved significantly over time, indicating that patients demonstrated improved understanding of their condition and improved their ability to manage and deal with their symptoms. These results suggest that involvement in peer-led self management education programs has a positive effect on patient self-management skill, confidence and health-related behaviour. PMID- 18447825 TI - Self-assessment of medico-legal risk by doctors: the Know Your Risk Version 1 - Short Form. AB - An instrument to measure medico-legal risk-management behaviours among medical practitioners was developed and tested. A cross-sectional survey was posted to 962 UNITED Medical Protection members receiving premium support. A final sample of 757 currently working medical practitioners responded, including general practitioners (21.9%), surgeons (29.9%), obstetricians and gynaecologists (12.7%), and others (35.5%). The Know Your Risk Version 1 - Short Form and other tools developed by this team are available for use by group practices, hospital administrators and practitioners. These tools have the potential to assist regulators and insurers to identify, monitor or screen individual medico-legal risk behaviours. PMID- 18447826 TI - Residents' satisfaction with multi-purpose services. AB - AIM: To establish a system for measuring resident satisfaction in multi-purpose services, benchmarking and performance improvement. SETTING: Six multi-purpose services in rural New South Wales were involved in the project. DESIGN: Residents were surveyed and the results benchmarked. Benchmarking included a comparison of results along with an exploration of work processes across participating sites. This preceded quality improvement activities conducted by individual multi purpose services. Resident surveys were repeated and staff and managers interviewed. OUTCOMES: Benchmarking was a useful method for identifying performance leaders and enabling the dissemination of better practice. The majority of staff members were comfortable with the PDSA (Plan, Do, Study, Act) quality improvement cycle to guide their improvement efforts. The ability of staff to complete quality improvement cycles was related to the management styles of their supervisors. Resident satisfaction was related to the understanding and confidence of staff. CONCLUSION: A resident satisfaction survey can provide the direction for effective quality improvement activities. Benchmarking results with other sites not only empowers staff members at those sites recognised as leaders, but can also stimulate dissemination of leading practice. Management styles which empower staff enhance their ability to implement quality improvement projects. PMID- 18447827 TI - The benefit and burden of "ageing-in-place" in an aged care community. AB - Ageing-in-place is usually viewed as a positive approach to meeting the needs of the older person, supporting them to live independently, or with some assistance, for as long as possible. It implies that older people prefer to live in their own home, rather than in an institution or care centre. However, there is little in the literature about the implications of ageing-in-place for the individual or their carers, or the burden this can place on service providers and aged care communities. In an action research study that investigated the complexities and challenges of change in an aged care community in Western Australia, the implications of ageing-in-pace were apparent. The study revealed how residents expressed a desire to age-in-place and identified it as a critical element of quality of life and an important component of social connection. The findings also revealed the burden of ageing-in-place on carers, family and the organisation, and sufficient attention must also be paid to the wider impact on the individual, the family and carers. PMID- 18447828 TI - Going online: experiences with a web survey. AB - This case study details the process and lessons learnt from converting a compulsory comprehensive organisational survey from email to online format. The conversion was undertaken to improve data quality and reduce respondent burden. Key considerations in developing the online survey were ease of use, security and access. The new intuitive system allowed simultaneous access for multiple users, and incorporated dynamic indicators of progress and validation of numeric data. Reactions to the survey were mainly positive -- about 75% of user feedback was positive or neutral, they reported the survey was "user friendly" and preferred the online format. Negative comments focused predominantly on the feature of expanding and collapsing questions which these respondents found difficult to manage. Administration of the survey was streamlined, with considerable reduction in time spent in checking and correcting responses for both respondents and data collectors. Although substantial improvements were recognised and appreciated by many users, it is important to acknowledge that users adapt to new technology at different speeds, and adequate support needs to be implemented for all users. PMID- 18447829 TI - Supramolecular organization of the yeast F1Fo-ATP synthase. AB - BACKGROUND INFORMATION: The yeast mitochondrial F(1)F(o)-ATP synthase is a large complex of 600 kDa that uses the proton electrochemical gradient generated by the respiratory chain to catalyse ATP synthesis from ADP and P(i). For a large range of organisms, it has been shown that mitochondrial ATP synthase adopts oligomeric structures. Moreover, several studies have suggested that a link exists between ATP synthase and mitochondrial morphology. RESULTS AND DISCUSSION: In order to understand the link between ATP synthase oligomerization and mitochondrial morphology, more information is needed on the supramolecular organization of this enzyme within the inner mitochondrial membrane. We have conducted an electron microscopy study on wild-type yeast mitochondria at different levels of organization from spheroplast to isolated ATP synthase complex. Using electron tomography, freeze-fracture, negative staining and image processing, we show that cristae form a network of lamellae, on which ATP synthase dimers assemble in linear and regular arrays of oligomers. CONCLUSIONS: Our results shed new light on the supramolecular organization of the F(1)F(o)-ATP synthase and its potential role in mitochondrial morphology. PMID- 18447830 TI - Identification of an iron-hepcidin complex. AB - Following its identification as a liver-expressed antimicrobial peptide, the hepcidin peptide was later shown to be a key player in iron homoeostasis. It is now proposed to be the 'iron hormone' which, by interacting with the iron transporter ferroportin, prevents further iron import into the circulatory system. This conclusion was reached using the corresponding synthetic peptide, emphasizing the functional importance of the mature 25-mer peptide, but omitting the possible functionality of its maturation. From urine-purified native hepcidin, we recently demonstrated that a proportion of the purified hepcidin had formed iron-hepcidin complexes. This interaction was investigated further by computer modelling and, based on the sequence similarity of hepcidin with metallothionein, a three-dimensional model of hepcidin, containing one atom of iron, was constructed. To characterize these complexes further, the interaction with iron was analysed using different spectroscopic methods. Monoferric hepcidin was identified by MS, as were possibly other complexes containing two and three atoms of iron respectively, although these were present only in minor amounts. UV/visible absorbance and CD studies identified the iron-binding events which were facilitated at a physiological pH. EPR spectroscopy identified the ferric state of the bound metal, and indicated that the iron-hepcidin complex shares some similarities with the rubredoxin iron-sulfur complex, suggesting the presence of Fe(3+) in a tetrahedral sulfur co-ordination. The potential roles of iron binding for hepcidin are discussed, and we propose either a regulatory function in the maturation of pro-hepcidin into active hepcidin or as the necessary link in the interaction between hepcidin and ferroportin. PMID- 18447831 TI - Topology mapping of the vacuolar Vcx1p Ca2+/H+ exchanger from Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae uses vacuolar storage to dynamically control the cytoplasmic calcium concentration. Vcx1p, a Ca(2+)/H(+) antiporter and a member of the CAX (Ca(2+)/anion exchanger) family of exchangers, is one of the proteins that sequesters calcium into the vacuole. Although the biological importance of Vcx1p is clear, the molecular mechanism by which Vcx1p and its family members mediate Ca(2+)/H(+) exchange activity remains poorly understood. To provide a basic structural framework for understanding functional studies of the CAX proteins, we have mapped Vcx1p's topology using three biochemical assays: C terminal reporter localization, glycosylation mapping and proteolysis. We have found that the protein has an odd number of TM (transmembrane) domains and that its termini are located on opposite sides of the membrane, with the N-terminus in the cytoplasm. Our results indicate that loops 1, 3, 7 and 9 are luminal, while loops 6 and 8 are cytosolic. Our experimentally-based topology model for Vcx1p is in agreement with models derived from topology algorithms and with biochemical data reported by other groups. In addition, our studies suggest that the calcium domain, a nine-residue domain found to be critical for function in CAX proteins from plants, is not essential to Vcx1p activity. PMID- 18447832 TI - [Peculiarities of psycho-vegetative status, myocardial perfusion, and neuro chemical blood composition in patients with cardiac syndrome X]. PMID- 18447833 TI - [Application of the system for rheolytic thrombectomy in patients with acute myocardial infarction]. AB - The authors present first experience of application of the system for rheolytic therapy AngioJet in a group of patients with acute myocardial infarction. They describe principle of the work of rheolytic systems, possible procedure related complications. They also discuss results of clinical studies analyzing efficacy of antithrombotic therapy, efficacy and safety of rheolytic therapy in patients with acute coronary syndrome and complicated atherosclerotic plaques in coronary arteries. PMID- 18447834 TI - [Prehospital thrombolytic therapy with tenecteplase in patients with ST-elevation myocardial infarction]. AB - We carried out prehospital thrombolytic therapy (TLT) with tenecteplase in 24 patients with ST-elevation myocardial infarction (MI) at the background of standard concomitant therapy with unfractionated heparin, aspirin, and clopidogrel and analyzed clinical course of MI, ECG dynamics, systolic left ventricular function according to echocardiography. In 20 patients coronary angiography was performed after TLT. Mean symptom - needle time was 113 min. In 14 patients (58%) TLT was carried out within 2 hours after appearance of symptoms. In 19 patients the course of disease was uncomplicated. Electrocardiographic criteria of effective reperfusion were registered in 14 patients (58%), angiographic criteria - in 13 patients (65% of subjected to angiography). Percutaneous intervention was performed in 18 patients (75%). Systolic left ventricular dysfunction was revealed in 5 patients (21%), aborted MI - in 4 patients. Significant correlation was found between aborted MI (r=0,38, p=0,034) and uncomplicated MI (r=0,40, p=0,027) and performance of TLT during first 2 hours. There were no hemorrhagic complications. Results of the study evidence for high efficacy of prehospital thrombolysis with tenecteplase and real possibility of its use under conditions of existing system of organization of urgent cardiological aid. PMID- 18447835 TI - [Effect of antihypertensive drugs of various pharmacological groups on reaction of arterial pressure under conditions of stree testing. Part II. Value of various strategies of potentiation of systemic vasodilatation]. PMID- 18447836 TI - [Changes of elastic properties of peripheral vessels and parameters of endothelial function at the background of the use of fixed combination of perindopril and indapamide in patients with hypertensive disease]. PMID- 18447837 TI - [Clinical efficacy of antihypertensive therapy of pregnant women with arterial hypertension with long acting nifedipine and bisoprolol]. AB - Study aim was assessment of clinical efficacy of mono therapy with nifedipine SR/GITS and combination of nifedipine SR/GITS and bisoprolol as well as investigation of functional state of sympathoadrenal system (SAS) in pregnant women with arterial hypertension. Examination and treatment with nifedipine SR/GITS 30 mg/day and bisoprolol 2,5 - 5 mg/day was carried out in 21 patients with stage II hypertensive disease (HD) during trimester II of pregnancy. Initially all women including 20 practically healthy pregnant women (control group) had elevation of functional activity of SAS what was determined by high values of b-adrenoception of membranes of erythrocytes. In patients with stage II HD this parameter significantly exceeded that of control group. Administration of antihypertensive drugs for 3 weeks promoted significant lowering of all parameters of 24 hour blood pressure monitoring down to optimal level, lessening of pathological types of 24 hour blood pressure profile and lowering of functional activity of SAS. PMID- 18447838 TI - [Clinical efficacy of the use of prolonged nifedipine in patients with arterial hypertension and chronic obstructive lung disease]. PMID- 18447839 TI - [Structural changes of brain and value of cerebroprotection in the treatment of arterial hypertension]. PMID- 18447840 TI - [Comparison of effects of nebivolol and atenolol on P-wave dispersion in patients with hypertension]. AB - BACKGROUND: P-wave dispersion has been shown to be a noninvasive electrocardiographic predictor for development of atrial fibrillation . Thus it may be possible to attenuate atrial fibrillation risk through normalization of P wave variables and improvement in P-wave dispersion may be an important goal in treatment of hypertension. OBJECTIVE: To compare the effects of nebivolol, a new b-blocker that have additional vasodilating activity via acting on endothelium and nitric oxide release, and atenolol on P-wave duration and dispersion in patients with mild-to-moderate hypertension. METHODS: A total of 34 newly diagnosed hypertensive patients were enrolled in the study. The patients were randomly assigned to receive treatment with either nebivolol (5 mg) or atenolol (50 mg). P-wave durations (Pmin and Pmax) and P-wave dispersion were measured before and one month after treatment. RESULTS: While Pmin increased (50,6 +/- 11,2 ms to 54,7 +/- 9,1 ms, p=0,05), Pmax decreased (111,9 +/- 9,1 ms to 104,0 +/ 12,4 ms, p=0,003) and P-wave dispersion decreased (62,5 +/- 10,6 ms to 51,3 +/- 8,9 ms, p < 0,001) with nebivolol, Pmin increased (44,4 +/- 9,8 ms to 58,0 +/- 15,5 ms, p=0,02), Pmax didn t change (106,1 +/- 13,8 ms to 107,0 +/- 11,6 ms, p=NS) and P-wave dispersion decreased (61,7 +/- 15,0 ms to 49,0 +/- 13,7 ms, p < 0.001) with atenolol. However, there was no statistical difference between pre- and post-treatment values of two groups. CONCLUSIONS: Both nebivolol and atenolol are effective in improvement of P-wave dispersion in patients with hypertension and there s no significant difference between them. PMID- 18447841 TI - [RELIPH - regular treatment and prevention - the key to improvement of situation with cardiovascular diseases in Russia: results of a Russian multicenter study (part III)]. AB - The first results of a big Russian multicenter study " RELIF - Regular treatment and prevention - the key of improvement of the situation with cardiovascular diseases in Russia " are presented. The study examines the accordance of arterial hypertension (AH) and coronary heart disease (CHD) treatment recommended by physicians to contemporary standards. Patients adherence to physicians recommendations is also studied. 512 general practitioners and 2517 patients with AH and CHD from 20 cities of Russia were included. In the present article the current situation with medical treatment of AH, isolated or in comorbidity with CHD is presented. PMID- 18447842 TI - [Physiological significance and normative parameters of rate adaptation of QT interval during holter monitoring in healthy persons of young age]. AB - Aim of the investigation consisted in to study parameters of " QT-dynamics " in healthy children and adolescents. We examined 26 children aged 7 - 17 years (mean 11,6 +/- 7 years) - 7 girls (9,3 +/- 2,3 years) and 19 boys (12,5 +/- 3,6 years). Holter monitoring with manual and automatic estimation of QT and QTc intervals. Dynamics of magnitude of QT interval was determined with the use of equation of linear regression Y = aX+b, where aX - coefficient of linear regression QT/RR (slope QT/RR), b - shear coefficient (intercept QT/RR). Values of QT interval at automatic analysis were 368,8 +/- 18,04 (340 - 410) ms for absolute QT and 424 +/ 14,99 (390 - 450) ms - for QTc, 289,4 +/- 14,6 (260 - 320). Mean values of " QT dynamics " were for slope QT/RR: 0,18 +/- 0,03 (0,13 - 0,24) for 24 hours, 0,16 +/- 0,03 (0,10 - 0,22) for daytime period, and 0,11 +/- 0,13 (0,05 - 0,18) for night time period; for intercept: QT/RR - 230,4 +/- 20,7 (192 - 282) for 24 hours, 299 +/- 25,5 (258 - 364) for day time period, and 242,7 +/- 21,8 (204 - 295) for night time period. Coefficient of correlation of intervals QT and RR (r QT/RR) was 0,79 +/- 0,05 (0,69 - 0,89) for 24 hours; 0,68 +/- 0,07 (0,52 - 0,82) for day time period, and 0,52 +/- 0,13 (0,19 - 0,74) for night time period. All values of " QT-dynamics " significantly differed from each other during various periods of day (p < 0,05). Negative relation was noted between 24 hour slope and intercept QT/RR (r= -0,88, p < 0,05), diurnal (r= -0,87, p < 0,05) and nocturnal slope and intercept QT/RR (r= -0,72, p < 0,05), positive relation was noted between 24 hour values of slope QT/RR and QT (r=0,49, p < 0,05), and intercept QT/RR with absolute QT (r=0,41, p < 0,05). Significantly higher values (p < 0,01) of slope QT/RR were in girls. Thus, increase of slope QT/RR is noted during augmentation of tone of sympathetic part of vegetative nervous system, lowering - when vagal influences are also enhanced. Intercept QT/RR appears to be combination parameter, increase of which reflects both lengthening of absolute mean value of QT interval and reciprocal nocturnal lowering of the slope parameter. It is necessary to assesses clinical and diagnostic significance of changes of novel parameters of " QT-dynamics " on the basis of normative sexual aging values and physiological mechanisms, determining their variability. PMID- 18447843 TI - [Neurocirculatory dystonia: diagnosis or syndrome]. PMID- 18447844 TI - [Neurocirculatory dystonia: myth or reality]. PMID- 18447845 TI - [Combination therapy of atherogenic dyslipidemias in women]. PMID- 18447846 TI - [Eighth congress of the Russian society of holter monitoring and noninvasive electrophysiology " noninvasive electrocardiology in clinical practice "]. PMID- 18447847 TI - [Circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation. Results of the APAF trial]. PMID- 18447852 TI - Topical administration of simvastatin recovers alveolar bone loss in rats. AB - BACKGROUND AND OBJECTIVE: Simvastatin, a cholesterol-lowering drug, has been reported to show anabolic effects on bone metabolism. We examined the effects of simvastatin in vitro using cultured rat calvaria cells and in vivo using periodontitis-induced rats. MATERIAL AND METHODS: Alkaline phosphatase activity and bone nodule formation were measured in cultured rat calvaria cells. Nylon ligature was placed around the maxillary molars of Fischer male rats for 20 d to induce alveolar bone resorption. After ligature removal, simvastatin was topically injected into the buccal gingivae for 70 d and then microcomputed tomography and histological examinations were performed. RESULTS: Simvastatin maintained high alkaline phosphatase activity and increased bone nodule formation in rat calvaria cells in a dose-dependent manner, showing that simvastatin increased and maintained a high level of osteoblastic function. Microcomputed tomography images revealed that treatment with simvastatin recovered the ligature induced alveolar bone resorption, showing a 46% reversal of bone height. Histological examination clarified that low-mineralized alveolar bone was formed in simvastatin-treated rats. CONCLUSION: These findings demonstrate that simvastatin has the potential to stimulate osteoblastic function and that topical administration of simvastatin may be effective for the recovery of alveolar bone loss in rats. PMID- 18447853 TI - Comparative analysis of putative periodontopathic bacteria by multiplex polymerase chain reaction. AB - BACKGROUND AND OBJECTIVE: The polymerase chain reaction (PCR) has been applied for the rapid and specific detection of periodontopathic bacteria in subgingival plaque and is potentially of clinical benefit in the diagnosis and treatment of periodontitis subjects. However, several technical points need to be modified before the conventional PCR detection system can be used by clinicians. MATERIAL AND METHODS: To develop a PCR-based technique more applicable for clinical use than conventional PCR, we established a multiplex PCR for five putative periodontopathic (Treponema denticola, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia and Tannerella forsythia) and two nonperiodontopathic (Streptococcus sanguinis and Streptococcus salivarius) species of bacteria using whole-plaque suspension as templates, and detected bacteria in subgingival plaque taken from 85 subjects at the supportive periodontal therapy stage after active periodontal treatments. RESULTS: Among putative periodontopathic bacteria, the detection frequency of T. denticola and P. gingivalis was elevated in parallel with higher probing pocket depth and clinical attachment loss, and had 4.2-14.1 times increasing odds of the clinical parameters tested. Detection of any of the five species of putative periodontopathic bacteria markedly increased the odds ratio of a higher probing pocket depth, clinical attachment loss and bleeding on probing. CONCLUSION: The multiplex PCR system developed in this study enabled the detection of all the bacteria under investigation in one reaction tube in a less time- and labor intensive manner than conventional PCR. These results support the potential clinical use of multiplex PCR for detecting periodontopathic bacteria and for evaluating therapeutic strategies and predicting the prognosis for each subject. PMID- 18447854 TI - Crevicular fluid endothelin-1 levels in periodontal health and disease. AB - BACKGROUND AND OBJECTIVE: Endothelin-1 is a 21-amino-acid peptide with multifunctional regulation. Initial research indicated that endothelin-1 levels in the gingival crevicular fluid from patients with chronic periodontitis were higher than those in the gingival crevicular fluid from healthy subjects. The aim of the present study was to assess the relationship between the clinical parameters and the concentrations of endothelin-1 within the gingival crevicular fluid from inflamed gingiva and periodontitis sites and, subsequently, after the treatment of periodontitis sites. MATERIAL AND METHODS: A total of 60 subjects were divided into three groups - healthy (group I), gingivitis (group II) and chronic periodontitis (group III) - based on gingival index, pocket probing depth and clinical attachment loss. A fourth group consisted of 20 subjects from group III, 6-8 wk after treatment (i.e. scaling and root planing). Gingival crevicular fluid samples collected from each patient were quantified for endothelin-1 using an enzymatic immunometric assay. RESULTS: Endothelin-1 was not detected in any sample from any of the study groups. CONCLUSION: The results showed that all the gingival crevicular fluid samples were negative for the endothelin-1 molecule. Therefore, endothelin-1 cannot be considered as a potential biomarker of periodontal disease progression. PMID- 18447855 TI - Modulation of gingival epithelial phenotypes by interactions with regionally defined populations of fibroblasts. AB - BACKGROUND AND OBJECTIVE: The unusual structure and functions of junctional epithelium, together with its pattern of migration in periodontal disease, raise interesting questions about the factors associated with the maintenance of its unique phenotype. To explore the effects of regionally differing fibroblast populations on the growth and patterns of differentiation of oral epithelia, this study used an organotypical in vitro model in an attempt to detect interactions occurring between populations of human oral fibroblasts and keratinocytes. MATERIAL AND METHODS: Keratinocytes and fibroblasts, isolated from the gingival region and periodontal ligament, were characterized by their patterns of growth and by their expression of known differentiation markers. Changes in cell behaviour and phenotypic marker expression were examined during in vitro passage as an indication of the maintenance of in vivo phenotypic traits. Using early passage cells, organotypical cultures were generated and patterns of epithelial growth and expression of phenotypic markers were examined. RESULTS: Phenotypically different populations of junctional and oral-gingival keratinocytes, and of oral-gingival and periodontal ligament fibroblasts, were successfully isolated, cultured and characterized. In the organotypic culture system, oral-gingival fibroblasts were found to have a markedly greater ability than periodontal ligament fibroblasts to support and maintain the growth of either type of epithelium. Shifts of epithelial phenotype were induced by different fibroblasts. CONCLUSION: Periodontal and gingival fibroblast subpopulations have differential effects on the growth and patterns of differentiation of oral and junctional epithelia. By modulating the epithelial phenotype, regionally differing fibroblasts can influence the stability and behaviour of the gingival attachment apparatus in health and disease. PMID- 18447856 TI - Progression of periodontal disease and interleukin-10 gene polymorphism. AB - BACKGROUND AND OBJECTIVE: Interleukin-10 is a key immunoregulatory cytokine that may be of significance in the immunopathogenesis of chronic inflammatory diseases such as periodontal disease. Molecular genetic studies have defined a number of haplotypes that may be associated with differing levels of interleukin-10 secretion. The present study investigated the possible association between interleukin-10 gene polymorphism and periodontal disease progression. MATERIAL AND METHODS: Genomic DNA was obtained from 252 adults who were part of a prospective longitudinal study on the progression of periodontal disease in a general adult Australian population. Single nucleotide polymorphisms at positions -592 and -1082 in the interleukin-10 promoter were analysed using an induced heteroduplex methodology and used to determine interleukin-10 promoter haplotypes in individual samples. Periodontitis progression was assessed by measuring probing depths and relative attachment levels at regular intervals over a 5-year period. A generalized linear model was used to analyse the data, with age, gender, smoking status, interleukin-1 genotype and Porphyromonas gingivalis included as possible confounders. RESULTS: There was a significant (p approximately 0.02) main effect of interleukin-10 haplotypes, with individuals having either the ATA/ACC or the ACC/ACC genotype experiencing around 20% fewer probing depths of >or= 4 mm compared to individuals with other genotypes. Age and smoking had significant (p < 0.001) additional effects. CONCLUSION: These data suggest that the interleukin-10 genotype contributes to the progression of periodontal disease. PMID- 18447857 TI - Effects of platelet-derived growth factor isoforms on plasminogen activation by periodontal ligament and gingival fibroblasts. AB - BACKGROUND AND OBJECTIVE: Platelet-derived growth factor isoforms and components of the plasminogen activator system are expressed at higher levels during periodontal regeneration. Recombinant platelet-derived growth factor-BB is approved for the treatment of periodontal defects. In the present study we investigated the effect of platelet-derived growth factor isoforms on the plasminogen activator system in periodontal fibroblasts. MATERIAL AND METHODS: Human periodontal ligament fibroblasts and gingival fibroblasts were exposed to platelet-derived growth factor isoforms. Changes in urokinase-type plasminogen activator, tissue-type plasminogen activator, plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 transcript levels by platelet-derived growth factor-BB were monitored with a quantitative reverse transcription polymerase chain reaction. Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 protein levels were assessed by immunoassays. The effects of platelet-derived growth factor-BB on mitogen-activated protein kinase and phosphoinositol-3 kinase/Akt signaling were investigated by western blot and inhibitor studies. Casein zymography and kinetic assays revealed the size and activity, respectively, of the plasminogen activators. RESULTS: We found that incubation of periodontal ligament fibroblasts and gingival fibroblasts with platelet-derived growth factor-BB resulted in enhanced levels of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 transcripts, but not of tissue-type plasminogen activator and plasminogen activator inhibitor-2. Platelet-derived growth factor-BB also increased urokinase-type plasminogen activator and plasminogen activator inhibitor-1 release into the culture medium. Phosphorylation of extracellular signal-regulated kinase, p38, c-Jun N-terminal kinase and Akt was observed in fibroblasts of both origin. Inhibition of phosphoinositol-3 kinase signaling abrogated the platelet-derived growth factor BB effect on plasminogen activator inhibitor-1 production. Casein zymography revealed enzymatic activity of the urokinase-type plasminogen activator in cell conditioned media and lysates of periodontal ligament fibroblasts and gingival fibroblasts. Exposure of gingival fibroblasts, but not of periodontal ligament fibroblasts, to platelet-derived growth factor isoforms moderately increased total plasminogen activation in the medium. CONCLUSION: These findings suggest that periodontal ligament fibroblasts attempt to maintain an equilibrium of the plasminogen activator system in the presence of platelet-derived growth factor isoforms. PMID- 18447858 TI - Secure versus fragile high self-esteem as a predictor of verbal defensiveness: converging findings across three different markers. AB - Why is it that many individuals verbally rationalize and distort self-esteem threatening information? We examined whether such verbal defensiveness (Feldman Barrett, Williams, & Fong, 2002) differs as a function of whether individuals' high self-esteem is secure or fragile. Our findings indicated that individuals whose self-esteem was stable, not contingent, or congruent with high implicit self-esteem exhibited especially low amounts of verbal defensiveness. In contrast, verbal defensiveness was considerably higher when individuals' high self-esteem was unstable, contingent, or paired with discrepant low implicit self esteem. Discussion centers on why the possession of well-anchored and secure high self-esteem obviates defensiveness directed toward enhancing, maintaining, or bolstering feelings of self-worth. PMID- 18447859 TI - The impact of research in bioethics. PMID- 18447860 TI - Mass-vaccination programmes and the value of respect for autonomy. AB - Respect for autonomy is problematic in relation to public health programmes such as vaccination, as the success of such programmes depends on widespread compliance. European countries have different policies for dealing with objectors to vaccination programmes. In some countries compliance is compulsory, while in others objectors are exempted or allowed to enter the programme under specific conditions. In this paper I argue that the objectors should not be treated as a homogenous group as is done in the above-mentioned policies. Objectors have different arguments for not participating in vaccination programmes. Considering the value of respect for autonomy, some but not all of these arguments need to be accommodated by authorities. The concept of 'narrative autonomy' provides criteria to distinguish between tenable and untenable claims to the right to refuse vaccination. Narrative autonomy understands autonomy as essentially linked to identity, as this provides the moral framework with which we assess our first order preferences. The above-mentioned concept of autonomy is derived from the concept of narrative identity as described by Marya Schechtman. She suggests that the application of the Articulation Constraint and the Reality Constraint enables us to establish the validity of personal narratives. Additionally, form and content features of identity, as proposed by Anthony Laden, will be used as criteria to establish the compatibility of the defectors' arguments with shared scientific and political values. Such compatibility is essential to accommodate respect for autonomy in the context of public health. PMID- 18447861 TI - Selecting potential children and unconditional parental love. AB - For now, the best way to select a child's genes is to select a potential child who has those genes, using genetic testing and either selective abortion, sperm and egg donors, or selecting embryos for implantation. Some people even wish to select against genes that are only mildly undesirable, or to select for superior genes. I call this selection drift--the standard for acceptable children is creeping upwards. The President's Council on Bioethics and others have raised the parental love objection: Just as we should love existing children unconditionally, so we should unconditionally accept whatever child we get in the natural course of things. If we set conditions on which child we get, we are setting conditions on our love for whatever child we get. Although this objection was prompted by selection drift, it also seems to cover selecting against genes for severe impairments. I argue that selection drift is not inconsistent with the ideal of unconditional parental love and, moreover, that the latter actually implies that we should practise selection drift--in other words, we should try to select potential children with the best genetic endowments. My endowment argument for the second claim works from an analogy between arranging an endowment prior to conception to fund a future child's education, and arranging a genetic endowment by selecting a potential child who already has it, where in both cases the child would not have existed without the endowment. I conclude with some programmatic remarks about the nonidentity problem. PMID- 18447862 TI - Enhancing autonomy in paid surrogacy. AB - The gestational surrogate--and her economic and educational vulnerability in particular--is the focus of many of the most persistent worries about paid surrogacy. Those who employ her, and those who broker and organize her services, usually have an advantage over her in resources and information. That asymmetry exposes her to the possibility of exploitation and abuse. Accordingly, some argue for banning paid surrogacy. Others defend legal permission on grounds of surrogate autonomy, but often retain concerns about the surrogate. In response to the dilemma of a ban versus bald permission, we propose a 'soft law' approach: states should require several hours of education of surrogates--education aimed at informing and enhancing surrogate autonomy. PMID- 18447863 TI - The moral distinction between killing and letting die in medical cases. AB - In some medical cases there is a moral distinction between killing and letting die, but in others there is not. In this paper I present an original and principled account of the moral distinction between killing and letting die. The account provides both an explanation of the moral distinction and an explanation for why the distinction does not always hold. If these explanations are correct, the moral distinction between killing and letting die must be taken seriously in medical contexts. Defeasibly, when an agent kills she takes responsibility, but when an agent lets die she does not take responsibility. Therein lies the moral distinction between killing and letting die. The distinction, however, is defeated when an agent is already responsible for the surrounding situation. In such cases, killing does not involve taking any further responsibility and letting die does not avoid taking any responsibility. Medical examples are frequently complicated because patients' autonomous choices impact upon medical practitioners' surrounding responsibility. PMID- 18447864 TI - Parental refusal of life-saving treatments for adolescents: Chinese familism in medical decision-making re-visited. AB - This paper reports two cases in Hong Kong involving two native Chinese adolescent cancer patients (APs) who were denied their rights to consent to necessary treatments refused by their parents, resulting in serious harm. We argue that the dynamics of the 'AP-physician-family-relationship' and the dominant role Chinese families play in medical decision-making (MDM) are best understood in terms of the tendency to hierarchy and parental authoritarianism in traditional Confucianism. This ethic has been confirmed and endorsed by various Chinese writers from Mainland China and Hong Kong. Rather than giving an unqualified endorsement to this ethic, based more on cultural sentimentalism than rational moral reasoning, we warn that a strong familism in MDM, which deprives 'weak' family members of rights, represents the less desirable elements of this tradition, against which healthcare professionals working in this cultural milieu need to safeguard. Specifically for APs, we suggest that parental authority and family integrity should be re-interpreted in terms of parental responsibility and the enhancement of children's interests respectively, as done in the West. This implies that when parents refuse to consent to necessary treatment and deny their adolescent children's right to consent, doctors, as the only remaining advocates of the APs' interest, have the duty to inform the state, which can override parental refusal to enable the doctors to fulfill their professional and moral obligations. In so doing the state exercises its 'parens patriae' power to defend the defenseless in society and the integrity of the medical profession. PMID- 18447869 TI - Proceedings of "Pig-to-Man Islet Transplant Summit" held at the Nobel Forum, Stockholm, June 4-5, 2007. PMID- 18447870 TI - A consensus document based on the Pig-to-Man Islet Transplant Summit held in Stockholm, June 4-5, 2007. PMID- 18447872 TI - What type of islets should be used? PMID- 18447873 TI - What strain of pig should be used? PMID- 18447874 TI - Gene-modified pigs. PMID- 18447875 TI - The rationale and practical issues for the maintenance of clean herds for clinical islet xenotransplantation. PMID- 18447876 TI - Isolation and assessment of islet quality. PMID- 18447877 TI - The instant blood-mediated inflammatory reaction in xenogeneic islet transplantation. PMID- 18447878 TI - Extrahepatic transplant sites for islet xenotransplantation. PMID- 18447879 TI - Selection of candidates for islet xenotransplantation. PMID- 18447880 TI - Islet xenotransplantation: the pig-to-non-human primate model. PMID- 18447881 TI - Immunosuppressive protocols for pig-to-human islet transplantation: lessons from pre-clinical non-human primate models. PMID- 18447882 TI - Co-transplantation of human and pig islets. PMID- 18447883 TI - Moving towards clinical application. PMID- 18447884 TI - Regulatory aspects of pig-to-human islet transplantation. PMID- 18447885 TI - No infection with porcine endogenous retrovirus in recipients of acellular porcine aortic valves: a two-year study. AB - BACKGROUND: Engineered tissue heart valves may become a promising therapeutics for heart valve disease. Compared with synthetic materials, acellular porcine scaffolds are considered as suitable matrices for tissue-engineered heart valves for the mechanical and structural properties of native tissue. Whether acellular porcine scaffolds can cause infection in recipients with porcine endogenous retrovirus (PERV) is critical for evaluating the safety of transplantation of tissue-engineered heart valves based on acellular porcine scaffolds. This study was completed to evaluate the risk of PERV transmission for application of acellular porcine aortic valves (PAVs). METHODS: Native aortic valves obtained from Chinese pigs of different species were acellularized by our modified detergent-enzymatic acellularization procedure. Polymerase chain reaction and reverse transcriptase polymerase chain reaction for pol sequences were used to detect PERV infection. In vitro, ovine endothelial cells (ECs) were inoculated and cocultured with supernatants of porcine aortic endothelial cells (PAECs) and acellualr PAVs, respectively. On 7th day, DNA and RNA of ovine ECs were isolated and tested for PERV. In vivo, acellular PAVs were implanted in the descending thoracic aorta in 40 sheep. Blood samples from the sheep and implanted acellular PAVs were collected 24 months after operation and tested for PERV. RESULTS: All cells were removed from the PAVs. Acellularized PAVs were repopulated by autologous cells of the host 24 months after implantation. PERV was detected in all native PAVs, porcine blood samples, acellularized PAVs and ovine ECs inoculated with supernatants of PAECs; no PERV was detected in ovine ECs cocultured with acellularized PAVs, ovine blood samples, and implanted acellular PAVs. CONCLUSIONS: Acellularized PAVs processed by modified detergent-enzymatic acellularization procedure can be used for cardiovascular tissue-engineered grafts as matrix scaffolds without risk of PERV transmission. PMID- 18447886 TI - Pig islet xenograft rejection in a mouse model with an established human immune system. AB - BACKGROUND: Xenotransplantation from pigs provides a potential solution to the severe shortage of human pancreata, but strong immunological rejection prevents its clinical application. A better understanding of the human immune response to pig islets would help develop effective strategies for preventing graft rejection. METHODS: We assessed pig islet rejection by human immune cells in humanized mice with a functional human immune system. Humanized mice were prepared by transplantation of human fetal thymus/liver tissues and CD34(+) fetal liver cells into immunodeficient mice. Islet xenograft survival/rejection was determined by histological analysis of the grafts and measurement of porcine C peptide in the sera of the recipients. RESULTS: In untreated humanized mice, adult pig islets were completely rejected by 4 weeks. These mice showed no detectable porcine C-peptide in the sera, and severe intra-graft infiltration by human T cells, macrophages, and B cells, as well as deposition of human antibodies. Pig islet rejection was prevented by human T-cell depletion prior to islet xenotransplantation. Islet xenografts harvested from T-cell-depleted humanized mice were functional, and showed no human cell infiltration or antibody deposition. CONCLUSIONS: Pig islet rejection in humanized mice is largely T-cell dependent, which is consistent with previous observations in non-human primates. These humanized mice provide a useful model for the study of human xenoimmune responses in vivo. PMID- 18447887 TI - Characterization of porcine UL16-binding protein 1 endothelial cell surface expression. AB - BACKGROUND: Natural killer (NK) cells participate in the immune response against solid organ allo- and xenografts and are tightly regulated through signals mediated by inhibiting and activating receptors expressed on their cell surface. Human NK cytotoxicity against porcine endothelial cells (pEC) is mediated by the interaction of the activating human NK receptor hNKG2D and its corresponding ligand on pEC, porcine UL-16 binding protein 1 (pULBP1). The aim of the present study was to characterize the regulation of pULBP1 cell-surface expression on primary porcine aortic endothelial cells (PAEC). METHODS: A monoclonal antibody (mAb; aE5-63) directed against pULBP1 was generated by immunizing C57BL/6 mice with the pEC line PEDSV.15, and used in cellular ELISA to determine pULBP1 cell surface expression. PAEC were either left untreated or stimulated with human or porcine cytokines [interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF alpha)], human serum, cultured under hypoxic conditions, or infected with human or porcine cytomegalovirus (CMV). RESULTS: Neither human nor porcine IFN-gamma stimulation changed pULBP1 expression, whereas both human and porcine TNF-alpha stimulation as well as human and porcine CMV infection significantly decreased pULBP1 expression on PAEC. Coculture of PAEC with human serum strongly increased pULBP1 expression depending on the binding of human anti-pig antibodies. Exposure of PAEC to hypoxia only slightly increased pULBP1 expression. CONCLUSIONS: In conclusion, (i) the novel anti-pULBP1 IgM mAb aE5-63 represents a useful tool to study pULBP1/hNKG2D-mediated responses in xenotransplantation, and (ii) the expression of pULBP1, a human-pig cross-species functional hNKG2D ligand, on the surface of PAEC is modulated by various stimuli associated with transplantation. PMID- 18447888 TI - Xenotransplantation literature update November-December, 2007. PMID- 18447890 TI - Authenticity: a concept analysis. AB - PURPOSE: This paper aims to analyze the concept of authenticity and propose a definition of authenticity that can be used to enhance the nurse-client relationship. SOURCES: Published research. CONCLUSIONS: Authenticity is a life long process of self-discovery that includes realizing personal potential and acting on that potential. A part of this process is accepting the responsibility for and the consequences of life choices that are consciously or unconsciously made. This is sometimes achieved through suffering. This process culminates in a demonstration of congruency in ideals, values, and actions in relation to self and others. PMID- 18447891 TI - Multiple relationships in nursing consultation. AB - In a consultation relationship, when boundaries are blurred or blended individuals become overinvested and overinvolved with each other. Therefore, nurse consultants must be wary of engaging in overinvolvement in consultation that leads to multiple relationships with their clients that can jeopardize the efficacy of their consultation practice. This article examines the nature of the consultation process, practice, and ethical standards that relate to nursing consultation and multiple relationships in consultation. Emphasis is placed on exploring the particularly problematic multiple relations that occur in nursing consultation and recommendation for dealing with them in practice. Clearly, engaging in multiple relationships in consultation is problematic because of the possibility of exploitation and harm. Nurse consultants must exercise caution before entering into a multiple relationship even when they feel that there is little potential for harm. They must learn how to effectively manage multiple relationships and be prepared to respond to the challenges that they present. PMID- 18447892 TI - Developing evidence-based nursing roles: lessons learned from the health care integrator role. AB - PURPOSE: This study examined a unique nursing role in the United States Air Force to determine if it had been well institutionalized and to identify barriers and facilitators during the implementation process. SOURCE OF INFORMATION: Individuals functioning in the role were surveyed to measure time spent on specific job-related tasks, additional duties, and positive and negative experiences. CONCLUSIONS: Eighty-seven percent of the respondents (n = 45) indicated that the role had been well implemented, although wide variation existed in tasks performed and major organizational barriers identified. Findings of this study can be used to guide the development of other evidence-based positions. PMID- 18447893 TI - Concept analysis: sexual decision-making in adolescence. AB - PURPOSE: This papers aims to clarify and explore the topic of adolescent decision making regarding sexual activity. SOURCES: Published literature. CONCLUSIONS: Adolescent decision-making regarding the initiation or continuation of sexual activity is influenced by desire for intimacy, perceived relationship safety, problem-solving ability, cognitive ability, family and peer relationships, and concern regarding pregnancy or sexually transmitted infection. PMID- 18447894 TI - Survivorship: a concept analysis. AB - TOPIC: Survivorship is a relevant concept to evaluate as technology is allowing people to survive previously terminal conditions. The act of surviving a life altering event can result in survivorship by altering continuity of identity. PURPOSE: This paper analyzes the concept of survivorship through the use of Walker and Avant's model of concept analysis. SOURCES OF INFORMATION: A comprehensive literature review and bibliographic search resulted in numerous sources available for analysis. CONCLUSIONS: The recognition of commonalities among all types of survivors could have important implications for support groups and rehabilitation therapies. PMID- 18447895 TI - Musculoskeletal problems experienced by older nurses in hospital settings. AB - The effects of musculoskeletal problems on older nurses working in hospital settings was examined, including what contributed to the problems, and preferred treatments selected. Inadequate sleep was significantly related to musculoskeletal symptoms in all regions of the body. Most frequent problems were in lower and upper back, neck, and shoulder areas. Rotating and/or 12-hr shifts, inadequate sleep, frequent patient handling, and nurses who felt little control over their work reported more lower back symptoms. Surprisingly, nurses relied on over-the-counter medications to treat their problems. Implications for supporting the nursing workforce and minimizing musculoskeletal problems are discussed. PMID- 18447897 TI - Review: Familial Parkinson's disease--genetics, clinical phenotype and neuropathology in relation to the common sporadic form of the disease. AB - The identification of the first gene in familial Parkinson's disease (PD) only 10 years ago was a major step in the understanding of the molecular mechanisms in neurodegeneration. Alpha-synuclein aggregation was not only recognized as a key event in neurodegeneration in patients carrying mutations in this gene, but it turned out to be the most consistent marker to define Lewy body pathology also in non-heritable idiopathic PD (IPD). Subsequent comprehensive pathoanatomical studies of IPD brains led to a novel concept of an ascending pathological process in variable stages that are reflected by alpha-synuclein aggregation at specific predilection sites. To date, more than seven genes are known to cause familial PD. The fact that these genetic forms of Parkinsonism present with clinical features indistinguishable from IPD, but may display neuropathological features that are not consistent with IPD, underscores the need of a more differentiated approach to familial and sporadic forms of Parkinsonism. Indeed, in distinct populations, mutations in one single gene were found to cause the disease in up to 40% of patients formerly described as 'idiopathic' cases. These findings indicate that IPD, as defined by a late-onset disorder with no (apparent) genetic contribution, is part of a clinical syndrome that becomes more and more heterogeneous in terms of aetiology, with overlapping clinical and pathoanatomical features. Thus in the present review, we discuss clues from familial PD to our understanding of the molecular pathogenesis of neurodegeneration with special consideration of the variable clinical and neuropathological aspects. PMID- 18447898 TI - Splinting after contracture release for Dupuytren's contracture (SCoRD): protocol of a pragmatic, multi-centre, randomized controlled trial. AB - BACKGROUND: Splinting as part of the overall post-surgical management of patients after release of Dupuytren's contracture has been widely reported, though there is variation in practice and criteria for using it. The evidence on its effectiveness is sparse, of poor quality and contradictory with studies reporting negative and positive effects. METHODS/DESIGN: A multi-centre, pragmatic, randomized, controlled trial is being conducted to evaluate the effect of static night splinting for six months on hand function, range of movement, patient satisfaction and recurrence at 1 year after fasciectomy or dermofasciectomy. Using a centrally administered computer randomization system consented patients will be allocated to one of two groups: i) splint group who will be given a static splint at approximately 10 to 14 days after surgery to be worn for 6 months at night time only as well as hand therapy; ii) non-splint group, who will receive hand therapy only. The primary outcome measure is the patient-reported Disabilities of the Arm, Hand and Shoulder Questionnaire (DASH). Secondary outcomes are total active flexion and extension of fingers, patient satisfaction and recurrence of contracture. Outcome measures will be collected prior to surgery, 3 months, 6 months and 1 year after surgery. Using the DASH as the primary outcome measure, where a difference of 15 points is considered to be a clinically important difference a total of 51 patients will be needed in each group for a power of 90%. An intention-to-treat analysis will be used. DISCUSSION: This pragmatic randomized controlled trial will provide much needed evidence on the clinical effectiveness of post-operative night splinting in patients who have undergone fasciectomy or dermofasciectomy for Dupuytren's contracture of the hand. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 57079614. PMID- 18447900 TI - Life-threatening biopsy of an iliopsoas pseudotumour in a patient with haemophilia: a case report. AB - Iliopsoas pseudotumour is a serious complication of haemophilia. We present the case of a 20-year-old male patient with a six-month history of left leg weakness, limitation of movement and wasting of the muscles. Clinically he was diagnosed as having a psoas muscle rhabdomyosarcoma. During a computed tomography (CT) scan guided Tru-cut biopsy he developed a serious and life-threatening bleeding from a retroperitoneal muscular haematoma. The patient underwent laparotomy prior to his final diagnosis of an Iliopsoas pseudotumour, which is a serious, as well as rare, complication of haemophilia. PMID- 18447899 TI - Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. AB - BACKGROUND: Targeting tumor angiogenesis and vasculature is a promising strategy for the inhibition of tumor growth and dissemination. Evidence suggests that tumor vasculature expresses unique markers that distinguish it from normal vasculature. Our efforts focused on the molecular characterization of endothelial cells (EC) in the search for selective markers of tumor vasculature that might be helpful for the development of effective therapeutic approaches. RESULTS: We investigated by microarray analysis the gene expression profiles of EC purified and cultured from tumor (ovarian carcinoma [HOC-EC]) and normal (human adrenal gland [HA-EC]) tissue specimens. We found distinct transcriptional features characterizing the EC of different origin, and identified 158 transcripts highly expressed by HOC-EC. We analyzed four of these genes, ADAM23, FAP, GPNMB and PRSS3, which were not previously known to be expressed by endothelium. In vitro experiments confirmed the higher expression of the selected genes in tumor derived endothelium with no expression in tumor cells. In vivo investigation by in situ hybridization established that ADAM23, GPNMB and PRSS3 expression is localized on blood vessels of human cancer specimens. CONCLUSION: These findings elucidate some of the molecular features of the tumor endothelium. Comparative transcriptomic analysis allowed us to determine molecular differences of tumor and normal tissue-derived endothelium and to identify novel markers that might be exploited to selectively target tumor vasculature. PMID- 18447901 TI - Mortality selection during the 2003 European heat wave in three-spined sticklebacks: effects of parasites and MHC genotype. AB - BACKGROUND: Ecological interaction strength may increase under environmental stress including temperature. How such stress enhances and interacts with parasite selection is almost unknown. We studied the importance of resistance genes of the major histocompatibility complex (MHC) class II in 14 families of three-spined sticklebacks Gasterosteus aculeatus exposed to their natural macroparasites in field enclosures in the extreme summer of 2003. RESULTS: After a mass die-off during the 2003-European heat wave killing 78% of 277 experimental fish, we found strong differences in survival among and within families. In families with higher average parasite load fewer individuals survived. Multivariate analysis revealed that the composition of the infecting parasite fauna was family specific. Within families, individuals with an intermediate number of MHC class IIB sequence variants survived best and had the lowest parasite load among survivors, suggesting a direct functional link between MHC diversity and fitness. The within family MHC effects were, however, small compared to between family effects, suggesting that other genetic components or non-genetic effects were also important. CONCLUSION: The correlation between parasite load and mortality that we found at both individual and family level might have appeared only in the extraordinary heatwave of 2003. Due to global warming the frequency of extreme climatic events is predicted to increase, which might intensify costs of parasitism and enhance selection on immune genes. PMID- 18447902 TI - SBMLsqueezer: a CellDesigner plug-in to generate kinetic rate equations for biochemical networks. AB - BACKGROUND: The development of complex biochemical models has been facilitated through the standardization of machine-readable representations like SBML (Systems Biology Markup Language). This effort is accompanied by the ongoing development of the human-readable diagrammatic representation SBGN (Systems Biology Graphical Notation). The graphical SBML editor CellDesigner allows direct translation of SBGN into SBML, and vice versa. For the assignment of kinetic rate laws, however, this process is not straightforward, as it often requires manual assembly and specific knowledge of kinetic equations. RESULTS: SBMLsqueezer facilitates exactly this modeling step via automated equation generation, overcoming the highly error-prone and cumbersome process of manually assigning kinetic equations. For each reaction the kinetic equation is derived from the stoichiometry, the participating species (e.g., proteins, mRNA or simple molecules) as well as the regulatory relations (activation, inhibition or other modulations) of the SBGN diagram. Such information allows distinctions between, for example, translation, phosphorylation or state transitions. The types of kinetics considered are numerous, for instance generalized mass-action, Hill, convenience and several Michaelis-Menten-based kinetics, each including activation and inhibition. These kinetics allow SBMLsqueezer to cover metabolic, gene regulatory, signal transduction and mixed networks. Whenever multiple kinetics are applicable to one reaction, parameter settings allow for user defined specifications. After invoking SBMLsqueezer, the kinetic formulas are generated and assigned to the model, which can then be simulated in CellDesigner or with external ODE solvers. Furthermore, the equations can be exported to SBML, LaTeX or plain text format. CONCLUSION: SBMLsqueezer considers the annotation of all participating reactants, products and regulators when generating rate laws for reactions. Thus, for each reaction, only applicable kinetic formulas are considered. This modeling scheme creates kinetics in accordance with the diagrammatic representation. In contrast most previously published tools have relied on the stoichiometry and generic modulators of a reaction, thus ignoring and potentially conflicting with the information expressed through the process diagram. Additional material and the source code can be found at the project homepage (URL found in the Availability and requirements section). PMID- 18447904 TI - Radiation-induced morphea of the breast: a case report. AB - Radiation-induced morphea (RIM) of the breast is a rare complication of radiotherapy. It is disfiguring, painful and defeats the purpose of achieving a good cosmesis in breast-conservation surgery. This report describes a severe case of RIM in a breast cancer patient together with photographic illustrations of the serial changes over time and histopathology slides. A review of the literature is provided. PMID- 18447903 TI - Comparative analysis of sequence features involved in the recognition of tandem splice sites. AB - BACKGROUND: The splicing of pre-mRNAs is conspicuously often variable and produces multiple alternatively spliced (AS) isoforms that encode different messages from one gene locus. Computational studies uncovered a class of highly similar isoforms, which were related to tandem 5'-splice sites (5'ss) and 3' splice sites (3'ss), yet with very sparse anecdotal evidence in experimental studies. To compare the types and levels of alternative tandem splice site exons occurring in different human organ systems and cell types, and to study known sequence features involved in the recognition and distinction of neighboring splice sites, we performed large-scale, stringent alignments of cDNA sequences and ESTs to the human and mouse genomes, followed by experimental validation. RESULTS: We analyzed alternative 5'ss exons (A5Es) and alternative 3'ss exons (A3Es), derived from transcript sequences that were aligned to assembled genome sequences to infer patterns of AS occurring in several thousands of genes. Comparing the levels of overlapping (tandem) and non-overlapping (competitive) A5Es and A3Es, a clear preference of isoforms was seen for tandem acceptors and donors, with four nucleotides and three to six nucleotides long exon extensions, respectively. A subset of inferred A5E tandem exons was selected and experimentally validated. With the focus on A5Es, we investigated their transcript coverage, sequence conservation and base-paring to U1 snRNA, proximal and distal splice site classification, candidate motifs for cis-regulatory activity, and compared A5Es with A3Es, constitutive and pseudo-exons, in H. sapiens and M. musculus. The results reveal a small but authentic enriched set of tandem splice site preference, with specific distances between proximal and distal 5'ss (3'ss), which showed a marked dichotomy between the levels of in- and out-of-frame splicing for A5Es and A3Es, respectively, identified a number of candidate NMD targets, and allowed a rough estimation of a number of undetected tandem donors based on splice site information. CONCLUSION: This comparative study distinguishes tandem 5'ss and 3'ss, with three to six nucleotides long extensions, as having unusually high proportions of AS, experimentally validates tandem donors in a panel of different human tissues, highlights the dichotomy in the types of AS occurring at tandem splice sites, and elucidates that human alternative exons spliced at overlapping 5'ss posses features of typical splice variants that could well be beneficial for the cell. PMID- 18447905 TI - Differential effects of antibiotics in combination with G-CSF on survival and polymorphonuclear granulocyte cell functions in septic rats. AB - BACKGROUND: In addition to their antimicrobial activity, antibiotics modulate cellular host defence. Granulocyte-colony stimulating factor (G-CSF) is also a well known immunomodulator; however little is known about the interactions of G CSF with antibiotics. We investigated in septic rats the effects of two antibiotic combinations with G-CSF. METHODS: In two clinic modelling randomised trials (CMRTs), male Wistar rats were anesthetized, given antibiotic prophylaxis, had a laparotomy with peritoneal contamination and infection (PCI), and were randomly assigned (n = 18 rats/group) to: 1) PCI only; 2) PCI+antibiotic; and, 3) PCI+antibiotic+G-CSF prophylaxis (20 mug/kg, three times). This sequence was conducted first with 10 mg/kg coamoxiclav, and then with ceftriaxone/metronidazole (Cef/met, 10/3 mg/kg). In additional animals, the blood cell count, migration and superoxide production of PMNs, systemic TNF-alpha and liver cytokine mRNA expression levels were determined. RESULTS: Only the combination coamoxiclav plus G-CSF improved the survival rate (82 vs. 44%, p < 0.001). Improved survival with this combination was accompanied by normalised antimicrobial PMN migratory activity and superoxide production, along with normalised systemic TNF-alpha levels and a reduced expression of TNF-alpha and IL 1 in the liver. CONCLUSION: There are substantial differences in the interaction of antibiotics with G-CSF. Therefore, the selection of the antibiotic for combination with G-CSF in sepsis treatment should be guided not only by the bacteria to be eliminated, but also by the effects on antimicrobial functions of PMNs and the cytokine response. PMID- 18447906 TI - Human-macaque comparisons illuminate variation in neutral substitution rates. AB - BACKGROUND: The evolutionary distance between human and macaque is particularly attractive for investigating local variation in neutral substitution rates, because substitutions can be inferred more reliably than in comparisons with rodents and are less influenced by the effects of current and ancient diversity than in comparisons with closer primates. Here we investigate the human-macaque neutral substitution rate as a function of a number of genomic parameters. RESULTS: Using regression analyses we find that male mutation bias, male (but not female) recombination rate, distance to telomeres and substitution rates computed from orthologous regions in mouse-rat and dog-cow comparisons are prominent predictors of the neutral rate. Additionally, we demonstrate that the previously observed biphasic relationship between neutral rate and GC content can be accounted for by properly combining rates at CpG and non-CpG sites. Finally, we find the neutral rate to be negatively correlated with the densities of several classes of computationally predicted functional elements, and less so with the densities of certain classes of experimentally verified functional elements. CONCLUSION: Our results suggest that while female recombination may be mainly responsible for driving evolution in GC content, male recombination may be mutagenic, and that other mutagenic mechanisms acting near telomeres, and mechanisms whose effects are shared across mammalian genomes, play significant roles. We also have evidence that the nonlinear increase in rates at high GC levels may be largely due to hyper-mutability of CpG dinucleotides. Finally, our results suggest that the performance of conservation-based prediction methods can be improved by accounting for neutral rates. PMID- 18447907 TI - Influence of genetic factors on toluene diisocyanate-related symptoms: evidence from a cross-sectional study. AB - BACKGROUND: Toluene diisocyanate (TDI) is a highly reactive compound used in the production of, e.g., polyurethane foams and paints. TDI is known to cause respiratory symptoms and diseases. Because TDI causes symptoms in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. METHODS: Workers (N = 132) exposed to TDI and a non-exposed group (N = 114) were analyzed for genotype (metabolising genes: CYP1A1*2A, CYP1A1*2B, GSTM1*O, GSTM3*B, GSTP1 I105V, GSTP1 A114V, GSTT1*O, MPO -463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, SULT1A1 R213H; immune-related genes: CCL5 -403, HLA-DQB1*05, TNF -308, TNF -863) and symptoms of the eyes, upper and lower airways (based on structured interviews). RESULTS: For three polymorphisms: CYP1A1*2A, CYP1A1*2B, and TNF -308 there was a pattern consistent with interaction between genotype and TDI exposure status for the majority of symptoms investigated, although it did reach statistical significance only for some symptoms: among TDI-exposed workers, the CYP1A1 variant carriers had increased risk (CYP1A1*2A and eye symptoms: variant carriers OR 2.0 95% CI 0.68-6.1, p value for interaction 0.048; CYP1A1*2B and wheeze: IV carriers OR = 12, 1.4-110, p-value for interaction 0.057). TDI-exposed individuals with TNF-308 A were protected against the majority of symptoms, but it did not reach statistical significance. In the non-exposed group, however, TNF -308 A carriers showed higher risk of the majority of symptoms (eye symptoms: variant carriers OR = 2.8, 1.1-7.1, p-value for interaction 0.12; dry cough OR = 2.2, 0.69-7.2, p-value for interaction 0.036). Individuals with SULT1A1 213H had reduced risk both in the exposed and non-exposed groups. Other polymorphisms, showed associations to certain symptoms: among TDI-exposed,NAT1*10 carriers had a higher risk of eye symptoms and CCL5 -403 AG+AA as well as HLA-DQB1 *05 carriers displayed increased risk of symptoms of the lower airways. GSTM1, GSTM3 and GSTP1 only displayed effects on symptoms of the lower airways in the non-exposed group. CONCLUSION: Specific gene-TDI interactions for symptoms of the eyes and lower airways appear to exist. The results suggest different mechanisms for TDI- and non-TDI-related symptoms of the eyes and lower airways. PMID- 18447908 TI - Assessing meiofaunal variation among individuals utilising morphological and molecular approaches: an example using the Tardigrada. AB - BACKGROUND: Meiofauna - multicellular animals captured between sieve size 45 mum and 1000 mum - are a fundamental component of terrestrial, and marine benthic ecosystems, forming an integral element of food webs, and playing a critical roll in nutrient recycling. Most phyla have meiofaunal representatives and studies of these taxa impact on a wide variety of sub-disciplines as well as having social and economic implications. However, studies of variation in meiofauna are presented with several important challenges. Isolating individuals from a sample substrate is a time consuming process, and identification requires increasingly scarce taxonomic expertise. Finding suitable morphological characters in many of these organisms is often difficult even for experts. Molecular markers are extremely useful for identifying variation in morphologically conserved organisms. However, for many species markers need to be developed de novo, while DNA can often only be extracted from pooled samples in order to obtain sufficient quantity and quality. Importantly, multiple independent markers are required to reconcile gene evolution with species evolution. In this primarily methodological paper we provide a proof of principle of a novel and effective protocol for the isolation of meiofauna from an environmental sample. We also go on to illustrate examples of the implications arising from subsequent screening for genetic variation at the level of the individual using ribosomal, mitochondrial and single copy nuclear markers. RESULTS: To isolate individual tardigrades from their habitat substrate we used a non-toxic density gradient media that did not interfere with downstream biochemical processes. Using a simple DNA release technique and nested polymerase chain reaction with universal primers we were able amplify multi-copy and, to some extent, single copy genes from individual tardigrades. Maximum likelihood trees from ribosomal 18S, mitochondrial cytochrome oxidase subunit 1, and the single copy nuclear gene Wingless support a recent study indicating that the family Hypsibiidae is a non-monophyletic group. From these sequences we were able to detect variation between individuals at each locus that allowed us to identify the presence of cryptic taxa that would otherwise have been overlooked. CONCLUSION: Molecular results obtained from individuals, rather than pooled samples, are a prerequisite to enable levels of variation to be placed into context. In this study we have provided a proof of principle of this approach for meiofaunal tardigrades, an important group of soil biota previously not considered amenable to such studies, thereby paving the way for more comprehensive phylogenetic studies using multiple nuclear markers, and population genetic studies. PMID- 18447909 TI - Chinese version of the Global Youth Tobacco Survey: cross-cultural instrument adaptation. AB - BACKGROUND: Tobacco smoking poses public health concerns because of its high risk for many chronic diseases. Most smokers begin using tobacco in their teens and recent reports indicate that smoking prevalence is climbing among youth. The Global Youth Tobacco Survey (GYTS) is a worldwide, school-based, tobacco-specific survey, but cross-cultural differences limit its effectiveness in international studies. Specifically, the GYTS assesses not only the prevalence of smoking, but also tobacco-related attitudes, school curricula, and advertisements, which are culturally influenced. Therefore, we conducted this study to develop a Chinese version of the GYTS for both national surveillance and international comparison. METHODS: The original English GYTS was translated and back translated using a cross-cultural adaptation process. The comprehensiveness and feasibility of using the Chinese-version GYTS were reviewed by a panel of 6 tobacco-control experts. The understandability and cultural relevance of the Chinese-version GYTS were discussed in a focus group of 5 schoolteachers and 8 students. The expert and focus group feedback was incorporated into a final Chinese version of the GYTS, which was administered to 382 students throughout Taiwan by multi-stage sampling from 10 randomly selected schools. RESULTS: The internal consistency (Cronbach's alpha) for the GYTS subscales (smoking susceptibility, attitude toward smoking, and media messages about smoking) ranged from 0.70 to 0.94. The internal logical agreement of responses ranged from 85.3 to 99.2%. CONCLUSION: The Chinese version of the GYTS has good reliability and validity and can serve as the foundation for international comparison and tobacco control in Chinese-speaking communities. PMID- 18447910 TI - On the potential for extinction by Muller's ratchet in Caenorhabditis elegans. AB - BACKGROUND: The self-fertile hermaphrodite worm C. elegans is an important model organism for biology, yet little is known about the origin and persistence of the self-fertilizing mode of reproduction in this lineage. Recent work has demonstrated an extraordinary degree of selfing combined with a high deleterious mutation rate in contemporary populations. These observations raise the question as to whether the mutation load might rise to such a degree as to eventually threaten the species with extinction. The potential for such a process to occur would inform our understanding of the time since the origin of self-fertilization in C. elegans history. RESULTS: To address this issue, here we quantify the rate of fitness decline expected to occur via Muller's ratchet for a purely selfing population, using both analytical approximations and globally distributed individual-based simulations from the evolution@home system to compute the rate of deleterious mutation accumulation. Using the best available estimates for parameters of how C. elegans evolves, we conclude that pure selfing can persist for only short evolutionary intervals, and is expected to lead to extinction within thousands of years for a plausible portion of parameter space. Credible lower-bound estimates of nuclear mutation rates do not extend the expected time to extinction much beyond a million years. CONCLUSION: Thus we conclude that either the extreme self-fertilization implied by current patterns of genetic variation in C. elegans arose relatively recently or that low levels of outcrossing and other factors are key to the persistence of C. elegans into the present day. We also discuss results for the mitochondrial genome and the implications for C. briggsae, a close relative that made the transition to selfing independently of C. elegans. PMID- 18447911 TI - Intentional injury reported by young people in the Federated States of Micronesia, Kingdom of Tonga and Vanuatu. AB - BACKGROUND: Intentional injury presents a threat to the physical and psychological well being of young people, especially in developing countries, which carry the greatest part of the global injury burden. While the importance of this problem is recognized, there are limited population data in low and middle income countries that can guide public health action. The present study investigates the prevalence and distribution of intentional injury among young people in three Pacific Island societies, and examines behavioural and psychosocial factors related to risk of intentional injury. METHODS: Population surveys were conducted with students aged 11-17 years in Pohnpei State in the Federated States of Micronesia (n = 1495), the Kingdom of Tonga (n = 2808) and Vanuatu (n = 4474). Surveys measured self-reported injury and intentional injury, sources of intentional injury, and the range of behavioural, psychological, educational and social variables that may be related to injury risk. RESULTS: Among boys and girls aged 14-17 years the respective period prevalence of intentional injury was 62% and 56% in Pohnpei, 58% and 41% in Tonga, and 33% and 24% in Vanuatu. The prevalence of intentional injury declined with age in Tonga and Vanuatu, but there was little evidence of an age-trend in Pohnpei. Across the three societies, the major sources of intentional injury among boys were 'other persons' followed by boyfriends/girlfriends and fathers. Mothers, boyfriends/girlfriends and other persons were primary sources of injury among girls. An intentional injury was reported more often by those who had been bullied (OR 1.40-1.66, P < 0.05), by regular smokers in Tonga and Vanuatu (OR 1.52-2.21, P < 0.05), and illicit drug users in Pohnpei and Vanuatu (OR 1.87 1.92, P < 0.05). CONCLUSION: Intentional injury was reported extensively in these three populations. Interventions directed towards the school environment and which take into account the role of bullying and drug use need to be considered. PMID- 18447912 TI - Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. AB - BACKGROUND: Among the most prominent metabolic alterations in cancer cells are the increase in glucose consumption and the conversion of glucose to lactic acid via the reduction of pyruvate even in the presence of oxygen. This phenomenon, known as aerobic glycolysis or the Warburg effect, may provide a rationale for therapeutic strategies that inhibit tumour growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat enriched with omega-3 fatty acids and medium-chain triglycerides (MCT). METHODS: Twenty-four female NMRI nude mice were injected subcutaneously with tumour cells of the gastric adenocarcinoma cell line 23132/87. The animals were then randomly split into two feeding groups and fed either a ketogenic diet (KD group; n = 12) or a standard diet (SD group; n = 12) ad libitum. Experiments were ended upon attainment of the target tumor volume of 600 mm3 to 700 mm3. The two diets were compared based on tumour growth and survival time (interval between tumour cell injection and attainment of target tumour volume). RESULTS: The ketogenic diet was well accepted by the KD mice. The tumour growth in the KD group was significantly delayed compared to that in the SD group. Tumours in the KD group reached the target tumour volume at 34.2 +/- 8.5 days versus only 23.3 +/- 3.9 days in the SD group. After day 20, tumours in the KD group grew faster although the differences in mean tumour growth continued significantly. Importantly, they revealed significantly larger necrotic areas than tumours of the SD group and the areas with vital tumour cells appear to have had fewer vessels than tumours of the SD group. Viable tumour cells in the border zone surrounding the necrotic areas of tumours of both groups exhibited a glycolytic phenotype with expression of glucose transporter-1 and transketolase-like 1 enzyme. CONCLUSION: Application of an unrestricted ketogenic diet enriched with omega-3 fatty acids and MCT delayed tumour growth in a mouse xenograft model. Further studies are needed to address the impact of this diet on other tumour-relevant functions such as invasive growth and metastasis. PMID- 18447913 TI - Copper deficiency and effects of copper supplementation in a herd of red deer (Cervus elaphus). AB - Copper (Cu) deficiency was diagnosed in a Norwegian red deer (Cervus elaphus) herd subsequent to deaths due to emaciation in late autumn 1999. The animals had free access to salt licks containing 3000 mg Cu/kg. An evaluation of the herd revealed poor calf growth rate, low weights of adult hinds, dull and light coloured hair coats and cases of diarrhoea. The herd was subsequently monitored throughout a three-year period of Cu-supplementation. The monitoring regimen included clinical observation, copper serum examination, weighing, faecal parasitological examination, and reproduction control by ultrasound. During the period January 2000 to May 2001, the animals were treated with Cu oxid capsules (1 g CuO/10 kg liveweight) at 2-4 months intervals, with the exception of March to September 2000. The animals were fed continuously with Cu-enriched concentrates containing 300 mg Cu/kg, at a rate of 1/2 kg per head and day, from May 2001 to January 2003. Following both copper supplementation regimens adequate serum Cu concentrations were measured, and markedly improved body weights, coat quality and reproductive results were observed, except for the period from March to September 2000 when no treatment was given. The results showed that in a deer herd, with a diet low in Cu, supplementation with CuO capsules had to be given at intervals of a few months to maintain adequate serum Cu levels. Free access to Cu containing salt licks did not meet the animals' Cu demand. Good and stable results were achieved by the daily feeding of Cu-enriched concentrates. PMID- 18447914 TI - Cupin: a candidate molecular structure for the Nep1-like protein family. AB - BACKGROUND: NEP1-like proteins (NLPs) are a novel family of microbial elicitors of plant necrosis. Some NLPs induce a hypersensitive-like response in dicot plants though the basis for this response remains unclear. In addition, the spatial structure and the role of these highly conserved proteins are not known. RESULTS: We predict a 3d-structure for the beta-rich section of the NLPs based on alignments, prediction tools and molecular dynamics. We calculated a consensus sequence from 42 NLPs proteins, predicted its secondary structure and obtained a high quality alignment of this structure and conserved residues with the two Cupin superfamily motifs. The conserved sequence GHRHDWE and several common residues, especially some conserved histidines, in NLPs match closely the two cupin motifs. Besides other common residues shared by dicot Auxin-Binding Proteins (ABPs) and NLPs, an additional conserved histidine found in all dicot ABPs was also found in all NLPs at the same position. CONCLUSION: We propose that the necrosis inducing protein class belongs to the Cupin superfamily. Based on the 3d-structure, we are proposing some possible functions for the NLPs. PMID- 18447915 TI - Disseminated cysticercosis: a case report and review of the literature. AB - INTRODUCTION: Cysticercosis is a common tropical disease. One of the uncommon manifestations of cysticercosis is its disseminated form. CASE PRESENTATION: We report an immunocompetent patient with disseminated cysticercosis, who had involvement of the brain, subcutaneous tissues, skeletal muscles, right orbit and thyroid gland. In addition, this patient developed a serum sickness which responded to therapy. CONCLUSION: Wide spread dissemination is a rare complication of cysticercosis. A planned approach to therapy is required. PMID- 18447916 TI - Efficacy of a training intervention on the quality of practitioners' decision support for patients deciding about place of care at the end of life: A randomized control trial: Study protocol. AB - BACKGROUND: Most people prefer home palliation but die in an institution. Some experience decisional conflict when weighing options regarding place of care. Clinicians can identify patients' decisional needs and provide decision support, yet generally lack skills and confidence in doing so. This study aims to determine whether the quality of clinicians' decision support can be improved with a brief, theory-based, skills-building intervention. THEORY: The Ottawa Decision Support Framework (ODSF) guides an evidence based, practical approach to assist clinicians in providing high-quality decision support. The ODSF proposes that decisional needs [personal uncertainty, knowledge, values clarity, support, personal characteristics] strongly influence the quality of decisions patients make. Clinicians can improve decision quality by providing decision support to address decisional needs [clarify decisional needs, provide facts and probabilities, clarify values, support/guide deliberation, monitor/facilitate progress]. METHODS/DESIGN: The efficacy of a brief education intervention will be assessed in a two-phase study. In phase one a focused needs assessment will be conducted with key informants. Phase two is a randomized control trial where clinicians will be randomly allocated to an intervention or control group. The intervention, informed by the needs assessment, knowledge transfer best practices and the ODSF, comprises an online tutorial; an interactive skills building workshop; a decision support protocol; performance feedback, and educational outreach. Participants will be assessed: a) at baseline (quality of decision support); b) after the tutorial (knowledge); and c) four weeks after the other interventions (quality of decision support, intention to incorporate decision support into practice and perceived usefulness of intervention components). Between group differences in the primary outcome (quality of decision support scores) will be analyzed using ANOVA. DISCUSSION: Few studies have investigated the efficacy of an evidence-based, theory guided intervention aimed at assisting clinicians to strengthen their patient decision support skills. Expanding our understanding of how clinicians can best support palliative patients' decision making will help to inform best practices in patient-centered palliative care. There is potential transferability of lessons learned to other care situations such as chronic condition management, advance directives and anticipatory care planning. Should the efficacy evaluation reveal clear improvements in the quality of decision support provided by clinicians who received the intervention, a larger scale implementation and effectiveness trial will be considered. TRIAL REGISTRATION: This study is registered as NCT00614003. PMID- 18447917 TI - Rapid detection of Chlamydia trachomatis and typing of the Lymphogranuloma venereum associated L-Serovars by TaqMan PCR. AB - BACKGROUND: Infection due to Chlamydia trachomatis is the most common sexually transmitted bacterial disease of global health significance, and especially the L serovars causing lymphogranuloma venereum are increasingly being found in Europe in men who have sex with men. RESULTS: The design and evaluation of a rapid, multiplex, real-time PCR targeting the major outer membrane protein (omp-1) -gene and a L-serovar-specific region of the polymorphic protein H (pmp-H) -gene for the detection of Chlamydia trachomatis is reported here. The PCR takes place as a single reaction with an internal control. For L1-, L2- and L3-serovar differentiation a second set of real-time PCRs was evaluated based on the amplification of serovar-specific omp-1-regions. The detection limit of each real time PCR, multiplexed or not, was 50 genome copies per reaction with an efficiency ranging from 90,5-95,2%. In a retrospective analysis of 50 ocular, rectal and urogenital specimens formerly tested to be positive for C. trachomatis we identified six L2-serovars in rectal specimens of HIV-positive men, one in a double-infection with L3, and one L2 in a urethral specimen of an HIV-negative male. CONCLUSION: This unique real-time PCR is specific and convenient for the rapid routine-diagnostic detection of lymphogranuloma venereum-associated L serovars and enables the subsequent differentiation of L1, L2 and L3 for epidemiologic studies. PMID- 18447918 TI - Coral kin aggregations exhibit mixed allogeneic reactions and enhanced fitness during early ontogeny. AB - BACKGROUND: Aggregated settlement of kin larvae in sessile marine invertebrates may result in a complex array of compatible and incompatible allogeneic responses within each assemblage. Each such aggregate can, therefore, be considered as a distinct self-organizing biological entity representing adaptations that have evolved to maximize the potential benefits of gregarious settlement. However, only sparse information exists on the selective forces and ecological consequences of allogeneic coalescence. RESULTS: We studied the consequences of aggregated settlement of kin larvae of Stylophora pistillata (a Red Sea stony coral), under controlled laboratory settings. When spat came into contact, they either fused, establishing a chimera, or rejected one another. A one-year study on growth and survivorship of 544 settled S. pistillata genotypes revealed six types of biological entities: (1) Single genotypes (SG); (2) Bi-chimeras (BC); (3) Bi-rejecting genotypes (BR); (4) Tri-chimera entities (TC); (5) Three rejecting genotypes (TR); and (6) Multi-partner entities (MP; consisting of 7.5 +/- 2.6 partners). Analysis of allorecognition responses revealed an array of effector mechanisms: real tissue fusions, transitory fusions and six other histoincompatible reactions (borderline formation, sutures, overgrowth, bleaching, rejection, and partner death), disclosing unalike onsets of ontogeny and complex modes of appearance within each aggregate. Evaluations at the entity level revealed that MP entities were the largest, especially in the first two months (compared with SG: 571% in the first month and 162% in the seventh month). However, at the genotype level, the SG entities were the largest and the colonies with the highest-cost-per-genotype were the TR and the MP colonies. The cost was calculated as reduced average genotype size, from 27% and 12% in the first month to 67% and 64% in the seventh month, respectively. In general, MP exhibited the highest survivorship rate (85%, after one year) and SG the lowest (54%). CONCLUSION: In view of the above, we suggest that the driving force behind gregarious kin settlements in Stylophora pistillata stems from gained benefits associated with the immediate and long-term increase in total size of the MP entity, whereas survivorship rates did not draw a parallel link. Furthermore, the biological organization of MP entity exhibits, simultaneously, an intricate network of rejecting and fusible interactions in a single allogeneic intimate arena, where proposed benefits surpass costs incurred by discord among founders. Above results and documentations on gregarious settlement in other marine taxa bring us to suggest that the 'group level' of kin aggregates may serve as a ubiquitous legitimate selection entity in the evolution of a sessile mode of life in marine organisms. PMID- 18447919 TI - Mucocele-like tumor and columnar cell hyperplasia of the breast occurring in a morphologic continuum. AB - INTRODUCTION: Mucocele-like tumor was originally described in 1986 as a benign breast proliferation consisting of multiple dilated cysts lined by cytologically bland, flat to cuboidal cells. Subsequent reports described the coexistence of, including the morphologic inter-transitions between, mucocele-like tumor and a variety of other breast proliferations, including intraductal carcinoma, invasive carcinoma, atypical ductal hyperplasia, and hyperplasia of the usual type. The spectrum of breast alterations characterized by variably enlarged terminal-ductal lobular units lined by variably hyperplastic and variably atypical columnar cells has been the subject of significant discussion in the recent literature. In one scheme, these lesions may be classified into four groups, that is, columnar cell change with and without atypia and columnar cell hyperplasia with and without atypia. Morphologic and molecular observations suggest an association, perhaps in a nonobligate precursor role, between some columnar cell lesions and a variety of other neoplastic lesions. CASE PRESENTATION: We describe the case of a 43-year old woman whose breast tumor contained areas diagnostic of mucocele-like tumor and columnar cell hyperplasia, with morphologic transitions in between. CONCLUSION: Our case represents the second broadly similar case that has been reported, and suggests a potential relationship between these two enigmatic lesions. PMID- 18447920 TI - Poverty and maternal mortality in Nigeria: towards a more viable ethics of modern medical practice. AB - Poverty is often identified as a major barrier to human development. It is also a powerful brake on accelerated progress toward the Millennium Development Goals. Poverty is also a major cause of maternal mortality, as it prevents many women from getting proper and adequate medical attention due to their inability to afford good antenatal care. This Paper thus examines poverty as a threat to human existence, particularly women's health. It highlights the causes of maternal deaths in Nigeria by questioning the practice of medicine in this country, which falls short of the ethical principle of showing care.Since high levels of poverty limit access to quality health care and consequently human development, this paper suggests ways of reducing maternal mortality in Nigeria. It emphasizes the importance of care ethics, an ethical orientation that seeks to rectify the deficiencies of medical practice in Nigeria, notably the problem of poor reproductive health services.Care ethics as an ethical orientation, attends to the important aspects of our shared lives. It portrays the moral agent (in this context the physician) as a self who is embedded in webs of relations with others (pregnant women). Also central to this ethical orientation is responsiveness in an interconnected network of needs, care and prevention of harm.This review concludes by stressing that many human relationships involve persons who are vulnerable, including pregnant women, dependent, ill and or frail, noting that the desirable moral response is that prescribed by care ethics, which thus has implications for the practice of medicine in Nigeria. PMID- 18447921 TI - The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. AB - BACKGROUND: A hypoxic-ischaemic insult occurring around the time of birth may result in an encephalopathic state characterised by the need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. There is an increasing risk of death or neurodevelopmental abnormalities with more severe encephalopathy. Current management consists of maintaining physiological parameters within the normal range and treating seizures with anticonvulsants. Studies in adult and newborn animals have shown that a reduction of body temperature of 3-4 degrees C after cerebral insults is associated with improved histological and behavioural outcome. Pilot studies in infants with encephalopathy of head cooling combined with mild whole body hypothermia and of moderate whole body cooling to 33.5 degrees C have been reported. No complications were noted but the group sizes were too small to evaluate benefit. METHODS/DESIGN: TOBY is a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling".Full-term infants will be randomised within 6 hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2 degrees C or to whole body cooling, with rectal temperature kept at 33-34 degrees C for 72 hours. Term infants showing signs of moderate or severe encephalopathy +/- seizures have their eligibility confirmed by cerebral function monitoring. Outcomes will be assessed at 18 months of age using neurological and neurodevelopmental testing methods. SAMPLE SIZE: At least 236 infants would be needed to demonstrate a 30% reduction in the relative risk of mortality or serious disability at 18 months. Recruitment was ahead of target by seven months and approvals were obtained allowing recruitment to continue to the end of the planned recruitment phase. 325 infants were recruited. PRIMARY OUTCOME: Combined rate of mortality and severe neurodevelopmental impairment in survivors at 18 months of age. Neurodevelopmental impairment will be defined as any of:* Bayley mental developmental scale score less than 70* Gross Motor Function Classification System Levels III - V* Bilateral cortical visual impairments TRIAL REGISTRATION: Current Controlled Trials ISRCTN89547571. PMID- 18447922 TI - Genetic diversity and silencing suppression effects of Rice yellow mottle virus and the P1 protein. AB - BACKGROUND: PTGS (post-transcriptional gene silencing) is used to counter pathogenic invasions, particularly viruses. In return, many plant viruses produce proteins which suppress silencing directed against their RNA. The diversity of silencing suppression at the species level in natural hosts is unknown. RESULTS: We investigated the functional diversity of silencing suppression among isolates of the African RYMV (Rice yellow mottle virus) in rice. The RYMV-P1 protein is responsible for cell-to-cell movement and is a silencing suppressor. Transgenic gus-silencing rice lines were used to investigate intra-specific and serogroup silencing suppression diversity at two different levels: that of the virion and the P1 silencing suppressor protein. Our data provide evidence that silencing suppression is a universal phenomenon for RYMV species. However, we found considerable diversity in their ability to suppress silencing which was not linked to RYMV phylogeny, or pathogenicity. At the level of the silencing suppressor P1 alone, we found similar results to those previously found at the virion level. In addition, we showed that cell-to-cell movement of P1 was crucial for the efficiency of silencing suppression. Mutagenesis of P1 demonstrated a strong link between some amino acids and silencing suppression features with, one on the hand, the conserved amino acids C95 and C64 involved in cell-to-cell movement and the strength of suppression, respectively, and on the other hand, the non conserved F88 was involved in the strength of silencing suppression. CONCLUSION: We demonstrated that intra-species diversity of silencing suppression is highly variable and by mutagenesis of P1 we established the first link between silencing suppression and genetic diversity. These results are potentially important for understanding virus-host interactions. PMID- 18447923 TI - Effort-reward imbalance and overcommitment in employees in a Norwegian municipality: a cross sectional study. AB - BACKGROUND: The aim of this study was to validate a Norwegian version of the Effort-Reward Imbalance Questionnaire (ERI-Q). METHODS: One thousand eight hundred and three employees in a medium-sized Norwegian municipality replied to the ERI-Q, and health-related variables such as self-reported general health, psychological distress, musculoskeletal complaints, and work-related burnout were examined. RESULTS: Sound psychometric properties were found for this Norwegian version of the ERI-Q. When the two dimensions of ERI and overcommitment were analyzed in four types of employees, the results showed that employees characterized by a combination of high values on ERI and overcommitment had more unfavorable health scores than others. Employees with low effort-reward and overcommitment scores had more favorable health scores. Employees with scores on the overcommitment and the effort-reward scales that are supposed to have opposite effects on health (that is, the combination of low overcommitment with a high effort-reward score and vice versa), had health scores somewhere in between the two other groups. CONCLUSION: Satisfactory psychometric properties were found for most of the latent factors in the ERI-Q. The findings also indicate that it may be fruitful to explore health conditions among employees with different combinations of effort-reward and overcommitment. PMID- 18447924 TI - GENOMEPOP: a program to simulate genomes in populations. AB - BACKGROUND: There are several situations in population biology research where simulating DNA sequences is useful. Simulation of biological populations under different evolutionary genetic models can be undertaken using backward or forward strategies. Backward simulations, also called coalescent-based simulations, are computationally efficient. The reason is that they are based on the history of lineages with surviving offspring in the current population. On the contrary, forward simulations are less efficient because the entire population is simulated from past to present. However, the coalescent framework imposes some limitations that forward simulation does not. Hence, there is an increasing interest in forward population genetic simulation and efficient new tools have been developed recently. Software tools that allow efficient simulation of large DNA fragments under complex evolutionary models will be very helpful when trying to better understand the trace left on the DNA by the different interacting evolutionary forces. Here I will introduce GenomePop, a forward simulation program that fulfills the above requirements. The use of the program is demonstrated by studying the impact of intracodon recombination on global and site-specific dN/dS estimation. RESULTS: I have developed algorithms and written software to efficiently simulate, forward in time, different Markovian nucleotide or codon models of DNA mutation. Such models can be combined with recombination, at inter and intra codon levels, fitness-based selection and complex demographic scenarios. CONCLUSION: GenomePop has many interesting characteristics for simulating SNPs or DNA sequences under complex evolutionary and demographic models. These features make it unique with respect to other simulation tools. Namely, the possibility of forward simulation under General Time Reversible (GTR) mutation or GTRxMG94 codon models with intra-codon recombination, arbitrary, user defined, migration patterns, diploid or haploid models, constant or variable population sizes, etc. It also allows simulation of fitness-based selection under different distributions of mutational effects. Under the 2-allele model it allows the simulation of recombination hot-spots, the definition of different frequencies in different populations, etc. GenomePop can also manage large DNA fragments. In addition, it has a scaling option to save computation time when simulating large sequences and population sizes under complex demographic and evolutionary situations. These and many other features are detailed in its web page [1]. PMID- 18447925 TI - Flow cytometric monitoring of influenza A virus infection in MDCK cells during vaccine production. AB - BACKGROUND: In cell culture-based influenza vaccine production the monitoring of virus titres and cell physiology during infection is of great importance for process characterisation and optimisation. While conventional virus quantification methods give only virus titres in the culture broth, data obtained by fluorescence labelling of intracellular virus proteins provide additional information on infection dynamics. Flow cytometry represents a valuable tool to investigate the influences of cultivation conditions and process variations on virus replication and virus yields. RESULTS: In this study, fluorescein-labelled monoclonal antibodies against influenza A virus matrix protein 1 and nucleoprotein were used for monitoring the infection status of adherent Madin Darby canine kidney cells from bioreactor samples. Monoclonal antibody binding was shown for influenza A virus strains of different subtypes (H1N1, H1N2, H3N8) and host specificity (human, equine, swine). At high multiplicity of infection in a bioreactor, the onset of viral protein accumulation in adherent cells on microcarriers was detected at about 2 to 4 h post infection by flow cytometry. In contrast, a significant increase in titre by hemagglutination assay was detected at the earliest 4 to 6 h post infection. CONCLUSION: It is shown that flow cytometry is a sensitive and robust method for the monitoring of viral infection in fixed cells from bioreactor samples. Therefore, it is a valuable addition to other detection methods of influenza virus infection such as immunotitration and RNA hybridisation. Thousands of individual cells are measured per sample. Thus, the presented method is believed to be quite independent of the concentration of infected cells (multiplicity of infection and total cell concentration) in bioreactors. This allows to perform detailed studies on factors relevant for optimization of virus yields in cell cultures. The method could also be used for process characterisation and investigations concerning reproducibility in vaccine manufacturing. PMID- 18447926 TI - Hypoxia-inducible factor-1alpha is a critical mediator of hypoxia induced apoptosis in cardiac H9c2 and kidney epithelial HK-2 cells. AB - BACKGROUND: Hypoxia inducible factor-1 (HIF-1) is a transcription factor that functions to maintain cellular homeostasis in response to hypoxia. There is evidence that HIF-1 can also trigger apoptosis, possibly when cellular responses are inadequate to meet energy demands under hypoxic conditions. METHODS: Cardiac derived H9c2 and renal tubular epithelial HK-2 cells expressing either the wild type oxygen regulated subunit of HIF-1 (pcDNA3-Hif-1alpha) or a dominant negative version that lacked both DNA binding and transactivation domains (pcDNA3-DN-Hif 1alpha), were maintained in culture and exposed to hypoxia. An RNA interference approach was also employed to selectively knockdown expression of Hif-1alpha. Apoptosis was analyzed in both H9c2 and HK-2 cells by Hoechst and TUNEL staining, caspase 3 activity assays and activation of pro-apoptotic Bcl2 family member Bax. RESULTS: Overexpression of pcDNA3-DN-Hif-1alpha led to a significant reduction in hypoxia -induced apoptosis (17 +/- 2%, P < 0.01) in H9c2 cells compared to both control-transfected and wild type Hif-1alpha transfected cells. Moreover, selective ablation of HIF-1alpha protein expression by RNA interference in H9c2 cells led to 55% reduction of caspase 3 activity and 46% reduction in the number of apoptotic cells as determined by Hoechst 33258 staining, after hypoxia. Finally, upregulation of the pro-apoptotic protein, Bax, was found in H9c2 cells overexpressing full-length pcDNA3-HA-HIF-1alpha exposed to hypoxia. In HK-2 cells overexpression of wild-type Hif-1alpha led to a two-fold increase in Hif-1alpha levels during hypoxia. This resulted in a 3.4-fold increase in apoptotic cells and a concomitant increase in caspase 3 activity during hypoxia when compared to vector transfected control cells. HIF-1alpha also induced upregulation of Bax in HK-2 cells. In addition, introduction of dominant negative Hif-1alpha constructs in both H9c2 and HK-2 -cells led to decreased active Bax expression. CONCLUSION: These data demonstrate that HIF-1alpha is an important component of the apoptotic signaling machinery in the two cell types. PMID- 18447927 TI - Fatal parvoviral myocarditis: a case report and review of literature. AB - BACKGROUND: Histologically documented cases of parvoviral myocarditis are exceedingly rare. CASE PRESENTATION: Here, we report a 41-year old African American immunocompetent patient who died of parvoviral myocarditis after a 10 day illness characterized by fever, headaches, generalized arthralgias, and a maculopapular rash.Autopsy revealed an infiltrate myocarditis composed primarily of T-lymphocytes and macrophages associated with extensive myocardial fibrosis. The diagnosis of parvovirus was determined by polymerase chain reaction (PCR) on both pre-mortem serum and post-mortem myocardial tissue METHODS: DNA was extracted from tissue and serum and primers were used to amplify DNA sequences of parvovirus B19 using nested polymerase chain reaction (PCR). CONCLUSION: The diagnosis of parvovirus should be considered in cases of fatal myocarditis, and diagnosis can be confirmed at autopsy by molecular techniques. PMID- 18447928 TI - Exploiting the pathway structure of metabolism to reveal high-order epistasis. AB - BACKGROUND: Biological robustness results from redundant pathways that achieve an essential objective, e.g. the production of biomass. As a consequence, the biological roles of many genes can only be revealed through multiple knockouts that identify a set of genes as essential for a given function. The identification of such "epistatic" essential relationships between network components is critical for the understanding and eventual manipulation of robust systems-level phenotypes. RESULTS: We introduce and apply a network-based approach for genome-scale metabolic knockout design. We apply this method to uncover over 11,000 minimal knockouts for biomass production in an in silico genome-scale model of E. coli. A large majority of these "essential sets" contain 5 or more reactions, and thus represent complex epistatic relationships between components of the E. coli metabolic network. CONCLUSION: The complex minimal biomass knockouts discovered with our approach illuminate robust essential systems-level roles for reactions in the E. coli metabolic network. Unlike previous approaches, our method yields results regarding high-order epistatic relationships and is applicable at the genome-scale. PMID- 18447929 TI - Human bite injuries in the oro-facial region at the Muhimbili National Hospital, Tanzania. AB - BACKGROUND: Human bites in the maxillofacial region compromise function and aesthetics, resulting in social and psychological effects. There is paucity of information regarding human bite injuries in Tanzania. The aim of the study was to assess the occurrence, treatment modalities and prognosis of human bite injuries in the oro-facial region at the Muhimbili National Hospital Dar es Salaam, Tanzania. METHODS: In a prospective study the details of patients with human bite injuries in the oro-facial region who attended at the Department of Oral and Maxillofacial Surgery of the Muhimbili National Hospital between January 2001 and December 2005 were recorded. Data included information on age, sex, site, duration of the injury at the time of reporting to hospital, reasons, details of treatment offered and outcome after treatment. RESULTS: A total of 33 patients, 13 males and 20 females aged between 12 and 49 years with human bite injuries in the oro-facial region were treated. Thirty patients presented with clean uninfected wounds while 3 had infected wounds. The most (45.5%) frequently affected site was the lower lip. Treatment offered included thorough surgical cleansing with adequate surgical debridement and primary suturing. Tetanus prophylaxis and a course of broad-spectrum antibiotics were given to all the patients. In 90% of the 30 patients who were treated by suturing, the healing was uneventful with only 10% experiencing wound infection or necrosis. Three patients who presented with wounds that had signs of infection were treated by surgical cleansing with debridement, antibiotics and daily dressing followed by delayed primary suturing. CONCLUSION: Most of the human bite injuries in the oro-facial region were due to social conflicts. Although generally considered to be dirty or contaminated they could be successfully treated by surgical cleansing and primary suture with a favourable outcome. Management of such injuries often need multidisciplinary approach. PMID- 18447930 TI - Metabolic control in a nationally representative diabetic elderly sample in Costa Rica: patients at community health centers vs. patients at other health care settings. AB - BACKGROUND: Costa Rica, like other developing countries, is experiencing an increasing burden of chronic conditions such as diabetes mellitus (DM), especially among its elderly population. This article has two goals: (1) to assess the level of metabolic control among the diabetic population age >or= 60 years old in Costa Rica, and (2) to test whether diabetic elderly patients of community health centers differ from patients in other health care settings in terms of the level of metabolic control. METHODS: Data come from the project CRELES, a nationally representative study of people aged 60 and over in Costa Rica. This article analyzes a subsample of 542 participants in CRELES with self reported diagnosis of diabetes mellitus. Odds ratios of poor levels of metabolic control at different health care settings are computed using logistic regressions. RESULTS: Lack of metabolic control among elderly diabetic population in Costa Rica is described as follows: 37% have glycated hemoglobin >or= 7%; 78% have systolic blood pressure >or= 130 mmHg; 66% have diastolic blood pressure >or= 80 mmHg; 48% have triglycerides >or= 150 mg/dl; 78% have LDL >or= 100 mg/dl; 70% have HDL or =18 years of age requiring admission for pneumonia, with no documented use of antibiotics in the 24 hours prior to ED presentation were included. Compliance with Pneumonia National Quality Measures was assessed including ED antibiotic administration, antibiotics within 4 hours, oxygenation assessment, and obtaining of blood cultures. Odds ratios were calculated for elders and non-elders. Logistic regression was used to identify independent predictors of process failure. RESULTS: One thousand, three hundred seventy patients met inclusion criteria, of which 560 were aged > or =65 years. In multiple variable logistic regression analysis, age > or =65 years was independently associated with receiving antibiotics in the ED (odds ratio [OR] = 2.03, 95% CI 1.28-3.21) and assessment of oxygenation (OR = 2.10, 95% CI, 1.18 3.32). Age had no significant impact on odds of receiving antibiotics within four hours of presentation (OR 1.10, 95% CI 0.84-1.43) or having blood cultures drawn (OR 1.02, 95%CI 0.78-1.32). Certain other patient characteristics were also independently associated with process failure. CONCLUSION: Elderly patients admitted from the ED with pneumonia are more likely to receive antibiotics while in the ED and to have oxygenation assessed in the ED than younger patients. The independent association of certain patient characteristics with process failure provides an opportunity to further increase compliance with recommended quality measures in admitted patients diagnosed with pneumonia. PMID- 18447937 TI - Intensivist supervision of resident-placed central venous catheters decreases the incidence of catheter-related blood stream infections. AB - Catheter-related blood stream infections (CRBSI) cause significant morbidity and mortality. A retrospective study of a performance improvement project in our teaching hospital's surgical intensive care unit (SICU) showed that intensivist supervision was important in reinforcing maximal sterile barriers (MSB) use during the placement of a central venous catheter (CVC) in the prevention of CRBSI. A historical control period, 1 January 2001-31 December 2003, was established for comparison. From 1 January 2003-31 December 2007, MSB use for central venous line placement was mandated for all operators. However, in 2003 there was no intensivist supervision of CVC placements in the SICU. The use of MSB alone did not cause a significant change in the CRBSI rate in the first year of the project, but close supervision by an intensivist in years 2004-2007, in conjunction with MSB use, demonstrated a significant drop in the CRBSI rate when compared to the years before intensivist supervision (2001-2003), p < .0001. A time series analysis comparing monthly rates of CRBSI (2001-2007) also revealed a significant downward trend, p = .028. Additionally, in the first year of the mandated MSB use (2003), 85 independently observed resident-placed CVCs demonstrated that breaks in sterile technique (34/85), as compared those placements that had no breaks in technique (51/85), had more CRBSI, 6/34 (17.6%) vs. 1/51 (1.9%), p < .01. Interventions to reduce CRBSI in our SICU needed emphasis on adequate supervision of trainees in CVC placement, in addition to use of MSB, to effect lower CRBSI rates. PMID- 18447938 TI - The role of tendon microcirculation in Achilles and patellar tendinopathy. AB - Tendinopathy is of distinct interest as it describes a painful tendon disease with local tenderness, swelling and pain associated with sonographic features such as hypoechogenic texture and diameter enlargement. Recent research elucidated microcirculatory changes in tendinopathy using laser Doppler flowmetry and spectrophotometry such as at the Achilles tendon, the patellar tendon as well as at the elbow and the wrist level. Tendon capillary blood flow is increased at the point of pain. Tendon oxygen saturation as well as tendon postcapillary venous filling pressures, determined non-invasively using combined Laser Doppler flowmetry and spectrophotometry, can quantify, in real-time, how tendon microcirculation changes over with pathology or in response to a given therapy. Tendon oxygen saturation can be increased by repetitive, intermittent short-term ice applications in Achilles tendons; this corresponds to 'ischemic preconditioning', a method used to train tissue to sustain ischemic damage. On the other hand, decreasing tendon oxygenation may reflect local acidosis and deteriorating tendon metabolism. Painful eccentric training, a common therapy for Achilles, patellar, supraspinatus and wrist tendinopathy decreases abnormal capillary tendon flow without compromising local tendon oxygenation. Combining an Achilles pneumatic wrap with eccentric training changes tendon microcirculation in a different way than does eccentric training alone; both approaches reduce pain in Achilles tendinopathy. The microcirculatory effects of measures such as extracorporeal shock wave therapy as well as topical nitroglycerine application are to be studied in tendinopathy as well as the critical question of dosage and maintenance. Interestingly it seems that injection therapy using color Doppler for targeting the area of neovascularisation yields to good clinical results with polidocanol sclerosing therapy, but also with a combination of epinephrine and lidocaine. PMID- 18447939 TI - An uncommon presentation for a severe invasive infection due to methicillin resistant Staphylococcus aureus clone USA300 in Italy: a case report. AB - BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) has been considered for many years a typical nosocomial pathogen. Recently MRSA has emerged as a frequent cause of infections in the community. More commonly, community-acquired (CA)-MRSA is a cause of infections of the skin and soft tissues, but life-threatening infections such as necrotizing pneumonia and sepsis can occasionally occur. CASE PRESENTATION: This report describes an uncommon presentation of invasive CA-MRSA infection in an adolescent without known risk factors. The presentation was typical for bacterial meningitis, but the clinical findings also revealed necrotizing pneumonia. Following the development of deep venous thrombosis, the presence of an inherited thrombophilic defect (factor V Leiden) was detected. The patient was successfully treated with an antibiotic combination including linezolid and with anticoagulant therapy. CA-MRSA was isolated from both cerebrospinal fluid and blood. The isolates were resistant to oxacillin and other beta-lactam antibiotics and susceptible to the other antibiotics tested including erythromycin. Molecular typing revealed that the strains contained the Panton-Valentine leukocidin genes and type IV SCCmec, and were ST8, spa type t008, and agr type 1. This genetic background is identical to that of the USA300 clone. CONCLUSION: This report highlights that meningitis can be a new serious presentation of CA-MRSA infection. CA-MRSA strains with the genetic background of the USA300 clone are circulating in Italy and are able to cause severe infections. PMID- 18447940 TI - Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. AB - BACKGROUND: Severe traumatic brain injury (TBI) has been increasing with greater incidence of injuries from traffic or sporting accidents. Although there are a number of animal models of TBI using progesterone for head injury, the effects of progesterone on neurologic outcome of acute TBI patients remain unclear. The aim of the present clinical study was to assess the longer-term efficacy of progesterone on the improvement in neurologic outcome of patients with acute severe TBI. METHODS: A total of 159 patients who arrived within 8 hours of injury with a Glasgow Coma Score 0.05). Instances of complications and adverse events associated with the administration of progesterone were not found. CONCLUSION: Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug. TRIAL REGISTRATION: ACTRN12607000545460. PMID- 18447941 TI - Changes in cholesterol kinetics following sugar cane policosanol supplementation: a randomized control trial. AB - BACKGROUND: Sugar cane policosanols (SCP) have been shown to exert cholesterol modulating properties in various studies conducted in Cuba by substantially reducing cholesterol synthesis. Independent research examining changes in cholesterol kinetics in response to SCP is limited to few studies, none of which was able to replicate findings of the original research. Moreover, no data are available on the effect of SCP on cholesterol absorption to date. The present study was undertaken to determine effects on cholesterol kinetics, namely synthesis and absorption, within hypercholesterolemic individuals consuming a SCP treatment. Twenty-one otherwise healthy hypercholesterolemic subjects participated in a randomized double-blind crossover study where they received 10 mg/day of policosanols or a placebo incorporated in margarine as an evening snack for a period of 28 days. The last week of the study phase, subjects were given 13C labelled cholesterol and deuterated water for the measurement of cholesterol absorption and synthesis respectively. Blood was collected on the first two and last five days of the trial. Cholesterol absorption and synthesis were determined by measuring red cell cholesterol 13C and deuterium enrichment, respectively. RESULTS: There was no significant change in LDL cholesterol levels as compared to control. In addition, the area under the curve for red cell cholesterol 13C enrichment across 96 hours was not significantly different in the SCP group as compared to control. Similarly, no difference was observed in the fractional rate of cholesterol synthesis over the period of 24 hours between the two treatment groups. CONCLUSION: The findings of the present study fail to support previous research concerning efficacy and mechanism of action for policosanols. PMID- 18447942 TI - On the optimality of the neighbor-joining algorithm. AB - The popular neighbor-joining (NJ) algorithm used in phylogenetics is a greedy algorithm for finding the balanced minimum evolution (BME) tree associated to a dissimilarity map. From this point of view, NJ is "optimal" when the algorithm outputs the tree which minimizes the balanced minimum evolution criterion. We use the fact that the NJ tree topology and the BME tree topology are determined by polyhedral subdivisions of the spaces of dissimilarity maps [equation; see text] to study the optimality of the neighbor-joining algorithm. In particular, we investigate and compare the polyhedral subdivisions for n > AG > AC, whereas among TNRs, AGC was the most abundant repeat. The SSR positive sequences were used to design 58 primer pairs of which 44 pairs could be validated as single locus markers using a panel of arabica and robusta genotypes. The analysis revealed an average of 3.3 and 3.78 alleles and 0.49 and 0.62 PIC per marker for the tested arabicas and robustas, respectively. It also revealed a high cumulative PI over all the markers using both sib-based (10-6 and 10-12 for arabicas and robustas respectively) and unbiased corrected estimates (10-20 and 10-43 for arabicas and robustas respectively). The markers were tested for Hardy-Weinberg equilibrium, linkage dis-equilibrium, and were successfully used to ascertain generic diversity/affinities in the tested germplasm (cultivated as well as species). Nine markers could be mapped on robusta linkage map. Importantly, the markers showed ~92% transferability across related species/genera of coffee. CONCLUSION: The conventional approach of genomic library was successfully employed although with low efficiency to develop a set of 44 new genomic microsatellite markers of coffee. The characterization/validation of new markers demonstrated them to be highly informative, and useful for genetic studies namely, genetic diversity in coffee germplasm, individualization/bar-coding for germplasm protection, linkage mapping, taxonomic studies, and use as conserved orthologous sets across secondary genepool of coffee. Further, the relative frequency and distribution of different SSR motifs in coffee genome indicated coffee genome to be relatively poor in microsatellites compared to other plant species. PMID- 18447948 TI - Gene structure evolution of the Na+-Ca2+ exchanger (NCX) family. AB - BACKGROUND: The Na+-Ca2+ exchanger (NCX) is an important regulator of cytosolic Ca2+ levels. Many of its structural features are highly conserved across a wide range of species. Invertebrates have a single NCX gene, whereas vertebrate species have multiple NCX genes as a result of at least two duplication events. To examine the molecular evolution of NCX genes and understand the role of duplicated genes in the evolution of the vertebrate NCX gene family, we carried out phylogenetic analyses of NCX genes and compared NCX gene structures from sequenced genomes and individual clones. RESULTS: A single NCX in invertebrates and the protochordate Ciona, and the presence of at least four NCX genes in the genomes of teleosts, an amphibian, and a reptile suggest that a four member gene family arose in a basal vertebrate. Extensive examination of mammalian and avian genomes and synteny analysis argue that NCX4 may be lost in these lineages. Duplicates for NCX1, NCX2, and NCX4 were found in all sequenced teleost genomes. The presence of seven genes encoding NCX homologs may provide teleosts with the functional specialization analogous to the alternate splicing strategy seen with the three NCX mammalian homologs. CONCLUSION: We have demonstrated that NCX4 is present in teleost, amphibian and reptilian species but has been secondarily and independently lost in mammals and birds. Comparative studies on conserved vertebrate homologs have provided a possible evolutionary route taken by gene duplicates subfunctionalization by minimizing homolog number. PMID- 18447949 TI - Experimental manipulation of immune-mediated disease and its fitness costs for rodent malaria parasites. AB - BACKGROUND: Explaining parasite virulence (harm to the host) represents a major challenge for evolutionary and biomedical scientists alike. Most theoretical models of virulence evolution assume that virulence arises as a direct consequence of host exploitation, the process whereby parasites convert host resources into transmission opportunities. However, infection-induced disease can be immune-mediated (immunopathology). Little is known about how immunopathology affects parasite fitness, or how it will affect the evolution of parasite virulence. Here we studied the effects of immunopathology on infection-induced host mortality rate and lifetime transmission potential - key components of parasite fitness - using the rodent malaria model, Plasmodium chabaudi chabaudi. RESULTS: Neutralizing interleukin [IL]-10, an important regulator of inflammation, allowed us to experimentally increase the proportion of virulence due to immunopathology for eight parasite clones. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in a shorter time to death that was independent of parasite density and was particularly marked for normally avirulent clones. This suggests that IL-10 induction may provide a pathway to avirulence for P. c. chabaudi. Despite the increased investment in transmission-stage parasites observed for some clones in response to IL-10R blockade, experimental enhancement of immunopathology incurred a uniform fitness cost to all parasite clones by reducing lifetime transmission potential. CONCLUSION: This is the first experimental study to demonstrate that infection induced immunopathology and parasite genetic variability may together have the potential to shape virulence evolution. In accord with recent theory, the data show that some forms of immunopathology may select for parasites that make hosts less sick. PMID- 18447950 TI - A flax fibre proteome: identification of proteins enriched in bast fibres. AB - BACKGROUND: Bast fibres from the phloem tissues of flax are scientifically interesting and economically useful due in part to a dynamic system of secondary cell wall deposition. To better understand the molecular mechanisms underlying the process of cell wall development in flax, we extracted proteins from individually dissected phloem fibres (i.e. individual cells) at an early stage of secondary cell wall development, and compared these extracts to protein extracts from surrounding, non-fibre cells of the cortex, using fluorescent (DiGE) labels and 2D-gel electrophoresis, with identities assigned to some proteins by mass spectrometry. RESULTS: The abundance of many proteins in fibres was notably different from the surrounding non-fibre cells of the cortex, with approximately 13% of the 1,850 detectable spots being significantly (> 1.5 fold, p < or = 0.05) enriched in fibres. Following mass spectrometry, we assigned identity to 114 spots, of which 51 were significantly enriched in fibres. We observed that a K+ channel subunit, annexins, porins, secretory pathway components, beta-amylase, beta-galactosidase and pectin and galactan biosynthetic enzymes were among the most highly enriched proteins detected in developing flax fibres, with many of these proteins showing electrophoretic patterns consistent with post translational modifications. CONCLUSION: The fibre-enriched proteins we identified are consistent with the dynamic process of secondary wall deposition previously suggested by histological and biochemical analyses, and particularly the importance of galactans and the secretory pathway in this process. The apparent abundance of beta-amylase suggests that starch may be an unappreciated source of materials for cell wall biogenesis in flax bast fibres. Furthermore, our observations confirm previous reports that correlate accumulation proteins such as annexins, and specific heat shock proteins with secondary cell wall deposition. PMID- 18447951 TI - Implementing EM and Viterbi algorithms for Hidden Markov Model in linear memory. AB - BACKGROUND: The Baum-Welch learning procedure for Hidden Markov Models (HMMs) provides a powerful tool for tailoring HMM topologies to data for use in knowledge discovery and clustering. A linear memory procedure recently proposed by Miklos, I. and Meyer, I.M. describes a memory sparse version of the Baum-Welch algorithm with modifications to the original probabilistic table topologies to make memory use independent of sequence length (and linearly dependent on state number). The original description of the technique has some errors that we amend. We then compare the corrected implementation on a variety of data sets with conventional and checkpointing implementations. RESULTS: We provide a correct recurrence relation for the emission parameter estimate and extend it to parameter estimates of the Normal distribution. To accelerate estimation of the prior state probabilities, and decrease memory use, we reverse the originally proposed forward sweep. We describe different scaling strategies necessary in all real implementations of the algorithm to prevent underflow. In this paper we also describe our approach to a linear memory implementation of the Viterbi decoding algorithm (with linearity in the sequence length, while memory use is approximately independent of state number). We demonstrate the use of the linear memory implementation on an extended Duration Hidden Markov Model (DHMM) and on an HMM with a spike detection topology. Comparing the various implementations of the Baum-Welch procedure we find that the checkpointing algorithm produces the best overall tradeoff between memory use and speed. In cases where sequence length is very large (for Baum-Welch), or state number is very large (for Viterbi), the linear memory methods outlined may offer some utility. CONCLUSION: Our performance-optimized Java implementations of Baum-Welch algorithm are available at http://logos.cs.uno.edu/~achurban. The described method and implementations will aid sequence alignment, gene structure prediction, HMM profile training, nanopore ionic flow blockades analysis and many other domains that require efficient HMM training with EM. PMID- 18447952 TI - Intra-abdominal pressures during voluntary and reflex cough. AB - BACKGROUND: Involuntary coughing such as that evoked from the larynx, the laryngeal cough reflex (LCR), triggers a coordinated contraction of the thoracic, abdominal and pelvic muscles, which increases intra-abdominal pressure (IAP), displaces the diaphragm upwards and generates the expiratory force for cough and airway clearance. Changes in the IAP during voluntary cough (VC) and the LCR can be measured via a pressure catheter in the bladder. This study evaluated the physiological characteristics of IAP generated during VC and the LCR including peak and mean pressures and calculations of the area under the curve (AUC) values during the time of the cough event or epoch. METHODS: Eleven female subjects between the ages of 18 and 75 underwent standard urodynamic assessment with placement of an intravesicular catheter with a fiberoptic strain gauge pressure transducer. The bladder was filled with 200 ml of sterile water and IAP recordings were obtained with VC and the induced reflex cough test (RCT) using nebulized inhaled 20% tartaric acid to induce the LCR. IAP values were used to calculate the area under the curve (AUC) by the numerical integration of intravesicular pressure over time (cm H2O.s). RESULTS: The mean (+/- SEM) AUC values for VC and the LCR were 349.6 +/- 55.2 and 986.6 +/- 116.8 cm H2O.s (p < 0.01). The mean IAP values were 45.6 +/- 4.65 and 44.5 +/- 9.31 cm H2O (NS = .052), and the peak IAP values were 139.5 +/- 14.2 and 164.9 +/- 15.8 cm H2O (p = 0.07) for VC and LCR, respectively. CONCLUSION: The induced LCR is the involuntary rapid and repeated synchronous expiratory muscle activation that causes and sustains an elevated IAP over time, sufficient for airway protection. VC and LCR have different neurophysiological functions. Quantification of the LCR using AUC values and mean or peak IAP values may be useful as a clinical tool for determining neurophysiological airway protection status and provide a quantitative assessment of changes in a patient's functional recovery or decline. PMID- 18447953 TI - Complementary and alternative medicine use among women at increased genetic risk of breast and ovarian cancer. AB - BACKGROUND: Complementary and alternative medicine (CAM) use is well documented among breast cancer patients and survivors, but little evidence is available to describe rates and patterns of use among women at increased genetic risk of breast cancer. METHODS: A pre-visit telephone interview was conducted to ascertain CAM use among the BRCA mutation carriers enrolled in a high-risk breast cancer screening study. Participants were asked to report on their use of thirteen therapies within the year prior to enrollment into the study. Logistic regression was used to evaluate the association between various factors and CAM use in this population. RESULTS: Among the 164 BRCA1 or BRCA2 mutation-positive (BRCA+) women in this analysis, 78% reported CAM use, with prayer and lifestyle diet being the two most commonly reported modalities. Many subjects used multiple CAM therapies, with 34% reporting use of three or more modalities. The most commonly used modalities were mind-body therapies and biologically-based practices, 61.6% and 51.8%, respectively. High-risk women were more likely to use CAM if they were older, more educated, more worried about ovarian cancer risk, or had a previous cancer diagnosis. CONCLUSION: This study suggests that the prevalence of CAM use is high among BRCA mutation carriers, with frequency of use comparable to that of breast cancer patients and survivors. Given the high prevalence of CAM use in our subjects, especially biologically-based therapies including herbal supplements, whose safety and efficacy in relation to cancer risk are unknown, our study suggests that future research is necessary to clarify these risks, and that it is important for providers to inquire about and to discuss the pros and cons of CAM use with their BRCA+ patients. PMID- 18447954 TI - Relation between myocardial edema and myocardial mass during the acute and convalescent phase of myocarditis--a CMR study. AB - BACKGROUND: Myocardial edema is a substantial feature of the inflammatory response in human myocarditis. The relation between myocardial edema and myocardial mass in the course of healing myocarditis has not been systematically investigated. We hypothesised that the resolution of myocardial edema as visualised by T2-weighted cardiovascular magnetic resonance (CMR) is associated with a decrease of myocardial mass in steady state free precession (SSFP)-cine imaging. METHODS: 21 patients with acute myocarditis underwent CMR shortly after onset of symptoms and 1 year later. For visualization of edema, a T2-weighted breath-hold black-blood triple-inversion fast spin echo technique was applied and the ratio of signal intensity of myocardium/skeletal muscle was assessed. Left ventricular (LV) mass, volumes and function were quantified from biplane cine steady state free precession images. 11 healthy volunteers served as a control group for interstudy reproducibility of LV mass. RESULTS: In patients with myocarditis, a significant decrease in LV mass was observed during follow-up compared to the acute phase (156.7 +/- 30.6 g vs. 140.3 +/- 28.3 g, p < 0.0001). The reduction of LV mass paralleled the normalization of initially increased myocardial signal intensity on T2-weighted images (2.4 +/- 0.4 vs. 1.68 +/- 0.3, p < 0.0001). In controls, the interstudy difference of LV mass was lower than in patients (5.1 +/- 2.9 g vs. 16.3 +/- 14.2 g, p = 0.02) resulting in a lower coefficient of variability (2.1 vs 8.9%, p = 0.04). CONCLUSION: Reversible abnormalities in T2-weighted CMR are paralleled by a transient increase in left ventricular mass during the course of myocarditis. Myocardial edema may be a common pathway explaining these findings. PMID- 18447955 TI - A simple reproducible method of preventing lobar torsion. AB - Torsion of remaining lobes after pulmonary resection is a potentially serious complication with high reported morbidity and mortality. A range of additional procedures has been described, we have used a simple, effective, quick and easy to reproduce minor procedure to prevents torsion. PMID- 18447956 TI - Legionella pneumophila infection induces programmed cell death, caspase activation, and release of high-mobility group box 1 protein in A549 alveolar epithelial cells: inhibition by methyl prednisolone. AB - BACKGROUND: Legionella pneumophila pneumonia often exacerbates acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Apoptosis of alveolar epithelial cells is considered to play an important role in the pathogenesis of ALI and ARDS. In this study, we investigated the precise mechanism by which A549 alveolar epithelial cells induced by L. pneumophila undergo apoptosis. We also studied the effect of methyl prednisolone on apoptosis in these cells. METHODS: Nuclear deoxyribonucleic acid (DNA) fragmentation and caspase activation in L. pneumophila-infected A549 alveolar epithelial cells were assessed using the terminal deoxyribonucleotidyl transferase-mediated triphosphate (dUTP)-biotin nick end labeling method (TUNEL method) and colorimetric caspase activity assays. The virulent L. pneumophila strain AA100jm and the avirulent dotO mutant were used and compared in this study. In addition, we investigated whether methyl prednisolone has any influence on nuclear DNA fragmentation and caspase activation in A549 alveolar epithelial cells infected with L. pneumophila. RESULTS: The virulent strain of L. pneumophila grew within A549 alveolar epithelial cells and induced subsequent cell death in a dose-dependent manner. The avirulent strain dotO mutant showed no such effect. The virulent strains of L. pneumophila induced DNA fragmentation (shown by TUNEL staining) and activation of caspases 3, 8, 9, and 1 in A549 cells, while the avirulent strain did not. High-mobility group box 1 (HMGB1) protein was released from A549 cells infected with virulent Legionella. Methyl prednisolone (53.4 muM) did not influence the intracellular growth of L. pneumophila within alveolar epithelial cells, but affected DNA fragmentation and caspase activation of infected A549 cells. CONCLUSION: Infection of A549 alveolar epithelial cells with L. pneumophila caused programmed cell death, activation of various caspases, and release of HMGB1. The dot/icm system, a major virulence factor of L. pneumophila, is involved in the effects we measured in alveolar epithelial cells. Methyl prednisolone may modulate the interaction of Legionella and these cells. PMID- 18447957 TI - A copula method for modeling directional dependence of genes. AB - BACKGROUND: Genes interact with each other as basic building blocks of life, forming a complicated network. The relationship between groups of genes with different functions can be represented as gene networks. With the deposition of huge microarray data sets in public domains, study on gene networking is now possible. In recent years, there has been an increasing interest in the reconstruction of gene networks from gene expression data. Recent work includes linear models, Boolean network models, and Bayesian networks. Among them, Bayesian networks seem to be the most effective in constructing gene networks. A major problem with the Bayesian network approach is the excessive computational time. This problem is due to the interactive feature of the method that requires large search space. Since fitting a model by using the copulas does not require iterations, elicitation of the priors, and complicated calculations of posterior distributions, the need for reference to extensive search spaces can be eliminated leading to manageable computational affords. Bayesian network approach produces a discretely expression of conditional probabilities. Discreteness of the characteristics is not required in the copula approach which involves use of uniform representation of the continuous random variables. Our method is able to overcome the limitation of Bayesian network method for gene-gene interaction, i.e. information loss due to binary transformation. RESULTS: We analyzed the gene interactions for two gene data sets (one group is eight histone genes and the other group is 19 genes which include DNA polymerases, DNA helicase, type B cyclin genes, DNA primases, radiation sensitive genes, repaire related genes, replication protein A encoding gene, DNA replication initiation factor, securin gene, nucleosome assembly factor, and a subunit of the cohesin complex) by adopting a measure of directional dependence based on a copula function. We have compared our results with those from other methods in the literature. Although microarray results show a transcriptional co-regulation pattern and do not imply that the gene products are physically interactive, this tight genetic connection may suggest that each gene product has either direct or indirect connections between the other gene products. Indeed, recent comprehensive analysis of a protein interaction map revealed that those histone genes are physically connected with each other, supporting the results obtained by our method. CONCLUSION: The results illustrate that our method can be an alternative to Bayesian networks in modeling gene interactions. One advantage of our approach is that dependence between genes is not assumed to be linear. Another advantage is that our approach can detect directional dependence. We expect that our study may help to design artificial drug candidates, which can block or activate biologically meaningful pathways. Moreover, our copula approach can be extended to investigate the effects of local environments on protein-protein interactions. The copula mutual information approach will help to propose the new variant of ARACNE (Algorithm for the Reconstruction of Accurate Cellular Networks): an algorithm for the reconstruction of gene regulatory networks. PMID- 18447958 TI - Suicide among adults aged 30-49: a psychological autopsy study in Hong Kong. AB - BACKGROUND: A surge in suicide rates in middle age people in Hong Kong and many Asian countries was recently observed. However, there is a paucity of suicide research on this subgroup of people in Asia. METHODS: The next-of-kin of 85 suicide cases and 85 community subjects aged 30-49 years were interviewed by a psychological autopsy approach. Information was triangulated by interview notes, coroner's court files, and police investigation reports. RESULTS: A multiple logistic regression analysis identified the following risk factors for suicide among the middle age people in Hong Kong: the presence of at least one psychiatric disorder (OR = 37.5, 95% CI 11.5-121.9, p < 0.001), indebtedness (OR = 9.4, 95% CI 2.2-40.8, p < 0.01), unemployment (OR = 4.8, 95% CI 1.3-17.5, p < 0.05), never married (OR = 4.2, 95% CI 1.1-16.3, p < 0.05), and lived alone (OR = 3.9, 95% CI 1.2-13.4, p < 0.05). CONCLUSION: The data show that socio-economical factors had a strong impact on suicide in the target group. Further research is needed to explore any positive qualities that protect the middle-aged from suicide. The prevention of suicide in the middle-aged requires multiple strategies. PMID- 18447960 TI - Predictors of outcome in first-episode schizophrenia over the first 4 years of illness. AB - BACKGROUND: The outcome of schizophrenia appears to be more favourable than once thought. However, methodological issues, including the reliance on diagnosis at first presentation have limited the validity of outcome studies to date. METHOD: We conducted a first-episode follow-up study of 97 patients with DSM-IV schizophrenia over the first 4 years of illness. First presentation and follow-up assessments were compared using paired t tests and a forced-entry regression analysis was used to determine prognostic variables. RESULTS: There were significant improvements in positive and negative symptoms and global assessment of functioning between first presentation and follow-up. At first presentation, fewer negative symptoms (t=-3.40, p<0.01), more years spent in education (t=3.25, p<0.01), and a shorter duration of untreated psychosis (DUP) (t=-2.77, p<0.01) significantly predicted a better outcome at follow-up. CONCLUSIONS: The outcome of schizophrenia may not be as pessimistic as once thought and most patients did not display a downward deteriorating course of illness. This study supports the relationship between DUP and outcome beyond the early stages of illness. PMID- 18447959 TI - Stage-specific gene expression during urediniospore germination in Puccinia striiformis f. sp tritici. AB - BACKGROUND: Puccinia striiformis f. sp. tritici is an obligate biotrophic pathogen that causes leaf stripe rust on wheat. Although it is critical to understand molecular mechanisms of pathogenesis in the wheat stripe rust fungus for developing novel disease management strategies, little is known about its genome and gene functions due to difficulties in molecular studies with this important pathogen. To identify genes expressed during early infection stages, in this study we constructed a cDNA library with RNA isolated from urediniospores of P. striiformis f. sp. tritici germinated for 10 h. RESULTS: A total of 4798 ESTs were sequenced from the germinated urediniospore library and assembled into 315 contigs and 803 singletons. About 23.9% and 13.3% of the resulting 1118 unisequences were homologous to functionally characterized proteins and hypothetical proteins, respectively. The rest 62.8% unisequences had no significant homologs in GenBank. Several of these ESTs shared significant homology with known fungal pathogenicity or virulence factors, such as HESP767 of the flax rust and PMK1, GAS1, and GAS2 of the rice blast fungus. We selected six ESTs (Ps28, Ps85, Ps87, Ps259, Ps261, and Ps159) for assaying their expression patterns during urediniospore germination and wheat infection by quantitative real-time PCR. All of them had the highest transcript level in germinated urediniospores and a much less transcript level in un-germinated urediniospores and infected wheat tissues (1-7 dpi). The transcript level of Ps159 increased at later infection stages (6-7 dpi). Our data indicated that these genes were highly expressed in germinated urediniospores and may play important roles in fungal plant interactions during early infection stages in the wheat stripe rust fungus. CONCLUSION: Genes expressed in germinated urediniospores of P. striiformis f. sp. tritici were identified by EST analysis. Six of them were confirmed by quantitative real-time PCR assays to be highly expressed in germinated urediniospores. PMID- 18447961 TI - The association between pre-morbid adjustment, duration of untreated psychosis and outcome in first-episode psychosis. AB - BACKGROUND: The association between the duration of untreated psychosis (DUP) and outcome of schizophrenia may be confounded by other factors such as poor pre morbid adjustment. The aim of the present study was to examine the independent contributions of DUP and of pre-morbid adjustment to the clinical and social outcomes of schizophrenia. METHOD: A longitudinal, prospective, 2-year follow-up study of 423 patients with first-episode schizophrenia-spectrum psychosis was conducted. Patients were comprehensively assessed at entry, 1-year and 2-year follow-up. At entry, DUP was measured by IRAOS (an instrument for the assessment of onset and early course of schizophrenia) and pre-morbid adjustment was measured by the Pre-morbid Adjustment Scale (PAS) as 'pre-morbid social adaptation' and 'pre-morbid school adaptation'. Outcome measures included the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), the Social Network Schedule and social information. Multiple linear regression models were used for data analysis. RESULTS: The median DUP was 48 weeks, which is long compared to other studies. Longer DUP was independently associated with more psychotic symptoms at entry, 1 year and 2-year follow-up. Poorer pre-morbid social adaptation was independently associated with more negative symptoms and smaller social network at entry and 1 year follow-up. Poorer pre-morbid school adaptation was independently associated with poor vocational outcome at 1-year and 2-year follow-up. CONCLUSIONS: Longer DUP is associated with poorer 2-year outcome of psychosis in schizophrenia spectrum disorders, when pre-morbid functioning and other prognostic factors are controlled for. Impaired pre-morbid development is independently associated with more negative symptoms and poorer social outcome. PMID- 18447962 TI - Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. AB - BACKGROUND: For more than a decade high-frequency repetitive transcranial magnetic stimulation (rTMS) has been applied to the left dorsolateral prefrontal cortex (DLPFC) in search of an alternative treatment for depression. The aim of this study was to provide an update on its clinical efficacy by performing a meta analysis involving double-blind sham-controlled studies. METHOD: A literature search was conducted in the databases PubMed and Web of Science in the period between January 1980 and November 2007 with the search terms 'depression' and 'transcranial magnetic stimulation'. Thirty double-blind sham-controlled parallel studies with 1164 patients comparing the percentage change in depression scores from baseline to endpoint of active versus sham treatment were included. A random effects meta-analysis was performed to investigate the clinical efficacy of fast frequency rTMS over the left DLPFC in depression. RESULTS: The test for heterogeneity was not significant (QT=30.46, p=0.39). A significant overall weighted mean effect size, d=0.39 [95% confidence interval (CI) 0.25-0.54], for active treatment was observed (z=6.52, p<0.0001). Medication resistance and intensity of rTMS did not play a role in the effect size. CONCLUSIONS: These findings show that high-frequency rTMS over the left DLPFC is superior to sham in the treatment of depression. The effect size is robust and comparable to at least a subset of commercially available antidepressant drug agents. Current limitations and future prospects are discussed. PMID- 18447963 TI - The neural correlates of fatigue: an exploratory imaginal fatigue provocation study in chronic fatigue syndrome. AB - BACKGROUND: Fatigue is the central symptom in chronic fatigue syndrome (CFS) and yet very little is known about its neural correlates. The aim of this study was to explore the functional brain response, using functional magnetic resonance imaging (fMRI), to the imaginal experience of fatigue in CFS patients and controls. METHOD: We compared the blood oxygen level dependent (BOLD) responses of 12 CFS patients and 11 healthy controls to a novel fatigue provocation procedure designed to mimic real-life situations. A non-fatiguing anxiety provoking condition was also included to control for the non-specific effects of negative affect. RESULTS: During the provocation of fatigue, CFS patients reported feelings of both fatigue and anxiety and, compared to controls, they showed increased activation in the occipito-parietal cortex, posterior cingulate gyrus and parahippocampal gyrus, and decreased activation in dorsolateral and dorsomedial prefrontal cortices. The reverse pattern of findings was observed during the anxiety-provoking scenarios. CONCLUSIONS: The results may suggest that, in CFS patients, the provocation of fatigue is associated with exaggerated emotional responses that patients may have difficulty suppressing. These findings are discussed in relation to the cognitive-behavioural model of CFS. PMID- 18447964 TI - Central coherence in eating disorders: a systematic review. AB - BACKGROUND: This review systematically appraised the research evidence for local versus global information processing to test the hypothesis that people with eating disorders (ED) had weak central coherence. METHOD: Searches on Medline, EMBASE, PsycINFO and ISI Web of Science databases were conducted in November 2006 and subsequently updated in September 2007. Each search was conducted in two steps: (1) neuropsychological tasks measuring central coherence and (2) words related to cognitive functioning in eating disorders. Data were summarized in a meta-analysis if the number of studies for a given test was >5. RESULTS: Data were extracted from 16 studies. Meta-analyses were conducted for four tasks obtaining moderate effect sizes. The majority of studies found global processing difficulties across the ED spectrum. The results are less clear regarding local processing. CONCLUSIONS: People with ED have difficulties in global processing. It is less certain as to whether they have superior local processing. Currently, there is insufficient evidence to refute the weak central coherence hypothesis. PMID- 18447965 TI - A study using transcranial magnetic stimulation to investigate motor mechanisms in psychomotor retardation in depression. AB - The pathophysiological basis of psychomotor retardation in depression is unclear. In this study, transcranial magnetic stimulation (TMS) was used to examine the functioning of the motor cortical system in 19 depressed patients and 10 healthy control subjects. Motor-evoked potentials were measured in the biceps brachii muscle during a series of tests with the muscle at rest and during voluntary elbow flexion contractions. Maximal voluntary force, as well as force and electromyographic responses to TMS were also measured during fatiguing maximal contractions. Depressed psychomotor-retarded subjects were less able to produce output from the motor cortex than non-psychomotor-retarded, depressed subjects and healthy controls during maximal exertion and fatigue. This finding was independent of depression severity. In contrast, responses to TMS elicited during relaxation or weak contractions did not differ between healthy and psychomotor retarded subjects. Our study suggests that although the motor pathway from the motor cortex to the muscle is unimpaired, psychomotor retardation in depression is characterized by a reduced ability to drive the motor cortex. PMID- 18447966 TI - Adrenergic blockade with phenoxybenzamine and propranolol in a cohort of 60 patients undergoing surgery for phaeochromocytoma. PMID- 18447967 TI - Lactate gap and ethylene glycol poisoning. PMID- 18447968 TI - A non-airway management use of the video laryngoscope (GlideScope). PMID- 18447969 TI - Low bispectral index values in a 2-yr-old with a large bifrontal porencephalic cyst. PMID- 18447970 TI - The distribution of hand preference is discrete: a taxometric examination. AB - The dominant genetic models of human handedness (Annett, 1985; McManus, 1985a) have contrasting views on its nature. Whereas Annett's model proposes that handedness is distributed continuously (following the distribution of performance asymmetries of the hands), McManus's model proposes that handedness is distributed dichotomously. The aim of this study was to investigate the nature of the underlying distribution. The taxonomy of hand preference was analysed by two independent taxometric procedures, 'mean-above-mean-below-a-cut' and 'maximum eigenvalue', separately in two geographically, demographically, and culturally distinct samples; one of Australian adults (N=787), and the other of Serbian high school students (N=1,224). The analyses revealed a latent categorical structure in both samples, with estimated mean base-rates of a right-handed taxon of 0.80 and 0.94 from the two analyses of the adult sample and of 0.79 and 0.93 from the two analyses of the high school sample. Subsequent analyses showed that the initial right-handed class could be subdivided into consistent and inconsistent right-handed subclasses in both samples. A supplementary analysis, including a measure of hand proficiency in a subset of the sample of Australian adults (N=596), also revealed a latent categorical structure, showing evidence for a categorical latent structure from a continuous measure of hand performance. We conclude that the distribution of hand preferences in humans is discrete and not continuous. PMID- 18447971 TI - Healthy ageing, perceived motor-efficacy, and performance on cognitively demanding action tasks. AB - Current measures assessing older adults' functional ability detect existing limitations on essential tasks rather than changes in other aspects of functioning that could indicate future limitations. The perceived motor-efficacy scale was developed to measure capability beliefs of healthy older adults across a range of daily action tasks. Subscales were developed through interviews with older volunteers and academics, then administered to participants aged 60-96 (N=300). Factor analysis of subscale scores produced 10 subscales. These demonstrated strong internal reliability, which was replicated with a second sample aged 60-92 (N=167). The influence of perceived motor-efficacy on performance of cognitively demanding action tasks was investigated with a third sample aged 60-88 (N=134). On a task assessing the inhibition of an inappropriate action, older adults in their 80s with high confidence produced minor errors, whereas those with lower confidence produced extreme errors. On another task assessing the ability to inhibit a previously learnt action, those with high levels of perceived motor-efficacy performed better amongst those least able to inhibit, but more poorly among those most able. Perceived motor-efficacy may therefore be useful in identifying older adults at risk of functional limitations and enabling interventions before the onset of illness. PMID- 18447972 TI - [Nasosinusal adenocarcinoma: molecular and genetic analysis by MLPA]. AB - INTRODUCTION AND AIM: Intestinal-type sinonasal adenocarcinomas (ITACs) are rare epithelial tumours, primarily originating in the nasal cavities and paranasal sinuses and characterized by glandular structures. The aims of this study are: to determine the genetic alterations in ITACs by MLPA (Multiplex ligation-dependent probe amplification) and to correlate the findings to the clinical behavior and follow-up information of the patients. MATERIAL AND METHOD: We performed a longitudinal prospective study on 20 patients with ITAC, seen in our department between 1998 and 2004. DNA was extracted from primary tumor samples and analyzed by MLPA. RESULTS: The T stage of our series was T2: 4 (20 %), T3: 6 (30 %), T4a: 3 (15 %) and T4b: 7 (35 %). All cases initially were N0 and M0. Seventeen patients (85 %) had professional exposure to wood dust. All patients underwent surgical intervention and 70 % received complementary radiotherapy. Overall 5 and 10 year survival was 42 % and 22 %, respectively. Gains were found most frequently for PTP4A3 and PDCD8 (65 %), TNRFSF7 (50 %), RECQL4 and LMO2 (45 %), and losses for BCL2 (70 %), IL13 (55 %), ABCB1 and RB1 (50 %), PIK3CA and CDH1 (45 %). CONCLUSIONS: Losses of F3, MIF, and BRCA1 significantly correlated with the posterior development of metastases and with worse survival. Also gains of PIK3CA, UTY, and RELA correlated with poor clinical outcome. Losses of BRCA1 and F3 were significant in multivariate analysis. PMID- 18447973 TI - [Hemithyroidectomy: when it is necessary an intraoperative frozen-section biopsy?]. AB - INTRODUCTION: Many surgeons use intraoperative frozen section biopsy of the thyroid nodules to confirm malignant disease, but it continues to generate considerable controversy. We reviewed our recent experience to determinate de clinical utility of frozen section in our surgical management and intraoperative decision-making. PATIENTS AND METHOD: All patients who had operations for the thyroid nodular disease between 2000 and 2006 were included in this retrospective study. We compared the results of frozen section diagnosis and definitive histologic results in a population of 212 patients. RESULTS: Frozen section was false negative in 3 patients (1.66 %) and false positive in 1 (0.47 %) and avoided 12 reoperations (5.6 %). When there was not suspicious malignant disease had a sensitivity of 0.75 %. In the group of follicular disease the sensitivity was 3.7 %, and in the group with suspicious malignant disease was 37.5 %. CONCLUSIONS: Frozen section was more helpful in the group of suspicious for malignant disease. It does not seem to be necessary when fine-needle biopsy indicates bening or follicular disease. PMID- 18447974 TI - [On the number and morphometrical parameters of the nucleus ambiguous neurons after the injury and regeneration of the recurrent laryngeal nerve in the rat]. AB - INTRODUCTION AND OBJECTIVES: In laryngeal nerves injuries it is essential to know the morpho-functional reorganization of the neurons which supply the larynx in order to be successful with the clinical techniques of functional reinnervation and/or orthotopic transplant. Due to the lack of this type of studies in the literature, we investigated the organization of laryngeal motoneurons in the nucleus ambiguous (NA) after the axotomy and regeneration of the recurrent laryngeal nerve (RLN) in adult rats. MATERIAL AND METHODS: We used biotinylated dextran amines (BDA, 3 kDa), this fact is an innovation in the field, because this is a novel methodological approach to this model. We studied a control group of 14 animals and four experimental groups of between 10 and 16 animals each one. In the experimental groups we studied the regeneration of the axotomized nerve in four different intervals of time after the injury: 21-28 days, 42-60 days, 90-120 days, and 150-180 days. In the control group we traced the RLN without injury while in the experimental groups we traced the axotomized RLN after each regeneration interval. RESULTS: The number of traced neurons in the control group was 143 +/- 38; in the experimental groups the number was always lower than in the control (21-28 days: 14 +/- 23 neurons; 42-60 days: 46 +/- 49; 90-120 days: 55 +/- 57; 150-180 days: 61 +/- 60). The morphologic parameters studied within the neuronal bodies in the experimental groups were no statistically different when compared with those in the control group. CONCLUSIONS: Results show that the tracing of the RLN after its axotomy and regeneration, in the adult rat, involves a decrease in the number of traced neurons within the NA but no changes in their size or shape during the analysed periods. PMID- 18447975 TI - [Is universal newborn hearing screening more efficient with auditory evoked potentials compared to otoacoustic emissions?]. AB - INTRODUCTION AND OBJECTIVES: Cost-effectivity of universal newborn hearing screening programmes is under constant review. In this context, the aim of the present study is to evaluate the performance of brainstem response audiometry (BERA) compared to otoacoustic emissions (OAE) as screening tools. METHODS: Observational and retrospective study on a universal screening programme started in 1998. We perform a comparative analysis between two groups of newborns evaluated in consecutive periods of time. We analyze outcome measures of the programme as a measure of effectivity, and dedicated resources to weight the costs. RESULTS: We compare a group of 862 newborns from year 2003, screened with transient evoked OAE with a clinical device, with a group of 2300 newborns from years 2005 and 2006, screened with automated BERA. We find a statistically significant difference in the percentage of pass in the first step, favoring BERA (99.7 % vs 91.8 %; P< .0005). The median of exploration time with BERA was 276 seconds. Costs evaluation points to a progressively decreasing difference between both tools. CONCLUSIONS: There are data indicating that BERA could be more cost effective as initial screening tool. This advantage should be added to the already known more comprehensive evaluation of the auditory pathway, which could lead to the recommendation of its preferential use in auditory screening programmes. PMID- 18447976 TI - [Risk factors leading to failure in myringoplasty: a case-control study]. AB - INTRODUCTION AND OBJECTIVES: To determine the risk factors associated with myringoplasty failure among the study population, a case-control study was carried out in 2 tertiary hospital centers. PATIENTS AND METHOD: Patients undergoing tympanic membrane perforation or atelectasis within 3 to 6 months following surgery were considered as cases, otherwise, they were considered to be controls. Patients having undergone any type of ossiculoplasty were excluded. Seventy cases and 210 controls were included, a sample size calculated for the following variables: inflammation at time of surgery, place and size of the tympanic membrane perforation, presence of tympanosclerosis, presence of cholesteatoma, and surgical technique. Odds ratio was calculated as main association measure, a stratified analysis was performed to rule out possible confusion factors. RESULTS: No significant differences were found between the 2 groups respect to the variables for which the sample was calculated. Although in total group the addition of a modified radical mastoidectomy showed better operative results (95 % CI OR = 0.13-0.72; P=.002), in isolated tympanic membrane perforation this association it was loosed (95 % CI OR = 0.06-7.44; P=.81). CONCLUSIONS: Results in this study suggest that the variables for which the sample size was calculated are not associated with myringoplasty failure in this population. PMID- 18447977 TI - [Bronchoscopy in children with foreign body aspiration]. AB - INTRODUCTION AND OBJECTIVES: Aspiration of foreign body presents a high incidence of mortality during the paediatric life period. Family suspect and detection of specific symptoms and signs determine the need of bronchoscopy. The objective of this study is to establish the clinical parameters that indicate foreign body in airway. METHODS: Retrospective study in 44 children with foreign body aspiration. We reviewed age, sex, family suspect, blood analysis, chest x-ray, time to consulting, location, type, complications, and time to discharge. RESULTS: Decisive clinical factors that indicate foreign body in airway are family suspect and respiratory clinic. Findings after auscultation and chest x-ray support suspect, but final diagnostic only can be made after bronchoscopy. Bronchoscopy with foreign body removal was performed during first 24 hours in 86.36 % of patients, and founded that those with delayed diagnosis had increased morbidity. CONCLUSIONS: Family's suspect is the most important parameter that indicates foreign body located in airway. Bronchoscopy performed during the first hours avoids morbidity. This is a secure technique when performed in adequate place with trained personnel. PMID- 18447978 TI - [Unusual clinical presentations of vestibular schwannomas]. AB - The aim of this study is evaluate the unusual ways of initial presentation of the vestibular schwannomas. We performed a retrospective study of the patients who underwent resection of acoustic neuromas on our service, including for analysis only the cases which initial symptom was not the hearing loss. Tumor size, localization, clinical presentation, and age of the patients were considered. Nine patients present with atypical symptoms. The most common complain in this group were facial paresthesias (22,2 %). None of them complained about other otological symptoms. A significant group of patients did not present with the otological symptoms classically associated with vestibular schwannoma. Clinical knowledge of these kinds of symptoms may lead to earlier detection of these lesions. PMID- 18447979 TI - [Systematic review and meta-analysis of diagnostic accuracy of 18F-FDG PET in suspected recurrent head and neck cancer]. AB - OBJECTIVES: A meta-analysis of the literature was performed in this article in order to evaluate the diagnostic accuracy of 18F-FDG PET in suspected recurrent head and neck cancer. MATERIAL AND METHODS: A systematic review of the literature was performed using 1987 to 2007 MEDLINE and CANCERLIT databases, applying selection criteria to the studies found. Sensitivity, specificity, positive and negative likelihood ratios, and odds ratio were calculated. The diagnostic accuracy was evaluated with ROC (receive-operating-characteristics) curves. RESULTS: Nineteen articles were included in the meta-analysis. Sensitivity of 18F FDG PET was 94 %, specificity 80 %, and the summary ROC curve showed a good trade off between sensitivity and specificity. CONCLUSIONS: 18F-FDG PET was useful in patients with suspected recurrence of head and neck cancer, showing a high sensitivity and intermediate-high specificity. PMID- 18447980 TI - [Oropharyngeal kaposiform hemangioendothelioma]. AB - The kaposiform hemangioendothelioma is a very infrequent tumor proceeding from the endothelial-derived spindle cells, more often found on the limbs, although peritoneal, retroperitoneal and sacrum locations are also prevailing. Head and neck are exceptional locations. The kaposiform hemangioendothelioma is almost exclusively found in children and early adolescents, and it is highly associated with the Kasabach-Merritt syndrome and lymphangiomatosis. The main treatment is the tumor surgical removal, including wide margins, plus supporting therapy when Kasabach-Merritt syndrome is linked. We report an isolated oropharyngeal kaposiform hemangioendothelioma 9-10-year old male case. PMID- 18447981 TI - [T cell non-Hodgkin's lymphoma of the external auditory canal]. AB - Developing of primary lymphoma of the external auditory canal is excepcional. We describe a 53 years old woman who developed a T cell non-Hodgkin's lymphoma and review literature. She was treated with surgery and chemotherapy and remains disease-free 10 months after the treatment. PMID- 18447982 TI - [Oro-pharyngeal mass in a patient with HIV infection]. PMID- 18447983 TI - [Universities, hospitals and paediatric needs. Are there solutions?]. PMID- 18447984 TI - [Spanish version of the TNO-AZL preschool children quality of life questionnaire (TAPQOL)]. AB - OBJECTIVES: To obtain a Spanish version of the TNO-AZL Preschool Children Quality of Life Questionnaire (TAPQOL) that would be both semantically and culturally equivalent to the original. MATERIAL AND METHODS: The TAPQOL questionnaire was designed to measure health-related quality of life in children aged 3 months to 5 years and contains 43 questions distributed in 12 subdimensions. The Spanish version was obtained by using the forward/back-translation method with expert, bilingual translators. Cognitive debriefing interviews were carried out with the parents of healthy children and with those of children with respiratory disease. RESULTS: During the adaptation phase, four items were modified after input from the authors of the original version to retain the meaning of the original. At the end of the adaptation process, 37 of the 43 items were classified as A, i.e. without difficulty in the adaptation. Four mothers and two fathers participated in the cognitive debriefing interviews. Four had secondary level education, and two had university level education. Their children were aged between 16 and 60 months. The average time taken to complete the questionnaire was 13.5 minutes. No comprehension problems regarding the questionnaire's content were found, and no items were modified after this phase of the study. The mothers of children with respiratory disease considered the questions related to their children's symptoms to be appropriate. CONCLUSIONS: The Spanish version of the TAPQOL has proven to be acceptable and culturally equivalent to the original version. Future studies should investigate the psychometric properties of this questionnaire and compare them with those of the original version. PMID- 18447985 TI - [Antiretroviral drug toxicity in human immunodeficiency virus infected children]. AB - Paediatric Human Immunodeficiency Virus infection (HIV) nowadays is a chronic disease with an excellent long term prognosis, but lifelong combined antiretroviral treatment is required. However, an improved quality of life in this population is limited by adverse drug effects. The highest risk of treatment toxicity is developing a complete metabolic syndrome including: Hyperlipemia, lipodystrophy, insulin resistance, lactic acidosis, osteopenia, hypertension, and specific system and organ toxicity, such as the kidney, liver, CNS or bone marrow. The risk of cardiovascular disease adult life and also definitive bone mass damage are the most significant metabolic costs that have to paid for increased survival. Most of these toxicities were able to be adequately treated but, pharmacological interferences, patient intolerance and the high number of drugs are the problems that limit the adherence to treatment, which is essential for a good therapeutical efficacy. In this article, we present four HIV paediatric patients who presented with almost the whole range of metabolic toxicities, and a practical overview of therapeutical management. PMID- 18447986 TI - [Infectious acute gastroenteritis in the emergency department of an urban hospital]. AB - OBJECTIVES: To examine the etiology, clinical, analytical and evolutionary characteristics of gastroenteritis in the pediatric population in the Emergency Department of Dr. Peset University Hospital in Health Care Area 10 in Valencia, Spain, over a 1-year period (2005). PATIENTS AND METHODS: Children < 15 years of age with acute diarrhea were prospectively enrolled in the Emergency Department. Data were collected through information sheets. Their stools were examined for diarrheagenic bacteria and viruses (rotavirus and adenovirus). RESULTS: 794 episodes of gastroenteritis were recorded. The incidence of rotavirus was 22 %, adenovirus 8 %, Campylobacter jejuni 7 % and Salmonella spp. 4 %. Socioeconomic characteristics were not helpful in differentiating disease due to specific enteropathogens. Ninety per cent cases caused by viruses only affected children under three years of age. Rotavirus gastroenteritis had a marked seasonal pattern (90 % cases in December-February). Among infants < or = 6 months of age rotavirus was less frequent as cause of diarrhea in breast-fed infants than in bottle-fed. Macroscopic blood in stools was reported almost exclusively among patients with a bacterial infection. In 96 % of all cases of diarrhea there was no dehydration, in 2 % it was mild, in 2 % moderate and none severe. Ten of the seventeen cases (59 %) of moderate dehydration were caused by rotavirus. Six percent of all children were hospitalised. CONCLUSIONS: Rotavirus was significantly more associated with the need for intravenous fluid therapy and hospitalisation than episodes negative for rotavirus. Rotavirus accounted for 3 % of hospitalisations in infants aged 1 month-2 years. PMID- 18447987 TI - [Drugs used in paediatric outpatients: do we have enough information available?]. AB - OBJECTIVE: To analyse the drugs taken in paediatric outpatients and the information available on these drugs. PATIENTS AND METHODS: A cross-sectional, observational, descriptive study was carried out. The study involved a sample of children under 14 years seen in the Emergency Room of the HGUV from June 2005 to August 2006. The medicines they received were quantified and classified, and the information on these drugs available in the Vademecum International Medicom and in the Summary of Product Characteristics, were analysed. RESULTS: Of the 462 children (mean age 5.2 (95 % CI 4.9-5.6)) included, 336 received 667 medicines (152 different medicines) that contained 864 drugs (161 different drugs). In 34.3 % of the cases it was for self-medication. Children under 4 years received more drugs than the older group (80.2 % in the younger group and 67.4 % in the older). Patients received from 1 to 7 medicines (mean 2.0). Children receiving 2 or 3 medicines were younger than those who received one. Five therapeutic groups of the Anatomical-Therapeutical-Chemical Classification (ATC) include the 93.1 % of the drugs administered (R: 26.5 %; M: 23.8 %; N: 22.8 %; J: 10.6 % and A: 10.0 %). In the information sources consulted there was no information available on paediatric use for 40 of the 152 medicines used. CONCLUSIONS: Almost 75 % of patients seen in the Emergency Room were already receiving drugs before they arrived at the hospital, in many cases as a result of self-medication. The information available on the paediatric use of drugs is deficient. Clinical research is required to study the effects of pharmacological treatment on children and to improve the information on their use. PMID- 18447988 TI - [Malama project in the Region of Murcia (Spain): environment and breastfeeding]. AB - OBJECTIVES: To identify protective factors and risk factors for the initiation and length of breastfeeding and full breastfeeding, in the Region of Murcia (Spain). PATIENTS AND METHODS: The Malama study (Medio Ambiente y Lactancia Materna) is a follow up study from birth up to years of 1,000 mother-child pairs. A description of breastfeeding practices are presented here, the survival curve of breastfeeding and a Cox regression model of the pilot study that includes 101 mother-child pairs and 6 months of follow-up. RESULTS: After six months the prevalence of breastfeeding was 35 %. The mean duration of full breastfeeding was 63 days (median 45 days) with six months prevalence of 8 %. Hazard ratios (HR) for full breastfeeding were, to be a smoker (1.89; 95 % CI: 1.18-3.02), older than 35 years of age (2.04; 95 % CI: 1.22-3.42), caesarean birth (1.63; 95 % CI: 1.00-2.66). As well as those previously mentioned risks for breastfeeding, there were also hazard ratios for primary school education or less (1.63; 95 % CI: 0.98 2.82); to have breastfed an earlier child for at least 16 weeks (0.33; 95 % CI: 0.13-0.79), and to be the first birth (0.50; 95 % CI: 0.27-0.95). The length of both breastfeeding and full breastfeeding increased with the length of the maternal leave (0.96; 95 % CI: 0.94-0.99). Pregestational occupational exposure to endocrine disruptors did not seem to interfere with the duration of breastfeeding. CONCLUSIONS: In order to improve quality and duration of breastfeeding programmes, paediatric research and training on breastfeeding practice should be encouraged, to reduce unnecessary caesarean sections, promote tobacco cessation, focus human and economic resources to women with less education, and include legal mechanisms to ensure longer maternal leave. PMID- 18447989 TI - [Predictive factors of smoking behaviour in secondary school children]. AB - INTRODUCTION: Many factors have been reported as being responsible for starting smoking during school age, but it is still not well known which cognitive determinants may be used as predictive factors of tobacco use. SUBJECTS AND METHODS: A prospective, longitudinal, study, including 417 pupils from 12 to 17 years, was carried out over three years in two rural Secondary Education Institutes in Castilla y Leon. The ESFA questionnaire was used, which included scales on attitudes and beliefs, social influences, self-efficacy, intention to smoke in the future and smoker behaviour. RESULTS: Of the 417 pupils studied, 36.7 % were smokers (38.6 % females and 34.4 % males). The mean of starting smoking was 12 years (11.83-12.15). In the initial analysis there was a clear relationship between cognitive determinants and smoker behaviour. The advertising and peer pressure lost predictive value after 3 years. The multivariate analysis showed that the determining factors of tobacco use are, besides age (OR = 3.85; 95 % CI, 1.27-11.64), to have a favourable attitude to smoking, (OR = 4.47; 95 % CI, 2.15-9.32), and the conduct perceived among peers (OR = 5.05; 95 % CI, 2.50 10.19). CONCLUSIONS: The determining factors that demonstrates a clear relationship with smoker behaviour are, age, favourable attitude of pupils towards smoking, and the perceived behaviour by smoker friends. Smoking prevention programs should take these factors into accounts when designing their activities. PMID- 18447990 TI - [Immigration, breastfeeding and smoking habit]. AB - OBJECTIVE: The advantages of breastfeeding for child and mother are widely recognised. Many factors seem to influence the mother's decision of breastfeed. The immigrant state of parents is one of the relevant factors considered. Previous studies founded higher breastfeeding rates among the immigrant population. The present work studies the rates of starting and duration of breastfeeding in the Spanish native population and in immigrants, as well as its relationship with other factors, such as tobacco habit and other perinatal factors. METHODS: The study included 911 children over a 10 months period. Age, sex, pregnancy duration, birth weight, parents' age, parent's smoking habits and smoking during pregnancy and their relationship the starting and duration of breastfeeding (OR and 95 % CI was obtained) in both immigrant and native population groups and a final multivariate analysis was performed for the starting of breastfeeding and continuing it at three months, including all studied variables. RESULTS: Immigrant and Native population were similar in all variables apart from mother age and smoking habit. Only mother smoking status (initial: OR 0.610 [ 0.429-0.867]; three months: OR 0.540 [0.458-0.636]) and birth weight (initial: OR 0.411 [0.268-0.629]; three months: OR 0.525 [0.407 0.677]) reached statistical significance in the final multivariate analysis. CONCLUSION: Our findings show that smoking habit and low birth weight are risk factors for not breastfeeding. Immigration status seems to be a confounding factor. PMID- 18447991 TI - [Rolandic epilepsy: epidemiological and clinical characteristics and outcome]. AB - OBJECTIVE: To analyse the epidemiological, clinical and developmental characteristics of Rolandic epilepsy as an aid to its suspected diagnosis in daily clinical practice. PATIENTS AND METHODS: The medical records of 56 patients with Rolandic epilepsy were reviewed in order to collect epidemiological and clinical features, results of complementary examinations and developmental data. The criteria defined by the International League Against Epilepsy (ILAE) were used in the diagnosis. RESULTS: Mean age at diagnosis was 7.7 years. In all, 62.5 % were diagnosed at school age, with a higher prevalence of males (58.9 %). Seizures occurred during sleep in 84.4 % of patients, and they were mainly characterised by hemifacial seizures with eye deviation and/or headaches (76.8 %), hypersalivation (44.6 %), guttural sounds (30.6 %), secondary generalised tonic-clonic (35.7 %) and/or unilateral clonic or tonic seizures (26.8 %), dysarthria (17.9 %) and unilateral paresthesias (16.1 %). Inter-ictal EEG showed paroxysms in the centrotemporal regions, frequently unilateral (78.6 %). Of all recurrences, 50.7 % occurred during the first 12 months after diagnosis, 24.6 % between 12 and 24 months after diagnosis, and 24.6 % between 2 and 4 years of follow up. Two patients with atypical progression were recorded: a case with epilepsy with continuous spikes and waves during slow-wave sleep, and another case with a Landau-Kleffner syndrome. CONCLUSIONS: Rolandic epilepsy is a common type of epilepsy in the pediatric age group and generally begins at school-aged children. Its semiological sequence is fairly characteristic, and finding centrotemporal spikes is considered as necessary for the syndromic diagnosis. The prognosis is excellent; however, as a few patients may progress to atypical outcomes and/or neuropsychological deficits, a rigorous developmental control of these patients should be of the highest priority. PMID- 18447992 TI - [Serum vitamin B12 levels in an adolescent population in Madrid]. AB - INTRODUCTION: Serum vitamin B12 concentration levels in children are essential to establish values in order to compare different regions or countries, and for considering e the possibility of supplementing diets with group B vitamins as a secondary prevention against cardiovascular diseases. MATERIAL AND METHODS: A cross-sectional epidemiological study was carried out to asses serum vitamin B12 levels in school children, 13-15 years of age, in Madrid. Folate and vitamin B12 vitamin determinations were performed on fasting blood samples. Genotype C677T of methylentetrahydrofolate reductase (MTHFR) enzyme was determined by PCR. RESULTS: The mean vitamin B12 level obtained in our study was 503 pmol/l; CI 95 % CI (478 528 pmol/l). The median was 471 pmol/l; interquartile range (IR) (337-632 pmol/l). No statistically significant differences were found by age or C677T genotype for MTHFR. Serum vitamin B12 concentrations were significantly higher in females. Prevalence of vitamin B12 deficiency (< 224 pmol/l) was 6 % in males and 4 % in females. CONCLUSIONS: Reference values for serum vitamin B12 concentrations in an adolescent population are presented. Prevalence of vitamin B12 deficiencies is higher in males. PMID- 18447994 TI - [Baboon syndrome]. AB - The cases of three children diagnosed with baboon syndrome are described, being defined by the appearance of dermatological lesions, with characteristic distribution and morphology, as a result of having been in contact with mercury. Other substances have been described associated with the appearance of this syndrome; however their pathogenis is not completely known, and it has been suggested that it could be another form of contact dermatitis. Diagnosis is based on patient clinical history and physical examination and there is no specific treatment. PMID- 18447993 TI - [18F-fluoro-L-DOPA PET-CT imaging combined with genetic analysis for optimal classification and treatment in a child with severe congenital hyperinsulinism]. AB - BACKGROUND: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy. The differential diagnosis between focal and diffuse forms of CHI is of great importance when planning surgery. The aim of this article is to show the first case of focal CHI diagnosed in Spain using PET CT imaging combined with genetic analysis. METHODS: A 13 month child with CHI and normal conventional radiological investigations treated with diazoxide, diet control and feeding by gastrostomy is presented. Genetic analysis of ABCC8 and KCNJ11 genes and PET-TAC using 18F-fluoro-L-DOPA were performed. RESULTS: A pathological mutation (G111R) in the paternal allele of ABCC8 was detected. PET CT scanning using 18F-fluoro-L-DOPA showed a focus of high uptake in the body of the pancreas compatible with adenoma that was hystopathologically confirmed. After surgical resection the patient is asymptomatic without needing either pharmacological treatment or dietetic control. CONCLUSIONS: The combination of genetic analysis and 18F-fluoro-L-DOPA PET-TAC shows a great potential for the identification, location and guideline for surgery in CHI. PMID- 18447995 TI - [Exposure to multiresisant tuberculosis: study and follow-up of nine children]. AB - A world increase in multidrug-resistant tuberculosis (MDR-TB) has been reported over the last few years. A larger number of diagnoses are being seen in Spain, due to the increase of immigration from high endemic TB countries. Articles published on this are anecdotal in children, and there is no clear directives for treatment of MDR-TB, or latent tuberculosis infection (ITBL) or on prophylaxis after exposure to active pulmonary MDR-TB. We present the initial management and progression of nine children after close contact exposure to an Ecuadorian woman diagnosed with active pulmonary TB, resistant to Isoniazid, Rifampicin and Pyrazinamide. PMID- 18447996 TI - [Exogenous lipoid pneumonia]. AB - The aspiration of lipoid material following the accidental ingestion of lipid formulations is the most frequent cause of exogenous lipoid pneumonia in paediatrics. The presence of cough, increasing dyspnea and chest pain, together with alveolar infiltrates in the chest radiography and the previous accidental intake of a lipid substance and vomiting should make us suspect this diagnosis. We present two cases of aspiration lipoid pneumonia in paediatric patients, with a different clinical presentation and radiological outcome, pointing out in one of them the appearance of pneumatoceles as a consequence of aspiration. PMID- 18447997 TI - [Infant botulism]. AB - We report a case of botulism in a 40 day old infant. The patient presented a descending flaccid paralysis requiring mechanical ventilation for 12 days. She is the first European patient treated with Human Botulism Immune Globulin. A few weeks later a second case of infant botulism was detected in our geographical region in Southern Spain. We emphasise the importance of an early diagnosis and treatment with Human Botulism Immune Globulin to decrease morbidity. PMID- 18447998 TI - [Accidental ingestion of superwarfarins]. AB - Superwarfarins were developed around 1970 in order to resolve the resistance developed by the rodents to the previously existing rodenticides. Superwarfarins cause, nowadays, most of the poisonings due to rodenticides. However, in our environment, it has been extremely uncommon to attend children with such poisonings. We present five children aged less than 4 years with unintentional ingestion of a superwarfarin, admitted in a Pediatric Emergency Department in 1 year time, and a revision of the literature. PMID- 18447999 TI - [Infantile hepatic hemangioendothelioma. A multifocal, bilobular and asymptomatic case with spontaneous regression]. AB - Infantile hepatic hemangioendothelioma is a severe disease with a high mortality rate. Nevertheless these vascular lesions may experience spontaneous regression within 12 to 18 months. The decision of trying a specific treatment and the choice among the several therapeutic options remains controversial, particularly in those asymptomatic cases of multifocal, bilobular involvement. We describe a case of multifocal, bilobular and asymptomatic infantile hepatic hemangioendothelioma, untreated, and with spontaneous regression before 2 years of age. PMID- 18448000 TI - [Protocol for tizanidine use in infantile cerebral palsy]. AB - INTRODUCTION: Cerebral palsy is usually spastic, and baclofen, benzodiazepines and tizanidine are considered as oral treatments. The aim of this paper is to demonstrate tizanidine management in children with generalized spasticity. PATIENTS AND METHODS: Scheduled medical uses and dosing of tizanidine in our hospital are shown. It was assessed in 45 children. Appearance and repercussions of side-effects were studied using Global Tolerance to Treatment Scale, and drug tolerance was studied by subjective assessment by parents, children or therapists. RESULTS: were analysed using SPSS version 11.5. RESULTS: Treatment with tizanidine was carried out with 1 mg/ day in 18 mo-7 yr old children, 2 mg/day in 7-12 yr old children as initial doses, and for those older than 12 yr similar dosing to that in adults. Tolerance was excellent in 79.3 % of children. Sedation was the most uncomfortable side- effect. Subjective assessment by 92.9 % of parents was good. DISCUSSION: Tizanidine shows greater capacity for binding to brain receptors, and therefore more effective for brain spasticity, better tolerance and higher approval. Therefore, it is an ideal treatment for generalised spasticity in cerebral palsy. PMID- 18448001 TI - [Recommendations for respiratory support in the newborn (I)]. AB - The recommendations included in this document will be part a series of updated reviews of the literature on respiratory support in the newborn infant. These recommendations are structured into twelve modules, with the first three modules being developed in this work. Each module it is the result of a consensus process amongst all members of the Surfactant and Respiratory Group of the Spanish Society of Neonatology. They represent a summary of the published papers on each specific topic and of the clinical experience of each one of the members of the group. Each module includes a summary of the scientific evidence available, graded into four levels of recommendations. PMID- 18448002 TI - [Lumbar disc hernia in the adolescent: conservative treatment with a dorsal lumbar corset]. PMID- 18448003 TI - [Hepatic adenomatosis]. PMID- 18448004 TI - [Phaeochromocytoma associated with a paraganglion syndrome]. PMID- 18448005 TI - [Paediatric use of levosimendan in septic shock]. PMID- 18448006 TI - [Intracranial hypertension secondary to neurocysticercosis]. PMID- 18448007 TI - [Griscelli syndrome]. PMID- 18448008 TI - [Haemoptysis after Heimlich manoeuvre]. PMID- 18448009 TI - [Peri-hepatitis in a sexually active adolescent]. PMID- 18448010 TI - [Suprapubic pain in a 14 year old schoolchild]. PMID- 18448011 TI - [Streptococcal pharyngitis in children less than 2 years old]. PMID- 18448012 TI - [Macrolides: not just antibiotics]. PMID- 18448013 TI - [Cardiovascular risk factors in chronic obstructive pulmonary disease: results of the ARCE study]. AB - OBJECTIVE: Cardiovascular disease is a common cause of death in patients with chronic obstructive pulmonary disease (COPD). It is not clear whether the high cardiovascular comorbidity is due to an increase in traditional risk factors or whether, in contrast, COPD can be considered an independent risk factor. The aim of this study was to analyze the prevalence of risk factors and cardiovascular comorbidity in a community-based population treated for COPD. PATIENTS AND METHODS: This was a concurrent multicenter, cross-sectional study that included 572 patients with confirmed diagnosis of COPD. Information on cardiovascular risk factors and comorbidity was collected by extracting data from the medical records of the participating center. RESULTS: The mean (SD) forced expiratory volume in 1 second (FEV1) was 53.7% (16.85%) of predicted and the ratio of FEV1 to forced vital capacity was 57.9% (10.9%). Hypertension was reported in 53%, obesity in 27%, dyslipidemia in 26%, and diabetes in 23% of the patients. The prevalence of risk factors was not related to disease severity, but there was a trend towards an association with age. In the study group, 16.4% had ischemic heart disease, 7% cerebrovascular disease, and 17% peripheral vascular disease. Cardiovascular disease was not associated with COPD severity, but such an association was reported for age and traditional risk factors. CONCLUSIONS: Cardiovascular risk factors are highly prevalent in patients with COPD. The prevalence of cardiovascular and cerebrovascular disease exceeds that reported in the general population. No relationship was found between the severity of airflow obstruction and the presence of cardiovascular comorbidity. PMID- 18448014 TI - [Activation of satellite cells in the intercostal muscles of patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: The respiratory muscles of patients with chronic obstructive pulmonary disease (COPD) display evidence of structural damage in parallel with signs of adaptation. We hypothesized that this can only be explained by the simultaneous activation of satellite cells. The aim of this study was to analyze the number and activation of those cells along with the expression of markers of microstructural damage that are frequently associated with regeneration. PATIENTS AND METHODS: The study included 8 patients with severe COPD (mean [SD] forced expiratory volume in 1 second, 33% [9%] of predicted) and 7 control subjects in whom biopsies were performed of the external intercostal muscle. The samples were analyzed by light microscopy to assess muscle fiber phenotype, electron microscopy to identify satellite cells, and real-time polymerase chain reaction to analyze the expression of the following markers: insulin-like growth factor 1, mechano growth factor, and embryonic and perinatal myosin heavy chains (MHC) as markers of microstructural damage; Pax-7 and m-cadherin as markers of the presence and activation of satellite cells, respectively; and MHC-I, IIa, and IIx as determinants of muscle fiber phenotype. RESULTS: The patients had larger fibers than healthy subjects (54 [6] vs 42 [4] microm(2); P< .01) with a similar or slightly increased proportion of satellite cells, as measured by ultrastructural analysis (4.3% [1%] vs 3.7% [3.5%]; P>.05) or expression of Pax-7 (5.5 [4.1] vs 1.6 [0.8] arbitrary units [AU]; P< .05). In addition, there was greater activation of satellite cells in the patients, as indicated by increased expression of m-cadherin (3.8 [2.1] vs 1.0 [1.2] AU; P=.05). This was associated with increased expression of markers of microstructural damage: insulin-like growth factor 1, 0.35 (0.34) vs 0.09 (0.08) AU (P< .05); mechano growth factor, 0.45 (0.55) vs 0.13 (0.17) AU (P=.05). CONCLUSIONS: The intercostal muscles of patients with severe COPD show indirect signs of microstructural damage accompanied by satellite cell activation. This suggests the presence of ongoing cycles of lesion and repair that could partially explain the maintenance of the structural properties of the muscle. PMID- 18448015 TI - [Knowledge of and attitudes and adherence to the Spanish Guidelines for Asthma Management (GEMA) among Spanish health care professionals: the GEMA test Project]. AB - OBJECTIVE: Health care professionals' adherence to asthma guidelines is believed to be low. The aim of the present study was to determine the knowledge, attitudes, and adherence of Spanish health care professionals with respect to the Spanish Guidelines for Asthma Management (GEMA). MATERIAL AND METHODS: A multiple choice test with 15 questions was constructed. Items assessed knowledge of and opinions and adherence to asthma guidelines in general and the GEMA in particular. Test completion was voluntary, individual, and anonymous. RESULTS: A total of 1,066 physicians and nurses took the test. The sample consisted of 241 (22.6%) respiratory medicine specialists and 244 (22.9%) nurses from the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), 221 (20.7%) pediatric pulmonologists from the Spanish Society of Pediatric Pulmonology (SENP), 220 (20.6%) general practitioners from the Spanish Society of Family and Community Medicine (semFYC), 181 (17%) general practitioners from the Spanish Society of Rural and General Medicine (SEMERGEN), and 38 (3.6%) others. Asthma guidelines were considered useful or very useful by 805 (76%), and 771 (72%) stated they were familiar with the GEMA. However, 388 (36%) admitted that they followed guidelines seldom or never. The level of adherence to the GEMA was poor for 243 (30.3%) respondents. The multivariate analysis revealed that low adherence was associated with the following characteristics: coming from the geographic center or south of Spain; being a primary care physician, unfamiliar with guidelines, or unconvinced of their utility; and not being a user of spirometry. CONCLUSIONS: Even though the majority of Spanish health care professionals surveyed seem to know of the GEMA, their adherence to those guidelines is very low. Educational programs that seek to improve knowledge of asthma guidelines should consider the profile of professionals with low adherence to the GEMA so as to include educational strategies that target them specifically. PMID- 18448016 TI - [Short-stay respiratory unit: a new option for inpatient care]. AB - OBJECTIVE: The current pressure on conventional inpatient care units represents a very serious problem for respiratory medicine departments. The aim of this study was to analyze the impact of a new instrument --a short-stay respiratory unit-- on the quality of care delivered by the respiratory medicine department of a tertiary care hospital. MATERIAL AND METHODS: The short-stay respiratory unit consisted of 4 conventional hospital beds managed by a pulmonologist. The beds were only used to treat patients diagnosed with exacerbation of chronic obstructive pulmonary disease or bronchial asthma, community-acquired pneumonia, or suspected lung cancer, and stays were intended to only last for up less than to 4 days. Analyzing a range of healthcare quality variables, we compared the quality of care delivered during the first 6 months the unit was in operation (October 2005 to March 2006) to that delivered in the same period 12 months earlier. RESULTS: The study included 147 patients admitted to the short-stay unit. The mean (SD) age of the patients was 64 (17) years and 79% were men. The mean length of stay was 3.3 (1.6) days--only 1.4% of patients stayed for longer than 4 days--and the readmission rate was 2.7%. There were no deaths. The existence of the short-stay respiratory unit led to a 30% decrease in the overall mean length of stay in the respiratory medicine department (11.8 [4.6] vs 8.3 [2.6] days; P< .001), and the readmission rate fell from 21% to 15% (P< .05). While there were no differences in mortality between the 2 periods, the complexity of diseases treated by the respiratory medicine department showed an increase of 9.2% (P< .001). CONCLUSIONS: A short-stay respiratory unit can improve the efficiency of care delivered by a respiratory medicine department by reducing both the mean duration of hospitalization and the readmission rate, without a reduction in the complexity of diseases treated or a need for additional resources. PMID- 18448017 TI - [Indicators of severity in chest trauma]. AB - OBJECTIVE: We undertook a review of patients with chest trauma attended between January 1992 and June 2005 in order to establish severity criteria in these cases. PATIENTS AND METHODS: During the study period, 1,772 cases (1,346 [76%] males) were treated, with ages ranging from 7 to 98 years (mean, 46.4 years). The Revised Trauma Score (RTS) was calculated and the following variables were also studied as potential indicators of severity: age, extent of the injury, number of rib fractures, presence of lung contusion, hemothorax, cardiorespiratory repercussions, and need for mechanical ventilation. RESULTS: At the time of admission, 84.4% of patients presented only symptoms related to the injury, with no general repercussions, and 66.7% had an RTS of 12. The number of rib fractures was a reliable indicator of severity, as was the presence of multiple injuries, lung contusion, need for mechanical ventilation, and cardiorespiratory repercussions. Neither age nor presence of hemothorax was found to be an indicator of severity. Pleural drainage was performed in 756 cases and was effective in 670 (88.6%). CONCLUSIONS: There are a number of indicators of severity in chest trauma, related more closely to the type and repercussions of the trauma than to the age of the patient. There is a high incidence of fluid or gas accumulation in the pleural space, though this can be easily managed by pleural drainage, which constitutes the main therapeutic procedure in chest trauma. PMID- 18448018 TI - [The evolution of the human species: a long journey for the respiratory system]. AB - Evolution has involved important changes in hominids, particularly in relation to the process of encephalization and the transition to bipedalism. Some of these changes involved structures related to the respiratory system and altered its functional behavior. Changes affecting the relationship between the skull and the spinal column, together with an improved laryngeal structure (allowing vocalization), resulted in a soft and elongated oropharynx, with part of the tongue integrated into its anterior wall, and thus in an increased tendency towards upper airway collapse during sleep. Vertebral bodies moved inwards into the thorax, which became slightly shorter and went from a bell-shaped appearance to that of a flatter barrel-shaped one. This resulted in respiratory muscle mechanics that were more efficient for upright posture. The pulmonary ventilation and perfusion gradients moved from a dorsoventral to a craniocaudal axis, while the structural organization of the respiratory muscles underwent only minor changes. PMID- 18448019 TI - [Diagnosis and management of chronic obstructive pulmonary disease: joint guidelines of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) and the Latin American Thoracic Society (ALAT)]. PMID- 18448020 TI - [A study of 73 cases of bronchial tuberculosis]. AB - We reviewed 73 cases of bronchial tuberculosis (59 adults and 14 children) diagnosed between 1973 and 2000 using histologic and bacteriologic criteria. The most frequent symptom was cough. Radiographic studies showed an alveolar pattern in 35 cases and obstructive pneumonitis or atelectasis in 28 cases. Endoscopy results showed that granuloma was more common in children under 16 years of age (64%) than in adults (22%). Granulomatous or ulcerative bronchitis was significantly more frequent in adults (66%; P< .005). Bronchial tuberculosis is not an exceptional occurrence. Clinical and radiographic signs are nonspecific. Endoscopy images of granuloma and granulomatous or ulcerative bronchitis may be similar to those of bronchial neoplasia. Diagnosis therefore requires fiberoptic bronchoscopy combined with histology and microbiology studies. PMID- 18448021 TI - [Pleural empyema secondary to pyonephrosis]. PMID- 18448022 TI - [Urinothorax: always a transdative pleural effusion?]. PMID- 18448023 TI - [Evidence-based medicine and laparoscopic surgery]. PMID- 18448024 TI - [Current treatment of hepatic trauma]. AB - The therapeutic and diagnostic approach of liver trauma injuries (by extension, of abdominal trauma) has evolved remarkably in the last decades. The current non surgical treatment in the vast majority of liver injuries is supported by the accumulated experience and optimal results in the current series. It is considered that the non-surgical treatment of liver injuries has a current rate of success of 83-100%, with an associated morbidity of 5-42%. The haemodynamic stability of the patient will determine the applicability of the non-surgical treatment. Arteriography with angioembolisation constitutes a key technical tool in the context of liver trauma. Patients with haemodynamic instability will need an urgent operation and can benefit from abdominal packing techniques, damage control and post-operative arteriography. The present review attempts to contribute to the current, global and practical management in the care of liver trauma. PMID- 18448025 TI - [Proposal for a new consensus classification for faecal incontinence]. AB - Due to the complexities of the mechanisms involved in incontinence, there are many potential causes for this disorder. The causes of incontinence and the grouping of patients according to aetiological factors are described in the literature in various forms, without there being a consensus as such. Therefore, the objective of this review is to propose a new classification of faecal incontinence to the scientific community, which will enable criteria to be unified, which should lead to an improvement in the diagnosis and treatment of patients with faecal incontinence. It is an aetiopathogenic classification that can be obtained from the clinical history of the patient along with an endoanal ultrasound. PMID- 18448026 TI - [Second time esophageal reconstruction surgery: coloplasty and gastroplasty]. AB - OBJECTIVE: To analyze the morbidity and mortality of second time esophageal reconstruction in an Esophagogastric Unit. PATIENTS AND METHOD: Second time esophageal reconstruction surgery with coloplasty and gastroplasty was performed on 20 patients, from January 2001 to October 2006. The morbidity and mortality of each technique has been analyzed retrospectively. RESULTS: The mean age of the 16 males and 4 women operated on was 54.3 +/- 17.5 years. The diagnoses at the first surgery were: 7 caustic ingestions, 7 Boerhaave syndrome, 3 iatrogenic perforations, 1 tracheal-esophageal fistula, 1 esophageal-jejunal dehiscence and 1 necrosis of the gastroplasty after transhiatal oesophagectomy. There were 14 (70%) right coloplasties, 4 (20%) left coloplasties and 2 (10%) gastroplasties with gastric conditioning. In 11 of the 20 patients gastroplasty was ruled out due to gastrectomy (8 cases) or previous gastric surgery (3 cases). It was noted on analyzing the morbidity: pleural effusion (65%), respiratory failure (45%), atelectasis (35%) and cervical anastomosis dehiscence (35%). Five patients were re-intervened: 3 due to intra-abdominal sepsis and 2 due to hemoperitoneum. Mortality was 10% (2 cases). In subsequent follow up there was 5% (1 case) of stenosis of the anastomosis. CONCLUSIONS: Esophageal reconstruction technique which in specialist units has an acceptable mortality rate (10%) and an insignificant morbidity. Coloplasty was the technique most used on these patients. PMID- 18448027 TI - [Right iliac fossa pain and Alvarado Score]. AB - INTRODUCTION: Unsuspected or undiagnosed acute appendicitis could progress to a perforation or could lead to the removal of a normal appendix. OBJECTIVES: using a clinical score system as a diagnostic tool for this pathology and can decrease negative appendectomies. MATERIAL AND METHOD: Prospective and protocolized study. SETTING: National Clinicas Hospital. Cordoba. Argentina. Between May 2007 and June 2007 224 patients were studied of which 117 were male and 107 were female with a mean age of 26.65 years. An Alvarado score was performed on all patients on admission. Based on the clinical evidence and a second assessment with the Alvarado Score, surgical exploration was decided in 207 patients. The remaining 17 were excluded due to other pathology. The diagnosis of acute appendicitis was confirmed by surgical finding and histopathological studies. RESULTS: In the surgical findings it was shown that 189 (91%) patients had acute appendicitis. There was no surgical mortality. As regards morbidity, 3.86% had medical and 27% had surgical complications. The histopathology reports showed a normal caecal appendix in 18. Whereas the incidence of negative appendicectomy was about 8.69%. CONCLUSIONS: The use of the Alvarado Score together with the surgical and histopathology findings confirmed it was sensitive from 6 points for the diagnosis of acute appendicitis. PMID- 18448028 TI - [Doppler-guided transanal haemorrhoidal dearterialisation. An alternative treatment for haemorrhoids]. AB - INTRODUCTION: The frequency of haemorrhoid disease and the deterioration in the quality of life in the immediate post-operative period has led to the appearance of new techniques in an attempt to obtain improve patient satisfaction. PATIENTS AND METHOD: A prospective study was carried out in which 50 consecutive patients with a diagnosis of Goligher grade III haemorrhoids were intervened. To perform the haemorrhoid dearterialisation, a device called THD R was used (designed by TKC SRL and distributed by Palex Medical). The technique consisted of, a reduction in arterial flow using ligation of the terminal branches above the anorectal ring, starting in the anterior position, it was carried out in a clockwise direction: 1, 3, 5, 7, 9, 11. Follow up was carried out at one week, 1 month, 3 months, 6 months and 1 year. RESULTS: We intervened 50 consecutive patients with a diagnosis of grade III haemorrhoids. The mean age was 45 years (range, 25-78). The surgical indication was, pain-discomfort, 40 (80%); bleeding, 35 (70%), prolapse 6 (12%). The procedure was always performed under local/regional anaesthesia. The mean duration of the procedure was 25 minutes (range, 20-35). Analgesia was required by 90% of the patients during the first 24 hours, decreasing to 15% for those who continued to require it until the third day and only 2 (4%) patients continued for one week. Pain was resolved 48 hours after surgery, in all patients who consulted for this reason, except for one patient (2.5%) who had a recurrence in the pain as well as in his prolapse. This meant that patients could re-start their daily living within 48-72 hours. CONCLUSIONS: Pending for randomised studies, we can say that in our experience, Doppler guided transanal haemorrhoidal dearterialisation is a technique that should be offered to the patient with haemor-rhoidal disease. PMID- 18448029 TI - [Results of videothorascopic sympathectomy in the treatment of facial redness and hyperhidrosis in 41 patients]. AB - OBJECTIVE: To evaluate the results and complications of thoracic sympathectomy in the treatment of patients with uncontrollable blushing and facial hyperhidrosis. PATIENTS AND METHOD: Between May 2000 and August 2006 we performed 82 VATS sympathectomies on 41 patients with the diagnosis of uncontrollable blushing and/or facial hyperhidrosis. Two of them had been previously operated on without good results. The technique employed was bilateral VATS sympathectomy varying the levels depending on the presence of palmar and/or axillary hyperhidrosis and the anatomical limitations. The results were evaluated one week after the procedure and 3-6 months later in 41 patients; and also one year later in 34 patients. RESULTS: Twenty-two men and 19 women, with mean age of 33.7 years (range, 18-56). In 17 patients (41.5%) main symptom was facial hyperhidrosis and in 24 (58.5%) uncontrollable blushing. All the patients were discharged before 24 hours after surgery, 14 of them in an ambulatory surgery program. There was improvement of the symptoms in all the cases of facial hyperhidrosis 17/17 (100%). In the blushing group the procedure was effective in 20/24 cases (83.3%). Results were good with the second surgery. Compensatory sweating was observed in 16/41 patients (39%), and was severe in 6 (14.6%). CONCLUSIONS: Sympathectomy is a safe and effective procedure in the management of facial hyperhidrosis and uncontrollable blushing. Compensatory sweating remains as the main secondary effect. PMID- 18448030 TI - [Factors associated with patient satisfaction and care of over 65 year olds in emergency departments]. AB - INTRODUCTION: The population over 65 years old represents 40-50% of the all visits made to an emergency department (ED). Some situations of stress and dehumanization can occur due to user overflow. Our target is to identify factors influencing overall satisfaction of patients older than 65 attended in the ED, in order to identify points of conflict and improve the deficiencies in our care. MATERIAL AND METHOD: We performed a prospective study from September 2005-June 2006 with those patients who accepted to take part by filling an anonymous and confidential questionnaire. We evaluated 19 epidemiological variables, medical and related to the quality of information provided. A single bivariate analysis was performed (chi2, t-Student or logistic regression). RESULTS: The questionnaire was filled out by 1389 (31.3%) out of 4437 patients that could potentially be included in the study. Mean patient age was 77 +/- 6 years and more than half of them were women (64%). Of the responses, 82% rated their ED care as excellent or good. Variables significantly related to satisfaction were perception of a not-too-long waiting time (p = 0.001), having been attended to previously in the hospital (p = 0.050), having explained the tests that patients had to undergo (p = 0.002) and having been given clear information from staff (p = 0.001). CONCLUSIONS: In order to improve the quality of care given in the ED, the staff should give more personalized and clear information and reduce the patient perception that waiting time is too long. PMID- 18448031 TI - [Intestinal obstruction due to multiple foreign bodies]. PMID- 18448032 TI - [Blue finger syndrome. Evaluation and treatment]. PMID- 18448033 TI - [Megalovirus-induced ileal perforation in a renal transplant patient]. PMID- 18448034 TI - [Squamous carcinoma in a branchial cyst]. PMID- 18448035 TI - [A combination of enteritis cystica profunda, Crohn's ileocolitis and endometriosis as a cause of intestinal obstruction]. PMID- 18448036 TI - [Celiac trunk thrombosis in a patient with situs inversus totalis]. PMID- 18448037 TI - [Pure neuroendocrine breast tumour]. PMID- 18448038 TI - [Severe acute pancreatitis presenting as an adenoma-induced hyperparathyroidism]. PMID- 18448040 TI - [Surgery and Jehovah's witnesses]. PMID- 18448042 TI - [The human papilloma virus vaccine: reflections on the dissemination process, scientific evidence and doubts]. PMID- 18448043 TI - [Evaluation of the situation of the elderly who live alone in a health zone]. AB - OBJECTIVE: To determine the needs of elderly individuals living alone and with some degree of dependency for activities of daily live. METHOD: We performed a cross-sectional descriptive study in an urban health center (San Andres-Torcal in Malaga, Spain). Persons aged more than 65 years old who lived alone and had some degree of dependency were studied. RESULTS: The sample was composed of 64 elderly individuals, 58 women and 6 men. The mean age was 83.3 years (SD 4.13). Sixteen people (25%) were independent for daily living when aided by others, while 48 (75%) had one or more needs that were not covered. The most frequent nursing diagnoses were: impaired physical mobility in 58, risk of falls in 54, diversional activity deficit in 48, impaired urinary elimination in 38, and social isolation or deterioration in social interaction in 36. Fifty-six individuals had family. Half had no contact with neighbors, 12 (18.8%), did not receive visits, and 26 (40.6%) had nobody to whom they could tell their problems. Architectonic barriers to the house were identified in 48 individuals and access barriers to the home were found in 29. The total sample received a pension of between 301 and 600 euros. CONCLUSIONS: The persons evaluated showed numerous areas of dependency and there was a high proportion whose basic needs were not suitably covered. Because of the multiple and distinct problems identified, we believe that active screening should be performed in this vulnerable population. In addition, special attention should be paid to these individuals and the required help should be offered so that they have information and access to the available health and social resources. PMID- 18448044 TI - [Non-pharmacological interventions for the treatment of erectile dysfunction in adult men: systematic review]. AB - OBJECTIVE: To review current evidence on the non-pharmacological (non-invasive) treatment of erectile dysfunction (ED). METHOD: We performed a systematic review of research articles that included adult men diagnosed with ED who had undergone some type of non-pharmacological and non-surgical intervention for this disorder. Free-access, complete texts with an available summary published between 2000 and 2006 were sought. Studies not published in English were excluded. RESULTS: A total for 124 articles were found, and after critical analysis only 8 matched the inclusion criteria (of the 8 articles, 2 were classified as showing quality criterion 1-B and none met the criterion for 1-A). Four types of non pharmacological, non-surgical therapy were found, which could reverse or improve ED in patients with organic, psychological or mixed impairment and could be applied by nurses. Among these therapies were lifestyle changes (losing weight, pelvic musculature strengthening, psychotherapy and/or psychoeducation and the use of Internet and/or other multimedia devices. CONCLUSIONS: Alternative therapies are available for men with ED. These therapies help to improve or reverse ED and guarantee satisfactory and lasting Results. Nevertheless, we stress that our aim is not to compete with invasive and non-invasive therapies but rather to provide a greater number of treatment alternatives. The low quality of studies could be attributed to the lack of economic resources and the fact that ED is still an emerging subject in current medicine. PMID- 18448045 TI - [Self-esteem level and correlation to risk behaviour of students at the University of Almeria (Spain)]. AB - OBJECTIVES: To evaluate self-esteem levels in college students at the University of Almeria (Spain) and their possible correlation with risk behaviors, specifically, drug use and sexual behavior. METHOD: We performed an observational, descriptive, cross-sectional, prolective study. A self-completed questionnaire was used to gather data. Students attending specific university services of the University of Almeria were selected by non-probabilistic sampling. Self-esteem was measured using Cooersmith's scale. RESULTS: In the 123 students studied, self-esteem was very low in 7.9%, medium-low in 29.3%, medium in 12.2 %, medium-high in 46.3% and very high in 4.9 %. No significant differences were found between the sexes. No significant correlation was found between sexual behavior and level of self-esteem. Consumption of alcohol, cannabis, cocaine, designer drugs, and amphetamines was higher in groups with higher self-esteem. CONCLUSIONS: Self-esteem is important in every sphere of life and can be considered a basic human need. Self-esteem increases the level of personal security and has been described as a protective factor against risk behaviors. However, our data indicate increased drug consumption among young people with higher self-esteem. Given the importance of the topic and the novelty of our results, in future studies we intend to broaden the sample and perform probabilistic stratified sampling in order to extrapolate the results to the entire population of the University of Almeria. PMID- 18448046 TI - [Usefulness and difficulties for the elaboration of the nursing discharge report, according to Hospital de Fuenlabrada (Spain) nursing group]. AB - OBJECTIVE: To evaluate the utility and difficulty of writing the nursing discharge report perceived by nurses working in the hospitalization unit of the Fuenlabrada Hospital in Spain. METHOD: We performed a cross-sectional, descriptive study in all nurses working in hospitalization units in the Fuenlabrada Hospital (Madrid) in the last trimester of 2006. A questionnaire was used to collect sociodemographic variables, variables related to perceived utility of the report in general and variables measuring the difficulty of completing the report. The questionnaires were delivered to the hospitalization units and collected personally. For the statistical analysis, the chi-square test and Student's t-test and/or analysis of variance were used. The SPSS/PC statistical package, version 12.0, was used. RESULTS: Seventy-four completed questionnaires were obtained (57.4 % of the population analyzed). Of the nurses surveyed, 61 (82.4 %) considered the report to be useful in assuring continuity of care and 57 nurses (77 %) thought it useful in providing information to the patients. In total, 60 nurses (82.1 %) considered the report's structure to be not very suitable or unsuitable. CONCLUSIONS: Nurses' satisfaction with the report is high. The report is seen as effective in assuring continuity of care and as useful to patients. However, the report's structure should be improved. PMID- 18448047 TI - [Review of the attributes of patient-based health outcomes instruments]. AB - Study of the quality and use of patient-based outcomes instruments has been and still is an area of growing interest in many health disciplines, including nursing. In the last 30 years, the number of measures has greatly increased. However, there is enormous disparity in their contents, hampering selection of one or other of these instruments for use in clinical medicine or research. The aim of this article was to describe the quality attributes that patient-based health instruments should meet before being used. For that purpose, we provide a detailed description of the attributes on which there is both national and international consensus. These instruments are grouped in 3 main axes: conceptual adequacy, applicability, and psychometric properties. PMID- 18448048 TI - [Nursing cares in constipation of the oncology patient]. AB - The importance of constipation lies in its frequency, even among the healthy. The incidence of constipation in oncological patients is 70-80% in the final stage, 40-50% in advanced disease, and 90% in patients with aggressive cancer. This disorder is not only uncomfortable for the patient but also causes complications. Prolonged constipation can cause abdominal pain and even increase the pain caused by the tumor and stronger pain relief can be required when the constipation is unresolved. Among the complications that can occur are intestinal obstruction, diarrhea by spillage, urinary dysfunction, anorexia, nausea and vomiting, restlessness, malaise, and confusion. When analyzing this problem, we aim to unify criteria and nursing interventions, emphasize the importance of prevention, and solve the problem. Health education of both the patient and the main caregiver aid control of this disorder after discharge. The patient will be able to identify the appearance of constipation, its causes and symptoms and will be familiar with the treatment and when and where to go to review it. PMID- 18448049 TI - [Abdominal aortic aneurysm treated by endovascular surgery: a case report]. AB - An aneurysm is an abnormal dilation or irreversible convex of a portion of an artery. The most common site of aneurysms is the abdominal aorta and their appearance is often due to degeneration of the arterial wall, associated with atherosclerosis and favored by risk factors such as smoking and hypertension, among others. Left untreated, aneurysm of the abdominal aorta usually leads to rupture. Treatment is surgical, consisting of the introduction of a prosthesis, composed basically of a stent and an introducer, into the aorta. We report the case of a person diagnosed with abdominal aortic aneurysm in a routine examination who was admitted for ambulatory surgical treatment. We designed a nursing care plan, following Virginia Henderson's conceptual model. The care plan was divided into 2 parts, a first preoperative phase and a second postimplantation or monitoring phase. The care plan contained the principal nursing diagnoses, based on the taxonomies of the North American Nursing Diagnosis Association (NANDA), nursing interventions classification (NIC) and nursing outcomes classifications (NOC), and collaboration problems/potential complications. The patient was discharged to home after contact was made with his reference nurse in the primary health center, since during the hospital phase, some NOC indicators remained unresolved. PMID- 18448050 TI - [Pelvic floor muscle training program improves urinary incontinence in women]. PMID- 18448051 TI - [Place of death: preferences of oncological patients and their carers]. PMID- 18448052 TI - [Team work: a necessary element in quality certification in the laboratory]. PMID- 18448053 TI - [Preventive vaccination against the human papilloma virus]. PMID- 18448054 TI - [Epidemiology of inflammatory bowel disease in the elderly]. AB - INTRODUCTION: Inflammatory bowel disease has classically been considered a disorder with onset in young people. However, between 5 and 15% of patients are diagnosed when aged more than 60 years old. Epidemiological studies comparing these two age groups are controversial and consequently new studies are required to define the characteristics in each group. OBJECTIVES: To determine the epidemiological characteristics specific to Crohn's disease and ulcerative colitis in the elderly and to compare these characteristics with the form of presentation in young people in Spain. METHOD: We performed a case-control, descriptive study. Patients with inflammatory bowel disease registered in the database of the Crohn-Colitis Unit were included. The patients were stratified in two groups according to age at symptom onset: the first group consisted of patients with onset at age 60 years or above and the second group was a control group consisting of patients aged less than 60 years old. The control group was composed of two patients for each case matched by sex and diagnosis. RESULTS: Thirty-three cases aged more than 60 years old (4.1%) were included, eight with Crohn's disease and 25 with ulcerative colitis. The control group included 66 patients (16 with Crohn's disease and 50 with ulcerative colitis). Statistically significant differences were observed between the two groups both in the form of presentation (tenesmus and occlusive symptoms were more frequent and abdominal pain was less frequent in the group aged more than 60 years than in the control group) and in treatment response (corticosteroid dependency and refractoriness and requirement for immunosuppressive treatment were more frequent in the elderly). CONCLUSION: The results of the present study suggest that there are epidemiological differences in inflammatory bowel disease among the elderly, notably a lower frequency of abdominal pain and a lower rate of refractoriness to steroid treatment. PMID- 18448055 TI - [Results of pegylated interferon and ribavirin for the treatment of chronic hepatitis C in clinical practice: a 5-year experience]. AB - INTRODUCTION: Numerous clinical trials have demonstrated the efficacy of treatment with pegylated interferon and ribavirin but little is known about the results obtained in clinical practice. OBJECTIVE: To evaluate treatment response and factors influencing the treatment of chronic hepatitis C in clinical practice. MATERIAL AND METHODS: Between August 2001 and December 2005, we treated 219 patients with pegylated interferon (alpha 2a -fixed dose, or alpha 2b, according to weight) and ribavirin. Patients with genotype 1 or 4 received treatment with pegylated interferon alpha 2a (180 microg/week) and ribavirin (1000 mg/day if body weight was <75 kg or 1200 mg/day if body weight was >75 kg) or interferon alpha 2b (1.5 microg/kg/week) and ribavirin (10.6 mg/kg/day) for 48 weeks. Patients with genotype 2 or 3 were treated for 24 weeks with the same regimen of pegylated interferon alpha-2a or alpha-2b, but with 800 mg of ribavirin divided in two daily doses. Sustained viral response was defined as absence of HCV-RNA 6 months after the end of treatment. RESULTS: A total of 219 patients were included (69% men; mean age 44+/-10). As epidemiological antecedents, 22.4% of the treated patients had previously consumed drugs parenterally and 22.4% had received blood transfusions before 1992. Forty-seven percent of the patients with liver biopsy had fibrosis bridges or established liver cirrhosis. The genotype was distributed as follows: 69.8% genotype 1, 4.1% genotype 2, 17.8% genotype 3, and 8.2% genotype 4. Of the 219 patients, 76 (35%) were treated with pegylated interferon alpha 2a and 143 (65%) with interferon alpha 2b. Analysis of response by genotype revealed that sustained viral response was obtained in 46% genotype 1, 88.9% genotype 2, 78.9% genotype 3, and 33.3% genotype 4. Univariate analysis showed that the only variable influencing sustained viral response was genotype. CONCLUSION: Treatment with pegylated interferon and ribavirin in clinical practice shows a similar pattern of sustained viral response to that obtained in clinical research. The main variable correlated with sustained viral response continues to be viral genotype. PMID- 18448056 TI - [Effectiveness of maintenance azathioprine therapy without oral cyclosporine after severe attacks of ulcerative colitis refractory to endovenous steroids]. AB - INTRODUCTION: Intravenous (i.v.) cyclosporine (CsA) has proved effective in controlling acute attacks of ulcerative colitis unresponsive to IV steroids. After the initial response to i.v. CsA, two alternatives for maintaining remission have been proposed: either double or triple association with immunosuppressors. The aim of this study was to evaluate the effectiveness of i.v. CsA, its adverse effects, and the subsequent long-term effectiveness of azathioprine/6-mercaptopurine without oral CsA. MATERIAL AND METHODS: Intravenous CsA was administered for 10 days, at a dose of 4 mg/kg per day, to 20 patients diagnosed with a severe attack of ulcerative colitis who did not respond to IV steroid treatment. Patients who responded to CsA and could be discharged were administered azathioprine or 6-mercaptopurine associated with a decreasing dose of oral steroids, without oral CsA. RESULTS: Sixty per cent (12/20) of the patients showed clinical-biological improvement after CsA administration, thus avoiding colectomy, and were discharged from hospital. Nine of the 12 responders (three withdrew from the study) were followed-up long term. Of these nine patients, four (44.4%) underwent colectomy, all before the sixth month of discharge. All adverse effects were mild, except for one death. CONCLUSIONS: Intravenous CsA is effective in inducing remission of ulcerative colitis in severe attacks resistant to i.v. steroids. When treatment with azathioprine is administered without oral CsA, patients requiring colectomy need this procedure within the first 6 months of discharge. PMID- 18448057 TI - [Inverted colonic diverticula: an uncommon endoscopic finding]. AB - BACKGROUND: The appearance of inverted colonic diverticula (ICD) is similar to that of elevated polypoid lesions. The aim of this study was to describe the endoscopic characteristics of ICD with a view to avoiding misdiagnosis, and to report the frequency of these lesions. MATERIAL AND METHOD: Using an endoscopic database, we retrospectively analyzed all patients who underwent colonoscopy at our institution between July 2001 and July 2004. Patients diagnosed with ICD were identified and both patient and ICD characteristics were recorded, including location, endoscopic characteristics, and the presence of synchronous colon polyps. RESULTS: Among the 4508 colonoscopies performed in the selected period, 33 patients (0.7%) were diagnosed with ICD. The mean age was 62.3 years, with a male-to-female ratio of 1:1.2. Most ICD (89%) were in an area of multiple colonic diverticula and 75% were located in the sigmoid colon. One patient had active bleeding directly from the inverted diverticulum and was treated with injection therapy. The endoscopic characteristics of ICDs were described. There were no complications in this series. CONCLUSIONS: ICD is a rare endoscopic finding that can be complicated by local bleeding. Misdiagnosis can be dangerous and biopsy or endoscopic resection could lead to serious complications. The endoscopic criteria described should be considered to avoid the complications associated with biopsy or resection. PMID- 18448058 TI - [Infectious mononucleosis in patients with inflammatory bowel disease under treatment with azathioprine]. AB - The use of immunomodulators for the treatment of inflammatory bowel disease is increasing. One of the most common adverse effects associated with this kind of drugs are infectious complications. In recent years, special attention has been paid to certain latent infections which, in patients under immunomodulatory therapy, can be reactivated and prove lethal. Consequently, preventive actions have been adopted, such as screening for hepatitis B virus and tuberculosis infection before starting these treatments. Primary infection with the Epstein Barr herpesvirus is usually asymptomatic. However, this virus can have an aggressive course and even lead to the development of lymphoma. We report two cases of atypical infectious mononucleosis in patients with inflammatory bowel disease under azathioprine therapy and review the available evidence on the most appropriate therapeutic approach in this subset of patients. PMID- 18448059 TI - [Influence of donor age and recipient gender on survival in transplantation due to hepatocarcinoma]. AB - Hepatocarcinoma (HCC) is one of the most frequent indications for liver transplantation. Survival in patients undergoing transplantation due to HCC is similar to that in patients undergoing this procedure for other indications. However, the current shortage of donors has led to longer waiting lists with a consequent risk of tumor progression. The use of older donors in these patients could increase the donor pool and shorten the time spent on the waiting list. We analyzed the influence of donor age on survival in 78 patients with HCC who underwent transplantation in the Santiago de Compostela Hospital between 1994 and 2003. PMID- 18448060 TI - [Acute generalized exanthematous pustulosis induced by omeprazole]. AB - Acute generalized exanthematous pustulosis (AGEP) comprises a group of eruptions characterized by several small sterile pustules over an erythematous-edematous skin. These eruptions are usually drug induced and show some characteristics that suggest an immunologic background. Treatment is based on withdrawal of the drug causing the eruption. Prognosis is generally good and the skin lesions usually resolve in a few days with characteristic postpustular pin-point desquamation. We report three cases of AGEP induced by omeprazole, a drug with a good safety profile. Some adverse cutaneous reactions have been described as secondary effects. However, to our knowledge, no cases of omeprazole-induced AGEP have previously been reported. AGEP related to other proton pump inhibitors is exceptional. PMID- 18448061 TI - [Adipose tissue-derived stem cells: hepatic plasticity]. AB - Currently, the only effective treatment for end-stage liver disease is liver transplantation. The number of patients on the waiting list increases considerably each year, giving rise to a wide imbalance between supply and demand for healthy livers. Knowledge of stem cells and their possible use have awakened great interest in the field of hepatology, these cells being one of the most promising short-term alternatives. Hepatic stem cell therapy consists of the implantation of healthy cells capable of performing the functions that damaged cells are unable to carry out. Recent observations indicate that several stem cells can differentiate into distinct cell lineages. Hepatic differentiation of adult stem cells from several origins has yielded highly promising results. Adipose tissue in adults contains a reservoir of stem cells that can be induced and differentiated into different types of cells, showing a high degree of plasticity. Because of its abundance and easy access, adipose tissue is a promising source of adult stem cells for hepatic stem cell therapy. The present article reviews the progress made in the differentiation of adult stem cells from adipose tissue into cells with hepatic phenotype. We also discuss the potential application of this technique as a therapy for temporary metabolic support in patients with end-stage liver failure awaiting whole organ transplantation, as a method to support liver function and facilitate regeneration of the native liver in cases of fulminant hepatic failure, and as a treatment in patients with genetic metabolic defects in vital liver functions. PMID- 18448062 TI - [Refractory celiac disease]. AB - The main cause of lack of response to a gluten-free diet is continued, usually inadvertent, gluten intake. Diagnosis of refractory celiac disease is established on the basis of exclusion of other disorders, persistence of malabsorption and villous atrophy. Refractory celiac disease affects a heterogeneous group of patients, usually adults and, fortunately, is infrequent (<5% of the population). Detection of alterations in the intraepithelial lymphocyte population is essential for diagnosis. Some alterations in these lymphocytes, such as the absence of T cell surface receptor expression (CD3 and CD), indicate an aggressive form of the disease with the potential for malignant transformation (type II refractory celiac disease). Treatment is based on adequate nutritional support and on the use of corticosteroids and/or immunosuppressive agents (mainly azathioprine and infliximab). Because of the high risk of progression to intestinal T cell lymphoma, patients diagnosed with type 2 refractory disease require different -generally more aggressive- therapeutic strategies. At present, no treatment has been demonstrated to be effective in the long term, but two options that should be considered in type II disease are immunotherapy with anti CD52 or similar agents, and autologous bone marrow transplantation. Trials with antibodies that block epithelial secretion of interleukin-15, a key molecule in the pathogenesis of the disease, are promising. PMID- 18448063 TI - [Extremely well-defined gastric adenocarcinoma. A difficult diagnosis]. PMID- 18448064 TI - [Sigmoid perforation secondary to spontaneous migration of a plastic biliary prosthesis]. PMID- 18448065 TI - Color development time of the Lowry protein assay. AB - Color development of the Lowry protein assay was tracked over time for bovine serum albumin (BSA) concentrations ranging from 40 to 600 microg/ml. The time interval between 2 and 4h produced the most stable readings. This time frame also improved linearity of the standard curve. PMID- 18448066 TI - Resurveying the Tris buffer solution: the specific interaction between tris(hydroxymethyl)aminomethane and lysozyme. AB - An unusual phenomenon, the specific interaction between tris(hydroxymethyl)aminomethane (Tris) and lysozyme (LZM), was demonstrated for the first time by rapid screen analysis of interactions using a quartz crystal microbalance (QCM) biosensor. This phenomenon was also observed in a surface plasmon resonance (SPR) system. Further study using high-performance affinity chromatography (HPAC) confirmed this specific interaction between LZM and immobilized Tris with an apparent dissociation constant (K(D)) of 6.7 x 10(-5)M. Molecular docking was carried out to identify possible modes of binding between LZM and Tris linked to a binding arm. The estimated binding free energy was -6.34 kcal mol(-1), corresponding to a K(D) of 2.3 x 10(-5)M, which correlated well with the experimental value. Based on the docking model, the three hydroxyl groups of Tris form intermolecular H bonds with Asp52, Glu35, and Ala107 in LZM. This study reinforces the importance of buffer selection in quantitative biochemical investigations. For a lysozyme ligand binding study, it is better to avoid using Tris when the ligands under study are weak binders. PMID- 18448067 TI - Peony root extract upregulates transthyretin and phosphoglycerate mutase in mouse cobalt focus seizure. AB - Cobalt focus is a seizure focus model in which cerebral neurons exhibit long lasting severe spike discharges, followed by neuronal death. However, the neuronal death is prevented when peony root extract (PR) is administered prior to cobalt application. We tested the hypothesis that PR modulates the expression of neuroprotective proteins in the cerebrum of mouse cobalt focus by proteomic analysis using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry to screen for differentially expressed proteins. Analyses revealed that transthyretin, a carrier protein for thyroid hormones and retinoids, and the brain form of phosphoglycerate mutase, a glycolytic enzyme, were upregulated in the cobalt-treated mouse cerebrum and further increased by PR administration in association with upregulation of neurogranin/RC3, a target of the transcriptional activation by thyroid hormones and retinoids. These findings suggest that PR induced protection of mouse cerebral neurons involves neurotrophic events caused by thyroid hormones and/or retinoids and enhanced glycolysis. PMID- 18448068 TI - Modulation of angiogenic factors by ursolic acid. AB - Investigations were carried out to understand the molecular basis of the effect of ursolic acid on angiogenesis by analysing its effects on the expression of modulators of angiogenesis by HUVECs in culture. Treatment with ursolic acid increased the expression of adhesion molecules such as E-selectin, CD-31 and I CAM, upregulated angiogenic growth factors such as VEGF and FGF-2 and their receptors and caused increase in the ratio of PGE(2) to PGD(2). Reversal of the effect of ursolic acid by inhibition of PI3K-Akt pathway and increase in the level of phospho Akt suggest that the ursolic acid effect is mediated through PI3K-Akt pathway. PMID- 18448069 TI - AIMP1/p43 downregulates TGF-beta signaling via stabilization of smurf2. AB - AIMP1 (also known as p43) is a factor associated with a macromolecular aminoacyl tRNA synthetase (ARS) complex but also plays diverse regulatory roles in various physiological processes. Here, we report that AIMP1 negatively regulates TGF-beta signaling via stabilization of Smurf2. TGF-beta-dependent phosphorylation and nuclear localization of R-Smads, induction of target genes, and growth arrest were increased in AIMP1-deficient or -suppressed cells. In AIMP1-deficient or suppressed cells, the Smurf2 level was decreased. Various binding assays demonstrated the direction interaction of the C-terminal region of AIMP1 directly with the Smad7-binding region of Smurf2. The association of Smurf2 with Smad7 and its ubiquitination were inhibited by AIMP1, thereby protecting its autocatalytic degradation stimulated by Smad7. Thus, this work suggests the novel activity of AIMP1 as a component of negative feedback loop of TGF-beta signaling. PMID- 18448070 TI - A lentiviral vector with novel multiple cloning sites: stable transgene expression in vitro and in vivo. AB - Gene delivery has become an important tool for biological research and gene therapy trials. Lentiviral vector (LV) mediated gene transfer is a preferred approach for stable, sustained transgenic expression. We report here step-wise development of an Indian human immunodeficiency virus type 2 (HIV-2) isolate derived third generation lentiviral vector with a novel, versatile multiple cloning site (MCS) that can also facilitate single step sub-cloning of a PCR amplified transgene cassette by T/A cloning strategy apart from useful cohesive/blunt end cloning. Efficiency of the vector systems was functionally demonstrated by development of a transgenic enhanced green fluorescence protein (GFP) expressing cell line. Further, a GFP down regulated cell line was derived from the said cell line through LV mediated shRNA expression by cloning the GFP shRNA cassette using the T/A cloning strategy. Subsequently long term expression of GFP transgene in nude mouse spleen/liver was also documented till 30 days. This LV platform with the enhanced user friendly cloning options will be an important advancement in gene transfer technology. PMID- 18448071 TI - Fibromodulin gene is expressed in human epidermal keratinocytes in culture and in human epidermis in vivo. AB - Fibromodulin is a small leucine-rich proteoglycan that has a central role in the maintenance of collagen fibrils structure, and in regulation of TGF-beta biological activity. Although, it is mainly found in cartilage and tendon, little is known regarding the expression of the fibromodulin gene in other cell types. By RT-PCR, real time PCR and immunohistochemistry, we describe the expression of the fibromodulin gene and the presence of the protein in human epidermal keratinocytes (HEK), both in culture and in normal human epidermis. Our results show, for the first time, that fibromodulin gene is constantly expressed in HEK during culture time. Immunostaining showed that fibromodulin is located intracytoplasmically in basal and stratified keratinocytes of the growing colonies, confluent cultures, and epidermis in vivo. The expression and intracellular localization of fibromodulin in HEK is a new finding and opens new possible biological roles for the SLRP family. PMID- 18448072 TI - PPARalpha gene expression is up-regulated by LXR and PXR activators in the small intestine. AB - LXR, PXR, and PPARalpha are members of a nuclear receptor family which regulate the expression of genes involved in lipid metabolism. Here, we show the administration of T0901317 stimulates PPARalpha gene expression in the small intestine but not in the liver of both normal and FXR-null mice. The administration of LXR specific ligand GW3965, or PXR specific ligand PCN has the same effect, indicating that ligand-dependent activation of LXR and PXR, but not FXR, is responsible for the increased gene expression of PPARalpha in the mouse small intestine. PMID- 18448073 TI - Receptor tyrosine kinase Tie-1 overexpression in endothelial cells upregulates adhesion molecules. AB - Tie-1 is an endothelial specific cell surface protein whose biology remains poorly understood. Using an overexpression system in vitro, we examined whether Tie-1 activity in endothelial cells in vitro would elicit a proinflammatory response. We found that when overexpressed in endothelial cells in vitro, Tie-1 is tyrosine-phosphorylated. We also showed that Tie-1 upregulates VCAM-1, E selectin, and ICAM-1, partly through a p38-dependent mechanism. Interestingly, upregulation of VCAM-1 and E-selectin by Tie-1 is significantly higher in human aortic endothelial cells than in human umbilical vein endothelial cells. Additionally, attachment of cells of monocytic lineage to endothelial cells is also enhanced by Tie-1 expression. Collectively, our data show that Tie-1 has a proinflammatory property and may play a role in the endothelial inflammatory diseases such as atherosclerosis. PMID- 18448074 TI - Unlike mammalian GRIFIN, the zebrafish homologue (DrGRIFIN) represents a functional carbohydrate-binding galectin. AB - Galectins, a family of beta-galactoside-binding proteins, participate in a variety of biological processes, such as early development, tissue organization, immune regulation, and tumor evasion and metastasis. Although as many as fifteen bona fide galectins have been identified in mammals, but the detailed mechanisms of their biological roles still remain unclear for most. This fragmentary knowledge extends to galectin-like proteins such as the rat lens crystallin protein GRIFIN (Galectin-related inter fiber protein) and the galectin-related protein GRP (previously HSPC159; hematopoietic stem cell precursor) that lack carbohydrate-binding activity. Their inclusion in the galectin family has been debated, as they are considered products of evolutionary co-option. We have identified a homologue of the GRIFIN in zebrafish (Danio rerio) (designated DrGRIFIN), which like the mammalian equivalent is expressed in the lens, particularly in the fiber cells, as revealed by whole mount in situ hybridization and immunostaining of 2 dpf (days post fertilization) embryos. As evidenced by RT PCR, it is weakly expressed in the embryos as early as 21 hpf (hour post fertilization) but strongly at all later stages tested (30 hpf and 3, 4, 6, and 7 dpf). In adult zebrafish tissues, however, DrGRIFIN is also expressed in oocytes, brain, and intestine. Unlike the mammalian homologue, DrGRIFIN contains all amino acids critical for binding to carbohydrate ligands and its activity was confirmed as the recombinant DrGRIFIN could be purified to homogeneity by affinity chromatography on a lactosyl-Sepharose column. Therefore, DrGRIFIN is a bona fide galectin family member that in addition to its carbohydrate-binding properties, may also function as a crystallin. PMID- 18448075 TI - Investigating the nucleic acid interactions and antimicrobial mechanism of buforin II. AB - Buforin II (BF2) is an antimicrobial peptide that is hypothesized to kill bacteria by entering cells and binding nucleic acids. To further investigate this proposed mechanism, we used computer modeling and experimental measurements to consider the interactions between BF2 and DNA. Computational and experimental results imply that the peptide forms specific interactions with DNA. Moreover, we observe a general correlation between DNA affinity and antimicrobial activity for a series of BF2 variants. Thus, our results support the proposed mechanism for BF2 and provide a useful approach for evaluating the nucleic acid interactions of other antimicrobial peptides. PMID- 18448076 TI - Congenital Chagas disease: diagnostic and clinical aspects in an area without vectorial transmission, Bermejo, Bolivia. AB - The authors carried out a 1-year study of a population of pregnant women delivering at Bermejo hospital, South Bolivia. In this area, vectorial transmission of Trypanosoma cruzi is negligible and women infect themselves during displacements in close endemic areas. The prevalence of T. cruzi in 508 pregnant women, diagnosed by several serological tests, was 33.9%. In eight infants, we observed T. cruzi in the umbilical cord (congenital transmission rate of 5.2%). The means of birth weights, lengths and hemoglobin rates were similar in the children from both seronegative and seropositive women, and in children infected or not by T. cruzi. This study could confirm a less severity of the congenital disease of Chagas in the absence of re-infestation of the mother during pregnancy. Serological screening of pregnant women by rapid diagnostic tests and examination of babies born from seropositive mothers by microhematocrit method at birth is a suitable strategy to detect and prevent congenital Chagas disease in non-endemic areas. PMID- 18448079 TI - Is there value for serial ultrasonographic assessment of cervical lengths after a cerclage? AB - OBJECTIVE: The objective of the study was to determine the value of serial ultrasonographic cervical length (CL) measurements after cerclage to predict preterm delivery. STUDY DESIGN: Retrospective ultrasonographic and outcome data from singleton pregnancies with cerclage were reviewed. Using transvaginal ultrasound (TVS), overall CL obtained before cerclage placement, 2 weeks after cerclage, and before delivery were compared between women who delivered preterm (less than 37 weeks) and term. The overall CL including CL above (CLA) and below the cerclage (CLB) were compared using the SAS program. RESULTS: Cerclage was placed at 15.7 +/- 3.6 weeks (mean +/- SD) in 57 women. The overall CL before cerclage, 2 weeks after cerclage, and the last TVS before delivery was not different in preterm and term births. The odds ratio of a measurable CLA for preterm delivery by TVS was 0.87 (0.78 to 0.95, 95% confidence interval). Thirty two patients (56%) had absent CLA at 26.7 +/- 4.4 weeks. Of these, 16 (50%) were delivered for preterm premature rupture of membranes (PPROM) and chorioamnionitis (sensitivity of 100%, specificity of 61%, positive predictive value of 50%, and negative predictive value of 100%). CONCLUSION: Although the overall cervical length by serial TVS after cerclage did not predict preterm birth, absent CLA is associated with preterm delivery, chorioamnionitis, and PPROM. PMID- 18448078 TI - Sequential first- and second-trimester TSH, free thyroxine, and thyroid antibody measurements in women with known hypothyroidism: a FaSTER trial study. AB - OBJECTIVE: The purpose of this study was to examine how closely hypothyroidism management in the general pregnancy population satisfies recently issued guidelines and to determine whether improvements are indicated. STUDY DESIGN: This was an observational study in which women at 5 recruitment centers in the first- and second-trimester evaluation of risk for aneuploidy trial allowed the use of sequentially obtained first- and second-trimester sera for additional research. Three hundred eighty-nine women had hypothyroidism by self-report. Thyroid-related measurements were performed on all samples between July 2004 and May 2005. RESULTS: Forty-three percent of the thyroid-stimulating hormone (TSH) values are at or above recently recommended guidelines in the first trimester (2.5 mU/L), as opposed to 33% of the values in the second trimester (3.0 mU/L). Twenty percent of the TSH values are at or above a less restrictive 98th percentile of normal in the first trimester, as opposed to 23% of the values in the second trimester. Mean TSH levels are higher in women with antibodies. Free thyroxine values are unremarkable. CONCLUSION: Future strategies should focus on more effectively treating women with hypothyroidism who have persistently elevated TSH values. PMID- 18448080 TI - Prenatal psychosocial stress exposure is associated with insulin resistance in young adults. AB - OBJECTIVE: The objective of the study was to examine the association in humans between maternal psychosocial stress exposure during pregnancy and measures of glucose-insulin metabolism in the adult offspring. STUDY DESIGN: Healthy young adults whose mothers experienced major stressful life events during their pregnancy (n = 36, prenatal stress, PS group, mean age 25 +/- 5.14 [SD] years) and a comparison group (n = 22, CG, mean age 24 +/- 3.7 [SD] years) underwent an oral glucose tolerance test. RESULTS: Glucose levels were not significantly different across the groups; however, prenatally stressed subjects showed significantly elevated 2-hour insulin (P = .01) and C-peptide levels (P = .03). These differences were independent of other major risk factors for insulin resistance, including birth phenotype (birthweight, length of gestation), a family history of diabetes, gestational diabetes, body mass index, proinflammatory state, and smoking. CONCLUSION: Higher insulin responses reflect relative insulin resistance in these prenatally stressed young adults. This study is the first to provide evidence for a link in humans between prenatal psychosocial stress exposure and alterations in glucose-insulin metabolic function. PMID- 18448082 TI - Health care costs associated with changing clinics and "walk-in" deliveries: evidence supporting a regionalized health information network. AB - OBJECTIVE: The objective of the study was to describe the prevalence of changing clinics and "walk-in" deliveries and estimate associated health care costs. STUDY DESIGN: This was a retrospective review at an urban teaching hospital over a 6 month period. Principal outcome measures were availability of laboratory data at delivery and the number, type, and costs of duplicated tests for patients receiving various amounts of prenatal care (PNC) at our site. The prevalence of changing clinics, walk-in deliveries, and availability of records in our hospital was applied to the Los Angeles County Medicaid population to calculate the estimated cost of repeated prenatal laboratory studies. RESULTS: Of the 1120 patients delivered by our service, 50% received all PNC at our site, 27% transferred PNC to our site, and 23% of patients were walk-ins for delivery only. Medical records were unavailable in 26% of cases, requiring prenatal laboratory studies repeated. Costs varied by amount of PNC on site (range, $107.00-201.00). CONCLUSION: Changing clinics and walk-in deliveries are associated with significant health care costs because of redundant laboratory services and personnel costs associated with reviewing and exchanging medical records. PMID- 18448083 TI - Pulses of extracellular K+ produce two cytosolic Ca2+ transients that display different temperature dependence and carbonyl cyanide m-chlorophenyl sensitivity in SH-SY5Y cells. AB - In SH-SY5Y cells we have shown that stimulation with high extracellular K+ ([K+]e) evokes a transient increase in cytoplasmic Ca2+ ([Ca2+]cyt) (K+on) that is triggered by the opening of voltage-dependent Ca2+ channels and followed by Ca2+ -induced Ca2+ release from the endoplasmic reticulum (Xu, F., Zhang, J., Recio-Pinto, E. and Blanck, T.J., Halothane and isoflurane augment depolarization induced cytosolic CA2+ transients and attenuate carbachol-stimulated CA2+ transients, Anesthesiology, 92 (2000) 1746-56). The removal of high-[K+]e results in a second transient increase in [Ca2+]cyt (K+off) that is independent of extracellular Ca2+ (Corrales, A., Montoya, G.J., Sutachan, J.J., Cornillez-Ty, G., Garavito-Aguilar, Z., Xu, F., Blanck, T.J. and Recio-Pinto, E., Transient increases in extracellular K+ produce two pharmacological distinct cytosolic Ca2+ transients, Brain Res., 1031 (2005) 174-184). In this study we further characterize the properties of K+off. We found that K+off was detectable at near physiological temperatures (34-36 degrees C) but, depending on the level of [K+]e, it was undetectable or highly diminished at room temperature. In contrast, K+on was increased by lowering the temperature. Extracellular Na+ -replacement with K+ did not affect K+off, indicating that K+off was not generated by osmolarity changes. Replacement of extracellular Na+ with choline+ did not affect K+off, indicating that K+off did not result from activity changes of the plasma membrane Na+/Ca2+ exchanger. Caffeine decreased K+on but not K+off. CCCP (carbonyl cyanide m-chlorophenyl), a protonophore uncoupler that decreases mitochondrial Ca2+ uptake, decreased K+on but not K+off. CGP37157, an inhibitor of the mitochondria Na+/Ca2+ exchanger, decreased K+off when added alone but not when added simultaneously with CCCP. Clonazepam had similar effects as CGP37157. These findings indicate that the generation of K+off is strongly temperature dependent and its pharmacology is distinct from the [Ca2+]cyt changes observed previously at room temperature. PMID- 18448084 TI - Tactile and visual distractors induce change blindness for tactile stimuli presented on the fingertips. AB - Recent studies of change detection have revealed that people are surprisingly poor at detecting changes between two consecutively-presented scenes, when they are separated by a distractor that masks the transients typically associated with change. This failure, known as 'change blindness', has been reported within vision, audition, and touch. In the three experiments reported here, we investigated people's ability to detect the change between two patterns of tactile stimuli presented to their fingertips. The two to-be-compared patterns were presented either consecutively, separated by an empty interval or else by a tactile, visual, or auditory mask. Participants' performance was impaired when an empty interval was inserted between the two consecutively-presented patterns as compared with the consecutive stimulus presentation. Participants' performance was further impaired not only when a tactile mask was introduced between the two to-be-compared displays, but also when a visual mask was used instead. Interestingly, however, the addition of an auditory mask to an empty interval did not have any effect on participants' performance. These results are discussed in relation to the multisensory/amodal nature of spatial attention. PMID- 18448085 TI - Synthesis of glycocluster peptides. AB - A new type of glycoconjugate mimetic is introduced that combines a glycocluster head group with a peptide part. These 'glycocluster peptides' are designed to serve as mimetics of glycocalyx constituents. A convergent synthetic scheme was followed, consisting of (i) the synthesis of a clustered carbohydrate head group carrying an amino acid at the focal point, and (ii) the solid phase synthesis of the peptide moiety. Finally, peptide coupling on resin furnished two prototype glycocluster peptides, which each exposes three alpha-mannosyl residues in the form of a dendritic wedge, with different conformational features. Extensive purification and NMR studies were necessary to characterize the target compounds and the results of these investigations are reported here together with the synthesis. PMID- 18448086 TI - Acetylcholinesterase activity in Clytia hemisphaerica (Cnidaria). AB - Cholinesterase activity is known in representatives of all living organisms phyla but the origin of the cholinergic system as known in bilaterian animals is still undeciphered. In particular the implication of cholinesterases in the nervous system of non-bilaterian Metazoa is not well known. We thus chose to investigate this activity in the Clytia hemisphaerica (Cnidaria) medusa. In toto histochemical staining revealed an acetylcholinesterase activity in the tentacle bulbs but not in the nervous system. Sequences homologous to acetylcholinesterase were searched within Clytia ESTs and compared to other sequences found in public databases. PMID- 18448087 TI - The conceptual grouping effect: categories matter (and named categories matter more). AB - Do conceptual categories affect basic visual processing? A conceptual grouping effect for familiar stimuli is reported using a visual search paradigm. Search through conceptually-homogeneous non-targets was faster and more efficient than search through conceptually-heterogeneous non-targets. This effect cannot be attributed to perceptual factors and is not explained by a long-term representational reorganization due to perceptual-learning. Rather, conceptual categories seem to modulate visual representations dynamically, and are sensitive to task-demands. Verbally labeling a visual target further exaggerates the degree to which conceptual categories penetrate visual processing. PMID- 18448088 TI - Application of the synergetic algorithm on the classification of lymph tissue cells. AB - A synergetic classification algorithm for lymphocyte discrimination is developed. By improving the ISODATA algorithm, it is possible to cluster the cell types in the training set with respect to the cluster center samples which plays a role as the cell prototype set types. Based on synergetic theory, a two-step synergetic competition mechanism was established: (1) the order parameter competition was introduced between the test cell sample and the prototypes of each prototype set, by setting the prototype of the maximum order parameter as the best prototype of each set; (2) similar matching competition was performed between the test cell sample and the best prototypes. After that the classification is achieved by selecting the most similar result as the final result. This classification method was applied on four cell groups, i.e. mantle cells, follicular centrocytes, follicular centroblastic cells and centroblastic lymphoma cells. The results show that the averaged lymphocyte classification accuracy is up to 94.1% PMID- 18448089 TI - Lamination of the cerebral cortex is disturbed in Gli3 mutant mice. AB - The layered organization of the cerebral cortex develops in an inside-out pattern, a process which is controlled by the secreted protein reelin. Here we report on cortical lamination in the Gli3 hypomorphic mouse mutant Xt(J)/Pdn which lacks the cortical hem, a major source of reelin(+) Cajal Retzius cells in the cerebral cortex. Unlike other previously described mouse mutants with hem defects, cortical lamination is disturbed in Xt(J)/Pdn animals. Surprisingly, these layering defects occur in the presence of reelin(+) cells which are probably derived from an expanded Dbx1(+) progenitor pool in the mutant. However, while these reelin(+) neurons and also Calretinin(+) cells are initially evenly distributed over the cortical surface they form clusters later during development suggesting a novel role for Gli3 in maintaining the proper arrangement of these cells in the marginal zone. Moreover, the radial glial network is disturbed in the regions of these clusters. In addition, the differentiation of subplate cells is affected which serve as a framework for developing a properly laminated cortex. PMID- 18448090 TI - Ventral closure, headfold fusion and definitive endoderm migration defects in mouse embryos lacking the fibronectin leucine-rich transmembrane protein FLRT3. AB - The three fibronectin leucine-rich repeat transmembrane (FLRT) proteins contain 10 leucine-rich repeats (LRR), a type III fibronectin (FN) domain, followed by the transmembrane region, and a short cytoplasmic tail. XFLRT3, a Nodal/TGFbeta target, regulates cell adhesion and modulates FGF signalling during Xenopus gastrulation. The present study describes the onset and pattern of FLRT1-3 expression in the early mouse embryo. FLRT3 expression is activated in the anterior visceral endoderm (AVE), and during gastrulation appears in anterior streak derivatives namely the node, notochord and the emerging definitive endoderm. To explore FLRT3 function we generated a null allele via gene targeting. Early Nodal activities required for anterior-posterior (A-P) patterning, primitive streak formation and left-right (L-R) axis determination were unperturbed. However, FLRT3 mutant embryos display defects in headfold fusion, definitive endoderm migration and a failure of the lateral edges of the ventral body wall to fuse, leading to cardia bifida. Surprisingly, the mutation has no effect on FGF signalling. Collectively these experiments demonstrate that FLRT3 plays a key role in controlling cell adhesion and tissue morphogenesis in the developing mouse embryo. PMID- 18448091 TI - An observational study of the potential for human exposures to pet-borne diazinon residues following lawn applications. AB - This study examined the potential for pet dogs to be an important pathway for transporting diazinon residues into homes and onto its occupants following residential lawn applications. The primary objectives were to investigate the potential exposures of occupants and their pet dogs to diazinon after an application to turf at their residences and to determine if personal contacts between occupants and their pet dogs resulted in measurable exposures. It was conducted from April to August 2001 before the Agency phased out all residential uses of diazinon in December 2004. Six families and their pet dogs were recruited into the study. Monitoring was conducted at pre-, 1, 2, 4, and 8 days post application of a commercial, granular formulation of diazinon to the lawn by the homeowner. Environmental samples collected included soil, indoor air, carpet dust, and transferable residues from lawns and floors. Samples collected from the pet dogs consisted of paw wipes, fur clippings, and transferable residues from the fur by a technician or child wearing a cotton glove(s). First morning void (FMV) urine samples were collected from each child and his/her parent on each sampling day. Diazinon was analyzed in all samples, except urine, by GC-MS. The metabolite 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy) was analyzed in the urine samples by HPLC-MS/MS. Mean airborne residues of diazinon on day 1 post application were at least six times higher in both the living rooms (235+/-267 ng/m(3)) and children's bedrooms (179+/-246 ng/m(3)) than at pre-application. Mean loadings of diazinon in carpet dust samples were at least 20 times greater on days 2, 4, and 8 post-application than mean loadings (0.03+/-0.04 ng/cm(2)) at pre-application. The pet dogs had over 900 times higher mean loadings of diazinon residues on their paws on day 1 post-application (88.1+/-100.1 ng/cm(2)) compared to mean loadings (<0.09 ng/cm(2)) at pre-application. The mean diazinon loadings on the fur clippings were at least 14 times higher on days 1, 2, 4, and 8 post application than mean loadings (0.8+/-0.4 ng/cm(2)) at pre-application. For transferable residues from dog fur, the mean loadings of diazinon on the technician's cotton glove samples were the lowest before application (0.04+/-0.08 ng/cm(2)) and the highest on day 1 post-application (10.4+/-23.9 ng/cm(2)) of diazinon to turf. Urinary IMPy concentrations for the participants ranged from <0.3 to 5.5 ng/mL before application and <0.3-12.5 ng/mL after application of diazinon. The mean urinary IMPy concentrations for children or adults were not statistically different (p>0.05) at pre-application compared to post-application of diazinon to turf. The results showed that the participants and their pet dogs were likely exposed to low levels of diazinon residues from several sources (i.e., air, dust, and soil), through several pathways and routes, after lawn applications at these residences. Lastly, the pet dog appears to be an important pathway for the transfer and translocation of diazinon residues inside the homes and likely exposed occupants through personal contacts (i.e., petting). PMID- 18448092 TI - Mice lacking d-amino acid oxidase activity exhibit marked reduction of methamphetamine-induced stereotypy. AB - The behavioral effects induced by methamphetamine (5.0 mg/kg) were compared in the mutant mice lacking d-amino acid oxidase activity and normal mice. The mutant mice exhibited marked decline in the methamphetamine-induced stereotypy compared to the normal mice, whereas the mutant mice displayed a drastic augmentation in the locomotor activity evoked by methamphetamine compared to the normal mice. Because the d-serine levels in the brain of the mutant mice are significantly higher than those in the normal mice, the enhanced d-serine in the brain of the mutant mice could antagonize the methamphetamine-induced stereotypy via the N methyl-d-aspartate receptors. PMID- 18448093 TI - Responses of differentiated MC3T3-E1 osteoblast-like cells to reactive oxygen species. AB - MC3T3-E1 osteoblast-like cells represent a suitable model for studying osteogenic development in vitro. The current investigation extends our previous work on the response of these cells to hydrogen peroxide by considering the effects of reactive oxygen species from other sources, and by determining whether differentiation alters sensitivity to oxidative damage. Aspects of hydrogen peroxide-mediated apoptotic and necrotic death were also examined. Cell viability was determined using the Alamar Blue assay; and accompanying morphological changes monitored by phase-contrast microscopy. Sensitivity to hydrogen peroxide increased significantly in cultures which had been induced to differentiate. Hydrogen peroxide and copper (II) ions, when combined, produced greater damage than hydrogen peroxide alone, whilst the hydroxyl radical scavengers mannitol or dimethylsulphoxide had no effect. Cyclosporin A and nicotinamide afforded partial protection. The tryptophan metabolite, 3-hydroxykynurenine significantly reduced viability, although 3-hydroxyanthranilic acid did not. The xanthine/xanthine oxidase system also reduced cell viability, an effect prevented by catalase but potentiated by superoxide dismutase. S-nitroso-N-acetylpenicillamine did not impair viability at the concentrations tested. Cultures were resistant to mitochondrial poisoning by potassium cyanide, but succumbed to 24-h exposures to 3-nitropropionic acid (1 mM). The results reveal a differential sensitivity of MC3T3-E1 cells to hydrogen peroxide-induced oxidative stress, an enhancement of sensitivity by cellular differentiation, and a potential preference for the glycolytic pathway by MC3T3-E1 cells. This study gives new insight into how bone cells may succumb to the toxic effects of oxidative stress generated by different stimuli and has relevance to conditions such as osteoporosis. PMID- 18448094 TI - (+)-Morphine attenuates the (-)-morphine-produced conditioned place preference and the mu-opioid receptor-mediated dopamine increase in the posterior nucleus accumbens of the rat. AB - An unbiased conditioned place preference paradigm and the microdialysis technique was used to evaluate the effect of (+)-morphine pretreatment on the conditioned place preference produced by (-)-morphine and the increased release of the dopamine produced by mu-opioid ligand endomorphin-1, respectively, in the posterior nucleus accumbens shell of the male CD rat. (-)-Morphine (2.5-10 microg) microinjected into the posterior nucleus accumbens shell dose-dependently produced the conditioned place preference. Pretreatment with (+)-morphine (0.1-10 pg) given into the posterior accumbens shell for 45 min dose-dependently attenuated the conditioned place preference produced by (-)-morphine (5 microg) given into the same posterior accumbens shell. However, higher doses of (+) morphine (0.1 and 1 ng) were less effective in attenuating the (-)-morphine produced conditioned place preference. Thus, like given systemically, (+) morphine given into the posterior nucleus accumbens shell also induces a U-shaped dose-response curve for attenuating the (-)-morphine-produced conditioned place preference. Microinjection of mu-opioid agonist endomorphin-1 (1-10 microg) given into the ventral tegmental area dose-dependently increased the release of the extracellular dopamine in the posterior nucleus accumbens shell in the urethane anesthetized rats. The increased dopamine caused by endomorphin-1 (10 microg) was completed blocked by the (+)-morphine (10 pg) pretreatment given into ventral tegmental area. It is concluded that (+)-morphine attenuates the (-)-morphine produced conditioned place preference and the mu-opioid receptor-mediated increase of extracellular dopamine in the posterior nucleus accumbens shell of the rat. PMID- 18448095 TI - Differential sensitivity of colorectal cancer cell lines to artesunate is associated with expression of beta-catenin and E-cadherin. AB - Artesunate, a remarkable antimalarial agent, also reveals profound cytotoxic activity. In the present investigation, we compared the anticancer effects of artesunate on three colorectal cancer cell lines and analyzed the relationship between drug sensitivity and malignant phenotype of the tumor cells. The findings are as follows: poorly-differentiated was colorectal cancer cell line CLY showing nuclear beta-catenin accumulation and loss of E-cadherin; moderately differentiated were Lovo cells with cytoplasmic distribution of the two proteins; and well-differentiated were HT-29 cells with membranous localization of them. Also, both in vitro and in vivo, poorly- or moderately-differentiated CLY and Lovo were more susceptible to artesunate treatment than well-differentiated HT 29. Furthermore, the sensitive response of CLY and Lovo to artesunate was associated with membranous translocation of beta-catenin and increased expression of E-cadherin, which indicated the inhibition of hyperactive Wnt signaling pathway and the reversion of the epithelial to mesenchymal transition, respectively. Due to the vital roles of Wnt pathway and the epithelial to mesenchymal transition in tumor differentiation, we thought artesunate could promote the re-differentiation and apoptosis of colorectal cancer cells by inhibition of hyperactive Wnt pathway and reversion of the epithelial to mesenchymal transition. PMID- 18448096 TI - Aurothiomalate inhibits COX-2 expression in chondrocytes and in human cartilage possibly through its effects on COX-2 mRNA stability. AB - Cyclooxygenase-2 (COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces pro-inflammatory prostanoids in the joint. In the present study, we investigated the effects of disease modifying anti-rheumatic drugs on COX-2 expression in chondrocytes. Unlike the other tested drugs, aurothiomalate was found to inhibit COX-2 expression in chondrocytes. In the further studies, effects and mechanisms of action of aurothiomalate were investigated in more detail. Aurothiomalate inhibited IL-1beta-induced COX-2 protein expression and PGE(2) production in chondrocytes in a dose-dependent manner. Because aurothiomalate did not alter IL-1beta-induced mRNA levels when measured 0-3 h after addition of IL-1beta, its effects on COX-2 mRNA degradation were tested by Actinomycin D assay. The half-life of COX-2 mRNA was reduced from 3 h to less than 1.5 h in aurothiomalate-treated cells. The 3'-untranslated region (3'-UTR) of COX-2 mRNA contains an ARE element which has been shown to bind mRNA stabilizing factor HuR. Interestingly, aurothiomalate inhibited HuR expression which may explain its destabilizing effect on COX-2 mRNA. Aurothiomalate reduced COX-2 expression and PGE(2) production also in human cartilage at drug concentrations which have been measured in serum and synovial fluid during treatment with aurothiomalate. The results show that aurothiomalate reduces COX-2 expression and PGE(2) production in chondrocyte cultures and in human cartilage. The action is likely mediated by enhanced COX-2 mRNA degradation possibly through a mechanism related to reduced expression of HuR. The results provide a novel mechanism of action for aurothiomalate which may be important in the treatment of arthritis. PMID- 18448097 TI - Increased marble-burying behavior in ethanol-withdrawal state: modulation by gonadotropin-releasing hormone agonist. AB - A characteristic behavior in alcohol abstinence state indicates the possibility of obsessive-compulsive behavior in alcoholics. Ethanol is known to reduce hypothalamic synthesis, release, and mRNA expression of gonadotropin-releasing hormone (GnRH) that modulates serotonergic, dopaminergic, and glutamatergic systems, which experience adaptive changes on chronic exposure to ethanol. Such changes are also evident in obsessive-compulsive disorder. Therefore, it was proposed to investigate the effect of ethanol-withdrawal on marble-burying behavior in mice, particularly because it simulates some aspects of obsessive compulsive behavior; further, the influence of GnRH agonist was studied on the same. Ethanol-withdrawal state was induced after its chronic administration, and marble-burying behavior was observed at 0, 6, 24, 48, and 96 h interval. Further, the influence of leuprolide--a GnRH agonist (50-600 microg/kg, s.c.) or fluoxetine (5-30 mg/kg, i.p.) was investigated on ethanol-withdrawal-induced changes in marble-burying behavior. The results indicated that ethanol-withdrawal led to a gradual increase in marble-burying behavior upto 48 h with peak at 24 h interval. Administration of leuprolide (100-600 microg/kg, s.c.), 30 min prior to 24 h interval, dose dependently reduced ethanol-withdrawal-induced increase in marble-burying behavior, and this effect was comparable to that of fluoxetine (15 and 30 mg/kg, i.p.). Further, twice daily administration of leuprolide (50 microg/kg, s.c), concomitant with ethanol, prevented the gradual increase in marble-burying behavior after ethanol-withdrawal and this effect was comparable to fluoxetine (5 mg/kg, i.p.). In conclusion, ethanol-withdrawal on chronic administration increases marble-burying behavior in mice; its development and expression is attenuated by leuprolide. PMID- 18448098 TI - Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis. AB - Human carcinomas arise through the acquisition of genetic changes that endow precursor cancer cells with a critical threshold of cancer-relevant genetic lesions. This complex genomic alterations confer upon precursor cancer cells the ability to grow indefinitely and to metastasize to distant sites. One important mechanism underlying a cell's tumorigenic potential is the status of its telomere. Telomeres are G-rich simple repeat sequences that serve to prevent chromosomal ends from being recognized as DNA double-strand breaks (DSBs). Dysfunctional telomeres resemble DSBs, leading to the formation of dicentric chromosomes that fuel high degrees of genomic instability. In the setting of an intact p53 pathway, this instability promotes cellular senescence, a potent tumor suppressor mechanism. However, rare cells that stochastically lose p53 function emerge from this sea of genomic instability and progress towards cancer. In this review, we describe the use of mouse models to probe the impact of dysfunctional telomeres on tumor initiation and suppression. PMID- 18448099 TI - Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve model. AB - Misdirection of regenerating axons is one of the factors that can explain the poor results often found after nerve injury and repair. In this study, we quantified the degree of misdirection and the effect on recovery of function after different types of nerve injury and repair in the rat sciatic nerve model; crush injury, direct coaptation, and autograft repair. Sequential tracing with retrograde labeling of the peroneal nerve before and 8 weeks after nerve injury and repair was performed to quantify the accuracy of motor axon regeneration. Digital video analysis of ankle motion was used to investigate the recovery of function. In addition, serial compound action potential recordings and nerve and muscle morphometry were performed. In our study, accuracy of motor axon regeneration was found to be limited; only 71% (+/-4.9%) of the peroneal motoneurons were correctly directed 2 months after sciatic crush injury, 42% (+/ 4.2%) after direct coaptation, and 25% (+/-6.6%) after autograft repair. Recovery of ankle motion was incomplete after all types of nerve injury and repair and demonstrated a disturbed balance of ankle plantar and dorsiflexion. The number of motoneurons from which axons had regenerated was not significantly different from normal. The number of myelinated axons was significantly increased distal to the site of injury. Misdirection of regenerating motor axons is a major factor in the poor recovery of nerves that innervate different muscles. The results of this study can be used as basis for developing new nerve repair techniques that may improve the accuracy of regeneration. PMID- 18448100 TI - Motor cortical stimulation promotes synaptic plasticity and behavioral improvements following sensorimotor cortex lesions. AB - Cortical stimulation (CS) as a means to modulate regional activity and excitability in cortex is emerging as a promising approach for facilitating rehabilitative interventions after brain damage, including stroke. In this study, we investigated whether CS-induced functional improvements are linked with synaptic plasticity in peri-infarct cortex and vary with the severity of impairments. Adult rats that were proficient in skilled reaching received subtotal unilateral ischemic sensorimotor cortex (SMC) lesions and implantation of chronic epidural electrodes over remaining motor cortex. Based on the initial magnitude of reaching deficits, rats were divided into severely and moderately impaired subgroups. Beginning two weeks post-surgery, rats received 100 Hz cathodal CS at 50% of movement thresholds or no-stimulation control procedures (NoCS) during 18 days of rehabilitative training on a reaching task. Stereological electron microscopy methods were used to quantify axodendritic synapse subtypes in motor cortical layer V underlying the electrode. In moderately, but not severely impaired rats, CS significantly enhanced recovery of reaching success. Sensitive movement analyses revealed that CS partially normalized reaching movements in both impairment subgroups compared to NoCS. Additionally, both CS subgroups had significantly greater density of axodendritic synapses and moderately impaired CS rats had increases in presumed efficacious synapse subtypes (perforated and multiple synapses) in stimulated cortex compared to NoCS. Synaptic density was positively correlated with post-rehabilitation reaching success. In addition to providing further support that CS can promote functional recovery, these findings suggest that CS-induced functional improvements may be mediated by synaptic structural plasticity in stimulated cortex. PMID- 18448101 TI - Beta-amyloid and glutamate receptors. PMID- 18448102 TI - A rat model of chronic gastric sensorimotor dysfunction resulting from transient neonatal gastric irritation. AB - BACKGROUND & AIMS: Although several pathophysiologic abnormalities have been noted in functional dyspepsia (FD), their pathogenesis is poorly understood. We hypothesized that chronic gastric hypersensitivity and gastric motor dysfunction seen in FD patients can be modeled in rats by transient gastric irritation during the neonatal period, a time of known neuronal vulnerability to long-term plasticity. METHODS: Ten-day-old male rats received 0.2 mL 0.1% iodoacetamide (IA) in 2% sucrose daily by oral gavages for 6 days; controls received 2% sucrose. Rats in both groups were then followed to adulthood (8-10 weeks) at which point behavioral, visceromotor, and great splanchnic nerve responses to graded gastric balloon distention (GD; 20-80 mm Hg) and gastric motor function were tested. RESULTS: IA-treated rats exhibited hypersensitivity to GD in a dose dependent manner, as compared with the control group. The threshold of afferent nerve activation was lower and nerve responses to GD were significantly increased in IA-treated rats. Although IA-treated rats ingested food at a lower rate, gastric emptying was not significantly different between IA and control groups. However, gastric accommodation was significantly reduced in the IA group. No significant gastric pathology was seen in hypersensitive adult rats compared with controls. CONCLUSIONS: These studies demonstrate that gastric irritation in the neonatal period can result in chronic gastric hypersensitivity and gastric motor dysfunction in adults even in the absence of significant detectable gastric pathology. Our results offer insight into the pathogenesis of chronic functional dyspepsia and provide a potential model for further study to this important clinical problem. PMID- 18448103 TI - Caustic ingestion in children: is endoscopy always indicated? The results of an Italian multicenter observational study. AB - BACKGROUND: The ingestion of caustic substances can represent a serious medical problem in children. OBJECTIVE: Whether or not an urgent endoscopy should be performed is still a matter of debate, particularly in asymptomatic patients. DESIGN: We conducted a multicenter observational study to investigate the predictive value of signs and symptoms in detecting severe esophageal lesions. SETTING AND PATIENTS: The records of 162 children who presented with accidental caustic substance ingestion were analyzed. INTERVENTIONS: Signs and symptoms were divided into minor (oral and/or oropharyngeal lesions and vomiting) and major (dyspnea, dysphagia, drooling, and hematemesis). An endoscopy was performed in all patients within 12 to 24 hours of the substance being ingested. MAIN OUTCOME MEASUREMENTS: The types of substance ingested, signs and symptoms, age, sex, and severity of esophageal injury were correlated. RESULTS: Mild esophageal lesions were identified in 143 of 162 patients (88.3%), and severe (third degree) esophageal lesions in 19 patients (11.7%). The risk of severe esophageal lesions without signs and/or symptoms was very low (odds ratio [OR] 0.13 [95% CI, 0.02 0.62], P = .002). Indeed, the presence of 3 or more symptoms is an important predictor of severe esophageal lesions (OR 11.97 [95% CI, 3.49-42.04], P = .0001). Multivariate analysis showed that the presence of symptoms is the most significant predictor of severe esophageal lesions (OR 2.3 [95% CI, 1.57-3.38], P = .001). CONCLUSIONS: The results demonstrated that the incidence of patients with third-degree lesions without any early symptoms and/or signs is very low, and an endoscopy could be avoided. The risk of severe damage increases proportionally with the number of signs and symptoms, and an endoscopy is always mandatory in symptomatic patients. PMID- 18448104 TI - Effects of arginine vasotocin and vasopressin receptor antagonists on Na+ and Cl- transport in the isolated skin of two frog species, Hyla japonica and Rana nigromaculata. AB - Physiological function of arginine vasotocin (AVT) and effect of receptor antagonists of vasopressin were electrophysiologically investigated on transepithelial transport of ions in the abdominal skin of Hyla japonica and Rana nigromaculata by means of the Ussing chamber system. Administrations of AVT and forskolin (adenylate cyclase activator) in the serosal side of normal Ringer's solution significantly increased transepithelial potential difference (PD) and short-circuit current (Isc) accounting for Na(+) influx, mucosal to serosal direction, across the skin of H. japonica. In contrast, AVT administrations significantly decreased PD but not Isc on the skin of R. nigromaculata in a concentration-dependent manner ranging from 10(-11) to 10(-8)M. Administration of 10(-5)M forskolin also significantly decreased PD in normal and low Na(+) Ringer's solution and in the presence of amiloride (Na(+) channel blocker) on the mucosal side of normal Ringer's solution. On the other hand, forskolin significantly increased PD and Isc in the Cl(-) free Ringer's solution. These results suggested that AVT and forskolin stimulated mainly Cl(-) influx across the skin of R. nigromaculata. In two frog species, the AVT actions on ion transports were inhibited by pretreatment of OPC-31260 (a vasopressin V(2) receptor antagonist) but not OPC-21268 (a vasopressin V(1) receptor antagonist). These results suggested that AVT activates adenylate cyclase via V(2)-like receptor and stimulates actively net Na(+) and net Cl(-) transports in the abdominal skin of H. japonica and R. nigromaculata, respectively. PMID- 18448105 TI - Steroid receptor expression in the developing copulatory system of the green anole lizard (Anolis carolinensis). AB - In adulthood, the copulatory system in male green anole lizards is characterized by the presence of two hemipenes, each controlled by ipsilateral muscles. These structures are present in both sexes early in development, but prior to hatching regress completely in females. Embryonic treatment with steroid hormones alters the morphology of the copulatory system, suggesting active roles for both androgens and estrogens in sexual differentiation. To elucidate the timing and sites of steroid hormone action in the embryonic copulatory system, the distributions of androgen receptor (AR) and estrogen receptor-alpha (ER alpha) mRNA expression were examined. In situ hybridization was conducted on the rostral tail of anoles at three stages spanning differentiation of the copulatory structures: embryonic days (E) 13, 18, and 24 (hatching occurs at approximately E34). At E13, males expressed significantly higher levels of AR mRNA in both hemipenes and muscles than did females, while females at the same age tended to express higher levels of ER alpha mRNA in these structures. By E18, hemipenes and copulatory muscles were regressed in most females, and were not present in any females at E24. In males, no effect of age was detected on the expression of either AR or ER alpha. These data suggest that peripheral copulatory structures in the embryonic anole are direct targets for the actions of both androgens and estrogens in sexual differentiation, consistent with the idea that estradiol facilitates regression in females and androgen promotes survival in males. However, the issue of whether or not a critical period exists remains open. PMID- 18448107 TI - Structure-function relationships in high-density docosylsilane bonded stationary phases by Raman spectroscopy and comparison to octadecylsilane bonded stationary phases: effects of aromatic compounds. AB - The effects of four aromatic compounds on alkyl chain conformational order for a series of high-density docosylsilane (C22) stationary phases with surface coverage ranging from 3.61 to 6.97 micromol/m2 are investigated using Raman spectroscopy. Aromatic compounds studied include benzene-d6, toluene-d8, aniline d7 and anisole-d8. In general, these aromatic solvents decrease the conformational order of the C22 phases relative to air suggesting partitioning of the aromatics into the alkyl chains of these stationary phases. Changes in alkyl chain conformational order are linearly dependent on the solvent hydrophobicity parameter, log K ow, and are also dependent on stationary phase properties (i.e. polymerization method and surface coverage). A comparison is made between C22 and C18 bonded phase systems. The conformational order of the alkyl chains in a mixed solute/mobile phase system is also studied using 80% methanol/water as the mobile phase and aniline-d7, anisole-d8 or toluene-d8 as solutes. Collectively, the Raman spectroscopic evidence at the molecular level suggests interaction of these aromatic species with the bonded alkyl chains through partitioning. PMID- 18448106 TI - Persistence of maternal effects in baboons: Mother's dominance rank at son's conception predicts stress hormone levels in subadult males. AB - Dominance status and reproductive experience are maternal characteristics that affect offspring traits in diverse taxa, including some cercopithecine primates. Maternal effects of this sort are widespread and are sources of variability in offspring fitness. We tested the hypothesis that maternal dominance rank and reproductive experience as well as a male's own age and dominance rank predicted chronic fecal glucocorticoid (fGC) concentrations in 17 subadult wild male baboons, Papio cynocephalus (median age 6.5 years), in the Amboseli basin, Kenya. Among these variables, maternal dominance rank at a subadult male's conception was the sole significant predictor of the male's fGC and accounted for 42% of fGC variance; sons of lower ranking mothers had higher fGC than did those of high ranking mothers. This result is striking because subadult male baboons are approximately 4-6 years past the period of infant dependence on their mothers, and are larger than and dominant to all adult females. In addition, many males of this age have survived their mothers' death. Consequently, the influence of maternal dominance rank persisted well beyond the stage at which direct maternal influence on sons is likely. Persistence of these major maternal influences from the perinatal period may signal organizational effects of mothers on sons' HPA axis. Although short-term, acute, elevations in GC are part of adaptive responses to challenges such as predators and other emergencies, chronically elevated GC are often associated with stress-related pathologies and, thereby, adverse effects on fitness components. PMID- 18448108 TI - An insight into the micellization of dodecyldimethylethylammonium bromide (DDAB) in the presence of bovine serum albumin (BSA). AB - In this work, we report the effect of concentration of bovine serum albumin (BSA) on the micellization of a cationic surfactant, dodecyldimethylethylammonium bromide (DDAB). Several samples covering a wide range of concentrations of protein and surfactant have been investigated. The interactions between the moieties are investigated by measuring fluorescence quenching of BSA molecules. The aggregation number of DDAB micelles is found to be small in the presence of BSA. The formation of DDAB-BSA complex is confirmed by FTIR. Absorbance spectroscopy indicates that at higher concentration, the conformational stability of BSA in DDAB is higher. The viscosity data for protein-surfactant systems confirm conformational changes in protein chains induced by the surfactant. The cmc values for DDAB increase with increasing concentration of BSA. At higher temperatures the micellization-complexation becomes enthalpy-dominated. PMID- 18448109 TI - Pyramidal assemblies of colloidal particles by micromolding underneath top gathering pillar arrays. AB - Assemblies of colloidal particles are known to have special photonic and optical properties. Periodic pyramidal assemblies of SiO2 particles with diameters of 0.5 and 1 microm were fabricated using top-gathering pillar arrays as a new template. These top-gathering pillar arrays consisted of four pillars gathered at the top, and were fabricated by photolithography of an organic-inorganic hybrid material. The top-gathering units were obtained by controlling both the capillary and restoring forces. When a colloidal water suspension was spread on the template and the water was allowed to evaporate, the SiO2 particles were molded under the top-gathering pillars according to particle size, resulting in pyramidal assembly arrays of the particles. From in situ observation during the evaporation of water, it was found that the particles were molded underneath the top-gathering pillars by flux generated by the evaporation and by the capillary force among the particles. PMID- 18448110 TI - Synthesis of well-defined poly(N-isopropylacrylamide)-b-poly(L-glutamic acid) by a versatile approach and micellization. AB - A novel Fmoc-protected chain transfer agent (CTA) was synthesized and applied in the reversible addition-fragmentation chain transfer (RAFT) polymerization of N isopropylacrylamide (NIPAAm), resulting in well-defined Fmoc-protected PNIPAAm and the amino-end capped PNIPAAm by the subsequent hydrolysis. Poly(N isopropylacrylamide)-b-poly(l-glutamic acid) (PNIPAAm-b-PLGA) with controlled molecular weight and narrow molecular weight distribution was synthesized successfully via ring-opening polymerization (ROP) of alpha-amino acid N carboxyanhydrides (NCAs) by using PNIPAAm-NH2 as the macroinitiator. Both pH- and thermo-responsive micellization behaviors of the block copolymer PNIPAAm55-b PLGA35 in dilute aqueous solution were investigated by means of the pyrene fluorescence, circular dichroism, 1H NMR, transmission electron microscopy and dynamic and static light scattering. Spherical PLGA-core and rod-like PNIPAAm core micelles are formed in response to pH and temperature. The reversible transition between the PLGA-core and PNIPAAm-core micelles was observed. This work provides a versatile approach for synthesizing well-defined stimuli responsive polypeptide-based double hydrophilic diblock copolymers (DHBCs), and is of great potential for generating useful stimuli-responsive materials in biomedical applications. PMID- 18448111 TI - Plasma treatments of PET meshes for fuel-water separation applications. AB - Sulphur hexafluoride (SF(6)) plasma treatments and hexamethyl disiloxane (HMDSO) plasma polymerisation were performed on poly(ethylene terephthalate) (PET) meshes and the resulting wettability against liquids having very different surface tensions were investigated at the light of a possible use of the materials in the fuel/water separation technology. Surface modification of the meshes owing to HMDSO plasma polymerisation followed by SF(6) plasma treatment was also investigated. Hydrophobic performances were characterised refining the conventional Wilhelmy dynamic contact angle (DCA) technique, using several reference solutions having the surface tension values between 20-72 mN/m. Measurements of the water intrusion pressure (WIP) of the treated samples were also performed. Surface modifications on the plasma treated meshes were investigated by means of Fourier-transform infrared absorption spectroscopy (FT IR) and X-ray photoelectron spectroscopy (XPS) analysis. SF(6) and HMDSO plasma treatments decrease the surface energy of the PET meshes, lowering the liquid surface tension at which the wettable/unwettable transition occurs and increasing the WIP. Moreover, an increase in hydrophobic performances was achieved with HMDSO plasma polymerisation followed by SF(6) plasma treatment. PMID- 18448112 TI - Preparation and photocatalytic properties of Fe3+-doped Ag@TiO2 core-shell nanoparticles. AB - Ag@TiO2 core-shell-type nanophotocatalysts have been prepared using a simple and convenient method. The products were characterized by TEM, XRD, and UV-vis spectra. To make the catalysts achieve the highest photocatalytic activity under UV light illumination, the Ag content of Ag@TiO2 was optimized. The results showed that Ag@TiO2-doped Fe3+ extend their absorption into the visible region. Among the Fe3+-doped samples, Ag@Fe-TiO2 with low Ag content showed higher photocatalytic activity under visible light illumination. An excessive added amount of Ag would reduce Fe3+ to Fe2+ and make them difficult to be incorporated into the lattice of titania. From the experiments, we found that Fe3+ ions could stabilize the Ag@TiO2 colloid by holding back the aggregation of the core-shell nanoparticles. PMID- 18448113 TI - Reversed micelle formation in a model liquid-liquid extraction system. AB - The formation of reversed micelles and the roles of extractant and extracted complexes were investigated in the Cyanex923/n-heptane/H(2)SO(4) system. Interfacial tension (gamma), electrical conductivity (kappa), and water content measurements showed that Cyanex923 had a tendency to self-assemble, forming reversed micelles. The changes in electrical conductivity with concentration of H(2)SO(4) in the organic phase (C(H2)SO(4), o) exhibited an S-type curve: a correlation was found between the change in electrical conductivity and the water content as a function of C(H2)SO(4), o. The changes of electrical conductivity were mainly induced by the components and microstructure in the organic phase, while the conversion of extracted complex also resulted in the changes of components and microstructure in the organic phase. Fourier transform infrared (FTIR) spectroscopy and dynamic light scattering (DLS) were used to characterize the organic phases and sizes of the reversed micelles, respectively. The extractant and extracted complexes, such as Cyanex923H(2)SO(4), were involved in the formation of reversed micelles. PMID- 18448114 TI - Learning and memory facilitate predictive tracking in 4-month-olds. AB - We investigated 4-month-olds' oculomotor anticipations when viewing occlusion stimuli consisting of a small target that moved back and forth repetitively while the center of its trajectory was occluded by a rectangular screen. We examined performance under five conditions. In the baseline condition, infants produced few predictive relative to reactive eye movements. In the full training condition, anticipations were increased in frequency following prior exposure to a target moving along a fully visible trajectory. The delay condition tested the effects of training after a 30-min interval elapsed between training and test, resulting in a return to baseline performance. However, the training effect was reinstated in the reminder condition following another brief exposure to the training stimulus prior to test. Finally, in the brief training condition, we found that the brief exposure alone was insufficient to induce the training effect. Results are interpreted in the context of learning from short-term experience and long-term memory. PMID- 18448115 TI - Rapid identification of CD4+ T-cell epitopes using yeast displaying pathogen derived peptide library. AB - Identification of CD4+ T-cell epitopes is a critical step in studying and modulating the immune responses to tumors, infectious agents, and autoantigens. Here we report a facile, accurate, and high-throughput method for CD4+ T-cell epitope identification using yeast displaying pathogen-derived peptide library. A library of DNA fragments that encode all the possible peptides with 10-20 amino acids from the antigens (single antigenic proteins or pathogenic organisms) are fused to the gene encoding the restriction single-chain MHC class II molecule in a yeast display vector. The resultant library of recombinant yeast cells are analyzed by FACS to identify those containing peptides with high affinity towards the restriction MHC molecule, which are subsequently screened for their ability to induce antigen-specific T-cell activation. DNA sequence analysis of selected positive clones results in direct identification of the antigenic peptides. We show that this method can be used to rapidly pinpoint the HA(306-322) epitope from the haemagglutinin protein and the entire influenza virus X31/A/Aichi/68 genome, respectively. PMID- 18448116 TI - Antibody detection employing sol-gel immobilized parasites. AB - Immunofluorescence assay (IFA) and immunoperoxidase assay (IPA) are useful diagnostic techniques for specific antibody detection for different diseases. Both involve several alternatives for immobilization of cells, such as solvent or heat fixation. Non-covalent immobilization implies rigorous storage conditions at -20 degrees C to preserve the slides, and usually numerous cells are detached during the washing steps, which can lead to inconsistencies in the results. Sol gel chemistry is usually used for coating different materials because of the mild conditions of the polymerization reaction and the ability to introduce functional groups to a wide variety of surfaces. We have developed a novel procedure for the attachment of Trypanosoma cruzi epimastigotes and Leishmania guyanensis promastigotes to a silicon oxide polymer covered glass surface. The film was prepared using standard microscope slides with tetraethoxysilane and 3 aminopropyl triethoxysilane as polymeric precursors. When acetone was used as the major coating solvent, the IFA showed the fluorescence of the attached parasites without matrix background interference. Similar results were observed when the IPA was evaluated. The sensitivity and specificity of the sol-gel immobilized parasite slides were comparable with the heat fixation technique. The performance of the coated slides was maintained for at least 2 months at 4 degrees C storage temperature. This immobilization method does not affect the molecular epitopes of the attached cells. Thus, homogeneous, ready to use, long lasting coated slides were obtained, which are appropriate for field conditions. PMID- 18448117 TI - Transcription factors GATA/ELT-2 and forkhead/HNF-3/PHA-4 regulate the tropomyosin gene expression in the pharynx and intestine of Caenorhabditis elegans. AB - Gene regulation during development is an important biological activity that leads to synthesis of biomolecules at specific locations and specific times. The single tropomyosin gene of Caenorhabditis elegans, tmy-1/lev-11, produces four isoforms of protein: two from the external promoter and two from the internal promoter. We investigated the internal promoter of tropomyosin to identify sequences that regulate expression of tmy-1 in the pharynx and intestine. By promoter deletion of tmy-1 reporters as well as by database analyses, a 100-bp fragment that contained binding sequences for a GATA factor, for a chicken CdxA homolog, and for a forkhead factor was identified. Both the forkhead and CdxA binding sequences contributed to pharyngeal and intestinal expression. In addition, the GATA site also influenced intestinal expression of tmy-1 reporter. We showed that ELT-2 and PHA-4 proteins interact directly with the GATA and forkhead binding sequences, respectively, in gel mobility shift assays. RNA interference knockdown of elt-2 diminished tmy-1::gfp expression in the intestine. In contrast to RNA interference knockdown of pha-4, expression of tmy-1::gfp in pha-4;smg-1 mutants was slightly weaker than that of the wild type. Ectopic expression of PHA-4 and ELT-2 by heat shock was sufficient to elicit widespread expression of tmy-1::lacZ reporter in embryos. We found no indication of a synergistic relation between ELT 2 and PHA-4. Based on our data, PHA-4 and CdxA function as general transcription factors for pharyngeal and intestinal regulation of tmy-1. We present models by which ELT-2, PHA-4, and CdxA orchestrate expression from the internal promoter of tmy-1. PMID- 18448118 TI - Structural insight into substrate binding and catalysis of a novel 2-keto-3-deoxy D-arabinonate dehydratase illustrates common mechanistic features of the FAH superfamily. AB - The archaeon Sulfolobus solfataricus converts d-arabinose to 2-oxoglutarate by an enzyme set consisting of two dehydrogenases and two dehydratases. The third step of the pathway is catalyzed by a novel 2-keto-3-deoxy-D-arabinonate dehydratase (KdaD). In this study, the crystal structure of the enzyme has been solved to 2.1 A resolution. The enzyme forms an oval-shaped ring of four subunits, each consisting of an N-terminal domain with a four-stranded beta-sheet flanked by two alpha-helices, and a C-terminal catalytic domain with a fumarylacetoacetate hydrolase (FAH) fold. Crystal structures of complexes of the enzyme with magnesium or calcium ions and either a substrate analog 2-oxobutyrate, or the aldehyde enzyme product 2,5-dioxopentanoate revealed that the divalent metal ion in the active site is coordinated octahedrally by three conserved carboxylate residues, a water molecule, and both the carboxylate and the oxo groups of the substrate molecule. An enzymatic mechanism for base-catalyzed dehydration is proposed on the basis of the binding mode of the substrate to the metal ion, which suggests that the enzyme enhances the acidity of the protons alpha to the carbonyl group, facilitating their abstraction by glutamate 114. A comprehensive structural comparison of members of the FAH superfamily is presented and their evolution is discussed, providing a basis for functional investigations of this largely unexplored protein superfamily. PMID- 18448119 TI - A recruited protease is involved in catabolism of pyrimidines. AB - In nature, the same biochemical reaction can be catalyzed by enzymes having fundamentally different folds, reaction mechanisms and origins. For example, the third step of the reductive catabolism of pyrimidines, the conversion of N carbamyl-beta-alanine to beta-alanine, is catalyzed by two beta-alanine synthase (beta ASase, EC 3.5.1.6) subfamilies. We show that the "prototype" eukaryote beta ASases, such as those from Drosophila melanogaster and Arabidopsis thaliana, are relatively efficient in the conversion of N-carbamyl-beta A compared with a representative of fungal beta ASases, the yeast Saccharomyces kluyveri beta ASase, which has a high K(m) value (71 mM). S. kluyveri beta ASase is specifically inhibited by dipeptides and tripeptides, and the apparent K(i) value of glycyl-glycine is in the same range as the substrate K(m). We show that this inhibitor binds to the enzyme active center in a similar way as the substrate. The observed structural similarities and inhibition behavior, as well as the phylogenetic relationship, suggest that the ancestor of the fungal beta ASase was a protease that had modified its profession and become involved in the metabolism of nucleic acid precursors. PMID- 18448120 TI - Nhp6p and Med3p regulate gene expression by controlling the local subunit composition of RNA polymerase II. AB - Nhp6p is an architectural Saccharomyces cerevisiae non-histone chromosomal protein that bends DNA and plays an important role in transcription and genome stability. We used the split-ubiquitin system to isolate proteins that interact with Nhp6p in vivo, and we confirmed 11 of these protein-protein interactions with glutathione S-transferase pull-down experiments in vitro. Most of the Nhp6p interacting proteins are involved in transcription and DNA repair. We utilized the ZDS1, PUR5 and UME6 genes, which are repressed by Nhp6p and its interacting partners Rpb4p and Med3p, to study the chromosomal localization of these three proteins in wild-type and gene deletion strains. Nhp6p, Med3p and Rpb4p were found at the promoters of ZDS1, PUR5 and UME6, indicating that the repressing effects the three proteins had on the expression of these three genes had been direct ones. We also found that Med3p inhibited promoter clearance of RNA polymerase II, which contained the dissociable subunit Rpb4p, while Nhp6p recruited Rpb4p to the basal promoters of ZDS1, PUR5 and UME6. Our results further suggest that Rpb4p inhibits transcription initiation but stimulates transcription elongation and that Nhp6p and Med3p regulate gene expression by controlling the local subunit composition of RNA polymerase II. PMID- 18448121 TI - Enzymatic activity of the Staphylococcus aureus SplB serine protease is induced by substrates containing the sequence Trp-Glu-Leu-Gln. AB - Proteases are of significant importance for the virulence of Staphylococcus aureus. Nevertheless, their subset, the serine protease-like proteins, remains poorly characterized. Here presented is an investigation of SplB protease catalytic activity revealing that the enzyme possesses exquisite specificity and only cleaves efficiently after the sequence Trp-Glu-Leu-Gln. To understand the molecular basis for such selectivity, we solved the three-dimensional structure of SplB to 1.8 A. Modeling of substrate binding to the protease demonstrated that selectivity relies in part on a canonical specificity pockets-based mechanism. Significantly, the conformation of residues that ordinarily form the oxyanion hole, an essential structural element of the catalytic machinery of serine proteases, is not canonical in the SplB structure. We postulate that within SplB, the oxyanion hole is only formed upon docking of a substrate containing the consensus sequence motif. It is suggested that this unusual activation mechanism is used in parallel with classical determinants to further limit enzyme specificity. Finally, to guide future development, we attempt to point at likely physiological substrates and thus the role of SplB in staphylococcal physiology. PMID- 18448122 TI - Snapshots of a Y-family DNA polymerase in replication: substrate-induced conformational transitions and implications for fidelity of Dpo4. AB - Y-family DNA polymerases catalyze translesion DNA synthesis over damaged DNA. Each Y-family polymerase has a polymerase core consisting of a palm, finger and thumb domain in addition to a fourth domain known as a little finger domain. It is unclear how each domain moves during nucleotide incorporation and what type of conformational changes corresponds to the rate-limiting step previously reported in kinetic studies. Here, we present three crystal structures of the prototype Y family polymerase: apo-Dpo4 at 1.9 A resolution, Dpo4-DNA binary complex and Dpo4 DNA-dTMP ternary complex at 2.2 A resolution. Dpo4 undergoes dramatic conformational changes from the apo to the binary structures with a 131 degrees rotation of the little finger domain relative to the polymerase core upon DNA binding. This DNA-induced conformational change is verified in solution by our tryptophan fluorescence studies. In contrast, the polymerase core retains the same conformation in all three conformationally distinct states. Particularly, the finger domain which is responsible for checking base pairing between the template base and an incoming nucleotide retains a rigid conformation. The inflexibility of the polymerase core likely contributes to the low fidelity of Dpo4, in addition to its loose and solvent-accessible active site. Interestingly, while the binary and ternary complexes of Dpo4 retain an identical global conformation, the aromatic side chains of two conserved tyrosines at the nucleotide-binding site change orientations between the binary and ternary structures. Such local conformational changes may correspond to the rate-limiting step in the mechanism of nucleotide incorporation. Together, the global and local conformational transitions observed in our study provide a structural basis for the distinct kinetic steps of a catalytic cycle of DNA polymerization performed by a Y-family polymerase. PMID- 18448123 TI - Determination of stoichiometry and conformational changes in the first step of the P22 tail assembly. AB - Large oligomeric portal assemblies have a central role in the life-cycles of bacteriophages and herpesviruses. The stoichiometry of in vitro assembled portal proteins has been a subject of debate for several years. The intrinsic polymorphic oligomerization of ectopically expressed portal proteins makes it possible to form rings of diverse stoichiometry (e.g., 11-mer, 12-mer, 13-mer, etc.) in solution. In this study, we have investigated the stoichiometry of the in vitro-assembled portal protein of bacteriophage P22 and characterized its association with the tail factor gp4. Using native mass spectrometry, we show for the first time that the reconstituted portal protein (assembled in vitro using a modified purification and assembly protocol) is exclusively dodecameric. Under the conditions used here, 12 copies of tail factor gp4 bind to the portal ring, in a cooperative fashion, to form a 12:12 complex of 1.050 MDa. We applied tandem mass spectrometry to the complete assembly and found an unusual dimeric dissociation pattern of gp4, suggesting a dimeric sub-organization of gp4 when assembled with the portal ring. Furthermore, native and ion mobility mass spectrometry reveal a major conformational change in the portal upon binding of gp4. We propose that the gp4-induced conformational change in the portal ring initiates a cascade of events assisting in the stabilization of newly filled P22 particles, which marks the end of phage morphogenesis. PMID- 18448124 TI - Structural analysis of the Saf pilus by electron microscopy and image processing. AB - Bacterial pili are important virulence factors involved in host cell attachment and/or biofilm formation, key steps in establishing and maintaining successful infection. Here we studied Salmonella atypical fimbriae (or Saf pili), formed by the conserved chaperone/usher pathway. In contrast to the well-established quaternary structure of typical/FGS-chaperone assembled, rod-shaped, chaperone/usher pili, little is known about the supramolecular organisation in atypical/FGL-chaperone assembled fimbriae. In our study, we have used negative stain electron microscopy and single-particle image analysis to determine the three-dimensional structure of the Salmonella typhimurium Saf pilus. Our results show atypical/FGL-chaperone assembled fimbriae are composed of highly flexible linear multi-subunit fibres that are formed by globular subunits connected to each other by short links giving a "beads on a string"-like appearance. Quantitative fitting of the atomic structure of the SafA pilus subunit into the electron density maps, in combination with linker modelling and energy minimisation, has enabled analysis of subunit arrangement and intersubunit interactions in the Saf pilus. Short intersubunit linker regions provide the molecular basis for flexibility of the Saf pilus by acting as molecular hinges allowing a large range of movement between consecutive subunits in the fibre. PMID- 18448125 TI - Interrelation between the inhibition of glycolytic flux by silibinin and the lowering of mitochondrial ROS production in perifused rat hepatocytes. AB - Silibinin, the most biologically active component of the polyphenolic extract from milk thistle seeds, is widely used to prevent many types of hepatobiliary disorders. Recent evidence suggests new applications for this ancient medication, notably for the treatment of type 2 diabetes owing to its antihyperglycemic properties. As we have lately demonstrated that silibinin lowered glucose production from various gluconeogenic substrates in perifused rat hepatocytes, the aim of this study was to examine the effect of silibinin on both oxidative glucose utilization and reactive oxygen species (ROS) generation since the release of ROS secondary to an increased mitochondrial metabolism may contribute to diabetic damage. We found that silibinin dose-dependently reduced glycolysis from carbohydrates in a cell perifusion system via an inhibitory effect targeted on pyruvate kinase activity. Furthermore, a dramatic effect upon oxidative phosphorylation was shown, as evidenced by a fall in ATP-to-ADP ratio, together with an increase in lactate-to-pyruvate ratio. The most attractive finding was that silibinin, at a concentration as low as 10 microM, fully mitigated the rise in metabolic flow-driven ROS formation. In addition, studies on isolated liver mitochondria revealed that this low dose of silibinin depressed ROS production linked to the electron transfer chain activity. From these results, one may tentatively suggest that interesting activities for silibinin, beyond its general antioxidant status, could be expected from its potential clinical use, especially in pathological conditions when mitochondrial ROS formation is severely enhanced. PMID- 18448126 TI - Reverse structure of carnosine-induced sedative and hypnotic effects in the chick under acute stress. AB - In the central nervous system, beta-alanine is thought to act as an inhibitory neurotransmitter, but the role or precise mechanism of beta-alanine in the brain has not been clearly defined. beta-Alanine is found in high levels in the chicken brain as a component of the dipeptides carnosine (beta-alanyl-L-histidine) and anserine, or as a free amino acid. We focused on the position of beta-alanine, i.e., at the carboxyl terminus. In Experiment 1, the central effects of glycyl beta-alanine, L-histidyl-beta-alanine and L-valyl-beta-alanine were compared with a saline control in chicks. L-Histidyl-beta-alanine significantly induced sedative and hypnotic effects. In Experiment 2, the effects of carnosine, its reverse (L-histidyl-beta-alanine), and their combination were investigated. Central carnosine-induced hyperactivity while reverse carnosine-induced hypoactivity, and the behaviors were intermediate following the combination of the two peptides. Finally, the central effect of reverse carnosine was compared with beta-alanine alone and L-seryl-beta-alanine in Experiment 3. Reverse carnosine showed similar effects to beta-alanine. In conclusion, L-histidyl-beta alanine not only has the reverse structure of carnosine, but also reverse function. Thus, we propose to name reverse carnosine (L-histidyl-beta-alanine) rev-carnosine. PMID- 18448127 TI - Effects of N-acetylcysteine amide (NACA), a thiol antioxidant on radiation induced cytotoxicity in Chinese hamster ovary cells. AB - Ionizing radiation is known to cause tissue damage in biological systems, mainly due to its ability to produce reactive oxygen species (ROS) in cells. Many thiol antioxidants have been used previously as radioprotectors, but their application has been limited by their toxicity. In this investigation, we have explored the possible radioprotective effects of a newly synthesized thiol antioxidant, N acetylcysteine amide (NACA), in comparison with N-acetylcysteine (NAC), a commonly used antioxidant. Protective effects of NACA and NAC were assessed using Chinese hamster ovary (CHO) cells, irradiated with 6 gray (Gy) radiation. Oxidative stress parameters, including levels of reduced glutathione (GSH), cysteine, malondialdehyde (MDA), and activities of antioxidant enzymes like glutathione peroxidase, glutathione reductase, and catalase, were measured. Results indicate that NACA was capable of restoring GSH levels in irradiated cells in a dose dependent manner. In addition, NACA prevented radiation-induced loss in cell viability. NACA further restored levels of malondialdehyde, caspase 3 activity, and antioxidant enzyme activities to control levels. Although NAC affected cells in a similar manner to NACA, its effects were not as significant. Further, NAC was also found to be cytotoxic to cells at higher concentrations, whereas NACA was non-toxic at similar concentrations. These results suggest that NACA may be able to attenuate radiation-induced cytotoxicity, possibly by its ability to provide thiols to cells. PMID- 18448128 TI - A cautionary tale about evaluating analytical methods to assess contamination after oil spills. PMID- 18448129 TI - Use of the clam Asaphis deflorata as a potential indicator of organochlorine bioaccumulation in Hong Kong coastal sediments. AB - In order to test its ability as a bioaccumulator, the deposit feeding clam Asaphis deflorata, collected from a clean coastal area in Hong Kong (Ding Chau, Ma On Shan), was exposed to field-collected sediments representing a gradient of contamination. Sediments were collected from four sites, namely Shek O in the southeast of Hong Kong Island, Ap Lei Chau in Aberdeen district, Tai Kok Tsui in the Mong Kok waterfront, and To Kwa Wan near Kowloon City pier. Shek O was the cleanest and To Kwa Wan was the most polluted site. Replicate 30L fiberglass tanks containing equal numbers of organisms were maintained for 28 days, with equal quantities of sediment and filtered seawater. Prior to this the animals were depurated for 10 days in clean sediment. During the 28-day holding period, sampling of both sediment and clams was performed on days 0, 10 and 28, along with condition index measurements. Concentrations of organochlorine pesticides and PCBs in sediments showed that Shek O was the cleanest of the sites, followed by Ap Lei Chau, Tai Kok Tsui and To Kwa Wan. There were marked differences among the sites, especially in PAH concentrations, with To Kwa Wan showing extremely high sediment concentrations. Following exposure, the biota concentrations of various organochlorine pesticides and PCBs suggested that there was sediment concentration-dependent accumulation by A. deflorata on day 10 of the experiment. However, there was no significant increase on day 28 for any of the compounds tested. Contaminant concentrations in clams feeding on Shek O sediments were minimal and almost the same on all sampling days, indicating the presence of only baseline contaminant concentrations. The condition indices (CI) of the clams on various sampling days showed that the animals were relatively more stable in sediment from Shek O. There were some deaths in all the test tanks (including those containing Shek O sediments). In addition, clams appeared to bury faster in the cleaner Shek O sediment and remained buried, unlike those in the sediment from the other locations, where some remained predominantly on the surface. Nevertheless, despite not completely burying, the clams in other test sediments still exhibited sediment concentration-dependent tissue accumulation. The results of the investigation indicate the possibility of developing a standard test protocol for bioaccumulation by sediment dwelling invertebrates, for practical use in Hong Kong, using A. deflorata. PMID- 18448130 TI - Controlling the number of HIV infectives in a mobile population. AB - The spread of the human immunodeficiency virus (HIV) depends prominently on the migration of people between different regions. An important consequence of this population mobility is that HIV control strategies that are optimal in a regional sense may not be optimal in a national sense. We formulate various mathematical control problems for HIV spread in mobile heterosexual populations, and show how optimal regional control strategies can be obtained that minimize the national spread of HIV. We apply the cross-entropy method to solve these highly multi modal and non-linear optimization problems. We demonstrate the effectiveness of the method via a range of experiments and illustrate how the form of the optimal control function depends on the mathematical model used for the HIV spread. PMID- 18448131 TI - Impaired flow-mediated vasodilation in type 2 diabetes: lack of relation to microvascular dysfunction. AB - A reduced availability of nitric oxide (NO) is an important feature of endothelial dysfunction occurring early in the course of type 2 diabetes. The measurement of flow-mediated dilation (FMD) of the brachial artery after forearm ischemia is supposed to be a non-invasive method to assess endothelial production and release of NO. The impairment of reactive hyperemia due to microvascular dysfunction in diabetes might cause an insufficient increase in shear stress stimulating the endothelial NO release, thus leading to an underestimation of FMD. Therefore, the aim of the present study was to investigate the relationship between microcirculatory disturbances and the impairment of FMD in type 2 diabetic patients. 63 type 2 diabetic patients and 44 non-diabetic control subjects were investigated. Capillary blood cell velocity (CBV) was assessed at the dorsal middle phalangeal area of the left ring finger. Lumen diameter of the brachial artery was measured by high-resolution ultrasound. Patients were investigated at rest and after 5-min suprasystolic arterial compression. Percentage change of CBV during reactive hyperemia (CBV%) and flow-mediated dilation (FMD%) of the brachial artery relative to the baseline measurement were calculated. CBV% (63.4+/-10.7% vs. 124.0+/-18.5%; p<0.01) and FMD% (3.8+/-0.8% vs. 6.9+/-0.9%; p<0.01) were reduced in the diabetic patients compared to their control subjects. FMD% was not related to CBV% (r=0.14; p=0.139). The lack of an association between the reduction of endothelium-dependent vasodilation of the brachial artery and the impairment of postocclusive microvascular hyperemia observed in the present study contradicts the assumption that a reduced FMD is only the consequence of an impaired reactive hyperemia due to microvascular dysfunction. It also lends support to the suggestion that endothelial dysfunction in conduit vessels and impaired cutaneous microvascular responses to reactive hyperemia might at least partly develop independently due to several differences in their pathogenesis. PMID- 18448132 TI - [Central nervous system neuromodulation for the treatment of epilepsy. II. Mechanisms of action and perspectives]. AB - OBJECTIVES: Review of available evidence of the mechanisms of action underlying the anticonvulsant effect of current applied to various CNS structures. MATERIAL AND METHODS: Studies were conducted from observations of patients with drug resistant seizures and treated with neuromodulation. Seizures originated from various cortical areas with secondary generalization or were initially generalized without a focal origin, either clinically or on EEG or SEEG. Intracranial recordings and SEEG were performed using subdural grids or depth electrodes implanted either for recordings or therapeutic deep brain stimulation (DBS). In a group of mesial temporal lobe epilepsy patients investigated with subdural or SEEG electrodes, the epileptogenic focus area was stimulated for 15 days before anterior temporal lobectomy. The surgical specimen was examined using standard and electronic microscopy and autoradiography in order to identify several neurotransmitter receptors. They also were compared to other surgical specimens from epileptic patients who had intracerebral recordings but without stimulation (epileptic controls) and to autopsy specimens from subjects with no history of epilepsy (nonepileptic controls). RESULTS: High-frequency (HF) stimulation increases the after-discharge threshold of the stimulated site and alters the cycles of potentials evoked by a test stimulation using a paradigm of coupled stimulations. HF stimulation also decreases local cerebral blood flow in the stimulated area as demonstrated on SPECT. Parahippocampal cortex HF stimulation significantly increases the GABAergic benzodiazepine receptor density in the stimulated area. In addition, centromedianum (CM) thalamic nucleus HF stimulation suppresses thalamic and cortical spike-waves, as well as secondary synchronous discharges visible on EEG. Conversely, low-frequency (3-Hz) bilateral CM stimulation induces a typical absence clinically and on EEG. CONCLUSION: High frequency stimulation is responsible for an inhibition of local and propagated epileptogenesis. Low-frequency stimulation may trigger or enhance epileptogenesis when applied on epileptogenic regions. PMID- 18448133 TI - [Central nervous system neuromodulation for the treatment of epilepsy]. AB - We present here a review of the work on neuromodulation - defined as application of an inhibitory or excitatory current - on intracranial structures for the treatment of drug-resistant epilepsy. Near 250 patients were treated using a neuromodulation technique of the cerebellum (paravermian cortex), the CM-pf nucleus of the thalamus, the hippocampus, epileptogenic foci, and anterior ventral nucleus of the thalamus, with a one- to 15-year follow-up. Four contact strips were used for cerebellar and functional region neuromodulation, and DBS type depth electrodes were stereotactically implanted for CM-pf and anterior nuclei of the thalamus and hippocampal neuromodulation. Electric stimulation was cyclic in almost all trials, using low frequency (10-40 Hz) for excitation and high frequency (60-185 Hz) for inhibition. Seizure frequency reduction was variable, depending on the neuromodulation site and patient selection, although seizure duration decreased in most patients. Cerebellar neuromodulation was followed by a 78% reduction in tonic and tonic-clonic seizures, CM-pf neuromodulation by an 83% reduction in tonic-clonic seizures and atypical absence of Lennox-Gastaut syndrome, with a 17.2% seizure-free and drug-free patient rate. Hippocampal neuromodulation was followed by a 73% reduction in partial complex seizures, with a 33% seizure-free patient rate. Anterior ventral nucleus of the thalamus was followed by a 63% reduction in tonic-clonic, tonic and atonic seizures. Several prognostic factors were identified in order to improve future results. There was no mortality and morbidity was limited to skin erosion at the neurostimulator site. Seizure reduction was associated with improved neuropsychological performance and better quality of life. Neuromodulation is safe and effective for the treatment of epileptic seizures of various origins. Several targets may be associated in a single patient, especially when bilateral hippocampal seizure foci are present. PMID- 18448134 TI - [Psychosocial adjustment after epilepsy surgical treatment]. AB - Epilepsy is a matter of interest to several medical specialities: neurology, neurosurgery, pathology, psychiatry, and other fields of knowledge such as psychology and sociology. Although a high prevalence of psychopathological disorders is often reported among epileptic patients who are candidates for neurosurgery, this cannot explain the problems that may be experienced by patients after surgery. Numerous related aspects such as neurological, psychological and sociological factors cause disturbances. This study suggests that systematic psychological and social management might help in the transition from chronic disability to wellness by means of improved adjustment potential. PMID- 18448135 TI - [Surgical treatments for epilepsy. Preface]. PMID- 18448136 TI - [Psychiatric assessment]. AB - Psychiatric disorders and behavioral disturbances may complicate the postsurgical outcome in patients and de novo psychiatric symptoms have been reported. In numerous, but not all epilepsy surgical centers, a psychiatric assessment is included as part of the presurgical evaluation of potential candidates for surgery. Affective disorders and psychosis are the most frequently reported postsurgical psychiatric disorders. There are no absolute psychiatric contraindications to surgery. Specific preexisting psychiatric conditions may need cautious consideration because there may be a risk of postsurgical psychiatric complications. Routine pre- and postsurgical psychiatric evaluations in patients undergoing epilepsy surgery are urgently needed. Clinicians involved in the care of surgical candidates should be aware of the possible psychiatric complications following surgery. PMID- 18448137 TI - [Indications for surgery in childhood epilepsies: when and how should children be operated?]. PMID- 18448139 TI - Cholesterol esterification reduces the neurotoxicity of prions. AB - The transmissible spongiform encephalopathies develop following the conversion of a host-encoded protein (PrP(C)) into abnormally folded, disease-related isoforms (PrP(Sc)). Here we report that three acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors, TMP-153, FR179254 or YIC-C8-434, were more toxic to prion infected neuronal cell lines (ScGT1 and ScN2a cells) than to their uninfected equivalents (GT1 and N2a cells). The toxicity of ACAT inhibitors for ScGT1 cells was not reversed by the addition of cholesterol esters, rather it was increased by the addition of free cholesterol indicating that the toxicity of ACAT inhibitors was related to the increased free cholesterol content of cells rather than reduced amounts of cholesterol esters. This hypothesis was strengthened by the observation that the addition of free cholesterol killed ScGT1, but not GT1 cells. Treatment with ACAT inhibitors increased caspase-3 activity and prostaglandin E(2) production in ScGT1 cells but not in GT1 cells. The addition of the phospholipase A(2) (PLA(2)) inhibitors (AACOCF(3) or MAFP) reduced prostaglandin E(2) production and protected ScGT1 cells against the toxicity of ACAT inhibitors. These results indicate that cholesterol esterification is an important cellular response that reduces PrP(Sc)-induced activation of PLA(2) and protects against cell death in ScGT1 cells. PMID- 18448138 TI - Extending the analysis of nicotinic receptor antagonists with the study of alpha6 nicotinic receptor subunit chimeras. AB - Heterologous expression systems have increased the feasibility of developing selective ligands to target nicotinic acetylcholine receptor (nAChR) subtypes. However, the alpha6 subunit, a component in nAChRs that mediates some of the reinforcing effects of nicotine, is not easily expressed in systems such as the Xenopus oocyte. Certain aspects of alpha6-containing receptor pharmacology have been studied by using chimeric subunits containing the alpha6 ligand-binding domain. However, these chimeras would not be sensitive to an alpha6-selective channel blocker; therefore we developed an alpha6 chimera (alpha4/6) that has the transmembrane and intracellular domains of alpha6 and the extracellular domain of alpha4. We examined the pharmacological properties of alpha4/6-containing receptors and other important nAChR subtypes, including alpha7, alpha4beta2, alpha4beta4, alpha3beta4, alpha3beta2, and alpha3beta2beta3, as well as receptors containing alpha6/3 and alpha6/4 chimeras. Our data show that the absence or presence of the beta4 subunit is an important factor for sensitivity to the ganglionic blocker mecamylamine, and that dihydro-beta-erythroidine is most effective on subtypes containing the alpha4 subunit extracellular domain. Receptors containing the alpha6/4 subunit are sensitive to alpha-conotoxin PIA, while receptors containing the reciprocal alpha4/6 chimera are insensitive. In experiments with novel antagonists of nicotine-evoked dopamine release, the alpha4/6 chimera indicated that structural rigidity was a key element of compounds that could result in selectivity for noncompetitive inhibition of alpha6-containing receptors. Our data extend the information available on prototypical nAChR antagonists, and establish the alpha4/6 chimera as a useful new tool for screening drugs as selective nAChR antagonists. PMID- 18448140 TI - Guaianolide sesquiterpenes from Pulicaria crispa (Forssk.) Oliv. AB - A phytochemical study of the asteraceous herb Pulicaria crispa (Forssk.) Oliv. resulted in the characterisation of three guaianolide sesquiterpenes, 2alpha,4alpha-dihydroxy-7alphaH,8alphaH,10alphaH-guaia-1(5),11(13)-dien-8beta,12 olide (1), 1alpha,2alpha-epoxy-4beta-hydroxy-5alphaH,7alphaH,8alphaH,10alphaH guaia-11(13)-en-8beta,12-olide (2) and 5,10-epi-2,3-dihydroaromatin (3). The structures were assigned on the basis of extensive 1 and 2D NMR experiments. Compound 3 exhibited weak antimycobacterial activity against Mycobacterium phlei with a minimum inhibitory concentration of 0.52 mM and cytotoxicity (IC50 of 5.8+/-0.2 microM) in a human bladder carcinoma cell line, EJ-138. PMID- 18448141 TI - Evidence for a blockwise distribution of acetyl groups onto homogalacturonans from a commercial sugar beet (Beta vulgaris) pectin. AB - Commercial acid-extracted sugar beet pectin was extensively hydrolysed using an endo-polygalacturonase (AnPGI from Aspergillus niger or AnPGII from A. niger or FmPG from Fusarium moniliforme) in combination with Aspergillus aculeatus pectin methyl-esterase (AaPME). The homogalacturonan-derived oligogalacturonates released were quantified by high-performance anion-exchange chromatography and their structure determined by mass spectrometry. The different endo polygalacturonases exhibited variable tolerance towards acetyl groups. AnPGI was the most active and FmPG the less. A hypothetical homogalacturonan was constructed using the AnPGI-recovered oligogalacturonates as building blocks and the validity of the model was checked taking into account FmPG observed requirements and hydrolysis products. A blockwise repartition of the acetyl groups onto sugar beet pectin homogalacturonan is proposed. PMID- 18448142 TI - Nucleic acid distribution pattern in avian erythrocytes and mammalian lymphocytes: comparative studies by fluorescence microscopy and digital imaging analytical techniques. AB - Nucleated erythrocytes of healthy domestic chicken and ducks, and lymphocytes of healthy Sprague Dawley rats were evaluated for nucleic acid distribution pattern, employing light and fluorescence microscopy procedures, as well as digital imaging analytical methods. The results demonstrate a unique organization of nuclear DNA of mature chicken and duck erythrocytes, as well as immature duck erythrocytes, as delineated spherical nuclear bodies that mostly corresponded with euchromatin zones of the cells in routine Wright-stain blood smears. The nuclear DNA of the rat lymphocytes, on the other hand, was observed as a more diffuse green fluorescing nuclear areas, with punctate variably-sized diffuse areas of RNA red fluorescence. RNA red color fluorescence was also evident in the narrow cytoplasm of the lymphocytes, especially in large lymphocytes, in comparison with the cytoplasm of the mature avian erythrocytes that completely lacked any nucleic acid fluorescence. Nuclear RNA fluorescence was lacking in the mature chicken erythrocytes, compared with those of the mature and immature duck erythrocytes as well as lymphocytes of both avian and rats blood. The significance of these findings lies in the establishment of normal benchmarks for the nuclear and cytoplasmic nucleic acid pattern in eukaryotic cells. These normal benchmarks become valuable in rapid diagnostic situations associated with pathologies, such as the presence of viral nuclear and cytoplasmic inclusion bodies that can alter the nucleic acid pattern of the host cells, and in conditions of cellular abnormal protein aggregations. Variability of cellular nucleic acid pattern can also aid in prognostic assessments of neoplastic conditions. PMID- 18448143 TI - Molecular cloning and characterization of acid phosphatase in venom of the endoparasitoid wasp Pteromalus puparum (Hymenoptera: Pteromalidae). AB - The present study describes cDNA cloning, sequencing, enzyme activity determination and localization, and mRNA expression of acid phosphatase in the venom apparatus of an endoparasitoid, Pteromalus puparum. This is the first report of cloning a venom acid phosphatase gene which has been described in parasitoid wasps. The cDNA consisted of 1378bp with 1215bp open reading frame and encoded a sequence of 405 amino acids. A 23 residues N-terminal signal peptide was followed by a short 15 residues (25-39) histidine acid phosphatases phosphohistidine signature and a long 302 residues (24-325) acid phosphatase family domain. The deduced amino acid sequence shared 32-88% identity to its counterparts from other insects. Enzyme activity was measured by using p nitrophenyl phosphate (p-NPP) as substrate, and a high level of acid phosphatase activity in venom was detected. Optimal pH and temperature for this enzyme activity was 4.8 and 45 degrees C, respectively. Ultracytochemical analyses further revealed that strong enzyme activity was located in the nuclei and secretory vesicles of the venom gland secretory cells. Expression of the acid phosphatase gene was observed to be regulated at different developmental stages by RT-PCR analysis as it expressed immediately with low abundance after adult emergence, then increased to the high level at 2-4 days, followed by a drop to the low abundance after 4 days. Compared to the mRNA expression, a time-course related enzyme activity in an individual venom apparatus was also found. PMID- 18448144 TI - Dimerization of BTas is required for the transactivational activity of bovine foamy virus. AB - The BTas protein of bovine foamy virus (BFV) is a 249-amino-acid nuclear regulatory protein which transactivates viral gene expression directed by the long terminal repeat promoter (LTR) and the internal promoter (IP). Here, we demonstrate the BTas protein forms a dimeric complex in mammalian cells by using mammalian two hybrid systems and cross-linking assay. Functional analyses with deletion mutants reveal that the region of 46-62aa is essential for dimer formation. Furthermore, our results show that deleting the dimerization region of BTas did not affect the localization of BTas, but that it did result in the loss of its transactivational activity on the LTR and IP. Furthermore, BTas (Delta46 62aa) retained binding ability to the LTR and IP similar to that of the wild-type BTas. These data suggest the dimerization region is necessary for the transactivational function of BTas and is crucial to the replication of BFV. PMID- 18448145 TI - Oxidation of chlorfenvinphos in ultrapure and natural waters by ozonation and photochemical processes. AB - The chemical oxidation of the organophosphorus insecticide chlorfenvinphos, a priority pollutant in aquatic environments, has been conducted in ultrapure water, by means of single degradation agents (ozone and UV radiation), and by the Advanced Oxidation Processes constituted by combinations of these oxidants (O(3)/H(2)O(2) and UV/H(2)O(2)). The influence of the operating variables was discussed, and the degradation rates were evaluated by determining the rate constants for the reactions with ozone (k(O)(3)=3.7+/-0.2 L mol(-1)s(-1)) and OH radicals (k(OH)=(3.2+/-0.2)x10(9) L mol(-1)s(-1)), as well as the quantum yield for the photodegradation (around 0.1 mol E(-1), depending on the pH). Additionally, the ozonation of chlorfenvinphos in a natural water system (a surface water from a reservoir) was studied. The influence of the operating conditions on the insecticide removal efficiency was established, and the R(ct) parameter was evaluated. A kinetic model was proposed for the prediction of the elimination rate of chlorfenvinphos in the ozonation process and the results obtained reveal a good agreement between experimental results and predicted values. PMID- 18448146 TI - Indolent systemic mastocytosis associated with atypical small lymphocytic lymphoma: a rare form of concomitant lymphoproliferative disease. AB - Patients with systemic mastocytosis (SM) may acquire an associated hematologic non-mast cell (MC)-lineage disease (AHNMD). In most cases, a myeloid neoplasm is diagnosed, whereas the occurrence of a lymphoproliferative disease is an extremely rare event. We report on a patient with indolent SM associated with small lymphocytic lymphoma (SLL). The patient presented with lymphadenopathy, maculopapular exanthema, and elevated serum tryptase. The bone marrow biopsy showed focal MC aggregates together with SLL. As assessed by immunostaining, neoplastic MC were found to exhibit CD117 and CD25 but did not display CD5 or CD20, whereas SLL cells were found to coexpress CD5 and CD20 but did not express MC antigens. The KIT mutation D816V was detected in sorted CD34(+) cells and unfractionated marrow cells but not in CD5(+) SLL cells, confirming the coexistence of 2 distinct neoplasms. PMID- 18448147 TI - Mercury budget of a small forested boreal catchment in southeast Norway. AB - We present input and output fluxes of total mercury (Hg(tot)) and methyl mercury (MeHg) based on throughfall, litterfall and stream water samples from 2004/2005 from a small forested catchment (Langtjern) in Norway. Hg(tot) input via throughfall and litterfall was estimated to 6.7 and 2.7 microg m(-2) yr(-1), respectively, which is considerably lower than previously reported from other boreal catchments in Scandinavia. A likely cause for the low input flux is the sparseness and low productivity of the forest in the Langtjern catchment, with less atmospheric scavenging and lower litterfall fluxes than previously studied sites. In addition there has been a general decrease in mercury (Hg) in the atmosphere on the northern hemisphere in the last decade. The estimated output flux of Hg(tot) with surface water was 2.5 microg m(-2) yr(-1), which is comparable to what has been reported elsewhere. The ratio of Hg(tot) output flux to input flux was 26%, which is considerably higher than reported from other sites. This illustrates that catchment properties have greater importance for surface water export of Hg than the current atmospheric input. The estimated total soil pool of Hg(tot) in the catchment was 17.4 mg m(-2). This corresponds to roughly 8000 years of the current surface water output flux and 2000 years of the current input flux. PMID- 18448148 TI - On-road vehicle emission inventory and its uncertainty analysis for Shanghai, China. AB - As vehicle population and activity increase, vehicle emissions are becoming the most predominant source of air pollution in Shanghai, China. It has become important to accurately estimate the traffic emissions in this city. This paper presents a bottom-up approach based on the International Vehicle Emission (IVE) model to develop the vehicle emission inventory for Shanghai. The results show that the total emissions of CO, VOC, NO(X) and PM from vehicles in Shanghai in 2004 were 57.06 x 10(4) t, 7.75 x 10(4) t, 9.20 x 10(4) t and 0.26 x 10(4) t, respectively. About 20% of the total emissions were emitted during the cold start period. Heavy-duty vehicles such as trucks and buses contributed over half of NO(X) and PM. Motorcycles and mopeds provided 45.0% of VOC and 36.3% of PM. Light duty vehicles are the main source of CO emissions. An assessment of vehicle emissions by time of day and road type was also discussed. The three peak emission periods accounted for 54% to 56% of the total emissions during the day and more than 50% of the total emissions were emitted on the arterial roads. Finally, the study focused on the uncertainty analysis of two critical factors: emission factors and the estimate of the total Vehicle Kilometers Traveled (VKT). The analysis indicates that the emission factors calculated in this paper are close to those factors measured during on-road testing, and the difference between the VKT used in this paper and other calculations is less than 10%. PMID- 18448149 TI - Source impacts by volatile organic compounds in an industrial city of southern Taiwan. AB - This study investigates source impacts by airborne volatile organic compounds (VOC) at two sites designated for traffic and industry, in the largest industrial area Kaohsiung, southern Taiwan. The samples were collected at the two sites simultaneously during rush and non-rush hours in summer and autumn seasons. Same pattern of VOC groups were found at both sites: most abundant aromatics (78-95%) followed by alkanes (2-16%) and alkenes (0-6%). The BTEX concentration measured at the two sites ranged from 69 to 301 ppbC. Toluene, isopentane, ethylbenzene, and benzene were found to be the most abundant species. Speciation of VOCs was characterized with several skills including principal component factor analysis and BTEX characteristic ratios. Each of the resulted principal factors at the two sites explained over 80% of the VOCs data variance, and indicated that both of the sampling sites were influenced by both traffic and industrial sources with separately different levels. The remarkable patterns of the first two factors described not only the similarity but also the discrepancy at the two sampling sites, in terms of the source impacts. The high T/B ratios (7.56-14.25) observed at the industrial site implied the important impact from mobile emissions. The indicators, m,p-xylene/benzene and o-xylene/benzene, also confirmed the potential source of motor vehicles at both of the sampling sites. Air age assessment showed that more than half of the total observations located in the domain of fresh air. Low X/E ratios implied somewhat aged air mass transported to the sampling sites. The industrial site might not only encounter emissions from the industry sources, but also under unavoidable impact from the traffic sources. PMID- 18448150 TI - An ultrastructural study of Porphyromonas gingivalis-induced platelet aggregation. AB - One of the major pathogens of periodontitis, Porphyromonas gingivalis (P. gingivalis), has the ability to aggregate human platelets. To investigate the interaction between P. gingivalis and human platelets in platelet rich plasma (PRP), platelet aggregation was measured by an aggregometer based on laser light scattering (LS) methods, and an ultrastructural study was performed using electron microscopy. A sharp and rapid increase of small-sized platelet aggregates was observed immediately after the addition of P. gingivalis to PRP, followed by the formation of medium- and large-sized aggregates in 2-3 min. In contrast, when Staphylococcus aureus (S. aureus) was used in the control experiment, only a slight increase in small-sized aggregates was detected. By electron microscopy, discoid-shaped platelets were observed prior to adding P. gingivalis. By 5 min after the addition of the bacteria, enormous platelet aggregates were observable. Most of the P. gingivalis were present between the adherent platelets, while some were internalized in platelet engulfment vacuoles. In contrast, when washed platelets were incubated with the bacteria under a non stirring condition to prevent platelet aggregation, and stained with ruthenium red (RR) as an electron dense tracer of the cell surface including the open canalicular system (OCS), both RR-positive and -negative vacuoles containing P. gingivalis were identified in the activated platelets. Thus, this observation suggests that P. gingivalis residing in the RR-negative vacuoles is incorporated into the platelet cytoplasm by phagocytosis. PMID- 18448151 TI - Computational study on effect of red blood cells on primary thrombus formation. AB - The primary thrombus formation is a critical phenomenon both physiologically and pathologically. It has been seen that various mechanical factors are involved the regulation of primary thrombus formation through a series of physiological and biochemical processes, including blood flow and intercellular molecular bridges. However, it has not been fully understood how the existence of red blood cells contributes to the process of platelet thrombus formation. We computationally analyzed the motions of platelets in plasma layer above which red blood cells flow assuming a background simple shear flow of a shear rate of 1000 s(-1) using Stokesian dynamics. In the computation, fluid mechanical interactions between platelets and red blood cells were taken into account together with the binding forces via plasma proteins between two platelets and between a platelet and injured vessel wall. The process of the platelets aggregation was significantly dependent on whether red blood cells were present. When red blood cells were absent, the aggregate formed grew more vertically compared to the case with red blood cells. Conversely, when red blood cells were present, the aggregate spread more horizontally because the red blood cells constrained the vertical growth when the height of the aggregate reached the level of the red blood cells. Our results suggest that red blood cells mechanically play a significant role in primary thrombus formation, which accelerates the horizontal spread of the thrombus, and point out the necessity of considering the presence of red blood cells when investigating the mechanism of thrombus formation. PMID- 18448152 TI - The modified Je-Ho-Tang, Korean herbal medicine, inhibits whole-blood aggregation and platelet adhesion to collagen under flow. AB - We investigated the in vitro effect of modified Je-Ho-Tang (MJHT) hot-water extract on platelet aggregation and activation induced by agonists in human whole blood, and on platelet adhesion to a collagen-coated surface under flow shear stress conditions. MJHT extract potently inhibited the collagen-induced platelet aggregation in human whole blood in a dose-dependent manner, with a half-maximal inhibitory dose (IC(50)) value of 526 microg/mL. We accessed several markers of platelet activation using receptor expression on platelet membranes, including GPIIb/IIIa-like expression (PAC-1) and P-selectin (CD62); we monitored the intracellular calcium mobilization response by flow cytometry in healthy subjects. A significant decrease in PAC-1 (P=0.002), CD62 (P=0.002), and intracellular calcium mobilization (P<0.001) were seen in the presence of MJHT extract. In addition, we have used image analysis to study human platelet adhesion to collagen under physiologic flow conditions in a perfusion chamber. MJHT extract markedly decreased platelet adhesion to the collagen-coated surface. These results show that MJHT has potent anti-platelet activity. PMID- 18448153 TI - Lipopolysaccharide augments venous and arterial thrombosis in the mouse. AB - BACKGROUND: Animal models of diseases are essential for therapeutic target validation, drug discovery and development. Increasing evidence has demonstrated the importance of inflammation in thrombosis. Here, murine models of vena cava thrombosis and carotid arterial thrombosis augmented by lipopolysaccharide (LPS) were established and characterized to study the association between inflammation and thrombosis. MATERIALS AND METHODS: Murine (C57BL/6 mice) models of ferric chloride (FeCl(3))-induced carotid arterial and vena cava thrombosis were established. Thrombus formation was measured indirectly by Doppler blood flow (i.e., clot functional interference with blood flow) in the arterial thrombosis model and directly by protein content of the clot in the venous thrombosis model. An optimal concentration of FeCl(3) was defined to induce thrombus formation and used to study the effects of LPS (i.e., a well-known inflammatory stimulus under these conditions). Real-time polymerase chain reaction (PCR) was used to examine the effect of LPS on TNFalpha and IL-1beta mRNA expression in thrombus formation. RESULTS: Dose-dependent analysis demonstrated that 2 mg/kg, i.p., LPS provided a maximal prothrombotic effect in 2.5% ferric chloride-induced vena cava thrombosis, with a 60% increase in thrombus size (n=8, p<0.05) compared to vehicle treatment. In contrast, 2 mg/kg LPS had no significant effect on thrombus formation in a more severe, 3.5% FeCl(3)-induced vena cava thrombosis. A similar prothrombotic effect was observed for LPS in 2.5% FeCl(3)-induced carotid arterial thrombosis model. Treatment of 2 mg/kg LPS significantly augmented arterial thrombosis immediately (between 5-30 minutes) following FeCl(3) injury as assessed by change of Doppler blood flow (n=8, p<0.05). Real-time PCR demonstrated significant induction of TNFalpha and IL-1beta mRNA expression in the thrombus formation in the vessels in response to LPS challenge. CONCLUSION: These data demonstrate that LPS augments thrombus formation in acute vascular injury and that LPS-augmented thrombosis might be a useful tool to study the relationship between inflammation and thrombosis. PMID- 18448154 TI - Transdermal 17-beta estradiol replacement therapy reduces megakaryocyte GPVI expression. AB - The platelet-collagen interaction is a critical early event in arterial thrombus formation, and platelet GPVI is the major activating receptor for collagen. We have previously used a mouse model to demonstrate that the estrogen effects on platelets depend upon the agonist, estrogen formulation and route of administration. In the current study we used a model of transdermal estradiol (E2) administration to ovariectomized mice to address the potential inhibitory effects of E2 on platelet GPVI. Platelet GPVI expression was reduced after transdermal E2 replacement therapy (p G) promoter polymorphisms and risk for cervical cancer. AB - OBJECTIVES: Matrix metalloproteinase (MMP-7) is a secreted matrilysin, which contributes to tumor progression through breakdown of basement membranes and angiogenesis. Therefore, we aimed to investigate the association of MMP-7 -181A>G gene polymorphism with risk of cervical cancer. METHODS: In the present case control study, we enrolled a total of 150 cervical cancer patients confirmed by histopathology and 162 unrelated healthy individuals. Polymorphism for MMP-7 gene (-181A>G) was genotyped by polymerase chain reaction and restriction enzyme length polymorphism. RESULTS: Frequency of MMP-7 -181GG genotype and -181G allele differed significantly between patients with cervical cancer (29.3%) and healthy individuals (19.4%) (P=0.041; OR(GG)=1.94 and P=0.048; OR(G)=1.94). Individuals with MMP-7 -181GG genotype were at higher risk of stage II of cervical cancer with borderline significance (P=0.05, OR=2.78; 95%CI: 0.89-8.69). However, interaction of MMP-7 -181AG and GG genotypes with tobacco usage did not modulate the cervical cancer risk significantly (OR 2.21, 95%CI=0.59-8.1 and OR 3.17, 95%CI=0.64-15.7). CONCLUSION: Individuals with MMP-7 -181GG genotype were at significantly higher risk of cervical cancer. PMID- 18448156 TI - Ovarian normal and tumor-associated fibroblasts retain in vivo stromal characteristics in a 3-D matrix-dependent manner. AB - OBJECTIVE: Due to a lack of experimental systems, little is known about ovarian stroma. Here, we introduce an in vivo-like 3-D system of mesenchymal stromal progression during ovarian tumorigenesis to support the study of stroma permissiveness in human ovarian neoplasias. METHODS: To sort 3-D cultures into 'normal,' 'primed' and 'activated' stromagenic stages, 29 fibroblastic cell lines from 5 ovarian tumor samples (tumor ovarian fibroblasts, TOFs) and 14 cell lines from normal prophylactic oophorectomy samples (normal ovarian fibroblasts, NOFs) were harvested and characterized for their morphological, biochemical and 3-D culture features. RESULTS: Under 2-D conditions, cells displayed three distinct morphologies: spread, spindle, and intermediate. We found that spread and spindle cells have similar levels of alpha-SMA, a desmoplastic marker, and consistent ratios of pFAKY(397)/totalFAK. In 3-D intermediate cultures, alpha-SMA levels were virtually undetectable while pFAKY(397)/totalFAK ratios were low. In addition, we used confocal microscopy to assess in vivo-like extracellular matrix topography, nuclei morphology and alpha-SMA features in the 3-D cultures. We found that all NOFs presented 'normal' characteristics, while TOFs presented both 'primed' and 'activated' features. Moreover, immunohistochemistry analyses confirmed that the 3-D matrix-dependent characteristics are reminiscent of those observed in in vivo stromal counterparts. CONCLUSIONS: We conclude that primary human ovarian fibroblasts maintain in vivo-like (staged) stromal characteristics in a 3-D matrix-dependent manner. Therefore, our stromal 3-D system offers a tool that can enhance the understanding of both stromal progression and stroma-induced ovarian tumorigenesis. In the future, this system could also be used to develop ovarian stroma-targeted therapies. PMID- 18448158 TI - Proximity of fast food restaurants to schools: do neighborhood income and type of school matter? AB - OBJECTIVES: To investigate the proximity of fast food restaurants to public schools and examine proximity by neighborhood income and school level (elementary, middle, or high school). METHODS: Geocoded school and restaurant databases from 2005 and 2003, respectively, were used to determine the percentage of schools with one or more fast food restaurants within 400 m and 800 m of all public schools in Los Angeles County, California. Single-factor analysis of variance (ANOVA) models were run to examine fast food restaurant proximity to schools by median household income of the surrounding census tract and by school level. Two-factor ANOVA models were run to assess the additional influence of neighborhood level of commercialization. RESULTS: Overall, 23.3% and 64.8% of schools had one or more fast food restaurants located within 400 m and 800 m, respectively. Fast food restaurant proximity was greater for high schools than for middle and elementary schools, and was inversely related to neighborhood income for schools in the highest commercial areas. No association with income was observed in less commercial areas. CONCLUSIONS: Fast food restaurants are located in close proximity to many schools in this large metropolitan area, especially high schools and schools located in low income highly commercial neighborhoods. Further research is needed to assess the relationship between fast food proximity and student dietary practices and obesity risk. PMID- 18448159 TI - Heat shock at the germinal vesicle breakdown stage induces apoptosis in surrounding cumulus cells and reduces maturation rates of porcine oocytes in vitro. AB - The objectives were to determine the effects of cumulus cells (CC) on porcine oocyte maturation in vitro (IVM) after heat shock (HS). Treated oocytes were cultured at 39 degrees C for 20h, followed by HS treatment (42 degrees C for 1h), and then matured in vitro for 23h. The CC were removed before maturation (H1), after HS (H2), or after maturation (H3). Control oocytes were continuously cultured under the same conditions and CC were similarly removed before maturation (C1), after 21h of IVM (C2), and after maturation (C3). Maturation rates were affected by HS (P<0.01) and by an interaction between HS and CC (P<0.01). A significant decrease in maturation rate only occurred when CC were not removed from cumulus oocyte complexes during IVM after HS (H3, 39.2+/-5.7% versus C3, 78.2+/-8.2%, P<0.01). Mature oocytes in all treatment groups were electrically activated and cultured for 8 d in NCSU23. Blastocyst rates in group H1 (7.2+/-3.5%) and C1 (6.3+/-3.1%) were lower than in other groups (H2, 21.4+/ 4.4%, C2, 20.5+/-7.0%, H3, 23.1+/-2.0%, C3, 24.3+/-3.1%, P<0.05). Damaged DNA was detected in CC by a comet assay at 0h after HS (60.8+/-12.5% compared with 9.2+/ 2.2% in control, P<0.05); in HS groups, both DNA damage (comet assay, 74.9+/-6.3% compared with 10.0+/-2.1% in control) and apoptosis (TUNEL assay, 21.6+/-1.6% compared with 5.6+/-0.6% in control) in CC were increased (P<0.05) at 44h of maturation. In conclusion, heat shock (42 degrees C for 1h) during IVM induced DNA damage and apoptosis of porcine CC; furthermore, apoptotic CC may contribute to maturation failure of oocytes in vitro. PMID- 18448160 TI - Induction of specific cell responses to a Ca(3)SiO(5)-based posterior restorative material. AB - OBJECTIVES: A Ca(3)SiO(5)-based cement has been developed to circumvent the shortcomings of traditional filling materials. The purpose of this work was to evaluate its genotoxicity, cytotoxicity and effects on the target cells' specific functions. METHODS: Ames' test was applied on four Salmonella typhimurium strains. The micronuclei test was studied on human lymphocytes. The cytotoxicity (MTT test), the Comet assay and the effects on the specific functions by immunohistochemistry were performed on human pulp fibroblasts. RESULTS: Ames' test did not show any evidence of mutagenicity. The incidence of lymphocytes with micronuclei and the percentage of tail DNA in the Comet assay were similar to the negative control. The percentage of cell mortality with the new cement as performed with the MTT test was similar to that of biocompatible materials such as mineral trioxide aggregate (MTA) and was less than that obtained with Dycal. The new material does not affect the target cells' specific functions such as mineralization, as well as expression of collagen I, dentin sialoprotein and Nestin. SIGNIFICANCE: The new cement is biocompatible and does not affect the specific functions of target cells. It can be used safely in the clinic as a single bulk restorative material without any conditioning treatment. It can be used as a potential alternative to traditionally used posterior restorative materials. PMID- 18448161 TI - Temperature excursions at the pulp-dentin junction during the curing of light activated dental restorations. AB - OBJECTIVES: Excessive heat produced during the curing of light-activated dental restorations may injure the dental pulp. The maximum temperature excursion at the pulp-dentin junction provides a means to assess the risk of thermal injury. In this investigation we develop and evaluate a model to simulate temperature increases during light-curing of dental restorations and use it to investigate the influence of several factors on the maximum temperature excursion along the pulp-dentin junction. METHODS: Finite element method modeling, using COMSOL 3.3a, was employed to simulate temperature distributions in a 2D, axisymmetric model tooth. The necessary parameters were determined from a combination of literature reports and our measurements of enthalpy of polymerization, heat capacity, density, thermal conductivity and reflectance for several dental composites. Results of the model were validated using in vitro experiments. RESULTS: Comparisons with in vitro experiments indicate that the model provides a good approximation of the actual temperature increases. The intensity of the curing light, the curing time and the enthalpy of polymerization of the resin composite were the most important factors. The composite is a good insulator and the greatest risk occurs when using the light to cure the thin layer of bonding resin or in deep restorations that do not have a liner to act as a thermal barrier. SIGNIFICANCE: The results show the importance of considering temperature increases when developing curing protocols. Furthermore, we suggest methods to minimize the temperature increase and hence the risk of thermal injury. The physical properties measured for several commercial composites may be useful in other studies. PMID- 18448162 TI - The use of N-terminal immobilization of PTH(1-34) on PLGA to enhance bioactivity. AB - The objective of this work was to control the orientation of bioactive molecules immobilized on a biodegradable substrate to improve their accessibility for binding to cell surface receptors and, therefore, to increase bioactivity. The osteotropic peptide, parathyroid hormone (1-34) (PTH(1-34)), was used to demonstrate the approach. To this end, the intrinsic N-terminal serine residue was oxidized to create an aldehyde group that specifically bound to hydrazide derivatized poly(lactide-co-glycolide) under neutral conditions to form a hydrazone bond. Use of dihydrazide spacers significantly increased the amount of peptide immobilized compared to simple adsorption or direct, random attachment. In probing accessibility of immobilized PTH(1-34), attachment using longer dihydrazide spacers enhanced binding of an antibody against an epitope in the N terminal region of the peptide. The longest spacer also increased binding of a C terminal antibody. Furthermore, substrates with peptide tethered via spacers stimulated intracellular synthesis of cAMP, with activity increasing with dihydrazide length. PTH(1-34) immobilized using the longest spacer was significantly more effective than both random binding and adsorption. Site directed binding of bioactive peptides to surfaces presents biomolecules for binding with cells so as to enhance interaction with receptors, and therefore the approach may be useful for obtaining preferred localized tissue responses. PMID- 18448164 TI - Development of biodegradable electrospun scaffolds for dermal replacement. AB - Our objective is to develop a synthetic biodegradable replacement dermal substitute for tissue engineering of skin and oral mucosa. Our in vivo criteria were that candidate scaffolds should allow surrounding cells to migrate fully into the scaffolds, enabling vasculogenesis and remodelling without invoking a chronic inflammatory response. We examined a total of six experimental electrospun polymer scaffolds: (1) poly-l-lactide (PLLA); (2) PLLA+10% oligolactide; (3) PLLA+rhodamine and (4-6) three poly(d,l)-lactide-co-glycolide (PLGA) random multiblock copolymers, with decreasing lactide/glycolide mole fractions (85:15, 75:25 and 50:50). These were evaluated for degradation in vitro up to 108 days and in vivo in adult male Wistar rats from 4 weeks to 12 months. In vivo, all scaffolds permitted good cellular penetration, with no adverse inflammatory response outside the scaffold margin and with no capsule formation around the periphery. The breakdown rate for each scaffold in vitro versus in vivo was similar, and an increase in the ratio of polyglycolide to polylactide correlated with an increase in breakdown rate, as expected. Scaffolds of PLLA were stable in vivo even after 12 months whereas scaffolds fabricated from PLGA 85:15 and 75:25 revealed a 50% loss of mass after 4 and 3 months, respectively. In vitro PLGA 85:15 and 75:25 scaffolds were able to support keratinocyte, fibroblast and endothelial cell growth and extracellular matrix production, with evidence of new collagen production after 7 days. In conclusion, the data supports the development of PLGA 85:15 and 75:25 electrospun polymer scaffolds as potential degradable biomaterials for dermal replacement. PMID- 18448163 TI - The role of aligned polymer fiber-based constructs in the bridging of long peripheral nerve gaps. AB - Peripheral nerve regeneration across long nerve gaps is clinically challenging. Autografts, the standard of therapy, are limited by availability and other complications. Here, using rigorous anatomical and functional measures, we report that aligned polymer fiber-based constructs present topographical cues that facilitate the regeneration of peripheral nerves across long nerve gaps. Significantly, aligned but not randomly oriented fibers elicit regeneration, establishing that topographical cues can influence endogenous nerve repair mechanisms in the absence of exogenous growth promoting proteins. Axons regenerated across a 17 mm nerve gap, reinnervated muscles, and reformed neuromuscular junctions. Electrophysiological and behavioral analyses revealed that aligned but not randomly oriented constructs facilitated both sensory and motor nerve regeneration, significantly improved functional outcomes. Additionally, a quantitative comparison of DRG outgrowth in vitro and nerve regeneration in vivo on aligned and randomly oriented fiber films clearly demonstrated the significant role of sub-micron scale topographical cues in stimulating endogenous nerve repair mechanisms. PMID- 18448165 TI - Clinical features and outcome of MLL gene rearranged acute lymphoblastic leukemia in infants with additional chromosomal abnormalities other than 11q23 translocation. AB - The treatment outcome for infant acute lymphoblastic leukemia (ALL) with positive MLL gene rearrangements remains poor. We analyzed whether additional chromosomal abnormalities (ACA) other than 11q23 translocation could affect the disease behavior and its prognosis. Eighteen of seventy-four patients with infant acute lymphoblastic leukemia showed ACA, including three-way translocations in four, other novel translocations in four, and complex structural chromosomal changes in four. Only age less than 6 months and positive central nervous system leukemia were significant prognostic factors by multivariate analysis. However, overall survival rates were worse in patients with ACA compared to those with non-ACA. Genetic alterations induced by additional chromosomal changes may be associated with disease progression and poorer overall survival rates in infants with MLL rearranged ALL. PMID- 18448166 TI - Emergence of therapy-unrelated CML on a background of BCR-ABL-negative JAK2V617F positive chronic idiopathic myelofibrosis. AB - We report the emergence of a chronic myeloid leukaemia (CML) during the course of a JAK2V617F-positive chronic idiopathic myelofibrosis (CIMF) in the absence of any myelosuppressive treatment. Although a response to imatinib was observed, the underlying myelofibrosis persisted after treatment and hydroxyurea was finally added to control the persistent thrombocytosis. Such rare patients with co existing BCR-ABL translocation and JAK2V617F mutation must be identified in view of the possibility of targeted therapies. Moreover, the detection of BCR-ABL translocation appears to be crucial especially in the case of treated CIMF with an atypical course to identify CML before acute transformation. PMID- 18448167 TI - Conventional and future diagnostics for avian influenza. AB - The significant and continued transboundary spread of Asian avian influenza H5N1 since 2003, paired with documented transmission from avian species to humans and other mammals, has focused global attention on avian influenza virus detection and diagnostic strategies. While the historic and conventional laboratory methods used for isolation and identification of the virus and for detection of specific antibodies continued to be widely applied, new and emerging technologies are rapidly being adapted to support avian influenza virus surveillance and diagnosis worldwide. Molecular tools in particular are advancing toward lab-on-chip and fully integrated technologies that are capable of same day detection, pathotyping, and phylogenetic characterization of influenza A viruses obtained from clinical specimens. The future of avian influenza diagnostics, rather than moving toward a single approach, is wisely adopting a strategy that takes advantage of the range of conventional and advancing technologies to be used in "fit-for-purpose" testing. PMID- 18448168 TI - Epidemiology of H5N1 avian influenza. AB - High pathogenic (HP) H5N1 avian influenza (AI) infection has been reported in domestic poultry, wildlife, and human populations since 1996. Risk of infection is associated with direct contact with infected birds. The mode of H5N1 spread from Asia to Europe, Africa and the Far East is unclear; risk factors such as legal and illegal domestic poultry and exotic bird trade, and migratory bird movements have been documented. Measures used to control disease such as culling, stamping out, cleaning and disinfection, and vaccination have not been successful in eradicating H5N1 in Asia, but have been effective in Europe. PMID- 18448169 TI - The effect of social roles on mental health: a matter of quantity or quality? AB - The effect of social roles (partner, parent, worker) on mental health may depend on the total number or the quality of the individual occupied social roles. With longitudinal data from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), the effect of the number and quality of occupied social roles on mental health over three years was examined among 2471 men and women aged 25-55 years without mental disorders at baseline. Mental health was assessed using 3 year change in the SF-36 mental health scale as well as using the 3-year incidence of anxiety and depressive disorders defined by DSM-III criteria. The quality of social roles was assessed by the GQSB (Groningen Questionnaire Social Behavior). The number of social roles had no significant effect on the risk of developing depressive and anxiety disorders, but particularly the partner-role had a significant positive effect on mental health (beta of mental health=1.19, p=0.01; HR of incident disorders=0.75, 95% CI:0.51-1.00, p=0.05). A good quality of each of the three social roles was associated with higher levels of mental health and lower risks of incident disorders over 3 years. More than the number of social roles, knowledge about social role quality might provide opportunities for prevention of depressive and anxiety disorders. PMID- 18448170 TI - Is the association of hypertension and panic disorder explained by clustering of autonomic panic symptoms in hypertensive patients? AB - BACKGROUND: Autonomic nervous system dysfunction may be implicated in the association of hypertension with panic attacks and panic disorder. We hypothesised that panic symptoms of autonomic origin are more common in attacks experienced by hypertensive than normotensive patients, that autonomic panic symptoms cluster together as a distinct factor, and that this factor is more prevalent in hypertensive patients with panic than in normotensives. METHODS: We analysed all 346 structured questionnaires completed by primary care and hospital clinic patients who had reported experiencing full (n=287) or limited symptom panic attacks (n=59) (268 with hypertension, and 78 never having had hypertension). Frequency of sweating, flushes, and racing heart, symptoms selected prospectively as being most likely of autonomic origin, were compared between hypertensive and normotensive patients. Principal component analysis was performed with varimax orthogonal rotation. Using logistic regression, odds ratios were calculated for association of factor scores with hypertension. RESULTS: Sweating and flushes were significantly more common among hypertensive patients than normotensives (sweating; 65% v 46%, p=0.003, flushes; 55% v 40%, p=0.019). There was no significant difference between groups for frequency of racing heart nor any of the remaining panic symptoms analysed as secondary endpoints. Principal component analysis yielded four factors with eigenvalues >1.0. Factor 1 was dominated by autonomic symptoms, notably sweating and flushes, which had loadings of 0.68 and 0.61. On regression only this autonomic factor showed a significant association with hypertension, the odds ratio being 1.37 (95% C.I. 1.05 to 1.77, p=0.018). CONCLUSIONS: These findings support the possibility that autonomic dysfunction contributes to the association of hypertension with panic. PMID- 18448171 TI - Impairment of motor dexterity in schizophrenia assessed by a novel finger movement test. AB - Schizophrenia is characterized by a series of serious mental disturbances, including social, cognitive, and emotional dysfunctions. Although motor dysfunctions as well as the cognitive impairments in schizophrenia have been noted since the era of Kraepelin, little attention has been paid to motor dysfunctions until recently. Here, we examined the characteristics of motor dysfunctions and their relationship to other cognitive functions in schizophrenia. Subjects were 27 patients who met the DSM-IV criteria for schizophrenia and 49 healthy volunteers. A series of motor tests, i.e., pegboard, mirror drawing, normal drawing, and finger movement tests, were administered, and cognitive functions were assessed with the Wechsler Adult Intelligence Scale Revised, the Wechsler Memory Scale Revised and the Wisconsin Card Sorting Test. The finger movement test is a novel motor test that we developed to assess motor dexterity independent of motor speed. A stepwise discriminant analysis revealed that the finger movement and delayed recall tests were able to distinguish patients and controls most effectively. The scores of these two tests showed no correlation. Educational level was correlated with the delayed recall score, but not with the finger movement score. A significant difference was observed in the finger movement test score between inpatients and outpatients. There was no significant correlation between dosage of antipsychotic drugs and finger movement score in the patient group. The present results suggest that impairment in motor dexterity is a major characteristic of schizophrenia, which might be independent of cognitive functions. PMID- 18448172 TI - Distribution of serotonin immunoreactivity in the spiral ganglion neurons of mouse cochlea. AB - OBJECTIVE: Serotonin (5-hydroxytryptamine, 5-HT) is a neuromodulator/neurotransmitter with multiple biological functions. Spiral ganglion cells in the cochlea are the primary neurons of the afferent system in the auditory transmission. In this study, we used the immunohistochemical technique to investigate the distribution of serotonin in the spiral ganglion of mouse cochlea. MATERIALS AND METHODS: The cochlea tissue of four adult mice was dissected and fixed. The immunohistochemical staining was applied by using goat anti-serotonin polyclonal antibody as primary antibody. Tissue sections were treated with biotin-labeled rabbit anti-goat immunoglobulin G, followed by adding streptavidin-biotin-peroxidase complex. Finally, the sections were stained with 3,3-diaminobenzidine (DAB) solution. RESULTS: The spiral ganglion exhibited pronounced immunoreactivity for serotonin. Specifically, serotonin immunoreactivity was detected in the cytoplasma of spiral ganglion neurons located in Rosenthal's canal of the bony modiolus of mouse cochlea. CONCLUSIONS: Since spiral ganglion neurons are the afferent neurons to the auditory sense organ, our result strongly suggests that serotonin molecule may function as a neuromodulator/neurotransmitter in the peripheral auditory processing. PMID- 18448173 TI - Aspiration following CO(2) laser-assisted supraglottoplasty. AB - OBJECTIVE: To review the incidence, risk factors, and treatment of aspiration following CO(2) laser-assisted supraglottoplasty for severe laryngomalacia (LM). DESIGN: IRB approved retrospective study of pediatric patients with severe LM treated with CO(2) laser supraglottoplasty over a 5-year period. SETTING: Tertiary pediatric hospital. PATIENTS: Fifty-two patients met inclusion criteria. Indication for supraglottoplasty was respiratory distress in 90% of patients and/or failure to thrive in 19%. INTERVENTIONS: All children underwent bilateral CO(2) laser supraglottoplasty and were assessed postoperatively with swallow evaluation by a speech pathologist. Videoflouroscopic evaluation was utilized to confirm aspiration and guide management. MAIN OUTCOME MEASURES: Aspiration, treatment required to manage aspiration, duration of treatment required. RESULTS: Thirty-seven percent (20/52) of patients had postoperative aspiration. Aspiration was demonstrated on videoflouroscopic swallow study (VFSS) after supraglottoplasty is 28% (12/43). All patients with newly diagnosed aspiration had treatment with thickened and/or nasogastric feedings with mean resolution time of 6 months. In nine children with preoperative aspiration, eight (89%) had postoperative aspiration and seven required gastrostomy tube placement for feeding management. All individuals requiring gastrostomy for aspiration management had neurological conditions. In the absence of preoperative clinically evident aspiration, children with neurological conditions have an equivalent rate of postoperative aspiration as healthy children. The only risk factor for postoperative aspiration was preoperative aspiration. CONCLUSION: Aspiration is more common after CO(2) laser-assisted supraglottoplasty than previously recognized. In otherwise healthy children, postoperative aspiration is of short duration and can be treated with conservative measures. Optimal treatment after supraglottoplasty includes screening for and management of aspiration in conjunction with a speech pathologist. PMID- 18448174 TI - Tadpole size, cholinesterase activity, and swim speed in four frog species after exposure to sub-lethal concentrations of chlorpyrifos. AB - While physiological biomarkers exist to verify exposure of amphibians in natural populations to agricultural chemicals, the ecological relevance of changes in these parameters is often difficult to determine. We compare the relationship between tadpole cholinesterase (ChE; a common enzymatic biomarker of exposure to OP pesticides) and measures of size and swim speed in four native North American species of anurans (Hyla chrysoscelis, Rana sphenocephala, Acris crepitans, and Gastrophryne olivacea). We used four environmentally realistic levels (1, 10, 100 and 200microg/l) of a commonly used organophosphate pesticide (OP), chlorpyrifos, and examined tadpole response at the conclusion of 4 days of exposure. We further examined if the presence or absence of pond sediment influenced tadpole responses, and, in two species, we determined how a 12-day exposure influenced responses. We found species-specific differences in response to the pesticide, with H. chrsysoscelis and G. olivacea being most sensitive; however, the levels of inhibition of ChE activity were generally not sufficient to exert an effect on swim speed as we measured it. Generally, tadpole mass was reduced 20-35% in the highest concentration after 4 days of exposure. We found the presence of sediment to influence these responses, although the effects were not consistent among species. Given these differences in ecologically relevant responses, we recommend exercising caution when making generalizations across different anuran amphibian taxa regarding responses to pesticide exposure. PMID- 18448176 TI - Measurements of secretogranins II, III, V and proconvertases 1/3 and 2 in plasma from patients with neuroendocrine tumours. AB - INTRODUCTION: Chromogranin (Cg) and secretogranin (Sg) are members of the granin family of proteins, which are expressed in neuroendocrine and nervous tissue. In recent publications we have presented generation of region-specific antibodies against CgA and CgB and also development of several region-specific radioimmunoassays for measurements of specific parts of the Cgs. In this study we describe generation of antibodies against SgII, SgIII, SgV and the proconvertases PC1/3 and PC2 and development of radioimmunoassays for measurements of these proteins. MATERIALS AND METHODS: Peptides homologous to defined parts of the secretogranin and proconvertase molecules were selected and synthesised. Antibodies were raised, radioimmunoassays were developed and circulating levels of the proteins in plasma samples from 22 patients with neuroendocrine tumours were measured in the assays. RESULTS: Increased plasma concentrations were recorded in 11, 4 and 3 of the patients with the SgII 154-165 (N-terminal secretoneurin), the SgII 172-186 (C-terminal Secretoneurin) and the SgII 225-242 assays respectively. The SgIII, SgV, PC1/3 and PC2 assays failed to detect increased concentrations in any of the patients. CONCLUSION: Increased concentrations of SgII, especially the N-terminal part of secretoneurin could be measured in plasma from patients with endocrine pancreatic tumours and in this case this assay was quite comparable to measurements of CgA and CgB. Even though secretoneurin was not as frequently increased as CgA and CgB in patients with carcinoid tumours or pheochromocytoma it may be a useful marker for endocrine pancreatic tumours. PMID- 18448175 TI - Cytotoxic interactions of methylene blue with trypanosomatid-specific disulfide reductases and their dithiol products. AB - Methylene blue (MB) is known to have trypanocidal activity. We tested the interactions of MB with a number of trypanosomatid-specific molecules of the antioxidant metabolism. At pH 7, trypanothione and other (di)thiols were oxidized to disulfides by the phenothiazine drug. MB inhibited Trypanosoma cruzi trypanothione reductase (TR) (K(i)=1.9 microM), and served as a significant subversive substrate of this enzyme (K(M)=30 microM, k(cat)=4.9s(-1)). With lipoamide dehydrogenase, the second thiol-generating flavoenzyme of T. cruzi, the catalytic efficiency for MB reduction was found to be almost 10(6)M(-1)s(-1). When the system MB-enzyme-molecular oxygen acts as a NAD(P)H-driven redox cycler, a reactive oxygen species, H(2)O(2) or superoxide, is produced in each cycle. Since MB is an affordable, available, and accessible drug it might be tested- alone or in drug combinations--against trypanosomatid-caused diseases of animal and man. PMID- 18448177 TI - Protein intake and energy balance. AB - Maintaining energy balance in the context of body-weight regulation requires a multifactorial approach. Recent findings suggest that an elevated protein intake plays a key role herein, through (i) increased satiety related to increased diet induced thermogenesis, (ii) its effect on thermogenesis, (iii) body composition, and (iv) decreased energy-efficiency, all of which are related to protein metabolism. Supported by these mechanisms, relatively larger weight loss and subsequent stronger body-weight maintenance have been observed. Elevated thermogenesis and GLP-1 appear to play a role in high protein induced satiety. Moreover, a negative fat-balance and positive protein-balance is shown in the short-term, whereby fat-oxidation is increased. Furthermore, a high protein diet shows a reduced energy efficiency related to the body-composition of the body weight regained, i.e. favor of fat free mass. Since protein intake is studied under various energy balances, absolute and relative protein intake needs to be discriminated. In absolute grams, a normal protein diet becomes a relatively high protein diet in negative energy balance and at weight maintenance. Therefore 'high protein negative energy balance diets' aim to keep the grams of proteins ingested at the same level as consumed at energy balance, despite lower energy intakes. PMID- 18448178 TI - Influence of nutritional status on cognitive, functional and neuropsychiatric deficits in Alzheimer's disease. AB - Nutrition is an important issue for elderly people, especially in patients with dementia. It is also related to clinical outcome, such as cognition, autonomy and behavior. The present study investigated the role of nutritional status on cognitive, functional and neuropsychiatric deficits in patients with Alzheimer's disease (AD). Forty-nine patients underwent neuropsychological, nutritional and neuropsychiatric assessments. The sample was divided into at risk of malnutrition (21 patients) and well-nourished (28 patients) according to the Mini Nutritional Assessment (MNA) score. The groups were similar for clinical and demographic variables, except for MNA score and age. The mean body mass index (BMI) was higher than the normal range. Patients at risk of malnutrition showed greater impairment, both in simple and instrumental activities of daily living (ADL and IADL) and a more severe ideomotor praxis deficit than well-nourished patients. Neuropsychiatric symptoms showed significant differences in hallucination, apathy, aberrant motor behavior and night-time subscales of Neuropsychiatric Inventory (NPI). These symptoms were more severe in patients at risk of malnutrition. Logistic regression analysis showed that malnutrition was an important risk factor for the onset of apathy. We hypothesized that changes in dietary habits and intake and the onset of these disorders reflect the involvement of a common neuroanatomical network. PMID- 18448179 TI - Negative aging stereotypes and their relation with psychosocial variables in the elderly population. AB - This study explores whether there is a relationship between the level of belief in negative aging stereotypes in 65-year-old people and their results concerning some psychosocial variables. These were selected for their relevance for health and well being in elderly people. These were: living situation, responsibilities toward others, subjective health, frequency of medical appointments, subjective age, participation in community social activities and regular physical activity. The sample consisted of 757 people of low educational level, ranged from 65 to 96 years. Age and gender were homogeneously distributed. Participants were non institutionalized people. Firstly, the psychosocial variables under focus were assessed by means of seven questions. Secondly, a questionnaire about negative aging stereotypes (CENVE) was administered. It was composed of three factors: health, motivational-social and character-personality. Results show that a high score in negative stereotypes is significantly associated to the studied variables, except for living situation, showing a worse quality of life (QoL) profile. Results are discussed in terms of their utility for assessment and psychosocial intervention, which is meant to improve health in the elderly. PMID- 18448180 TI - Investigations of structure and metabolism within Shewanella oneidensis MR-1 biofilms. AB - Biofilms possess spatially and temporally varying metabolite concentration profiles at the macroscopic and microscopic scales. This results in varying growth environments that may ultimately drive species diversity, determine biofilm structure and the spatial distribution of the community members. Using non-invasive nuclear magnetic resonance (NMR) microscopic imaging/spectroscopy and confocal imaging, we investigated the kinetics and stratification of anaerobic metabolism within live biofilms of the dissimilatory metal-reducing bacterium Shewanella oneidensis strain MR-1. Biofilms were pre-grown using a defined minimal medium in a constant-depth film bioreactor and subsequently transferred to an in-magnet sample chamber under laminar flow for NMR measurements. Biofilms generated in this manner were subjected to changing substrate/electron acceptor combinations (fumarate, dimethyl sulfoxide, and nitrate) and the metabolic responses measured. Localized NMR spectroscopy was used to non-invasively measure hydrogen-containing metabolites at high temporal resolution (4.5 min) under O(2)-limited conditions. Reduction of electron acceptor under anaerobic conditions was immediately observed upon switching feed solutions indicating that no gene induction (transcriptional response) was needed for MR-1 to switch metabolism from O(2) to fumarate, dimethyl sulfoxide or nitrate. In parallel experiments, confocal microscopy was used with constitutively expressed fluorescent reporters to independently investigate changes in population response to the availability of electron acceptor and to probe metabolic competition under O(2)-limited conditions. A clearer understanding of the metabolic diversity and plasticity of the biofilm mode of growth as well as how these factors relate to environmental fitness is made possible through the use of non-invasive and non-destructive techniques such as described herein. PMID- 18448181 TI - Comparative evaluation of Strepto B ID chromogenic medium and Granada media for the detection of Group B streptococcus from vaginal samples of pregnant women. AB - Two types of selective media, the chromogenic medium Strepto B ID and two non chromogenic media Strepto B agar and the Granada medium, were tested and compared to blood agar plates (BAP) for screening of Group B streptococcus vaginal colonization in pregnant women. All tested media were comparable in terms of sensitivity however, their use in routine laboratories may markedly facilitate the rapid detection of GBS in vaginal samples. PMID- 18448182 TI - Clostridium difficile in broiler chickens sold at market places in Zimbabwe and their antimicrobial susceptibility. AB - Clostridium difficile has been shown to be a nosocomial pathogen associated with diarrhoea and pseudomembranous colitis in hospitalised patients and the infection is believed to be acquired nosocomially. Community-acquired C. difficile associated diarrhoea has also been reported. Recent studies have shown the occurrence of C. difficile in food animals which may act as a source of infection to humans. The aim of this study was to determine the occurrence of C. difficile in broiler chickens sold at market places in an urban area in Zimbabwe. Faeces of broiler chickens were collected from the cages at the market places and soils were collected from areas around the market places. The chicken faeces and soil samples were cultured for C. difficile. The C. difficile isolates were tested for toxins A or B production as well as for their susceptibility to antimicrobial drugs. C. difficile was isolated from 29.0% of 100 chicken faeces samples and 22.0% of 100 soil samples. Some of the C. difficile isolates from chickens (89.7%) and soils (95.5%) were toxigenic. All the isolates were susceptible to metronidazole, vancomycin, doxycycline, chloramphenicol and tetracycline. Over 70% of the isolates were susceptible to erythromycin, co-trimoxazole and ampicillin. They were all resistant to cefotaxime, gentamicin, ciprofloxacin, norfloxacin and nalidixic acid. The results of the present study suggest that broiler chickens sold at market places in the urban area are an important source of C. difficile, which may infect humans through consumption of chicken meat. PMID- 18448183 TI - An XBP-1 dependent bottle-neck in production of IgG subtype antibodies in chemically defined serum-free Chinese hamster ovary (CHO) fed-batch processes. AB - The optimization of production processes for therapeutic antibodies is a continuing challenge in pharmaceutical biotechnology. Although it could be demonstrated that vector design and host cell engineering can improve transcriptional and translational efficiency and thereby result in generation of high producer cell lines, it is not clear whether introduction of transgenes that regulate protein transport or affect post-translational modifications could further improve such industrial processes. Here, we show that heterologous expression of the transcription factor X-box binding protein-1 (XBP-1) can lead to an increase in endoplasmic reticulum (ER) content and specific therapeutic antibody productivity of Chinese hamster ovary (CHO)-DG44 cells in inoculum suspension cultures. This effect translates into 40% increased overall antibody titers in a fed-batch format where cells are grown in chemically defined serum free media. Protein-A purified antibody products from mock-transfected cells and XBP-1 transfected cells were found to be of comparable quality with regard to glycosylation pattern and physicochemical characteristics. The data demonstrate the potential of XBP-1 engineering to improve mammalian cell culture production processes to yield high amounts of a therapeutic protein product of desired quality. PMID- 18448184 TI - The cycle for a Siphoviridae-like phage (VHS1) of Vibrio harveyi is dependent on the physiological state of the host. AB - In a previous report, we isolated Vibrio harveyi (VH) 1114 together with its bacteriophage, VHS1, from a black tiger shrimp-rearing pond. The VHS1 has its lysogenic relationship to the VH1114 host as either true lysogen (TL) or pseudolysogen (PL). The characters of TL are based on the extrachromosomal existence of the VHS1 phage genome in the VH host which also simultaneously produces the VHS1 phage particles and is resistant to super-infection. The original VH1114 host exhibits a clear plaque after infection with VHS1 phage. The PL, on the other hand, exhibits a turbid plaque and does not possess the phage genome but shows toleration to the phage infection. Maintaining the PL in artificial seawater (ASW) for 1h causes the PL to be sensitive to VHS1 infection and results in clear plaques as in the original clone. A chloramphenical-added ASW treated pseudolysogen clone (PLC), however, prevented VHS1 infection. It is postulated that the infection of VHS1 phage is regulated with a phage binding receptor which supposed to be inducible. PMID- 18448185 TI - Insights into the oligomerization state-helicase activity relationship of West Nile virus NS3 NTPase/helicase. AB - West Nile virus (WNV) is a member of the Flaviviridae family of positive-strand RNA viruses. Its viral RNA is translated to produce a polyprotein precursor that is further processed into three structural and seven non-structural proteins. The non-structural protein 3 (NS3) possess both protease and helicase activities. The C-terminal portion of the NS3 contains the ATPase/helicase domain presumably involved in viral replication. This domain has been expressed in Escherichia coli, purified in soluble form and structurally characterized. As judged by analytical centrifugation and size exclusion chromatography, the purified enzyme behaves as a monomer in solution. It has ATPase activity that is stimulated by the presence of RNA and single-stranded DNA molecules (ssDNA). However, we were unable to detect helicase activity at protein concentrations up to 500nM. It has been reported that longer constructions of NS3 helicase domains from other flavivirus, like those which include residues of the linker region between the protease and the helicase domains, have helicase activity. Since all the conformational features of the purified WNV NS3 domain are those of a native protein, it is tempting to assume that the linker region plays a critical role in determining the protein-protein interactions that leads to the formation of the active oligomer. PMID- 18448186 TI - Lipidization of human interferon-alpha: a new approach toward improving the delivery of protein drugs. AB - Human interferon-alpha (IFN-alpha), a 19.2 KD protein containing two disulfide bonds (cys1-cys98; cys29-cys138), was reduced and modified with a reversible lipidization agent. The product of the lipidization, PAL-IFN, was homogenous, with four palmitoyl moieties linked to the four Cys residues in the protein molecule via reversible disulfide linkages. The far-UV circular dichroism (CD) spectrum of PAL-IFN was virtually overlapped with that of IFN, indicating that the IFN structure was not altered by the modification. After iv injection in mice of 0.1 mg/kg of PAL-IFN, a low level of serum IFN activity was sustained for more than 8 h, while serum IFN activity was rapidly diminished to an undetectable level at 2 h post IFN injection at the same dose. Evidence suggested that IFN was slowly released from PAL-IFN into blood circulation upon reduction of the disulfide bonds in vivo. Furthermore, the liver-targeting effect of PAL-IFN was demonstrated by the observation that the level of 2'-5' oligoadenylate synthetase (OAS) expressed in the liver of mice treated with PAL-IFN was significantly higher than that with IFN. In conclusion, reversible lipidization can potentially achieve both a prolonged plasma half-life and an enhanced liver-targeting effect of IFN in antiviral therapy. PMID- 18448187 TI - Therapeutic and diagnostic applications of dendrimers for cancer treatment. AB - Dendrimers are prepared with a level of control not attainable with most linear polymers, leading to nearly monodisperse, globular macromolecules with a large number of peripheral groups. As a consequence, dendrimers are an ideal delivery vehicle candidate for explicit study of the effects of polymer size, charge, composition, and architecture on biologically relevant properties such as lipid bilayer interactions, cytotoxicity, internalization, blood plasma retention time, biodistribution, and tumor uptake. Over the last several years, substantial progress has been made towards the use of dendrimers for therapeutic and diagnostic purposes for the treatment of cancer, including advances in the delivery of anti-neoplastic and contrast agents, neutron capture therapy, photodynamic therapy, and photothermal therapy. The focus of this review is on dendrimer developments from the last four years for oncological applications, with emphasis on distinct architectures and the biological responses these structures elicit. PMID- 18448188 TI - Mutational status of EGFR and KIT in thymoma and thymic carcinoma. AB - This study was conducted to evaluate the prevalence of EGFR and KIT mutations in thymomas and thymic carcinomas as a means of exploring the potential for molecularly targeted therapy with tyrosine kinase inhibitors. Genomic DNA was isolated from 41 paraffin-embedded tumor samples obtained from 24 thymomas and 17 thymic carcinomas. EGFR exons 18, 19, and 21, and KIT exons 9, 11, 13, and 17, were analyzed for mutations by PCR and direct sequencing. Protein expression of EGFR and KIT was evaluated immunohistochemically. EGFR mutations were detected in 2 of 20 thymomas, but not in any of the thymic carcinomas. All of the EGFR mutations detected were missense mutations (L858R and G863D) in exon 21. EGFR protein was expressed in 71% of the thymomas and 53% of the thymic carcinomas. The mutational analysis of KIT revealed only a missense mutation (L576P) in exon 11 of one thymic carcinoma. KIT protein was expressed in 88% of the thymic carcinomas and 0% of the thymomas. The results of this study indicate that EGFR and KIT mutations in thymomas and thymic carcinomas are rare, but that many of the tumors express EGFR or KIT protein. PMID- 18448189 TI - What has the meta-analysis contributed to today's standard of care in the treatment of thoracic malignancies? AB - Meta-analyses dealing with the treatment of thoracic malignancies (non-small cell lung cancer, small cell lung cancer and mesothelioma) are reviewed including those performed in the context of a systematic review of the literature or based on individual patients data. Their results have been used as an effective tool for resolving various clinical questions, providing more reliable evidence for some clinical practice: (neo)adjuvant chemotherapy after surgery for resectable NSCLC, radiochemotherapy for patients with unresectable limited NSCLC and limited SCLC, advantage of chemotherapy for advanced NSCLC and identification of the most active drugs. However, it is important to understand the limits of their methodology in order to avoid inappropriate interpretations. PMID- 18448190 TI - Concentration statistics for mixing-controlled reactive transport in random heterogeneous media. AB - Uncertainty in the distribution of hydraulic parameters leads to uncertainty in flow and reactive transport. Traditional stochastic analysis of solute transport in heterogeneous media has focused on the ensemble mean of conservative-tracer concentration. Studies in the past years have shown that the mean concentration often is associated with a high variance. Because the range of possible concentration values is bounded, a high variance implies high probability weights on the extreme values. In certain cases of mixing-controlled reactive transport, concentrations of conservative tracers, denoted mixing ratios, can be mapped to those of constituents that react with each other upon mixing. This facilitates mapping entire statistical distributions from mixing ratios to reactive constituent concentrations. In perturbative approximations, only the mean and variance of the mixing-ratio distribution are used. We demonstrate that the second-order perturbative approximation leads to erroneous or even physically impossible estimates of mean reactive-constituent concentrations when the variance of the mixing ratio is high and the relationship between the mixing ratio and the reactive-constituent concentrations strongly deviates from a quadratic function. The latter might be the case in biokinetic reactions or in equilibrium reactions with small equilibrium constant in comparison to the range of reactive-constituent concentrations. When only the mean and variance of the mixing ratio is known, we recommend assuming a distribution that meets the known bounds of the mixing ratio, such as the beta distribution, and mapping the assumed distribution of the mixing ratio to the distributions of the reactive constituents. PMID- 18448191 TI - Mass flux from a non-aqueous phase liquid pool considering spontaneous expansion of a discontinuous gas phase. AB - The partitioning of non-aqueous phase liquid (NAPL) compounds to a discontinuous gas phase results in the repeated spontaneous expansion, snap-off, and vertical mobilization of the gas phase. This mechanism has the potential to significantly affect the mass transfer processes that control the dissolution of NAPL pools by increasing the vertical transport of NAPL mass and increasing the total mass transfer rate from the surface of the pool. The extent to which this mechanism affects mass transfer from a NAPL pool depends on the rate of expansion and the mass of NAPL compound in the gas phase. This study used well-controlled bench scale experiments under no-flow conditions to quantify for the first time the expansion of a discontinuous gas phase in the presence of NAPL. Air bubbles placed in glass vials containing NAPL increased significantly in volume, from a radius of 1.0 mm to 2.0 mm over 215 days in the presence of tetrachloroethene (PCE), and from a radius of 1.2 mm to 2.3 mm over 22 days in the presence of trans-1,2-dichloroethene (tDCE). A one-dimensional mass transfer model, fit to the experimental data, showed that this expansion could result in a mass flux from the NAPL pool that was similar in magnitude to the mass flux expected for the dissolution of a NAPL pool in a two-fluid (NAPL and water) system. Conditions favouring the significant effect of a discontinuous gas phase on mass transfer were identified as groundwater velocities less than approximately 0.01 m/day, and a gas phase that covers greater than approximately 10% of the pool surface area and is located within approximately 0.01 m of the pool surface. Under these conditions the mass transfer via a discontinuous gas phase is expected to affect, for example, efforts to locate NAPL source zones using aqueous concentration data, and predict the lifetime and risk associated with NAPL source zones in a way that is not currently included in the common conceptual models used to assess NAPL-contaminated sites. PMID- 18448192 TI - Wheat cysteine proteases triticain alpha, beta and gamma exhibit mutually distinct responses to gibberellin in germinating seeds. AB - We cloned three novel papain-type cysteine proteases (CPs), triticain alpha, beta and gamma, from 1-d-germinating wheat seeds. Triticain alpha, beta and gamma were constituted with 461, 472 and 365 amino acid residues, respectively, and had Cys His-Asn catalytic triads as well as signal and propeptide sequences. Triticain gamma contained a putative vacuole-sorting sequence. Phylogenetic analysis showed that these CPs were divided into mutually different clusters. Triticain alpha and gamma mRNAs were expressed in seeds at an early stage of maturation and at the stage of germination 2d after imbibition, while triticain beta mRNA appeared shortly after imbibition. The expression of mRNAs for triticain alpha and gamma was suppressed by uniconazol, a gibberellin synthesis inhibitor. All the three CP mRNAs were strongly expressed in both embryo and aleurone layers. These results suggest that triticain alpha, beta and gamma play differential roles in seed maturation as well as in digestion of storage proteins during germination. PMID- 18448193 TI - Accumulation of phenylpropanoid derivatives in chitosan-induced cell suspension culture of Cocos nucifera. AB - Chitosan-induced elicitation responses of dark-incubated Cocos nucifera (coconut) endosperm cell suspension cultures led to the rapid formation of phenylpropanoid derivatives, which essentially mimics the defense-induced biochemical changes in coconut palm as observed under in vivo conditions. An enhanced accumulation of p hydroxybenzoic acid as the major wall-bound phenolics was evident. This was followed by p-coumaric acid and ferulic acid. Along with enhanced peroxidases activities in elicited lines, the increase in activities of the early phenylpropanoid pathway enzymes such as, phenylalanine ammonia lyase (PAL), p coumaroyl-CoA ligase (4CL) and p-hydroxybenzaldehyde dehydrogenase (HBD) in elicited cell cultures were also observed. Furthermore, supplementation of specific inhibitors of PAL, C4H and 4CL in elicited cell cultures led to suppressed accumulation of p-hydroxybenzoic acid, which opens up interesting questions regarding the probable route of the biosynthesis of this phenolic acid in C. nucifera. PMID- 18448194 TI - Source-sink regulation of cotyledonary reserve mobilization during cashew (Anacardium occidentale) seedling establishment under NaCl salinity. AB - Seedling establishment is a critical process to crop productivity, especially under saline conditions. This work was carried out to investigate the hypothesis that reserve mobilization is coordinated with salt-induced inhibition of seedling growth due to changes in source-sink relations. To test this hypothesis, cashew nuts (Anacardium occidentale) were sown in vermiculite irrigated daily with distilled water (control) or 50mM NaCl and they were evaluated at discrete developmental stages from the seed germination until the whole seedling establishment. The salt treatment coordinately delayed the seedling growth and the cotyledonary reserve mobilization. However, these effects were more pronounced at late seedling establishment than in earlier stages. The storage protein mobilization was affected by salt stress before the lipid and starch breakdown. The globulin fraction represented the most important storage proteins of cashew cotyledons, and its mobilization was markedly delayed by NaCl along the seedling establishment. Free amino acids were mostly retained in the cotyledons of salt-treated seedlings when the mobilization of storage proteins, lipids and starch was strongly delayed. Proline was not considerably accumulated in the cotyledons of cashew seedlings as a response to NaCl salinity. According to these results it is noteworthy that the salt-induced inhibition of seedling growth is narrowly coordinated with the delay of reserve mobilization and the accumulation of hydrolysis products in cotyledons. Also, it was evidenced that free amino acids, especially those related to nitrogen transport, are potential signals involved in the regulation of storage protein hydrolysis during cashew seedling establishment under NaCl salinity. PMID- 18448195 TI - Involvement of polyamine biosynthesis in somatic embryogenesis of Valencia sweet orange (Citrus sinensis) induced by glycerol. AB - Culture of Citrus sinensis embryogenic callus on the embryo-inducing medium (EIM) containing glycerol gave rise to a large number of embryos, whereas very few embryos were observed on the callus growth medium (CGM). In the current paper, attempts were made to investigate whether polyamine biosynthesis was involved in glycerol-mediated somatic embryogenesis. Quantification of free polyamines by high-performance liquid chromatography showed that the cultures on EIM had less putrescine than those on CGM. However, increase in spermidine and spermine was detected in cultures on EIM during the first 20d of culture, coincident with abundant somatic embryogenesis. The globular embryos contained more polyamines than embryos at other stages. Semi-quantitative reverse transcriptase-polymerase chain reaction assay showed that expression levels of all of the five key genes involved in polyamine biosynthesis, with the exception of S-adenosylmethionine decarboxylase, were induced in cultures on EIM, and that their transcriptional levels were increased with maturation of the embryos. Addition of alpha difluoromethylornithine, a polyamine biosynthesis inhibitor, to EIM resulted in remarkable inhibition of somatic embryogenesis, concurrent with notable reduction of endogenous putrescine and spermidine, particularly at higher concentrations. Exogenous application of 1mM putrescine to EIM together with 5mM alpha difluoromethylornithine led to dramatic enhancement of endogenous polyamines, which successfully restored somatic embryogenesis. All of these, collectively, demonstrated that free polyamines, at least spermidine and spermine herein, were involved in glycerol-mediated promotion of somatic embryogenesis, which will open a new avenue for establishing a sophisticated system for somatic embryogenesis based on the modulation of endogenous polyamines. PMID- 18448196 TI - Restraint, disinhibition and food-related processing bias. AB - This study examined associations between restraint, disinhibition and food related processing bias (FPB, assessed by the emotional Stroop task) in males and females in the UK, Greece and Iran. Results showed high restraint was associated with higher FPB. However, high restrained current dieters showed lower FPB that high restrained non-dieters. There was no significant difference in FPB for those showing high versus low disinhibition. Results are discussed in relation to theories of incentive salience and current concerns. PMID- 18448197 TI - Attentional biases for food stimuli in external eaters: possible mechanism for stress-induced eating? AB - External eaters reportedly increase snack intake when stressed, which could be due to an attentional shift towards food stimuli. Attentional biases for food stimuli were tested in high and low external eaters in stress and control conditions, using a computerised Stroop. A significant interaction was observed between external eating group and condition for snack word bias. This suggested that low external eaters have a greater bias for snack words when unstressed and that stressed, high external eaters have a greater bias for snack words than stressed, low external eaters, which could contribute to stress-induced snack intake in high external eaters. PMID- 18448198 TI - Prevalence of anti-legionella antibodies among Italian hospital workers. AB - This study evaluated the prevalence of anti-legionella antibodies in workers at hospitals with a long-term history of legionella contamination. The hospitals are located in Milan and Turin, northern Italy, and in Naples and Bari, southern Italy. Antibody prevalence and titres of healthcare workers, medical and dental students and blood donors were assessed. In total 28.5% of subjects were antibody positive, most frequently to L. pneumophila serogroups 7-14. Major differences were observed in seroprevalence and type of legionella antibody in persons from different geographic areas. Healthcare workers had a significantly higher frequency of antibodies compared with blood donors in Milan (35.4 vs 15.9%, P<0.001), whereas in Naples both groups exhibited high antibody frequency (48.8 vs 44.0%) and had a higher proportion of antibodies to legionella serogroups 1-6. Dental workers had a higher seroprevalence than office staff in Bari, but not in Turin, where daily disinfecting procedures had been adopted to avoid contamination of dental unit water. No association was found between the presence of antibodies and the presence of risk factors for legionellosis, nor with the occurrence of pneumonia and/or flu-like symptoms. In conclusion, the presence of legionella antibodies may be associated with occupational exposure in the hospital environment, but there was no evidence of any association with disease. PMID- 18448199 TI - Estimating sensitivity and specificity from positive predictive value, negative predictive value and prevalence: application to surveillance systems for hospital acquired infections. AB - Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) are terms usually associated with diagnostic testing. Although these concepts have been expanded from diagnostic assays to surveillance systems, these systems are not like diagnostic assays. In attempting to estimate the sensitivity and specificity of surveillance systems, situations may arise where only the PPV, NPV and prevalence are known. We aim to demonstrate the equivalence of two methods for calculating sensitivity and specificity from PPV, NPV and prevalence. The formulae for sensitivity and specificity are calculated from first principles and compared with the adjustment of a standard contingency table. We have illustrated this method using a review of a sample of surgical site infection cases following coronary artery bypass grafting. The derived prevalence from the sample is an estimate of the population prevalence and is the value that must be used in the formulae for sensitivity and specificity as functions of PPV, NPV and prevalence to obtain the same estimates as those obtained from the adjusted contingency table. The general proof of this principle is provided as an Appendix. The sensitivity and specificity of surveillance systems can be calculated by two equivalent methods when only PPV, NPV and prevalence are known. PMID- 18448200 TI - Predicted versus expressed adipokinetic hormones, and other small peptides from the corpus cardiacum-corpus allatum: a case study with beetles and moths. AB - This mass spectrometric study confines itself to peptide masses in the range of 500-1500Da. Adipokinetic hormones (AKHs) that are predicted from the genome of the red flour beetle, Tribolium castaneum, and the silk moth, Bombyx mori, are shown to exist as expressed peptides in the corpora cardiaca (CC) of the respective species as evidenced by various mass spectrometric methods. Additionally, some related species were included in this study, such as the tenebrionid beetles Tribolium brevicornis and Tenebrio molitor, as well as the moths Spodoptera frugiperda, Spodoptera littoralis, Mamestra brassicae and Lacanobia oleracea, to investigate whether AKH peptides are structurally conserved in the same genus or family. Interestingly, the AKH peptide of T. brevicornis is identical to that of T. molitor but not to the ones of its close relative T. castaneum. Moreover, other peptides in T. brevicornis, such as various FXPRL amides (=pyrokinins), also match the complement in T. molitor but differ from those in T. castaneum. All the CC of beetles lacked the signal for the mass of the peptide corazonin. All moths have the nonapeptide Manse-AKH expressed in their CC. In addition, whereas the silk moth has the decapeptide Bommo-AKH as a second peptide, all other moths (all noctuids) express the decapeptide Helze-HrTH. In M. brassicae and L. oleracea a novel amidated Gly extended Manse-AKH is found as a possible third AKH. The noctuid moth species also all express the same FLRF amide-I, corazonin, and a group-specific isoform of a gamma-PGN-(=gamma-SGNP) peptide. In L. oleracea, however, the latter peptide has a novel sequence which is reported for the first time, and the peptide is code-named Lacol-PK. PMID- 18448201 TI - Identification of a novel storage glycine-rich peptide from guava (Psidium guajava) seeds with activity against Gram-negative bacteria. AB - Bacterial pathogens cause an expressive negative impact worldwide on human health, with ever increasing treatment costs. A significant rise in resistance to commercial antibiotics has been observed in pathogenic bacteria responsible for urinary and gastro-intestinal infections. Towards the development of novel approaches to control such common infections, a number of defense peptides with antibacterial activities have been characterized. In this report, the peptide Pg AMP1 was isolated from guava seeds (Psidium guajava) and purified using a Red Sepharose Cl-6B affinity column followed by a reversed-phase HPLC (Vydac C18-TP). Pg-AMP1 showed no inhibitory activity against fungi, but resulted in a clear growth reduction in Klebsiella sp. and Proteus sp., which are the principal pathogens involved in urinary and gastro-intestinal hospital infections. SDS-PAGE and mass spectrometry (MALDI-ToF) characterized Pg-AMP1 a monomer with a molecular mass of 6029.34Da and small quantities of a homodimer. Amino acid sequencing revealed clear identity to the plant glycine-rich protein family, with Pg-AMP1 the first such protein with activity towards Gram-negative bacteria. Furthermore, Pg-AMP1 showed a 3D structural homology to an enterotoxin from Escherichia coli, and other antibacterial proteins, revealing that it might act by formation of a dimer. Pg-AMP1 shows potential, in a near future, to contribute to development of novel antibiotics from natural sources. PMID- 18448203 TI - 'Sum of activities' as dependent parameter: a new CoMFA-based approach for the design of pan PPAR agonists. AB - A 'sum-model' (3D QSAR - CoMFA) has been developed to design PPAR(alpha/gamma/delta) (peroxisome proliferator activated receptor) pan agonists by using the sum of activities (EC(50)) of compounds against individual subtypes as a dependent parameter. In addition, the three subtype specific CoMFA models were also generated using the identical training set molecules (N=28). All four models were validated using the popular 'leave-one-out' (LOO) method and with a test set of 9 molecules. The generated models were found to be statistically significant with r(cv)(2)>0.5 and r(ncv)(2)>0.9 and the lower values of standard error of estimation (SEE) ranging from 0.097 to 0.160. From the contour map analyses the 'sum-model' was found to represent the three subtype specific models and also predicted the sum of activities of the training set molecules with reasonable accuracy. The new molecules were designed based on the 'sum-model' and were found to dock well in the PPARgamma active site. This approach may find wider applications in the research related to other classes of 'designed multiple ligands'. PMID- 18448202 TI - Activation of endothelial nitric oxide synthase is critical for erythropoietin induced mobilization of progenitor cells. AB - The present study aimed to define the ability of erythropoietin (EPO) to mobilize hematopoietic stem cells (c-kit(+)/sca-1(+)/lin-1(-); KSL-cells) and hematopoietic progenitor cells (CD34(+) cells), including vascular endothelial growth factor receptor 2 expressing hematopoietic progenitor cells (CD34(+)/Flk 1(+) cells). We also sought to determine the role of endothelial nitric oxide synthase (eNOS) in EPO-induced mobilization. Wild type (WT) and eNOS(-/-) mice were injected bi-weekly with recombinant erythropoietin (EPO, 1000U/kg, s.c.) for 14 days. EPO increased the number of KSL, CD34(+), CD34(+)/Flk-1(+) cells in circulating blood of wild type mice. These effects of EPO were abolished in eNOS( /-) mice. Our results demonstrate that, EPO stimulates mobilization of hematopoietic stem and progenitor cells. This effect of EPO is critically dependent on activation of eNOS. PMID- 18448204 TI - Improved synthesis of seven aromatic Baylis-Hillman adducts (BHA): evaluation against Artemia salina Leach. and Leishmania chagasi. AB - We described a very efficient procedure to prepare seven aromatic compounds (1 7), a new class of antileishmanial substances, through Baylis-Hillman reaction (BHR). With one, all the Baylis-Hillman adducts were prepared in quantitative yields by reaction of the corresponding aromatic aldehydes in acrylonitrile at 0 degrees C in only 10-40min reaction time. We present our results about the toxicities of these compounds evaluated on the microcrustaceous Artemia salina Leach. and against promastigote Leishmania chagasi. All substances evaluated in this work have showed high bioactivity. The 3-hydroxy-2-methylene-3-(4 bromopheny)propanenitrile (4) (LC(50)=30.9 microg/mL on A. salina; IC(50)=25.2 microM on L. chagasi) was the most active compound evaluated on A. salina Leach. and on promastigote L. chagasi. The 2-[hydroxy(pyridin-4-yl)methyl]acrylonitrile (7) (LC(50)=30.9 microg/mL on A. salina Leach.; IC(50)=4.8 microg/mL on L. chagasi) was also a very active substance evaluated in this work on promastigote L. chagasi. PMID- 18448205 TI - [A voluminous and asymptomatic hepatic tumor]. PMID- 18448206 TI - The experiences of students with English as a second language in a baccalaureate nursing program. AB - Teaching nursing students with English as a second language (ESL) can be a challenge for nursing faculty in many English speaking countries. This qualitative study purported to answer the research question, "How do students with ESL describe their experiences in a nursing program"? to develop a better understanding of the reasons for their course failure. Seidman's Model of in depth interviewing (1998) consisting of three successive interviews with the same participant was used. The first interview focused on the students' life histories, the second allowed the participants to reconstruct the details of their experiences, and the third encouraged the students to reflect on the meaning of their experiences. Three themes emerged, "walking the straight and narrow", "an outsider looking in", and "doing whatever it takes to be successful." Although each participant shared instances where ESL may have contributed to his/her academic difficulty, the participants did not perceive that ESL was the primary reason for course failure, but attributed it to the discrimination and stereotyping they experienced. In spite of the discrimination and stereotyping, participants reported a strong desire to persist in the nursing program. Findings from this study provided an in-depth understanding of the perceptions of three nursing students with ESL. Also, the findings are applicable to nursing faculty in that a better understanding of students with ESL can enhance their learning. PMID- 18448207 TI - The experience of faculty practice: developing and evaluating a newly established program. AB - While the notion of faculty practice, that is clinical practice by an academic in a health service environment, is not new, Australian Universities have been slow in providing practice environments where academics' theoretical understanding is informed through the service environment. Although there is a plethora of published academic opinion on the benefits, there is a dearth of meaningful data describing the subjective experience of academics that participate in faculty practice. Developing an understanding of the issues academics experience, while on faculty practice, provides a vital opportunity for those seeking to adopt a faculty practice model in their institution. The paper describes the genesis of the faculty practice program and outlines both the benefits and challenges that were encountered during implementation. A program evaluation conducted by an independent consultant indicated that all faculty practice participants found the process to be empowering and revitalising, despite their initial apprehension. The personal and professional gains achieved while on faculty practice were considered to compensate for the additional workload involved. The immediate dividends of enhanced self-esteem, classroom practices and credibility with students for faculty practice participants were outcomes achieved. PMID- 18448208 TI - Generation and evaluation of the trivalent inactivated reassortant vaccine using human, avian, and swine influenza A viruses. AB - Reassortant technology was used to obtain three interspecific reassortant influenza viruses using three influenza viruses of A/Puerto Rico/8/34(H1N1), A/swine/Hebei/1/2005(H3N2) and A/chicken/Guangdong/126/2002(H9N2). The high growth reassortant strains were H9/PR8, H3/H9N2 and H1/H9N2 that contained hemagglutinin (HA) and neuraminidase (NA) genes from the inactivated parental viruses and the other 6 internal genes from the live parental viruses. The trivalent formalin-inactivated vaccine, containing H1, H3 and H9 subtype antigens from human, swine and avian influenza viruses respectively, was prepared using these reassortant viruses. Animal studies showed that the vaccine was safe and immunogenic. Two-dosing regimen of the influenza vaccine induced high titers of hemagglutination inhibiting (HI) antibodies and influenza-specific IgG antibodies without antigenic cross-interference. It protected 100% chickens from challenge of A/chicken/Guangdong/126/2002 virus and protected 100% mice against challenges with different combinations of the three infective parental viruses. These results indicated that the trivalent vaccine could offer multi-protection against multi-influenza viruses synchronously. This kind of multivalent inactivated reassortant influenza vaccine maybe enlightens the pandemic influenza preparedness as the emergency measure. PMID- 18448209 TI - Vaccination against foot-and-mouth disease virus using peptides conjugated to nano-beads. AB - Vaccination against foot-and-mouth disease virus (FMDV) is a major problem as current vaccines do not allow easy differentiation between infected and vaccinated animals. Furthermore, large scale production of inactivated virus poses significant risks. To address this we investigated the feasibility of using inert nano-beads that target antigen to dendritic cells (DCs) to induce immune responses against FMDV-specific synthetic peptides in sheep. Our results demonstrate that while single peptides induce responses in most sheep, the combination of multiple peptides either conjugated separately to individual nano beads or conjugated as a mixture induce significant cell-mediated (CM) and humoral immune responses. PMID- 18448210 TI - Influenza vaccination in paediatric nurses: cross-sectional study of coverage, refusal, and factors in acceptance. AB - BACKGROUND: Influenza vaccination among health-care workers is poor, and the effectiveness of hospital vaccination programs remains unclear. Little is known about the effectiveness of intensive evidence-based vaccination programs in nursing staff. We determined whether the recommended vaccination rate could be achieved among paediatric nurses during an intensive promotional program for influenza vaccination. We also sought to identify the reasons for which nurses refuse the influenza vaccine and predictors of future vaccination intent. METHODS: We offered influenza vaccination to nursing staff during an influenza season through a multi-component program that included intensive promotional activities. We analysed vaccination data to determine uptake rates. In a cross sectional survey, self-administered questionnaires were distributed to all nurses with patient contact during that season. The questionnaire evaluated their vaccine use, site of work, absenteeism and physician visits due to respiratory illness, vaccination intent for the subsequent influenza season, and other items. We surveyed vaccinated nurses regarding their program experiences and the frequency and severity of adverse reactions. Unvaccinated nurses were asked their reasons for refusing vaccination. Multiple logistic-regression analysis was conducted to identify variables that predicted the likelihood of future vaccine acceptance. RESULTS: More than 75% (895/1,182) of applicable nurses were vaccinated in the program. The questionnaire response rate was nearly 48% (585/1,230). Vaccination in the program during the current season (odds ratio [OR] 101.99, 95% confidence interval [CI] 52.54-197.98), program convenience (OR 199.19, 95% CI 98.01-404.11), and a physician visit for respiratory illness (OR 2.44, 95% CI 1.29-4.61) were found to be independent predictors of intent to receive the vaccine the following season. A lack of perceived personal need was the most common reason for vaccine refusal, given in 30% (77/258) of unvaccinated respondents. CONCLUSIONS: Adequate coverage of nurses is achievable during an intensive voluntary immunisation program against influenza, using best-known practices. Perceived lack of personal benefit is a major deterrent, while program convenience and previous vaccination strongly predict future vaccine acceptance. Our findings support interventions that improve the convenience of hospital immunisation programs for influenza, particularly those that are aimed at nurses and that promote vaccine efficacy and benefits. PMID- 18448212 TI - An optimal vaccination strategy against rotavirus. PMID- 18448211 TI - A double-blind, placebo-controlled study of the safety and immunogenicity of live, oral type 4 and type 7 adenovirus vaccines in adults. AB - Adenovirus serotypes 4 (ADV-4) and 7 (ADV-7) are important causes of febrile acute respiratory disease (ARD) in US military recruits. Previously licensed vaccines, which effectively controlled adenovirus-associated ARD, are no longer available. In the Fall of 2004 we conducted this Phase 1 randomized, double blind, placebo-controlled trial of the live, oral ADV-4 and ADV-7 vaccines made by a new manufacturer to assess their safety and immunogenicity. The adenovirus vaccines were administered orally together in a single dose to thirty subjects. Twenty eight additional subjects received placebo. Subjects were then observed for 8 weeks. The most commonly reported adverse events were nasal congestion (33%), cough (33%), sore throat (27%), headache (20%), abdominal pain (17%), arthralgia (13%), nausea (13%) and diarrhea (13%). None of these rates differed significantly from placebo. The duration of vaccine virus fecal shedding was 7-21 days. Seventy three percent of vaccine recipients seroconverted to ADV-4 (GMT 23.3) while 63% seroconverted to ADV-7 (GMT 51.1) by Day 28. The new ADV-4 and ADV-7 vaccines were safe and induced a good immune response in the study population. Expanded trials for safety and efficacy are in progress. PMID- 18448213 TI - Reconstruction of atmospheric concentrations and deposition of uranium and decay products released from the former uranium mill at Uravan, Colorado. AB - Radionuclide concentrations in air from uranium milling emissions were estimated for the town of Uravan, Colorado, USA and the surrounding area for a 49-yr period of mill operations beginning in 1936 and ending in 1984. Milling processes with the potential to emit radionuclides to the air included crushing and grinding of ores; conveyance of ore; ore roasting, drying, and packaging of the product (U(3)O(8)); and fugitive dust releases from ore piles, tailings' piles, and roads. The town of Uravan is located in a narrow canyon formed by the San Miguel River in western Colorado. Atmospheric transport modeling required a complex terrain model. Because historical meteorological data necessary for a complex terrain model were lacking, meteorological instruments were installed, and relevant data were collected for 1 yr. Monthly average dispersion and deposition factors were calculated using the complex terrain model, CALPUFF. Radionuclide concentrations in air and deposition on ground were calculated by multiplying the estimated source-specific release rate by the dispersion or deposition factor. Time-dependent resuspension was also included in the model. Predicted concentrations in air and soil were compared to measurements from continuous air samplers from 1979 to 1986 and to soil profile sampling performed in 2006. The geometric mean predicted-to-observed ratio for annual average air concentrations was 1.25 with a geometric standard deviation of 1.8. Predicted-to-observed ratios for uranium concentrations in undisturbed soil ranged from 0.67 to 1.22. Average air concentrations from 1936 to 1984 in housing blocks ranged from about 2.5 to 6 mBq m(-3) for (238)U and 1.5 to 3.5 mBq m(-3) for (230)Th, (226)Ra, and (210)Pb. PMID- 18448214 TI - Juvenile nasopharyngeal angiofibroma presenting as an intraoral mass. PMID- 18448215 TI - Simple way to secure an occlusal wafer in patients with compromised dentition. PMID- 18448216 TI - Leiomyosarcoma of the tongue: a case report. AB - Primary leiomyosarcomas arising from within the tongue are extremely rare. Only eight cases have been previously reported on Medline to our knowledge. We describe a case of a 46-year-old woman who presented with a lesion rapidly increasing in size on the lateral aspect of her tongue, which was excised. We present a completed-5-year follow-up. PMID- 18448217 TI - The establishment of a mechanobiology model of bone and functional adaptation in response to mechanical loading. AB - BACKGROUND: Mechanical stimuli affected bone adaptation, however, the mechanism on a dose-response relationship between mechanical stimuli and bone response is unclear. Therefore, we established a mechanobiology model to evaluated the adaptive response of bone to strain deformation at high-frequencies (5-15 Hz) of externally applied strain. METHODS: The ulnae of adult female rats were subjected to dynamic axial loading in vivo using Instron materials-testing machine. The applied loading at frequencies of 5 Hz, 10 Hz, and 15 Hz for 10 min with a haversine, low-magnitude waveform for a 2 weeks period, the peak strains is 2000 muepsilon and 3000 muepsilon. Strain was recorded using strain gauge conditioner and compared to physiological values obtained after testing. FINDINGS: At frequencies of 10 Hz, 15 Hz groups, loading promoted obviously secreted of osteocalcin and collagen; a relative benefit in Bone Mineral Density (BMD) was found compare to the control (P < 0.05) followed the decline of material mechanical properties (modulus of elasticity, ultimate stress) (P < 0.01). INTERPRETATION: These data show that a mechanobiology model of the axial ulna loading technique had been established successfully in rat. A short daily period of low-magnitude, high-frequency mechanical stimuli results in an osteogenic response related to peak strain magnitude, which do not result in significant differences in mechanical properties between the groups. PMID- 18448218 TI - New prognostic markers in chronic lymphocytic leukemia. AB - The prognosis of patients with chronic lymphocytic leukemia (CLL) is extremely variable. Prognostication of patients with CLL has been classically based on clinical parameters. In the last few years, several biologic markers such as cytogenetics, IgVH mutations, CD38 and ZAP-70 expression in leukemic cells have shown to offer important prognostic information. However, before being incorporated into daily practice these markers require standardization and validation in prospective trials. Meanwhile, prognosis of patients with CLL should remain to be based on clinical stages and other easily obtainable clinical parameters. An important area of research is the identification of markers useful for predicting response to therapy. Among them, 17p- reflecting p53 abnormalities is particularly important. Also relevant is 11q- pointing out to ATM defects. The correlation of IgVH mutations, ZAP-70 and CD38 expression with response is unclear and needs further investigation. Finally, there is increasing evidence that response to therapy, particularly when all measurable disease is eradicated, is associated with longer survival. PMID- 18448219 TI - Exposure to inorganic arsenic from rice: a global health issue? PMID- 18448220 TI - Haematology, genotoxicity, enzymatic activity and histopathology as biomarkers of metal pollution in the shrew Crocidura russula. AB - Haematological (WBC, RBC, Hgb and Hct) and genotoxicity (MNT) parameters, hepatic enzymatic activities (GST, GPx and GR), and a histopathological evaluation of liver, kidneys and gonads were assessed as general biomarkers of metal pollution in the shrew Crocidura russula inhabiting a pyrite mining area. Specimens exposed to metals presented a few significant alterations when compared with reference animals: GST activity decreased; micronuclei increased; and evident liver alterations related to metal exposure were observed. On the basis of all the parameters studied, age was an important factor that partly explained the observed variation, whereas sex was the least important factor. Significant correlations were also found between heavy metal concentrations and biomarkers evaluated, demonstrating the great influence of these metals in the metabolic alterations. To the best of our knowledge, these data constitute the first measurements of a battery of biomarkers in shrews from a mine site and are among the few available for insectivorous mammals. PMID- 18448221 TI - Social norms information enhances the efficacy of an appearance-based sun protection intervention. AB - This experiment examined whether the efficacy of an appearance-based sun protection intervention could be enhanced by the addition of social norms information. Southern California college students (N=125, predominantly female) were randomly assigned to either an appearance-based sun protection intervention that consisted of a photograph depicting underlying sun damage to their skin (UV photo) and information about photoaging or to a control condition. Those assigned to the intervention were further randomized to receive information about what one should do to prevent photoaging (injunctive norms information), information about the number of their peers who currently use regular sun protection (descriptive norms information), both injunctive and descriptive norms information, or neither type of norms information. The results demonstrated that those who received the UV photo/photoaging information intervention expressed greater sun protection intentions and subsequently reported greater sun protection behaviors than did controls. Further, the addition of both injunctive and descriptive norms information increased self-reported sun protection behaviors during the subsequent month. PMID- 18448222 TI - Looking both ways through time: the Janus model of lateralized cognition. AB - Existing models of laterality, while often successful at describing circumscribed domains, have not been successful as explanations of the overall patterns of hemispheric asymmetries. It is therefore suggested that a new approach is needed based on shared contributions to adaptive hemispheric roles rather than functional and structural intrahemispheric similarities. This paper proposes a model of laterality, the Janus model, based on evolutionary considerations of complementary hemispheric roles. It is proposed that the left hemisphere has the role of anticipating future scenarios and choosing between them while the right hemisphere has the role of integrating ongoing information into a unitary view of the past in order to immediately detect and respond to novel and unexpected events. Evidence for these complementary roles is provided in research on motor control and semantic priming. Finally, the Janus model is contrasted with efforts to cast the frequency model as a general model of laterality. PMID- 18448223 TI - Toxic effects of acrylamide on survival, development and haemocytes of Musca domestica. AB - The influence of acrylamide, a potentially toxic substance present in some types of food, on survival, postembryonic development and haemocytes, insect's blood cells, of the housefly was examined. Larvae were reared on media contaminated with acrylamide at concentrations of 82 microg/g, 164 microg/g or 246 microg/g. The length of larval and pupal stages as well as the survival of larvae and pupae was examined. To study the effects of acrylamide on haemocytes, the analysis of their index and morphology was performed in the third instar larva. The obtained data showed that the survival of larvae exposed to 82 microg/g and 164 microg/g concentrations of acrylamide decreased by 50% and 85%, respectively, whereas 246 microg/g concentration was lethal. In both groups of flies, larval and pupal stages were significantly lengthened by about 1.5 day in comparison with control. Moreover, acrylamide increased the number of prohaemocytes and intermediate cells while the number of plasmatocytes and granulocytes decreased. The size of plasmatocytes decreased in acrylamide-treated larvae when compared with these cells of control flies. The reduced survival of animals is probably due to affecting haemocytes involved in immune responses in insects. Moreover, the housefly's blood cells showed to be sensitive to toxin, which suggests their usefulness to test toxicity of substances present in food products. PMID- 18448224 TI - 90-Day repeated-dose toxicity study of licorice flavonoid oil (LFO) in rats. AB - Licorice flavonoid oil (LFO) is a new functional food ingredient consisting of licorice hydrophobic polyphenols in medium-chain triglycerides (MCT). As part of a safety evaluation, a 90-day oral toxicity study in rats was conducted using an LFO concentrate solution (2.90% glabridin). Male and female animals were assigned to one of 12 groups (10 males or females per group) and received corn oil (negative control), MCT (vehicle control), or 400, 600, 800 or 1600 mg/kg of the LFO concentrate solution. In conclusion, LFO concentrate solution induced an anticoagulation effect in both sexes, although there was a clear sex difference. Based on these findings, it is concluded that the no-observed-adverse-effect level (NOAEL) for the LFO concentrate solution is estimated to be 800 mg/kg/day for female rats, and approximately 400 mg/kg/day for male rats. PMID- 18448225 TI - Total phenols, antioxidant potential and antimicrobial activity of walnut (Juglans regia L.) green husks. AB - The total phenols content and antioxidant and antimicrobial activities were studied in walnut (Juglans regia L.) green husks aqueous extracts of five different cultivars (Franquette, Mayette, Marbot, Mellanaise and Parisienne). Total phenols content was determined by colorimetric assay and their amount ranged from 32.61 mg/g of GAE (cv. Mellanaise) to 74.08 mg/g of GAE t (cv. Franquette). The antioxidant capacity of aqueous extracts was assessed through reducing power assay, scavenging effects on DPPH (2,2-diphenyl-1-picrylhydrazyl) radicals and beta-carotene linoleate model system. A concentration-dependent antioxidative capacity was verified in reducing power and DPPH assays, with EC50 values lower than 1 mg/mL for all the tested extracts. The antimicrobial capacity was screened against Gram positive and Gram negative bacteria, and fungi. All the extracts inhibited the growth of Gram positive bacteria, being Staphylococcus aureus the most susceptible one with MIC of 0.1 mg/mL for all the extracts. The results obtained indicate that walnut green husks may become important in the obtainment of a noticeable source of compounds with health protective potential and antimicrobial activity. PMID- 18448226 TI - Toxicokinetics and metabolisms of benzophenone-type UV filters in rats. AB - Sunscreens containing UV filters are recommended to reduce damage caused by solar UV radiation. Recently, benzophenone (BP)-type UV filters have become widely used as UV stabilizers in skin-moisturizing products and sunscreen lotions; however, very little information is available regarding the potential harmful effects of prolonged exposure to these compounds. Therefore, we investigated the toxicokinetics and metabolism of BP-type UV filters in rats using gas chromatography-mass spectrometry (GC-MS). To examine the metabolism of BP-type UV filters, we analyzed the parent compounds BP and 2-hydroxy-4-methoxybenzophenone (HMB). In rats, BP was mainly converted to benzhydrol (BH) and 4 hydroxybenzophenone (HBP) (i.e., type A UV filters). In contrast, HMB was converted into at least three intermediates, including 2,4-dihydroxybenzophenone (DHB), which was formed via o-demethylation and subsequently converted into 2,3,4 trihydroxybenzophenone (THB), and 2,2'-dihydroxy-4-methoxybenzophenone (DHMB), which formed via the aromatic hydroxylation of HMB (i.e., type B UV filters). Next, the toxicokinetic curve for BP showed a peak concentration (Cmax) of 2.06+/ 0.46 microg/ml at approximately 4h after BP administration. After a single oral dose of HMB, the Cmax of HMB reached 21.21+/-11.61 microg/ml within 3h (Tmax), and then declined rapidly compared to the kinetic curve of BP. The concentration of these metabolites in rat blood decreased much more slowly over time compared to the parent compounds. Thus, our results indicate that such metabolites might have more significant adverse effects than the parent compounds over the long term. PMID- 18448227 TI - Prevalence, intensity and nature of bacteraemia after toothbrushing. AB - OBJECTIVE: To estimate the prevalence, intensity and microbial identity of bacteraemia associated with toothbrushing. METHODS: A total of 141 children and adolescents, aged between 3 and 17 years, having dental treatment under general anaesthesia at the Eastman Dental Hospital were recruited. Six millilitre of blood was taken before toothbrushing (baseline) with (1) Oral B 30 toothbrush or (2) Braun or (3) Sonicare electric toothbrush or (4) dental handpiece and rubber cup. A second 6-ml sample was taken 30s after toothbrushing. All blood samples were processed using lysis filtration and bacteria were identified to species level. RESULTS: There was a significantly greater prevalence of bacteraemia following the dental handpiece only (p=0.02). There was a significantly greater aerobic and anaerobic intensity of bacteraemia following brushing with both the Sonicare (p=0.03 and p=0.05) and the dental handpiece (p=0.001 and p=0.005). CONCLUSIONS: Toothbrushing causes a bacteraemia that is often statistically significantly greater than baseline. Toothbrushing is an important contributory factor in cumulative dental bacteraemia. PMID- 18448228 TI - Microtubule-associated protein tau in development, degeneration and protection of neurons. AB - As a principal neuronal microtubule-associated protein, tau has been recognized to play major roles in promoting microtubule assembly and stabilizing the microtubules and to maintain the normal morphology of the neurons. Recent studies suggest that tau, upon alternative mRNA splicing and multiple posttranslational modifications, may participate in the regulations of intracellular signal transduction, development and viability of the neurons. Furthermore, tau gene mutations, aberrant mRNA splicing and abnormal posttranslational modifications, such as hyperphosphorylation, have also been found in a number of neurodegenerative disorders, collectively known as tauopathies. Therefore, changes in expression of the tau gene, alternative splicing of its mRNA and its posttranslational modification can modulate the normal architecture and functions of neurons as well as in a situation of tauopathies, such as Alzheimer's disease. The primary aim of this review is to summarize the latest developments and perspectives in our understanding about the roles of tau, especially hyperphosphorylation, in the development, degeneration and protection of neurons. PMID- 18448229 TI - The neuronal ubiquitin-proteasome system: murine models and their neurological phenotype. AB - The ubiquitin-proteasome system (UPS) is the main intracellular pathway for regulated protein turnover. This system is of vital importance for maintaining cellular homeostasis and is essential for neuronal functioning. It is therefore not surprising that impairment of this system is implicated in the pathogenesis of a variety of diseases, including neurological disorders, which are pathologically characterized by the presence of ubiquitin-positive protein aggregates. A direct correlation between intact neuronal functioning and the UPS is exemplified by a range of transgenic mouse models wherein mutations in components of the UPS lead to a neurodegenerative or neurological phenotype. These models have been proven useful in determining the role of the UPS in the nervous system in health and disease. Furthermore, recently developed in vivo models harboring reporter systems to measure UPS activity could also substantially contribute to understanding the effect of neurodegeneration on UPS function. The role of the UPS in neurodegeneration in vivo is reviewed by discussing the currently available murine models showing a neurological phenotype induced by genetic manipulation of the UPS. PMID- 18448230 TI - Effect of potassium citrate salts on the vapor-liquid equilibrium properties of aqueous solutions of alanine at different temperatures. AB - Water activity measurements by isopiestic method have been carried out on the aqueous solutions of alanine+potassium di-hydrogen citrate (KH(2)Cit) and alanine+tri-potassium citrate (K(3)Cit) over a range of temperatures at atmospheric pressure. From these measurements, values of the vapor pressure of solutions were determined. The effect of temperature and charge on the anion of salts on the vapor-liquid equilibrium of the investigated systems has been studied. The experimental water activities have been correlated successfully with the segment-based local composition Wilson and NRTL models. The agreement between the correlations and the experimental data is good. PMID- 18448231 TI - Tricationic pyridium porphyrins appending different peripheral substituents: experimental and DFT studies on their interactions with DNA. AB - Four tricationic pyridium porphyrins appending hydroxyphenyl, methoxyphenyl, propionoxyphenyl or carboxyphenyl group at meso-20-position of porphyrin core have been synthesized and their abilities to bind and cleave DNA have been investigated. Using a combination of absorption, fluorescence, circular dichroism (CD) spectra, thermal DNA denaturation as well as viscosity measurements, their binding modes and intrinsic binding constants (K(b)) to calf DNA (CT DNA) were comparatively studied and also compared with those of 5,10,15,20-tetrakis(1 methylpyridinium-4-yl)porphyrin (TMPyP). The results suggest that the K(b) values of these porphyrins are greatly influenced by the number of positive charges and steric hindrance. Theoretical calculations applying the density functional theory (DFT) have been carried out and explain their DNA-binding properties reasonably. The efficiency of DNA photocleavage by these porphyrins shows high dependence on the values of K(b). PMID- 18448232 TI - Editorial comment on: does physiotherapist-guided pelvic floor muscle training reduce urinary incontinence after radical prostatectomy? A randomised clinical trial. PMID- 18448233 TI - Does physiotherapist-guided pelvic floor muscle training reduce urinary incontinence after radical prostatectomy? A randomised controlled trial. AB - BACKGROUND: Urinary incontinence after radical prostatectomy (RP) is a common problem and may lead to reduced quality of life. OBJECTIVE: To assess the effects of guided pelvic floor muscle training on continence status and perceived problems with urinary function after RP. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomised controlled trial at St. Olavs Hospital/Trondheim University Hospital in Norway between September 2005 and December 2007. All men with clinically localised prostate cancer who underwent surgery with open RP were invited to participate, until 85 participants were included. Dropout rate was 6%. INTERVENTION: Two intervention groups (A and B). Both groups received instructions in correct pelvic floor muscle contractions and were encouraged to train the pelvic floor muscles. Group A was offered additional follow-up training instructions by a physiotherapist throughout the 1-yr period. MEASUREMENTS: Primary outcome was continence (0 pads) status, and secondary outcomes were perceived problems with urinary function 6 wk and 3, 6, and 12 mo postoperatively. RESULTS: No statistically significant difference in continence status between groups was found at 3 mo; 46% were continent in group A versus 43% in group B (p=0.73). In group A, 97% reported no or only mild problems with urinary function compared to 78% in group B (p=0.010). After 6 mo there was a clinically relevant difference in continence status between groups: 79% were continent in group A and 58% in group B (p=0.061). Twelve months postsurgery the difference was clinically and statistically significant (p=0.028) in favour of group A; 92% were continent in group A and 72% in group B. CONCLUSIONS: Continence rates were similar 3 mo after RP in groups performing intensive pelvic floor muscle training with or without follow-up instructions by a physiotherapist. However, in the following period up to 1 yr, the group receiving physiotherapist-guided training reduced urinary incontinence significantly more compared to patients training on their own. PMID- 18448234 TI - Serving the readers of European urology: a platinum honour and privilege. PMID- 18448235 TI - Editorial comment on: does physiotherapist-guided pelvic floor muscle training reduce urinary incontinence after radical prostatectomy? A randomised controlled trial. PMID- 18448236 TI - Editorial comment on: does physiotherapist-guided pelvic floor muscle training reduce urinary incontinence after radical prostatectomy? A randomised clinical trial. PMID- 18448238 TI - On the Gompertzian growth in the fractal space-time. AB - An analytical approach to determination of time-dependent temporal fractal dimension b(t)(t) and scaling factor a(t)(t) for the Gompertzian growth in the fractal space-time is presented. The derived formulae take into account the proper boundary conditions and permit a calculation of the mean values b(t)(t) and a(t)(t) at any period of time. The formulae derived have been tested on experimental data obtained by Schrek for the Brown-Pearce rabbit's tumor growth. The results obtained confirm a possibility of successful mapping of the experimental Gompertz curve onto the fractal power-law scaling function y(t)=a(t)tb(t) and support a thesis that Gompertzian growth is a self-similar and allometric process of a holistic nature. PMID- 18448237 TI - Cross-scale sensitivity analysis of a non-small cell lung cancer model: linking molecular signaling properties to cellular behavior. AB - Sensitivity analysis is an effective tool for systematically identifying specific perturbations in parameters that have significant effects on the behavior of a given biosystem, at the scale investigated. In this work, using a two dimensional, multiscale non-small cell lung cancer (NSCLC) model, we examine the effects of perturbations in system parameters which span both molecular and cellular levels, i.e. across scales of interest. This is achieved by first linking molecular and cellular activities and then assessing the influence of parameters at the molecular level on the tumor's spatio-temporal expansion rate, which serves as the output behavior at the cellular level. Overall, the algorithm operated reliably over relatively large variations of most parameters, hence confirming the robustness of the model. However, three pathway components (proteins PKC, MEK, and ERK) and eleven reaction steps were determined to be of critical importance by employing a sensitivity coefficient as an evaluation index. Each of these sensitive parameters exhibited a similar changing pattern in that a relatively larger increase or decrease in its value resulted in a lesser influence on the system's cellular performance. This study provides a novel cross scaled approach to analyzing sensitivities of computational model parameters and proposes its application to interdisciplinary biomarker studies. PMID- 18448239 TI - Ecological boundaries in the context of hierarchy theory. AB - Ecological boundaries have been described as being multiscalar or hierarchical entities. However, the concept of the ecological boundary has not been explicitly examined in the context of hierarchy theory. We explore how ecological boundaries might be envisioned as constituents of scalar hierarchical systems. Boundaries may be represented by the surfaces of constituents or as constituents themselves. Where surfaces would correspond to abrupt transition zones, boundary systems might be quite varied depending on hierarchical context. We conclude that hierarchy theory is compatible with a functional vision of ecological boundaries where functions can be largely represented as the processing or filtering of ecological signals. Furthermore, we postulate that emergent ecological boundaries that arise on a new hierarchical level may contribute to the overconnectedness of mature ecosystems. Nevertheless, a thermodynamic approach to the emergence and development of boundary systems does indicate that in many situations, ecological boundaries would persist in time by contributing to the energy production of higher hierarchical levels. PMID- 18448241 TI - Potent antitumor effects of a novel actinomycin D analog Leu5AMD. AB - Leu5AMD ([D-Val2, L-MeLeu5]2 AMD) is a novel actinomycin D (AMD) analog, in which both N-methylvalines were replaced by N-methylleucines. In the present study, an attempt has been made to investigate the effects of Leu5AMD on the proliferation of human gastric carcinoma cell line SGC-7901. The results showed that Leu5AMD inhibited the proliferation and induces apoptosis in SGC-7901 cells in a dose dependent manner. Apoptosis induced by Leu5AMD was further confirmed by annexin V FITC/PI dual staining assay. After treatment with Leu5AMD, the loss of mitochondrial potential and the decrease of bcl-2 gene expression were observed in apoptotic cells, suggesting that Leu5AMD may be involved in mitochondria and bcl-2 related apoptotic pathway. In addition, the in vivo antitumor effects of Leu5AMD on S-180 bearing mice and the acute toxicity on healthy mice were investigated. Treatment with Leu5AMD markedly suppressed the growth of Sarcoma xenograft. These results suggest that Leu5AMD may be used as a promising chemotherapeutical agent for patients affected by gastric carcinoma and other solid cancer. PMID- 18448242 TI - Cancer related inflammation: the macrophage connection. AB - Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. In the tumor microenvironment neoplastic cells shape the differentiation and functional orientation of TAM which, in turn, express several protumoral functions, including secretion of growth factors and matrix-proteases, promotion of angiogenesis and suppression of adaptive immunity. This review analyzes our current knowledge of TAM and their involvement in tumor development and progression. The interplay between TAM and neoplastic cells represents a promising target of future therapeutic approaches. PMID- 18448240 TI - Multigenic control of thyroid hormone functions in the nervous system. AB - Thyroid hormone (TH) has a remarkable range of actions in the development and function of the nervous system. A multigenic picture is emerging of the mechanisms that specify these diverse functions in target tissues. Distinct responses are mediated by alpha and beta isoforms of TH receptor which act as ligand-regulated transcription factors. Receptor activity can be regulated at several levels including that of uptake of TH ligand and the activation or inactivation of ligand by deiodinase enzymes in target tissues. Processes under the control of TH range from learning and anxiety-like behaviour to sensory function. At the cellular level, TH controls events as diverse as axonal outgrowth, hippocampal synaptic activity and the patterning of opsin photopigments necessary for colour vision. Overall, TH coordinates this variety of events in both central and sensory systems to promote the function of the nervous system as a complete entity. PMID- 18448243 TI - Toxicity characterization of waste mobile phone plastics. AB - Waste plastic housing units (N=60) of mobile phones (of different models, and brands), were collected and analyzed for lead, cadmium, nickel and silver using atomic absorption spectrophotometry after acid digestion using a 1:1 mixture of H2SO4 and HNO3. The mean (+/-S.D.) and range of the results are 58.3+/-50.4mg/kg (5.0-340mg/kg) for Pb, 69.9+/-145mg/kg (4.6-1005mg/kg) for Cd, 432+/-1905mg/kg (5.0-11,000mg/kg) for Ni, and 403+/-1888mg/kg (5.0-12,500mg/kg) for Ag. Approximately 90% of the results for the various metals were < or =100mg/kg. Results greater than 300mg/kg were generally less than 7% for each metal and could be attributed to exogenous contamination of the samples. These results suggest that there may not be any immediate danger from end-of-life (EoL) mobile phone plastic housing if appropriately treated/managed. However, considering the large quantities generated and the present low-end management practices in most developing countries, such as open burning, there appears a genuine concern over the potential for environmental pollution and toxicity to man and the ecology. PMID- 18448244 TI - Removal of cesium ions from aqueous solution by adsorption onto local Taiwan laterite. AB - Utilization of local Taiwan laterite (LTL) to remove aqueous cesium was investigated in this work under the conditions of various contact time, cesium (Cs) loading and temperature. Experimental results show that adsorption is instantaneous. Freundlich and Langmuir simulation results demonstrate that local Taiwan laterite has high affinity and sorption capacity for Cs at low temperatures, which may be attributed to enhanced desorption as temperature increased. Thermodynamic parameters including DeltaH, DeltaG and DeltaS were calculated and it is indicated that Cs adsorption on LTL is an exothermic, spontaneous and physical adsorption reaction. Moreover, the adsorbed Cs is distributed evenly on the LTL surface, which is confirmed by SEM/EDS mapping images. Furthermore, the absence of apparent shifting or broadening of the kaolinite signal in XRD patterns after Cs adsorption is an indication of the non expanding characteristic of kaolinite structure. PMID- 18448245 TI - Study on a new surfactant for removal of phenol from wastewater by emulsion liquid membrane. AB - Removal of phenol from wastewater using emulsion liquid membrane (ELM) is studied in present study. A new polyamine-type surfactant was synthesized and used for stabilizing of the emulsion phase. The results for the emulsion made by the synthesized surfactant showed much better stability and performance in the separation process compared to that by conventionally used Span 80. To determine the optimum operation conditions, the effect of several parameters such as emulsifier concentration, concentration of NaOH in the internal phase, oil to internal phase volume ratio, mixing intensity, temperature, solvent type, and stabilizer concentration have been investigated. It was found that under the optimum conditions, more than 98% of phenol can be removed in a single-stage process. The removal efficiency can be increased to 99.8% in a two-stage process. PMID- 18448246 TI - Biosorption of heavy metals and uranium by starfish and Pseudomonas putida. AB - Biosorption of heavy metals and uranium from contaminated wastewaters may represent an innovative purification process. This study investigates the removal ability of unit mass of Pseudomonas putida and starfish for lead, cadmium, and uranium by quantifying the adsorption capacity. The adsorption of heavy metals and uranium by the samples was influenced by pH, and increased with increasing Pb, Cd, and U concentrations. Dead cells adsorbed the largest quantity of all heavy metals than live cells and starfish. The adsorption capacity followed the order: U(VI)>Pb>Cd. The results also suggest that bacterial membrane cells can be used successfully in the treatment of high strength metal-contaminated wastewaters. PMID- 18448247 TI - Groundwater protection from cadmium contamination by permeable reactive barriers. AB - This work studies the reliability of an activated carbon permeable reactive barrier in removing cadmium from a contaminated shallow aquifer. Laboratory tests have been performed to characterize the equilibrium and kinetic adsorption properties of the activated carbon in cadmium-containing aqueous solutions. A 2D numerical model has been used to describe pollutant transport within a groundwater and the pollutant adsorption on the permeable adsorbing barrier (PRB). In particular, it has been considered the case of a permeable adsorbing barrier (PAB) used to protect a river from a Cd(II) contaminated groundwater. Numerical results show that the PAB can achieve a long-term efficiency by preventing river pollution for several months. PMID- 18448248 TI - Removal of disperse dye from aqueous solution by novel adsorbent prepared from biomass plant material. AB - The adsorption of Disperse Orange 25 (3-[N-ethyl-4-(4-nitrophenylazo) phenylamino] propionitrile) onto activated carbon was investigated in a batch system with respect to contact time, carbon dosage, pH and temperature from aqueous solutions. The Langmuir, Freundlich and Dubinin-Radushkevich (D-R) adsorption models were applied to describe the equilibrium isotherms and the isotherm constants were also determined. The Langmuir isotherm model agrees with the experimental data well. Maximum adsorption capacity (qmax) of Disperse Orange 25 onto adsorbent was 118.93mgg(-1) at 20 degrees C. The first-order, pseudo second-order kinetic models and the intraparticle diffusion model were used to describe the kinetic data and the rate constants were evaluated as well. The experimental data fitted very well to pseudo-second-order kinetic model. The results show that activated carbon prepared from Euphorbia rigida by sulfuric acid chemical activation could be employed as low-cost material to compare with commercial activated carbon for the removal of disperse dyes from effluents. PMID- 18448249 TI - In situ modification of activated carbons developed from a native invasive wood on removal of trace toxic metals from wastewater. AB - Activated carbons were developed by phosphoric acid activation of sawdust from Prosopis ruscifolia wood, an indigenous invasive species of degraded lands, at moderate conditions (acid/precursor ratio=2, 450 degrees C, 0.5h). For in situ modification of their characteristics, either a self-generated atmosphere or flowing air was used. The activated carbons developed in the self-generated atmosphere showed higher BET surface area (2281m2/g) and total pore volume (1.7cm3/g) than those obtained under flowing air (1638m2/g and 1.3cm3/g). Conversely, the latter possessed a higher total amount of surface acidic/polar oxygen groups (2.2meq/g) than the former (1.5meq/g). To evaluate their metal sorption capability, adsorption isotherms of Cu(II) ion from model solutions were determined and properly described by the Langmuir model. Maximum sorption capacity (Xm) for the air-derived carbons (Xm=0.44mmol/g) almost duplicated the value for those obtained in the self-generated atmosphere (Xm=0.24mmol/g), pointing to a predominant effect of the surface functionalities on metal sequestering behaviour. The air-derived carbons also demonstrated a superior effectiveness in removing Cd(II) ions as determined from additional assays in equilibrium conditions. Accordingly, effective phosphoric acid-activated carbons from Prosopis wood for toxic metals removal from wastewater may be developed by in situ modification of their characteristics operating under flowing air. PMID- 18448250 TI - Silica particles settling characteristics and removal performances of oxide chemical mechanical polishing wastewater treated by electrocoagulation technology. AB - The purpose of this study was to explore the feasibility of removing silica particles and reducing turbidity from oxide chemical mechanical polishing (oxide CMP) wastewater. Based on the dynamic characteristics of batch electrocoagulation, three operating stages (lag, reactive, and stabilizing) are proposed to identify the relationships among the zeta potential of the silica particles, solution turbidity, and the corresponding mean particle size of the silica. Experimental results show that the silica particles were destabilized and settled at the critical mean particle size, which was estimated to be above 520nm after 10min, and the corresponding turbidity removal mostly occurred during the reactive stage. Furthermore, the corresponding mean particle size varied from 520 to 1900nm as the treatment time progressed from 10 to 20min, which also occurred during the reactive stage. Several parameters, including different electrode pairs, electrolyte concentration, applied voltage, and the optimum condition of power input were investigated. Experimental results indicate that a Fe/Al electrode pair is the most efficient choice of the four electrode pair combinations in terms of energy consumption. The optimum electrolyte concentration and applied voltage were found to be 200ppm NaCl and 30V, respectively. PMID- 18448251 TI - Relationship between platelet serotonin content and rejections of unfair offers in the ultimatum game. AB - The ultimatum game (UG), a well-studied decision task used in experimental neuroeconomics, represents a simple two-person bargaining between a proposer and a responder. The proposer offers the responder how to split a sum of money. The responder decides whether to accept or reject the offer. When the responder accepts it, each player earns money according to the proposer's offer. If the offer is rejected, neither player gets anything. Rejections of "free" money in the UG represent a deviation from the standard economic model of rationality. This behaviour could be linked to adverse psychological reactions to unfair offers, including anger, hostility and impulsiveness. Currently, it is believed that the most plausible biological system related to anger and impulsivity is the serotonergic system. We hypothesize that serotonergic activity, as measured by platelet serotonin levels, will differentiate subjects who either reject or accept low UG offers. A sample of 60 economy students (31 males and 29 females, mean age: 24.4+/-2.3 years) was investigated. As predicted, the mean platelet serotonin level was significantly lower in participants who reject unfair offers (euro 1 out of euro 10) than in those who accept (2.86+/-0.13 versus 3.48+/-0.11 nmol/10(9) platelets, respectively, p<0.001). We conclude that low platelet serotonin may serve as a reliable biomarker to identify people who are more likely to reject unfair ultimatum offers in an experimental neuroeconomic setting. Our pilot data seem to indicate that the serotonergic system may play an important role in the UG rejection behaviour. PMID- 18448252 TI - Spinal changes associated with mechanical hypersensitivity in a model of Guillain Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an inflammatory disease of the peripheral nervous system which can cause pain via mechanisms that are poorly understood. Here, we show that in rat experimental autoimmune neuritis (EAN) mechanical allodynia developed up to 9 days before the onset of detectable neurological deficits. Allodynia was associated with an increase in the number of microglial cells in the dorsal horn of the spinal cord. The expression of the chemokine CX3CL1 (fractalkine) and its receptor CX3CR1 were also higher in EAN than in control dorsal horns suggesting spinal microglia and CX3CL1/CX3CR1 may play a role in the pain-like behaviour. PMID- 18448253 TI - Dynein cleavage and microtubule accumulation in okadaic acid-treated neurons. AB - Impairment of protein phosphatase 2A (PP2A) activity is implicated in tau hyperphosphorylation and microtubule (MT) instability in Alzheimer's disease (AD). Here, we report that okadaic acid, an effective PP2A inhibitor, suppresses the levels of acetylated and detyrosinated tubulins, but enhances tyrosinated tubulins in rat primary cortical neuron cultures. Immunocytochemistry experiments reveal that MTs accumulate intensely around soma and proximal neurites, implying impairment of MT transport to distal neurites which is mediated by dynein and dynactin. Here, we reveal that they can be cleaved by calpain. Notably, shortening of process length in OA-treated neurons is alleviated when calpain cleavage activity is inhibited. Based on these results, we propose that calpain mediated dynein cleavage in OA-treated neurons is responsible for the MT transport deficit, and consequently, neurite retraction. PMID- 18448254 TI - EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats. AB - Bidirectional signaling between ephrins and Eph receptor tyrosine kinases was first found to play important roles during development, but recently has been implicated in synaptic plasticity and pain processing in the matured nervous system. We show that ephrinB-EphB receptor signaling plays a critical role is induction and maintenance of neuropathic pain by regulating neural excitability and synaptic plasticity in the dorsal root ganglion (DRG) and the spinal dorsal horn (DH). Intrathecal application of blocking reagents for EphB-receptors, EphB1 Fc and EphB2-Fc chimeras inhibits the induction and maintenance of nerve injury induced thermal hyperalgesia and mechanical allodynia. These blockers also prevent and suppress the nerve injury-induced hyperexcitability of nociceptive small DRG neurons, sensitization of DH neurons and long-term potentiation (LTP) of synapses between C fibers and DH neurons. In naive, uninjured animals intrathecal administration of EphB-receptor activators ephrinB1-Fc and ephrinB2 Fc, respectively, induces thermal hypersensitivity and lowers the threshold for LTP, while EphB1-Fc prevents induction of the LTP. Western Blot analysis shows that nerve injury triggers an upregulation of the ephrinB1 and EphB1 receptor proteins in DRG and the spinal cord. These results indicate that, by regulating excitability of nociceptive-related neurons in DRG and DH and the synaptic plasticity at the spinal level, ephrinB-EphB receptor signaling contributes to neuropathic pain. This novel role for ephrinB-EphB receptor signaling suggests that these molecules may be useful therapeutic targets for treating pain after nerve injury. PMID- 18448256 TI - Self-organization and neuronal avalanches in networks of dissociated cortical neurons. AB - Dissociated cortical neurons from rat embryos cultured onto micro-electrode arrays exhibit characteristic patterns of electrophysiological activity, ranging from isolated spikes in the first days of development to highly synchronized bursts after 3-4 weeks in vitro. In this work we analyzed these features by considering the approach proposed by the self-organized criticality theory: we found that networks of dissociated cortical neurons also generate spontaneous events of spreading activity, previously observed in cortical slices, in the form of neuronal avalanches. Choosing an appropriate time scale of observation to detect such neuronal avalanches, we studied the dynamics by considering the spontaneous activity during acute recordings in mature cultures and following the development of the network. We observed different behaviors, i.e. sub-critical, critical or super-critical distributions of avalanche sizes and durations, depending on both the age and the development of cultures. In order to clarify this variability, neuronal avalanches were correlated with other statistical parameters describing the global activity of the network. Criticality was found in correspondence to medium synchronization among bursts and high ratio between bursting and spiking activity. Then, the action of specific drugs affecting global bursting dynamics (i.e. acetylcholine and bicuculline) was investigated to confirm the correlation between criticality and regulated balance between synchronization and variability in the bursting activity. Finally, a computational model of neuronal network was developed in order to interpret the experimental results and understand which parameters (e.g. connectivity, excitability) influence the distribution of avalanches. In summary, cortical neurons preserve their capability to self-organize in an effective network even when dissociated and cultured in vitro. The distribution of avalanche features seems to be critical in those cultures displaying medium synchronization among bursts and poor random spiking activity, as confirmed by chemical manipulation experiments and modeling studies. PMID- 18448255 TI - Expression of reelin, its receptors and its intracellular signaling protein, Disabled1 in the canary brain: relationships with the song control system. AB - Songbirds produce learned vocalizations that are controlled by a specialized network of neural structures, the song control system. Several nuclei in this song control system demonstrate a marked degree of adult seasonal plasticity. Nucleus volume varies seasonally based on changes in cell size or spacing, and in the case of nucleus HVC and area X on the incorporation of new neurons. Reelin, a large glycoprotein defective in reeler mice, is assumed to determine the final location of migrating neurons in the developing brain. In mammals, reelin is also expressed in the adult brain but its functions are less well characterized. We investigated the relationships between the expression of reelin and/or its receptors and the dramatic seasonal plasticity in the canary (Serinus canaria) brain. We detected a broad distribution of the reelin protein, its mRNA and the mRNAs encoding for the reelin receptors (VLDLR and ApoER2) as well as for its intracellular signaling protein, Disabled1. These different mRNAs and proteins did not display the same neuroanatomical distribution and were not clearly associated, in an exclusive manner, with telencephalic brain areas that incorporate new neurons in adulthood. Song control nuclei were associated with a particular specialized expression of reelin and its mRNA, with the reelin signal being either denser or lighter in the song nucleus than in the surrounding tissue. The density of reelin-immunoreactive structures did not seem to be affected by 4 weeks of treatment with exogenous testosterone. These observations do not provide conclusive evidence that reelin plays a prominent role in the positioning of new neurons in the adult canary brain but call for additional work on this protein analyzing its expression comparatively during development and in adulthood with a better temporal resolution at critical points in the reproductive cycle when brain plasticity is known to occur. PMID- 18448257 TI - The localization of proteins encoded by CRYM, KIAA1199, UBA52, COL9A3, and COL9A1, genes highly expressed in the cochlea. AB - Genes that are highly expressed in the inner ear, as revealed by cDNA microarray analysis, may have a crucial functional role there. Those that are expressed specifically in auditory tissues are likely to be good candidates to screen for genetic alterations in patients with deafness, and several genes have been successfully identified as responsible for hereditary hearing loss. To understand the detailed mechanisms of the hearing loss caused by the mutations in these genes, the present study examined the immunocytochemical localization of the proteins encoded by Crym, KIAA1199 homolog, Uba52, Col9a3, and Col9a1 in the cochlea of rats and mice. Confocal microscopic immunocytochemistry was performed on cryostat sections. Ultrastructurally, postembedding immunogold cytochemistry was applied using Lowicryl sections. Crym protein was predominantly distributed in the fibrocytes in the spiral ligament, as well as the stria vascularis in rats. KIAA1199 protein homolog was localized in various supporting cells, including inner phalangeal, border, inner and outer pillar, and Deiters' cells. Uba52 protein was restrictedly localized within the surface of the marginal cells of the stria vascularis. Collagen type IX was found within the tectorial membrane as well as fibrocytes in the spiral ligament. The present results showed cell specific localization of the encoded proteins of these highly expressed genes, indicating that the coordinated actions of various molecules distributed in different parts of the cochlea are essential for maintenance of auditory processing in the cochlea. PMID- 18448258 TI - HPA-axis activity and externalizing behavior problems in early adolescents from the general population: the role of comorbidity and gender The TRAILS study. AB - Contradictory findings on the relationship between hypothalamus-pituitary-adrenal (HPA)-axis activity and externalizing behavior problems could be due to studies not accounting for issues of comorbidity and gender. In a population-based cohort of 1768 (10- to 12-year-old) early adolescents, we used a person-oriented approach and a variable-oriented approach to investigate whether comorbidity with internalizing behavior problems and gender moderate the relationship between HPA axis activity (cortisol awakening response and evening cortisol levels) and externalizing behavior problems. We found that: (1) in early adolescents with pure externalizing behavior problems, there was a particularly strong effect of gender, in that girls showed significantly higher total cortisol levels after awakening (AUC(G) levels) and a significantly higher cortisol awakening response (AUC(I) levels) than boys. (2) Girls with pure externalizing behavior problems showed a significantly higher cortisol awakening response (AUC(I) levels) than girls without behavior problems or girls with comorbid internalizing behavior problems. This effect was absent in boys. (3) Externalizing behavior problems, in contrast to internalizing behavior problems, were associated with higher evening cortisol levels. This effect might, however, result from girls with externalizing behavior problems showing the highest evening cortisol levels. Overall, we were unable to find the expected relationships between comorbidity and HPA-axis activity, and found girls with pure externalizing behavior problems to form a distinct group with regard to their HPA-axis activity. There is need for prospective longitudinal studies of externalizing behavior problems in boys and girls in relation to their HPA-axis activity. It would be useful to consider how other risk factors such as life events and family and parenting factors as well as genetic risks affect the complex relationship between externalizing behavior problems and HPA-axis activity. PMID- 18448259 TI - What caused lymphopenia in SARS and how reliable is the lymphokine status in glucocorticoid-treated patients? AB - Severe Acute Respiratory Syndrome (SARS) outbreak in 2002-03 caused morbidity in over 8000 individuals and mortality in 744 in 29 countries. Lymphopenia along with neutrophilia was a feature of SARS, as it is in respiratory syncytial virus (RSV) and Ebola infections, to name a few. Direct infestation of lymphocytes, neutrophils and macrophages by SARS coronavirus (CoV) has been debated as a cause of lymphopenia, but there is no convincing data. Lymphopenia can be caused by glucocorticoids, and thus any debilitating condition has the potential to induce lymphopenia via stress mechanism involving the hypothalamic-pituitary-adrenal axis. Cortisol levels are elevated in patients with RSV and Ebola, and cortisol was higher in SARS patients with lymphopenia before any steroid therapy. Glucocorticoids also down-regulate the production of proinflammatory lymphokines. Because of the insidious presentation, SARS was treated with antibacterial, antiviral and supra-physiological doses of glucocorticoids. Treatment with glucocorticoids complicated the issue regarding lymphopenia, and certainly calls into question the status of lymphokines and their prognostic implications in SARS. PMID- 18448260 TI - Serum transforming growth factor-beta1 as a risk stratifier of sudden cardiac death. AB - Sudden cardiac death prematurely claims the lives of some 7 million each year worldwide. It occurs primarily in patients with an underlying structural cardiac abnormality, and regardless of the type of the underlying pathology (heart failure, dilated and hypertrophic cardiomyopathies, myocardial infarction and aging), death is almost always caused by ventricular tachycardia (VT) which rapidly degenerates to ventricular fibrillation (VF). Implantable cardioverter defibrillator is an effective but expensive therapy for preventing SCD, and finding a reasonably specific, sensitive and cost-effective risk stratification tool for patients at high risk of sudden cardiac death will have great clinical utility in preventing premature sudden cardiac death. Increased myocardial fibrosis has been shown to develop in a wide range of cardiac diseases all manifesting increased risk of VT and VF. Clinical and experimental studies attribute a major role for fibrosis in the initiation of VT, VF and sudden cardiac death. Transforming growth factor-beta1 (TGF-beta1) has been shown to promote myocardial tissue fibrosis and perhaps more importantly in cardiac conditions associated with increased myocardial fibrosis are shown to be positively correlated with increased serum levels of TGF-beta1. In the present hypothesis we suggest that monitoring the serum levels of TGF-beta1 may be a cost effective risk stratifier to identify patients at high risk of sudden cardiac death caused by VT and VF. PMID- 18448261 TI - Maternal vitamin D in pregnancy may influence not only offspring bone mass but other aspects of musculoskeletal health and adiposity. AB - Osteoporotic fractures, falls and obesity are major health problems in developed nations. Evidence suggests that there are antenatal factors predisposing to these conditions. Data are emerging from Australia and elsewhere to suggest that maternal vitamin D status in pregnancy affects intrauterine skeletal mineralisation and skeletal growth together with muscle development and adiposity. Given that low levels of vitamin D have been documented in many urbanised populations, including those in countries with abundant sunlight, an important issue for public health is whether maternal vitamin D insufficiency during pregnancy has adverse effects on offspring health. The developing fetus may be exposed to low levels of vitamin D during critical phases of development as a result of maternal hypovitaminosis D. We hypothesise that this may have adverse effects on offspring musculoskeletal health and other aspects of body composition. Further research focused on the implications of poor gestational vitamin D nutrition is warranted as these developmental effects are likely to have a sustained influence on health during childhood and in adult life. We suggest that there is a clear rationale for randomised clinical trials to assess the potential benefits and harmful effects of vitamin D supplementation during pregnancy. PMID- 18448262 TI - Possible involvement of tobacco-derived advanced glycation end products (AGEs) in an increased risk for developing cancers and cardiovascular disease in former smokers. AB - Tobacco smoking is one of the strongest risk factors for various disorders such as lung cancers and cardiovascular disease (CVD). Further, former smokers remain at an increased risk for developing lung cancers and CVD even years after they stop smoking. These observation suggest that expression levels of some of the genes related to tobacco smoking may not return to levels similar to never smokers and could be permanently altered despite prolonged smoking cessation, thereby being involved in the development of lung cancers and CVD. The modification, aggregation, and deposition of proteins are a prominent part of many pathological processes and can play a direct role in tissue damage. Advanced glycation end products (AGEs) have been shown to play a role in the development of many of the pathological sequelae of aging and diabetes such as CVD and cancer growth and metastasis. Moreover, there are several papers to show that tobacco smoke is a source of toxic reactive glycation products. Further, recent epidemiological and prospective data have supported the concept of 'metabolic memory', a long-term influence of previous hyperglycemia on the development of CVD in diabetes. Potential mechanism for propagating this 'memory' is considered to be the non-enzymatic glycation of proteins because the process of formation and accumulation of AGEs are most compatible with the theory. Therefore, it is conceivable that tobacco-derived AGEs are also involved in the increased risk for developing cancers and CVD in former smokers. In this paper, we would like to propose the possible ways of testing our hypotheses. Are tissue levels of AGEs still higher in former smokers, compared with age-, sex- and other confounders matched non-smokers? If the answer is yes, are the tissue levels of AGEs following smoking cessation decreased? If we examine the effects of smoking cessation as a function of years since quitting, is the extent of decrease in tissue AGEs levels parallel to that of risk reduction for developing cancers and CVD? Further, are genes that are permanently altered despite prolonged smoking cessation identical to those that regulated by AGEs? These investigations could clarify whether tobacco-derived AGEs are involved in sustained tissue injury in former smokers. PMID- 18448263 TI - Visceral adipose tissue specific persistence of Mycobacterium tuberculosis may be reason for the metabolic syndrome. AB - Mycobacterium tuberculosis (Mtb) is highly successful intracellular pathogen. Infection is maintained in spite of acquired immunity and resists eradication by antimicrobials. Following bacillaemia, small numbers of bacteria are disseminated to the extrapulmonary organs most likely including visceral adipose tissue by a mechanism that may involve the migration of M. tuberculosis within dendritic cells. In this lipid rich environment, Mtb can metabolize the fatty acids in a glyoxylate cycle dependent manner, and a state of chronic persistence may ensue. The persistent bacilli primarily use fatty acids as their carbon source. Expression of isocitrate lyase (ICL), gating enzyme of glyoxylate cycle, is upregulated during infection. ICL is important for survival during the persistent phase of infection. Expression of adipokines, particularly monocyte chemoattractant protein-1 (MCP-1), which is a potent proinflammatory cytokine, may be increased. MCP-1 contributes both to the recruitment of macrophages to adipose tissue and to the development of insulin resistance in humans. In addition, prolonged low level immune stimulation induces local adipolipogenesis, increasing visceral fat. Increased delivery of free fatty acid to the liver may stimulate the glyoxylate cycle-induced gluconeogenesis, raising hepatic glucose output. Hence, inhibition of the triggering enzyme ICL, which initiates all the pathologies related to persistent Mtb infection, may block the growth of the bacteria and may resolve the systemic metabolic complications. PMID- 18448264 TI - Sepsis: time has come to focus on the later stages. AB - Despite numerous advances in intensive care medicine, sepsis remains a deadly disease. Today, conventional therapeutic approaches and mainstream scientific research mostly focus on symptomatic early goal directed organ support therapy. This includes fluid resuscitation, choice and timing of antibiotics and vasopressors, mechanical ventilation, and renal replacement strategies. Furthermore, great effort has been undertaken to investigate whether tightly controlled blood glucose levels, the application of corticosteroids, and early medication using activated protein C improves survival. However, most of these mainstream approaches have recently been shown unsuccessful in large-scale clinical trials. Current data now suggest that besides giving fluids, antibiotics, and symptomatic organ support, little - if at all - can be done to improve mortality from sepsis. This might be due to the fact that in the presence of modern intensive care medicine, most patients with severe sepsis or septic shock will survive the early "shock phase" of the disease. Mounting evidence suggests that in the course of the disease, most septic patients are then subjected to a secondary phase, which is characterised by a failure of cell mediated immunity. This leads to repeated and uncontrolled infections, "chronic" multiple organ failure, and death in a large number of cases. Here we hypotheses that in order to profoundly influence survival from sepsis, future therapeutic efforts in the field should concentrate on this later "hypo-immune" stage of sepsis, associated immune phenomena, and novel immunomodulatory strategies. This may lead to the development of advanced immunomodulatory therapies available for widespread clinical use. Today, in the era of antibiotics and advanced organ system support therapy, it is not the bug that kills you- survival has become a matter of whether your cellular immune system can cope. PMID- 18448265 TI - Endogenous pro-resolving and anti-inflammatory lipid mediators: the new hope of atherosclerotic diseases. AB - Atherosclerosis is a complex disease process in which genetic, lipid, cellular, and immunological factors combine to determine the location, severity, and timing of lesion development and clinical events. It has been demonstrated, however, that inflammation governed atherosclerosis during the course of development of atherosclerosis. It has also been demonstrated to be effective to decrease the cardiovascular events and improve the prognosis of atherosclerotic diseases by regulating inflammatory reaction (e.g., statins). However, endogenous mechanisms of limiting inflammation in atherosclerosis are still unclear. Recent studies showed that lipoxidase/leukotrienes (LOX/LTs) pathway played important role in the ignition and development of atherosclerosis, whereas resolvins (E-series resolvins and D-series resolvins) and protectins [protectin D1 (PD1) and neuroprotectin D1 (NPD1)], endogenous lipid-derived mediators, inhibited inflammation through pro-resolution and counter-modulating immune inflammation reaction in atherosclerosis. Hence, we hypothesize that increased endogenous lipid mediators mentioned above play a vital role in anti-atherosclerosis and plaque stabilization through pro-resolution and anti-inflammation by LOX/LTs pathway. In addition, we predict that the endogenous lipid mediators may be a new target for treatment of atherosclerotic diseases. PMID- 18448266 TI - Etiology of dizziness, tinnitus, and nausea in idiopathic intracranial hypertension. PMID- 18448267 TI - Development and validation of a standardized method for contouring the brachial plexus: preliminary dosimetric analysis among patients treated with IMRT for head and-neck cancer. AB - PURPOSE: Although Radiation Therapy Oncology Group protocols have proposed a limiting dose to the brachial plexus for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, essentially no recommendations exist for the delineation of this structure for treatment planning. METHODS AND MATERIALS: Using anatomic texts, radiologic data, and magnetic resonance imaging, a standardized method for delineating the brachial plexus on 3-mm axial computed tomography images was devised. A neuroradiologist assisted with identification of the brachial plexus and adjacent structures. This organ at risk was then contoured on 10 consecutive patients undergoing intensity-modulated radiotherapy for head-and-neck cancer. Dose-volume histogram curves were generated by applying the proposed brachial plexus contour to the initial treatment plan. RESULTS: The total dose to the planning target volume ranged from 60 to 70 Gy (median, 70). The mean brachial plexus volume was 33 +/- 4 cm(3) (range, 25.1-39.4). The mean irradiated volumes of the brachial plexus were 50 Gy (17 +/- 3 cm(3)), 60 Gy (6 +/- 3 cm(3)), 66 Gy (2 +/- 1 cm(3)), 70 Gy (0 +/- 1 cm(3)). The maximal dose to the brachial plexus was 69.9 Gy (range, 62.3-76.9) and was >/=60 Gy, >/=66 Gy, and >/=70 Gy in 100%, 70%, and 30% of patients, respectively. CONCLUSIONS: This technique provides a precise and accurate method for delineating the brachial plexus organ at risk on treatment planning computed tomography scans. Our dosimetric analysis suggest that for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, brachial plexus routinely receives doses in excess of historic and Radiation Therapy Oncology Group limits. PMID- 18448268 TI - Primary causes of death after permanent prostate brachytherapy. AB - PURPOSE: To evaluate the primary causes of death in low-risk (low-risk), intermediate-risk (intermediate-risk), and high-risk (high-risk) patients undergoing permanent prostate brachytherapy with or without supplemental therapies. METHODS AND MATERIALS: From April 1995 through November 2004, a total of 1,354 consecutive patients underwent prostate brachytherapy. All patients underwent brachytherapy >3 years before analysis. Of the patients, 532 (39.3%) received androgen deprivation therapy and 703 (51.9%) received supplemental radiation therapy. The median follow-up was 5.4 years. Multiple parameters were evaluated as predictors of cause-specific, biochemical progression-free, and overall survival. RESULTS: The 10-year cause-specific survival was 97.0% (99.7%, 99.0%, and 90.1% for low-risk, intermediate-risk, and high-risk patients). Overall survival was 76.7% (82.5%, 78.3%, and 67.6% for low-, intermediate-, and high-risk patients, respectively). The cumulative death rate for cardiovascular disease was 11.5% (8.7%, 9.3%, and 19.8% for low-, intermediate-, and high-risk patients). The death rate from second malignancies (nonprostate cancer) was 7.2% and was not substantially different when stratified by risk group. Death from all other causes was 6.5% for the entire cohort but 1.3%, 5.0%, and 10.8% for low-, intermediate-, and high-risk patients. In multivariate analysis, death from prostate cancer was best predicted by Gleason score and risk group, whereas death from cardiovascular disease, nonprostate cancer, and all other causes were most closely related to patient age and tobacco use. CONCLUSIONS: Although cardiovascular mortality was the predominant cause of death, prostate cancer was responsible for approximately 10% of all deaths. In particular, overall survival was poorest in the high-risk group. Although high-risk patients were most likely to die of prostate cancer, the divergence in overall survival between high-risk and lower-risk patients primarily resulted from an excess of cardiovascular deaths. Changes in lifestyle to improve cardiovascular health may improve overall survival in patients with clinically localized prostate cancer. PMID- 18448269 TI - Influence of lipiodol agent on proton beam range in radiotherapy planning using computed tomography for hepatocellular carcinoma. AB - PURPOSE: To evaluate the influence of lipiodol on the proton beam range, which has not yet been determined. METHODS AND MATERIALS: Two computed tomography (CT) data sets were obtained with a T25-flask containing lipiodol and water that was placed above a water phantom. The plan with the lipiodol CT images was performed, and then a verification plan was applied to the water CT images. The actual proton beam ranges in the lipiodol and water were measured under same conditions, and we compared the calculated proton beam range in the treatment planning system with measured values. RESULTS: The calculated distal range in the treatment planning system was 12 cm in water, which was 3.87 cm longer than that in lipiodol (8.13 cm). In contrast, the measured distal range was 12 +/- 0.01 cm in water, which was 0.21 +/- 0.01 cm longer than that of lipiodol (11.78 +/- 0.01 cm). A 3.65 +/- 0.01-cm range shift was found in the calculated range compared with the measured range. For 10 hepatocellular carcinoma patients, the distal range in the verification plan with the corrected CT images in which the Hounsfield unit (HU) value of lipiodolized lesion was replaced with the average HU value of the surrounding tissue was 0.61 +/- 0.26 cm (range, 0.26-0.99) longer than that in the plan with uncorrected CT images. CONCLUSIONS: It could be relevant for the purposes of range calculation of proton beams in the treatment planning system that the HU value of a lipiodolized lesion is replaced by the average HU value of the surrounding normal tissue. PMID- 18448270 TI - Memory function before and after whole brain radiotherapy in patients with and without brain metastases. AB - PURPOSE: To prospectively compare the effect of prophylactic and therapeutic whole brain radiotherapy (WBRT) on memory function in patients with and without brain metastases. METHODS AND MATERIALS: Adult patients with and without brain metastases (n = 44) were prospectively evaluated with serial cognitive testing, before RT (T0), after starting RT (T1), at the end of RT (T2), and 6-8 weeks (T3) after RT completion. Data were obtained from small-cell lung cancer patients treated with prophylactic cranial irradiation, patients with brain metastases treated with therapeutic cranial irradiation (TCI), and breast cancer patients treated with RT to the breast. RESULTS: Before therapy, prophylactic cranial irradiation patients performed worse than TCI patients or than controls on most test scores. During and after WBRT, verbal memory function was influenced by pretreatment cognitive status (p < 0.001) and to a lesser extent by WBRT. Acute (T1) radiation effects on verbal memory function were only observed in TCI patients (p = 0.031). Subacute (T3) radiation effects on verbal memory function were observed in both TCI and prophylactic cranial irradiation patients (p = 0.006). These effects were more pronounced in patients with above-average performance at baseline. Visual memory and attention were not influenced by WBRT. CONCLUSIONS: The results of our study have shown that WBRT causes cognitive dysfunction immediately after the beginning of RT in patients with brain metastases only. At 6-8 weeks after the end of WBRT, cognitive dysfunction was seen in patients with and without brain metastases. Because cognitive dysfunction after WBRT is restricted to verbal memory, patients should not avoid WBRT because of a fear of neurocognitive side effects. PMID- 18448271 TI - Effectiveness of radiotherapy in myxoid sarcomas is associated with a dense vascular pattern. AB - PURPOSE: Surgery and adjuvant radiotherapy (RT) have long been the standard treatment for most deep-seated sarcomas; however, since the randomized trial from the National Cancer Institute of Canada, which described similar local control for pre- vs. postoperative RT, both modalities are now widely accepted. As a group, sarcomas are classified as radiation resistant. The subgroup of myxoid liposarcoma (MLS), a sarcoma with a typical vascular crow's feet pattern, is highly radiosensitive, but a mechanism for this phenomenon is unknown. Here we describe our results with preoperative RT and propose a mechanism explaining the high sensitivity based on the distinctive vascularization pattern of MLS. METHODS AND MATERIALS: Between 2002 and 2006, 31 sarcoma patients, including 10 with MLS, underwent preoperative RT at our institute. Resected specimens were histologically evaluated, focusing on classification, grade, and vascularization patterns. RESULTS: Twenty sarcomas showed more than 80% pathologic response after preoperative RT. A pathologic complete response was found in all "pure" MLS specimens after preoperative RT (n = 8). There were no pathologic complete responses in the remaining sarcoma patients (n = 23), although 12 showed 80% to 90% pathologic response. In contrast to the remaining RT-resistant sarcomas, the highly responding specimens contained branching vasculature, partial thrombus formation and inflammation of medium sized arterioles, similar to the vascular changes in MLS. CONCLUSIONS: Both MLS and sarcomas with MLS-like vasculature are highly radiosensitive. Radiation sensitivity may be explained by changes in medium-sized arterioles, obstructing the specific crow's feet vascularization and inducing hypoxia with secondary tumor cell death. PMID- 18448272 TI - High-dose-rate brachytherapy of a single implant with two fractions combined with external beam radiotherapy for hormone-naive prostate cancer. AB - PURPOSE: To evaluate the preliminary outcomes of high-dose-rate (HDR) brachytherapy of a single implant with two fractions and external beam radiotherapy (EBRT) for hormone-naive prostate cancer. METHODS AND MATERIALS: Between March 2000 and Sept 2003, a total of 53 patients with tumor Stage T1c-T3b N0 M0 prostate cancer were treated with HDR brachytherapy boost doses (7.5 Gy/fraction) and 50-Gy EBRT during a 5.5-week period. Median follow-up was 61 months. Patients were divided into groups with localized (T1c-T2b) and advanced disease (T3a-T3b). We used the American Society for Therapeutic Radiology and Oncology (ASTRO) definition for biochemical failure. According to recommendations of the Radiation Therapy Oncology Group-ASTRO Phoenix Consensus Conference, biochemical failure-free control rates (BF-FCRs) at 3 years were investigated as 2 years short of the median follow-up. RESULTS: Between April 2000 and Sept 2007, Common Terminology Criteria for Adverse Events Version 2.0 late Grade 2 genitourinary and gastrointestinal toxicity rates were 0% and 3.8%, respectively. Erectile preservation was 25% at 5 years. Overall survival was 88.1% and cause specific survival was 100%. At 3 years, ASTRO BF-FCRs of the localized and advanced groups were 100% and 42%, respectively (p = 0.001). CONCLUSIONS: The HDR brachytherapy of a single implant with two fractions plus EBRT is effective in treating patients with localized hormone-naive prostate cancer, with the least genitourinary and gastrointestinal toxicities; however, longer median BF-FCR follow-up is required to assess these findings. PMID- 18448273 TI - Estimation of optimal brachytherapy utilization rate in the treatment of malignancies of the uterine corpus by a review of clinical practice guidelines and the primary evidence. AB - PURPOSE: Brachytherapy (BT) is an important treatment technique for uterine corpus malignancies. We modeled the optimal proportion of these cases that should be treated with BT-the optimal rate of brachytherapy utilization (BTU). We compared this optimal BTU rate with the actual BTU rate. METHODS AND MATERIALS: Evidence-based guidelines and the primary evidence were used to construct a decision tree for BTU for malignancies of the uterine corpus. Searches of the literature to ascertain the proportion of patients who fulfilled the criteria for BT were conducted. The robustness of the model was tested by sensitivity analyses and peer review. A retrospective Patterns of Care Study of BT in New South Wales for 2003 was conducted, and the actual BTU for uterine corpus malignancies was determined. The actual BTU in other geographic areas was calculated from published reports. The differences between the optimal and actual rates of BTU were assessed. RESULTS: The optimal uterine corpus BTU rate was estimated to be 40% (range, 36-49%). In New South Wales in 2003, the actual BTU rate was only 14% of the 545 patients with uterine corpus cancer. The actual BTU rate in 2001 was 11% in the Surveillance, Epidemiology, and End Results areas and 30% in Sweden. CONCLUSION: The results of this study have shown that BT for uterine corpus malignancies is underused in New South Wales and in the Surveillance, Epidemiology, and End Results areas. Our model of optimal BTU can be used as a quality assurance tool, providing an evidence-based benchmark against which can be measured actual patterns of practice. It can also be used to assist in determining the adequacy of BT resource allocation. PMID- 18448274 TI - The mitochondrial genome of Gyrodactylus derjavinoides (Platyhelminthes: Monogenea)--a mitogenomic approach for Gyrodactylus species and strain identification. AB - Systematists and evolutionary biologists are constantly on the lookout for new sources of characters to discriminate amongst taxa and estimate interrelationships within and between taxa. Entire mitochondrial genomes provide a wealth of data, both at the nucleotide and amino acid level. Molecular markers are of particular utility when applied to small, morphologically conserved taxa, as is the case for many monogenean ectoparasites of fish. Gyrodactylus species display a considerable degree of anatomical conservatism, complicating diagnostics based solely on morphology, and some are significant pests of wild and cultured fish. Here we sequenced the complete mitochondrial genome of Gyrodactylus derjavinoides Malmberg, Collins, Cunningham & Behiar 2007, one of the most frequently found gyrodactylid species on salmonids in Scandinavia, and compared it with the recently published genomes of Gyrodactylus salaris Malmberg, 1957 and Gyrodactylus thymalli Zitnan 1960. Through comparative sliding window analysis we identified regions of high sequence variability and designed new primer sequences. In total, 6 new primer pairs have been developed, amplifying fragments of cox1, cox3, nad1, nad2, nad4, nad5 and atp6. Together, they amplify regions capturing almost half the nucleotide variability present in the complete mitochondrial genome. These degenerate primers should also work for other Gyrodactylus species parasitizing salmonids. In addition, we developed a multiplex assay that simultaneously amplifies four fragments in a single PCR reaction. Besides the diagnostic value, these fragments can be used for studying the transmission dynamics of Gyrodactylus, providing crucial information for an improved understanding of the spread and epidemiology of these important fish pathogens. PMID- 18448275 TI - Association of severity of enteric granulomatous inflammation with disseminated Mycobacterium avium subspecies paratuberculosis infection and antemortem test results for paratuberculosis in dairy cows. AB - Disseminated infection (DI) of Mycobacterium avium subspecies paratuberculosis (MAP) in cattle may impair cow health, potentiate spread of disease, and is a potential food-safety risk. The objectives of this study were to determine the association between severity of histologic enteric lesions and the occurrence of DI, clinical signs, and positive fecal culture and serum ELISA results. Bacteriologic fecal culture and serum ELISA were performed on 40 dairy cows from MAP-infected herds. Cows were classified as having DI if MAP was isolated from any of 11 extra-intestinal tissues collected postmortem. A grade of 0-3, corresponding to the severity of histologically evident granulomatous inflammation was determined for sections of ileum, jejunum, mesenteric lymph node, and ileocolic lymph node. An overall intestinal inflammation (OII) grade of 0-3 was assigned to each cow. The proportion of cows with DI increased with tissue-specific lesion grade and OII grade. All cows with grade 3 inflammation in any single tissue had DI, however, some cows with DI had grade 1 inflammation or no lesions. In general, there was a positive association between OII grade and clinical signs, gross enteric lesions, and positive ELISA and fecal culture results. However, 12% of OII grade 0 cows had clinical signs (explained by other conditions recognized with necropsy), and the proportion of positive ELISA results was lower for OII grade 3 cows relative to grade 2 cows. Although MAP dissemination may occur early in the disease process, histopathology of intestinal tissues may be used to detect a substantial proportion of DI cows. PMID- 18448276 TI - General movements in infants born from mothers with early-onset hypertensive disorders of pregnancy in relation to one year's neurodevelopmental outcome. AB - BACKGROUND: Assessment of general movements (GMs) at three months is considered useful for prediction of adverse neurological outcome in high risk infants. AIMS: To study the prevalence of abnormal GMs in infants born from women with early onset hypertensive disorders of pregnancy and the association of GMs with neurodevelopmental outcome at one year. STUDY DESIGN: Prospective study, part of a randomised controlled trial of pre-birth management strategies. SUBJECTS: Infants born from women with early-onset hypertensive disorders of pregnancy. OUTCOME MEASURES: GMs observation and neurological examination at term and three months corrected age; at one year neurological examination and Bayley Scales of Infant Development. RESULTS: From 216 women included, 175 of 178 surviving infants (mean gestational age 31.6 weeks [SD 2.3], mean birth weight 1346 grams [SD 458]), were examined at three months. At term age normal, mildly abnormal and definitely abnormal GMs were observed in 54%, 36% and 10% respectively; and at three months in 47%, 40% and 13%. Mildly or definitely abnormal GMs at three months were not associated with abnormal neurological examination at one year, however, they were associated with delayed psychomotor development at one year (p = 0.01). CONCLUSIONS: In this prospective study, including small for gestational age, preterm infants about half of them did not have normal GMs at term and three months. There was no association of GMs at term nor three months with neurological outcome at one year, but there was a significant association of GMs at three months with one year psychomotor development. PMID- 18448278 TI - Semen variables of sheep (Ovis aries) experimentally infected with Toxoplasma gondii. AB - The influence of Toxoplasma gondii on semen variables and sperm morphology of sheep was evaluated in eight reproductive males distributed into three experimental groups: GI, three sheep inoculated with 2.0x10(5) of P strain oocytes; GII, three sheep infected with 1.0x10(6) of RH strain tachyzoites and; GIII two control sheep. Clinical (rectal temperature, cardiac and respiratory frequencies), parasite and serology exams (IIF) were realized. Sperm variables (volume, motility, vigor and concentration) and semen morphology for each sheep were also evaluated. Thus, semen and blood collections were assessed on post inoculation days (PIDs)-1,3,5,7,11,14 and weekly thereafter up to PID 70. Clinical alterations were observed (hypothermia and anorexia) in infected sheep from groups GI and GII. Parasitic outbreaks were detected in five sheep. All the infected sheep produced antibodies against T. gondii from PID 5 onwards, reaching a peak of 4096 and 8192 for group GI and GII sheep, respectively. Differences (P<0.05) were observed regarding the ejaculate volume between the inoculated groups (oocytes and tachyzoites) and control. Even though experimental toxoplasmic infection resulted in clinical symptomology in the inoculated sheep, the minimal alterations in sperm pathologies could not be directly attributed to T. gondii. PMID- 18448277 TI - Benzo(a)pyrene-caused increased G1-S transition requires the activation of c-Jun through p53-dependent PI-3K/Akt/ERK pathway in human embryo lung fibroblasts. AB - Benzo(a)pyrene (B(a)P) is a potent lung carcinogen mainly derived from tobacco smoking and environmental contamination, however, the molecular mechanisms by which it accelerates the cell cycle progression and induces the abnormal cell proliferation are still far away from understood. Our current analysis of human embryo lung fibroblasts (HELF) showed that B(a)P exposure was able to promote cell cycle G(1)-S phase transition. This effect was correlated with c-Jun activation because inhibition of c-Jun by its dominant negative mutant (TAM67) reversed B(a)P action on cell cycle with the down-regulation of expression of cyclin D1, pRb and E2F1. Further study found that overexpression of dominant negative mutants of, PI-3K or Akt, dramatically reduced B(a)P-induced the activation of c-Jun and extracellular signaling regulated kinase (ERK), but not c Jun NH2 terminal kinase (JNK). Inhibition of p53 by either its inhibitor pifithrin-alpha or p53 siRNA markedly increased B(a)P-induced the activation of c Jun, Akt and ERK in this context. Take together, our results indicate that c-Jun activation by p53-dependent PI-3K/Akt/ERK pathway is responsible for B(a)P induced cell cycle alternations in human embryo lung fibroblasts. PMID- 18448279 TI - Passage of postovulatory follicular fluid into the peritoneal cavity and the effect on concentrations of circulating hormones in mares. AB - Reported data were reviewed and reexamined to evaluate the concept that most of the follicular fluid enters the peritoneal cavity at ovulation in mares and transiently alters the circulating concentrations of LH, FSH, estradiol, and inhibin. A transrectal ultrasonographic study supported the hypothesis that the large volume (40-50 ml) of evacuated follicular fluid passes through the infundibular fimbriae into the peritoneal cavity. A spike in circulating inhibin and a decrease in the rate of reduction in circulatory estradiol occurs at ovulation. Simultaneously, a disruption occurs in the increasing concentrations of the ovulatory LH surge and in the FSH surge that begins before ovulation. The concept was further supported by the present finding that the estradiol content of follicular fluid within a few hours before ovulation is equivalent to the amount reported to be needed for a negative effect on LH and for a synergistic negative effect of estradiol and inhibin on FSH. PMID- 18448280 TI - Aromatase inhibitors and the endometrium. AB - OBJECTIVE: To investigate the potential impact of aromatase inhibitors, given after stopping tamoxifen treatment, on the endometrium of postmenopausal breast cancer patients. METHODS: Review of all available literature of studies on aromatase inhibitor therapy in postmenopausal breast cancer patients previously treated with tamoxifen. RESULTS: (1) Endometrial thickness was found to be significantly lower in patients switched from tamoxifen treatment to aromatase inhibitor therapy, compared to those who continued tamoxifen treatment. This significant difference between the 2 groups was maintained throughout the entire treatment. (2) Vaginal bleeding was significantly more common in patients who continued tamoxifen therapy as compared to those who switched to aromatase inhibitors. (3) Replacement of tamoxifen treatment by aromatase inhibitors in postmenopausal breast cancer patients resulted in the appearance of only few, benign endometrial pathologies. The different endometrial pathologies were more common in patients who continued tamoxifen therapy, compared to patients who switched to aromatase inhibitors. (4) Endometrial cancer was recovered in significantly more patients who continued tamoxifen therapy as compared to those switched to aromatase inhibitors. However, some studies showed no significant statistical differences in the frequency of endometrial cancer diagnosed in the tamoxifen group as compared to the aromatase inhibitor group. CONCLUSION: These findings may hint on the possibility that aromatase inhibitors may provide a potential protective effect on the endometrium in patients previously treated with tamoxifen. PMID- 18448281 TI - Does a short cessation of HRT decrease mammographic density? AB - BACKGROUND: Hormone replacement therapy (HRT) is known to increase breast density, thus decreasing the sensitivity of cancer screening by mammography. Some authors recommend short cessation of HRT before mammography, but evidence showing the effect of such short cessation is limited. The purpose of this study is to examine whether a short cessation of HRT changes mammographic density. METHODS: Forty-eight women taking HRT agreed to have mammograms taken before and after stopping HRT for 4 weeks. Mammographic density was measured by Wolfe's four-point classification, six-categorical visual scale and two different computer methods (interactive-thresholding and SMF). Density values of mammography before and after the cessation of HRT were compared using Wilcoxon signed-rank test for categorical variables and paired t-test for continuous variables. Changes in breast pain and tenderness during mammography, radiation dose, compression force, and breast thickness were also recorded. RESULTS: No significant changes in mammographic density were observed by either visual or computer methods. There were no significant changes in breast pain or in tenderness on mammograms before and after the month's cessation of HRT. Radiographic measurements were not significantly altered by the 4-week cessation of HRT. CONCLUSION: In this screening population, a 4-week cessation of HRT before mammograms did not significantly alter mammographic density. PMID- 18448282 TI - Knotted urethral catheter in an 80-year-old woman: prevention and management of this unusual complication. AB - Intravesical catheter knotting represents a rare event, especially described in paediatric literature. We report a case of a catheter knot, occurring in an 80 year-old woman, managed by means of sustained traction. PMID- 18448283 TI - Cyclosporine A and Rapamycin induce in vitro cholesteryl ester transfer protein activity, and suppress lipoprotein lipase activity in human plasma. AB - PURPOSE: Cyclosporine A (CsA), Rapamycin (RAPA), Tacrolimus (FK-506) and Mycophenolate mofetil (MMF) are immunosuppressants that are widely used in solid organ transplant patients. However, some of these drugs have been reported to cause dyslipidemia in patients. Our aim was to determine the effects of these drugs on in vitro cholesteryl ester transfer protein (CETP), hepatic lipase (HL) and lipoprotein lipase (LPL) activity within human plasma. METHODS: We measured CETP activity in human normolipidemic plasma with and without drug treatment, by measuring the incorporation of labeled cholesteryl ester into lipoproteins. To further confirm the result, we also measured recombinant CETP (rCETP) activity with and without drug treatment. We measured HL and LPL activity in post-heparin normal human plasma in the presence and absence of the drugs by measuring the release of fatty acids from radiolabeled triolein. RESULTS: We found an increase in CETP activity in human normolipidemic plasma and rCETP treated with CsA and RAPA. By contrast, CETP activity was not altered significantly in the presence of FK-506 and MMF. LPL activity in post-heparin normal human plasma was suppressed following the co-incubation with CsA, RAPA, FK-506 or MMF whereas HL activity remained unaffected. CONCLUSIONS: The increase in CETP activity and suppression in LPL activity following CsA and RAPA treatment observed in the present study may be associated with elevated LDL cholesterol levels and hypertriglyceridemia seen in patients administered these drugs. PMID- 18448284 TI - Liposomal bismuth-ethanedithiol formulation enhances antimicrobial activity of tobramycin. AB - Pseudomonas aeruginosa and Burkholderia cenocepacia (formally, genomovar III genotype of Burkholderia cepacia complex) have emerged as serious opportunistic resistant pathogens in patients with cystic fibrosis (CF). We have developed a liposomal formulation containing bismuth-ethanedithiol (BiEDT) and tobramycin to overcome bacterial resistance. The stability of liposomal BiEDT-tobramycin (LipoBiEDT-TOB) was studied in phosphate buffered saline (PBS) and human pooled plasma at 4 and 37 degrees C. Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) for free tobramycin and LipoBiEDT-TOB against clinical isolates of P. aeruginosa and B. cenocepacia were determined by the broth dilution method. The toxicity profile and the influence on bacterial adhesion of LipoBiEDT-TOB formulation were determined using a human lung carcinoma cell line (A549). LipoBiEDT-TOB exhibited lower MICs than the conventional antibiotic (0.25mg/L vs. 1024 mg/L) and eradicated this highly resistant bacterial strain of P. aeruginosa (PA-48913) at very low concentrations (4 mg/L vs. 4096 mg/L). LipoBiEDT-TOB was significantly less toxic when compared to the free BiEDT, as evaluated by the MTT and LDH assay. The LipoBiEDT-TOB formulation suppressed bacterial adhesion (B. cenocepacia M13642R) to A549 cells. These data suggest that the novel LipoBiEDT-TOB drug delivery system could be utilized as a new strategy to enhance the efficacy of existing antibiotics against resistant organisms that commonly affect individuals with chronic lung infections. PMID- 18448285 TI - Determination of water vapor transmission rate (WVTR) of HDPE bottles for pharmaceutical products. AB - The objective of this study was to investigate the effects of experimental conditions for measuring the water vapor transmission rate (WVTR) of high-density polyethylene (HDPE) bottles using a steady-state sorption method. Bottles were filled with desiccant, closed with caps and heat induction sealed, and then stored in stability chambers at controlled temperature and relative humidity. Weight gain of the bottles was determined every 1 or 2 weeks until a linear weight gain profile was obtained. WVTR of the bottles was determined from the slope of the linear portion of the weight gain versus time profile. The effects of desiccants and temperature/humidity were studied. Results show that, with a sufficient amount of anhydrous calcium chloride in bottles, a negligibly low and sufficiently constant headspace humidity is maintained, and a steady-state permeation rate is achieved. For all 8 sizes of bottles used in this study, steady-state was achieved in 1 or 2 weeks after the experiment was started. This method provided reproducible WVTR data for HDPE bottles. Apparent moisture permeability of all 8 sizes of bottles was (2.3+/-0.3)x10(-7), (2.6+/-0.2)x10( 7), and (3.4+/-0.2)x10(-7)cm(2)/s at 25 degrees C, 30 degrees C, 40 degrees C, respectively. Moisture permeability determined from the current study was similar to data reported in the literature, indicating that the steady-state weight gain method can be used to obtain reliable WVTR of containers for pharmaceutical products. PMID- 18448286 TI - A novel injectable local hydrophobic drug delivery system: Biodegradable nanoparticles in thermo-sensitive hydrogel. AB - In this article, a novel local hydrophobic drug delivery system: nanoparticles in thermo-sensitive hydrogel, was demonstrated. First, honokiol, as a model hydrophobic drug, loaded poly(epsilon-caprolactone)-poly(ethylene glycol) poly(epsilon-caprolactone) (PCEC) nanoparticles were prepared by emulsion solvent evaporation method, and then were incorporated into thermo-sensitive F127 hydrous matrix. The obtained injectable hydrophobic drug delivery system can act as a depot for sustained release of honokiol in situ. The lower critical solution temperature (LCST) of the composite matrix increases with increase in the mass of incorporated nanoparticles, or with decrease in the amount of residual organic solvent in the system. Honokiol release profile in vitro was studied, and the results showed that honokiol could be sustained released from the system. The described injectable drug delivery system might have great potential application for local delivery of hydrophobic drugs such as honokiol. PMID- 18448287 TI - Rumen bypass and biodistribution of l-carnitine from dual-layered coated pellets in cows, in vitro and in vivo. AB - A ruman bypass delivery system was investigated to improve the delivery efficiency of L-carnitine in biological samples of cows. Highly water-soluble L carnitine used for dietary supplement in ruminants was chosen. L-Carnitine-loaded compact pellets were prepared by extrusion method and then coated with various coating materials such as ethylcellulose (EC), Eudragit E100 (E100), Eudragit RS100 (RS100), stearyl alcohol and glyceryl monostearate, for single-layered coated pellets (SCP). Two types of dual-layered coated pellets (DCP) were also designed as DCP-A (inner E100/outer EC) or DCP-B (inner EC/outer E100). Preparation of compact pellet and methods of polymeric coatings are the most important strategies for modulated release and rumen bypass efficiency based on chewing behaviors and physiology of veterinary species. DCPs were more efficient in retarding L-carnitine release in rumen fluid (pH 6.8) than the SCP but DCP-B gave much faster release in abomasums fluid (pH 1.2). Both DCP-A and DCP-B showed high in vivo rumen bypass efficiency in cows compared with the nonprotected preparation and most of l-carnitine was readily absorbed. DCP-B was also efficient for delivering L-carnitine in biological samples of cows, mainly in muscle but no statistical differences were observed among the tested preparations after the multiple oral feeding to cows for 3 months. Interestingly, DCP-B produced higher L-carnitine levels in milk in a dose-dependent manner. However, delivery efficiency of L-carnitine preparations in biological samples of cows would rather be more dependent on feeding schedules. PMID- 18448288 TI - A comparative study of a range of polymeric microspheres as potential carriers for the inhalation of proteins. AB - The aim of this study was to compare protein-loaded inhalable microparticles manufactured using a range of biocompatible polymers including hydroxypropyl cellulose (HPC), chitosan, hyaluronic acid, alginate, gelatin, ovalbumin and poly(lactide-co-glycolide) (PLGA). Spray-drying was used to prepare microparticles containing bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC). Particles of respirable size and high protein loading were obtained. No evidence of BSA degradation was seen from PAGE analysis. The microparticles were mixed with mannitol as a carrier and powder aerosolization was assessed with a multi-dose dry powder inhaler (DPI) using a multi-stage cascade impactor. The mass median aerodynamic diameter (MMAD) ranged between 2.9 and 4.7 microm. Potential polymer toxicity in the lungs was compared by impinging the particles on Calu-3 monolayers and assessing the cytotoxicity, induction of cytokine release, changes in transepithelial permeability and electrical resistance. No toxic effects were observed with most of the polymers though some evidence of compromised cell monolayer integrity was seen for PLGA and ovalbumin. PLGA and gelatin microparticles caused a significant increase in IL-8 release. Of the polymers studied, PLGA showed the greatest toxicity. Certain polymers showed particular promise for specific protein delivery needs in the lungs, such as HPC to improve flow properties, sodium hyaluronate for controlled release, and chitosan and ovalbumin for systemic delivery. PMID- 18448289 TI - Determinants for in vivo anti-tumor effects of PEG liposomal doxorubicin: importance of vascular permeability within tumors. AB - To elucidate the determinants of the in vivo anti-tumor efficacy of polyethylene glycol (PEG)-modified liposomal doxorubicin (DOX), we examined its anti-tumor effect against three different tumor cell lines (Lewis lung cancer (LLC), Colon 26 (C26) and B16BL6 melanoma (B16)) in vitro and in vivo. In vitro, LLC was the most sensitive tumor to DOX and liposomal DOX based on the MTT assay. However, the strongest in vivo anti-tumor effect was observed in the C26 tumor-bearing mice. The in vivo accumulation of radiolabelled PEG liposome in the C26 tumor after intravenous injection was significantly larger than in other tumors. The extent of vascularity assessed by immunohistochemical staining of CD31 was not directly related with the tumor accumulation of PEG liposome. On the other hand, Evans blue extravasation and secretion of VEGF in C26 tumors were higher than in LLC tumors, clearly demonstrating that the vasculature permeability was higher within C26 tumors. These results indicated that the vascular permeability within the tumor substantially affects the tumor accumulation of PEG liposome and may be one of the important determinants in the in vivo anti-tumor efficacy of PEG liposomal DOX. PMID- 18448290 TI - Preparation and biodisposition of methoxypolyethylene glycol amine-poly(DL-lactic acid) copolymer nanoparticles loaded with pyrene-ended poly(DL-lactic acid). AB - A formyl group-ended poly(DL-lactic acid) (PLA-aldehyde), synthesized in the same manner as reported previously, was utilized to produce the polymeric marker for PLA-related nanoparticles. Namely, pyrene-ended poly(DL-lactic acid) (PLA-pyrene) was prepared as a polymeric marker by the reductive amination of PLA-aldehyde and aminopyrene. Methoxypolyethylene glycol amine-poly(DL-lactic acid) block copolymer (PLA-(MeO-PEG) nanoparticles loaded with PLA-pyrene were prepared, and examined on retention of PLA-pyrene in the nanoparticles, and biodisposition in normal and sarcoma-180 solid tumor-bearing mice. PLA-pyrene was retained stably in PLA-(MeO-PEG) nanoparticles in a PBS-ethanol (7:3, v/v) mixture and a plasma PBS (1:1, v/v) mixture, indicating that PLA-pyrene might be a useful marker of PLA-(MeO-PEG) nanoparticles themselves. After i.v. injection in normal rats, the plasma level of PLA-pyrene was very high for initial 8h, and accumulated gradually into organs, especially spleen and liver. After i.v. injection in tumor bearing mice, similar biodistribution profiles of PLA-pyrene were observed, and PLA-pyrene was accumulated well in tumor, suggesting that PLA-(MeO-PEG) nanoparticles should be delivered efficiently to solid tumors. It is suggested that PLA-pyrene might be a useful probe of the nanoparticles themselves. In addition, it was demonstrated that PLA-(MeO-PEG) nanoparticles should be a useful drug carrier for passive tumor targeting. PMID- 18448291 TI - Antifungal activity of the plant Dodonaea viscosa var. angustifolia on Candida albicans from HIV-infected patients. AB - THE AIM OF THIS STUDY: was to determine the minimum inhibitory concentration (MIC) and the time taken by Dodonaea viscosa var. angustifolia (PLE) a South African medicinal plant, chlorhexidine gluconate (CHX) and triclosan (TRN) to kill Candida albicans. 41 strains of Candida albicans were investigated, 20 from HIV-positive patients, 20 from HIV-negative subjects and Candida albicans ATCC 90028. The MICs of an acetone extract of PLE, CHX and TRN were measured using a microtitre double dilution technique, and the time taken to kill 99.5% of the strains was determined. The MICs of PLE, CHX and TRN were 6.25-25, 0.008-0.16 and 0.0022-0.009 mg/ml, respectively. PLE killed all the test strains within 30s and CHX 40% of the isolates from HIV-positive patients and 20% of strains from HIV negative subjects in 1 min. During the same time TRN killed 55% and 35% of isolates from HIV-positive and HIV-negative patients. Dodonaea viscosa var. angustifolia has antifungal properties and is more effective than commercially available mouthrinses. PMID- 18448292 TI - Flavonoids with iNOS inhibitory activity from Pogonatherum crinitum. AB - Pogonatherum crinitum has long been used as a folk remedy for the treatment of many inflammatory diseases in Taiwan, and till now there is still no report concerning its active principles as well as their pharmacological studies. That prompted us to investigate the bioactive constituents of Pogonatherum crinitum. Two novel chemical entities, luteolin 6-C-beta-boivinopyranoside (1) and 6-trans (2''-O-alpha-rhamnopyranosyl)ethenyl-5,7,3',4'-tetrahydroxyflavone (2), along with luteolin (3), kaempferol (4), luteolin 6-C-beta-fucopyranoside (5), kaempferol 3-O-alpha-L-rhamnopyranoside (6), luteolin 6-C-beta-glucopyranoside (7), rutin (8) and kaempferol 3-O-rutinoside (9) were isolated from this plant, and identified by spectroscopic analysis. The effect of these compounds on the inhibition of NO production in LPS-activated macrophages was further evaluated. All these compounds inhibited NO production in activated RAW 264.7 cells to various degrees without affecting the cellular viability. Among the compounds examined, both compounds 1 and 2 suppressed LPS-induced NO production, with E(max) values of 99.51+/-0.23% and 92.41+/-3.22%, respectively. The most potent compounds, 3 and 4, inhibited NO production with IC(50) values of 10.41+/-0.02 microM and 10.61+/-0.44 microM, respectively. These effects were attributed to suppression of mRNA expression of inducible NO synthase (iNOS). Our results clearly demonstrated that these naturally occurring iNOS inhibitors may be beneficial to the treatment of inflammatory diseases associated with overproduction of NO, which provides an explanation, at least a part, for the anti-inflammatory property of Pogonatherum crinitum. PMID- 18448294 TI - [Practical use of anti-TNF monoclonal antibodies in inflammatory bowel diseases]. PMID- 18448295 TI - Imaging features of portal biliopathy: frequency of involvement patterns with emphasis on MRCP. AB - PURPOSE: To investigate the imaging features of portal biliopathy with emphasis on MR cholangiopancreatography (MRCP). The ancillary vascular findings of portal biliopathy were also evaluated by accompanying MR portography, dynamic contrast enhanced (CE) CT, and dynamic CE MRI studies. MATERIALS AND METHODS: Sixteen patients with portal cavernoma were included in the study. Patients had undergone MRCP (n=16) studies accompanied by MR portography (n=13), dynamic CE CT (n=3) or dynamic CE MRI (n=2) of the liver. Two patients had undergone both dynamic CE CT and dynamic CE MRI. Two radiologists evaluated all the examinations together, retrospectively. MRCP images were analyzed for the presence of biliary stenosis, upstream (prestenotic) dilatation, wavy appearance of the bile ducts, angulation of the common bile duct (CBD), and choledocholithiasis. MR portography, dynamic CE CT and dynamic CE MRI studies were evaluated for the existence of portal cavernomas, and the presence of gall bladder/choledochal varices. RESULTS: All patients had signs of portal biliopathy on MRCP. Frequencies of the biliary findings on MRCP were as follows: biliary stenosis, 93.7%; upstream dilatation, 68.7%; wavy appearance of the biliary tree, 87.5%; angulation of the CBD, 75%. None of the patients had choledocholithiasis. Frequencies of the ancillary vascular findings detected on CE studies were as follows: gall bladder varices, 100%, choledochal varices, 93.7%. CONCLUSION: MRCP features of portal biliopathy in order to their frequencies were as follows: biliary stenosis, wavy appearance of the bile ducts, angulation of the CBD, and upstream dilatation of the bile ducts. PMID- 18448296 TI - Radiation dose reduction in direct digital panoramic radiography. AB - OBJECTIVES: (a) To measure the absorbed radiation doses at 16 anatomical sites of a Rando phantom and (b) to calculate the effective doses including and excluding the salivary gland doses in panoramic radiography using a conventional and a digital panoramic device. STUDY DESIGN: Thermoluminescent dosimeters (TLD-100) were placed at 16 sites in a Rando phantom, using a conventional, Planmeca Promax and a digital, Planmeca PM2002CC Proline 2000 (Planmeca Oy, 00880 Helsinki, Finland) panoramic device for panoramic radiography. During conventional radiography the selected exposure settings were 66 kVp, 6 mA and 16s, while during digital radiography two combinations were selected 60 kVp, 4 mA, 18 s and 66 kVp, 8 mA, 18s with and without image processing function. The dosimeters were annealed in a PTW-TLDO Harshaw oven. TLD energy response was studied using RQN beam narrow series at GAEC's Secondary Standard Calibration Laboratory. The reader used was a Harshaw, 4500. Effective dose was estimated according to ICRP(60) report (E(ICRP60)). An additional estimation of the effective dose was accomplished including the doses of the salivary glands (E(SAL)). A Wilcoxon signed ranks test was used for statistical analysis. RESULTS: The effective dose, according to ICRP report (E(ICRP60)) in conventional panoramic radiography was 17 microSv and E(SAL) was 26 microSv. The respective values in digital panoramic radiography were E(ICRP60)=23 microSv and E(SAL)=38 microSv; while using the lowest possible radiographic settings E(ICRP60) was 8 microSv and E(SAL) was 12 microSv. CONCLUSIONS: The effective dose reduction in digital panoramic radiography can be achieved, if the lowest possible radiographic settings are used. PMID- 18448297 TI - Spanish Radiology in the second half of the XX Century: a view from inside. AB - Radiology was born in 1896 with the immediate recognition of the diagnostic value of X-rays in medicine and progressed throughout the XX Century with the increasing knowledge of its properties and clinical applications. By mid-century Radiology was a respected clinical specialty in advanced countries, the radiological report was a requirement in hospital practice and radiologists' opinions requested in scientific meetings. In the last decades of the century has had a spectacular expansion with the emergence of new imaging modalities and revolutionary technologies that have transformed the specialty worldwide. In Spain Radiology lagged behind needs and demand in 1950. Radiological practice was unregulated and performance of X-ray exams by non-radiologists was common. Teaching of Radiology was non-existent in Medical Schools or postgraduation. The diagnostic value of the specialty was unrecognized by physicians and the role of radiologists ignored. Most hospital radiology services were poorly equipped and functionally inadequate. The shadow of the Civil War (1936-39) was conditioning Radiology in the country. The point of inflexion in the development of Radiology in Spain was the inclusion of film reading sessions in the 1965 academic program of the Society of Radiology. It was in the presentation of cases at these conferences that Clinical Radiology found the finest demonstration ground and as a result was immediately adopted by radiologists and progressively applied in scientific meetings, clinical practices and training programs. Its influence was important in reforming hospital practice, legislation on specialization and education, as well as in national health care plans. At the end of the century radiology in Spain was at a par with the standards of other western nations. The author was a witness of the evolution of Radiology during his 50 years of professional life. This article does not pretend to be exhaustive in names or contributions. It is an overview of the period from the perspective of his past experience and seen from the distance of events that influenced the course of developments. I hope that those interested in the subject find that the effort has been worthwhile and helpful. PMID- 18448298 TI - Functional magnetic resonance: new applications in epilepsy. AB - Functional magnetic resonance imaging technique is a non-invasive tool that is capable to detect the subtle hemodynamic changes produced during regional brain activation. Functional MRI applications in epilepsy patients are language lateralization and mapping, memory function assessment and localization of ictal and interictal changes. Functional MRI for language lateralization is currently used in clinical practice and provides comparable results to the intracarotid amobarbital test. In functional MRI studies for memory function assessment, results show changes in epileptic patients, but further studies are required to validate this technique for individual cases. A new application is ictal or interictal functional MRI with EEG recording that provides more detailed information about simultaneous electrographic and hemodynamic changes during interictal discharges or EEG seizures. This technique seems to have encouraging results to localize the epileptogenic area and to study propagation patterns. PMID- 18448299 TI - Macrocystic pancreatic lesions: differentiation of benign from premalignant and malignant cysts by CT. AB - OBJECTIVE: To assess useful CT features for differentiating benign from premalignant and malignant macrocystic pancreatic lesions. METHODS: Seventy-four patients with pathologically proven macrocystic pancreatic lesions were enrolled: 17 benign cysts (macrocystic serous cystadenoma, n=12; congenital cyst; n=5) and 57 premalignant and malignant cysts (mucinous cystic neoplasm, n=28; intraductal papillary mucinous neoplasm of branch duct type, n=20; tumor with cystic change, n=9). Size, location, shape (lobulated, round or oval, or complex cystic with tubular cyst), wall thickness (thin, < or =1mm; thick, >1mm), internal surface (smooth or irregular), and other findings were analyzed with multiphasic CT with thin-section (2.5-3mm) images. CT features between two groups were compared using univariate and multivariate stepwise logistic regression analyses. RESULTS: On univariate analysis, the differences for the shape (p=0.007), wall thickness (p=0.011), and internal surface (p=0.012) between benign and premalignant and malignant cysts were significant. A lobulated shape, a thin wall and a smooth internal surface were more frequent in benign cysts, whereas a round or oval shape or a complex cystic shape with tubular cyst, a thick wall and an irregular internal surface were more frequent in premalignant and malignant cysts. On multivariate analysis, the shape (p=0.002) and wall thickness (p=0.025) were significant CT features for differentiating benign from premalignant and malignant cysts. CONCLUSION: Shape and wall thickness are the main CT features for differentiating benign from premalignant and malignant macrocystic pancreatic lesions. PMID- 18448301 TI - Prospective trial of a navigator setting under left hepatic lobe on magnetic resonance cholangiopancreatography using a free-breathing prospective acquisition correction technique. AB - PURPOSE: To prospectively compare the image acquisition time and image quality obtained by navigator setting under the left hepatic lobe vs. on the right diaphragm on magnetic resonance cholangiopancreatography (MRCP) using a free breathing navigator-triggered prospective acquisition correction technique (PACE). MATERIALS AND METHODS: Fifty consecutive patients prospectively underwent three-dimensional T2-weighted turbo spin-echo MRCP using PACE with the navigator randomly set either under the left hepatic lobe or on top of the right diaphragm. Image acquisition time and subjective image quality were compared on a five-point scale using Student's t-test and Mann-Whitney's U test, respectively. RESULTS: There was no significant difference for mean acquisition time (6.1+/-1.6 vs. 6.3+/-1.2 min, P=.689) between the left hepatic lobe group and right diaphragm group. Mean subjective image quality was significantly worse in the left hepatic lobe group than in the right diaphragm group (4.1 vs. 4.7, P=.044). CONCLUSION: Setting the navigator under the left hepatic lobe for MRCP using PACE causes the data processing to be more difficult. As well, under current circumstances, it does not contribute to reducing acquisition time or improving the image quality. PMID- 18448300 TI - Real-time animal functional magnetic resonance imaging and its application to neuropharmacological studies. AB - In pharmacological magnetic resonance imaging (phMRI) with anesthetized animals, there is usually only a single time window to observe the dynamic signal change to an acute drug administration since subsequent drug injections are likely to result in altered response properties (e.g., tolerance). Unlike the block-design experiments in which fMRI signal can be elicited with multiple repetitions of a task, these single-event experiments require stable baseline in order to reliably identify drug-induced signal changes. Such factors as subject motion, scanner instability and/or alterations in physiological conditions of the anesthetized animal could confound the baseline signal. The unique feature of such functional MRI (fMRI) studies necessitates a technique that is able to monitor MRI signal in a real-time fashion and to interactively control certain experimental procedures. In the present study, an approach for real-time MRI on a Bruker scanner is presented. The custom software runs on the console computer in parallel with the scanner imaging software, and no additional hardware is required. The utility of this technique is demonstrated in manganese-enhanced MRI (MEMRI) with acute cocaine challenge, in which temporary disruption of the blood-brain barrier (BBB) is a critical step for MEMRI experiments. With the aid of real-time MRI, we were able to assess the outcome of BBB disruption following bolus injection of hyperosmolar mannitol in a near real-time fashion prior to drug administration, improving experimental success rate. It is also shown that this technique can be applied to monitor baseline physiological conditions in conventional fMRI experiments using blood oxygenation level-dependent (BOLD) contrast, further demonstrating the versatility of this technique. PMID- 18448302 TI - Are signal intensity and homogeneity useful parameters for distinguishing between benign and malignant soft tissue masses on MR images? Objective evaluation by means of texture analysis. AB - OBJECTIVES: To objectively identify possible differences in the signal characteristics of benign and malignant soft tissue masses (STM) on magnetic resonance (MR) images by means of texture analysis and to determine the value of these differences for computer-assisted lesion classification. METHOD: Fifty eight patients with histologically proven STM (benign, n=30; malignant, n=28) were included. STM texture was analyzed on routine T1-weighted, T2-weighted and short tau inversion recovery (STIR) images obtained with heterogeneous acquisition protocols. Fisher coefficients (F) and the probability of classification error and average correlation coefficients (POE+ACC) were calculated to identify the most discriminative texture features for separation of benign and malignant STM. F>1 indicated adequate discriminative power of texture features. Based on the texture features, computer-assisted classification of the STM by means of k-nearest-neighbor (k-NN) and artificial neural network (ANN) classification was performed, and accuracy, sensitivity and specificity were calculated. RESULTS: Discriminative power was only adequate for two texture features, derived from the gray-level histogram of the STIR images (first and 10th gray-level percentiles). Accordingly, the best results of STM classification were achieved using texture information from STIR images, with an accuracy of 75.0% (sensitivity, 71.4%; specificity, 78.3%) for the k-NN classifier, and an accuracy of 90.5% (sensitivity, 91.1%; specificity, 90.0%) for the ANN classifier. CONCLUSION: Texture analysis revealed only small differences in the signal characteristics of benign and malignant STM on routine MR images. Computer assisted pattern recognition algorithms may aid in the characterization of STM, but more data is necessary to confirm their clinical value. PMID- 18448303 TI - Novel and selective potentiometric membrane sensor for amiloride determination in pharmaceutical compounds and urine. AB - A new PVC membrane sensor is described as a potentiometric sensor for amiloride. The sensor having amiloride-sodium tetraphenyl phthalate (ion-pair) as an electroactive material and dibutyl phthalate (DBP) as an anion excluder in PVC matrix in the percentage ratio of 4:66:30 (ion-pair: DBP:PVC) (w/w). The membrane sensor exhibits suitable response to amiloride in a concentration range of 1.0 x 10(-2) to 1.0 x 10(-6)mol L(-1) with a limit of detection of 9.9 x 10(-7)mol L( 1). The slope of the system was -54.3+/-1.0 mV decade(-1) over pH range of 2.0 7.0. Selectivity coefficients for amiloride relative to a numbers of potential interfering substances were investigated. The sensor was highly selective for amiloride over a large number of similar compounds. The sensor showing a fast response time of 6s and was used over a period of 2 months with a good reproducibility. The sensor was successfully applied to determination of amiloride in pharmaceutical samples with satisfactory results. PMID- 18448304 TI - HPTLC fingerprinting and quantification of lignans as markers in sesame oil and its polyherbal formulations. AB - Sesamum (Sesamum indicum) seed and its oil have been in use in Indian traditional medicine, 'Ayurveda' since antiquity. However, there has been no attempt to standardize the polyherbal formulations containing sesamum oil as the main ingredient in terms of its active principle or marker compound. Biologically active lignans in sesamum oil are identified as the marker compound for the oil and its formulations. In this report, a simple, rapid and sensitive HPTLC method is described for the first time to identify and quantify sesamin and sesamolin, the major lignans of the sesamum oil and the method was applied to polyherbal formulations containing the oil for their quantitative estimation. The method was validated in terms of its calibration curve, limits of detection and quantification, precision, accuracy and robustness following standard protocols. The method thus developed was applied to sesamum oil and its commercial herbal formulations to quantify sesamin and sesamolin. The method for fingerprints of the formulations in the form of densitogram following charring of the chromatographic plate was also developed that could be useful for marker-based quality assurance of the polyherbal products containing sesamum oil. PMID- 18448305 TI - Determination of paracetamol and its main impurity 4-aminophenol in analgesic preparations by micellar electrokinetic chromatography. AB - A micellar electrokinetic chromatographic (MEKC) method was developed for the quality control of paracetamol containing pharmaceutical preparations. The influence of several factors (surfactant concentration, buffer concentration, pH and applied voltage) was studied during development and optimisation of the method. Phosphate buffer (pH 9.0) containing sodium dodecyl sulphate (75 mM) was found as the ideal running buffer for the separation; the applied voltage was 25 kV and the analysis time was 10 min. The limit of quantitation for 4-aminophenol was 6 microgml(-1); the linearity of the method was studied in the concentration ranges 20-260 microgml(-1) for paracetamol and 20-150 microgml(-1) for 4 aminophenol. The method was successfully applied for the quality control of paracetamol containing products. PMID- 18448306 TI - Luteotrophic and luteolytic effects of nitric oxide in sheep are dose-dependent in vivo. AB - It has been suggested that nitric oxide (NO) acts in either an anti-luteolytic or in a luteolytic manner, but the mechanism for these opposing roles is unclear. We hypothesized that NO may act in a dose-dependent manner to regulate luteal function, whereby low concentrations of NO might stimulate luteal progesterone production (i.e. luteotrophic) and high concentrations of NO might reduce concentrations of plasma progesterone (i.e. luteolytic). To test this hypothesis we infused increasing concentrations of the fast-acting NO donor, dipropylenetriamine NONOate (DPTA), into the arterial supply of sheep with ovarian transplants bearing a corpus luteum (CL). Infusions were performed on sheep with CL 11 days of age (n=9) or over 30 days of age (n=15). We measured changes in the concentration of progesterone in ovarian venous plasma during the 1-h infusion and for 24h after the infusion, and then compared the mean concentration of progesterone between treatment groups for effects by dose and dose by period interactions. Compared with saline-treated controls (n=6), the highest dose of 1000 microg/min DPTA (n=6) reduced (P0.05) in sheep infused with the lowest dose of 1 microg/min DPTA (n=6) compared with controls. We conclude that NO regulates luteal function in a dose-dependent manner in sheep in vivo. PMID- 18448307 TI - [New antiplatelet drugs]. AB - Platelet-aggregation inhibitors are the cornerstone of the treatment and prevention of atherothrombotic events. Long limited to aspirin alone, new drugs have appeared in the past two decades. But only very recently have new targets been developed. The synergy of their mechanisms of action now makes it possible to obtain ever stronger inhibition of platelet aggregation. PMID- 18448308 TI - Validation of the Wisconsin Brief Pain Questionnaire in a multilingual South African population. AB - Assessment of pain intensity and its effect on quality of life is important for proper management of pain, but no validated pain assessment tools that assess pain intensity and the interference pain has on daily life are available in indigenous South African languages. Therefore, the aim of this study was to validate translated versions of the Wisconsin Brief Pain Questionnaire (WBPQ) in South African HIV-positive patients. The WBPQ was translated into three indigenous South African languages, Setswana, isiZulu, and Xitsonga. We interviewed 452 ambulatory HIV-positive patients (327 urban and 125 rural patients) between the ages of 20 and 76 years old. Factor analysis to assess construct validity identified a two-factor structure (pain intensity and pain interference) for the isiZulu (n=132), Xitsonga (n=125), and Setswana (n=66) versions of the WBPQ, whereas a three-factor structure (pain intensity, mood interference, and activity interference) was identified for the English (completed by English second-language speakers, n=129) version of the WBPQ. Cronbach alphas, calculated to assess the reliability of the pain intensity and pain interference scales, were greater than 0.70 for all scales in all four versions of the WBPQ, showing internal consistency within the dimensions. These results provide evidence of validity for an easily administered questionnaire, which assesses pain intensity and pain interference, in three indigenous South African languages, and for English second-language speakers, in a population of South African HIV-positive patients. PMID- 18448309 TI - An examination of the construct validity and factor structure of the Groton Maze Learning Test, a new measure of spatial working memory, learning efficiency, and error monitoring. AB - This study examined the construct validity of the Groton Maze Learning Test (GMLT) in assessing processing speed, working memory, and aspects of executive function in healthy adults. Performance on GMLT outcome measures was compared to performance on tests of psychomotor speed, working memory, and learning from the CogState computerized cognitive test battery (CGS; http://www.cogstate.com/). The factor structure of the GMLT was evaluated using exploratory factor analysis. The stability of this factor structure was examined in a large sample of patients undergoing parathyroidectomy or thyroidectomy. Results of this study suggest that the GMLT measures of spatial learning efficiency and error monitoring correlate with CogState measures of attention, working memory, and learning. Exploratory factor analysis yielded a two-factor solution of error monitoring and learning efficiency, which was stable across repeated assessments. PMID- 18448310 TI - Neuropsychological performance of a clinical sample of extremely obese individuals. AB - Obesity is a leading cause of preventable death in America and its prevalence is increasing at an alarming rate. While it is known that individuals with specific obesity-related medical conditions perform poorly on neuropsychological tasks, recent evidence suggests that cognitive dysfunction in obese individuals may occur independently of medical co-morbidities. This study examined neuropsychological performance in a clinical sample of extremely obese patients. Individuals seeking surgical treatment of obesity (N=68) were administered cognitive tests as part of a standard pre-surgical evaluation. Results indicated significant differences in performances of extremely obese individuals on tests of executive functioning (planning, problem solving, mental flexibility) in comparison to normative data. No significant differences emerged between obese patients with and without co-morbid medical conditions of hypertension, type II diabetes, and obstructive sleep apnea on the neuropsychological tasks specific to executive functioning. Taken together, these results provide further evidence of specific cognitive dysfunction in extremely obese individuals. PMID- 18448312 TI - Comment to: Diabetic hyperglycemia is associated with the severity of epileptic seizures in adults. PMID- 18448311 TI - c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand independent EGF receptor activation and signaling. AB - c-Src is a non-receptor tyrosine kinase that associates with both the plasma membrane and endosomal compartments. In many human cancers, especially breast cancer, c-Src and the EGF receptor (EGFR) are overexpressed. Dual overexpression of c-Src and EGFR correlates with a Src-dependent increase in activation of EGFR, and synergism between these two tyrosine kinases increases the mitogenic activity of EGFR. Despite extensive studies of the functional interaction between c-Src and EGFR, little is known about the interactions in the trafficking pathways for the two proteins and how that influences signaling. Given the synergism between c Src and EGFR, and the finding that EGFR is internalized and can signal from endosomes, we hypothesized that c-Src and EGFR traffic together through the endocytic pathway. Here we use a regulatable c-SrcGFP fusion protein that is a bona fide marker for c-Src to show that c-Src undergoes constitutive macropinocytosis from the plasma membrane into endocytic compartments. The movement of c-Src was dependent on its tyrosine kinase activity. Stimulation of cells with EGF revealed that c-Src traffics into the cell with activated EGFR and that c-Src expression and kinase activity prolongs EGFR activation. Surprisingly, even in the absence of EGF addition, c-Src expression induced activation of EGFR and of EGFR-mediated downstream signaling targets ERK and Shc. These data suggest that the synergy between c-Src and EGFR also occurs as these two kinases traffic together, and that their co-localization promotes EGFR-mediated signaling. PMID- 18448313 TI - Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: a putative mechanism of antiseizure action. AB - PURPOSE: Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known. METHODS: To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (beta-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes. RESULTS: We found that PUFAs at concentrations down to 21microM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing. CONCLUSIONS: These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels. PMID- 18448314 TI - CF2 activity and enhancer integration are required for proper muscle gene expression in Drosophila. AB - The creation of the contractile apparatus in muscle involves the co-activation of a group of genes encoding muscle-specific proteins and the production of high levels of protein in a short period of time. We have studied the transcriptional control of six Drosophila muscle genes that have similar expression profiles and we have compared these mechanisms with those employed to control the distinct expression profiles of other Drosophila genes. The regulatory elements controlling the transcription of co-expressed muscle genes share an Upstream Regulatory Element and an Intronic Regulatory Element. Moreover, similar clusters of MEF2 and CF2 binding sites are present in these elements. Here, we demonstrate that CF2 depletion alters the relative expression of thin and thick filament components. We propose that the appropriate rapid gene expression responses during muscle formation and the maintenance of each muscle type is guaranteed in Drosophila by equivalent duplicate enhancer-like elements. This mechanism may be exceptional and restricted to muscle genes, reflecting the specific requirement to mediate rapid muscle responses. However, it may also be a more general mechanism to control the correct levels of gene expression during development in each cell type. PMID- 18448315 TI - Anticancer cisplatin interactions with bilayers of total lipid extract from pig brain: A13C, 31P and 15N solid-state NMR study. AB - Cisplatin (cis-diamminedichloroplatinum(II)) is used in chemotherapy and it is well established that cisplatin forms platinum-DNA adducts that initiate tumor cell death. Drawbacks are side effects such as neurotoxicity and cellular cisplatin resistance and it is possible that part of these effects are linked to cisplatin interaction with lipids and the phospholipid bilayer. 13C magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra of total lipid extract from pig brain with and without cisplatin show that the phosphatidylserine (PS) carboxyl resonance disappears in presence of cisplatin and that a new resonance of similar intensity appears at 185.5 ppm. Thus, indicating cisplatin interaction with the PS head-group. Static and MAS 31P NMR spectra of lipid extract with and without cisplatin show that the phospholipids to a large extent reside in a bilayer environment in pure lipid extract, and that the presence of cisplatin promotes isotropic and/or hexagonal lipid phases. PMID- 18448316 TI - A critical look at the embodied cognition hypothesis and a new proposal for grounding conceptual content. AB - Many studies have demonstrated that the sensory and motor systems are activated during conceptual processing. Such results have been interpreted as indicating that concepts, and important aspects of cognition more broadly, are embodied. That conclusion does not follow from the empirical evidence. The reason why is that the empirical evidence can equally be accommodated by a 'disembodied' view of conceptual representation that makes explicit assumptions about spreading activation between the conceptual and sensory and motor systems. At the same time, the strong form of the embodied cognition hypothesis is at variance with currently available neuropsychological evidence. We suggest a middle ground between the embodied and disembodied cognition hypotheses--grounding by interaction. This hypothesis combines the view that concepts are, at some level, 'abstract' and 'symbolic', with the idea that sensory and motor information may 'instantiate' online conceptual processing. PMID- 18448317 TI - Rhythmic processing in children with developmental dyslexia: auditory and motor rhythms link to reading and spelling. AB - Potential links between the language and motor systems in the brain have long attracted the interest of developmental psychologists. In this paper, we investigate a link often observed (e.g., [Wolff, P.H., 2002. Timing precision and rhythm in developmental dyslexia. Reading and Writing, 15 (1), 179-206.] between motor tapping and written language skills. We measure rhythmic finger tapping (paced by a metronome beat versus unpaced) and motor dexterity, phonological and auditory processing in 10-year old children, some of whom had a diagnosis of developmental dyslexia. We report links between paced motor tapping, auditory rhythmic processing and written language development. Motor dexterity does not explain these relationships. In regression analyses, paced finger tapping explained unique variance in reading and spelling. An interpretation based on the importance of rhythmic timing for both motor skills and language development is proposed. PMID- 18448318 TI - Supervised pattern recognition for the prediction of contrast-enhancement appearance in brain tumors from multivariate magnetic resonance imaging and spectroscopy. AB - OBJECTIVE: The purpose of this study was to develop a pattern classification algorithm for use in predicting the location of new contrast-enhancement in brain tumor patients using data obtained via multivariate magnetic resonance (MR) imaging from a prior scan. We also explore the use of feature selection or weighting in improving the accuracy of the pattern classifier. METHODS AND MATERIALS: Contrast-enhanced MR images, perfusion images, diffusion images, and proton spectroscopic imaging data were obtained from 26 patients with glioblastoma multiforme brain tumors, divided into a design set and an unseen test set for verification of results. A k-NN algorithm was implemented to classify unknown data based on a set of training data with ground truth derived from post-treatment contrast-enhanced images; the quality of the k-NN results was evaluated using a leave-one-out cross-validation method. A genetic algorithm was implemented to select optimal features and feature weights for the k-NN algorithm. The binary representation of the weights was varied from 1 to 4 bits. Each individual parameter was thresholded as a simple classification technique, and the results compared with the k-NN. RESULTS: The feature selection k-NN was able to achieve a sensitivity of 0.78+/-0.18 and specificity of 0.79+/-0.06 on the holdout test data using only 7 of the 38 original features. Similar results were obtained with non-binary weights, but using a larger number of features. Overfitting was also observed in the higher bit representations. The best single variable classifier, based on a choline-to-NAA abnormality index computed from spectroscopic data, achieved a sensitivity of 0.79+/-0.20 and specificity of 0.71+/-0.11. The k-NN results had lower variation across patients than the single variable classifiers. CONCLUSIONS: We have demonstrated that the optimized k-NN rule could be used for quantitative analysis of multivariate images, and be applied to a specific clinical research question. Selecting features was found to be useful in improving the accuracy of feature weighting algorithms and improving the comprehensibility of the results. We believe that in addition to lending insight into parameter relevance, such algorithms may be useful in aiding radiological interpretation of complex multimodality datasets. PMID- 18448319 TI - Reversible protein precipitation to ensure stability during encapsulation within PLGA microspheres. AB - Proteins were precipitated to ensure their stability upon subsequent encapsulation within PLGA microspheres. Spherical, nanosized protein particles were formed by the addition of a salt (sodium chloride) and a water-miscible organic solvent (glycofurol) to protein solutions. Various process parameters were modified to optimize the precipitation efficiency of four model proteins: lysozyme, alpha-chymotrypsin, peroxidase and beta-galactosidase. As monitored by enzymatic activity measurement of the rehydrated particles, conditions to obtain more than 95% of reversible precipitates were defined for each protein. The study of the structure of the rehydrated particles by absorbance spectroscopy, fluorescence spectroscopy and circular dichroism showed an absence of structural perturbation after precipitation. Protein particles were then microencapsulated within PLGA microspheres using s/o/w technique. The average encapsulation yield was around 80% and no loss of protein activity occurred after the encapsulation step. Additionally, a lysozyme in vitro release study showed that all of the released lysozyme was biologically active. This method of protein precipitation is appropriate for the encapsulation in PLGA microspheres of various proteins without inactivation. PMID- 18448320 TI - Protective effects of Angelica sinensis extract on amyloid beta-peptide-induced neurotoxicity. AB - The protective effects of alcohol extract from the root of Angelica sinensis (AS) on beta-amyloid peptide (Abeta)-induced toxicity and the mechanism of these effects were investigated. Abeta is a pathological hallmark of Alzheimer's disease; it decreased viability of Neuro 2A cells in a concentration-dependent manner with IC(50) of 14.9 microM. AS extract resulted in dose-dependent anti Abeta toxicity according to MTT assay. Reactive oxygen species (ROS) analysis revealed a significant production of hydrogen peroxide, decreased glutathione (GSH) levels and increased lipid peroxidation (TBARS value) in the Abeta-treated Neuro 2A cells. The Abeta-treated cells also showed a significant decline in the mitochondrial transmembrane potential (DeltaPsim) and increase in the mitochondrial volume, and portions of the cytoplasm were sequestered by a membrane-bound vacuole. The malfunctions of Neuro 2A cells caused by Abeta were attenuated using AS extract. The AS extract protected cell viability against Abeta-induced oxidative damage (ROS, TBARS, and GSH contents) and rescued the DeltaPsim levels in a dose-dependent manner: the dosages of 25, 50, 100, and 200 microg/ml recovered 77%, 87%, 102%, and 105% of DeltaPsim, respectively. AS extract also recovered the enlarged mitochondria mass with dosages from 25 to 200 microg/ml. The results of this study demonstrated that AS extract possessed the activity to prevent the neurotoxicity induced by Abeta-associated oxidative stress, implying that AS has a potential role in the prevention of Alzheimer's diseases. PMID- 18448321 TI - Clarifying the ethnographer's role in Chicago's HIV behavioural surveillance injecting drug users cycle, 2005: response to Scott. PMID- 18448322 TI - Municipal solid waste management in Rasht City, Iran. AB - Pollution and health risks generated by improper solid waste management are important issues concerning environmental management in developing countries. In most cities, the use of open dumps is common for the disposal of wastes, resulting in soil and water resource contamination by leachate in addition to odors and fires. Solid waste management infrastructure and services in developing countries are far from achieving basic standards in terms of hygiene and efficient collection and disposal. This paper presents an overview of current municipal solid waste management in Rasht city, Gilan Province, Iran, and provides recommendations for system improvement. The collected data of different MSW functional elements were based on data from questionnaires, visual observations of the authors, available reports and several interviews and meetings with responsible persons. Due to an increase in population and changes in lifestyle, the quantity and quality of MSW in Rasht city has changed. Lack of resources, infrastructure, suitable planning, leadership, and public awareness are the main challenges of MSW management of Rasht city. However, the present situation of solid waste management in this city, which generates more than 400tons/d, has been improved since the establishment of an organization responsible only for solid waste management. Source separation of wastes and construction of a composting plant are the two main activities of the Rasht Municipality in recent years. PMID- 18448323 TI - Estimation of biogas produced by the landfill of Palermo, applying a Gaussian model. AB - In this work, a procedure is suggested to assess the rate of biogas emitted by the Bellolampo landfill (Palermo, Italy), starting from the data acquired by two of the stations for monitoring meteorological parameters and polluting gases. The data used refer to the period November 2005-July 2006. The methane concentration, measured in the CEP suburb of Palermo, has been analysed together with the meteorological data collected by the station situated inside the landfill area. In the present study, the methane has been chosen as a tracer of the atmospheric pollutants produced by the dump. The data used for assessing the biogas emission refer to night time periods characterized by weak wind blowing from the hill toward the city. The methane rate emitted by the Bellolampo dump has been evaluated using a Gaussian model and considering the landfill both as a single point source and as a multiple point one. The comparison of the results shows that for a first approximation it is sufficient to consider the landfill of Palermo as a single point source. Starting from the monthly percentage composition of the biogas, estimated for the study period, the rate of biogas produced by the dump was evaluated. The total biogas produced by the landfill, obtained as the sum of the emitted component and the recovered one, ranged from 7519.97 to 10,153.7m3/h. For the study period the average monthly estimations of biogas emissions into the atmosphere amount to about 60% of the total biogas produced by the landfill, a little higher than the one estimated by the company responsible for the biogas recovery plant at the landfill. PMID- 18448324 TI - Microarray detection of food-borne pathogens using specific probes prepared by comparative genomics. AB - In order to design a method for the accurate detection and identification of food borne pathogens, we used comparative genomics to select 70-mer oligonucleotide probes specific for 11 major food-borne pathogens (10 overlapping probes per pathogen) for use in microarray analysis. We analyzed the hybridization pattern of this constructed microarray with the Cy3-labeled genomic DNA of various food borne pathogens and other bacteria. Our microarray showed a highly specific hybridization pattern with the genomic DNA of each food-borne pathogen; little unexpected cross-hybridization was observed. Microarray data were analyzed and clustered using the GenePix Pro 6.0 and GeneSpring GX 7.3.1 programs. The analyzed dendrogram revealed the discriminating power of constructed microarray. Each food-borne pathogen clustered according to its hybridization specificity and non-pathogenic species were discriminated from pathogenic species. Our method can be applied to the rapid and accurate detection and identification of food-borne pathogens in the food industry. In addition, this study demonstrates that genome sequence comparison and DNA microarray analysis have a powerful application in epidemiologic and taxonomic studies, as well as in the food safety and biodefense fields. PMID- 18448325 TI - Evolution and dynamics of protein interactions and networks. AB - The central role of protein-protein interactions (PPIs) in biology has stimulated colossal efforts to identify thousands of them in several organisms. The resulting PPI maps are commonly represented as graphs, where nodes denote proteins and edges represent physical interactions. However, the methods used to generate PPI data on a large scale do not readily allow one to discriminate features such as interaction strength (affinity), type (protein-protein or protein-peptide interaction) or spatiotemporal existence (where and when the proteins are present and interact). Yet, in recent years, a number of studies have tackled these limitations by projecting additional information onto PPIs, revealing novel properties in terms of their evolution and dynamics. In this review we examine these properties both at the binary interaction level and at the network level. We suggest that the diverse and sometimes contradictory results described by different research groups are mostly due to incomplete data coverage and limited data types. Finally, we discuss recently developed methods that will improve this picture in the future. PMID- 18448326 TI - When to start cytotoxic therapy in asymptomatic patients with hormone refractory prostate cancer? AB - Until the publication of two pivotal trials, there were no treatment options available that did prolong the overall survival in men with hormone refractory prostate cancer (HRPC). Currently, docetaxel-based cytotoxic treatment is considered as a standard of care in all the patients with progressive metastatic HRPC. The use of this treatment regimen renders an equal survival benefit in all the subgroups of patients; however, there is a substantial difference in the overall survival between the subgroups. This review addresses the optimal timing of the cytotoxic treatment in asymptomatic patients with HRPC. PMID- 18448327 TI - Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C. AB - Enzastaurin (LY317615.HCI), a protein kinase C (PKC)-beta inhibitor, has a radiosensitising effect on 4T1 murine breast cancer and human glioma cells; however, the exact mechanism of this action has not been evaluated. The present study investigated the effects of enzastaurin and gamma irradiation on PKC activity in MCF-7 human breast cancer cells in vitro and in vivo. Enzastaurin (5 microM) in combination with irradiation (2-8 Gy) produced a synergistic decline in MCF-7 clonogenic cell survival. Analysis of MCF-7 cells stained with Annexin V and 7-aminoactinomycin D showed a dose-dependent increase in apoptosis in response to enzastaurin (3, 5 and 7 microM) and irradiation (10 Gy) compared to irradiation alone. This pro-apoptotic effect was confirmed by increases in caspase-3 and -9 activity. In a MCF-7 xenograft model, irradiation with 25 Gy increased PKC-alpha activity by 2.5-fold compared to untreated controls, whereas PKC-epsilon and -betaII activity was increased by 1.8-fold. Radiation-induced activation of all three anti-apoptotic isoforms of PKC was reversed by pre treatment with enzastaurin (75 mg/kg, twice daily for 3 days). We conclude that enzastaurin has a radiosensitising effect on MCF-7 human xenograft tumours through the reversal of anti-apoptotic activation of PKC isoforms. PMID- 18448328 TI - Pharmacogenetic approach for capecitabine or 5-fluorouracil selection to be combined with oxaliplatin as first-line chemotherapy in advanced colorectal cancer. AB - We studied the role of TS (5'VNTR, 5'SNP and 3'UTR), XRCC1-399, XPD-751, ERCC1 118 and XRCC3-241 genetic polymorphisms in tailoring fluroropyrimidine/oxaliplatin treatment. For this purpose, 110 XELOX (capecitabine/oxaliplatin)- or FUOX (fluorouracil/oxaliplatin)-treated metastatic colorectal cancer patients were selected prospectively for genotyping. In the FUOX group, TS-3'UTR +6bp/+6bp (hazards ratio, HR=2.62, p=0.007) and ERCC1-118C/T or C/C (HR=1.96, p=0.050) genotypes correlated with a shorter progression-free survival (PFS). When analysed jointly, the higher the number of favourable genotypes (FG) the longer the PFS (6.8m, 9.6m and 25.8m for 0, 1 or 2 FG; p=0.005). Disease-control rate was 100% in patients with 2 FG (87% and 38.5% for 1 or 0 FG; p=0.001). In the multivariate analysis, ERCC1-118 (HR=2.12, p=0.0037) and TS-3'UTR (HR=2.68, p=0.006) were strong independent prognostic factors. According to this, patients harbouring TS-3'UTR +6bp/+6bp and ERCC1-118C/T or C/C genotypes may better receive capecitabine instead of 5FU in an oxaliplatin-based first-line treatment. PMID- 18448329 TI - Human models of aromatase deficiency. AB - Estrogens exert a wide range of biological effects in both sexes also on non reproductive systems and organs. Human congenital estrogen deficiency, due to an inactivating mutation of the aromatase gene, leads to the lack of the estrogen synthesis, with gonadotropins and circulating testosterone ranging from normal to elevated. The aromatese-deficient females show hyperandrogenism and virilization at birth with ambiguous genitalia. During childhood there are a dysfunction in the LHRH-LH/FSH axis and a progressive delay in bone age. At puberty they show primary amenorrhea, no breast development, worsening of the virilization and the absence of growth spurt. The clinical phenotype in the male affected subjects comprises tall stature, persistent linear growth and delayed bone age, osteopenia/osteoporosis, eunuchoid body proportion, different degrees of glucose insulin and of fertility impairment. These phenotypes suggest the physiological role of estrogens on the skeleton, on pituitary function, on the reproductive system, on glucose metabolism, being the precise mechanism on each of these functions not yet known in detail. The estradiol replacement treatment leads to a complete epiphyseal closure and to the skeletal maturation. Moreover, the increasing knowledge on the role of estrogen in several metabolic pathways could be important for a better management of several metabolic diseases. PMID- 18448330 TI - Purification of nitrate-rich agricultural runoff by a hydroponic system. AB - The purification of nitrate-rich agricultural runoff by a floating-raft (FR) hydroponic system was investigated at 3-, 2- and 1-d hydraulic retention times (HRTs) with particular emphasis on nitrogen conversion and removal through the system. The FR system has a dissolved oxygen (DO) environment similar to the horizontal subsurface flow system, generally 0.00mgL(-1), that facilitates denitrification. An efficient nitrate-nitrite-nitrogen (NOx-N) removal, 91%, 97% and 71% on average at 3-, 2- and 1-d HRT, respectively, was frequently achieved. The mean retentions were 17-47% for chemical oxygen demand, 31-64% for total nitrogen, and 8-15% for total phosphorus for the FR system. Mass balance analysis implied that the detectable DO concentration in the reactor, as low as 0.7mgL( 1), played a very important role in the conversion and removal of NH3-N and NOx N, which finally affected the NOx-N removal at 3-d HRT. PMID- 18448331 TI - Effect of steam explosion on biodegradation of lignin in wheat straw. AB - The effect of steam explosion pretreatment on biodegradation of lignin in wheat straw was studied in this paper. Through experiments and analysis, 0.8MPa operation pressure and 1:20 wheat straw to water ratio are optimum for destroying lignin and the maximum of lignin loss rate is 19.94%. After steam explosion pretreatment, the wheat straw was retted by Trametes versicolor for 40 days. Biodegradation rate of lignin was tested and the maximum of 55.40% lignin loss rate was found on day 30. During the whole process of both steam explosion pretreatment and biodegradation, 75.34% lignin was degraded, without steam explosion the biodegradation of raw material the degradation rate of lignin was 31.23% only. FT-IR spectroscopy, TGA and SEM were used for further validating the results of biodegradation. PMID- 18448332 TI - Electrooxidation as the anaerobic pre-treatment of fats: oleate conversion using RuO2 and IrO2 based anodes. AB - Electrochemical treatment of oleate using RuO2 and IrO2 type dimensionally stable anodes in alkaline medium was performed to develop a feasible anaerobic pre treatment of fatty effluents. The results showed that the pre-treated solutions over RuO2 were faster degraded by anaerobic consortium than the raw oleate solutions or the electrolysed solutions using IrO2. In batch experiments carried out with pre-treated solutions over RuO2 (100-500mg/L), no lag phases were observed before the methane production onset. On the other hand, raw oleate and pre-treated oleate over IrO2 had originated lag phases of 0-140 and 0-210h, respectively. This study demonstrated that it is advantageous to apply the electrochemical treatment carried out on the RuO2 type DSA in order to achieve a faster biodegradation of lipid-containing effluent and consequently to obtain a faster methane production. PMID- 18448333 TI - Medium optimization for antifungal active substances production from a newly isolated Paenibacillus sp. using response surface methodology. AB - Statistics based experimental designs were used to optimize the medium for antifungal active substances production from a newly isolated Paenibacillus polymyxa Cp-S316 in shaker flask cultivation. The medium components having significant effect on the production were first identified using a fractional factorial design. Then steepest ascent method was employed to approach the experimental design space, followed by an application of response surface methodology for further optimization. A quadratic model was found to fit the antifungal active substances production. Response surface analysis revealed that the optimum values of the tested variables for the production of active substances were 12.3 (g/l) lactose, 17.5 (g/l) peptone, 0.4 (g/l) sodium nitrate, 4.5 (g/l) magnesium sulfate and 100 (g/l) potato. A production of 4687.71microg/ml, which was in agreement with the prediction, was observed in verification experiment. In comparison to the production of basal medium, 3.05 fold increase had been obtained. PMID- 18448334 TI - Competitive reaction kinetics of sulfate-reducing bacteria and methanogenic bacteria in anaerobic filters. AB - A kinetic model for the anaerobic filter (AF) that takes into account the mass fractions of sulfate-reducing bacteria (SRB) (fSRB) and methanogenic bacteria (MB) (fMB) and an inhibiting effect of H2S on bacterial groups is proposed. When the acetate-fed AFs were maintained at the low organic loading rate of 2.5kg COD/m3d, variations of the influent COD/SO4(2-) ratio (0.5-3.0) does not materially affect the acetate removal efficiency (all varying between 98.1% and 99.7%). With an increase in influent COD/SO4(2-) ratio, both the biofilm thickness and the specific substrate utilization rate decreased slightly but f(SRB) decreased markedly. The estimated results of fSRB and fMB showed that SRB out-competed MB for bacterial growth if the influent COD/SO4(2-) ratio was maintained at less than 1.3, whereas MB out-competed SRB for bacterial growth if the influent COD/SO4(2-) ratio was maintained at greater than 2.0. The specific substrate utilization rate of SRB (0.19-0.24mg acetate/mg VSSd) was lower than that of MB (0.31-0.59mg acetate/mg VSSd). The estimated kinetic parameters disclosed that the affinity of acetate to MB was higher and unionized H2S imposed a greater inhibiting effect on MB. The model simulation results (acetate and sulfate removal) agreed well with the experimental results. PMID- 18448335 TI - Particle size distribution of distillers dried grains with solubles (DDGS) and relationships to compositional and color properties. AB - Eleven distillers dried grains with solubles (DDGS), processed from yellow corn, were collected from different ethanol processing plants in the US Midwest area. Particle size distribution (PSD) by mass of each sample was determined using a series of six selected US standard sieves: Nos. 8, 12, 18, 35, 60, and 100, and a pan. The original sample and sieve sized fractions were measured for surface color and contents of moisture, protein, oil, ash, and starch. Total carbohydrate (CHO) and total non-starch CHO were also calculated. Results show that there was a great variation in composition and color among DDGS from different plants. Surprisingly, a few DDGS samples contained unusually high amounts of residual starch (11.1-17.6%, dry matter basis, vs. about 5% of the rest), presumably resulting from modified processing methods. Particle size of DDGS varied greatly within a sample and PSD varied greatly among samples. The 11 samples had a mean value of 0.660mm for the geometric mean diameter (dgw) of particles and a mean value of 0.440mm for the geometric standard deviation (Sgw) of particle diameters by mass. The majority had a unimodal PSD, with a mode in the size class between 0.5 and 1.0mm. Although PSD and color parameters had little correlation with composition of whole DDGS samples, distribution of nutrients as well as color attributes correlated well with PSD. In sieved fractions, protein content, L and a color values negatively while contents of oil and total CHO positively correlated with particle size. It is highly feasible to fractionate DDGS for compositional enrichment based on particle size, while the extent of PSD can serve as an index for potential of DDGS fractionation. The above information should be a vital addition to quality and baseline data of DDGS. PMID- 18448336 TI - The membrane role in an anaerobic membrane bioreactor for purification of dairy wastewaters: a numerical simulation. AB - A simplified modelling and a simulation of a membrane-coupled anaerobic bioreactor, AMBR were performed to assess the potential of controlled retention of solutes by the membrane, R, on biomass growth and of purified water quality. R was shown to be a major parameter, which enables to uncouple the hydraulic resistance time, HRT from the solute retention time, independent of biomass retention, and has a significant effect on purified water quality. Therefore, from a theoretical point of view, it facilitates reaching high biodegradation in a small volume membrane reactor. The simulation makes it possible: (i) to anticipate the effect and relative weight of model parameters in the mechanisms that rule the AMBR behaviour and (ii) to identify the AMBR parameters and operating modes in order to avoid reactor washout or overload, amplified by R. From the analysis, it appears that it is possible to use any type of membrane, which at least retain the biomass: (i) low R values using microfiltration or ultrafiltration membranes require long HRT or small influent concentration and larger reactor volume to achieve good water quality; (ii) high R values using nanofiltration or reverse osmosis membranes, which will retain the solutes as well as the small-degraded molecules within the anaerobic reactor volume, require short HRT for highly purified water, but necessitate a large investment. PMID- 18448337 TI - Novel ORL1-selective antagonists with oral bioavailability and brain penetrability. AB - Following the discovery of 5-chloro-6-[piperazin-1-yl]-1H-benzimidazole as a novel pharmacophore for potent and selective ORL1 antagonist activity, optimization of this new lead by introduction of a methyl substitution on the piperazine ring resulted in a highly potent and selective, orally available, and brain penetrable ORL1 antagonist, 2-(tert-butylthio)-5-chloro-6-[(2R)-4-(2 hydroxyethyl)-2-methylpiperazin-1-yl]-1H-benzimidazole. Stereochemistry of the methyl substituent on the piperazine ring to control the functional activity of other opioid receptors is also described. PMID- 18448338 TI - Demonstration of direct binding of cIAP1 degradation-promoting bestatin analogs to BIR3 domain: Synthesis and application of fluorescent bestatin ester analogs. AB - Overexpression of cIAP1 correlates with resistance to radiotherapy and chemotherapy in various cancers. Recently, we reported that a class of bestatin ester analogs represented by MeBS (2) destabilized and promoted the degradation of cIAP1 through auto-ubiquitination, and thereby sensitized cancer cells to apoptosis. Herein, we present chemical evidence that bestatin ester analogs directly interact with the cIAP1-BIR3 domain by means of fluorescence polarization assay and photoaffinity labeling assay using fluorescent probes. PMID- 18448339 TI - Potent triazolyl-proline-based inhibitors of HCV NS3 protease. AB - The design and synthesis of tripeptide-based inhibitors of the HCV NS3 protease containing a novel P2-triazole is described. Replacement of the P2 quinoline with a triazole moiety provided a versatile handle which could be expediently modified to generate a diverse series of inhibitors. Further refinement by the incorporation of an aryl-substituted triazole and replacement of the P1 acid with an acyl sulfonamide ultimately provided inhibitors with interesting cellular activity. PMID- 18448340 TI - Aminopyrazine CB1 receptor inverse agonists. AB - A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity. PMID- 18448341 TI - Peptomeric analogues of trypsin inhibitor SFTI-1 isolated from sunflower seeds. AB - A series of linear and monocyclic analogues of trypsin inhibitor SFTI-1 isolated from sunflower seeds, modified by N-(4-aminobutyl)glycine (Nlys) and N benzylglycine (Nphe), were obtained by the solid-phase method. Some of these peptomers displayed trypsin or chymotrypsin inhibitory activity. In contradiction to the literature data, in most analogues peptide bonds formed by these peptoid monomers were at least partially hydrolyzed by the experimental enzymes at two different pH (3.5 and 8.3). Nevertheless, the replacement of Phe present in the P(1) substrate specificity of linear inactive SFTI-1 analogue with Nphe, yielded a potent chymotrypsin inhibitor. The introduction of one cyclic element (a disulfide bridge or head-to-tail cyclization) to the analogues synthesized significantly increased their proteinase resistance. PMID- 18448342 TI - Support vector machines classification of hERG liabilities based on atom types. AB - Drug-induced long QT syndrome (LQTS) can cause critical cardiovascular side effects and has accounted for the withdrawal of several drugs from the market. Blockade of the potassium ion channel encoded by the human ether-a-go-go-related gene (hERG) has been identified as a major contributor to drug-induced LQTS. Experimental measurement of hERG activity for each compound in development is costly and time-consuming, thus it is beneficial to develop a predictive hERG model. Here, we present a hERG classification model formulated using support vector machines (SVM) as machine learning method and using atom types as molecular descriptors. The training set used in this study was composed of 977 corporate compounds with hERG activities measured under the same conditions. The impact of soft margin and kernel function on the performance of the SVM models was examined. The robustness of SVM was evaluated by comparing the predictive power of the models built with 90%, 50%, and 10% of the training set data. The final SVM model was able to correctly classify 94% of an external testing set containing 66 drug molecules. The most important atom types with respect to discriminative power were extracted and analyzed. PMID- 18448343 TI - Sensitization to p-amino aromatic compounds: Study of the covalent binding of 2,5 dimethyl-p-benzoquinonediimine to a model peptide by electrospray ionization tandem mass spectrometry. AB - To understand the hapten-protein complex formation in the context of skin contact allergy to p-amino aromatic derivatives, 2,5-dimethyl-p-benzoquinonediimine was used as a model compound to study the reactivity of p-benzoquinonediimines, first oxidation intermediates of allergenic p-amino aromatic compounds, toward a model peptide containing naturally occurring and potential reactive amino acids. LC-MS analysis, together with electrospray ionization MS/MS, was used for the determination of amino acid selectivity by studying the chemical modifications induced on the peptide due to covalent binding of the p-benzoquinonediimine. Results reported in this paper indicated that 2,5-dimethyl-p-benzoquinonediimine reacted with the epsilon-NH(2) group of lysine to first form a covalent adduct of the Schiff's base kind. Besides, an oxido-reduction process started that induced an oxidative deamination of lysine to form a peptidyl alpha-aminoadipic-delta semialdehyde, by a mechanism similar to the one known for several enzymatic quinonoid co-factors, followed by an intramolecular cyclization of the peptide. From these results it could be concluded that lysine must be considered as an important amino acid for the hapten-protein complex formation in the case of p benzoquinonediimines and that, in addition to direct covalent binding, further degradation of the peptide can be produced. PMID- 18448344 TI - The use of surface charging in the SEM for lithium niobate domain structure investigation. AB - The different lithium niobate crystals with opposite domain structure (ODLN) were studied in the SEM using e-beam negative surface charging. In the ODLN the polarization vector Ps alternates periodically "tail-to-tail" and "head-to-head" and arranges perpendicular to the domain boundaries. In the investigation we have used congruent LiNbO(3) crystals (CLN) and Cr(2)O(3)- and In(2)O(3)-doped LN with the ODLN structure. Initial surface potential images in secondary electron (SE) mode and charge accumulation on the Y-cut surfaces of different LiNbO(3) crystals were compared. The initial surface potential relief in ODLN was found to depend on the position of "tail-to-tail" and "head-to-head" domain walls in the structure. In the doped LN with the periodical domain structure formed during the growth process, the surface potential changes near the domain walls are much weaker than in the structures of CLN obtained by the aftergrowth thermoelectrical treatment technique. A well-defined SE image of "tail-to-tail" domain walls was observed upon special surface negative charging in all types of investigated LN crystals. The negative surface charging in the "tail-to-tail" domain wall areas proceeded slower and the SE exit from these areas decreased as compared to other crystal areas. The charging conditions for the domain wall observation in all samples were comparatively analyzed. The width and uniformity along the boundary images were different and correlated with doping in the crystals. The formation of different charge images could be explained by a variety of positive point defect distributions near the "tail-to-tail" domain walls in different LN crystals. The defects and doping ions screen polarization charges in the "tail-to tail" wall area and can influence recombination rates of charges induced by an electron beam. Therefore, these domain wall areas are charged much weaker at negative surface charging than other domain areas. This SEM approach could afford a possibility to compare the distribution of the defects that screen the polarization charges and accumulate near the ferroelectric domain wall areas in LN crystals. PMID- 18448345 TI - Mononuclear phagocytes in the blood of turtles characterized by ultrastructural and cytochemical analyses and by phagocytic activity. AB - Ultrastructural and cytochemical characteristics of mononuclear phagocyte cells in turtles are not well described in the literature, especially in Phrynops hilarii. Thus, the aim of this study was to evaluate these characteristics in the mononuclear phagocyte cells and their phagocytic activity "in vitro" using the turtle P. hilarii as an experimental animal model. The six turtles used in the study were observed in two seasons, spring and summer. Results showed that mononuclear phagocytes incubated only in diluted solution or with colloidal charcoal have cytoplasm phagolysosomes. The cells incubated with colloidal charcoal and further exposed to the cytochemical reaction for acid beta glycerophosphatase, showed cytoplasm phagolysosomes filled by charcoal particles being digested and some positively stained lysosomes. Acid beta glycerophosphatase positive reaction was present in lysosomes and inside the phagolysosomes, while acid cytidine 5-monophosphatase staining occurred in lysosome surroundings. A positive reaction for trimetaphosphatase was also found inside phagolysosomes. In conclusion, the presence of lysosomal enzymes like trimetaphosphatase and cytidine-5'-sodium monophosphate, in the circulating blood of P. hilarii indicate that mononuclear phagocytes participate in the phagocytic process by gathering many phagocytic cells and forming multinucleated giant cells, which probably have a role in the blood "clearance" process. PMID- 18448346 TI - The significance of changes in Mytella falcata (Orbigny, 1842) gill filaments chronically exposed to polluted environments. AB - The impact of pollutants in an organism can be observed by changes in functional complexity at different levels. Bivalve gills are suitable for histopathological analysis because of their structure and function. This study aimed at examining the morphology of Mytella falcata gill filaments from three sites in the Santos estuary (Sao Paulo, Brazil) with different levels of environmental degradation to identify possible changes in gill structure and discuss the significance of these alterations. For this purpose, histological, histochemical and ultrastructural techniques were used. The filaments of animals from site A (less impacted site) were intact, while in sites B and C, pathological changes were observed, such as: detachment of the epithelium in the intermediate zone, morphological changes of this epithelium, inflammatory process, increase in the number of mucous cells and cell turnover processes. These results suggest that the related changes are an attempt to prevent the entrance of pollutants through gill filaments into the entire organism and that cell turnover is the final way to compensate cell injury. PMID- 18448347 TI - Recent peat accumulation rates in minerotrophic peatlands of the Bay James region, Eastern Canada, inferred by 210Pb and 137Cs radiometric techniques. AB - (210)Pb and (137)Cs dating techniques are used to characterise recent peat accumulation rates of two minerotrophic peatlands located in the La Grande Riviere hydrological watershed, in the James Bay region (Canada). Several cores were collected during the summer 2005 in different parts of the two selected peatlands. These minerotrophic patterned peatlands are presently affected by erosion processes, expressed by progressive mechanical destruction of their pools borders. This erosion process is related to a water table rise induced by a regional increase of humidity since the last century. The main objective of the present paper is to (1) evaluate if (210)Pb and (137)Cs dating techniques can be applied to build accurate chronologies in these environments and (2) detect changes in the peat accumulation rates in regard to this amplification of humidity. In both sites, unsupported (210)Pb shows an exponential decreasing according to the depth. Chronologies inferred from (210)Pb allow to reconstruct peat accumulation rates since ca. 1855 AD. The (137)Cs data displayed evident mobility and diffusion, preventing the establishment of any sustained chronology based on these measurements. In the two sites, peat accumulation rates inferred from (210)Pb chronologies fluctuate between 0.005 and 0.038 g cm(-2) yr(-1). As a result, the rise of the water table during the last decade has not yet affected peat accumulation rates. PMID- 18448348 TI - The development of plate osteosynthesis for the treatment of fractures of the mandibular body - a literature review. AB - PURPOSE: Today plate and screw osteosynthesis of mandibular fractures is a standard procedure in routine clinical practice. In this review, the breakthroughs and drawbacks of the development of this important aspect of maxillofacial surgery are followed-up. METHODS: Medline search of relevant English and German literature. RESULTS: In 1886, Carl Hansmann was the first who applied steel screws and plates. Until today the material, the types of plates and applications have been continually improved. Over the last two decades miniplate osteosynthesis has induced a revolution in mandibular fracture treatment. The modern systems provide better handling, higher stability and less pressure on the bone. CONCLUSION: Modern miniplates have great advantages, like the intra-oral approach and the easy adaptability. In addition, it is no longer necessary to expose bone as extensively. PMID- 18448349 TI - Age cut-off for the loss of benefit from bilateral internal thoracic artery grafting. AB - OBJECTIVES: To identify the age-related benefit of single and bilateral internal thoracic artery (ITA) grafting on long-term cardiac-related survival in patients who survived from primary isolated coronary artery bypass grafting (CABG). METHODS: A unicenter study was conducted on 12,231 consecutive survivors from primary isolated CABG who received single (n=9566 patients) or bilateral (n=1388 patients) ITA grafts, or vein grafts only (n=1277 patients) between 1992 and 2005. Data was collected prospectively. The Cox regression model estimates the hazard ratio of each independent variable on cardiac-specific survival over the entire length of follow-up. Age was a significant covariate into the statistical model. The mean follow-up was 5.7+/-3.7 years and 100% complete as of December 2005. The date and cause of death were obtained from the regional statistical institute. RESULTS: After adjustments for different risk factors, the cardiac related survival benefit in patients undergoing CABG with two ITAs was superior to that of single ITA grafting up to 60 years of age, displaying a constant decrease over time. The use of a single ITA was beneficial on cardiac-related survival in all age groups, including octogenarians, compared to patients receiving only vein grafts. CONCLUSIONS: The use of at least one ITA is associated with increased long-term cardiac-specific survival in all age groups compared to venous-only CABG, even in octogenarians. The additional survival benefit of using a second ITA decreases gradually with age, and is lost after 60 years of age. PMID- 18448350 TI - Aspirin in coronary artery bypass surgery: new aspects of and alternatives for an old antithrombotic agent. AB - The success of coronary artery bypass graft surgery (CABG) depends mainly on the patency of the graft vessels. Aortocoronary vein graft disease is comprised of three distinct but interrelated pathological processes: thrombosis, intimal hyperplasia and atherosclerosis. Early thrombosis is a major cause of vein graft attrition during the first month after CABG, while during the remainder of the first year, intimal hyperplasia forms a template for subsequent atherogenesis, which thereafter predominates. Platelets play a crucial role in the pathophysiology of graft thrombosis and aspirin is the primary antiplatelet drug that has been shown to improve vein graft patency within the first year after CABG. Nevertheless, a significant number of grafts still occlude in the early postoperative period despite 'appropriate' aspirin treatment. Moreover, laboratory investigations showed that the expected inhibition of platelet function is not always achieved. This has been called 'aspirin nonresponse' or 'aspirin resistance', although a uniform definition is lacking. The finding that a considerable number of patients show an impaired antiplatelet effect of aspirin after CABG brought new insight into the discussion concerning poor patency rates of bypass grafts: the early period after CABG shows a coincidence of an increased risk for bypass thrombosis (amongst others, due to platelet activation and endothelial cell disruption of the graft) and an increased prevalence of aspirin resistance. Hitherto, the underlying mechanisms of aspirin resistance are uncertain and largely hypothetical; amongst others, increased platelet turnover, enhanced platelet reactivity, systemic inflammation, and drug-drug interaction are discussed. Up to now available data concerning the clinical outcome of aspirin resistant CABG patients are limited, and there is evidence that platelets of patients with graft thrombosis are more likely to be resistant to aspirin compared with patients without thrombotic events. Many publications concerning aspirin resistance are available today, but reports addressing this topic in CABG patients are sparse. This review summarises recent insights into the antiplatelet treatment after CABG and describes the clinical benefit, but also the therapeutic failure of the well-established drug aspirin. Moreover, possible pharmacological approaches to improve antithrombotic therapy in aspirin nonresponders among CABG patients are discussed. PMID- 18448351 TI - Cryoablation for surgical treatment of chronic atrial fibrillation combined with mitral valve surgery: a clinical observation. AB - OBJECTIVE: Although the classical Cox-Maze III is the gold standard surgical therapy with a proven efficacy in the treatment of atrial fibrillation (AF), complexity of this procedure has resulted in a search for a simpler, less invasive and more cost-effective method. In this study we evaluated the results of cryosurgical ablation in the treatment of chronic AF in patients undergoing concomitant mitral valve surgery. METHODS: Ninety patients (mean age: 50.9+/-12 years) with chronic AF who were having mitral valve surgery as the main procedure underwent cryoablation with a newly designed N(2)O-based cryotherapy device. Pulmonary vein isolation with or without left atrial appendage closure (group A) was carried out in 65 cases and cryoablative bi-atrial Cox-Maze III (group B) in 25 patients. This additional procedure took only an extra 10 min for group A and about 20 min for group B. Half of the patients received a beta-blocker following the procedure. RESULTS: The overall success rate of cryoablation was 65.5%. Normal sinus rhythm was achieved in 26.7% in the operating room, 10% in ICU and the remaining cases reverted to sinus rhythm during the follow-up period. There were no major ablation-related complications such as bleeding, thromboembolic events or A-V block. The only predictor for failure of ablative procedure was left atrial size of greater than 6 cm. CONCLUSION: Although in this study the efficacy rate of cryoablative surgery was not the same as classical Cox-Maze III, it seems that this procedure is safe, simple, cost-effective and at the same time does not increase the operative time significantly. Using cryoablation may enhance the cure rate of chronic AF during mitral valve surgery. PMID- 18448352 TI - Right atrial aneurysm. PMID- 18448353 TI - Human leptin induces angiogenesis in vivo. AB - Leptin is an adipocyte-produced peptide, which plays a crucial role in the regulation of body weight. There is also evidence that leptin stimulates endothelial cell proliferation and the formation of capillary-like tubes in vitro. The disc angiogenesis system was used to measure the angiogenic effect of leptin in vivo. Discs containing 25, 50, 100 and 250ng/ml of leptin were implanted subcutaneously in Wistar rats, removed after a growth period of 7 and 14 days, and compared with spontaneous growth controls and with positive controls containing equivalent doses of vascular endothelial growth factor (VEGF). Discs were examined morphologically for stroma and vessel development and by immunohistochemistry for quantitative evaluation of angiogenesis. The specificity of the angiogenic effect of leptin was tested by blocking leptin with a polyclonal anti-leptin antibody. Leptin induced a significant level of angiogenesis in a dose-dependent manner both at 7 and 14 days, with a peak at the dose of 100ng/ml. The angiogenic activity of leptin was completely abolished by the anti-leptin neutralizing antibody. VEGF also induced significant dose dependent angiogenesis at the same time points with a peak observed at a concentration of 100ng/ml. The angiogenic response to leptin was significantly higher at 7 days compared with VEGF but not at the 14-day time point. In conclusion, leptin has a specific angiogenic effect in vivo, which is dose- and time-dependent in a concentration range of 25-250ng/ml. This effect is equivalent to the angiogenic effect of VEGF but is evident earlier compared with VEGF. PMID- 18448354 TI - Localization of the noncovalent binding site between amyloid-beta-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry. AB - Abnormal accumulation and aggregation of amyloid-beta-peptide (Abeta) eventually lead to the formation and cerebral deposition of amyloid plaques, the major pathological hallmark in Alzheimer's disease (AD). Oleuropein (OE), an Olea europaea L. derived polyphenol, exhibits a broad range of pharmacological properties, such as antioxidant, anti-inflammatory, and antiatherogenic, which could serve as combative mechanisms against several reported pathways involved in the pathophysiology of AD. The reported noncovalent interaction between Abeta and OE could imply a potential antiamyloidogenic role of the latter on the former via stabilization of its structure and prevention of the adaptation of a toxic beta sheet conformation. The established beta-sheet conformation of the Abeta hydrophobic carboxy-terminal region and the dependence of its toxicity and aggregational propensity on its secondary structure make the determination of the binding site between Abeta and OE highly important for assessing the role of the interaction. In this study, two different proteolytic digestion protocols, in conjunction with high-sensitivity electrospray ionization mass spectrometric analysis of the resulting peptide fragments, were used to determine the noncovalent binding site of OE on Abeta and revealed the critical regions for the interaction. PMID- 18448356 TI - Cancer development at tissue level. PMID- 18448357 TI - Heterologous expression of functionally active enterolysin A, class III bacteriocin from Enterococcus faecalis, in Escherichia coli. AB - The heterologous expression of enterolysin A (EnlA), heat-labile class III bacteriocin from Enterococcus faecalis II/1 with anti-listerial activity, was studied in Escherichia coli. The PCR amplified products of enterolysin A structural gene, N-terminal part of EnlA with endopeptidase-like activity and C terminal part of EnlA similar to a lysis gene of bacteriophage, were cloned in prelinearized pQE-30UA expression vector. The expression of EnlA structural gene led to the synthesis and secretion of functional-active His-tagged enterolysin A protein, which was purified to homogeneity using His-Select Cartridge and was shown to be fully active against the indicator strain. The expression of N terminal or C-terminal part of EnlA and deletion of last 58 amino acids from C terminal domain of EnlA led to the synthesis of biologically non-active proteins. PMID- 18448355 TI - Hyalurondiase: both a tumor promoter and suppressor. AB - Originally termed as the "spreading factor", hyaluronidases (HAases) are present in a variety of toxins and venoms. For example, HAase is the virulent factor of beta-hemolytic Streptococci and it is also present in the venoms of snake, bee, wasp, scorpion, etc, where it aids in the spread of these venoms in the body. In mammals, testicular HAase present in the sperm acrosome is necessary for the fertilization of the ovum. Despite a lot of work on bacterial, invertebrate and testicular HAases, a connection between HAase and cancer was unequivocally established just over a decade ago and the functional significance of HAases in cancer was demonstrated just about a year ago. In this part of the review, we will focus on the recent advances in our understanding of the role of HAases in cancer. PMID- 18448358 TI - What happens to the DNA vaccine in fish? A review of current knowledge. AB - The primary function of DNA vaccines, a bacterial plasmid DNA containing a construct for a given protective antigen, is to establish specific and long lasting protective immunity against diseases where conventional vaccines fail to induce protection. It is acknowledged that less effort has been made to study the fate, in terms of cellular uptake, persistence and degradation, of DNA vaccines after in vivo administration. However, during the last year some papers have given new insights into the fate of DNA vaccines in fish. By comparing the newly acquired information in fish with similar knowledge from studies in mammals, similarities with regard to transport, blood clearance, cellular uptake and degradation of DNA vaccines have been found. But the amount of DNA vaccine redistributed from the administration site after intramuscular administration seems to differ between fish and mammals. This review presents up-to-date and in depth knowledge concerning the fate of DNA vaccines with emphasis on tissue distribution, cellular uptake and uptake mechanism(s) before finally describing the intracellular hurdles that DNA vaccines need to overcome in order to produce their gene product. PMID- 18448359 TI - Molecular cloning, characterization and expression analysis of the PKZ gene in rare minnow Gobiocypris rarus. AB - Double-stranded RNA-activated protein kinase (PKR) plays an important role in interferon-induced antiviral responses, and is also involved in intracellular signaling pathways, including the apoptosis, proliferation, and transcription pathways. In the present study, a PKR-like gene was cloned and characterized from rare minnow Gobiocypris rarus. The full length of the rare minnow PKR-like (GrPKZ) cDNA is 1946 bp in length and encodes a polypeptide of 503 amino acids with an estimated molecular mass of 57,355 Da and a predicted isoelectric point of 5.83. Analysis of the deduced amino acid sequence indicated that the mature peptide contains two Zalpha domains and one S_TKc domain, and is most similar to the crucian carp (Carassius auratus) PKR-like amino acid sequence with an identity of 77%. Quantitative RT-PCR analysis showed that GrPKZ mRNA expression is at low levels in gill, heart, intestine, kidney, liver, muscle and spleen tissues in healthy animals and up-regulated by viruses and bacteria. After being infected by grass carp reovirus, GrPKZ expression was up-regulated from 24h post injection and lasted until the fish became moribund (P<0.05). Following infection with Aeromonas hydrophila, GrPKZ transcripts were induced at 24h post-injection (P<0.05) and returned to control levels at 120 h post-injection. These data imply that GrPKZ is involved in antiviral defense and Toll-like receptor 4 signaling pathway in bacterial infection. PMID- 18448360 TI - Motor unit firing behavior during prolonged 50% MVC dorsiflexion contractions in young and older adults. AB - The purpose of this study was to investigate changes in motor unit firing behavior during prolonged contractions in young and older adults. Motor unit activity was recorded from the tibialis anterior of 16 subjects (8 young and 8 older), while they performed isometric dorsiflexion at 50% MVC until task failure. Mean motor unit firing rate, the standard deviation (SD), and coefficient of variation (CV) of the interspike intervals, and number of doublet discharges were calculated for a total of 52 motor units, tracked for an average of 92.9+/-68.6s. There was no age-related difference in the time to task failure. A modest decline in firing rate was observed in 71% of the motor units, with no significant age-related difference. The SD and CV of the interspike interval had a positive slope in 65% and 69% of the motor units, respectively, with no significant age-related differences. The number of doublet discharges remained stable throughout the contraction. Both groups exhibited motor unit dropout (discharge cessation) during the contraction. Thus, a fatiguing task producing modest changes in firing rate in young and older adults is accompanied by an appreciable increase in firing rate variability. The incidence of doublet discharges is not increased during fatiguing contractions. PMID- 18448361 TI - Conscious emotional experience emerges as a function of multilevel, appraisal driven response synchronization. AB - In this paper we discuss the issue of the processes potentially underlying the emergence of emotional consciousness in the light of theoretical considerations and empirical evidence. First, we argue that componential emotion models, and specifically the Component Process Model (CPM), may be better able to account for the emergence of feelings than basic emotion or dimensional models. Second, we advance the hypothesis that consciousness of emotional reactions emerges when lower levels of processing are not sufficient to cope with the event and regulate the emotional process, particularly when the degree of synchronization between the components reaches a critical level and duration. Third, we review recent neuroscience evidence that bolsters our claim of the central importance of the synchronization of neuronal assemblies at different levels of processing. PMID- 18448362 TI - The molecules of social recognition memory: implications for social cognition, extended mind, and neuroethics. AB - Social cognition, cognitive neuroscience, and neuroethics have reached a synthesis of late, but some troubling features are present. The neuroscience that currently dominates the study of social cognition is exclusively cognitive neuroscience, as contrasted with the cellular and increasingly molecular emphasis that has gripped mainstream neuroscience over the past three decades. Furthermore, the recent field of molecular and cellular cognition has begun to unravel some molecular mechanisms involved in social cognition, especially pertaining to the consolidation of memories of particular conspecific organisms. Some new experimental techniques for positive interventions into these hypothesized mechanisms offer opportunities for establishing direct causal linkages between intra-neuronal molecular events and the behaviors used to measure social cognitive phenomena. Predicted results from an experiment described below also cast doubt on the application of the "extended mind" approach from recent cognitive science to ground the neuroscience of social cognition. Since neuroethics relies heavily on our best neuroscience of social cognition, that field may soon need to extend its attention beyond cognitive neuroscience, and into neuroscience's cellular and molecular mainstream. PMID- 18448363 TI - Pharmacological characterization of P2X1 and P2X3 purinergic receptors in bovine chondrocytes. AB - OBJECTIVE: The aim of the present study is that of characterizing, for the first time in a quantitative way, from a biochemical, physico chemical and functional point of view P2X(1) and P2X(3) purinergic receptors in bovine chondrocytes. The affinity and the potency of typical purinergic ligands were studied through competition binding experiments and their role in modulating chondrocyte actvities was investigated by analyzing nitric oxide (NO) and prostaglandin E2 (PGE(2)) release. METHODS: Saturation, competition binding experiments, western blotting and immunohistochemistry assays on the P2X(1) and P2X(3) purinergic receptors in bovine chondrocytes were performed. Thermodynamic analysis of the P2X(1) and P2X(3) purinergic binding was studied to investigate the forces driving drug-receptor coupling. In the functional assays (NO and PGE(2) release) the potency of purinergic agonists and antagonists was evaluated. RESULTS: Bovine chondrocytes expressed P2X(1) and P2X(3) purinergic receptors and thermodynamic parameters indicated that purinergic binding is enthalpy- and entropy-driven for agonists and totally entropy-driven for antagonists. Typical purinergic agonists such as adenosine 5'-triphosphate (ATP) and alpha,beta-methyleneATP were able to increase NO and PGE(2) release. A purinergic antagonist, A317491, was able to block the stimulatory effect on functional experiments mediated by the agonists. CONCLUSIONS: These data demonstrate for the first time the presence of functional P2X(1) and P2X(3) purinergic receptors in bovine chondrocytes. Agonists and antagonists are thermodynamically discriminated and are able to modulate functional responses such as NO and PGE(2) release. These results suggest the potential role of novel purinergic antagonists in the treatment of pathophysiological diseases linked to the inflammation and involved in articular cartilage resorption. PMID- 18448364 TI - The Paxillin-like protein AgPxl1 is required for apical branching and maximal hyphal growth in A.gossypii. AB - The development from young, slowly growing hyphae to fast growing hyphae in filamentous fungi is referred to as hyphal maturation. We have identified the Paxillin-like protein AgPxl1 in Ashbyagossypii as a developmental protein that is specifically required for hyphal maturation. The early development of A.gossypii strains lacking AgPxl1 is indistinguishable from wild-type. However, at later developmental stages the maximal hyphal extension rate is less than half compared to wild-type and apical branching is affected. Apical branching is characterised as the symmetric division of fast growing hyphal tips resulting in two sister hyphae. In Agpxl1Delta strains two thirds of the apical branching events lead to asymmetric sister hyphae where growth of one branch is either completely aborted or slowed down while extension of the other branch is not affected. This suggests that AgPxl1 plays a role in the organisation of growth and efficient division of growth upon apical branching in mature mycelia. The conserved C-terminal LIM domains are necessary for AgPxl1 function and also contribute to tip localisation. AgCLA4, a PAK-like kinase, is epistatic to AgPXL1 and robust localisation of AgPxl1 depends on AgCla4. This suggests that AgCla4 acts upstream of AgPxl1. PMID- 18448365 TI - The role of a fadA ortholog in the growth and development of Colletotrichum graminicola in vitro and in planta. AB - A transposon-based split-marker protocol was used to produce insertional mutations in the fadA ortholog of the maize anthracnose pathogen Colletotrichum graminicola. The mutants grew more slowly in culture, produced fewer oval spores, produced fusiform rather than falcate phialospores, lost their normal clockwise spiral growth pattern in culture, and were significantly reduced in their pathogenicity to maize stalks and leaves. The differential effect of the fadA mutation on oval spore versus phialospore production suggests that there are differences in the signaling pathways that regulate these two types of sporulation. It has been suggested that oval spores function in anthracnose lesion extension. In maize stalks, production of oval spores appeared to be relatively unaffected in the mutant strains, but production of vegetative hyphae and elongation of primary lesions were both reduced. This suggests that vegetative hyphae play a more important role than oval spores in primary lesion development. However, production of discontinuous secondary lesions in maize stalks infected by mutant strains did not appear to be seriously affected, and thus oval spores may play a more important role in that process. PMID- 18448366 TI - Aspergillus oryzae atfB encodes a transcription factor required for stress tolerance in conidia. AB - Using an Aspergillus oryzae EST database, we identified a gene encoding a transcription factor (atfB), which is a member of the ATF/CREB family. Expression of atfB was barely detectable during vegetative growth, but was readily detected during conidiation in solid-state culture. Microarray analyses showed that expression of many other genes, including catalase (catA), were downregulated in an atfB-disruptant. The expression of most of these genes was upregulated in the wild-type strain during the conidiation phase in solid-state culture, and the expression pattern was similar to that of atfB itself. In the absence of stress, e.g. heat-shock or hydrogen peroxide, the conidial germination ratios for the DeltaatfB strain and the wild-type strain were similar, but the stress tolerance of conidia carrying the DeltaatfB deletion was less than that of the wild-type conidia. CRE-like DNA motifs, which are bound by ATF/CREB proteins, were found in the promoters of most of the downregulated genes in the DeltaatfB strain. Thus, atfB appears to encode a transcription factor required for stress tolerance in conidia. PMID- 18448367 TI - Basidiomycete Lentinula edodes CDC5 and a novel interacting protein CIPB bind to a newly isolated target gene in an unusual manner. AB - We isolated a target gene for the Lentinula edodes putative transcription factor Le.CDC5 that contains a c-Myb-type DNA-binding domain. The gene, termed ctg1, encodes a novel protein (159 amino acid residues) with a leucine zipper-like sequence and contains a 7-bp Le.CDC5-binding sequence, 5'GCAATCT3', in its transcribed region downstream of the start codon. Chromatin immunoprecipitation analysis strongly suggested that intracellular Le.CDC5 binds to this 7-bp sequence on L. edodes chromatin. Binding was most efficient on chromatin from the stipes of mature fruiting bodies. Two Le.CDC5-interaction partners were identified in L. edodes and named CIPA and CIPB. The CIPB protein (127 amino acid residues) binds to a 6-bp sequence with the consensus sequence 5'CAACAC/T/G3'. The ctg1 gene contains nine 6-bp consensus (or consensus-like) sequences, six are in the 5'-upstream region and three in the transcribed region downstream of the start codon. At least two each of the upstream and downstream sequences appear to bind CIPB in vitro. We suggest that Le.CDC5 and CIPB can cooperatively regulate the expression of ctg1. PMID- 18448368 TI - A structured review of the evidence for pacing as a chronic pain intervention. AB - Pacing as an intervention appears with great regularity in the chronic pain management literature and yet what service providers actually mean by pacing is unclear and poorly defined. This short communication reports the findings of a structured review of the literature which examined the strength of the evidence for pacing as an intervention for people with chronic pain. The McMaster critical review guidelines were followed and the relevant electronic databases were searched. Findings revealed a paucity of outcome studies specific to pacing as an intervention. Although background literature demonstrates that pacing is often one part of a multidisciplinary intervention program, the research conducted on these programs presents pacing itself as an ill- or undefined construct. It is evident from this review that "pacing," while a widely employed term, lacks consensus of definition and a demonstrable evidence-base. PMID- 18448369 TI - Can rate of recovery be predicted in patients with acute low back pain? Development of a clinical prediction rule. AB - Some patients with low back pain recover quickly while others continue to experience pain beyond 3 months. The primary aim of this study was to develop a simple prediction rule to help clinicians identify patients with acute low back pain likely to recover at different rates. The secondary aim was to compare a clinician's prognosis judgement to the prediction rule. The study sample included 239 patients with acute low back pain who participated in a randomised controlled trial. The primary outcome was days to recovery from pain. Potential prognostic factors were initially tested for univariate association with recovery using Cox regression (p<0.1). Continuous prognostic factors with a significant association were dichotomised using a median split. Significantly associated prognostic factors were then included in a multivariate forward stepwise Cox regression. We then separated participants into strata according to the number of predictors in the final model for which they were positive. Our results suggest that a clinical prediction rule using three simple prognostic factors was able to differentiate between patients who recover quickly and those who recover slowly. Patients with lower than average initial pain intensity, shorter duration of symptoms and fewer previous episodes recovered more quickly (HR=3.5, 95% CI, 1.8-7.0) than patients without these characteristics. Therapists were able to predict patients likely to recover at different rates, (HR=1.6, 95% CI, 1.2-2.1), however, they did not perform as well as the clinical prediction rule. The rule requires validation in a different sample of patients. PMID- 18448370 TI - Catastrophizing about their children's pain is related to higher parent-child congruency in pain ratings: an experimental investigation. AB - Little is known about the variables that account for why parents underestimate the pain of their child. In the present experiment, the joint impact of parental catastrophizing about their child's pain and children's facial pain expressions was examined upon pain estimates of their child undergoing a pressure pain test. In line with previous research, parents underestimated their children's pain. Interestingly, it was found that pain was estimated as higher when the child showed more facial pain expressions and when parents catastrophized more about their child's pain. An intriguing finding was that catastrophizing about their child's pain was related to less parent-child incongruence in pain ratings. The discussion addresses the possible functions of catastrophizing of parents about their children's pain, and delineates avenues for future research. PMID- 18448371 TI - The contribution of self-efficacy and depression to disability and work status in chronic pain patients: a comparison between Australian and Brazilian samples. AB - There is evidence that cognitions (beliefs) and mood contribute to physical disability and work status in people with chronic pain. However, most of the current evidence comes from North America and Europe. This study examined the contribution of demographic, pain and psychosocial factors to disability and work status in chronic pain patients in two matched samples from quite different countries (Australia and Brazil). Data were collected from 311 chronic pain patients in each country. The results suggest that although demographic and pain variables (especially pain levels) contribute to disability, self-efficacy beliefs made a significant contribution to disability in both samples. Age and educational level also contributed to unemployment in both samples. But there were some differences, with self-efficacy and physical disability contributing to work status only in the Brazilian sample. In contrast, depression was the only psychological risk factor for unemployment in the Australian sample. Catastrophising and pain acceptance did not contribute to disability or unemployment in either sample. These findings confirm key aspects of biopsychosocial models of pain in two culturally and linguistically different chronic pain samples from different countries. They suggest that different chronic pain populations may share more similarities than differences. PMID- 18448372 TI - Exploring the extent of postmenopausal osteoporosis among Saudi Arabian women using dynamic simulation. AB - The prevalence of postmenopausal osteoporosis among Saudi Arabian women is difficult to estimate because it is a large country with a diverse widely dispersed population. There have been reports of localized prevalence estimates but these are difficult to compare. In the absence of reliable national data, a theoretical approach may be useful. We have extended our mathematical model of the WHO scheme for osteoporosis diagnosis so that it is capable of predicting the prevalence of postmenopausal osteoporosis in a population of women on a year-by year basis. These calculations are based on the area under a theoretical Gaussian bone mineral density (BMD) distribution bounded by the WHO thresholds for osteoporosis and osteopenia. This simulation approach confirms the pivotal role played by the standard deviation of BMD in the young, healthy normal reference group and it permits the model's sensitivity to other parameters (amplitude and time constant of the postmenopausal decline in BMD) and circumstances (age related changes in standard deviation) to be accurately quantified: For Saudi Arabian women aged 50-70 yr, we estimate the prevalence of osteoporosis to be approximately 23%. The precise value depends strongly on the underlying standard deviation of BMD across the various age groups, which still remains to be accurately determined within the Saudi Arabian population. PMID- 18448373 TI - First update of the Lebanese guidelines for osteoporosis assessment and treatment. AB - With the demographic explosion, the human, social, and economic costs of osteoporosis in developing countries, including the Middle East, will continue to rise. In 2002, the Lebanese Guidelines for Osteoporosis Assessment and Treatment were developed to optimize quality of osteoporosis care in Lebanon and the region. They were endorsed by 5 Lebanese medical scientific societies, and by the Eastern Mediterranean Regional Office branch of the World Health Organization (WHO). In April 2006, the Lebanese Society for Osteoporosis and Metabolic Bone Disorders (OSTEOS) led an initiative to update several recommendations detailed in the original document, based on relevant new local and international data. Data from a population-based sample of elderly Lebanese validated the following recommendations: fracture risk assessment, expressed as relative risk per standard deviation (RR/SD) decrease, was comparable in Lebanese subjects to similarly derived estimates from Western studies; the use of the NHANES database (hip), and the densitometer American database (spine) was as good, if not superior to the use of a Lebanese database for identifying subjects with prevalent vertebral fractures. The original recommendation regarding the use of a gender-specific western database, densitometer for spine and NHANES for T-score derivation for men, remains unchanged. For skeletal site selection, the update recommends measuring the spine and hip for women < or =65 yr, hip only for subjects >65 yr, and adding the forearm in conditions associated with cortical bone loss or in the case of inability to measure axial sites. The original recommendations for conservative management in premenopausal women were reiterated. This First Update of the Lebanese Osteoporosis Guidelines validates previous recommendations using evidence from a population-based sample of elderly Lebanese, and lays the ground for transitioning the Lebanese Osteoporosis Guidelines to the WHO global fracture risk assessment model. PMID- 18448374 TI - Partial trypsin digestion as an indicator of mis-folding of mutant alanine:glyoxylate aminotransferase and chaperone effects of specific ligands. Study of a spectrum of missense mutants. AB - Alanine:glyoxylate aminotransferase (AGT) is a liver peroxisomal enzyme whose deficiency results in primary hyperoxaluria type 1 (PH1). More than 75 PH1 mutations are now documented in the AGT gene (AGXT), of which about 50% are missense. We have previously demonstrated that many such mutants expressed by transcription/translation are subject to generalized degradation by the proteasome and a specific limited trimming by an endogenous ATP-independent protease activity. Here, we report the results of partial digestion using trypsin as a mimic for the endogenous non-proteasomal protease and the use of N-terminal protein sequencing to determine the sensitive site. Partial trypsin digestion also provided an indicator of proper folding of the mutant enzyme. For selected mutations the sensitivity to trypsin could be ameliorated by addition of pyridoxal phosphate or aminooxy acetic acid as specific pharmacological chaperones. PMID- 18448375 TI - Combined administration in a single injection of a feline multivalent modified live vaccine against FHV, FCV, and FPLV together with a recombinant FeLV vaccine is both safe and efficacious for all four major feline viral pathogens. AB - Nobivac Tricat, a lyophilised trivalent modified live attenuated vaccine is routinely used to protect cats against three commonly diagnosed feline viral pathogens namely herpesvirus, calicivirus and panleukopenia virus. The recognition of feline leukaemia virus (FeLV) as an important viral pathogen has prompted the development of an efficacious liquid recombinant subunit FeLV vaccine (p45 envelope protein). Lyophilised Tricat vaccine was dissolved in the liquid FeLV vaccine and no detectable deleterious effect on the titre of any of the live virus components was observed after 2h incubation. In vivo studies where the vaccines were mixed in the same syringe prior to inoculation showed no alteration to the safety profile assessed by repeat and overdose studies. Serological comparisons of the modified live viral antibody titres showed no evidence of reduced responses following administration of the mixed products. Challenge studies using pathogenic herpesvirus and FeLV revealed no difference in the degree of clinical protection. This paper shows that neither safety nor efficacy is adversely affected as a result of mixing the two vaccines. PMID- 18448376 TI - Effects of acute exercise on insulin sensitivity, glucose effectiveness and disposition index in type 2 diabetic patients. AB - AIM: The aim of this work was to quantify the magnitude of changes in insulin sensitivity (S(I)) and glucose effectiveness (S(G)) in response to acute exercise in type 2 diabetic (T2D) patients, as previously studied in non-diabetic subjects. METHODS: Seven T2D patients and seven non-diabetic controls participated in the study. Two intravenous glucose tolerance tests (0.5 g/kg) with frequent blood sampling over 180 minutes and mathematical modelling were carried out in a randomized fashion, one at rest and the other immediately following 15 minutes of exercise at 50% of the maximum theoretical heart rate (HR(max)) followed by five minutes at 85% of the HR(max). S(I) and S(G) were calculated using Bergman's minimal model. RESULTS: After exercise, S(I) was increased by 773% (from 0.62+/-0.16 to 5.41+/-1.59 min(-1) x 10(-4)/(microU/mL) and even reached the zone of control values at rest (5.52+/-2.28), whereas S(G) remained unchanged. The disposition index acute insulin response (AIR(G)) x S(I) and the product of fasting insulin (I(B)) x S(I) also increased after exercise. CONCLUSION: A single bout of exercise at moderate intensity in type 2 diabetics did not improve S(G), but markedly improved the low S(I) values found in these patients, indicating that the acute effects of exercise on S(I) are quantitatively important in the interpretation of training-related S(I) changes and may even be therapeutically useful on their own. Surrogates such as homoeostasis model assessment (HOMA) and quantitative insulin-sensitivity check index (QUICKI) were not sensitive enough to detect this increase in S(I) and should probably be used with caution in the follow-up of exercise protocols in diabetic patients. PMID- 18448377 TI - In vivo MR imaging tracking of magnetic iron oxide nanoparticle labeled, engineered, autologous bone marrow mesenchymal stem cells following intra articular injection. AB - OBJECTIVE: To track superparamagnetic iron oxide nanoparticle (SPIO)-labeled, bone-derived mesenchymal stem cells (MSCs) by in vivo magnetic resonance imaging (MRI) with a 1.5T-system following injection of engineered autologous MSCs into the knee joint cavity in rabbit articular cartilage defect models. METHODS: Rabbit MSCs were labeled with SPIO and a transfection agent. Cell viability, proliferation and differentiation capacity were assessed in vitro using appropriate functional assays. Cells underwent GRE T2*-weighted MRI in vitro. The autologous MSCs seeded in chitosan and glycerophosphate (C-GP) gel were injected into the knee joint cavity of rabbit models for cartilage defects. All rabbits underwent GRE T2*-weighted MRI 1, 4, 8 and 12 weeks post-injection. MR imaging findings were compared histologically. RESULTS: Nanoparticles were stained with Prussian blue and observed by transmission electron microscopy inside the cells. Cell viability, proliferation, and differentiation were comparable between labeled and non-labeled cells. After intra-articular injection of labeled autologous MSCs, marked hypointense signal void areas representing the injected MSCs can be observed for at least 12 weeks on GRE T2*-weighted images. At 12 weeks post-injection, labeled MSCs migrated into the synovial fluid at the suprapatellar bursa, the popliteal space site and subchondral bone of the femur but no MSCs were detected in the defect. Histochemical staining confirmed the presence of Prussian blue-positive cells and BrdU-positive cells. CONCLUSIONS: MRI would be an efficient noninvasive technique to visually track SPIO-labeled seed cells in vivo; the engineered autologous MSCs do not actively participate in the repair of articular cartilage defects following intra-articular injection. PMID- 18448378 TI - Prevalence of ossification of the posterior longitudinal ligament of the cervical spine. AB - OBJECTIVES: To determine the prevalence of ossification of the posterior longitudinal ligament (OPLL) in cervical spines in Koreans. METHODS: We reviewed the reports of the radiologic examination of cervical spines from January 2002 to September 2005 in Hanyang University Hospital, Seoul, Korea. OPLL was indicated by the presence of heterotopic ossification in the posterior longitudinal ligament on lateral cervical radiograph. RESULTS: Among 11,774 adults aged 16 years or more, 71 cases of OPLL were found (0.60%). The male to female ratio was 42:29 (1.45:1). The highest prevalence was in patients aged 50-59 years. In terms of the types of OPLL, the continuous type was noted in 32.0% of the patients, the segmental type in 31.0%, the mixed type in 31.0%, and the localized type in 5.6%. C4, C5, and C3 were most commonly involved, in that order of frequency. Diffuse idiopathic skeletal hyperostosis, which is another common hyperostotic disorder, was also found in eight male patients. CONCLUSIONS: The prevalence of cervical OPLL in Koreans was 0.60%, which was lower than that of Japanese and some previous western reports. PMID- 18448379 TI - The genetics of intervertebral disc degeneration. Familial predisposition and heritability estimation. AB - OBJECTIVES: To review current knowledge on heritability of intervertebral disc degeneration (IDD). IDD can contribute to the development of low back pain and acute lumbar radiculopathy. Dramatic change in the current view of risk factors for IDD from one where age and mechanical factors were paramount to the current theory that genetic risk factors are predominant, we thought that it is important to review the studies of the genetic influences on IDD beginning from familial aggregation and heritability estimation and finishing with specific studies of genes associated with IDD. METHODS: A literature-based narrative review of English language medical literature. RESULTS AND CONCLUSIONS: Prior research has demonstrated the existence of familial predisposition to IDD with generally high heritabilities that range from 34% to 61% in different spine locations. Segregation analysis shows that the mode of inheritance is complex with multiple factors and multiple genes likely involved in intergenerational transmission. PMID- 18448380 TI - Regulation of retinal blood flow in health and disease. AB - Optimal retinal neuronal cell function requires an appropriate, tightly regulated environment, provided by cellular barriers, which separate functional compartments, maintain their homeostasis, and control metabolic substrate transport. Correctly regulated hemodynamics and delivery of oxygen and metabolic substrates, as well as intact blood-retinal barriers are necessary requirements for the maintenance of retinal structure and function. Retinal blood flow is autoregulated by the interaction of myogenic and metabolic mechanisms through the release of vasoactive substances by the vascular endothelium and retinal tissue surrounding the arteriolar wall. Autoregulation is achieved by adaptation of the vascular tone of the resistance vessels (arterioles, capillaries) to changes in the perfusion pressure or metabolic needs of the tissue. This adaptation occurs through the interaction of multiple mechanisms affecting the arteriolar smooth muscle cells and capillary pericytes. Mechanical stretch and increases in arteriolar transmural pressure induce the endothelial cells to release contracting factors affecting the tone of arteriolar smooth muscle cells and pericytes. Close interaction between nitric oxide (NO), lactate, arachidonic acid metabolites, released by the neuronal and glial cells during neural activity and energy-generating reactions of the retina strive to optimize blood flow according to the metabolic needs of the tissue. NO, which plays a central role in neurovascular coupling, may exert its effect, by modulating glial cell function involved in such vasomotor responses. During the evolution of ischemic microangiopathies, impairment of structure and function of the retinal neural tissue and endothelium affect the interaction of these metabolic pathways, leading to a disturbed blood flow regulation. The resulting ischemia, tissue hypoxia and alterations in the blood barrier trigger the formation of macular edema and neovascularization. Hypoxia-related VEGF expression correlates with the formation of neovessels. The relief from hypoxia results in arteriolar constriction, decreases the hydrostatic pressure in the capillaries and venules, and relieves endothelial stretching. The reestablished oxygenation of the inner retina downregulates VEGF expression and thus inhibits neovascularization and macular edema. Correct control of the multiple pathways, such as retinal blood flow, tissue oxygenation and metabolic substrate support, aiming at restoring retinal cell metabolic interactions, may be effective in preventing damage occurring during the evolution of ischemic microangiopathies. PMID- 18448381 TI - Diamonds in the rough: mRNA-like non-coding RNAs. AB - Non-coding RNAs are increasingly being identified as crucial regulators of gene expression and other cellular functions in plants. Experimental and computational methods have revealed the existence of mRNA-like non-coding RNAs (mlncRNAs), a class of non-coding RNAs that, in plants, are associated with tissue-specific expression, development and the phosphate-starvation response. Although their mechanisms of action are largely unknown, one can speculate that mlncRNAs act through secondary structures or specific sequences that bind to proteins or metabolites, or that have catalytic activity. This review summarizes the computational methods developed to identify candidate mlncRNAs, and the current experimental evidence regarding the function of several known mlncRNAs. PMID- 18448382 TI - Automatic recognition of the common carotid artery in longitudinal ultrasound B mode scans. AB - Many morphological and dynamic properties of the common carotid artery (CCA), e.g. lumen diameter, distension and wall thickness, can be measured non invasively with ultrasound (US) techniques. As common to other medical image segmentation processes, this requires as a preliminary step the manual recognition of the artery of interest within the ultrasound image. In real-time US imaging, such manual initialization procedure interferes with the difficult task of the sonographer to select and maintain a proper image scan plane. Even for off-line US segmentation the requirement for human supervision and interaction precludes full automation. To eliminate user interference and to speed up processing for both real-time and off-line applications, we developed an algorithm for the automatic artery recognition in longitudinal US scans of the CCA. It acts directly on the envelopes of received radio frequency echo signals, eventually composing the ultrasound image. In order to properly exploit the information content of the arterial structure the envelopes are decimated, according to the two-dimensional resolution characteristics of the echo system, thereby substantially decreasing computational load. Subsequently, based upon the expected diameter range and a priori knowledge of the typical pattern in the echo envelope of the arterial wall-lumen complex, parametrical template matching is performed, resulting in the location of the lumen position along each echo line considered. Finally, in order to reject incorrect estimates, a spatial and temporal clustering method is applied. Adequate values for the parameters involved in the processing are obtained via off-line testing of the proposed algorithm on 128 echo data recordings from 45 subjects. Using those robust parameter values, correct and fast recognition of the artery is achieved in more than 98% of the 6185 processed frames. Since these results are obtained via rigorous data decimation and using a cascade of rather simple steps, the proposed automatic algorithm is suitable for real-time recognition of the CCA. PMID- 18448383 TI - Molecular structure and vibrational spectra of 3-chloro-4-fluoro benzonitrile by ab initio HF and density functional method. AB - In this work, the experimental and theoretical spectra of 3-chloro-4-fluoro benzonitrile (3C4FBN) were studied. The Fourier transform infrared and Fourier transform Raman spectra of 3C4FBN were recorded in the solid phase. The optimized geometry was calculated by HF and B3LYP methods with 6-311++G(d,p) basis set. The harmonic-vibrational frequencies, infrared intensities and Raman scattering activities of the title compound were performed at and HF/B3LYP/6-311++G(d,p) level of theories. The scaled theoretical wave number showed very good agreement with the experimental values. The thermodynamic functions of the title compound was also performed at HF/6-31G(d,p) and B3LYP/6-311++G(d,p) level of theories. A detailed interpretation of the infrared and Raman spectra of 3C4FBN was reported. The theoretical spectrograms for FT-IR and FT-Raman spectra of the title molecule have been constructed. PMID- 18448385 TI - Computerizing medical records in Japan. AB - PURPOSE: The present study reports the current status of computerizing medical records in Japan. In 2001, the Ministry of Health, Labour and Welfare formulated the Grand Design for the Development of Information Systems in the Healthcare and Medical Fields. The Grand Design stated a numerical target for "spreading the use of electronic medical records (EMR) in at least 60% of Japan's hospitals with 400 or more beds by 2006." The objective of this study was to examine the extent to which EMR and order entry systems (OES) have been adopted as of February 2007 and to evaluate the Japanese government's policy regarding the computerization of medical records. METHODS: We conducted a postal survey targeting medical institutions throughout Japan. In February 2007, we mailed self-administered questionnaires to all 1574 hospitals with 300 or more beds, and to a random selection of 1000 hospitals with less than 300 beds in addition to 4000 clinics. Responses were received from 812 (51.6%), 504 (50.5%), and 1769 (44.8%), respectively. We asked questions concerning: (i) the extent to which EMR and OES had been introduced; (ii) the reasons why certain institutions had not introduced EMR and (iii) the subjective evaluation of the efficacy and cost-effectiveness of EMR. RESULTS: The percentage of institutions that had introduced EMR as of February 2007 was 10.0% for hospitals and 10.1% for clinics. Even the percentage for hospitals with 400 or more beds was just 31.2%, illustrating that the government's target had not been reached. The most common reason given for not introducing EMR was: "The cost is high" which was observed in 82.0% of hospitals. It was considered that the introduction of EMR could improve 'inter-hospital networks', and 'time efficiency for physicians' by around 45% and 25% of hospitals, respectively. CONCLUSION: Healthcare information computerization in Japan is behind schedule because the introductory costs are high. For the computerization of healthcare information to be further promoted, prices of EMR systems should be lowered to a level which individual hospitals can afford. Furthermore, the communication between EMR systems should be further standardized to secure functional and semantic interoperability in Japan. PMID- 18448384 TI - 1-(2-methoxybenzylidene)-4-phenylthiosemicarbazide as OFF-ON fluorescent chemodosimeter for detection of Cu2+ in acetonitrile-water binary solvents. AB - A novel fluorescent chemodosimeter, 1-(2-methoxybenzylidene)-4 phenylthiolsemicarbazide, was studied. In 90:10 (v/v) mixture of CH3CN and water binary solution, it exhibits high selectivity toward Cu2+ but very low response toward other competitive cations. The Cu2+ promoting cyclization of the thiosemicarbazide to 1,2,4-triazole-3(4H)-thione ring results in observation of the turn-on fluorescence. PMID- 18448386 TI - Validation of a strategy for HCV antibody testing with two enzyme immunoassays in a routine clinical laboratory. AB - BACKGROUND: Centers for Disease Control (CDC) guidelines require confirmation of hepatitis C virus (HCV) screening-test-positive sera with a low signal/cut-off (S/CO) ratio by recombinant immunoblot or PCR. The UK Health Protection Agency has suggested that a second enzyme immunoassay (EIA) could be used as an alternative for confirmation in non-immunocompromised patients. OBJECTIVE: To evaluate the UK HPA approach in 17,936 consecutive in-house sera submitted for HCV testing. STUDY DESIGN: AxSYM-positive sera (S/CO> or =1.0) were tested with Monolisa Plus. AxSYM-positive sera of patients that were confirmed PCR-positive were considered HCV+. All other AxSYM-positive sera were confirmed with immunoblot according to CDC guidelines. RESULTS: 17,299 sera were negative with AxSYM. Of the 637 AxSYM-positive sera, 384 were from patients confirmed as PCR positive. Of other 250 sera, 120 were negative with immunoblot, 103 were positive and 30 were indeterminate. All 30 immunoblot-indeterminate sera were PCR negative. Two patients were Monolisa Plus+ and immunoblot- and PCR-. One patient was known as immunoblot-, while the other patient was diagnosed with non-A non-B hepatitis in 1980s. Nine sera from HCV-positive patients were Monolisa Plus-. Two PCR- sera were from immunocompetent patients who were PCR- for > or =8 years and six PCR- sera and one PCR+ serum were from immunocompromised patients. Sensitivity and specificity of confirmation with Monolisa Plus were 98.15% and 98.33% and the positive and negative predictive values were 99.58% and 92.91% in AxSYM-positive sera (excluding immunoblot-indeterminate/PCR-negative sera). If immunocompromised patients that were false-negative were excluded, sensitivity was 99.58%. CONCLUSION: Monolisa Plus can be used as an alternative to immunoblot for the confirmation of AxSYM-positive sera. PMID- 18448387 TI - Prevalence of hepatitis B virus infection among women at reproductive age at a German university hospital. AB - BACKGROUND: Mother to infant transmission of hepatitis B virus (HBV) represents a major factor in maintaining chronic infection and depends on the degree of maternal infectivity status. OBJECTIVES: To examine the seroprevalence of hepatitis B virus surface antigen (HBsAg) in women at reproductive age admitted to the Department of Gynaecology at a German university hospital. STUDY DESIGN: The seroprevalence of hepatitis B surface antigen (HBsAg) in 5518 women at reproductive age was examined, HBsAg-positive samples were tested for additional HBV markers to verify the infection status. RESULTS: Out of 5518 samples from women at reproductive age, 88 women (1.59%) were positive for HBsAg and 7 of these HBV-positive women (7.95%) were additionally positive for HBeAg. The majority of the study population were German citizens, however most HBV infected persons originated from countries with a high HBV prevalence. The HBV seroprevalence in our study group is about two times higher compared to the average seroprevalence in the German citizen adult population, thus probably resulting in an underestimation of the infection rate in a multinational setting. CONCLUSIONS: Screening for HBsAg during pregnancy is still necessary and important for reduction of perinatal HBV transmission even in countries with low HBV prevalence. PMID- 18448388 TI - Sub-processes of working memory in the N-back task: an investigation using ERPs. AB - OBJECTIVE: The N-back task is frequently used in working memory studies. N parameters allow experimental psychologists to analyze the sub-processes of N back tasks in addition to general processing. However, previous imaging studies have not closely scrutinized these sub-processes. In the current study, three sub processes in the N-back task were proposed using a logical task analysis: matching, replacement and shift. Domain-specific lateralization in spatial and verbal working memory was investigated in terms of this model. METHODS: This model was tested with two ERP experiments during N-back tasks, one conceptual (top-down) and one data-driven (bottom-up). RESULTS: Domain-specific lateralization was observed as predicted in the shift sub-process of the conceptual task and in the replacement sub-process of the data-driven task. Match specific lateralization was also found. CONCLUSIONS: The results support our three-sub-process model of the N-back task and our hypothesis that replacement is a data-driven process with a posterior locus whereas shift is a more conceptual process with a more frontal locus. SIGNIFICANCE: The proposed model correctly predicted ERP patterns in conceptual and data-driven N-back tasks and is potentially useful in understanding the neurophysiologic basis of N-back task performance. The similarity between match- and domain-specific lateralization in N-back tasks raised several issues for further investigation. PMID- 18448389 TI - Electroencephalography burst suppression in a patient with dengue encephalopathy: A case report. AB - OBJECTIVE: To report a rare case of dengue fever presenting with reversible encephalopathy and burst suppression in the EEG. METHODS: We describe an 85-year old man with dengue encephalopathy and EEG burst suppression and review the related literature. RESULTS: The patient presented with an acute comatose state and absent brainstem reflexes. Blood pressure, pulse rate, temperature and oxygen saturation were 94/49mmHg, 82beats/min, 34.7 degrees C, and 83% respectively. Thrombocytopenia and skin rash were found initially. Oxygen saturation was 100% immediately after endotracheal intubation and mechanical ventilation. On the second day he remained comatose with EEG burst suppression but blood pressure and temperature were within normal limits. He regained consciousness and was alert on the 12th day and there was normalization of EEG and thrombocytopenia. CONCLUSIONS: Patients with dengue fever may present as encephalopathy with EEG burst suppression. SIGNIFICANCE: EEG burst suppression does not necessarily suggest a poor prognosis in patients with dengue fever. PMID- 18448390 TI - Immunoregulatory gene polymorphisms are associated with ANCA-related vasculitis. AB - T cell activation is regulated by inhibitory molecules such as PD-1 and CTLA-4, whose expression may be affected by gene polymorphisms. Increased T cell activation is present in patients with ANCA-associated vasculitis (AAV). We investigated two single-nucleotide polymorphisms (SNPs) in PDCD1 and five polymorphisms in CTLA4 in 102 patients with AAV and 188 healthy controls (HC). The distributions of the PD-1.3 and PD-1.5 SNPs, and the distributions of the CTLA4 promoter polymorphisms -1722T/C, -1661A/G, -318 C/T, and the (AT)(n) microsatellite in the 3'-untranslated region of CTLA4, did not differ between patients and HC. However, the +49 G allele was significantly more often present in patients with AAV. Furthermore, the co-occurrence of the PD-1.5 T allele with CTLA4 +49 AA homozygosity (i.e., the absence of a G allele) was less often present in patients compared to HC. These genetic polymorphisms may lead to hyperreactivity of T cells and thus may contribute to the pathogenesis of AAV. PMID- 18448391 TI - Comparing the convergent validity and clinical utility of the Behavior Assessment System for Children-Parent Rating Scales and Child Behavior Checklist in children with epilepsy. AB - The convergent validity and clinical utility of two parent-report child behavior rating scales, the Behavior Assessment System for Children-Parent Rating Scales (BASC-PRS) and Child Behavior Checklist/Ages 6-18 (CBCL), in children with epilepsy were examined. Analogous broadband and narrowband behavior rating scales were evaluated in 60 subjects aged 6-17 years (mean=11.0, SD=3.4) with Full Scale IQ >70. Correlations for each similarly labeled scale were statistically significant (P<0.002) and greater with broadband (r=0.71-0.79) than with narrowband (r=0.41-0.78) scales. The BASC captured significantly less composite internalizing symptoms (P<0.002), but more unusual thought processes (P<0.0002) and attention problems versus a CBCL DSM-oriented attention-deficit/hyperactivity disorder scale (P<0.002). Variation in the correlations between measures may stem from underlying differences between rationally-and empirically-derived approaches to test construction. Both the CBCL and BASC have diagnostic and clinical utility in assessing behavior problems in pediatric epilepsy. PMID- 18448392 TI - Could n-gram analysis contribute to genomic island determination? AB - There are two approaches to identifying genomic and pathogenesis islands (GI/PAIs) in bacterial genomes: the compositional and the functional, based on DNA or protein level composition and gene function, respectively. We applied n gram analysis in addition to other compositional features, combined them by union and intersection and defined two measures for evaluating the results-recall and precision. Using the best criteria (by training on the Escherichia coli O157:H7 EDL933 genome), we predicted GIs for 14 Enterobacteriaceae family members and for 21 randomly selected bacterial genomes. These predictions were compared with results obtained from HGT DB (based on the compositional approach) and PAI DB (based on the combined approach). The results obtained show that intersecting n grams with other compositional features improves relative precision by up to 10% in case of HGT DB and up to 60% in case of PAI DB. In addition, it was demonstrated that the union of all compositional features results in maximum recall (up to 37%). Thus, the application of n-gram analysis alongside existing or newly developed methods may improve the prediction of GI/PAIs. PMID- 18448393 TI - Louisiana (LA) Health: design and methods for a childhood obesity prevention program in rural schools. AB - There is a worldwide epidemic of obesity with far-reaching consequences for the health of our nation. Prevention of obesity, especially in children, has been deemed by public health policy makers to be one of the most important objectives for our country. This prevention project, called Louisiana (LA) Health, will test whether modification of environmental and behavioral factors can prevent inappropriate weight gain in children from rural parishes of Louisiana who are enrolled in the fourth to sixth grades during Year 1. The primary aim of the LA Health project is to test the efficacy of two school-based approaches for obesity prevention: primary prevention alone and a combination of primary and secondary prevention which will be compared to a no-intervention control group using a cluster randomization research design, with 17 school clusters randomly assigned to the three treatment arms. The study will span 3 years and will provide critical tests of strategies that: 1) modify the child's environment as a primary prevention strategy and 2) provide health behavior modification via classroom instruction and internet counseling as a secondary prevention strategy. The study will also recruit a similar sample of students to measure changes in body weight relative to height, gender, and age over the same three-year period. PMID- 18448395 TI - Spatiotemporal organization of frog respiratory neurons visualized on the ventral medullary surface. AB - We visualized the spatiotemporal activity of respiratory-related neurons in the frog using the isolated brainstem spinal cord preparation. We recorded optical signals from the ventral surface of the medulla using a voltage-sensitive dye, and calculated cross-correlations with the integrated respiratory activity of the trigeminal nerve. Lung burst-related depolarizing optical signals were observed bilaterally as longitudinal columns in the ventrolateral medulla between the levels of trigeminal and hypoglossal rootlets, mostly caudal to the vagal rootlet. However, we could not differentiate between neurons involved in rhythm generation and motoneurons. The dye weakened the buccal rhythm and slowed the lung rhythm, which might have influenced the results. Extracellular recording of respiratory neurons verified the optically identified area. Strychnine disrupted the spatiotemporal organization of optical signals, although trigeminal periodic bursts persisted. We conclude that the pattern generator but not the rhythm generator of lung burst in the frog involves glycinergic mechanisms and lies as longitudinal columns in the reticular formation of the ventrolateral medulla. PMID- 18448394 TI - The Fanconi anemia core complex is required for efficient point mutagenesis and Rev1 foci assembly. AB - Fanconi anemia (FA) is a chromosome instability syndrome characterized by congenital abnormalities, cellular hypersensitivity to DNA crosslinking agents, and heightened cancer risk. Eight of the thirteen identified FA genes encode subunits of a nuclear FA core complex that monoubiquitinates FANCD2 and FANCI to maintain genomic stability in response to replication stress. The FA pathway has been implicated in the regulation of error-prone DNA damage tolerance via an undefined molecular mechanism. Here, we show that the FA core complex is required for efficient spontaneous and UVC-induced point mutagenesis, independently of FANCD2 and FANCI. Consistent with the observed hypomutability of cells deficient in the FA core complex, we also demonstrate that these cells are impaired in the assembly of the error-prone translesion DNA synthesis polymerase Rev1 into nuclear foci. Consistent with a role downstream of the FA core complex and like known FA proteins, Rev1 is required to prevent DNA crosslinker-induced chromosomal aberrations in human cells. Interestingly, proliferating cell nuclear antigen (PCNA) monoubiquitination, known to contribute to Rev1 recruitment, does not require FA core complex function. Our results suggest a role for the FA core complex in regulating Rev1-dependent DNA damage tolerance independently of FANCD2, FANCI, and PCNA monoubiquitination. PMID- 18448396 TI - The VO2 response to submaximal ramp cycle exercise: Influence of ramp slope and training status. AB - The aim of the study was to test whether ramp slope and training status interact in the oxygen uptake (VO2) response during submaximal ramp exercise. Eight cyclists (VO2 peak=67.8+/-3.7 ml min(-1)kg(-1)) and eight physically active students (PA students) (VO2 peak=49.1+/-4.3 ml min(-1)kg(-1)) performed several ramp protocols, respectively, 25 and 40 W min(-1) for the cyclists and 10, 25 and 40 W min(-1) for the PA students. Vo(2) was plotted as a function of time and work rate up to the gas exchange threshold (GET). Faster ramp elicited a significantly shorter mean response time (MRT) in both groups, and MRT was significantly longer for each ramp protocol in the PA students (126+/-32s, 76+/ 15s and 50+/-6s for ramp 10, ramp 25 and ramp 40, respectively) compared to the cyclists (61+/-9s and 40+/-11s for ramp 25 and ramp 40, respectively). Ramp 40 showed less steep Delta VO2/Delta W than ramp 25 in both groups (p<0.01) and Delta VO2/Delta W was less steep for each ramp protocol in PA students (p<0.01) (9.82+/-0.30 ml min(-1)W(-1) and 9.33+/-0.45 ml min(-1)W(-1) for ramp 25 and ramp 40, respectively) compared to cyclists (10.31+/-0.40 ml min(-1)W(-1) and 10.05+/ 0.48 ml min(-1)W(-1) for ramp 25 and ramp 40, respectively). In the PA students, Delta VO2/Delta W did not differ between ramp 10 and ramp 25. Statistical analysis showed no interaction effects between ramp slope and training status for MRT (p=0.62) and Delta VO2/Delta W (p=0.35). PMID- 18448397 TI - Circadian changes of D-alanine and related compounds in rats and the effect of restricted feeding on their amounts. AB - The circadian changes of D-alanine (D-Ala), an intrinsic D-amino acid found in mammals, were investigated in rats with diurnal and nocturnal habits, and the profiles were compared to those of L-Ala, other D-amino acids and several hormones. Determination of D-Ala in the rat plasma, pancreas and anterior pituitary gland was carried out using a sensitive and selective two-dimensional HPLC system combining a micro-ODS column and an enantioselective column after fluorescence derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). The amount of D-Ala was high during the sleeping period and low during the active period in rats with both diurnal and nocturnal habits, indicating for the first time that the D-Ala is closely related to the activity rhythm of animals. In contrast, L-Ala and other D-amino acids did not show any clear circadian changes. The circadian change of D-Ala inversely correlated with that of the plasma insulin level in rats with both diurnal and nocturnal habits. Considered together with our previous findings that D-Ala is localized in the insulin secreting beta cells in the rat pancreas, it is strongly suggested that D-Ala has some functional relationships to insulin in mammals. PMID- 18448398 TI - Effect of gonadectomy on HCC development in HBV transgenic mice. AB - BACKGROUND AND AIMS: Epidemiological data demonstrate that HCC is prevalent in men compared to women. Herein, we examined the effect of gonadectomy in a murine model that spontaneously develops HCC. ANIMALS AND METHODS: Thirty-two male and 26 female HBV transgenic mice [Tg (Alb-1 HBV) Bri 44] underwent surgical castration or sham operation. At the 18th month, serum samples were collected and all mice were sacrificed. Liver weight and volume were evaluated, each liver was cut into 1.5-mm-thick consecutive slices and nodules were examined on freshly isolated tissue. Consecutive histological sections obtained from each liver slice were evaluated to confirm the diagnosis of HCC. RESULTS: Sham-operated females showed a significantly lower neoplastic growth compared to sham-operated males. This difference disappeared when females underwent gonadectomy. In males, neoplastic growth was not influenced by gonadectomy. Testosterone and estradiol levels were profoundly modified by gonadectomy in both males and females. The testosterone/estradiol ratio in gonadectomized females increased 4.5-fold compared to that in sham-operated females, becoming more similar to the ratio observed in castrated and sham-operated male mice. CONCLUSIONS: HCC growth in our experimental model was not simply influenced by the levels of testosterone or estradiol, taken singularly, but depended on their ratio. PMID- 18448399 TI - Valve proteoglycan content and glycosaminoglycan fine structure are unique to microstructure, mechanical load and age: Relevance to an age-specific tissue engineered heart valve. AB - This study characterized valve proteoglycan and glycosaminoglycan composition during development and aging. This knowledge is important for the development of age-specific tissue-engineered heart valves as well as treatments for age specific valvulopathies. Aortic valves and mitral valves from first-third trimester, 6-week, 6-month and 6-year-old pigs were examined using immunohistochemistry for versican, biglycan, decorin and hyaluronan, as well as elastin and fibrillin. The fine structure of glycosaminoglycans was examined by fluorophore-assisted carbohydrate electrophoresis. Decorin expression was strongest in the 6-year-old valves, particularly in the aortic valve spongiosa. The quantity of iduronate was also highest in the 6-year-old valves. The central tensile-loading region of the anterior mitral leaflet demonstrated reduced glycosaminoglycan content, chain length and hydration and a larger fraction of 4 sulfated iduronate and lower fraction of 6-sulfation. With age, the anterior leaflet center showed a further increase in 4-sulfated iduronate and decrease in 6-sulfation. In contrast, the anterior leaflet free edge showed decreased iduronate and 4-sulfated glucuronate content with age. The young aortic valve was similar to the mitral valve free edge with a higher concentration of glycosaminoglycans and 6-rather than 4-sulfation, but aged to resemble the mitral anterior leaflet center, with an increase in 4-sulfated iduronate content and a decrease in the 6-sulfation fraction. Elastin and fibrillin often co-localized with the proteoglycans studied, but elastin co-localized most specifically with versican. In conclusion, composition and fine structure changes in valve proteoglycans and glycosaminoglycans with age are complex and distinct within valve type, histological layers and regions of different mechanical loading. PMID- 18448400 TI - Preliminary evaluation of molecular imprinting of 5-fluorouracil within hydrogels for use as drug delivery systems. AB - Molecular imprinting is a new and rapidly evolving technique used to create synthetic receptors and it possesses great potential in a number of applications in the life sciences. Keeping in mind the therapeutic importance of 5 fluorouracil (5-FU) and the technological significance of molecular imprinting polymers, the present study is an attempt to synthesize 2-hydroxyethylmetacrylate and acrylic acid-based 5-FU imprinted hydrogels. For the synthesis of these hydrogels, N,N'-methylenebisacrylamide was used as a crosslinker, ammonium persulfate as an initiator and N,N,N',N'-tetramethylethylenediamine as an accelerator. Both molecular imprinted polymers (MIPs) and non-imprinted polymers were synthesized at the optimum crosslinker concentration obtained from swelling studies and used to study their recognition affinity, their swelling and the in vitro release dynamics of the drug. It was observed from this study that the recognition affinity of MIPs is increased when these are synthesized in a high concentration template solution. PMID- 18448401 TI - Weight loss, ion release and initial mechanical properties of a binary calcium phosphate glass fibre/PCL composite. AB - Composites comprising a biodegradable polymeric matrix and a bioactive filler show considerable promise in the field of regenerative medicine, and could potentially serve as degradable bone fracture fixation devices, depending on the properties obtained. Therefore, glass fibres from a binary calcium phosphate (50P(2)O(5)+50CaO) glass were used to reinforce polycaprolactone, at two different volume fractions (V(f)). As-drawn, non-treated and heat-treated fibres were assessed. Weight loss, ion release and the initial mechanical properties of the fibres and composites produced have been investigated. Single fibre tensile testing revealed a fibre strength of 474MPa and a tensile modulus of 44GPa. Weibull analysis suggested a scale value of 524. The composites yielded flexural strength and modulus of up to 30MPa and 2.5GPa, respectively. These values are comparable with human trabecular bone. An 8% mass loss was seen for the lower V(f) composite, whereas for the two higher V(f) composites an approximate 20% mass loss was observed over the course of the 5week study. A plateau in the degradation profile at 350h indicated that fibre dissolution was complete at this interval. This assertion was further supported via ion release studies. The leaching of fibres from the composite created a porous structure, including continuous channels within the polymer matrix. This offers further scope for tailoring scaffold development, as cells from the surrounding tissue may be induced to migrate into the resulting porous matrix. PMID- 18448402 TI - Mechanical properties of tricalcium phosphate single crystals grown by molten salt synthesis. AB - Mechanical properties of flux-grown tricalcium phosphate (TCP) single crystals ranging in size from 50 to 75microm have been characterized by performing micro- and nanoindentation on their facets. Notwithstanding the inherent brittleness and anisotropy, these single crystals exhibit nanoscale plasticity in the form of pile-up around the edges of indents. A similar plastic response was observed in hydroxyapatite (HA) single crystals during nanoindentation in an earlier study. The hardness and elastic modulus obtained during nanoindentation are discussed in comparison with the polycrystalline forms of both TCP and HA found in the literature. The indentation fracture toughness values of TCP single crystals were found to be higher than those of HA single crystals. The higher values are attributed not only to the difference in crystal structure and corresponding differences in surface energy, but also to extensive crack bridging by ligament formation across crack faces during crack propagation. PMID- 18448403 TI - The evolution of burn fluid resuscitation. AB - This article reviews the important developments, recent and historical, in burn fluid resuscitation. Modern managements, debates, and research directions are discussed, with a key question of how to transcend the current therapeutic plateau. PMID- 18448404 TI - Managing death and end of life decisions in perinatal medicine. PMID- 18448405 TI - The obesity imperative: lessons learned. PMID- 18448406 TI - A new flap design for tongue reconstruction after total or subtotal glossectomy in thin patients. AB - OBJECTIVE: For tongue reconstruction after total or subtotal glossectomy, a rectus abdominis musculocutaneous flap is often used to obtain sufficient flap volume. However, thin patients often have too little fat tissue to ensure adequate flap volume. For this reason we developed a new flap design to compensate for insufficient flap volume in thin patients. METHODS: In this series, total or subtotal glossectomy was performed in 20 thin men with a mean age of 58.3 years. The patients had a mean body mass index of 18.22 kg/m(2) and most were considered emaciated. The defects were reconstructed using a rectus abdominis musculocutaneous flap with two skin islands. The first skin island was used to reconstruct the mucosal defect, and the second was de-epithelialised and used to increase flap volume. RESULTS: Flaps were transferred successfully in 19 out of 20 patients. Most patients could tolerate more than a soft diet without severe aspiration and could engage in conversation. However, four patients required total laryngectomy or a permanent stoma owing to severe aspiration. In this series, the larynx could be preserved in 80% of thin patients, and satisfactory postoperative oral function was obtained. CONCLUSION: The most important point for obtaining satisfactory oral function is to reconstruct a tongue with a protuberant shape and sufficient volume. We could maintain sufficient flap volume with the de-epithelialised skin island of a rectus abdominis musculocutaneous free flap. We believe our new flap design is effective for tongue reconstruction in thin patients. PMID- 18448408 TI - Alar groove plasty using a subcutaneous flap technique in bulbous nose repair after cleft lip plasty. AB - BACKGROUND: Bulbous nose is a ball-like nasal deformity, frequently seen in postoperative cleft lip patients, that is hard to prevent despite numerous techniques available for nasal tip plasty. Here we describe a new method for correcting bulbous nose in cleft lip patients by creating an ideal alar groove. METHODS: A subcutaneous flap with the pedicle of the overlying skin connected circumferentially is made just beneath the position for the ideal alar groove. The subcutaneous flap is fixed to the septum cartilage to create the alar groove depression on the nasal tip. This method is generally performed in conjunction with other rhinoplasty using the open nasal approach. RESULTS: Three postoperative cleft lip and nose patients underwent alar groove plasty combined with rhinoplasty. All retained good contour after the operation. CONCLUSION: Alar groove plasty using the subcutaneous flap technique improves bulbous nose deformities of cleft lip patients and can retain good postoperative contour. PMID- 18448409 TI - The ideal rotation flap: an experimental study. AB - BACKGROUND/PURPOSE: Numerous modifications exist and opinions vary between surgeons with regard to the design of the ideal rotation flap. A literature review revealed inconsistencies as well as three different designs of rotation flap (standard rotation flap, Ahuja's modified rotation flap, divine rotation flap) based on entirely different concepts. It is not clear which of these designs serves its purpose best in wound reconstruction since they have not been previously examined experimentally and directly compared. The aim of this study is to determine the optimal rotation flap design in wound reconstruction. Several modifications of the standard rotation flap are examined and the three different rotation flap designs are directly compared. METHODS: This study tests the ability of various rotation flaps to close triangulated defects on sheets of neoprene, a synthetic rubber compound. Section A examines four important features in the design of the standard rotation flap: triangulation of a lesion, rotation flap circumference, pivot point and the back cut. Section B compares the standard rotation flap, Ahuja's modified rotation flap and the divine rotation flap. Tension resulting from wound closure is measured and the length of scar calculated. RESULTS/CONCLUSION: The standard rotation flap remains superior in comparison to the modified rotation flap and the divine rotation flap. Triangulation of a lesion should be performed with care and, in particular, the apex of the triangle should coincide with the geometrical pivot point. A flap circumference more than five times the width of the defect is of minimal benefit. The back cut is an effective modification and should be used if necessary. PMID- 18448410 TI - Giant thoracic neurofibromatosis type 1 with massive intratumoral haemorrhage: a case report. AB - A 44-year-old man known to have neurofibromatosis type 1 (NF1) presented with an acute enlargement of a long-standing pedunculated thoracic mass and a 4.5 kg weight gain. He was recently treated with anticoagulation for a newly diagnosed atrial fibrillation. Intratumoral bleed was thus suspected to explain the sudden enlargement. Chest computerised tomography confirmed the presence of a large extrathoracic tumour of soft tissue density compatible with a diagnosis of neurofibromatosis and a recent massive intratumoral haematoma. Perioperative angiography demonstrated remarkable hypervascularity. The treatment plan involved embolisation and surgical resection. The histological specimen confirmed a diagnosis of neurofibromatosis type I without malignant transformation. Neurofibromatosis associated with an intratumoral haemorrhage is rare. This is the first scientific report of a massive intratumoral bleed in NF1 subsequent to anticoagulant administration. Anticoagulation should be monitored very closely in neurofibromatosis patients due to their propensity to bleed secondary to the abnormal vascular intima. PMID- 18448411 TI - [Contribution of monogenic hypertension models to understanding of other hypertensions]. AB - Therapeutic control of primary or secondary hypertension remains insufficient because of the presence of individual phenotypic variations of factors acting on sodium excretion and vasoconstriction. The study of monogenic models of hypertension allows to highlight some genetic mutations, mainly responsible of sodium regulation. In some cases, polymorphisms of such genes are found with an increased frequency in hypertensive patients. Each polymorphism by itself is not sufficient to cause hypertension, but their accumulation in a patient increases the hypertensive risk in primary or secondary hypertension. Understanding familial hyperaldosteronism type 1, Liddle or Ulick syndrome, activating mutations of mineralocorticoide receptor or Gordon syndrome give indications on pathophysiology of primary hypertension. Study of some mitochondrial defects or of genes implicated in renal dysplasia also seems interesting area of research. In the future, search for such mechanisms would allow a rational and oriented use of diuretics and antihypertensive therapies. PMID- 18448412 TI - [SDIALOR: a dialysis patient satisfaction questionnaire]. AB - AIMS: To develop and evaluate the psychometric properties of a dialysis satisfaction questionnaire in the French language. METHODS: Firstly the translation and adaptation to French context in cooperation with dialysis patients and nephrologists. The satisfaction questionnaire was built using items banking, based on the Choice Satisfaction Questionnaire and Satisfaction of Patients in Chronic Dialysis (SEQUS((R))). The tool, named SDIALOR, was comprised of 41 items. Satisfaction scores are standardized from 0 (poor) to 100 (excellent). Secondly, the estimation of the questionnaire's psychometric properties. This work was realized in the Nephrolor network. The sample consisted in all of 1008 adults, prevalent patients, treated in the 12 dialysis structures of the Lorraine region on the 1st February 2004. All of them were mailed a questionnaire. RESULTS: Response rate was 44.3%. Mean age of patients was 65.9 years; 67% were men and 61% retired. Mean length of dialysis was 4.5 years. Women, residents of the Meurthe and Moselle region, patients having a diabetes, having a low haemoglobin level returned the questionnaires less frequently than the other patients (p<0.05). Principal components analysis evidenced seven specific dimensions, in addition to the overall satisfaction dimension. Cronbach's alpha coefficients were greater than 0.73 for five dimensions, but "relation between nephrologist and GP" dimension (0.54). Mean scores of satisfaction varied from 53.9 ("relation between nephrologists and GP") to 74.1 ("overall satisfaction"). Older patients tended to more satisfied than the younger ones. Global satisfaction was significantly higher in peritoneal dialyses (81.7), in hemodialysis at residence (83.1) compared with that in autodialyse (70.9) and in hemodialysis at center (73.3). A significant variability from one care team to another was evidenced. CONCLUSIONS: Our study proves the feasibility of satisfaction measurement at the dialyzed patient. Dialysis Patient Satisfaction Questionnaire in the French version exhibits satisfying psychometric properties. The level of satisfaction is better in peritoneal dialysis and differs according to medical care centers. PMID- 18448413 TI - Correlates of bone mineral density among postmenopausal women of African Caribbean ancestry: Tobago women's health study. AB - Population dynamics predict a drastic growth in the number of older minority women, and resultant increases in the number of fractures. Low bone mineral density (BMD) is an important risk factor for fracture. Many studies have identified the lifestyle and health-related factors that correlate with BMD in Whites. Few studies have focused on non-Whites. The objective of the current analyses is to examine the lifestyle, anthropometric and health-related factors that are correlated with BMD in a population based cohort of Caribbean women of West African ancestry. We enrolled 340 postmenopausal women residing on the Caribbean Island of Tobago. Participants completed a questionnaire and had anthropometric measures taken. Hip BMD was measured by DXA. We estimated volumetric BMD by calculating bone mineral apparent density (BMAD). BMD was >10% and >25% higher across all age groups in Tobagonian women compared to US non Hispanic Black and White women, respectively. In multiple linear regression models, 35-36% of the variability in femoral neck and total hip BMD respectively was predicted. Each 16-kg (one standard deviation (SD)) increase in weight was associated with 5% higher BMD; and weight explained over 10% of the variability of BMD. Each 8-year (1 SD) increase in age was associated with 5% lower BMD. Current use of both thiazide diuretics and oral hypoglycemic medication were associated with 4-5% higher BMD. For femoral neck BMAD, 26% of the variability was explained by a multiple linear regression model. Current statin use was associated with 5% higher BMAD and a history of breast feeding or coronary heart disease was associated with 1-1.5% of higher BMAD. In conclusion, African Caribbean women have the highest BMD on a population level reported to date for women. This may reflect low European admixture. Correlates of BMD among Caribbean women of West African ancestry were similar to those reported for U.S. Black and White women. PMID- 18448414 TI - Poor condition and infection: a vicious circle in natural populations. AB - Pathogens may be important for host population dynamics, as they can be a proximate cause of morbidity and mortality. Infection dynamics, in turn, may be dependent on the underlying condition of hosts. There is a clear potential for synergy between infection and condition: poor condition predisposes to host infections, which further reduce condition and so on. To provide empirical data that support this notion, we measured haematological indicators of infection (neutrophils and monocytes) and condition (red blood cells (RBCs) and lymphocytes) in field voles from three populations sampled monthly for 2 years. Mixed-effect models were developed to evaluate two hypotheses, (i) that individuals with low lymphocyte and/or RBC levels are more prone to show elevated haematological indicators of infection when re-sampled four weeks later, and (ii) that a decline in indicators of condition is likely to follow the development of monocytosis or neutrophilia. We found that individuals with low RBC and lymphocyte counts had increased probabilities of developing monocytosis and higher increments in neutrophils, and that high indices of infection (neutrophilia and monocytosis) were generally followed by a declining tendency in the indicators of condition (RBCs and lymphocytes). The vicious circle that these results describe suggests that while pathogens overall may be more important in wildlife dynamics than has previously been appreciated, specific pathogens are likely to play their part as elements of an interactive web rather than independent entities. PMID- 18448416 TI - Orientation of eddy fluxes in geostrophic turbulence. AB - Given its importance in parametrizing eddies, we consider the orientation of eddy flux of potential vorticity (PV) in geostrophic turbulence. We take two different points of view, a classical ensemble- or time-average point of view and a second scale decomposition point of view. A net alignment of the eddy flux of PV with the appropriate mean gradient or the large-scale gradient of PV is required. However, we find this alignment to be very weak. A key finding of our study is that in the scale decomposition approach, there is a strong correlation between the eddy flux and a nonlinear combination of resolved gradients. This strong correlation is absent in the classical decomposition. This finding points to a new model to parametrize the effects of eddies in global ocean circulation. PMID- 18448415 TI - Encoding choosiness: female attraction requires prior physical contact with individual male scents in mice. AB - Scents, detected through both the main and vomeronasal olfactory systems, play a crucial role in regulating reproductive behaviour in many mammals. In laboratory mice, female preference for airborne urinary scents from males (detected through the main olfactory system) is learnt through association with scents detected through the vomeronasal system during contact with the scent source. This may reflect a more complex assessment of individual males than that implied by laboratory mouse studies in which individual variation has largely been eliminated. To test this, we assessed female preference between male and female urine using wild house mice with natural individual genetic variation in urinary identity signals. We confirm that females exhibit a general preference for male over female urine when able to contact urine scents. However, they are only attracted to airborne urinary volatiles from individual males whose urine they have previously contacted. Even females with a natural exposure to many individuals of both sexes fail to develop generalized attraction to airborne male scents. This implies that information gained through contact with a specific male's scent is essential to stimulate attraction, providing a new perspective on the cues and olfactory pathways involved in sex recognition and mate assessment in rodents. PMID- 18448417 TI - Peer-group and price influence students drinking along with planned behaviour. AB - AIMS: To examine the theory of planned behaviour (TPB), as a framework for explaining binge drinking among young adults. METHODS: One hundred and seventy eight students in a cross-sectional design study completed self-report questionnaires examining attitudes to drinking, intention to drink and drinking behaviour in university. Binge drinking was defined for females (and males) as consuming 'four (males-five) or more pints of beer/glasses of wine/measures of spirits' in a single session. RESULTS: Drinking alcohol was common; 39.6% of males and 35.9% of females reported binge drinking. The TPB explained 7% of the variance in intention to drink. Overall, 43% of the variance in intention, 83% of the variance in total weekly consumption and 44% of the variance in binge drinking was explained. The frequency of drinking and the drinking behaviour of friends significantly predicted intention to drink and binge drinking, respectively. Binge drinkers were influenced by peers and social-situational factors. Pressure to drink was greater for males; undergraduates were influenced by the size of the drinking group, 'special offer' prices, and the availability of alcohol. CONCLUSIONS: The TPB appeared to be a weak predictor of student drinking but this may be a result of how constructs were measured. With friends' drinking behaviour emerging as a significant predictor of alcohol consumption, interventions seeking to reduce excessive drinking should target the role of peers and the university environment in which drinking occurs. PMID- 18448418 TI - Premedication with pregabalin 75 or 150 mg with ibuprofen to control pain after day-case gynaecological laparoscopic surgery. AB - BACKGROUND: Multimodal pain management has been suggested to improve postoperative analgesia. In this study, we evaluated the quality of analgesia in women undergoing day-case gynaecological laparoscopic surgery, after premedication with pregabalin 75 mg (P75) or 150 mg (P150), compared with diazepam 5 mg (D5). All patients were given ibuprofen 800 mg orally. METHODS: Altogether 90 consenting women were anaesthetized in a standardized fashion. Postoperative analgesia was provided by ibuprofen 800 mg twice a day with fentanyl i.v. on request in the recovery room (RR), and combination tablets with acetaminophen and codeine after the RR. The visual analogue scale (VAS) scores for pain and side-effects and the amounts of postoperative analgesics were recorded for 24 h after surgery. The areas under the curves (AUC) were calculated for the VAS scores for pain at rest, pain in motion, and pain at cough 1-8 and 1 24 h after surgery. RESULTS: The median AUC values for VAS scores for pain at rest (P=0.048) and in motion (P=0.046) 1-8 h after surgery were lower in the P150 group than that in the D5 group. The amounts of rescue analgesics or the degree of drowsiness did not differ in the three study groups. CONCLUSIONS: Analgesia was better after premedication with pregabalin 150 mg than after diazepam 5 mg, both with ibuprofen 800 mg, during the early recovery after day-case gynaecological laparoscopic surgery. Pregabalin 150 mg did not reduce the amount of postoperative analgesics required. PMID- 18448420 TI - A novel chromatographic method allows on-line reanalysis of the proteome. AB - Liquid chromatography combined with electrospray ionization is widely used for direct analysis of polar and labile molecules by LCMS. The on-line coupling in LCMS is a major strength but also causes a principal limitation that each eluting analyte has to be analyzed immediately and is not available for detailed interrogation after the LCMS run. Here we developed a new chromatographic strategy, which removes this limitation. After column separation the flow is split, one portion is analyzed directly, and the other is diverted to a capture capillary. After the direct LCMS run, the flow is switched, and the portion stored in the capillary is analyzed ("replay run"). We describe a setup consisting of an analytical column, a splitting valve, and a focusing column, which performs at full sensitivity and undiminished chromatographic resolution. We demonstrate three principal advantages of this system: nearly continuous MS utilization, duplicate analysis without requirement for additional sample, and targeting of important but undersampled features in the replay run. PMID- 18448419 TI - The identification of potential factors associated with the development of type 2 diabetes: a quantitative proteomics approach. AB - Type 2 diabetes (T2D) arises when pancreatic beta-cells fail to compensate for systemic insulin resistance with appropriate insulin secretion. However, the link between insulin resistance and beta-cell failure in T2D is not fully understood. To explore this association, we studied transgenic MKR mice that initially develop insulin resistance in skeletal muscle but by 8 weeks of age have T2D. In the present study, global islet protein and gene expression changes were characterized in diabetic MKR versus non-diabetic control mice at 10 weeks of age. Using a quantitative proteomics approach (isobaric tags for relative and absolute quantification (iTRAQ)), 159 proteins were differentially expressed in MKR compared with control islets. Marked up-regulation of protein biosynthesis and endoplasmic reticulum stress pathways and parallel down-regulation in insulin processing/secretion, energy utilization, and metabolism were observed. A fraction of the differentially expressed proteins identified (including GLUT2, DNAJC3, VAMP2, RAB3A, and PC1/3) were linked previously to insulin-secretory defects and T2D. However, many proteins for the first time were associated with islet dysfunction, including the unfolded protein response proteins (ERP72, ERP44, ERP29, PPIB, FKBP2, FKBP11, and DNAJB11), endoplasmic reticulum-associated degradation proteins (VCP and UFM1), and multiple proteins associated with mitochondrial energy metabolism (NDUFA9, UQCRH, COX2, COX4I1, COX5A, ATP6V1B2, ATP6V1H, ANT1, ANT2, ETFA, and ETFB). The mRNA expression level corresponding to these proteins was examined by microarray, and then a small subset was validated using quantitative real time PCR and Western blot analyses. Importantly approximately 54% of differentially expressed proteins in MKR islets (including proteins involved in proinsulin processing, protein biosynthesis, and mitochondrial oxidation) showed changes in the proteome but not transcriptome, suggesting post-transcriptional regulation. These results underscore the importance of integrated mRNA and protein expression measurements and validate the use of the iTRAQ method combined with microarray to assess global protein and gene changes involved in the development of T2D. PMID- 18448423 TI - QRS alternans and cycle length oscillation during narrow QRS tachycardia. PMID- 18448421 TI - A generic approach for the purification of signaling complexes that specifically interact with the carboxyl-terminal domain of G protein-coupled receptors. AB - G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and are major drug targets. Recent progress has shown that GPCRs are part of large protein complexes that regulate their activity. We present here a generic approach for identification of these complexes that is based on the use of receptor subdomains and that overcomes the limitations of currently used genetics and proteomics approaches. Our approach consists of a carefully balanced combination of chemically synthesized His6-tagged baits, immobilized metal affinity chromatography, one- and two-dimensional gel electrophoresis separation and mass spectrometric identification. The carboxyl-terminal tails (C-tails) of the human MT1 and MT2 melatonin receptors, two class A GPCRs, were used as models to purify protein complexes from mouse brain lysates. We identified 32 proteins that interacted with the C-tail of MT1, 14 proteins that interacted with the C tail of MT2, and eight proteins that interacted with both C-tails. Several randomly selected proteins were validated by Western blotting, and the functional relevance of our data was further confirmed by showing the interaction between the full-length MT1 and the regulator of G protein signaling Z1 in transfected HEK 293 cells and native tissue. Taken together, we have established an integrated and generic purification strategy for the identification of high quality and functionally relevant GPCR-associated protein complexes that significantly widens the repertoire of available techniques. PMID- 18448424 TI - Patient- and lead-related factors affecting lead fracture in children with transvenous permanent pacemaker. AB - AIMS: Fracture in transvenous pacing leads is one of the most common reasons for lead abandonment. Although the factors affecting lead failure rates have been investigated, there is no study evaluating the clinical parameters that affect lead fracture in children. We report our experience with lead fracture in children with transvenous pacemakers. METHODS AND RESULTS: The follow-up results of 264 leads from 184 patients were evaluated using pacemaker follow-up data. Underlying conditions, implant data, and lead features were evaluated for the analysis of lead fracture. During a mean follow-up of 72.8 +/- 39.7 months (range 3.2-160.6, median 70), lead fracture developed in 19 leads (7.2%) from 18 patients. The mean duration between implantation and lead fracture was 57.3 +/- 35 months (range 6.8-130, median 51). All fractures occurred in the leads implanted by the infraclavicular subclavian approach. Cumulative survival at the end of 5 years was 92.7% in terms of lead fracture. None of the patient-related risk factors correlated with lead fracture. Multivariate analyses of lead-related risk factors revealed a significant correlation only between lead fracture and fixation mechanism (P < 0.05). CONCLUSION: Our results indicated that none of the patient-related risk factors was correlated with lead fracture. Among lead related risk factors, only the fixation mechanism was found to be correlated with lead fracture; thus, it seems that passive fixation mechanism is safer in terms of lead fracture. Although all fractures occurred in the leads implanted by the intrathoracic subclavian approach, statistical analysis revealed no significance for this parameter. The effect of the extrathoracic approach should be investigated in a large group of patients. PMID- 18448425 TI - Protease-activated receptor-2 increases exocytosis via multiple signal transduction pathways in pancreatic duct epithelial cells. AB - Protease-activated receptor-2 (PAR-2) is activated when trypsin cleaves its NH(2) terminus to expose a tethered ligand. We previously demonstrated that PAR-2 activates ion channels in pancreatic duct epithelial cells (PDEC). Using real time optical fluorescent probes, cyan fluorescence protein-Epac1-yellow fluorescence protein for cAMP, PH(PLC-delta1)-enhanced green fluorescent protein for phosphatidylinositol 4,5-bisphosphate, and protein kinase Cgamma (PKCgamma) C1-yellow fluorescence protein for diacylglycerol, we now define the signaling pathways mediating PAR-2 effect in dog PDEC. Although PAR-2 activation does not stimulate a cAMP increase, it induces phospholipase C to hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol. Intracellular Ca(2+) mobilization from inositol 1,4,5 trisphosphate-sensitive Ca(2+) stores and a subsequent Ca(2+) influx through store-operated Ca(2+) channels cause a biphasic increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), measured with Indo-1 dye. Single-cell amperometry demonstrated that this increase in [Ca(2+)](i) in turn causes a biphasic increase in exocytosis. A protein kinase assay revealed that trypsin also activates PKC isozymes to stimulate additional exocytosis. Paralleling the increased exocytosis, mucin secretion from PDEC was also induced by trypsin or the PAR-2 activating peptide. Consistent with the serosal localization of PAR-2, 1 microm luminal trypsin did not induce exocytosis in polarized PDEC monolayers; on the other hand, 10 microm trypsin at 37 degrees C damaged the epithelial barrier sufficiently so that it could reach and activate the serosal PAR-2 to stimulate exocytosis. Thus, in PDEC, PAR-2 activation increases [Ca(2+)](i) and activates PKC to stimulate exocytosis and mucin secretion. These functions may mediate the reported protective role of PAR-2 in different models of pancreatitis. PMID- 18448426 TI - Perturbation of the tRNA tertiary core differentially affects specific steps of the elongation cycle. AB - The tRNA tertiary core region is important for both tRNA stability and activity in the translation elongation cycle. Here we report the effects of mutating each of two highly conserved base pairs in the tertiary core of Phe-tRNA(Phe), 18-55 and 19-56, on rate and equilibrium constants for specific steps of this cycle, beginning with formation of aminoacyl-tRNA.EF-Tu.GTP ternary complexs and culminating with translocation of A-site-bound peptidyl-tRNA into the P-site. We find that codon-dependent binding of aminoacyl-tRNA to the A/T-site and proofreading of near-cognate tRNA are sensitive to perturbation of either base pair; formation of the ternary complex and accommodation from the A/T to the A site are sensitive to 18-55 perturbation only, and translocation of peptidyl-tRNA from the A- to P-site is insensitive to perturbation of either. These results underline the importance of the core region in promoting the efficiency and accuracy of translation, and they likely reflect different requirements for structural integrity of the core during specific steps of the elongation cycle. PMID- 18448427 TI - A conserved proliferating cell nuclear antigen-interacting protein sequence in Chk1 is required for checkpoint function. AB - Human checkpoint kinase 1 (Chk1) is an essential kinase required for cell cycle checkpoints and for coordination of DNA synthesis. To gain insight into the mechanisms by which Chk1 carries out these functions, we used mass spectrometry to identify previously uncharacterized interacting partners of Chk1. We describe a novel interaction between Chk1 and proliferating cell nuclear antigen (PCNA), an essential component of the replication machinery. Binding between Chk1 and PCNA was reduced in the presence of hydroxyurea, suggesting that the interaction is regulated by replication stress. A highly conserved PCNA-interacting protein (PIP) box motif was identified in Chk1. The intact PIP box is required for efficient DNA damage-induced phosphorylation and release of activated Chk1 from chromatin. We find that the PIP box of Chk1 is crucial for Chk1-mediated S-M and G(2)-M checkpoint responses. In addition, we show that mutations in the PIP box of Chk1 lead to decreased rates of replication fork progression and increased aberrant replication. These findings suggest an additional mechanism by which essential components of the DNA replication machinery interact with the replication checkpoint apparatus. PMID- 18448429 TI - The Human RecQ helicases, BLM and RECQ1, display distinct DNA substrate specificities. AB - RecQ helicases maintain chromosome stability by resolving a number of highly specific DNA structures that would otherwise impede the correct transmission of genetic information. Previous studies have shown that two human RecQ helicases, BLM and WRN, have very similar substrate specificities and preferentially unwind noncanonical DNA structures, such as synthetic Holliday junctions and G quadruplex DNA. Here, we extend this analysis of BLM to include new substrates and have compared the substrate specificity of BLM with that of another human RecQ helicase, RECQ1. Our findings show that RECQ1 has a distinct substrate specificity compared with BLM. In particular, RECQ1 cannot unwind G-quadruplexes or RNA-DNA hybrid structures, even in the presence of the single-stranded binding protein, human replication protein A, that stimulates its DNA helicase activity. Moreover, RECQ1 cannot substitute for BLM in the regression of a model replication fork and is very inefficient in displacing plasmid D-loops lacking a 3'-tail. Conversely, RECQ1, but not BLM, is able to resolve immobile Holliday junction structures lacking an homologous core, even in the absence of human replication protein A. Mutagenesis studies show that the N-terminal region (residues 1-56) of RECQ1 is necessary both for protein oligomerization and for this Holliday junction disruption activity. These results suggest that the N terminal domain or the higher order oligomer formation promoted by the N terminus is essential for the ability of RECQ1 to disrupt Holliday junctions. Collectively, our findings highlight several differences between the substrate specificities of RECQ1 and BLM (and by inference WRN) and suggest that these enzymes play nonoverlapping functions in cells. PMID- 18448428 TI - SDF-1alpha promotes invasion of head and neck squamous cell carcinoma by activating NF-kappaB. AB - CXCL12/stromal cell-derived factor-1alpha (SDF-1alpha), a chemokine ligand for the G protein-coupled receptor CXCR4, plays an important role in the directed movement of cells. Many studies have documented the importance of CXCR4 in tumor progression and organ-specific metastasis. Recently, several studies have implicated a role for SDF-1alpha in head and neck squamous cell carcinoma (HNSCC) metastasis, but currently there is little information about how SDF-1alpha promotes HNSCC metastasis. In this report we show that the NF-kappaB signaling pathway is activated in response to SDF-1alpha in HNSCC while primary and immortalized keratinocytes show no SDF-1alpha-mediated NF-kappaB activity. We found that SDF-1alpha-mediated NF-kappaB signaling is independent of phosphoinositide 3-kinase/Akt and ERK/MAPK pathways. We observed that SDF-1alpha induces IkappaBalpha phosphorylation and degradation and the nuclear translocation of NF-kappaB in HNSCC cell lines, suggesting that SDF-1alpha activates the classical NF-kappaB signaling pathway. Contrary to previous reports, SDF-1alpha-induced NF-kappaB activation is not mediated by tumor necrosis factor alpha. Furthermore, blocking the NF-kappaB signaling pathway with an IKKbeta inhibitor significantly reduces SDF-1alpha-mediated HNSCC invasion. Taken together, our data suggest SDF-1alpha/CXCR4 may promote HNSCC invasion and metastasis by activating NF-kappaB and that targeting NF-kappaB may provide therapeutic opportunities in preventing HNSCC metastasis mediated by SDF-1alpha. PMID- 18448430 TI - The structure and interactions of the proline-rich domain of ASPP2. AB - ASPP2 is a pro-apoptotic protein that stimulates the p53-mediated apoptotic response. The C terminus of ASPP2 contains ankyrin (Ank) repeats and a SH3 domain, which mediate its interactions with numerous partner proteins such as p53, NFkappaB, and Bcl-2. It also contains a proline-rich domain (ASPP2 Pro), whose structure and function are unclear. Here we used biophysical and biochemical methods to study the structure and the interactions of ASPP2 Pro, to gain insight into its biological role. We show, using biophysical and computational methods, that the ASPP2 Pro domain is natively unfolded. We found that the ASPP2 Pro domain interacts with the ASPP2 Ank-SH3 domains, and mapped the interaction sites in both domains. Using a combination of peptide array screening, biophysical and biochemical techniques, we found that ASPP2 Ank-SH3, but not ASPP2 Pro, mediates interactions of ASPP2 with peptides derived from its partner proteins. ASPP2 Pro-Ank-SH3 bound a peptide derived from its partner protein NFkappaB weaker than ASPP2 Ank-SH3 bound this peptide. This suggested that the presence of the proline-rich domain inhibited the interactions mediated by the Ank-SH3 domains. Furthermore, a peptide from ASPP2 Pro competed with a peptide derived from NFkappaB on binding to ASPP2 Ank-SH3. Based on our results, we propose a model in which the interaction between the ASPP2 domains regulates the intermolecular interactions of ASPP2 with its partner proteins. PMID- 18448431 TI - GIT1 paxillin-binding domain is a four-helix bundle, and it binds to both paxillin LD2 and LD4 motifs. AB - The G protein-coupled receptor kinase-interacting protein 1 (GIT1) is a multidomain protein that plays an important role in cell adhesion, motility, cytoskeletal remodeling, and membrane trafficking. GIT1 mediates the localization of the p21-activated kinase (PAK) and PAK-interactive exchange factor to focal adhesions, and its activation is regulated by the interaction between its C terminal paxillin-binding domain (PBD) and the LD motifs of paxillin. In this study, we determined the solution structure of rat GIT1 PBD by NMR spectroscopy. The PBD folds into a four-helix bundle, which is structurally similar to the focal adhesion targeting and vinculin tail domains. Previous studies showed that GIT1 interacts with paxillin through the LD4 motif. Here, we demonstrated that in addition to the LD4 motif, the GIT1 PBD can also bind to the paxillin LD2 motif, and both LD2 and LD4 motifs competitively target the same site on the PBD surface. We also revealed that paxillin Ser(272) phosphorylation does not influence GIT1 PBD binding in vitro. These results are in agreement with the notion that phosphorylation of paxillin Ser(272) plays an essential role in regulating focal adhesion turnover. PMID- 18448432 TI - Identification of a new motif required for the 3'-5' exonuclease activity of Escherichia coli DNA polymerase I (Klenow fragment): the RRRY motif is necessary for the binding of single-stranded DNA substrate and the template strand of the mismatched duplex. AB - The Klenow fragment of Escherichia coli DNA polymerase I houses catalytic centers for both polymerase and 3'-5' exonuclease activities that are separated by about 35 A. Upon the incorporation of a mismatched nucleotide, the primer terminus is transferred from the polymerase site to an exonuclease site designed for excision of the mismatched nucleotides. The structural comparison of the binary complexes of DNA polymerases in the polymerase and the exonuclease modes, together with a molecular modeling of the template strand overhang in Klenow fragment, indicated its binding in the region spanning residues 821-824. Since these residues are conserved in the "A" family DNA polymerases, we have designated this region as the RRRY motif. The alanine substitution of individual amino acid residues of this motif did not change the polymerase activity; however, the 3'-5' exonuclease activity was reduced 2-29-fold, depending upon the site of mutation. The R821A and R822A/Y824A mutant enzymes showed maximum cleavage defect with single stranded DNA, mainly due to a large decrease in the ssDNA binding affinity of these enzymes. Mismatch removal by these enzymes was only moderately affected. However, data from the exonuclease-polymerase balance assays with mismatched template-primer suggest that the mutant enzymes are defective in switching mismatched primer from the polymerase to the exonuclease site. Thus, the RRRY motif provides a binding track for substrate ssDNA and for nonsubstrate single stranded template overhang, in a polarity-dependent manner. This binding then facilitates cleavage of the substrate at the exonuclease site. PMID- 18448433 TI - The transfer of heavy chains from bikunin proteins to hyaluronan requires both TSG-6 and HC2. AB - Tumor necrosis factor-stimulated gene-6 protein (TSG-6) is involved in the transfer of heavy chains (HCs) from inter-alpha-inhibitor (IalphaI), pre-alpha inhibitor, and as shown here HC2.bikunin to hyaluronan through the formation of covalent HC.TSG-6 intermediates. In contrast to IalphaI and HC2.bikunin, pre alpha-inhibitor does not form a covalent complex in vitro using purified proteins but needs the presence of another factor (Rugg, M. S., Willis, A. C., Mukhopadhyay, D., Hascall, V. C., Fries, E., Fulop, C., Milner, C. M., and Day, A. J. (2005) J. Biol. Chem. 280, 25674-25686). In the present study we purified the required component from human plasma and identified it as HC2. Proteins containing HC2 including IalphaI, HC2.bikunin, and free HC2 promoted the formation of HC3.TSG-6 and subsequently HC3.hyaluronan complexes. HC1 or HC3 did not possess this activity. The presented data reveal that both HC2 and TSG-6 are required for the transesterification reactions to occur. PMID- 18448434 TI - The Cdc42 effector IRSp53 generates filopodia by coupling membrane protrusion with actin dynamics. AB - The Cdc42 effector IRSp53 is a strong inducer of filopodia formation and consists of an Src homology domain 3 (SH3), a potential WW-binding motif, a partial Cdc42/Rac interacting binding region motif, and an Inverse-Bin-Amphiphysins-Rvs (I-BAR) domain. We show that IRSp53 interacts directly with neuronal Wiskott Aldrich syndrome protein (N-WASP) via its SH3 domain and furthermore that N-WASP is required for filopodia formation as IRSp53 failed to induce filopodia formation in N-WASP knock-out (KO) fibroblasts. IRSp53-induced filopodia formation can be reconstituted in N-WASP KO fibroblasts by full-length N-WASP, by N-WASPDeltaWA (a mutant unable to activate the Arp2/3 complex), and by N WASPH208D (a mutant unable to bind Cdc42). IRSp53 failed to induce filopodia in mammalian enabled (Mena)/VASP KO cells, and N-WASP failed to induce filopodia when IRSp53 was knocked down with RNA interference. The IRSp53 I-BAR domain alone induces dynamic membrane protrusions that lack actin and are smaller than normal filopodia ("partial-filopodia") in both wild-type N-WASP and N-WASP KO cells. We propose that IRSp53 generates filopodia by coupling membrane protrusion through its I-BAR domain with actin dynamics through SH3 domain binding partners, including N-WASP and Mena. PMID- 18448435 TI - Monte-Carlo calculations of particle fluences and neutron effective dose rates in the atmosphere. AB - Monitoring of radiation exposure of aircrew is a legal requirement for many airlines in the EU and a challenging task in dosimetry. Monte-Carlo simulations of cosmic particles in the atmosphere can contribute to the understanding of the corresponding radiation field. Calculations of secondary neutron fluences in the atmosphere produced by galactic cosmic rays together with the resulting neutron effective dose rates are shown in this paper and compared with results from the AIR project. The PLANETOCOSMICS package based on GEANT4 and two models for the local interstellar spectra of galactic cosmic rays have been used for the calculations. Furthermore, secondary muon fluences have been computed and are compared with CAPRICE measurements. PMID- 18448436 TI - Effect of background radiation on the lower limit of detection for extended dosemeter issue periods. AB - An extension of dosemeter issue period brings significant economic and logistic benefits. Therefore, it is desirable to have an extended period as long as possible without significant loss of the quality of dose measurements. There are many studies devoted to the investigation of fading or reduction of the dose accumulated in dosemeters with time. However, this is one of many critical factors that need's to be taken into account when extending the dosemeter issue period. Background radiation is also a critical factor that needs to be appropriately accounted. In this report, a new approach has been suggested for evaluating the effect of background radiation on the lower limit of detection (LLD) of occupational radiation dose. This approach is based on the data collected from control dosemeters that are routinely used for subtraction of background radiation from occupational dose measurements. The results show that for LiF:Mg,Cu,P thermoluminescence dosemeters, variations in background radiation have a higher impact on the LLD than dose fading and the absolute value of background radiation. Although there is no significant dose fading in LiF:Mg,Cu,P for a dosemeter issue period up to 1 y, variations in background radiation during this period of time can significantly increase photon LLDs (up to 700 microSv) for workers operating in an environment of variable radiation background. PMID- 18448437 TI - Changing from image intensifier to flat detector technology for interventional cardiology procedures: a practical point of view. AB - A small-scale internal audit has been used to evaluate the impact of the use of a dynamic flat panel detector in the clinical routine in the National Interventional Cardiology Centre in Luxembourg. The parameters tested during commissioning and constancy control of an X-ray system, the introduction of new clinical protocols, the patient and the personal staff dosimetry were considered. The technical parameters tested by the hospital physicist stay the same as for the image intensifier. No innovative protocols have been adopted due to the existence of the flat panel detector. A reduction in dose was noted after the installation of a flat detector, due mostly to the continuing education of the interventional cardiologists as well as the initial calibration of the radiological system. The understanding of the X-ray system and its possibilities is vital for the optimisation of clinical procedures in patient and staff exposure. PMID- 18448438 TI - Organisational aspects of mammography screening in digital settings: first experiences of Luxembourg. AB - Luxembourg has been conducting a breast cancer screening programme since 1992, like a large number of other European countries, as early detection and treatment of breast cancer have been proven to reduce mortality. The majority of these screening programmes are based on analogue X-ray technology and have optimised their organisation of transporting, archiving and reading with respect to films. Last decade is marked by enormous developments in digital mammography. Different technologies such as flat panel-, computed radiography- and scanning systems became available. Digital mammography is expected to have a major impact on quality and organisation of breast cancer screening programmes. Screening programmes are now faced with a huge challenge of incorporating the digital technology, including implementation of electronic image exchange, conception of new electronic workflow, establishing adapted quality assurance programmes and training of radiologists and technical personnel. Initial experiences of the Luxembourg approach in organising digital mammography screening and its quality assurance are reported. PMID- 18448439 TI - Performance measurements of mammographic systems. AB - Performance measurements of 30 mammographic installations were carried out in order to see the current level of image quality and breast doses.The half of the systems tested in this survey indicated automatic exposure control and beam collimation problems. Film processing and dark room conditions were not optimum for the majority of the installations. Image quality phantoms were exposed by the user and team of the survey at each visited center. Lower breast doses were obtained at equal image qualities for the radiographs of the team indicating the importance of adequate handling of some exposure parameters. Corrective actions were suggested to each installation and necessary guidance was advised for the implementation of routine quality control activities. PMID- 18448440 TI - An overview on extremity dosimetry in medical applications. AB - Some activities of EURADOS Working Group 9 (WG9) are presently funded by the European Commission (CONRAD project). The objective of WG9 is to promote and co ordinate research activities for the assessment of occupational exposures to staff at workplaces in interventional radiology (IR) and nuclear medicine. For some of these applications, the skin of the fingers is the limiting organ for individual monitoring of external radiation. Therefore, sub-group 1 of WG9 deals with the use of extremity dosemeters in medical radiation fields. The wide variety of radiation field characteristics present in a medical environment together with the difficulties in measuring a local dose that is representative for the maximum skin dose, usually with one single detector, makes it difficult to perform accurate extremity dosimetry. Sub-group 1 worked out a thorough literature review on extremity dosimetry issues in diagnostic and therapeutic nuclear medicine and positron emission tomography, interventional radiology and interventional cardiology and brachytherapy. Some studies showed that the annual dose limits could be exceeded if the required protection measures are not taken, especially in nuclear medicine. The continuous progress in new applications and techniques requires an important effort in radiation protection and training. PMID- 18448441 TI - Risk of breast cancer and gynecologic cancers in a large population of nearly 50,000 infertile Danish women. AB - Infertility is considered to influence the risk of breast cancer and gynecologic cancers. To assess this association, the authors used data from a large cohort of 54,362 women with a diagnosis of infertility who were referred to Danish fertility clinics between 1963 and 1998. Through 2003, 1,975 cancers were identified by linkage to the Danish Cancer Registry. Cancer risk was assessed through standardized incidence ratios (SIRs) and corresponding 95% confidence intervals, using general and parity-specific cancer incidence rates in the general population of Denmark as a reference. After adjustment for parity status, significantly increased SIRs were observed for breast (SIR = 1.08, 95% confidence interval: 1.01, 1.16) and ovarian (SIR = 1.46, 95% confidence interval: 1.24, 1.71) cancer. The risk of breast cancer increased with follow-up time. Similar risk patterns were observed for the different histologic types of breast cancer and all nonmucinous types of ovarian cancer, whereas the risk of mucinous ovarian cancers seemed not to be increased. These data thus suggest higher risks of breast and ovarian cancer among infertile women. However, since these results could not distinguish the effects of underlying infertility from the effects of fertility treatment, additional studies are needed to disentangle the effects of these two factors. PMID- 18448442 TI - Conjugated equine estrogens and breast cancer risk in the Women's Health Initiative clinical trial and observational study. AB - The Women's Health Initiative randomized controlled trial found a trend (p = 0.09) toward a lower breast cancer risk among women assigned to daily 0.625-mg conjugated equine estrogens (CEEs) compared with placebo, in contrast to an observational literature that mostly reports a moderate increase in risk with estrogen-alone preparations. In 1993-2004 at 40 US clinical centers, breast cancer hazard ratio estimates for this CEE regimen were compared between the Women's Health Initiative clinical trial and observational study toward understanding this apparent discrepancy and refining hazard ratio estimates. After control for prior use of postmenopausal hormone therapy and for confounding factors, CEE hazard ratio estimates were higher from the observational study compared with the clinical trial by 43% (p = 0.12). However, after additional control for time from menopause to first use of postmenopausal hormone therapy, the hazard ratios agreed closely between the two cohorts (p = 0.82). For women who begin use soon after menopause, combined analyses of clinical trial and observational study data do not provide clear evidence of either an overall reduction or an increase in breast cancer risk with CEEs, although hazard ratios appeared to be relatively higher among women having certain breast cancer risk factors or a low body mass index. PMID- 18448443 TI - Invited commentary: Postmenopausal unopposed estrogen and breast cancer risk in the Women's Health Initiative--before and beyond. AB - Three large clinical trials provoked major debate when hormone replacement therapy (HRT) did not reduce coronary heart disease in postmenopausal women as expected from observational epidemiologic studies. Less discussion has ensued about breast cancer or other adverse events. In this issue of the Journal, investigators from the Women's Health Initiative (WHI) compare breast cancer findings from the randomized trial of unopposed estrogen with those from the large WHI observational study. This commentary briefly summarizes historical highlights of menopausal hormone use; risk-versus-benefit evaluations; scientific, clinical, and policy influences immediately before and during the WHI trial; breast cancer incidence trends; and the post-trial response in US clinical practice. Factors complicating interpretation of the results include differences in breast cancer risk profiles between women in the trial and those in the observational study cohort as well as heterogeneity in the definitions of menopause and prior use of HRT as applied by the WHI investigators to the two populations. Because millions of women use HRT, it is important to consider how the WHI and other research investigations might contribute to reducing gaps in understanding the relation between HRT and breast cancer risk. PMID- 18448444 TI - Sharps injuries in healthcare waste handlers. AB - Clinical waste disposal carries with it a risk of serious and possibly life threatening infection. Combining confidential questionnaires and structured interviews with discrete observation, the attitudes and approach to safe handling of bulk clinical wastes by staff in a specialist waste treatment facility were assessed. With particular attention to glove use and hand hygiene, observations were supplemented by review of group-wide accident and incident records, with emphasis on sharps injuries and related blood and bloodstained body fluid exposures. Deficiencies in glove selection and use, and in hand hygiene, were noted despite extensive and on-going training and supervision of waste handlers. Though ballistic puncture-resistant gloves protect against sharps injury, these were uncomfortable in use and were sometimes rejected by waste handlers who preferred thin-walled nitrile gloves that were more comfortable in use though provide no resistance to penetrating injury. Among the waste handlers working for a single specialist waste disposal company, sharps injuries (n = 40) occurred at a rate of approximately 1 per 29 000 man hours. Injuries were caused by hypodermic needles from improperly closed or overfilled sharps boxes (n = 6) or from sharps incorrectly discarded into thin-walled plastic sacks intended only for soft wastes (n = 34). Most injuries occurred to the fingers or hands. No seroconversions occurred, though two individuals suffered anxiety/stress disorder necessitating prolonged leave of absence with professional counselling and support. Glove use and hand hygiene must feature prominently in the on-going training of waste handlers. Though ballistic gloves afford protection against sharps injury, the initial segregation and safe disposal of clinical wastes by healthcare professionals must provide the primary control measure. Despite robust and unambiguous legislation and good practice guidelines, serious errors by healthcare staff that result in the disposal of hypodermic needles and other sharps to thin-walled plastic waste sacks places waste handlers at risk of bloodborne virus infection. Further improvement in the standards of waste segregation and disposal by healthcare professionals are still required to protect ancillary and support staff and waste handlers working in the disposal sector. PMID- 18448445 TI - Size-separated sampling and analysis of isocyanates in workplace aerosols--Part II: aging of aerosols from thermal degradation of polyurethane. AB - A new type of isocyanate sampler has been used to investigate aging aerosols generated during thermal degradation of polyurethane (PUR). The sampler consists of a denuder connected in series with a three-stage cascade impactor and a filter. The denuder collects gas-phase isocyanates. The three impactor stages had cut-off diameters (d(50)) of 2.5, 1.0 and 0.5 mum, respectively. The end filter collects particles <0.5 mum. For derivatization of isocyanates in the sampler, di n-butylamine mixed with an equimolar amount of acetic acid was used for impregnation of the sampler stages. Consecutive sampling using three denuder impactor samplers was performed in a test chamber, with a total sampling time of 9 min. Analysis of air samples was performed using liquid chromatography-mass spectrometry (LC-MS)/MS. Particle size measurements were performed using a scanning mobility particle sizer (SMPS). A time-dependent behavior was observed for aromatic diisocyanates during aging of the aerosol. Thermal degradation of different PUR materials showed different distribution of isocyanates between gas and particles. Aromatic diisocyanates (toluene diisocyanate (TDI) and methylene diphenyl diisocyanate) were initially in gas phase and associated to very small particles. After a few minutes most of these isocyanates were associated with particles <1 mum. Monoisocyanates and hexamethylene diisocyanate (HDI) were not found to be associated with particles. PMID- 18448446 TI - Polyester composite mesh for laparoscopic paraesophageal hernia repair. AB - Recent evidence supports the use of prosthetic reinforcement material during laparoscopic hiatal hernia repair; however, the search for appropriate prosthetic materials is still under investigation. In this article, the technical feasibility and the short-term outcomes of the use of polyester composite mesh for crural reinforcement was determined. A small series of patients with large paraesophageal hiatal hernias underwent laparoscopic repair with mesh (5 males; mean age = 62 +/- 10 years; mean body mass index = 29 +/- 1 kg/m2, and mean American Society of Anesthesiologists = 3 +/- .4). There were no postoperative complications, deaths, or evidence of hernia recurrence documented by barium study at a median follow-up of 9 months. The use of the polyester composite mesh is technically feasible, has excellent intracorporeal handling characteristics, and holds suture readily. The short-term outcomes of the use of the polyester composite mesh for paraesophageal hernia repair reinforcement appeared to be favorable and are encouraging. PMID- 18448447 TI - Risk factors for bile duct injury during laparoscopic cholecystectomy: a case control study. AB - Common bile duct injury is a serious but uncommon complication of laparoscopic cholecystectomy. A case-control epidemiologic study of patients who had undergone cholecystectomy in Ontario, Canada, between 1991 and 1997 was performed. Four patients who had undergone a laparoscopic cholecystectomy at the same hospital 2 months prior to a case were selected as controls. The risk of bile duct injury associated with various exposures was estimated by unconditional logistic regression. There were 28 cases and 88 controls. Emergency operation (adjusted odds ratio = 5.0; 95% confidence interval, 1.4-17.8) and failure to identify the cystic duct (adjusted odds ratio = 13.7; 95% confidence interval, 2.5-76.3) were statistically significant risk factors for operative bile duct injury. No other characteristics were independent risk factors for bile duct injury. Failure to identify the cystic duct and the emergency surgery are independent risk factors for bile duct injury. PMID- 18448448 TI - Mechanical stimuli regulate the allocation of biomass in trees: demonstration with young Prunus avium trees. AB - BACKGROUND AND AIMS: Plastic tree-shelters are increasingly used to protect tree seedlings against browsing animals and herbicide drifts. The biomass allocation in young seedlings of deciduous trees is highly disturbed by common plastic tree shelters, resulting in poor root systems and reduced diameter growth of the trunk. The shelters have been improved by creating chimney-effect ventilation with holes drilled at the bottom, resulting in stimulated trunk diameter growth, but the root deficit has remained unchanged. An experiment was set up to elucidate the mechanisms behind the poor root growth of sheltered Prunus avium trees. METHODS: Tree seedlings were grown either in natural windy conditions or in tree-shelters. Mechanical wind stimuli were suppressed in ten unsheltered trees by staking. Mechanical stimuli (bending) of the stem were applied in ten sheltered trees using an original mechanical device. KEY RESULTS: Sheltered trees suffered from poor root growth, but sheltered bent trees largely recovered, showing that mechano-sensing is an important mechanism governing C allocation and the shoot-root balance. The use of a few artificial mechanical stimuli increased the biomass allocation towards the roots, as did natural wind sway. It was demonstrated that there was an acclimation of plants to the imposed strain. CONCLUSIONS: This study suggests that if mechanical stimuli are used to control plant growth, they should be applied at low frequency in order to be most effective. The impact on the functional equilibrium hypothesis that is used in many tree growth models is discussed. The consequence of the lack of mechanical stimuli should be incorporated in tree growth models when applied to environments protected from the wind (e.g. greenhouses, dense forests). PMID- 18448449 TI - ContentSnapshots. Plant growth modelling and applications. PMID- 18448450 TI - A rationale for starting breast cancer screening under age 50. PMID- 18448451 TI - Practical guidance for the management of aromatase inhibitor-associated bone loss. AB - BACKGROUND: Recent studies indicate that women with breast cancer are at increased risk of fracture compared with their age-matched peers. Current treatment guidelines are inadequate for averting fractures in osteopenic women, especially those receiving aromatase inhibitor (AI) therapy. Therefore, we sought to identify clinically relevant risk factors for fracture that can be used to assess overall fracture risk and to provide practical guidance for preventing and treating bone loss in women with breast cancer receiving AI therapy. METHODS: Systematic review of pertinent information from published literature and meeting abstracts through December 2007 was carried out to identify factors contributing to fracture risk in women with breast cancer. An evidence-based medicine approach was used to select risk factors that can be used to determine when to initiate bisphosphonate treatment of aromatase inhibitor-associated bone loss (AIBL). RESULTS: Fracture risk factors were chosen from large, well-designed, controlled, population-based trials in postmenopausal women. Evidence from multiple prospective clinical trials in women with breast cancer was used to validate AI therapy as a fracture risk factor. Overall, eight fracture risk factors were validated in women with breast cancer: AI therapy, T-score <-1.5, age >65 years, low body mass index (BMI <20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking. Treatment recommendations were derived from randomized clinical trials. CONCLUSIONS: The authors recommend the following for preventing and treating AIBL in women with breast cancer. All patients initiating AI therapy should receive calcium and vitamin D supplements. Any patient initiating or receiving AI therapy with a T-score >/=-2.0 and no additional risk factors should be monitored every 1-2 years for change in risk status and bone mineral density (BMD). Any patient initiating or receiving AI therapy with a T-score <-2.0 should receive bisphosphonate therapy. Any patient initiating or receiving AI therapy with any two of the following risk factors-T-score <-1.5, age >65 years, low BMI (<20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking-should receive bisphosphonate therapy. BMD should be monitored every 2 years, and treatment should continue for at least 2 years and possibly for as long as AI therapy is continued. To date, the overwhelming majority of clinical evidence supports zoledronic acid 4 mg every 6 months to prevent bone loss in women at high risk. Although there is a trend towards fewer fractures with zoledronic acid, studies completed to date have not been designed to capture significant differences in fracture rate, and longer follow-up is needed. PMID- 18448452 TI - The human dorsal action control system develops in the absence of vision. AB - The primate dorsal pathway has been proposed to compute vision for action. Although recent findings suggest that dorsal pathway structures contribute to somatosensory action control as well, it is yet not clear whether or not the development of dorsal pathway functions depends on early visual experience. Using functional magnetic resonance imaging, we investigated the pattern of cortical activation in congenitally blind and matched blindfolded sighted adults while performing kinesthetically guided hand movements. Congenitally blind adults activated similar dorsal pathway structures as sighted controls. Group-specific activations were found in the extrastriate cortex and the auditory cortex for congenitally blind humans and in the precuneus and the presupplementary motor area for sighted humans. Dorsal pathway activity was in addition observed for working memory maintenance of kinesthetic movement information in both groups. Thus, the results suggest that dorsal pathway functions develop in the absence of vision. This favors the idea of a general mechanism of movement control that operates regardless of the sensory input modality. Group differences in cortical activation patterns imply different movement control strategies as a function of visual experience. PMID- 18448453 TI - Enhanced processing of threat stimuli under limited attentional resources. AB - The ability to process stimuli that convey potential threat, under conditions of limited attentional resources, confers adaptive advantages. This study examined the neurobiology underpinnings of this capacity. Employing an attentional blink paradigm, in conjunction with functional magnetic resonance imaging, we manipulated the salience of the second of 2 face target stimuli (T2), by varying emotionality. Behaviorally, fearful T2 faces were identified significantly more than neutral faces. Activity in fusiform face area increased with correct identification of T2 faces. Enhanced activity in rostral anterior cingulate cortex (rACC) accounted for the benefit in detection of fearful stimuli reflected in a significant interaction between target valence and correct identification. Thus, under conditions of limited attention resources activation in rACC correlated with enhanced processing of emotional stimuli. We suggest that these data support a model in which a prefrontal "gate" mechanism controls conscious access of emotional information under conditions of limited attentional resources. PMID- 18448454 TI - Bam32: a novel mediator of Erk activation in T cells. AB - Bam32 (B lymphocyte adapter molecule of 32 kDa) is an adapter protein expressed in some hematopoietic cells including B and T lymphocytes. It was previously shown that Bam32-deficient mice have defects in various aspects of B cell activation including B cell receptor (BCR)-induced Erk activation, BCR-induced proliferation and T-independent antibody responses. In this study, we have examined the role of Bam32 in T cell activation using Bam32-deficient mice. By comparing CD4(+) T cells from lymph nodes of wild-type and Bam32-deficient mice, we found that Bam32 was required for optimal TCR-induced Erk activation, cytokine production, proliferation and actin-mediated spreading of CD4(+) T cells. These results indicate a novel pathway to Erk activation in T cells involving the adapter protein Bam32. PMID- 18448455 TI - Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. AB - Systemic administration of IL-18 induces polyclonal IgE responses by causing NKT cells to express CD40 ligand and to produce IL-4. Administration of IL-33 also induces IgE response, although the mechanism underlying IgE response is unclear. Here, we compared the effects of IL-18 and IL-33 on bone marrow-derived mast cells and basophils as well as non-polarized and T(h)2-polarized CD4(+) T cells in vitro. Basophils, comprising IL-18Ralpha(+) cells (14.2%) and IL-33Ralpha(+) cells (34.6%), and mast cells, comprising IL-18Ralpha(+) cells (2.0%) and IL 33Ralpha(+) cells (95.6%), produce IL-4, IL-6, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF) and chemokines (RANTES, MIP-1alpha, MIP-1beta and MCP-1), upon stimulation with IL-18 and/or IL-33 in the presence of IL-3. Only basophils strongly produce IL-4. Furthermore, compared with mast cells, basophils produce larger amounts of the above cytokines and chemokines in response to IL-33. Level of IL-33Rbeta-mRNA expression in basophils is higher than that in mast cells. Effect of IL-33 is dependent on ST2 binding, and its signal is transduced via MyD88 in vitro. We also found that IL-2 plus IL-18 or IL 33 alone stimulates non-polarized or T(h)2-polarized CD4(+) T cells to produce IL 4 and IL-13 or IL-5 and IL-13, respectively. We finally showed that administration of IL-33 into mice ST2/MyD88 dependently induces airway hyperresponsiveness (AHR) and goblet cell hyperplasia by induction of IL-4, IL-5 and IL-13 in the lungs. Furthermore, same treatment of RAG-2(-/-) mice, lacking T and B cells, more strikingly induced AHR with marked goblet cell hyperplasia and eosinophilic infiltration in the lungs. Thus, IL-33 induces asthma-like symptom entirely independent of acquired immune system. PMID- 18448456 TI - The probiotic Escherichia coli strain Nissle 1917 induces gammadelta T cell apoptosis via caspase- and FasL-dependent pathways. AB - Human gammadelta T cells play a vital role in the innate and adaptive immune response to microbial antigens by acting as antigen-presenting cells while at the same time being capable of directly activating CD4(+) T cells. Pathogenic microbes or loss of tolerance toward the host's own microflora trigger many diseases including inflammatory bowel diseases. We previously demonstrated that Escherichia coli Nissle 1917 directly interacts with the adaptive immune system by regulating central T cell functions. Here we aimed to investigate whether E. coli Nissle regulates gammadelta T cell function, thereby linking the innate and adaptive immune system. In our study, we demonstrate that, in contrast to the other probiotic strains tested, E. coli Nissle increased activation, cell cycling and expansion of gammadelta, but not alphabeta T cells. In gammadelta T cells, E. coli Nissle reduced tumor necrosis factor-alpha secretion but increased IL-6 and CXCL8 release. However, after activation, only E. coli Nissle induced gammadelta T cell apoptosis, mediated via Toll-like receptor-2 by caspase- and FasLigand dependent pathways. gammadelta T cells play an important role in the recognition of microbial antigens and the perpetuation of inflammatory processes. The demonstration that E. coli Nissle, but not the other bacteria tested, profoundly regulate gammadelta T cell function contributes to explaining the biological function of this probiotic strain in inflammatory diseases and provides us with a better understanding of the role of gammadelta T cells. PMID- 18448457 TI - CD4+ T cell hyper-responsiveness in CD45 transgenic mice is independent of isoform. AB - The CD45 tyrosine phosphatase is required for T cell development and function by virtue of its role as a positive regulator of src family kinase activity. In addition, recent data have highlighted that CD45 also acts as a negative regulator of Lck function by dephosphorylation of critical tyrosine residues. Lck functionality and TCR responsiveness are elevated in transgenic mice expressing the CD45RO isoform at 'intermediate' (10-40% of wild type) levels, indicating that the expression level of CD45 is critical in determining the sensitivity of T cells to TCR stimulation. However, it is unclear whether such a phenotype is specific for the CD45RO isoform, typically expressed by activated T cells. In the present work, the roles of three isoforms of CD45, RO, RB and RABC, in thymocyte development, T cell responses and TCR signalling pathways were directly compared. The data demonstrate that expression of CD45RB or CD45RABC at intermediate levels also results in CD4(+) T cell hyper-reactivity, as previously published for CD45RO. These data emphasize the dual functions of CD45 as both a positive and a negative regulators of TCR signalling irrespective of specific isoform expression. PMID- 18448458 TI - Combination treatment with IL-2 and anti-IL-2 mAbs reduces tumor metastasis via NK cell activation. AB - Combination treatment consisting of IL-2 together with anti-IL-2 mAbs results in markedly larger increases in the numbers of CD8(+) T cells, dendritic cells (DCs) and NK cells in vivo compared with the results observed with injections of IL-2 or the antibodies alone. We previously showed that this combination treatment overcomes the problems associated with the short half-life of IL-2 in vivo. Importantly, the combination treatment but not IL-2 or the anti-IL-2 mAbs alone protected the mice against tumor metastases in the lungs. Here we have investigated which cell types are responsible for this protective immunity against tumors. We analyzed tumor metastases in mice that were depleted of DCs, CD8(+) T cells or NK cells. DC-deficient, diphtheria toxin receptor-expressing mice injected with diphtheria toxin as well as B cell- and T cell-deficient RAG-2 knockout mice were protected against tumors after they were administered the combination treatment. On the other hand, mice that were depleted of NK cells using anti-asialo-GM1 antibodies did not exhibit the anti-tumor activity after treatment with IL-2 combined with anti-IL-2 mAbs. Thus, these data demonstrate that NK cells, but not DCs, or CD8(+) T cells mediate the anti-tumor effect induced by this combination treatment. Therefore, combining neutralizing anti-IL 2 mAbs with IL-2 may be clinically useful to effectively enhance IL-2-mediated NK cell activities. PMID- 18448466 TI - Stroke in the very old: clinical presentations and outcomes. PMID- 18448467 TI - MassNet: a functional annotation service for protein mass spectrometry data. AB - Although mass spectrometry has been frequently used to identify proteins, there are no web servers that provide comprehensive functional annotation of those identified proteins. It is necessary to provide such web service due to a rapid increase in the data. We, therefore, introduce MassNet, which provides (i) physico-chemical analysis information, (ii) KEGG pathway assignment (iii) Gene Ontology mapping and (iv) protein-protein interaction (PPI) prediction for the data from MASCOT, Prospector and Profound. MassNet provides the prediction information for PPIs using both 3D structural interaction and experimental interaction deposited in PSIMAP, BIND, DIP, HPRD, IntAct, MINT, CYGD and BioGrid. The web service is freely available at http://massnet.kr or http://sequenceome.kobic.re.kr/MassNet/. PMID- 18448468 TI - MolAxis: a server for identification of channels in macromolecules. AB - MolAxis is a freely available, easy-to-use web server for identification of channels that connect buried cavities to the outside of macromolecules and for transmembrane (TM) channels in proteins. Biological channels are essential for physiological processes such as electrolyte and metabolite transport across membranes and enzyme catalysis, and can play a role in substrate specificity. Motivated by the importance of channel identification in macromolecules, we developed the MolAxis server. MolAxis implements state-of-the-art, accurate computational-geometry techniques that reduce the dimensions of the channel finding problem, rendering the algorithm extremely efficient. Given a protein or nucleic acid structure in the PDB format, the server outputs all possible channels that connect buried cavities to the outside of the protein or points to the main channel in TM proteins. For each channel, the gating residues and the narrowest radius termed 'bottleneck' are also given along with a full list of the lining residues and the channel surface in a 3D graphical representation. The users can manipulate advanced parameters and direct the channel search according to their needs. MolAxis is available as a web server or as a stand-alone program at http://bioinfo3d.cs.tau.ac.il/MolAxis. PMID- 18448469 TI - NOBAI: a web server for character coding of geometrical and statistical features in RNA structure. AB - The Numeration of Objects in Biology: Alignment Inferences (NOBAI) web server provides a web interface to the applications in the NOBAI software package. This software codes topological and thermodynamic information related to the secondary structure of RNA molecules as multi-state phylogenetic characters, builds character matrices directly in NEXUS format and provides sequence randomization options. The web server is an effective tool that facilitates the search for evolutionary history embedded in the structure of functional RNA molecules. The NOBAI web server is accessible at 'http://www.manet.uiuc.edu/nobai/nobai.php'. This web site is free and open to all users and there is no login requirement. PMID- 18448470 TI - Snap-to-it probes: chelate-constrained nucleobase oligomers with enhanced binding specificity. AB - We describe snap-to-it probes, a novel probe technology to enhance the hybridization specificity of natural and unnatural nucleic acid oligomers using a simple and readily introduced structural motif. Snap-to-it probes were prepared from peptide nucleic acid (PNA) oligomers by modifying each terminus with a coordinating ligand. The two coordinating ligands constrain the probe into a macrocyclic configuration through formation of an intramolecular chelate with a divalent transition metal ion. On hybridization with a DNA target, the intramolecular chelate in the snap-to-it probe dissociates, resulting in the probe 'snapping-to' and binding the target nucleic acid. Thermal transition analysis of snap-to-it probes with complementary and single-mismatch DNA targets revealed that the transition between free and target-bound probe conformations was a reversible equilibrium, and the intramolecular chelate provided a thermodynamic barrier to target binding that resulted in a significant increase in mismatch discrimination. A 4-6 degrees C increase in specificity (DeltaT(m)) was observed from snap-to-it probes bearing either terminal iminodiacetic acid ligands coordinated with Ni(2+), or terminal dihistidine and nitrilotriacetic acid ligands coordinated with Cu(2+). The difference in specificity of the PNA oligomer relative to DNA was more than doubled in snap-to-it probes. Snap-to-it probes labeled with a fluorophore-quencher pair exhibited target-dependent fluorescence enhancement upon binding with target DNA. PMID- 18448471 TI - Enzymatic synthesis of structure-free DNA with pseudo-complementary properties. AB - Long single-stranded DNAs and RNAs possess considerable secondary structure under conditions that support stable hybrid formation with oligonucleotides. Consequently, different oligomeric probes can hybridize to the same target with efficiencies that vary by several orders of magnitude. The ability to enzymatically generate structure-free single-stranded copies of any nucleic acid without impairing Watson-Crick base pairing to short probes would eliminate this problem and significantly improve the performance of many oligonucleotide-based applications. Synthetic nucleic acids that exhibit these properties are defined as pseudo-complementary. Previously, we described a pseudo-complementary A-T couple consisting of 2-aminoadenine (nA) and 2-thiothymine (sT) bases. The nA-sT couple is a mismatch even though nA-T and A-sT are stable base pairs. Here we show that 7-alkyl-7-deazaguanine and N(4)-alkylcytosine (where alkyl = methyl or ethyl) can be used in conjunction with nA and sT to render DNA largely structure free and pseudo-complementary. The deoxynucleoside triphosphates (dNTPs) of these bases are incorporated into DNA by selected mesophilic and thermophilic DNA polymerases and the resulting primer extension products hybridize with good specificity and stability to oligonucleotide probes composed of the standard bases. Further optimization and characterization of the synthesis and properties of pseudo-complementary DNA should lead to an ideal target for use with oligonucleotide probes that are <25 nt in length. PMID- 18448472 TI - Base-pair neutral homozygotes can be discriminated by calibrated high-resolution melting of small amplicons. AB - Genotyping by high-resolution melting analysis of small amplicons is homogeneous and simple. However, this approach can be limited by physical and chemical components of the system that contribute to intersample melting variation. It is challenging for this method to distinguish homozygous G::C from C::G or A::T from T::A base-pair neutral variants, which comprise approximately 16% of all human single nucleotide polymorphisms (SNPs). We used internal oligonucleotide calibrators and custom analysis software to improve small amplicon (42-86 bp) genotyping on the LightScanner. Three G/C (PAH c.1155C>G, CHK2 c.1-3850G>C and candidate gene BX647987 c.261+22,290C>G) and three T/A (CPS1 c.3405-29A>T, OTC c.299-8T>A and MSH2 c.1511-9A>T) human single nucleotide variants were analyzed. Calibration improved homozygote genotyping accuracy from 91.7 to 99.7% across 1105 amplicons from 141 samples for five of the six targets. The average T(m) standard deviations of these targets decreased from 0.067 degrees C before calibration to 0.022 degrees C after calibration. We were unable to generate a small amplicon that could discriminate the BX647987 c.261+22,290C>G (rs1869458) SNP, despite reducing standard deviations from 0.086 degrees C to 0.032 degrees C. Two of the sites contained symmetric nearest neighbors adjacent to the SNPs. Unexpectedly, we were able to distinguish these homozygotes by T(m) even though current nearest neighbor models predict that the two homozygous alleles would be identical. PMID- 18448473 TI - Occurrence of plastids in the sperm cells of Caprifoliaceae: biparental plastid inheritance in angiosperms is unilaterally derived from maternal inheritance. AB - It is widely held that organelles inherit from the maternal lineage. However, the plastid genome in quite a few angiosperms appears to be biparentally transmitted. It is unclear how and why biparental inheritance of the genome became activated. Here, we detected widespread occurrence of plastids in the sperm cells (a cellular prerequisite for biparental inheritance) of traditional Caprifoliaceae. Of the 12 genera sampled, the sperm cells of Abelia, Dipelta, Heptacodium, Kolkwitzia, Leycesteria, Linnaea, Lonicera, Symphoricarpos, Triosteum and Weigela possessed inheritable plastids. The other genera, Sambucus and Viburnum, lacked plastids in sperm cells. Interestingly, such exclusion of plastids in the sperm cells of some Caprifoliaceae appeared to be associated with the divergence of Dipsacales phylogeny. Closer examination of Weigela florida revealed that both plastids and plastid DNA were highly duplicated in the generative cells. This implies that the appearance of plastids in sperm cells involved cellular mechanisms. Because such mechanisms must enhance the strength of plastid transmission through the paternal lineage and appear ubiquitous in species exhibiting biparental or potential biparental plastid inheritance, we presume that biparental plastid genetics may be a derived trait in angiosperms. This is consistent with our extended phylogenetic analysis using species with recently discovered modes of potential plastid inheritance. The results show that basal and early angiosperms have maternal plastid transmission, whereas all potential biparental transmission occurs at terminal branches of the tree. Thus, unlike previous studies, we suggest that biparental plastid inheritance in angiosperms was unilaterally converted from the maternal transmission mode during late angiosperm evolution. PMID- 18448474 TI - Severe disseminated hydatid disease successfully treated medically with prolonged administration of albendazole. PMID- 18448475 TI - Obstruction or renal allograft rejection--potential clinical markers of BK virus nephropathy. PMID- 18448477 TI - Genetic variability for leaf growth rate and duration under water deficit in sunflower: analysis of responses at cell, organ, and plant level. AB - Plants under water deficit reduce leaf growth, thereby reducing transpiration rate at the expense of reduced photosynthesis. The objective of this work was to analyse the response of leaf growth to water deficit in several sunflower genotypes in order to identify and quantitatively describe sources of genetic variability for this trait that could be used to develop crop varieties adapted to specific scenarios. The genetic variability of the response of leaf growth to water deficit was assessed among 18 sunflower (Helianthus annuus L.) inbred lines representing a broad range of genetic diversity. Plants were subjected to long term, constant-level, water-deficit treatments, and the response to water deficit quantified by means of growth models at cell-, leaf-, and plant-scale. Significant variation among lines was found for the response of leaf expansion rate and of leaf growth duration, with an equal contribution of these responses to the variability in the reduction of leaf area. Increased leaf growth duration under water deficit is usually suggested to be caused by changes in the activity of cell-wall enzymes, but the present results suggest that the duration of epidermal cell division plays a key role in this response. Intrinsic genotypic responses of rate and duration at a cellular scale were linked to genotypic differences in whole-plant leaf area profile to water deficit. The results suggest that rate and duration responses are the result of different physiological mechanisms, and therefore capable of being combined to increase the variability in leaf area response to water deficit. PMID- 18448476 TI - Release of sunflower seed dormancy by cyanide: cross-talk with ethylene signalling pathway. AB - Freshly harvested sunflower (Helianthus annuus L.) seeds are considered to be dormant because they fail to germinate at relatively low temperatures (10 degrees C). This dormancy results mainly from an embryo dormancy and disappears during dry storage. Although endogenous ethylene is known to be involved in sunflower seed alleviation of dormancy, little attention had been paid to the possible role of cyanide, which is produced by the conversion of 1-aminocyclopropane 1 carboxylic acid to ethylene, in this process. The aims of this work were to investigate whether exogenous cyanide could improve the germination of dormant sunflower seeds and to elucidate its putative mechanisms of action. Naked dormant seeds became able to germinate at 10 degrees C when they were incubated in the presence of 1 mM gaseous cyanide. Other respiratory inhibitors showed that this effect did not result from an activation of the pentose phosphate pathway or the cyanide-insensitive pathway. Cyanide stimulated germination of dormant seeds in the presence of inhibitors of ethylene biosynthesis, but its improving effect required functional ethylene receptors. It did not significantly affect ethylene production and the expression of genes involved in ethylene biosynthesis or in the first steps of ethylene signalling pathway. However, the expression of the transcription factor Ethylene Response Factor 1 (ERF1) was markedly stimulated in the presence of gaseous cyanide. It is proposed that the mode of action of cyanide in sunflower seed dormancy alleviation does not involve ethylene production and that ERF1 is a common component of the ethylene and cyanide signalling pathways. PMID- 18448478 TI - Clinical course and outcome of schizophrenia in a predominantly treatment-naive cohort in rural Ethiopia. AB - The established view that schizophrenia may have a favorable outcome in developing countries has been recently challenged; however, systematic studies are scarce. In this report, we describe the clinical outcome of schizophrenia among a predominantly treatment-naive cohort in a rural community setting in Ethiopia. The cohort was identified in a 2-stage sampling design using key informants and measurement-based assessment. Follow-up assessments were conducted monthly for a mean duration of 3.4 years (range 1-6 years). After screening 68 378 adults, ages 15-49 years, 321 cases with schizophrenia (82.7% men and 89.6% treatment naive) were identified. During follow-up, about a third (30.8%) of cases were continuously ill while most of the remaining cohort experienced an episodic course. Only 5.7% of the cases enjoyed a near-continuous complete remission. In the final year of follow-up, over half of the cases (54%) were in psychotic episode, while 17.6% were in partial remission and 27.4% were in complete remission for at least the month preceding the follow-up assessment. Living in a household with 3 or more adults, later age of onset, and taking antipsychotic medication for at least 50% of the follow-up period predicted complete remission. Although outcome in this setting appears better than in developed countries, the very low proportion of participants in complete remission supports the recent observation that the outcome of schizophrenia in developing countries may be heterogeneous rather than uniformly favorable. Improving access to treatment may be the logical next step to improve outcome of schizophrenia in this setting. PMID- 18448480 TI - Rheumatoid cachexia: a clinical perspective. AB - Rheumatoid cachexia is under-recognized in clinical practice. The loss of lean body tissue, which characterizes cachexia, is often compensated for by gain in body fat-so called 'cachectic obesity'-so that 85% or more RA patients have a normal BMI. Severe cachexia with loss of weight leads to increased morbidity and premature mortality but loss of muscle bulk with a normal BMI also associates with poor clinical outcomes. Increasing BMI, even into the obese range, is associated with less joint damage and reduced mortality. Measurement of body composition using DXA and other techniques is feasible but the results must be interpreted with care. Newer techniques such as whole-body MRI will help define with more confidence the mass and distribution of fat and muscle and help elucidate the relationships between body composition and outcomes. Cachexia shows little response to diet alone but progressive resistance training and anti-TNF therapies show promise in tackling this potentially disabling extra-articular feature of RA. PMID- 18448481 TI - Mechanism of basic calcium phosphate crystal-stimulated cyclo-oxygenase-1 up regulation in osteoarthritic synovial fibroblasts. AB - OBJECTIVES: Basic calcium phosphate (BCP) crystals have been implicated in the pathogenesis of OA and stimulate cyclo-oxygenase (COX) expression and PGE(2) production. This study aimed to elucidate the mechanism of COX-1 up-regulation by BCP crystals and to characterize the PGs produced in OA synovial fibroblasts (OASFs) in response to BCP crystals. METHODS: OASFs were stimulated with BCP crystals in vitro. mRNA expression was measured by real-time PCR, PG production by EIA and protein production by western blot. RESULTS: Maximal (19-fold) up regulation of COX-1 mRNA occurred 32 h after stimulation with BCP crystals; increased COX-1 protein production was also seen. At 32 h post-stimulation with BCP crystals, PGE(2) (and prostacyclin) production was COX-1 dependent. In contrast, maximal (17-fold) up-regulation of COX-2, with corresponding COX-2 dependent PG production, occurred 4 h after BCP crystal stimulation. There was no appreciable increased production of other PGs such as PGF(2alpha), thromboxane A(2) or cyclopentanone PGs including 15d-PGJ(2). Inhibition of protein kinase C (PKC) and extracellular regulated kinase 1/2 (ERK1/2) signal transduction pathways blocked BCP crystal-induced COX-1 mRNA expression. Bafilomycin A1, an inhibitor of intra-lysosomal BCP crystal dissolution, diminished BCP crystal induced COX-1 mRNA expression. CONCLUSIONS: These findings indicate that BCP crystals can augment PG production in OASF through induction of COX-1 and COX-2. Intra-lysosomal BCP crystal dissolution and activity of the PKC and ERK1/2 signal transduction pathways are required for BCP crystal-induced COX-1 up-regulation. These data add to the evidence suggesting that the constitutive COX-1/inducible COX-2 concept is an over-simplification and suggest that non-selective COX inhibition may be preferable to COX-2 selective inhibition in BCP crystal associated OA. PMID- 18448482 TI - Age-dependent inhibition of ectopic calcification: a possible role for fetuin-A and osteopontin in patients with juvenile dermatomyositis with calcinosis. AB - OBJECTIVES: To assess if age and/or age-dependent variations in the levels of two major calcification regulatory proteins, fetuin-A and osteopontin, could be associated with an increased risk of calcinosis in children with juvenile dermatomyositis (JDM). METHODS: The frequency of calcinosis was derived from a national UK database of 212 cases of JDM. Serum fetuin-A and plasma osteopontin levels were determined using ELISA in 15 JDM patients with calcinosis and 15 JDM patients without calcinosis. Healthy controls were 19 age-matched children, 24 adolescents and 13 adults. Sixteen patients with juvenile idiopathic arthritis (JIA) were additional paediatric disease controls. RESULTS: Of the 212 JDM cases 10% had calcinosis. Calcinosis patients had younger age of disease onset than those without calcinosis (mean age of 5.3 yrs vs 7.1 yrs, respectively, P = 0.016). No significant difference in fetuin-A or osteopontin could be detected between the two JDM groups. Fetuin-A levels in all groups of children and the adolescent group were much lower than described previously in adults, and there was a significant positive correlation between age and fetuin-A level, and also between osteopontin levels in plasma and serum fetuin-A. CONCLUSIONS: Children who develop JDM at an younger age may have increased risk of developing calcinosis. Physiologically low levels of fetuin-A in young children combined with an additional negative acute-phase effect on fetuin-A due to chronic inflammation could explain in part the propensity to develop ectopic calcification observed in JDM patients, and why calcinosis is less frequent in adults with dermatomyositis. PMID- 18448479 TI - Neurocognitive allied phenotypes for schizophrenia and bipolar disorder. AB - Psychiatric disorders are genetically complex and represent the end product of multiple biological and social factors. Links between genes and disorder-related abnormalities can be effectively captured via assessment of phenotypes that are both associated with genetic effects and potentially contributory to behavioral abnormalities. Identifying intermediate or allied phenotypes as a strategy for clarifying genetic contributions to disorders has been successful in other areas of medicine and is a promising strategy for identifying susceptibility genes in complex psychiatric disorders. There is growing evidence that schizophrenia and bipolar disorder, rather than being wholly distinct disorders, share genetic risk at several loci. Further, there is growing evidence of similarity in the pattern of cognitive and neurobiological deficits in these groups, which may be the result of the effects of these common genetic factors. This review was undertaken to identify patterns of performance on neurocognitive and affective tasks across probands with schizophrenia and bipolar disorder as well as unaffected family members, which warrant further investigation as potential intermediate trait markers. Available evidence indicates that measures of attention regulation, working memory, episodic memory, and emotion processing offer potential for identifying shared and illness-specific allied neurocognitive phenotypes for schizophrenia and bipolar disorder. However, very few studies have evaluated neurocognitive dimensions in bipolar probands or their unaffected relatives, and much work in this area is needed. PMID- 18448483 TI - Comment on: Comparing morphometric X-ray absorptiometry and radiography in defining vertebral wedge fractures in patients with ankylosing spondylitis. PMID- 18448484 TI - Epigenetic remodeling during arsenical-induced malignant transformation. AB - Humans are exposed to arsenicals through many routes with the most common being in drinking water. Exposure to arsenic has been associated with an increase in the incidence of cancer of the skin, lung and bladder. Although the relationship between exposure and carcinogenesis is well documented, the mechanisms by which arsenic participates in tumorigenesis are not fully elucidated. We evaluated the potential epigenetic component of arsenical action by assessing the histone acetylation state of 13 000 human gene promoters in a cell line model of arsenical-mediated malignant transformation. We show changes in histone H3 acetylation occur during arsenical-induced malignant transformation that are linked to the expression state of the associated gene. DNA hypermethylation was detected in hypoacetylated promoters in the select cases analyzed. These epigenetic changes occurred frequently in the same promoters whether the selection was performed with arsenite [As(III)] or with monomethylarsonous acid, suggesting that these promoters were targeted in a non-random fashion, and probably occur in regions important in arsenical-induced malignant transformation. Taken together, these data suggest that arsenicals may participate in tumorigenesis by altering the epigenetic terrain of select genes. PMID- 18448485 TI - Interleukin promoter polymorphisms and prognosis in colorectal cancer. AB - There is strong evidence that cancer-associated inflammation promotes tumor growth and progression. This is especially true for colorectal cancer (CRC). Interleukins (ILs) are important modulators for inflammation. We examined whether promoter polymorphisms in key IL genes (IL4, IL4R, IL6, IL8 and IL10) are associated with the risk or clinical outcome of CRC. Five single-nucleotide polymorphisms (SNPs) were analyzed in genomic DNA from a cohort including 308 Swedish incident cases of CRC with data on Dukes' stage and up to 16 years of follow-up and 585 healthy controls. The selected SNPs have previously been shown to be functional and/or associated with cancer. None of the analyzed SNPs associated with the risk of CRC. When stratifying by tumor stage, significantly more patients carrying at least one G allele of IL10-1082 had tumors with Dukes' stages A + B than with stages C + D (P(trend) = 0.035 for genotype distribution). Analyzing associations with overall survival time, we found the rare T allele of IL4-590 to be related to a longer survival [CT versus CC Cox proportional hazard ratio 0.69, 95% confidence intervals 0.46-1.03, TT versus CC 0.32 (0.10-1.03)]. For IL6-174, the CG genotype was associated with a longer survival when compared with the CC genotype [0.64 (0.40-1.01)]. The present study was particularly suitable for survival analysis because all patients were sampled before the diagnosis of CRC. Our results suggest that the SNPs IL4-590 and IL6-174 may be useful markers for CRC prognosis. The predicted biological effect of these SNPs in relation to promotion of cancer progression is consistent with the observed increased survival time. PMID- 18448486 TI - Sleep duration, melatonin and breast cancer among Chinese women in Singapore. AB - BACKGROUND: Sleep duration has been hypothesized to be inversely associated with breast cancer risk, possibly due to greater overall melatonin production in longer sleepers. However, data are inconclusive from the three studies conducted in Western populations on sleep duration and breast cancer risk. METHODS: We investigated the relationship between self-reported usual sleep duration determined at baseline and subsequent risk of breast cancer in the prospective, population-based cohort of the Singapore Chinese Health Study. We excluded from the study women with <2 years of follow-up due to possible change in sleep pattern among breast cancer cases close to the time of diagnosis. Five hundred and twenty-five incident cases of breast cancer were identified among the remaining 33 528 women after up to 11 years of follow-up. RESULTS: Among women postmenopausal at baseline, breast cancer risk decreased with increasing sleep duration (P trend = 0.047); those who reported 9+ h of sleep showed a relative risk of 0.67 (95% confidence interval = 0.4-1.1) compared with women who reported < or =6 h of sleep. This inverse association was observed primarily in lean women [i.e. body mass index below the median value (23.2 kg/m(2))] (P = 0.024). In this study population, irrespective of gender, urinary 6-sulfatoxymelatonin levels increased with increasing self-reported hours of sleep (P trend = 0.035) after adjustment for age and time of day of urine collection. Melatonin levels were 42% higher in those with 9+ versus those with < or =6 h of sleep. CONCLUSION: Sleep duration may influence breast cancer risk, possibly via its effect on melatonin levels. PMID- 18448487 TI - Dietary magnesium and DNA repair capacity as risk factors for lung cancer. AB - Magnesium (Mg) is required for maintenance of genomic stability; however, data on the relationship between dietary Mg intake and lung cancer are lacking. In an ongoing lung cancer case-control study, we identified 1139 cases and 1210 matched healthy controls with data on both diet and DNA repair capacity (DRC). Dietary intake was assessed using a modified Block-NCI food frequency questionnaire and DRC was measured using the host-cell reactivation assay to assess repair in lymphocyte cultures. After adjustment for potential confounding factors including DRC, the odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer with increasing quartiles of dietary Mg intake were 1.0, 0.83 (0.66-1.05), 0.64 (0.50-0.83) and 0.47 (0.36-0.61), respectively, for all subjects (P-trend < 0.0001). Similar results were observed by histology and clinical stage of lung cancer. Low dietary Mg intake was associated with poorer DRC and increased risk of lung cancer. In joint effects analyses, compared with those with high dietary Mg intake and proficient DRC, the OR (95% CI) for lung cancer in the presence of both low dietary Mg and suboptimal DRC was 2.36 (1.83-3.04). Similar results were observed for men and women. The effects were more pronounced among older subjects (>60 years), current or heavier smokers, drinkers, those with a family history of cancer in first-degree relatives, small cell lung cancer and late-stage disease. These intriguing results need to be confirmed in prospective studies. PMID- 18448488 TI - Rapid activation of Stat3 and ERK1/2 by nicotine modulates cell proliferation in human bladder cancer cells. AB - Cigarette smoke is a major risk factor for bladder cancer. The main component in cigarette smoke, nicotine, can be detected in the urine of smokers. Nicotine has been implicated as a cocarcinogen that promotes lung cancer development through prosurvival pathways. Although the mechanisms of nicotine-induced cell proliferation have been well studied in lung epithelial cells, the molecular mechanism of its action in bladder epithelial cells is still unclear. The aims of this study were to investigate whether there is nicotine-induced bladder epithelial cell proliferation and to identify the signaling transduction pathway regulated by nicotine. We found that nicotine simultaneously activates Stat3 and extracellular signal regulated kinase 1/2 (ERK1/2) in T24 cells. Stat3 activation via nicotinic acetylcholine receptor (nAChR)/protein kinase C signaling pathway was closely linked to Stat3 induction and nuclear factor-kappaB DNA binding activity, which is associated with Cyclin D1 expression and cell proliferation. ERK1/2 activation through nAChR and beta-adrenoceptors plays a dual role in cell proliferation; it phosphorylates Stat3 at Ser727 and regulates cell proliferation. We conclude that through nAChR and beta-adrenoceptors, nicotine activates ERK1/2 and Stat3 signaling pathways, leading to Cyclin D1 expression and cell proliferation. This is the first study to investigate signaling effects of nicotine in bladder cells. The current findings suggest that people exposed to nicotine could be at risk for potential deleterious effects, including bladder cancer development. PMID- 18448490 TI - Upper airway collapse and reopening induce inflammation in a sleep apnoea model. AB - The upper airway of obstructive sleep apnoea patients is subjected to recurrent negative pressure swings promoting its collapse and reopening. The aim of the present study was to ascertain whether this mechanical stress induces upper airway inflammation in a rat model. The upper airway of Sprague-Dawley rats was subjected to a periodic pattern of recurrent negative (-40 cmH2O, 1 s) and positive (4 cmH2O, 2 s) pressures inducing collapse and reopening for 5 h. Rats that were instrumented but not subjected to negative pressure swings were used as controls. The gene expression of the pro-inflammatory biomarkers macrophage inflammatory protein (MIP)-2, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and P-selectin in the soft palate and larynx tissues was assessed by real-time PCR. A marked overexpression of MIP-2, TNF-alpha, IL-1beta and P selectin (approximately 40-, 24-, 47- and 7-fold greater than controls, respectively) was observed in the larynx tissue; similar results were found in the soft palate tissue (approximately 14-, 7-, 35- and 11-fold greater than controls, respectively). Recurrent upper airway collapse and reopening mimicking those experienced by obstructive sleep apnoea patients triggered an early local inflammatory process. These results could explain the inflammation observed in the upper airway of obstructive sleep apnoea patients. PMID- 18448489 TI - Serial viral infections in infants with recurrent respiratory illnesses. AB - To better understand the viral aetiology of recurrent and prolonged illnesses, nasal secretions were prospectively collected from 285 infants at increased risk of developing asthma. Of these, 27 infants had recurrent (at least five) moderate to-severe respiratory illnesses (MSIs). The viral aetiology of the 150 MSIs and 86 scheduled visits was analysed by molecular diagnostics. The demographic and clinical data were compared with infants who had 0-4 MSIs. Frequently ill infants had higher exposure to other children and more wheezing illnesses than less symptomatic children. Viruses were detected in 136 (91%) out of 150 MSIs, 14 (67%) out of 21 mild illnesses and 29 (45%) out of 65 asymptomatic visits. Human rhinovirus was the most common aetiological agent (61, 43 and 35% in MSIs, mild illnesses and asymptomatic visits, respectively). Mixed viral infections were generally associated with more severe illnesses (27, 0 and 5%, respectively). Among the 27 frequently ill infants, only eight (5.3%) out of 150 MSIs were prolonged (> or =2 weeks duration). Considering all samples, detection of the same virus strain > or =2 weeks apart was unusual (5.3% of all 244 positive findings). Human rhinovirus infections occur early, pervasively and repetitively in these high-risk infants. Infants with prolonged or recurrent respiratory illnesses most often have a series of infections rather than persistent infection with one virus strain. PMID- 18448491 TI - Case volume and mortality in haematological patients with acute respiratory failure. AB - High case volume is associated with improved survival in medical and surgical conditions. The present study sought to determine whether intensive care unit (ICU) case volume was associated with survival of critically ill patients with haematological malignancies and acute respiratory failure (ARF). A regional database containing data from 1,753 haematological patients with ARF admitted to 28 medical ICUs from 1997 to 2004 was used. Multivariate analysis using mixed models was performed to adjust for severity of illness and other confounding factors, including a propensity score that incorporates differences between ICUs with different case volumes. The three case volume tertiles were: low volume (<12 admissions per year), intermediate volume (12-30 admissions per year), and high volume (>30 admissions per year). In univariate analyses, ICU case volume was not associated with ICU mortality. After adjusting for prognostic factors for ICU mortality and the propensity score, patients in high-volume ICUs had lower mortality than other patients. A case volume increase of one admission per year led to a significant mortality reduction with an odds ratio of 0.98 (95% confidence limits 0.97-0.99). Mortality was independently associated with severity of organ dysfunction. In intensive care units admitting larger numbers of critically ill haematological patients with acute respiratory failure, mortality was lower than in other intensive care units. The mechanisms of the relationship between volume and outcome among haematological patients with acute respiratory deserve additional studies. PMID- 18448492 TI - The impact on risk-factor analysis of different mortality outcomes in COPD patients. AB - The aim of the present study was to analyse the role of potential selection processes and their impact when evaluating risk factors for 30-day mortality among patients hospitalised for chronic obstructive pulmonary disease (COPD). A cohort of 26,039 patients aged > or = 35 yrs and hospitalised with COPD were enrolled. A 30-day follow-up was carried out using both the cause mortality register (CMR) and the hospital discharge register (HDR). Individual and hospital factors associated with 30-day mortality were studied using both mortality outcomes. The 30-day mortality rate was 1.21.1,000 patient-days(-1) (95% confidence interval (CI) 1.14-1.29) using the CMR, and 1.06.1,000 patient-days( 1) (95% CI 0.98-1.13) using the HDR. Male patients, the most poorly educated, those who resided outside Rome and those who had more than one hospitalisation in the previous 2 yrs were more likely to die after discharge than when hospitalised. The most frequent cause of in-hospital death was respiratory disease and after discharge, heart disease. Older age, male sex, comorbidities, previous hospitalisations for respiratory failure, and admission to a ward not appropriate to treat respiratory diseases were the most important predictors of 30-day mortality. Using in-hospital 30-day mortality provides a significantly different estimate of the role of specific risk factors. PMID- 18448493 TI - Farm exposure in utero may protect against asthma, hay fever and eczema. AB - The aim of the present study was to assess which factors contribute to the lower prevalence of allergic diseases in farmers' children, and the importance of timing of exposure. In a cross-sectional questionnaire survey, asthma symptoms, hay fever and eczema were assessed, as well as current, early and prenatal farm related exposures in 1,333 farmers' children and 566 reference children aged 5-17 yrs. Farmers' children had a lower incidence of asthma symptoms and eczema. Current and maternal exposure during pregnancy to animals and/or grain and hay reduced the risk of asthma symptoms, hay fever and eczema. The exposure-response association for maternal exposure was nonlinear for most outcomes. After mutual adjustment, the effects of prenatal exposure remained unchanged whereas current exposure remained protective only for asthma medication, asthma ever and hay fever. Exposure during the first 2 yrs was not associated with symptoms, after controlling for prenatal exposure. A combination of prenatal and current exposure was most strongly associated with wheeze (odds ratio (OR) 0.48, 95% confidence interval (CI) 0.28-0.80), asthma medication (OR 0.50, 95% CI 0.30-0.82), asthma ever (OR 0.50, 95% CI 0.33-0.76), hay fever (OR 0.47, 95% CI 0.30-0.73) and eczema (OR 0.46, 95% CI 0.30-0.70). Prenatal exposure may contribute to the low prevalence of asthma, hay fever and eczema in farmers' children, but continued exposure may be required to maintain optimal protection. PMID- 18448494 TI - The association between HIV and antituberculosis drug resistance. AB - In the UK, HIV is considered to be a risk factor for antituberculosis drug resistance. Evidence of the association is, however, inconclusive and there are few population-level data. The present study investigated the association in England and Wales during the period 1999-2005. National tuberculosis surveillance data for adults were matched to HIV/AIDS reports. Unmatched cases were assumed to be HIV-negative. Separate analyses were conducted on new tuberculosis cases and those with a previous diagnosis. Logistic regression was used for univariable and multivariable analyses. There were 1,657 previously diagnosed cases (80 HIV positive) and 18,130 new cases (1,156 HIV-positive). Isoniazid resistance was found in 8.1% of previously diagnosed cases and 6.6% of new cases, and multidrug resistance in 2.8% and 0.7%, respectively. There was no evidence of an association between HIV and antituberculosis drug resistance among previously diagnosed cases. Among new cases, there was no overall association between HIV and isoniazid or multidrug resistance after adjusting for confounding factors. White HIV-positive patients were more likely to have multidrug resistance, but numbers were small. In contrast to some previous studies, this large, up-to-date study provides little evidence that HIV co-infected tuberculosis patients in England and Wales are at increased risk of firstline antituberculosis drug resistance. PMID- 18448496 TI - Remodelling of peripheral lung tissue in COPD. PMID- 18448495 TI - A randomised, controlled trial of bosentan in severe COPD. AB - Pulmonary hypertension during exercise is common in severe chronic obstructive pulmonary disease (COPD). It was hypothesised that the use of the endothelin receptor antagonist bosentan can improve cardiopulmonary haemodynamics during exercise, thus increasing exercise tolerance in patients with severe COPD. In the present double-blind, placebo-controlled study, 30 patients with severe or very severe COPD were randomly assigned in a 2:1 ratio to receive either bosentan or placebo for 12 weeks. The primary end-point was change in the 6-min walking distance. Secondary end-points included changes in health-related quality of life, lung function, cardiac haemodynamics, maximal oxygen uptake and pulmonary perfusion patterns. Compared with placebo, patients treated with bosentan during 12 weeks showed no significant improvement in exercise capacity as measured by the 6-min walking distance (mean+/-SD 331+/-123 versus 329+/-94 m). There was no change in lung function, pulmonary arterial pressure, maximal oxygen uptake or regional pulmonary perfusion pattern. In contrast, arterial oxygen pressure dropped, the alveolar-arterial gradient increased and quality of life deteriorated significantly in patients assigned bosentan. The oral administration of the endothelin receptor antagonist bosentan not only failed to improve exercise capacity but also deteriorated hypoxaemia and functional status in severe chronic obstructive pulmonary disease patients without severe pulmonary hypertension at rest. PMID- 18448497 TI - Heart biomarkers as prognostic tools for chronic thromboembolic pulmonary hypertension: a step forward by the fatty acid-binding protein. PMID- 18448498 TI - A place for T(L,NO) with T(L,CO)? PMID- 18448499 TI - Patient-centred asthma education in the emergency department: the case in favour. PMID- 18448500 TI - Patient-centred asthma education in the emergency department: the case against. PMID- 18448501 TI - The Innovative Medicines Initiative (IMI): a new opportunity for scientific collaboration between academia and industry at the European level. PMID- 18448502 TI - Determinants of hospital costs in community-acquired pneumonia. AB - Community-acquired pneumonia (CAP) has a high incidence and involves an important consumption of healthcare resources. The present authors analysed the influence of comorbidity, initial severity and complications upon the direct costs associated with hospitalised CAP patients. Direct hospitalisation costs (room cost, treatment, laboratory and diagnostic tests) were assessed in a prospective, observational study of 271 patients admitted to a hospital ward due to CAP. The mean+/-SD patient age was 70+/-15 yrs. The mortality rate was 11.1%. Complications were found in 72.3% and comorbidities in 74.9%. The median (interquartile range) total cost was 1,683 euros (1,291-2,471 euros) and the component costs were: room cost 1,286 euros (857-1,714 euros); laboratory tests 212 euros (171-272 euros); treatment 187 euros (114-304 euros); and diagnostic procedures 58 euros (29-122 euros). Complications and higher Pneumonia Severity Index increased the costs, but age and comorbidity did not. A logistic regression analysis to predict high cost (>1,683 euros) showed that infectious (odds ratio 6.8, 95% confidence interval 1.3-36), digestive (5.9 (1.5-22.8)), pulmonary (2.6 (1.4-4.7)) and other complications (3.9 (1.8-8.4)) were independent risk factors, as were previous hospitalisation (2.3 (1.2-4.3)) and hypoalbuminaemia (2 (1.1 3.6)). Complications, hypoalbuminaemia and previous hospitalisation were the main determinants of high direct costs of hospitalisation due to community-acquired pneumonia. Neither age nor comorbidities were independently associated with cost. PMID- 18448503 TI - Supervised and induced sputum among patients with smear-negative pulmonary tuberculosis. AB - Sputum culture is essential for monitoring drug resistance. Although sputum induction may optimise culture yield, better selection criteria and simpler algorithms are needed for countries with intermediate tuberculosis burdens. From a cohort of 660 patients who registered for antituberculosis treatment in a government chest clinic from May 21, 2005 to February 28, 2007, 187 patients with pulmonary disease and a negative smear in two unsupervised sputum specimens were enrolled prospectively for collection of one specimen each of supervised and induced sputum in succession. Among enrolled patients, induced sputum significantly improved ease of expectoration on a subjective five-point scale. Among 78 patients with culture-proven pulmonary tuberculosis, analysis of matched sputum culture results showed that: 1) induced sputum outperformed supervised sputum; 2) the second unsupervised sputum was significantly inferior to the first and redundant in the presence of the others; 3) adding one specimen each of supervised and induced sputum to two unsupervised specimens increased culture yield significantly; and 4) patients with either extent of disease less than right upper lobe or no respiratory symptoms were more likely to benefit. In summary, it may be practical to collect a sample of unsupervised, supervised and induced sputum for smear-negative patients with extent of disease less than the right upper lobe, especially when respiratory symptoms are absent. PMID- 18448504 TI - Novel tests for diagnosing tuberculous pleural effusion: what works and what does not? AB - Tuberculous pleuritis is a common manifestation of extrapulmonary tuberculosis and is the most common cause of pleural effusion in many countries. Conventional diagnostic tests, such as microscopic examination of the pleural fluid, biochemical tests, culture of pleural fluid, sputum or pleural tissue, and histopathological examination of pleural tissue, have known limitations. Due to these limitations, newer and more rapid diagnostic tests have been evaluated. In this review, the authors provide an overview of the performance of new diagnostic tests, including markers of specific and nonspecific immune response, nucleic acid amplification and detection, and predictive models based on combinations of markers. Directions for future development and evaluation of novel assays and biomarkers for pleural tuberculosis are also suggested. PMID- 18448505 TI - Regulation of alveolar epithelial function by hypoxia. AB - Patients with acute respiratory distress syndrome and high-altitude pulmonary oedema build up excess lung fluid, which leads to alveolar hypoxia. In patients with acute respiratory distress syndrome and hypoxia, there is a decrease in oedema fluid clearance, due in part to the downregulation of plasma membrane sodium-potassium adenosine triphosphatase (Na,K-ATPase). In alveolar epithelial cells, acute hypoxia promotes Na,K-ATPase endocytosis from the plasma membrane to intracellular compartments, resulting in inhibition of Na,K-ATPase activity. Exposure to prolonged hypoxia leads to degradation of plasma membrane Na,K ATPase. The downregulation of plasma membrane Na,K-ATPase reduces adenosine triphosphate demand, as part of a survival mechanism of cellular adaptation to hypoxia. Hypoxia has also been shown to disassemble and degrade the keratin intermediate filament network, a fundamental component of the cell cytoskeleton, affecting epithelial barrier function. Accordingly, better understanding of the mechanisms regulating cellular adaptation to hypoxia may lead to the development of novel therapeutic strategies for acute respiratory distress syndrome and high altitude pulmonary oedema patients. PMID- 18448506 TI - Drugs (including oxygen) in severe COPD. AB - Access to comprehensive guidelines on the management of chronic obstructive pulmonary disease (COPD) is now available, and several treatment goals of therapy have been identified from these guidelines, which have since been studied in clinical trials. Drug therapy is a key component of an individual patient's management plan, particularly in more severe disease. During the past few years, a number of new drug treatments have become available, although these are not always appropriately prescribed; this is particularly the case for oxygen. For patients with a history of exacerbations, there is good evidence for the use of inhaled long-acting anticholinergic agents or combined inhaled steroids and long acting beta-agonists. Evidence for prophylactic antibiotics and antioxidant agents is lacking. Nutritional and calorie supplementation have not been shown to improve exercise capacity. Statins may improve outcomes in COPD, but prospective trials are needed to confirm this. The evidence for the use of long-term oxygen therapy in hypoxaemic patients is robust. Ambulatory oxygen improves exercise capacity, but whether it is used appropriately is in doubt. Overall, short burst oxygen therapy does not offer a benefit and therefore cannot be recommended. PMID- 18448507 TI - Comparison of imaging techniques in the diagnosis of bridging bronchus. AB - Bridging bronchus (BB) is a rare, congenital bronchial anomaly that is frequently associated with congenital cardiac malformations, especially left pulmonary artery sling. It represents an anomalous bronchus to the right originating from the left main bronchus. Discrimination from other bronchial anomalies is important, since BB is frequently associated with bronchial stenoses due to abnormal cartilage rings. This case study describes the findings of bronchoscopy, bronchography and multidetector computed tomography (MDCT) in three patients. Bronchoscopy was helpful in the description of the severity and length of bronchial stenoses. However, it was not possible to establish a diagnosis of BB based on this method in two patients, since it is difficult or even impossible to differentiate the bifurcation from the pseudocarina. It was not possible to establish the correct diagnosis in all patients based on bronchography or MDCT. MDCT was able to depict the relationship of bronchial and vascular structures, which is particularly important in patients with pulmonary artery sling. Multidetector computed tomography is preferable to bronchography as it is less invasive and due to its short acquisition time it can be performed in children with severe respiratory disease. In the current authors' experience, detection of cartilage rings still requires flexible bronchoscopy. PMID- 18448508 TI - Rapid diagnosis of pulmonary TB by BAL enzyme-linked immunospot assay in an immunocompromised host. AB - Immunocompromised patients with acid-fast bacilli (AFB) smear-negative active pulmonary tuberculosis (pTB) often present with nonspecific clinical symptoms and findings. T-cell interferon-gamma release assays (TIGRA) performed on whole blood (using ELISA) or peripheral blood mononuclear cells (using enzyme-linked immunospot assay (ELISPOT)) are more sensitive for the diagnosis of Mycobacterium tuberculosis (MTB) infection than the tuberculin skin test (TST), but cannot distinguish active from latent MTB infection. The present authors report a 38-yr old female presenting with a 3-week history of malaise, dyspnoea, fevers and coughing, who had received immunosuppressive therapies over 8 months for mixed connective tissue disease. Chest radiograph and thoracic computed tomography showed ground glass opacities in both lower lobes. The TST-induration was 0 mm and AFBs or MTB nucleic acid was not detected on sputum and bronchial secretions. However, TIGRAs performed on peripheral blood cells were reactive. A high frequency of MTB-specific T-cells compatible with the immunodiagnosis of active pTB was detected among bronchoalveolar lavage cells using ELISPOT. Antituberculous therapy was initiated 18 days before MTB was discovered on sputum cultures. Detection of Mycobacterium tuberculosis-specific T-cells in the bronchoalveolar lavage using enzyme-linked immunospot assay is a promising tool for the diagnosis of active pulmonary tuberculosis in immunocompromised patients with negative acid-fast bacilli smears. PMID- 18448509 TI - Noninvasive ventilation in severe stable COPD: is it effective, and if so, in what way? PMID- 18448510 TI - Is air travel safe for those with lung disease? PMID- 18448511 TI - Prevention of ventilator-associated pneumonia: possible role of antimicrobials administered via the respiratory tract. PMID- 18448512 TI - Competitive swimmers with allergic asthma show a mixed type of airway inflammation. PMID- 18448513 TI - Idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia should stay separate. PMID- 18448514 TI - Aqua jogging-induced pulmonary oedema. PMID- 18448515 TI - Evidence that the gene encoding insulin degrading enzyme influences human lifespan. AB - Studies in model organisms have demonstrated that components of insulin and insulin-like signaling pathways are involved in the regulation of lifespan but the relevance of those findings to humans has remained obscure. Here we provide evidence suggesting that variants of the gene encoding insulin-degrading enzyme (IDE) may be influencing human lifespan. We have employed a variety of models and diverse samples that reproducibly indicate the relative change in IDE genotype frequency across the age spectrum as well as allow the detection of association with age-at-death. A tenable molecular basis of this is suggested by the observation of genetic association with both fasting plasma insulin levels and IDE mRNA expression. Across populations the emergent genetic model is indicative of over-dominance, where heterozygotes of critical markers have increased IDE mRNA expression and insulin levels, and this is reflected in diminished heterozygosity at advanced age. A critical and replicating feature of this study is that change in IDE genotype frequency with advancing age appears to be occurring only in men, and this is supported in that insulin levels are only associated with IDE in men. Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans, but over-dominance and gender specificity will be important parameters to consider clarifying the biological importance of these findings. PMID- 18448516 TI - Ebstein anomaly and hypertrophic cardiomyopathy. PMID- 18448517 TI - Annexin II incorporated into influenza virus particles supports virus replication by converting plasminogen into plasmin. AB - For influenza viruses to become infectious, the proteolytic cleavage of hemagglutinin (HA) is essential. This usually is mediated by trypsin-like proteases in the respiratory tract. The binding of plasminogen to influenza virus A/WSN/33 leads to the cleavage of HA, a feature determining its pathogenicity and neurotropism in mice. Here, we demonstrate that plasminogen also promotes the replication of other influenza virus strains. The inhibition of the conversion of plasminogen into plasmin blocked influenza virus replication. Evidence is provided that the activation of plasminogen is mediated by the host cellular protein annexin II, which is incorporated into the virus particles. Indeed, the inhibition of plasminogen binding to annexin II by using a competitive inhibitor inhibits plasminogen activation into plasmin. Collectively, these results indicate that the annexin II-mediated activation of plasminogen supports the replication of influenza viruses, which may contribute to their pathogenicity. PMID- 18448518 TI - The nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibits cell cytokinesis and proliferation by interacting with translation elongation factor 1alpha. AB - Severe acute respiratory syndrome coronavirus (SARS-CoV) is the etiological agent of SARS, an emerging disease characterized by atypical pneumonia. Using a yeast two-hybrid screen with the nucleocapsid (N) protein of SARS-CoV as a bait, the C terminus (amino acids 251 to 422) of the N protein was found to interact with human elongation factor 1-alpha (EF1alpha), an essential component of the translational machinery with an important role in cytokinesis, promoting the bundling of filamentous actin (F-actin). In vitro and in vivo interaction was then confirmed by immuno-coprecipitation, far-Western blotting, and surface plasmon resonance. It was demonstrated that the N protein of SARS-CoV induces aggregation of EF1alpha, inhibiting protein translation and cytokinesis by blocking F-actin bundling. Proliferation of human peripheral blood lymphocytes and other human cell lines was significantly inhibited by the infection of recombinant retrovirus expressing SARS-CoV N protein. PMID- 18448519 TI - Differential antigen requirements for protection against systemic and intranasal vaccinia virus challenges in mice. AB - The development of a subunit vaccine for smallpox represents a potential strategy to avoid the safety concerns associated with replication-competent vaccinia virus. Preclinical studies to date with subunit smallpox vaccine candidates, however, have been limited by incomplete information regarding protective antigens and the requirement for multiple boost immunizations to afford protective immunity. Here we explore the protective efficacy of replication incompetent, recombinant adenovirus serotype 35 (rAd35) vectors expressing the vaccinia virus intracellular mature virion (IMV) antigens A27L and L1R and extracellular enveloped virion (EEV) antigens A33R and B5R in a murine vaccinia virus challenge model. A single immunization with the rAd35-L1R vector effectively protected mice against a lethal systemic vaccinia virus challenge. The rAd35-L1R vector also proved more efficacious than the combination of four rAd35 vectors expressing A27L, L1R, A33R, and B5R. Moreover, serum containing L1R specific neutralizing antibodies afforded postexposure prophylaxis after systemic vaccinia virus infection. In contrast, the combination of rAd35-L1R and rAd35-B5R vectors was required to protect mice against a lethal intranasal vaccinia virus challenge, suggesting that both IMV- and EEV-specific immune responses are important following intranasal infection. Taken together, these data demonstrate that different protective antigens are required based on the route of vaccinia virus challenge. These studies also suggest that rAd vectors warrant further assessment as candidate subunit smallpox vaccines. PMID- 18448520 TI - Severe acute respiratory syndrome coronavirus protein 6 accelerates murine hepatitis virus infections by more than one mechanism. AB - The severe acute respiratory syndrome coronavirus (SARS-CoV) encodes numerous accessory proteins whose importance in the natural infection process is currently unclear. One of these accessory proteins is set apart by its function in the context of a related murine hepatitis virus (MHV) infection. SARS-CoV protein 6 increases MHV neurovirulence and accelerates MHV infection kinetics in tissue culture. Protein 6 also blocks nuclear import of macromolecules from the cytoplasm, a process known to involve its C-terminal residues interacting with cellular importins. In this study, protein 6 was expressed from plasmid DNAs and accumulated in cells prior to infection by wild-type MHV. Output of MHV progeny was significantly increased by preexisting protein 6. Protein 6 with C-terminal deletion mutations no longer interfered with nuclear import processes but still retained much of the capacity to augment MHV infections. However, some virus growth-enhancing activity could be ascribed to the C-terminal end of protein 6. To determine whether this augmentation provided by the C terminus was derived from interference with nuclear import, we evaluated the virus-modulating effects of small interfering RNAs (siRNAs) directed against importin-beta mRNAs, which down-regulated classical nuclear import pathways. The siRNAs did indeed prime cells for enhanced MHV infection. Our findings indicated that protein 6-mediated nuclear import blocks augmented MHV infections but is clearly not the only way that this accessory protein operates to create a milieu conducive to robust virus growth. Thus, the SARS-CoV protein 6 accelerates MHV infections by more than one mechanism. PMID- 18448521 TI - Mutations in the spacer peptide and adjoining sequences in Rous sarcoma virus Gag lead to tubular budding. AB - All orthoretroviruses encode a single structural protein, Gag, which is necessary and sufficient for the assembly and budding of enveloped virus-like particles from the cell. The Gag proteins of Rous sarcoma virus (RSV) and human immunodeficiency virus type 1 (HIV-1) contain a short spacer peptide (SP or SP1, respectively) separating the capsid (CA) and nucleocapsid (NC) domains. SP or SP1 and the residues immediately upstream are known to be critical for proper assembly. Using mutagenesis and electron microscopy analysis of insect cells or chicken cells overexpressing RSV Gag, we defined the SP assembly domain to include the last 8 residues of CA, all 12 residues of SP, and the first 4 residues of NC. Five- or two-amino acid glycine-rich insertions or substitutions in this critical region uniformly resulted in the budding of abnormal, long tubular particles. The equivalent SP1-containing HIV-1 Gag sequence was unable to functionally replace the RSV sequence in supporting normal RSV spherical assembly. According to secondary structure predictions, RSV and HIV-1 SP/SP1 and adjoining residues may form an alpha helix, and what is likely the functionally equivalent sequence in murine leukemia virus Gag has been inferred by mutational analysis to form an amphipathic alpha helix. However, our alanine insertion mutagenesis did not provide evidence for an amphipathic helix in RSV Gag. Taken together, these results define a short assembly domain between the folded portions of CA and NC, which is essential for formation of the immature Gag shell. PMID- 18448523 TI - Hypovirus papain-like protease p48 is required for initiation but not for maintenance of virus RNA propagation in the chestnut blight fungus Cryphonectria parasitica. AB - The prototypic hypovirus CHV1-EP713, responsible for virulence attenuation (hypovirulence) of the chestnut blight fungus Cryphonectria parasitica, encodes two papain-like proteases, p29 and p48. Protein p29 has been shown to be dispensable for hypovirus RNA replication and to act as a suppressor of RNA silencing. Here we describe a role for p48 in hypovirus RNA propagation. CHV1 EP713 infectious cDNA clones in which the p48 coding region was deleted, Delta p48, were unable to establish infection in C. parasitica when introduced as a DNA form by transformation or as a coding strand transcript by electroporation. However, the Delta p48 mutant virus RNA was rescued when p48 was provided in trans. Surprisingly, the Delta p48 mutant viruses retained replication competence in the apparent absence of p48 following transmission to wild-type C. parasitica and successive subculturing. The replicating Delta p48 mutant virus was reduced in RNA accumulation by 60% both in the absence and presence of p48 provided in trans and was transmitted through asexual spores (conidia) at a rate 3 to 8% of that for full-length CHV1-EP713. Complementary analysis of strains expressing p48 or containing the replicating Delta p48 mutant virus showed that like p29, p48 contributes to virus-mediated suppression of host pigmentation and conidiation, although to a lesser extent, and is dispensable for hypovirus-mediated hypovirulence. The combined results suggest that papain-like protease p48 plays an essential role in the initiation but not the maintenance of virus RNA propagation and also contributes to the regulation of viral RNA accumulation and vertical transmission. PMID- 18448522 TI - Functional domains and the antiviral effect of the double-stranded RNA-dependent protein kinase PKR from Paralichthys olivaceus. AB - The double-stranded RNA (dsRNA)-dependent protein kinase PKR is thought to mediate a conserved antiviral pathway by inhibiting viral protein synthesis via the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha). However, little is known about the data related to the lower vertebrates, including fish. Recently, the identification of PKR-like, or PKZ, has addressed the question of whether there is an orthologous PKR in fish. Here, we identify the first fish PKR gene from the Japanese flounder Paralichthys olivaceus (PoPKR). PoPKR encodes a protein that shows a conserved structure that is characteristic of mammalian PKRs, having both the N-terminal region for dsRNA binding and the C-terminal region for the inhibition of protein translation. The catalytic activity of PoPKR is further evidence that it is required for protein translation inhibition in vitro. PoPKR is constitutively transcribed at low levels and is highly induced after virus infection. Strikingly, PoPKR overexpression increases eIF2alpha phosphorylation and inhibits the replication of Scophthalmus maximus rhabdovirus (SMRV) in flounder embryonic cells, whereas phosphorylation and antiviral effects are impaired in transfected cells expressing the catalytically inactive PKR-K421R variant, indicating that PoPKR inhibits virus replication by phosphorylating substrate eIF2alpha. The interaction between PoPKR and eIF2alpha is demonstrated by coimmunoprecipitation assays, and the transfection of PoPKR-specific short interfering RNA further reveals that the enhanced eIF2alpha phosphorylation is catalyzed by PoPKR during SMRV infection. The current data provide significant evidence for the existence of a PKR-mediated antiviral pathway in fish and reveal considerable conservation in the functional domains and the antiviral effect of PKR proteins between fish and mammals. PMID- 18448524 TI - Cell adhesion promotes Ebola virus envelope glycoprotein-mediated binding and infection. AB - Ebola virus infects a wide variety of adherent cell types, while nonadherent cells are found to be refractory. To explore this correlation, we compared the ability of pairs of related adherent and nonadherent cells to bind a recombinant Ebola virus receptor binding domain (EboV RBD) and to be infected with Ebola virus glycoprotein (GP)-pseudotyped particles. Both human 293F and THP-1 cells can be propagated as adherent or nonadherent cultures, and in both cases adherent cells were found to be significantly more susceptible to both EboV RBD binding and GP-pseudotyped virus infection than their nonadherent counterparts. Furthermore, with 293F cells the acquisition of EboV RBD binding paralleled cell spreading and did not require new mRNA or protein synthesis. PMID- 18448525 TI - Interaction between polypeptide 3ABC and the 5'-terminal structural elements of the genome of Aichi virus: implication for negative-strand RNA synthesis. AB - Secondary structural elements at the 5' end of picornavirus genomic RNA function as cis-acting replication elements and are known to interact specifically with viral P3 proteins in several picornaviruses. In poliovirus, ribonucleoprotein complex formation at the 5' end of the genome is required for negative-strand synthesis. We have previously shown that the 5'-end 115 nucleotides of the Aichi virus genome, which are predicted to fold into two stem-loops (SL-A and SL-C) and one pseudoknot (PK-B), act as a cis-acting replication element and that correct folding of these structures is required for negative-strand synthesis. In this study, we investigated the interaction between the 5'-terminal 120 nucleotides of the genome and the P3 proteins, 3AB, 3ABC, 3C, and 3CD, by gel shift assay and Northwestern analysis. The results showed that 3ABC and 3CD bound to the 5' terminal region specifically. The binding of 3ABC was observed on both assays, while that of 3CD was detected only on Northwestern analysis. No binding of 3AB or 3C was observed. Binding assays using mutant RNAs demonstrated that disruption of the base pairings of the stem of SL-A and one of the two stem segments of PK-B (stem-B1) abolished the 3ABC binding. In addition, the specific nucleotide sequence of stem-B1 was responsible for the efficient 3ABC binding. These results suggest that the interaction of 3ABC with the 5'-terminal region of the genome is involved in negative-strand synthesis. On the other hand, the ability of 3CD to interact with the 5'-terminal region did not correlate with the RNA replication ability. PMID- 18448526 TI - Molecular basis of cytotoxicity of Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) in EBV latency III B cells: LMP1 induces type II ligand independent autoactivation of CD95/Fas with caspase 8-mediated apoptosis. AB - The Epstein-Barr virus (EBV) oncoprotein latent membrane protein 1 (LMP1) is thought to act as the major transforming protein in various cell types, by rerouting the tumor necrosis factor receptor family signaling pathway. Despite this implication in EBV-associated transformation of cells, LMP1 toxicity is a well-known but poorly studied feature, perhaps because it contradicts its role in transformation. We show that LMP1 physiological levels are very heterogeneous and that the highest levels of LMP1 correlate with Fas overexpression and spontaneous apoptosis in lymphoblastoid cell lines (LCLs). To understand the cytotoxic effect of LMP1 in LCLs, we cloned wild-type LMP1 into a doxycycline double-inducible episomal vector pRT-1, with a truncated version of NGFR as a surrogate marker of inducibility. We found that LMP1 overexpression induced apoptosis in LCL B cells, as shown by annexin V labeling, sub-G(1) peak, and poly(ADP ribose) polymerase cleavage. Knocking down Fas expression by small interfering RNA abolished LMP1 induced apoptosis. The absence of detectable levels of Fas ligand mRNA suggested a ligand-independent activation of Fas. LMP1 induced Fas overexpression with its relocalization in lipid raft microdomains of the membrane. Fas immunoprecipitation detected FADD (Fas-associated death domain protein) and caspase 8, suggesting a Fas-dependent formation of the death-inducing signaling complex. Caspases 8, 9, 3, and 7 were activated by LMP1. Caspase 8 activation was associated with BID cleavage and truncated-BID mitochondrial relocalization, consistent with type II apoptosis. Therefore, our results are in agreement with a model where LMP1-dependent NF-kappaB activation induces Fas overexpression and autoactivation that could overwhelm the antiapoptotic effect of NF-kappaB, revealing an ambivalent function of LMP1 in cell survival and programmed cell death. PMID- 18448527 TI - Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections. AB - It is believed that a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), was passed from palm civets to humans and caused the epidemic of SARS in 2002 to 2003. The major species barriers between humans and civets for SARS-CoV infections are the specific interactions between a defined receptor-binding domain (RBD) on a viral spike protein and its host receptor, angiotensin-converting enzyme 2 (ACE2). In this study a chimeric ACE2 bearing the critical N-terminal helix from civet and the remaining peptidase domain from human was constructed, and it was shown that this construct has the same receptor activity as civet ACE2. In addition, crystal structures of the chimeric ACE2 complexed with RBDs from various human and civet SARS-CoV strains were determined. These structures, combined with a previously determined structure of human ACE2 complexed with the RBD from a human SARS-CoV strain, have revealed a structural basis for understanding the major species barriers between humans and civets for SARS-CoV infections. They show that the major species barriers are determined by interactions between four ACE2 residues (residues 31, 35, 38, and 353) and two RBD residues (residues 479 and 487), that early civet SARS-CoV isolates were prevented from infecting human cells due to imbalanced salt bridges at the hydrophobic virus/receptor interface, and that SARS-CoV has evolved to gain sustained infectivity for human cells by eliminating unfavorable free charges at the interface through stepwise mutations at positions 479 and 487. These results enhance our understanding of host adaptations and cross-species infections of SARS-CoV and other emerging animal viruses. PMID- 18448528 TI - Genetic interactions among the West Nile virus methyltransferase, the RNA dependent RNA polymerase, and the 5' stem-loop of genomic RNA. AB - Flavivirus methyltransferase catalyzes both guanine N7 and ribose 2'-OH methylations of the viral RNA cap (GpppA-RNA-->m(7)GpppAm-RNA). The methyltransferase is physically linked to an RNA-dependent RNA polymerase (RdRp) in the flaviviral NS5 protein. Here, we report genetic interactions of West Nile virus (WNV) methyltransferase with the RdRp and the 5'-terminal stem-loop of viral genomic RNA. Genome-length RNAs, containing amino acid substitutions of D146 (a residue essential for both cap methylations) in the methyltransferase, were transfected into BHK-21 cells. Among the four mutant RNAs (D146L, D146P, D146R, and D146S), only D146S RNA generated viruses in transfected cells. Sequencing of the recovered viruses revealed that, besides the D146S change in the methyltransferase, two classes of compensatory mutations had reproducibly emerged. Class 1 mutations were located in the 5'-terminal stem-loop of the genomic RNA (a G35U substitution or U38 insertion). Class 2 mutations resided in NS5 (K61Q in methyltransferase and W751R in RdRp). Mutagenesis analysis, using a genome-length RNA and a replicon of WNV, demonstrated that the D146S substitution alone was lethal for viral replication; however, the compensatory mutations rescued replication, with the highest rescuing efficiency occurring when both classes of mutations were present. Biochemical analysis showed that a low level of N7 methylation of the D146S methyltransferase is essential for the recovery of adaptive viruses. The methyltransferase K61Q mutation facilitates viral replication through improved N7 methylation activity. The RdRp W751R mutation improves viral replication through an enhanced polymerase activity. Our results have clearly established genetic interactions among flaviviral methyltransferase, RdRp, and the 5' stem-loop of the genomic RNA. PMID- 18448529 TI - Hepatitis B virus HBx protein localizes to mitochondria in primary rat hepatocytes and modulates mitochondrial membrane potential. AB - Over 350 million people are chronically infected with hepatitis B virus (HBV), and a significant number of chronically infected individuals develop primary liver cancer. HBV encodes seven viral proteins, including the nonstructural X (HBx) protein. The results of studies with immortalized or transformed cells and with HBx-transgenic mice demonstrated that HBx can interact with mitochondria. However, no studies with normal hepatocytes have characterized the precise mitochondrial localization of HBx or the effect of HBx on mitochondrial physiology. We have used cultured primary rat hepatocytes as a model system to characterize the mitochondrial localization of HBx and the effect of HBx expression on mitochondrial physiology. We now show that a fraction of HBx colocalizes with density-gradient-purified mitochondria and associates with the outer mitochondrial membrane. We also demonstrate that HBx regulates mitochondrial membrane potential in hepatocytes and that this function of HBx varies depending on the status of NF-kappaB activity. In primary rat hepatocytes, HBx activation of NF-kappaB prevented mitochondrial membrane depolarization; however, when NF-kappaB activity was inhibited, HBx induced membrane depolarization through modulation of the mitochondrial permeability transition pore. Collectively, these results define potential pathways through which HBx may act in order to modulate mitochondrial physiology, thereby altering many cellular activities and ultimately contributing to the development of HBV-associated liver cancer. PMID- 18448530 TI - Enhanced mucosal immunoglobulin A response and solid protection against foot-and mouth disease virus challenge induced by a novel dendrimeric peptide. AB - The successful use of a dendrimeric peptide to protect pigs against challenge with foot-and-mouth disease virus (FMDV), which causes the most devastating animal disease worldwide, is described. Animals were immunized intramuscularly with a peptide containing one copy of a FMDV T-cell epitope and branching out into four copies of a B-cell epitope. The four immunized pigs did not develop significant clinical signs upon FMDV challenge, neither systemic nor mucosal FMDV replication, nor was its transmission to contact control pigs observed. The dendrimeric construction specifically induced high titers of FMDV-neutralizing antibodies and activated FMDV-specific T cells. Interestingly, a potent anti-FMDV immunoglobulin A response (local and systemic) was observed, despite the parenteral administration of the peptide. On the other hand, peptide-immunized animals showed no antibodies specific of FMDV infection, which qualifies the peptide as a potential marker vaccine. Overall, the dendrimeric peptide used elicited an immune response comparable to that found for control FMDV-infected pigs that correlated with a solid protection against FMDV challenge. Dendrimeric designs of this type may hold substantial promise for peptide subunit vaccine development. PMID- 18448531 TI - The UL25 gene product of herpes simplex virus type 1 is involved in uncoating of the viral genome. AB - Studies on the herpes simplex virus type 1 UL25-null mutant KUL25NS have shown that the capsid-associated UL25 protein is required at a late stage in the encapsidation of viral DNA. Our previous work on UL25 with the UL25 temperature sensitive (ts) mutant ts1204 also implicated UL25 in a role at very early times in the virus growth cycle, possibly at the stage of penetration of the host cell. We have reexamined this mutant and discovered that it had an additional ts mutation elsewhere in the genome. The ts1204 UL25 mutation was transferred into wild-type (wt) virus DNA, and the UL25 mutant ts1249 was isolated and characterized to clarify the function of UL25 at the initial stages of virus infection. Indirect immunofluorescence assays and in situ hybridization analysis of virus-infected cells revealed that the mutant ts1249 was not impaired in penetration of the host cell but had an uncoating defect at the nonpermissive temperature. When ts1249-infected cells were incubated initially at the permissive temperature to allow uncoating of the viral genome and subsequently transferred to the restrictive temperature, a DNA-packaging defect was evident. The results suggested that ts1249, like KUL25NS, had a block at a late stage of DNA packaging and that the packaged genome was shorter than the full-length genome. Examination of ts1249 capsids produced at the nonpermissive temperature revealed that, in comparison with wt capsids, they contained reduced amounts of UL25 protein, thereby providing a possible explanation for the failure of ts1249 to package full-length viral DNA. PMID- 18448532 TI - Impact of endogenous intronic retroviruses on major histocompatibility complex class II diversity and stability. AB - The major histocompatibility complex (MHC) represents a multigene family that is known to display allelic and gene copy number variations. Primate species such as humans, chimpanzees (Pan troglodytes), and rhesus macaques (Macaca mulatta) show DRB region configuration polymorphism at the population level, meaning that the number and content of DRB loci may vary per haplotype. Introns of primate DRB alleles differ significantly in length due to insertions of transposable elements as long endogenous retrovirus (ERV) and human ERV (HERV) sequences in the DRB2, DRB6, and DRB7 pseudogenes. Although the integration of intronic HERVs resulted sooner or later in the inactivation of the targeted genes, the fixation of these endogenous retroviral segments over long time spans seems to have provided evolutionary advantage. Intronic HERVs may have integrated in a sense or an antisense manner. On the one hand, antisense-oriented retroelements such as HERV K14I, observed in intron 2 of the DRB7 genes in humans and chimpanzees, seem to promote stability, as configurations/alleles containing these hits have experienced strong conservative selection during primate evolution. On the other hand, the HERVK3I present in intron 1 of all DRB2 and/or DRB6 alleles tested so far integrated in a sense orientation. The data suggest that multigenic regions in particular may benefit from sense introgressions by HERVs, as these elements seem to promote and maintain the generation of diversity, whereas these types of integrations may be lethal in monogenic systems, since they are known to influence transcript regulation negatively. PMID- 18448533 TI - Viral proteins interfering with antigen presentation target the major histocompatibility complex class I peptide-loading complex. PMID- 18448534 TI - Dendritic cell internalization of foot-and-mouth disease virus: influence of heparan sulfate binding on virus uptake and induction of the immune response. AB - Dendritic cells (DC), which are essential for inducing and regulating immune defenses and responses, represent the critical target for vaccines against pathogens such as foot-and-mouth disease virus (FMDV). Although it is clear that FMDV enters epithelial cells via integrins, little is known about FMDV interaction with DC. Accordingly, DC internalization of FMDV antigen was analyzed by comparing vaccine virus dominated by heparan sulfate (HS)-binding variants with FMDV lacking HS-binding capacity. The internalization was most efficient with the HS-binding virus, employing diverse endocytic pathways. Moreover, internalization relied primarily on HS binding. Uptake of non-HS-binding virus by DC was considerably less efficient, so much so that it was often difficult to detect virus interacting with the DC. The HS-binding FMDV replicated in DC, albeit transiently, which was demonstrable by its sensitivity to cycloheximide treatment and the short duration of infectious virus production. There was no evidence that the non-HS-binding virus replicated in the DC. These observations on virus replication may be explained by the activities of viral RNA in the DC. When DC were transfected with infectious RNA, only 1% of the translated viral proteins were detected. Nevertheless, the transfected cells, and DC which had internalized live virus, did present antigen to lymphocytes, inducing an FMDV specific immunoglobulin G response. These results demonstrate that DC internalization of FMDV is most efficient for vaccine virus with HS-binding capacity, but HS binding is not an exclusive requirement. Both non-HS-binding virus and infectious RNA interacting with DC induce specific immune responses, albeit less efficiently than HS-binding virus. PMID- 18448535 TI - Interactions of murine APOBEC3 and human APOBEC3G with murine leukemia viruses. AB - APOBEC3 proteins are cytidine deaminases which help defend cells against retroviral infections. One antiviral mechanism involves deaminating dC residues in minus-strand DNA during reverse transcription, resulting in G-to-A mutations in the coding strand. We investigated the effects of mouse APOBEC3 (mA3) and human APOBEC3G (hA3G) upon Moloney murine leukemia virus (MLV). We find that mA3 inactivates MLV but is significantly less effective against MLV than is hA3G. In contrast, mA3 is as potent against human immunodeficiency virus type 1 (HIV-1, lacking the protective Vif protein) as is hA3G. The two APOBEC3 proteins are packaged to similar extents in MLV particles. Dose-response profiles imply that a single APOBEC3 molecule (or oligomer) is sufficient to inactivate an MLV particle. The inactivation of MLV by mA3 and hA3G is accompanied by relatively small reductions in the amount of viral DNA in infected cells. Although hA3G induces significant levels of G-to-A mutations in both MLV and HIV DNAs, and mA3 induces these mutations in HIV DNA, no such mutations were detected in DNA synthesized by MLV inactivated by mA3. Thus, MLV has apparently evolved to partially resist the antiviral effects of mA3 and to totally resist the ability of mA3 to induce G-to-A mutation in viral DNA. Unlike the resistance of HIV-1 and human T-cell leukemia virus type 1 to hA3G, the resistance of MLV to mA3 is not mediated by the exclusion of APOBEC from the virus particle. The nature of its resistance and the mechanism of inactivation of MLV by mA3 are completely unknown. PMID- 18448536 TI - Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. AB - Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH), suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus induced growth factors and cytokines in the CMV secretome. PMID- 18448537 TI - The temperate marine phage PhiHAP-1 of Halomonas aquamarina possesses a linear plasmid-like prophage genome. AB - A myovirus-like temperate phage, PhiHAP-1, was induced with mitomycin C from a Halomonas aquamarina strain isolated from surface waters in the Gulf of Mexico. The induced cultures produced significantly more virus-like particles (VLPs) (3.73 x 10(10) VLP ml(-1)) than control cultures (3.83 x 10(7) VLP ml(-1)) when observed with epifluorescence microscopy. The induced phage was sequenced by using linker-amplified shotgun libraries and contained a genome 39,245 nucleotides in length with a G+C content of 59%. The PhiHAP-1 genome contained 46 putative open reading frames (ORFs), with 76% sharing significant similarity (E value of <10(-3)) at the protein level with other sequences in GenBank. Putative functional gene assignments included small and large terminase subunits, capsid and tail genes, an N6-DNA adenine methyltransferase, and lysogeny-related genes. Although no integrase was found, the PhiHAP-1 genome contained ORFs similar to protelomerase and parA genes found in linear plasmid-like phages with telomeric ends. Southern probing and PCR analysis of host genomic, plasmid, and PhiHAP-1 DNA indicated a lack of integration of the prophage with the host chromosome and a difference in genome arrangement between the prophage and virion forms. The linear plasmid prophage form of PhiHAP-1 begins with the protelomerase gene, presumably due to the activity of the protelomerase, while the induced phage particle has a circularly permuted genome that begins with the terminase genes. The PhiHAP-1 genome shares synteny and gene similarity with coliphage N15 and vibriophages VP882 and VHML, suggesting an evolutionary heritage from an N15-like linear plasmid prophage ancestor. PMID- 18448538 TI - Comparison of G-to-A mutation frequencies induced by APOBEC3 proteins in H9 cells and peripheral blood mononuclear cells in the context of impaired processivities of drug-resistant human immunodeficiency virus type 1 reverse transcriptase variants. AB - APOBEC3 proteins can inhibit human immunodeficiency virus type 1 (HIV-1) replication by inducing G-to-A mutations in newly synthesized viral DNA. However, HIV-1 is able to overcome the antiretroviral activity of some of those enzymes by the viral protein Vif. We investigated the impact of different processivities of HIV-1 reverse transcriptases (RT) on the frequencies of G-to-A mutations introduced by APOBEC3 proteins. Wild-type RT or the M184V, M184I, and K65R+M184V RT variants, which are increasingly impaired in their processivities, were used in the context of a vif-deficient molecular HIV-1 clone to infect H9 cells and peripheral blood mononuclear cells (PBMCs). After two rounds of infection, a part of the HIV-1 env gene was amplified, cloned, and sequenced. The M184V mutation led to G-to-A mutation frequencies that were similar to those of the wild-type RT in H9 cells and PBMCs. The frequencies of G-to-A mutations were increased after infection with the M184I virus variant. This effect was augmented when using the K65R+M184V virus variant (P < 0.001). Overall, the G-to-A mutation frequencies were lower in PBMCs than in H9 cells. Remarkably, 38% +/- 18% (mean +/- standard deviation) of the env clones derived from PBMCs did not harbor any G-to-A mutation. This was rarely observed in H9 cells (3% +/- 3%). Our data imply that the frequency of G-to-A mutations induced by APOBEC3 proteins can be influenced by the processivities of HIV-1 RT variants. The high number of nonmutated clones derived from PBMCs leads to several hypotheses, including that additional antiretroviral mechanisms of APOBEC3 proteins other than their deamination activity might be involved in the inhibition of vif-deficient viruses. PMID- 18448539 TI - A seven-segmented influenza A virus expressing the influenza C virus glycoprotein HEF. AB - Influenza viruses are classified into three types: A, B, and C. The genomes of A- and B-type influenza viruses consist of eight RNA segments, whereas influenza C viruses only have seven RNAs. Both A and B influenza viruses contain two major surface glycoproteins: the hemagglutinin (HA) and the neuraminidase (NA). Influenza C viruses have only one major surface glycoprotein, HEF (hemagglutinin esterase fusion). By using reverse genetics, we generated two seven-segmented chimeric influenza viruses. Each possesses six RNA segments from influenza virus A/Puerto Rico/8/34 (PB2, PB1, PA, NP, M, and NS); the seventh RNA segment encodes either the influenza virus C/Johannesburg/1/66 HEF full-length protein or a chimeric protein HEF-Ecto, which consists of the HEF ectodomain and the HA transmembrane and cytoplasmic regions. To facilitate packaging of the heterologous segment, both the HEF and HEF-Ecto coding regions are flanked by HA packaging sequences. When introduced as an eighth segment with the NA packaging sequences, both viruses are able to stably express a green fluorescent protein (GFP) gene, indicating a potential use for these viruses as vaccine vectors to carry foreign antigens. Finally, we show that incorporation of a GFP RNA segment enhances the growth of seven-segmented viruses, indicating that efficient influenza A viral RNA packaging requires the presence of eight RNA segments. These results support a selective mechanism of viral RNA recruitment to the budding site. PMID- 18448540 TI - Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of hepatitis C virus genotype 1 and their relationships to pegylated interferon-ribavirin treatment responses. AB - Mutations in several subgenomic regions of hepatitis C virus (HCV) have been implicated in influencing the response to interferon (IFN) therapy. Sequences within HCV NS5A (PKR binding domain [PKRBD], IFN sensitivity-determining region [ISDR], and variable region 3 [V3]) were analyzed for the pretreatment serum samples of 60 HCV genotype 1-infected patients treated with pegylated IFN plus ribavirin (1b, n = 47; 1a, n = 13) but with different treatment outcomes, those with sustained virologic responses (SVR; n = 36) or nonresponders (NR; n = 24). Additionally, the sequence of the PKR/eIF-2alpha phosphorylation homology domain (E2-PePHD) region was determined for 23 patients (11 SVR and 12 NR). The presence of > 4 mutations in the PKRBD region was associated with SVR (P = 0.001) and early virologic responses (EVR; 12 weeks) (P = 0.037) but not rapid virologic responses (4 weeks). In the ISDR, the difference was almost statistically significant (68% of SVR patients with mutations versus 45% without mutations; P = 0.07). The V3 region had a very high genetic variability, but this was not related to SVR. Finally, the E2-PePHD (n = 23) region was well conserved. The presence of > 4 mutations in the PKRBD region (odds ratio [OR] = 9.9; P = 0.006) and an age of < or = 40 years (OR = 3.2; P = 0.056) were selected in a multivariate analysis as predictive factors of SVR. NS5A sequences from serum samples taken after 1 month of treatment and posttreatment were examined for 3 SVR and 15 NR patients to select treatment-resistant viral subpopulations, and it was found that in the V3 and flanking regions, the mutations increased significantly in posttreatment sera (P = 0.05). The genetic variability in the PKRBD (> 4 mutations) is a predictive factor of SVR and EVR in HCV genotype 1 patients treated with pegylated IFN and ribavirin. PMID- 18448541 TI - Small interfering RNAs that deplete the cellular translation factor eIF4H impede mRNA degradation by the virion host shutoff protein of herpes simplex virus. AB - The herpes simplex virus (HSV) virion host shutoff (Vhs) protein is an endoribonuclease that accelerates decay of many host and viral mRNAs. Purified Vhs does not distinguish mRNAs from nonmessenger RNAs and cuts target RNAs at many sites, yet within infected cells it is targeted to mRNAs and cleaves those mRNAs at preferred sites including, for some, regions of translation initiation. This targeting may result in part from Vhs binding to the translation initiation factor eIF4H; in particular, several mutations in Vhs that abrogate its binding to eIF4H also abolish its mRNA-degradative activity, even though the mutant proteins retain endonuclease activity. To further investigate the role of eIF4H in Vhs activity, HeLa cells were depleted of eIF4H or other proteins by transfection with small interfering RNAs (siRNAs) 48 h prior to infection or mock infection in the presence of actinomycin D. Cellular mRNA levels were then assayed 5 h after infection. In cells transfected with an siRNA for the housekeeping enzyme glyceraldehyde-3-phosphate dehydrogenase, wild-type HSV infection reduced beta-actin mRNA levels to between 20 and 30% of those in mock infected cells, indicative of a normal Vhs activity. In contrast, in cells transfected with any of three eIF4H siRNAs, beta-actin mRNA levels were indistinguishable in infected and mock-infected cells, suggesting that eIF4H depletion impeded Vhs-mediated degradation. Depletion of the related factor eIF4B did not affect Vhs activity. The data suggest that eIF4H binding is required for Vhs-induced degradation of many mRNAs, perhaps by targeting Vhs to mRNAs and to preferred sites within mRNAs. PMID- 18448542 TI - Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II. AB - The antibody response to the envelope (E) glycoprotein of dengue virus (DENV) is known to play a critical role in both protection from and enhancement of disease, especially after primary infection. However, the relative amounts of homologous and heterologous anti-E antibodies and their epitopes remain unclear. In this study, we examined the antibody responses to E protein as well as to precursor membrane (PrM), capsid, and nonstructural protein 1 (NS1) of four serotypes of DENV by Western blot analysis of DENV serotype 2-infected patients with different disease severity and immune status during an outbreak in southern Taiwan in 2002. Based on the early-convalescent-phase sera tested, the rates of antibody responses to PrM and NS1 proteins were significantly higher in patients with secondary infection than in those with primary infection. A blocking experiment and neutralization assay showed that more than 90% of anti-E antibodies after primary infection were cross-reactive and nonneutralizing against heterologous serotypes and that only a minor proportion were type specific, which may account for the type-specific neutralization activity. Moreover, the E-binding activity in sera of 10 patients with primary infection was greatly reduced by amino acid replacements of three fusion loop residues, tryptophan at position 101, leucine at position 107, and phenylalanine at position 108, but not by replacements of those outside the fusion loop of domain II, suggesting that the predominantly cross-reactive anti-E antibodies recognized epitopes involving the highly conserved residues at the fusion loop of domain II. These findings have implications for our understanding of the pathogenesis of dengue and for the future design of subunit vaccine against DENV as well. PMID- 18448543 TI - Cholesterol effectively blocks entry of flavivirus. AB - Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2) are enveloped flaviviruses that enter cells through receptor-mediated endocytosis and low pH-triggered membrane fusion and then replicate in intracellular membrane structures. Lipid rafts, cholesterol-enriched lipid-ordered membrane domains, are platforms for a variety of cellular functions. In this study, we found that disruption of lipid raft formation by cholesterol depletion with methyl-beta cyclodextrin or cholesterol chelation with filipin III reduces JEV and DEN-2 infection, mainly at the intracellular replication steps and, to a lesser extent, at viral entry. Using a membrane flotation assay, we found that several flaviviral nonstructural proteins are associated with detergent-resistant membrane structures, indicating that the replication complex of JEV and DEN-2 localizes to the membranes that possess the lipid raft property. Interestingly, we also found that addition of cholesterol readily blocks flaviviral infection, a result that contrasts with previous reports of other viruses, such as Sindbis virus, whose infectivity is enhanced by cholesterol. Cholesterol mainly affected the early step of the flavivirus life cycle, because the presence of cholesterol during viral adsorption greatly blocked JEV and DEN-2 infectivity. Flavirial entry, probably at fusion and RNA uncoating steps, was hindered by cholesterol. Our results thus suggest a stringent requirement for membrane components, especially with respect to the amount of cholesterol, in various steps of the flavivirus life cycle. PMID- 18448544 TI - Multifunctional T-cell characteristics induced by a polyvalent DNA prime/protein boost human immunodeficiency virus type 1 vaccine regimen given to healthy adults are dependent on the route and dose of administration. AB - A phase I clinical vaccine study of a human immunodeficiency virus type 1 (HIV-1) vaccine regimen comprising a DNA prime formulation (5-valent env and monovalent gag) followed by a 5-valent Env protein boost for seronegative adults was previously shown to induce HIV-1-specific T cells and anti-Env antibodies capable of neutralizing cross-clade viral isolates. In light of these initial findings, we sought to more fully characterize the HIV-1-specific T cells by using polychromatic flow cytometry. Three groups of participants were vaccinated three times with 1.2 mg of DNA administered intradermally (i.d.; group A), 1.2 mg of DNA administered intramuscularly (i.m.; group B), or 7.2 mg of DNA administered i.m. (high-dose group C) each time. Each group subsequently received one or two doses of 0.375 mg each of the gp120 protein boost vaccine (i.m.). Env-specific CD4 T-cell responses were seen in the majority of participants; however, the kinetics of responses differed depending on the route of DNA administration. The high i.m. dose induced the responses of the greatest magnitude after the DNA vaccinations, while the i.d. group exhibited the responses of the least magnitude. Nevertheless, after the second protein boost, the magnitude of CD4 T cell responses in the i.d. group was indistinguishable from those in the other two groups. After the DNA vaccinations and the first protein boost, a greater number of polyfunctional Env-specific CD4 T cells (those with > or = 2 functions) were seen in the high-dose group than in the other groups. Gag-specific CD4 T cells and Env-specific CD8 T cells were seen only in the high-dose group. These findings demonstrate that the route and dose of DNA vaccines significantly impact the quality of immune responses, yielding important information for future vaccine design. PMID- 18448545 TI - The hepatitis E virus ORF3 protein modulates epidermal growth factor receptor trafficking, STAT3 translocation, and the acute-phase response. AB - The hepatitis E virus (HEV) causes acute viral hepatitis, but its characterization is hampered by the lack of an efficient in vitro infection system that can be used to study the effects of HEV proteins on cellular processes. Previous studies suggest that the viral ORF3 protein (pORF3) is essential for infection in vivo and is likely to modulate the host response. Here, we report that pORF3 localizes to early and recycling endosomes and causes a delay in the postinternalization trafficking of epidermal growth factor receptor (EGFR) to late endosomes/lysosomes. The cytoplasmic phosphorylated signal transducer and activator of transcription 3 (pSTAT3) proteins require growth factor receptor endocytosis for their translocation from the cytoplasm to nucleus. Consequently, lower levels of pSTAT3 were found in the nuclei of ORF3 expressing Huh7 human hepatoma cells stimulated with EGF. This results in downregulation of the acute-phase response, a major determinant of inflammation in the host. We propose that through its effects on EGFR trafficking, pORF3 prolongs endomembrane growth factor signaling and promotes cell survival. The effects on STAT3 translocation would result in a reduced inflammatory response. Both of these events are likely to contribute positively to viral replication. PMID- 18448547 TI - Smoke, then fire: lung cancer screening studies under further scrutiny. PMID- 18448546 TI - Neutralizing antibody blocks adenovirus infection by arresting microtubule dependent cytoplasmic transport. AB - Neutralizing antibodies are commonly elicited by viral infection. Most antibodies that have been characterized block early stages of virus entry that occur before membrane penetration, whereas inhibition of late stages in entry that occurs after membrane penetration has been poorly characterized. Here we provide evidence that the neutralizing antihexon monoclonal antibody 9C12 inhibits adenovirus infection by blocking microtubule-dependent translocation of the virus to the microtubule-organizing center following endosome penetration. These studies identify a previously undescribed mechanism by which neutralizing antibodies block virus infection, a situation that may be relevant for other nonenveloped viruses that use microtubule-dependent transport during cell entry. PMID- 18448548 TI - Current status of prognostic profiling in breast cancer. AB - Breast cancer is a clinically heterogeneous disease that can affect individuals with seemingly identical clinicopathologic parameters differently. This clinical heterogeneity is driven to a large extent by abnormal gene expression within tumors. Investigators now have the ability to identify the gene-expression fingerprint of an individual's tumor. This information may be used to rationally design therapeutic targets in the future, and also to predict the clinical course of an individual's disease, including response to a specific treatment. Genetic profiles of tumors are now being correlated with clinical outcome, and several prognostic and predictive indicators have emerged based on this research. There are at least four commercially available predictive or prognostic tests, and several more are looming on the horizon. The data gathered from these tests augment standard diagnostic and prognostic information obtained from traditional clinical pathological variables. The advent of gene-profiling technologies started to change the conduct of clinical trials. In the not too distant future, prospective tissue collection for molecular analysis may become routine in order to stratify patients for treatment arms and to optimize treatment strategies based on molecular features of the cancer. Coordinated efforts among oncologists, pathologists, surgeons, laboratory scientists, statisticians, and regulators will be essential in the quest to incorporate genetic profiling and molecular hypotheses into clinical trial planning and conduct. PMID- 18448549 TI - Trastuzumab plus paclitaxel or docetaxel in HER-2-negative/HER-2 ECD-positive anthracycline- and taxane-refractory advanced breast cancer. AB - Trastuzumab is considered effective against human epidermal growth factor receptor (HER)-2-positive breast cancer as assessed by immunohistochemistry (IHC) and fluorescence or chromogenic in situ hybridization (FISH/CISH) on biopsy material. Trastuzumab is now approved in both the adjuvant and metastatic settings for this patient population. Because HER-2 extracellular domain (ECD) levels have been correlated with disease progression in the metastatic setting, we considered trastuzumab salvage therapy plus a taxane in heavily pretreated trastuzumab-naive relapsed breast cancer patients with high serum levels of HER-2 ECD (> or =15 ng/ml). All patients had previously failed at least two lines of anthracycline- and taxane-based regimens and were HER-2 negative by IHC and FISH/CISH prior to a centralized reanalysis, and were serum positive for HER-2 ECD (> or =15 ng/ml) at baseline. Regular serum accounts of HER-2 ECD were recorded and compared with response and survival outcomes. Twenty-two patients were finally eligible for salvage therapy. Minor responses were observed in five (23%) and stable disease (SD) was observed in 11 patients, leading to a clinical benefit rate of 73% (16 of 22 patients). The median time to progression and overall survival time were 5 (6.5 months in minor responders and SD) and 12 months, respectively; 11 and eight patients remained progression free for >6 and >12 months, respectively. Eleven and seven patients were alive at 12 and 15 months, respectively, after treatment start. Furthermore, in total, 13 (59.1%) patients obtained a biochemical response. In our study, patients with conventionally HER-2-negative disease but with expression of HER-2 ECD above the normal limit (> or =15 ng/ml) displayed a rapid response, both biochemically and clinically, to the trastuzumab-taxane combination. This is the first study assessing anti-HER-2-based treatment in HER-2-negative advanced breast cancer according to HER-2 ECD positivity; if our results are confirmed, additional patients with "hidden" HER-2-positive breast cancer might benefit from anti-HER-2 treatment. PMID- 18448550 TI - Commentary: can circulating HER-2 extracellular domain predict response to trastuzumab in HER-2-negative breast cancer? PMID- 18448551 TI - Targeted therapies for the treatment of breast cancer in the post-trastuzumab era. AB - Targeted therapies for breast cancer are evolving rapidly. Trastuzumab has revolutionized breast cancer treatment and outcome, reducing the risk for recurrence and significantly increasing survival, at least for a subgroup of patients. Other targeted therapies, such as bevacizumab, a monoclonal antibody targeting angiogenesis, lapatinib, a dual human epidermal growth factor receptor (HER)-1 and HER-2 inhibitor, other small-molecule tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors, have been developed in phase II and III clinical trials. Although there has been rapid approval of these new drugs by health authorities, some questions have emerged about their application in clinical practice. What is the appropriate drug or sequence of drugs? What is the ideal target? How should tumor response be evaluated? Are financial resources sufficient to treat patients? How do we design trials with these molecules? These are emerging as current dilemmas for clinical oncologists. PMID- 18448552 TI - Utility of radiolabeled somatostatin receptor analogues for staging/restaging and treatment of somatostatin receptor-positive pediatric tumors. AB - In this paper, we review the pediatric oncologic applications of somatostatin receptor-targeted imaging and therapy. Somatostatin receptors are expressed in high densities by embryonal tumors, such as neuroblastoma and medulloblastoma, and neuroendocrine tumors like carcinoids and islet cell tumors. We first review the distribution of these receptors in normal tissues and tumor cells. We then discuss the technique of somatostatin receptor scintigraphy (SRS) in the pediatric population. Next, the specific clinical applications of SRS with regard to the imaging of neuroblastoma, central nervous system tumors, and gastroenteropancreatic neuroendocrine tumors of childhood are discussed. Finally, we discuss the potential role of somatostatin receptor-targeted radiotherapy for improving the duration and quality of life of children with these tumors. PMID- 18448553 TI - Chemotherapy in elderly patients with colorectal cancer. AB - Significant advancements in chemotherapy for metastatic colorectal cancer (mCRC) have been achieved over the past decade, and the median overall survival duration is now close to 24 months with appropriate treatment. The most widely recommended chemotherapy regimens are based on the use of irinotecan or oxaliplatin in combination with 5-fluorouracil and leucovorin; some data suggest further benefit with the addition of the targeted agents bevacizumab or cetuximab. Colorectal cancer primarily affects the elderly; however, much of the defining clinical research in this field has excluded subjects of advanced age or with a poor performance status, making it difficult for clinicians to interpret current treatment paradigms for their older patients. Most clinical trials that have included elderly patients document similar survival rates and toxicity profiles to those seen in younger patients. Moreover, survey data suggest that >70% of elderly patients with cancer are willing to undergo strong, palliative chemotherapy. While these findings suggest that age itself should not determine candidacy for chemotherapy, it is important to note the great heterogeneity of the elderly population with regard to overall health, independence, and performance status. The use of a comprehensive geriatric assessment is recommended to evaluate chemotherapy appropriateness. The management of frail elderly patients and those with a short life expectancy should be focused on palliation, while fit elderly patients can receive aggressive therapy in a similar fashion to younger patients. PMID- 18448554 TI - Intraperitoneal chemotherapy for women with epithelial ovarian cancer. AB - In 2006, i.p. chemotherapy re-emerged as a controversial topic in debates about the optimal treatment for women with advanced epithelial ovarian cancer. In this paper, we address the rationale behind i.p. chemotherapy, the data supporting its use, the selection of appropriate patients for i.p. chemotherapy, how best to avoid and manage the toxicities observed with i.p. chemotherapy, and directions for future research. PMID- 18448555 TI - Intraperitoneal chemotherapy in patients with advanced ovarian cancer: the con view. AB - OBJECTIVES: In this paper we wish to present the reasons why i.p. chemotherapy cannot be accepted as standard of care for first-line systemic treatment of advanced ovarian carcinoma. METHODS: The recent literature on i.p. chemotherapy is critically reviewed. All possible arguments against i.p. chemotherapy are reviewed. CONCLUSIONS: Intraperitoneal chemotherapy is associated with a higher toxicity rate than i.v. chemotherapy. For this reason, none of the regimens investigated in the three Gynecologic Oncology Group (GOG) studies can be used as standard treatment outside clinical protocols. The trials on i.p. chemotherapy have suggested a survival difference. However, in the two most recent trials, i.p. chemotherapy or not was not the only research question because different schedules and dosages were used. In addition, the significance of the most recent GOG 172 study was only weak (p = .03), and the result was nonsignificant for progression-free survival. Intraperitoneal chemotherapy should be used only in the context of properly designed clinical trials. These trials must either assess i.p. therapy in comparison with the standard treatment or address the issue of route of administration for equivalent dosages and schedules of the same drugs, and not a mosaic of these questions. In addition, these trials should investigate i.p. regimens that are less toxic than the regimens used in the three GOG trials, and which can be combined with molecular targeted therapies. PMID- 18448556 TI - Systemic therapy for biliary tract cancers. AB - Biliary tract cancers (BTCs) are invasive carcinomas that arise from the epithelial lining of the gallbladder and bile ducts. These include intrahepatic, perihilar, and distal biliary tree cancers as well as carcinoma arising from the gallbladder. Complete surgical resection offers the only chance for cure; however, only 10% of patients present with early-stage disease and are considered surgical candidates. Among those patients who do undergo "curative" resection, recurrence rates are high; thus, for the majority of BTC patients, systemic chemotherapy is the mainstay of their treatment plan. Patients with unresectable or metastatic BTC have a poor prognosis, with a median overall survival time of <1 year. Despite a paucity of randomized phase III data, a consensus on first line systemic therapy is emerging. In this review, we discuss the clinical experience with systemic treatment of BTC, focusing on the rationale for a first line regimen as well as future directions in the field. PMID- 18448557 TI - Therapy options in imatinib failures. AB - Chronic myelogenous leukemia (CML) is defined by the presence of the constitutively active tyrosine kinase breakpoint cluster region/Abelson (Bcr Abl), which activates numerous signal transduction pathways leading to uncontrolled cell proliferation. The development of the Bcr-Abl-targeted imatinib represents a paradigm shift in the treatment of CML, because treatment with imatinib resulted in significantly better patient outcome, response rates, and overall survival compared with previous standards. Despite this advance, not all patients benefit from imatinib because of resistance and intolerance. Resistance to imatinib can develop from a number of mechanisms that can be defined as Bcr Abl-dependent (e.g., most commonly resulting from point mutations in the Abl kinase domain) and Bcr-Abl-independent mechanisms (including the constitutive activation of downstream signaling molecules, e.g., Src family kinases), which could result in the activation of the pathway regardless of Bcr-Abl inhibition. Clearly, new treatment approaches are required for patients resistant to or intolerant of imatinib, which can be dose escalated in patients who demonstrate resistance. This does not result in long-term responses. Hematopoietic stem cell transplantation is limited by the availability of matched donors and the potential for morbidity. Dasatinib, a dual Bcr-Abl/Src kinase inhibitor, has shown efficacy against all imatinib-resistant Bcr-Abl mutations except for T315I. A large trial program showed that dasatinib is effective in patients previously exposed to imatinib and has a manageable safety profile in all phases of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, resulting in its approval. Nilotinib, an analogue of imatinib, also has demonstrated activity in a similar patient population. These agents and less clinically advanced strategies are discussed in this review. PMID- 18448558 TI - Commentary: lung cancer screening--progress or peril. PMID- 18448559 TI - Commentary: CT screening for lung cancer--caveat emptor. PMID- 18448560 TI - Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy. AB - Management of anthracycline extravasation is problematic and most reports are anecdotal. On September 6, 2007, the U.S. Food and Drug Administration approved Totect 500 mg (dexrazoxane hydrochloride for injection) for the treatment of extravasation resulting from i.v. anthracycline chemotherapy. In two studies, a total of 57 evaluable patients experienced extravasation from peripheral vein or central venous access sites with local swelling, pain, or redness. The presence of anthracycline in skin biopsy tissue was confirmed by tissue fluorescence, and treatment with a 3-day schedule of dexrazoxane began within 6 hours of the event. The primary endpoint was a reduction in the need for surgical intervention. Only one patient required surgical repair of the injury site, and late sequelae in the remainder were absent or mild. Also, the sponsor, TopoTarget A/S, Copenhagen, Denmark, performed controlled nonclinical studies in support of dexrazoxane dose and timing for the reduction of tissue injury resulting from anthracycline extravasation. For this uncommon but serious complication of anthracycline therapy, the need for surgical intervention was 1.7% with this regimen. PMID- 18448561 TI - Histologic alterations from neoadjuvant chemotherapy in high-grade extremity soft tissue sarcoma: clinicopathological correlation. AB - Histologic response to chemotherapy is generally regarded as an independent prognostic variable in bone sarcomas, both osteosarcoma and Ewing's sarcoma. In soft tissue sarcomas, however, descriptions of histologic alterations from chemotherapy and correlative outcome studies are much more limited. Herein we report clinicopathological findings from a homogeneously treated group of 31 patients with tumor stage T2 grade 3 extremity soft tissue sarcomas treated with the same neoadjuvant chemotherapy followed by surgical excision, treated by the same medical oncologist and orthopedic surgeon. Histologic response to therapy was evaluated by multiple parameters using a semiquantitative grading system. Based upon the percentage of post-treatment viable tumor, tumors were arbitrarily categorized similarly to Huvos score as showing excellent (< or =5% viability), moderate (6%-49% viability), or poor (> or =50% viability) responses. Nineteen percent had excellent, 10% had moderate, and 71% had poor responses. These histologic response groups did not correlate with overall or event-free survival. For example, of the 22 patients showing a "poor" response, 13 were cured. Similarly, other histologic parameters, including percentages of necrosis, fibrosis/hyalinization, and cellular degeneration, did not correlate with outcome. Chemotherapy induces profound tissue alterations in soft tissue sarcomas. However, histologic alteration by itself may not be a reliable prognostic variable. Correlation of all data from clinical, imaging, and pathological observations by a multidisciplinary tumor board should have greater prognostic value than histology alone. Finally, although the histologic grading system used in this study could not be validated, the criteria we employed are simple and reproducible and take into account the major histologic patterns seen after therapy, and would be amenable for use in future studies. PMID- 18448562 TI - Epidermal growth factor receptor expression and mutational analysis in synovial sarcomas and malignant peripheral nerve sheath tumors. AB - BACKGROUND: Synovial sarcomas (SnSrcs) and malignant peripheral nerve sheath tumors (MPNSTs) are rare mesenchymal tumors of adolescence and young adulthood. Previous work from our laboratory has demonstrated that SnSrcs express epidermal growth factor receptor (EGFR) and human EGFR (HER)-2/neu. The present study extends that work to examine the expression of EGFR in MPNSTs and the characterization of potential targets of the EGFR tyrosine kinase domain. METHODS: Tissue microarrays containing 48 cases of SnSrc and 32 cases of MPNST were stained for EGFR, EGFRvIII, and activated EGFR (pY1068-EGFR). Tumor DNA was extracted from fresh and formalin-fixed, paraffin-embedded tissue blocks and sequenced for exons 17-21 of EGFR and exon 2 of K-ras and b-raf. RESULTS: Immunohistochemistry (IHC) demonstrated that EGFR is expressed in a majority of SnSrcs and MPNSTs (71% and 62.5%, respectively). EGFRvIII immunoreactivity was negative. IHC was weakly immunopositive for activated EGFR (18.7% and 3.1%, respectively). Sequence analysis of the EGFR genomic DNA did not demonstrate mutations in exons 17-21. No K-ras or b-raf mutations were observed in either tumor type. CONCLUSIONS: Expression of EGFR in SnSrcs and MPNSTs with an intact EGFR/mitogen-activated protein kinase pathway has been hypothesized to contribute to the malignant potential of these tumors. Our study reveals the absence of known activating mutations in EGFR, which suggests that trials of small-molecule inhibitors would be of little clinical benefit. A clinical study of treatment with cetuximab is ongoing and may help elucidate whether blockade of EGFR with antibodies is likely to be more active. PMID- 18448563 TI - A phase II study of gefitinib for patients with advanced HER-1 expressing synovial sarcoma refractory to doxorubicin-containing regimens. AB - RATIONALE: Advanced synovial sarcomas (SyS) refractory to doxorubicin and ifosfamide are highly resistant to the currently available cytotoxic agents. Based on a report showing a specific overexpression of HER-1 in SyS, we investigated an HER-1 inhibitor, gefitinib, in refractory SyS. SUBJECTS AND METHODS: To establish the efficacy and safety of gefitinib in HER-1 - positive SyS refractory to one or two lines of doxorubicin- and ifosfamide-based chemotherapy, a phase II study was conducted from December 2002 to October 2005 by 12 centers of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Gefitinib was given at a 500-mg/day oral dose until progression or intolerance. RESULTS: Forty-eight patients were included (46 eligible). All patients had previously received chemotherapy for metastatic disease, with a median number of two lines (range, 1-4). The most frequent metastatic sites were the lungs (n = 44, 92%), lymph nodes (n = 11, 23%), and soft tissues (n = 10, 21%). The median duration of treatment was 43 days (range, 13-315). Treatment was interrupted in five patients (10%). Treatment was halted for progression in 45 (94%) patients. The best response was stable disease in 10 patients (21%). Disease progression occurred in 32 patients (70%), with a median time to disease progression of 6 weeks. Progression-free survival at 4 and 6 months was 21% and 6%, respectively. CONCLUSION: The results show that gefitinib monotherapy in advanced SyS refractory to conventional chemotherapy did not demonstrate sufficient activity to warrant further investigation in this setting. This may suggest that HER-1 is not a critical protein in tumor progression in this disease. PMID- 18448564 TI - Early patterning of the chorion leads to the trilaminar trophoblast cell structure in the placental labyrinth. AB - The labyrinth of the rodent placenta contains villi that are the site of nutrient exchange between mother and fetus. They are covered by three trophoblast cell types that separate the maternal blood sinusoids from fetal capillaries--a single mononuclear cell that is a subtype of trophoblast giant cell (sinusoidal or S TGC) with endocrine function and two multinucleated syncytiotrophoblast layers, each resulting from cell-cell fusion, that function in nutrient transport. The developmental origins of these cell types have not previously been elucidated. We report here the discovery of cell-layer-restricted genes in the mid-gestation labyrinth (E12.5-14.5) including Ctsq in S-TGCs (also Hand1-positive), Syna in syncytiotrophoblast layer I (SynT-I), and Gcm1, Cebpa and Synb in syncytiotrophoblast layer II (SynT-II). These genes were also expressed in distinct layers in the chorion as early as E8.5, prior to villous formation. Specifically, Hand1 was expressed in apical cells lining maternal blood spaces (Ctsq is not expressed until E12.5), Syna in a layer immediately below, and Gcm1, Cebpa and Synb in basal cells in contact with the allantois. Cebpa and Synb were co-expressed with Gcm1 and were reduced in Gcm1 mutants. By contrast, Hand1 and Syna expression was unaltered in Gcm1 mutants, suggesting that Gcm1-positive cells are not required for the induction of the other chorion layers. These data indicate that the three differentiated trophoblast cell types in the labyrinth arise from distinct and autonomous precursors in the chorion that are patterned before morphogenesis begins. PMID- 18448565 TI - Activation of Eklf expression during hematopoiesis by Gata2 and Smad5 prior to erythroid commitment. AB - The hierarchical progression of stem and progenitor cells to their more-committed progeny is mediated through cell-to-cell signaling pathways and intracellular transcription factor activity. However, the mechanisms that govern the genetic networks underlying lineage fate decisions and differentiation programs remain poorly understood. Here we show how integration of Bmp4 signaling and Gata factor activity controls the progression of hematopoiesis, as exemplified by the regulation of Eklf during establishment of the erythroid lineage. Utilizing transgenic reporter assays in differentiating mouse embryonic stem cells as well as in the murine fetal liver, we demonstrate that Eklf expression is initiated prior to erythroid commitment during hematopoiesis. Applying phylogenetic footprinting and in vivo binding studies in combination with newly developed loss of-function technology in embryoid bodies, we find that Gata2 and Smad5 cooperate to induce Eklf in a progenitor population, followed by a switch to Gata1 controlled regulation of Eklf transcription upon erythroid commitment. This stage and lineage-dependent control of Eklf expression defines a novel role for Eklf as a regulator of lineage fate decisions during hematopoiesis. PMID- 18448566 TI - Neurogenin 2 has an essential role in development of the dentate gyrus. AB - The dentate gyrus (DG) of the hippocampus has a central role in learning and memory in adult rodents. The DG is generated soon after birth, although new neurons continue to be generated in the DG throughout life. The proneural factors Mash1 (Ascl1) and neurogenin 2 (Ngn2) are expressed during formation of the DG but their role in the development of this structure has not yet been addressed. Here, we show that Ngn2 is essential for the development of the DG. Ngn2 mutant mice have fewer DG progenitors and these cells present defects in neuronal differentiation. By contrast, the DG is normal in Mash1 mutant mice at birth, and loss of both Mash1 and Ngn2 does not aggravate the defect observed in Ngn2 single mutants. These data establish a unique role of Ngn2 in DG neurogenesis during development and raise the possibility that Ngn2 has a similar function in adult neurogenesis. PMID- 18448567 TI - Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. AB - BACKGROUND: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease. AIM: To assess the value of TE for predicting the stage of fibrosis. METHODS: Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated. RESULTS: The areas under the curve for the prediction of significant fibrosis (> or = F2), advanced fibrosis (> or = F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE < 6 or > or = 12, < 9 or > or = 12, and < 12 or > or = 18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p<0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis. CONCLUSIONS: TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis. PMID- 18448568 TI - The European consensus on ulcerative colitis: new horizons? PMID- 18448569 TI - Effects of ketoconazole and quinidine on pharmacokinetics of pactimibe and its plasma metabolite, R-125528, in humans. AB - Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases. Pactimibe has two equally dominant clearance pathways forming R-125528 by CYP3A4 and M-1 by CYP2D6 in vitro. R-125528 is a plasma metabolite and is cleared solely by CYP2D6 despite its acidity. To evaluate contributions of the cytochrome P450 enzymes on the pharmacokinetics of pactimibe and R-125528 in humans, drug-drug interaction studies using ketoconazole and quinidine were conducted. Eighteen healthy male subjects were given a single dose of pactimibe sulfate without and with 400 mg of ketoconazole (q.d.). With the concomitant treatment, the area under the plasma concentration-time curve (AUC(0-inf)) of pactimibe modestly increased 1.7-fold and AUC(0-tz) of R-125528 decreased by 55%. In addition, 17 healthy male subjects were given a single dose of pactimibe sulfate without and with 600 mg of quinidine (b.i.d.). With the concomitant treatment, the AUC(0-inf) for pactimibe modestly increased 1.7-fold. On the other hand, the AUC(0-tz) of R-125528 was markedly elevated 5.0-fold, although the AUC(0-inf) could not be adequately defined because the terminal elimination phase of R-125528 was not obtained in the study period up to 72 h. As the f(m CYP3A4) and f(m CYP2D6) values of pactimibe estimated from in vitro studies were 0.40 and 0.33, respectively, AUC increase ratios of pactimibe were estimated to be 1.7 with ketoconazole and 1.5 with quinidine. These values were well in accordance with the values observed in this study. Moreover, the f(m CYP2D6) of R-125528 estimated to be almost 1 would well explain the accumulation of R-125528 observed with the quinidine treatment. PMID- 18448570 TI - In vitro drug-drug interaction screens for canine veterinary medicines: evaluation of cytochrome P450 reversible inhibition. AB - Little information regarding the metabolic pathways of pharmaceutical agents administered to dogs, or the inhibition of those metabolic pathways, is available. Without this information, it is difficult to assess how combinations of drugs, whether new or old or approved or nonapproved, may increase the risk for metabolic drug-drug interactions in dogs. Because mammalian xenobiotic metabolism pathways often involve the hepatic cytochrome P450 (P450) monooxgenases, canine liver microsome P450 inhibition screens were tested to evaluate the potential metabolic drug interaction risk of commonly used veterinary medicines. A probe substrate cocktail was developed for four of the five major hepatic canine P450s and used to evaluate their inhibition by 45 canine therapeutic agents in a single-point IC(50) screen. Moderate inhibitors (>25%) were further characterized with an automated ninepoint IC(50) assay that identified ketoconazole, clomipramine, and loperamide as submicromolar CYP2D15 inhibitors. Additional inhibitors belonged to the antiemetic, antimitotic, and anxiolytic therapeutic classes. According to the marker activities, the relative frequency of P450 inhibition by isoform followed the sequence CYP2D15 > CYP2B11 > CYP2C21/41 > CYP3A12/26 > CYP1A1/2. The findings presented suggest there is some overlap in canine and human P450 inhibition specificity. However, occasional differences may give human drugs used off-label in dogs unexpected P450 inhibition profiles and, therefore, cause an unexpected drug-drug interaction risk. PMID- 18448571 TI - The macrolide everolimus forms an unusual metabolite in animals and humans: identification of a phosphocholine ester. AB - The immunosuppressant macrolide everolimus was found to be metabolized in animals and humans to a phosphocholine ester (ATG181), a hitherto unknown type of conjugate in xenobiotic metabolism. The structure of ATG181 was elucidated by mass spectrometry and confirmed by synthesis. ATG181 was among the most prominent metabolites of everolimus in rat, monkey, and human blood and was found also in various tissues of the rat, whereas no ATG181 was identified in the urine and feces of the species investigated. The metabolite showed binding to FK506 binding protein with a 2- to 3-fold higher affinity than everolimus. However, ATG181 exhibited only marginal in vitro immunosuppressive activity and is therefore very unlikely to contribute in a relevant manner to the immunosuppressive effect of everolimus. PMID- 18448572 TI - Ethanol stimulates endothelial cell angiogenic activity via a Notch- and angiopoietin-1-dependent pathway. AB - AIMS: Our aims were to determine the effect of alcohol (EtOH) on endothelial angiogenic activity and to delineate the cell signalling mechanisms involved. METHODS AND RESULTS: Treatment of human umbilical vein endothelial cells (HUVECs) with EtOH (1-100 mM, 24 h) dose-dependently increased their network formation on Matrigel (an index of angiogenesis) with a maximum response (2.5- to 3-fold increase) at 25 mM. Ethanol also stimulated the proliferation (by cell count and proliferating cell nuclear antigen expression) and migration (by scratch wound assay) of HUVECs. In parallel cultures, EtOH stimulated Notch receptor (1 and 4) and Notch target gene (hrt-1, -2, and -3) mRNA and protein expression and enhanced CBF-1/RBP-Jk promoter activity. EtOH also stimulated, at the mRNA and protein level, the expression of angiopoietin-1 (Ang1) and its Tie2 receptor in these cells. Knockdown of Notch 1 or 4 by siRNA or inhibition of Notch-mediated, CBF-1/RBP-Jk-regulated gene expression by the Epstein-Barr virus-encoded protein RPMS-1 inhibited both ethanol-induced Ang1/Tie2 expression in HUVECs and their network formation on Matrigel. Moreover, knockdown of Ang1 or Tie2 by siRNA inhibited ethanol-induced endothelial network formation. CONCLUSION: These data demonstrate that ethanol, at levels consistent with moderate consumption, enhances endothelial angiogenic activity in vitro by stimulating a novel Notch/CBF-1/RBP-JK-Ang1/Tie2-dependent pathway. These actions of ethanol may be relevant to the cardiovascular effects of alcohol consumption purported by epidemiological studies. PMID- 18448573 TI - Isolated absence of the Moro reflex in a baby with CHARGE syndrome could reflect vestibular abnormalities. AB - We describe a term baby girl with (CHARGE syndrome coloboma, heart anomaly, choanal atresia, retardation, and genital and ear anomalies association) who had persistent complete absence of the Moro reflex but preservation of other primary neonatal reflexes. A computed tomography scan revealed bilateral absence of the semicircular canals and hypoplastic vestibules. We suggest that isolated absence of the Moro reflex may reflect underlying abnormalities of the vestibular system and may, therefore, not necessarily be associated with a generalized disturbance of the central nervous system as is usually the case. This suggestion has implications for the diagnostic and prognostic relevance of an isolated absent Moro reflex. PMID- 18448574 TI - Transient bilateral oculomotor palsy in pseudotumor cerebri. AB - Pseudotumor cerebri is a clinical condition marked by papilledema, normal cerebrospinal fluid composition, normal or small ventricles on radiography, and absence of an intracranial mass. In this condition, headache, tinnitus, dizziness, blurred vision, and diplopia are frequently observed. The cause is often unknown but can occur with certain drug ingestions or systemic inflammatory and metabolic diseases. The treatment is primarily focused on the correction of the underlying cause with measures to reduce the raised intracranial pressure. The most important complication is optic atrophy, which results in visual loss. The sixth cranial nerve is most commonly affected. The involvement of the third cranial nerve is distinctly unusual. The present report describes a unique case of bilateral oculomotor palsy with sparing of the papillary fibers. It resolved promptly on administration of acetazolamide. PMID- 18448575 TI - Efficacy of levetiracetam in children with epilepsy younger than 2 years of age. AB - Despite the high incidence of epilepsy in very young children, the availability of approved antiepileptic drugs for this population is limited. This study assessed the efficacy and tolerability of levetiracetam in children younger than 2 years of age with various types of epilepsy. A single-center, retrospective chart review of 28 patients ranging in age from 2 weeks to 22 months treated with levetiracetam over a 2.5-year period was conducted. The mean dosage of levetiracetam was 39 mg/kg per day, and the mean duration of treatment was 6.3 months. The majority of patients (54%) were also taking 1 or 2 other antiepileptic drugs. A reduction in seizure frequency was found in 54%, with 14% achieving seizure freedom. Eight patients showed no response to levetiracetam treatment. Efficacy was highest among patients with generalized epilepsy. Adverse effects occurred in 2 patients and were behavioral in nature. Levetiracetam treatment was safe and effective in this group of very young patients with various types of epilepsy. PMID- 18448577 TI - Lower extremity jumping mechanics of female athletes with and without patellofemoral pain before and after exertion. AB - BACKGROUND: Patellofemoral pain is especially common among female athletes and is traditionally associated with lower extremity mechanics thought to increase retropatellar stress. These detrimental mechanics may increase with exertion. HYPOTHESIS: Differences in lower extremity mechanics during single-legged jumps between female athletes with and without patellofemoral pain will increase after exertion. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty women with patellofemoral pain and 20 healthy female controls participated in a functional lower extremity exertion protocol of repetitive single-legged jumps. Pain, exertion, hip and trunk strength, and 3-dimensional lower extremity joint mechanics were recorded at the beginning and end of the protocol. RESULTS: The patellofemoral pain group reported increased pain at the conclusion of the protocol. However, all subjects terminated the protocol due to complaints of fatigue. Mean strength measurements for the patellofemoral pain group were 24% lower for lateral trunk flexion (P = .06), 13% lower for hip abduction (P = .09), and 14% lower for hip external rotation (P = .03) than for controls. Subjects with patellofemoral pain demonstrated greater contralateral pelvic drop at the end of the exertion protocol compared with the control group (P = .003). Group differences in lower extremity mechanics, including increased hip adduction angle, hip flexion angle, hip abduction angular impulse, and decreased hip internal rotation angles, were observed among women with patellofemoral pain throughout the exertion protocol. These group differences were consistent despite increased pain for the patellofemoral pain group after exertion. Both groups demonstrated decreased jump height, hip flexion and internal rotation, knee flexion, and hip extension impulse at the end of the protocol. CONCLUSION: Women with patellofemoral pain demonstrated lower extremity mechanics that differed from the healthy control group during single-legged jumping, particularly at the hip. These differences do not appear to vary with exertion level or pain among patellofemoral pain subjects during single-legged jumps. CLINICAL RELEVANCE: Lower extremity jumping mechanics appear to be consistently different among women with patellofemoral pain. Conservative treatment programs that include kinematic retraining as well as hip and trunk strengthening may improve patient outcomes and prevent recurrence of this common orthopaedic condition. PMID- 18448578 TI - Strength imbalances and prevention of hamstring injury in professional soccer players: a prospective study. AB - BACKGROUND: The relationship between muscle injury and strength disorders remains a matter of controversy. PURPOSE: Professional soccer players performed a preseason isokinetic testing aimed at determining whether (1) strength variables could be predictors of subsequent hamstring strain and (2) normalization of strength imbalances could reduce the incidence of hamstring injury. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 1. METHODS: A standardized concentric and eccentric isokinetic assessment was used to identify soccer players with strength imbalances. Subjects were classified among 4 subsets according to the imbalance management content. Recording subsequent hamstring injuries allowed us to define injury frequencies and relative risks between groups. RESULTS: Of 687 players isokinetically tested in preseason, a complete follow-up was obtained in 462 players, for whom 35 hamstring injuries were recorded. The rate of muscle injury was significantly increased in subjects with untreated strength imbalances in comparison with players showing no imbalance in preseason (relative risk = 4.66; 95% confidence interval: 2.01-10.8). The risk of injury remained significantly higher in players with strength imbalances who had subsequent compensating training but no final isokinetic control test than in players without imbalances (relative risk = 2.89; 95% confidence interval: 1.00 8.32). Conversely, normalizing the isokinetic parameters reduced the risk factor for injury to that observed in players without imbalances (relative risk = 1.43; 95% confidence interval: 0.44-4.71). CONCLUSION: The outcomes showed that isokinetic intervention gives rise to the preseason detection of strength imbalances, a factor that increases the risk of hamstring injury. Restoring a normal strength profile decreases the muscle injury incidence. PMID- 18448579 TI - Open capsular repair without bone block for recurrent anterior shoulder instability in patients with and without bony defects of the glenoid and/or humeral head. AB - BACKGROUND: Bony defects of the humeral head and glenoid have been associated with high failure rates after arthroscopic stabilization for anterior instability. Biomechanical studies have indicated that such lesions reduce stability and may predispose to failure and motion loss after capsular repair. PURPOSE: The present investigation was designed to evaluate the effect of bony deficiency of the glenoid and/or humeral head on recurrence rates with a conventional open technique of anterior stabilization without a bone block. STUDY DESIGN: Case series; Level of evidence, 4. MATERIALS AND METHODS: One hundred nineteen consecutive patients with recurrent anterior shoulder instability were treated by a single surgeon with an open anterior stabilization procedure. Patients were studied prospectively for recurrent instability after the presence and size of bony defects of the humeral head and/or glenoid were recorded during an arthroscopic examination before the open procedure. One hundred three patients (mean age, 20.7 years), including 98 men and 5 women, were available for 2-year minimum follow-up. Eighty-three of the patients participated in contact athletics. RESULTS: Eighty-four percent of the patients had demonstrable Hill Sachs lesions at the time of arthroscopy (27% "engaging" and 57% "nonengaging"). Fourteen percent had deficiency of the anterior glenoid, 9% had large (Rowe classification) defects of the humeral head, and 4% had severe (>20%) defects of the glenoid. The overall recurrence rate was 2%. Both recurrences were noted in patients with Hill-Sachs lesions, but the recurrence rate in patients with Hill Sachs lesions was not significantly higher (P = .71). There was 1 recurrence among the 9 patients with large defects of the humeral head (P = .17). Patients with engaging Hill-Sachs lesions did not have a statistically significant increase in recurrence (4%) (P = .47). There were no recurrences in patients with glenoid deficiency. Patients with large defects of the glenoid lost a mean of 7 degrees of external rotation (P = .001) when compared with the remaining population (12 degrees vs 5 degrees ). Patients with large defects of the humeral head lost a mean of 4 degrees more external rotation (P = .003) when compared with the remaining population (9 degrees vs 5 degrees ). Two patients in the series lost > or =20 degrees of external rotation. When contact athletes were isolated as a population, there were no statistically significant increases in recurrence due to the presence of bony lesions of the glenoid or humeral head. CONCLUSION: Bony defects of the humeral head or glenoid did not appear to result in a statistically significant increase in the risk of recurrence with conventional open techniques of stabilization. Large defects on either side of the joint were uncommon in the study population. Bone-block or grafting procedures do not appear to be necessary to restore stability in the majority of patients with bone loss. Although the loss of external rotation in patients with large defects is a relative cause for concern, the author recommends open capsular repair as the primary method of treatment given the high complication rate historically associated with bone-block techniques. PMID- 18448580 TI - Intraobserver and interobserver reliability of the kneeling technique of stress radiography for the evaluation of posterior knee laxity. AB - BACKGROUND: Stress radiography provides an objective tool to measure posterior knee instability. Intraobserver and interobserver reliability has been reported for the Telos device, but it has not been studied using the kneeling technique. PURPOSE: This study was conducted to evaluate the intraobserver and interobserver reliability of measurements made using kneeling stress radiography to quantify posterior knee instability. STUDY DESIGN: Case series (diagnosis); Level of evidence, 4. METHODS: One hundred thirty-two stress radiographs in 44 patients with suspected posterior knee instability were prospectively taken using the kneeling technique. The amount of posterior displacement on the radiographs was then measured independently by 3 blinded testers (an orthopaedic sports medicine faculty member, an orthopaedic chief resident, and a medical student) on 2 separate occasions. Changes in mean and intraclass correlation coefficients (ICCs) were examined to assess the intraobserver and interobserver reliability of the measurements. RESULTS: Intraobserver changes in displacement means were small (-0.307 mm, -0.294 mm, and +0.035 mm) and only significant for observer 1. The combined intraobserver ICC was 0.973 for the 3 observers (0.976, 0.959, and 0.981). Interobserver comparisons revealed significant differences in trial 1 between observers 2 and 3 (0.675 mm), no differences in trial 2, and significant differences between observers 1 and 2 (0.333 mm) and observers 2 and 3 (0.510 mm) in the combined trial data. The combined interobserver ICC was 0.955 for the 3 observers (0.959 and 0.951 for the 2 trials). CONCLUSIONS: The kneeling technique for posterior cruciate ligament stress radiography provides a reproducible method to quantify posterior knee instability. PMID- 18448581 TI - Proximal hamstring strains of stretching type in different sports: injury situations, clinical and magnetic resonance imaging characteristics, and return to sport. AB - BACKGROUND: Hamstring strains can be of at least 2 types, 1 occurring during high speed running and the other during motions in which the hamstring muscles reach extreme lengths, as documented for sprinters and dancers. HYPOTHESIS: Hamstring strains in different sports, with similar injury situations to dancers, also show similarities in symptoms, injury location, and recovery time. STUDY DESIGN: Case series (prognosis); Level of evidence, 4. METHODS: Thirty subjects from 21 different sports were prospectively included. All subjects were examined clinically and with magnetic resonance imaging (MRI). The follow-up period lasted until the subjects returned to or finished their sport activity. RESULTS: All injuries occurred during movements reaching a position with combined extensive hip flexion and knee extension. They were located proximally in the posterior thigh, close to the ischial tuberosity. The injuries were often complex, but 83% involved the semimembranosus and its proximal free tendon. Fourteen subjects (47%) decided to end their sports activity. For the remaining 16 subjects, the median time for return to sport was 31 weeks (range, 9-104). There were no significant correlations between specific clinical or MRI parameters and time to return to sport. CONCLUSIONS: In different sports, an injury situation in which the hamstring muscles reach extensive length causes a specific injury to the proximal posterior thigh, earlier described in dancers. Because of the prolonged recovery time associated with this type of injury, correct diagnosis, based on history and palpation, and adequate information to the subject are essential. PMID- 18448582 TI - Injury-induced changes in mRNA levels differ widely between anterior cruciate ligament and medial collateral ligament. AB - BACKGROUND: The drastic difference in healing capacity between the anterior cruciate ligament and the medial collateral ligament is still largely unexplained. Few studies have compared the profiles of messenger ribonucleic acid expression for healing-associated molecules in ligaments during the course of healing. HYPOTHESIS: Injury responses of the injured anterior cruciate ligament and medial collateral ligament are characterized by very different profiles of angiogenesis-promoting and repair-associated gene expression during the healing process. STUDY DESIGN: Controlled laboratory study. METHODS: Reverse transcriptase polymerase chain reaction was used to assay expression of messenger ribonucleic acid for 11 healing- and angiogenesis-associated molecules at 3 days and 2, 6, and 16 weeks after anterior cruciate ligament or medial collateral ligament injury in adult female New Zealand White rabbits. RESULTS: Marked differences were found in the postinjury changes in messenger ribonucleic acid levels in the anterior cruciate ligament compared to the medial collateral ligament. Notably, messenger ribonucleic acid levels for the important repair associated growth factor transforming growth factor-beta1 did not increase in injured anterior cruciate ligament at any time point. Similarly, unlike the injured medial collateral ligament, no statistically significant increases in messenger ribonucleic acid levels for the important scar matrix protein collagen III were detected in injured anterior cruciate ligament. In contrast, matrix metalloproteinase messenger ribonucleic acid levels were markedly elevated in injured anterior cruciate ligament but only modestly increased in medial collateral ligament. CONCLUSION: The results suggest that injury leads to an antifibrotic, catabolic response in the rabbit anterior cruciate ligament, possibly to prevent fibrosis and diminish the risk for loss of joint motion. CLINICAL RELEVANCE: The development of effective biologically based treatments for anterior cruciate ligament injuries will need to incorporate strategies to deal with the significant differences in the molecular responses to injury of these tissues. PMID- 18448583 TI - X inactivation, female mosaicism, and sex differences in renal diseases. AB - A good deal of sex differences in kidney disease is attributable to sex differences in the function of genes on the X chromosome. Males are uniquely vulnerable to mutations in their single copy of X-linked genes, whereas females are often mosaic, having a mixture of cells expressing different sets of X-linked genes. This cellular mosaicism created by X inactivation in females is most often advantageous, protecting carriers of X-linked mutations from the severe clinical manifestations seen in males. Even subtle differences in expression of many of the 1100 X-linked genes may contribute to sex differences in the clinical expression of renal diseases. PMID- 18448584 TI - Hemoglobin is expressed by mesangial cells and reduces oxidant stress. AB - Hemoglobin (Hb) serves as the main oxygen transporter in erythrocytes, but it is also expressed in nonhematopoietic organs, where it serves an unknown function. In this study, microarray and proteomic analyses demonstrated Hb expression in the kidney. Rat kidneys were perfused extensively with saline, and glomeruli were isolated by several techniques (sieving, manual dissection, and laser capture microdissection). Reverse transcriptase-PCR revealed glomerular alpha- and beta globin expression, and immunoblotting demonstrated expression of the protein. In situ hybridization studies showed expression of the globin subunits in the mesangium, and immunostaining confirmed this localization of Hb. Furthermore, globin mRNA expression was detected in primary cultures of rat mesangial cells but not in cultured glomerular endothelial or epithelial cells. For investigation of Hb function in mesangial cells, the SV40-MES13 murine mesangial cell line was transfected with a vector expressing alpha- and beta-globins; this overexpression reduced production of hydrogen peroxide-induced intracellular radical oxygen species and enhanced cell viability against oxidative stress. In summary, Hb is expressed by rat mesangial cells, and its potential functions may include antioxidative defense. PMID- 18448585 TI - Mechanism of urinary calcium regulation by urinary magnesium and pH. AB - Urinary magnesium and pH are known to modulate urinary calcium excretion, but the mechanisms underlying these relationships are unknown. In this study, the data from 17 clinical trials in which urinary magnesium and pH were pharmacologically manipulated were analyzed, and it was found that the change in urinary calcium excretion is directly proportional to the change in magnesium excretion and inversely proportional to the change in urine pH; a regression equation was generated to relate these variables (R(2) = 0.58). For further exploration of these relationships, intravenous calcium chloride, magnesium chloride, or vehicle was administered to rats. Magnesium infusion significantly increased urinary calcium excretion (normalized to urinary creatinine), but calcium infusion did not affect magnesium excretion. Parathyroidectomy did not prevent this magnesium induced hypercalciuria. The effect of magnesium loading on calciuria was still observed after treatment with furosemide, which disrupts calcium and magnesium absorption in the thick ascending limb, suggesting that the effect may be mediated by the distal nephron. The calcium channel TRPV5, normally present in the distal tubule, was expressed in Xenopus oocytes. Calcium uptake by TRPV5 was directly inhibited by magnesium and low pH. In summary, these data are compatible with the hypothesis that urinary magnesium directly inhibits renal calcium absorption, which can be negated by high luminal pH, and that this regulation likely takes place in the distal tubule. PMID- 18448586 TI - Urinary proteomics in diabetes and CKD. AB - Urinary biomarkers for diabetes, diabetic nephropathy, and nondiabetic proteinuric renal diseases were sought. For 305 individuals, biomarkers were defined and validated in blinded data sets using high-resolution capillary electrophoresis coupled with electrospray-ionization mass spectrometry. A panel of 40 biomarkers distinguished patients with diabetes from healthy individuals with 89% sensitivity and 91% specificity. Among patients with diabetes, 102 urinary biomarkers differed significantly between patients with normoalbuminuria and nephropathy, and a model that included 65 of these correctly identified diabetic nephropathy with 97% sensitivity and specificity. Furthermore, this panel of biomarkers identified patients who had microalbuminuria and diabetes and progressed toward overt diabetic nephropathy over 3 yr. Differentiation between diabetic nephropathy and other chronic renal diseases reached 81% sensitivity and 91% specificity. Many of the biomarkers were fragments of collagen type I, and quantities were reduced in patients with diabetes or diabetic nephropathy. In conclusion, this study shows that analysis of the urinary proteome may allow early detection of diabetic nephropathy and may provide prognostic information. PMID- 18448588 TI - Contribution of intrarenal cells to cellular repair after acute kidney injury: subcapsular implantation technique. AB - The kidney is capable of regeneration following injury, particularly following acute insults. Although the mechanisms underlying cellular regeneration are incompletely understood, emerging evidence suggests a role for cells of renal origin in the repair and replacement of damaged renal tubule cells. The overall hypothesis of this study is that native kidney cells that reside in a niche in the kidney provide robust contribution to the repair of kidney tubules following injury. To test this hypothesis, we utilized a model of renal ischemia reperfusion injury that results in extensive morphological changes, particularly in the outer medulla. Renal tissue obtained from mice constitutively expressing Escherichia coli beta-galactosidase (ROSA26) was dissected from the cortex, outer medulla, or papilla and implanted under the renal capsule of the injured mice. Mice were allowed to recover for 7 days. Sections through the injured kidney demonstrated the presence of implant-derived cells in renal tubules in the outer medulla. The implanted renal region that exhibited the most robust response was the papilla, whereas tissue pieces from the cortex and outer medulla showed less contribution to recipient renal tubules. These results provide proof-of-principle evidence that renal-derived reparative cells reside in all regions of the kidney, perhaps more predominantly in the renal papilla. A greater understanding of the cell biology of renal repair by native kidney cells will provide further insight into the design of novel therapies in acute kidney injury, and the subcapsular implant technique described in this study may offer unique advantages to evaluate renal repair mechanisms. PMID- 18448587 TI - Vitamin D receptor activators can protect against vascular calcification. AB - An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification. PMID- 18448589 TI - Regulation of epithelial sodium transport by promyelocytic leukemia zinc finger protein. AB - Aldosterone is the principal regulator of Na homeostasis, and thereby blood pressure. One of the main targets of aldosterone is the epithelial Na channel (ENaC) located in the apical membrane of target cells. Previous studies identified several genes involved in the regulation of ENaC such as SGK1; however, SGK1 knockout mice have only a mild salt-losing phenotype, indicating that further genes must be involved in the action of aldosterone. In our search for further aldosterone-regulated genes, we discovered that aldosterone, at physiological concentrations, induces the expression of the promyelocytic leukemia zinc finger protein (PLZF) in renal cortical collecting duct (CCD) cell lines that stably express mineralocorticoid receptors (MRs). This effect is rapid and does not require de novo protein synthesis, suggesting a direct action. Surprisingly, stable overexpression of human or mouse PLZF isoforms significantly decreased transepithelial Na transport in CCD cells while having no effect on the integrity of the monolayers. In parallel with the decline in Na transport, PLZF suppressed the mRNA levels of beta- and gamma-ENaC subunits. These observations suggest that PLZF is a negative regulator of ENaC in renal epithelial cells and might be part of a negative feedback loop that limits aldosterone's stimulatory effects on sodium reabsorption. PMID- 18448590 TI - Human FXYD2 G41R mutation responsible for renal hypomagnesemia behaves as an inward-rectifying cation channel. AB - A mutation in the human FXYD2 polypeptide (Na-K-ATPase gamma subunit) that changes a conserved transmembrane glycine to arginine is linked to dominant renal hypomagnesemia. Xenopus laevis oocytes injected with wild-type FXYD2 or the mutant G41R cRNAs expressed large nonselective ion currents. However, in contrast to the wild-type FXYD2 currents, inward rectifying cation currents were induced by hyperpolarization pulses in oocytes expressing the G41R mutant. Injection of EDTA into the oocyte removed inward rectification in the oocytes expressing the mutant, but did not alter the nonlinear current-voltage relationship of the wild type FXYD2 pseudo-steady-state currents. Extracellular divalent ions, Ca2+ and Ba2+, and trivalent cations, La3+, blocked both the wild-type and mutant FXYD2 currents. Site-directed mutagenesis of G41 demonstrated that a positive charge at this site is required for the inward rectification. When the wild-type FXYD2 was expressed in Madin-Darby canine kidney cells, the cells in the presence of a large apical-to-basolateral Mg2+ gradient and at negative potentials had an increase in transepithelial current compared with cells expressing the G41R mutant or control transfected cells. Moreover, this current was inhibited by extracellular Ba2+ at the basolateral surface. These results suggest that FXYD2 can mediate basolateral extrusion of magnesium from cultured renal epithelial cells and provide new insights into the understanding of the possible physiological roles of FXYD2 wild-type and mutant proteins. PMID- 18448591 TI - Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. AB - Hyponatremia is the most common electrolyte abnormality in hospitalized patients. When symptomatic (hyponatremic encephalopathy), the overall morbidity is 34%. Individuals most susceptible to death or permanent brain damage are prepubescent children and menstruant women. Failure of the brain to adapt to the hyponatremia leads to brain damage. Major factors that can impair brain adaptation include hypoxia and peptide hormones. In children, physical factors--discrepancy between skull size and brain size--are important in the genesis of brain damage. In adults, certain hormones--estrogen and vasopressin (usually elevated in cases of hyponatremia)--have been shown to impair brain adaptation, decreasing both cerebral blood flow and oxygen utilization. Initially, hyponatremia leads to an influx of water into the brain, primarily through glial cells and largely via the water channel aquaporin (AQP)4. Water is thus shunted into astrocytes, which swell, largely preserving neuronal cell volume. The initial brain response to swelling is adaptation, utilizing the Na(+)-K(+)-ATPase system to extrude cellular Na(+). In menstruant women, estrogen + vasopressin inhibits the Na(+) K(+)-ATPase system and decreases cerebral oxygen utilization, impairing brain adaptation. Cerebral edema compresses the respiratory centers and also forces blood out of the brain, both lowering arterial Po(2) and decreasing oxygen utilization. The hypoxemia further impairs brain adaptation. Hyponatremic encephalopathy leads to brain damage when brain adaptation is impaired and is a consequence of both cerebral hypoxia and peptide hormones. PMID- 18448592 TI - Chronic L-arginine administration increases oxidative and nitrosative stress in rat hyperoxaluric kidneys and excessive crystal deposition. AB - Hyperoxaluric kidneys show an impaired diuretic response to acute infusion of L arginine. In this study, we examined the chronic effect of l-arginine supplementation on CaOx crystal formation in hyperoxaluric rat kidneys. Eight groups were tested: control (received drinking water), L group (received L arginine, 0.6%), LN group [received NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg)], L + LN group (received L-arginine + l-NAME), HP group [received hydroxyl L-proline (HP, 5%) mixed with chow to induce hyperoxaluria], L + HP group (received HP + L-arginine), HP + LN group, and L + HP + LN group. The duration was 42 days, and each group had eight animals. Urinary biochemistry and renal CaOx amounts were measured, as well as renal expressions of nitric oxide synthase (NOS) isoforms and NAD(P)H oxidase. The distribution of inducible NOS (iNOS), NAD(P)H oxidase, ED1-positive cells, and nitrotyrosine was examined by immunohistochemical and immunofluorescence studies, whereas superoxide production from the kidneys was examined by fluorescence spectrometric assay. Compared with the HP group, the L + HP group had excessive CaOx crystal accumulation and enhanced endothelial NOS (eNOS), iNOS, and NAD(P)H oxidase protein expression in the kidney. Urinary excretion of nitrotyrosine was markedly increased. Increased superoxide formation in the L + HP kidney was derived from NAD(P)H oxidase and uncoupled eNOS, and increased nitrotyrosine formation might derive from iNOS and ED1-positive cells that gathered around the CaOx crystals. L-NAME cotreatment (L + HP + LN group) reduced renal oxidative nitrosative stress and tubular damage, which were induced by L + HP. The results showed that chronic l-arginine treatment to the hyperoxaluric kidney with massive CaOx crystal deposition may have a toxic effect by enhancing intrarenal oxidative and nitrosative stress. PMID- 18448593 TI - A p38 mitogen-activated protein kinase inhibitor protects against renal damage in a non-heart-beating donor model. AB - Ischemia-reperfusion injury is one of the central nonimmunologic processes involved in renal allograft dysfunction. Kidneys from non-heart beating donors (NHBD) exhibit higher rates of delayed graft function (DGF) than those from other donors. Primary nonfunction and DGF are the main barriers to the use of kidneys from NHBD. Using a pig model of NHBD transplantation, we studied the effect of FR167653 (a p38 MAP kinase inhibitor) on the recovery and reparation of kidneys exposed to both warm (WI: 1 h) and cold ischemia (24 h). Our results demonstrate that the addition of FR167653 increases the kinetics of proximal tubule cell regeneration after 60 min of WI. Hypoxia-inducible factor and vascular endothelial growth factor expression was also more important in FR167653-treated kidneys compared with those in nontreated groups. Also, expression of peripheral type benzodiazepine receptor, involved in tissue repair, was increased in the FR167653-treated groups. At 3 mo, the protective effects of FR167653 were accompanied by a reduction of long-term inflammation process and tubulointerstitial fibrosis development associated with a limitation of ischemia induced remodeling. This study suggests that such treatment may be useful in protocols aimed at improving the quality of renal transplants from NHBD. In addition, the beneficial role of FR167653 in limiting early injury is associated with secondary reduction in development of tubular atrophy and interstitial fibrosis which are together the hallmark of failing renal transplants. The more efficient effect was observed when FR167653 was added in combination before WI, during cold storage and reperfusion. PMID- 18448594 TI - Acute inhibition of the betaine transporter by ATP and adenosine in renal MDCK cells. AB - Extracellular ATP interacts with purinergic P2 receptors to regulate a range of physiological responses, including downregulation of transport activity in the nephron. ATP is released from cells by mechanical stimuli such as cell volume changes, and autocrine signaling by extracellular ATP could occur in renal medullary cells during diuresis. This was tested in Madin-Darby canine kidney (MDCK) cells, a model used frequently to study P1 and P2 receptor activity. ATP was released within 1 min after transfer from 500 to 300 mosmol/kgH2O medium. A 30-min incubation with ATP produced dose-dependent inhibition (0.01-0.10 mM) of the renal betaine/GABA transporter (BGT1) with little effect on other osmolyte transporters. Inhibition was reproduced by specific agonists for P2X (alpha,beta methylene-ATP) and P2Y (UTP) receptors. Adenosine, the final product of ATP hydrolysis, also inhibited BGT1 but not taurine transport. Inhibition by ATP and adenosine was blocked by pertussis toxin and A73122, suggesting involvement of inhibitory G protein and PLC in postreceptor signaling. Both ATP and adenosine (0.1 mM) produced rapid increases in intracellular Ca2+, due to the mobilization of intracellular Ca2+ stores and Ca2+ influx. Blocking these Ca2+ increases with BAPTA-AM also blocked the action of ATP and adenosine on BGT1 transport. Finally, immunohistochemical studies indicated that inhibition of BGT1 transport may be due to endocytic accumulation of BGT1 proteins from the plasma membrane. We conclude that ATP and adenosine, through stimulation of PLC and intracellular Ca2+, may be rapidly acting regulators of BGT1 transport especially in response to a fall in extracellular osmolarity. PMID- 18448595 TI - Silencing megalin and cubilin genes inhibits myeloma light chain endocytosis and ameliorates toxicity in human renal proximal tubule epithelial cells. AB - Using target-specific short interfering (si) RNAs, we silenced the tandem endocytic receptors megalin and cubilin genes in cultured human renal proximal tubule epithelial cells. Transfection by siRNA resulted in up to 90% suppression of both megalin and cubilin protein and mRNA expression. In HK-2 cells exposed to kappa-light chain for up to 24 h, light chain endocytosis was reduced in either megalin- or cubilin-silenced cells markedly but incompletely. Simultaneous silencing of both the cubilin and megalin genes, however, resulted in near complete inhibition of light chain endocytosis, as determined by measuring kappa light chain protein concentration in cell cytoplasm and by flow cytometry using FITC-labeled kappa-light chain. In these cells, light chain-induced cytokine responses (interleukin-6 and monocyte chemoattractant protein-1) and epithelial to-mesenchymal transition as well as the associated cellular and morphological alterations were also markedly suppressed. The results demonstrate that light chain endocytosis is predominantly mediated by the megalin-cubilin tandem endocytic receptor and identify endocytosis as a key step in light chain cytotoxicity. Blocking light chain endocytosis prevents its nephrotoxic effects on human kidney proximal tubule cells. PMID- 18448596 TI - Vasopressin regulates the renin-angiotensin-aldosterone system via V1a receptors in macula densa cells. AB - The neuropeptide hormone arginine-vasopressin (AVP) is well known to exert its antidiuretic effect via the vasopressin V2 receptor (V2R), whereas the role of the vasopressin V1a receptor (V1aR) in the kidney remains to be clarified. Previously, we reported decreased plasma volume and blood pressure in V1a receptor-deficient (V1aR-/-) mice (Koshimizu T, Nasa Y, Tanoue A, Oikawa R, Kawahara Y, Kiyono Y, Adachi T, Tanaka T, Kuwaki T, Mori T. Proc Natl Acad Sci USA 103: 7807-7812, 2006). In this study, we investigated the role of V1aR in urine concentration, renal function, and the renin-angiotensin system (RAS) using V1aR-/- mice. Urine volume of V1aR-/- mice was greater than that of wild-type mice, particularly when water was loaded, while the glomerular filtration rate (GFR), urinary NaCl excretion, AVP-dependent cAMP generation, V2R, and aquaporin 2 (AQP2) expression in the kidney were lower, indicating that the diminished GFR and V2R-AQP2 system led to impaired urinary concentration in V1aR-/- mice. Since the GFR and V2R-AQP2 system are regulated by RAS, we analyzed renin and angiotensin II in V1aR-/- mice and found that the plasma renin and angiotensin II were decreased. The expression of renin in granule cells was decreased in V1aR-/- mice, which led to a decreased level of plasma renin. In addition, the expression of renin stimulators such as neuronal nitric oxide synthase and cyclooxygenase-2 in macula densa (MD) cells, where V1aR was specifically expressed, was decreased in V1aR-/- mice. These data indicate that AVP regulates body fluid homeostasis and GFR via the V1aR in MD cells by activating RAS and subsequently the V2R-AQP2 system. PMID- 18448598 TI - The peer in peer review. PMID- 18448597 TI - Mice overexpressing latent TGF-beta1 are protected against renal fibrosis in obstructive kidney disease. AB - Transforming growth factor (TGF)-beta1, once activated, binds to its receptors and mediates renal fibrosis via the downstream Smad signaling pathway. We reported here that mice overexpressing latent TGF-beta1 in keratinocytes were protected against renal fibrosis in a model of obstructive kidney disease. In normal mice, both transgenic (Tg) and wild-type (WT) mice had normal renal histology and function, despite a 10-fold increase in plasma latent TGF-beta1 in Tg mice. A severe renal fibrosis was developed in WT mice at 7 days after urinary obstruction. Unexpectedly, renal fibrosis was prevented in Tg mice, although levels of latent TGF-beta1 in both circulation and renal tissues remained high. Compared with the WT mice, quantitative real-time PCR showed that upregulation of renal alpha-smooth muscle actin (SMA), collagen I, and collagen III mRNA was inhibited in Tg mice (60-70% reduced, all P < 0.01). These were further confirmed by immunohistochemistry with a marked inhibition of tubulointerstitial accumulation of alpha-SMA+ fibroblasts, collagen I, and collagen III matrix in Tg mice (all P < 0.001). Further studies showed that inhibition of renal fibrosis in Tg mice was associated with a significant reduction in renal TGF-beta1 and CTGF (60% reduced, P < 0.05), an increase in renal Smad7, a suppression of TSP-1 (a critical factor for TGF-beta1 activation), and an inhibition of Smad2/3 activation (all P < 0.001). In conclusion, latent TGF-beta may play a protective role in renal fibrosis. Inhibition of renal TGF-beta1 expression and activation, thereby blocking the downstream TGF-beta signaling pathway, may be a critical mechanism by which latent TGF-beta1 protects against renal fibrosis. PMID- 18448599 TI - Assessing the microstructure of written language using a retelling paradigm. AB - PURPOSE: The primary goal of this study was to document the progression of the microstructural elements of written language in children at 4 grade levels. The secondary purpose was to ascertain whether the variables selected for examination could be classified into valid categories that reflect the multidimensional nature of writing. METHOD: Written language samples were collected and transcribed from 120 children in Grades 3 through 6 using an expository text retelling paradigm. Nine variables at various levels of language were analyzed. RESULTS: Using a text-retelling paradigm, measures of productivity (e.g., total number of words and ideas) improved steadily with age, whereas measures of complexity (e.g., mean length of T-unit) did not. Results for measures of accuracy (e.g., spelling and writing conventions) were mixed, with some showing improvement across grades. Grade 3 students showed consistently poorer performance than students in Grades 4, 5, and 6. Grade 4 students showed poorer performance than students in Grades 5 and 6. Exploratory factor analysis suggests that writing can be represented by 3 factors: Productivity, Complexity, and Accuracy. CONCLUSIONS: Clinicians can use this multidimensional scheme for examining writing skills using text-retelling formats with children from Grades 3 through 6. This empirically based framework for measuring microstructural variables of writing provides clinicians with a 3-prong conceptual framework for determining children's strengths and weaknesses within the translational stage of writing. PMID- 18448600 TI - Expected test scores for preschoolers with a cochlear implant who use spoken language. AB - PURPOSE: The major purpose of this study was to provide information about expected spoken language skills of preschool-age children who are deaf and who use a cochlear implant. A goal was to provide "benchmarks" against which those skills could be compared, for a given age at implantation. We also examined whether parent-completed checklists of children's language were correlated with results of standardized language tests and whether scores increased linearly with decreasing age of implantation and increasing duration of cochlear implant use. METHOD: Participants were a nationwide sample of 76 children who were deaf and orally educated and who received an implant by 38 months of age. Formal language tests were administered at age 4.5 years. The MacArthur-Bates Communicative Development Inventories (CDI) instrument was completed by parents when children were ages 3.5 and 4.5 years. RESULTS: Based on regression analyses, expected scores for each age at implant were provided for 2 commonly administered language tests at 4.5 years of age and CDI subscale scores at 3.5 and 4.5 years. Concurrent test scores were significantly correlated on all measures. A linear relation was found that predicted increasing test scores with younger ages at implantation for all scales administered. CONCLUSIONS: While the expected scores reported here should not be considered as normative data, they are benchmarks that may be useful for evaluating spoken language progress of children with cochlear implants who are enrolled in spoken language-based programs. PMID- 18448601 TI - A phase II trial of telehealth delivery of the Lidcombe Program of Early Stuttering Intervention. AB - PURPOSE: The aims of this study were to evaluate the efficacy of telehealth delivery of the Lidcombe Program of Early Stuttering Intervention, compared with a control group, and to determine the number of children who could be regarded as "responders." METHOD: A speech-language pathologist provided telehealth delivery of the Lidcombe Program during telephone consultations with parents in their homes, remote from the clinic. The study design was an open plan, parallel group, randomized controlled trial with blinded outcome assessment. Children in the no treatment control group who were still stuttering after 9 months then received the same treatment. The primary outcome measure was frequency of stuttering, gathered from audiotape recordings of participants' conversational speech in everyday, nontreatment situations, before and after treatment. RESULTS: Analysis of covariance showed a 73% decrease in frequency of stuttering at 9 months after randomization in the treatment group, as compared with the control group (95% confidence interval = 25%-90%, p = .02). Measures of treatment time showed that telehealth delivery of the Lidcombe Program requires around 3 times more resources than standard presentation. CONCLUSIONS: Telehealth delivery of the Lidcombe Program is an efficacious treatment for preschool children who cannot receive the standard, clinic-based Lidcombe Program. Avenues for improving efficiency are considered. PMID- 18448602 TI - Oral and written language development of children adopted from china. AB - PURPOSE: The sharp increase in the number of international adoptions in the United States has prompted a heightened interest in the language development of internationally adopted children. Although recent studies have investigated the early language development of adoptees, little is known about the school-age language and literacy skills of internationally adopted children. The focus of this study was the oral and written language skills of school-age adoptees from China. METHOD: The participants were 24 children between the ages of 7;0 (years;months) and 8;8. Oral and written language skills were assessed using standardized measures and a narrative retell task. RESULTS: As a group, the majority of children exhibited scores in the average to above average range for all oral and written standardized language measures. Narrative analysis indicated that an increase in the number of grammatical errors was moderately correlated with lower reading comprehension scores. Age at adoption was negatively correlated with several measures, including a narrative measure of grammatical errors per T-unit. CONCLUSION: These findings provide an encouraging outlook on the oral and written language outcomes of internationally adopted children from China through the early elementary grades. Moreover, these findings support earlier research that speaks to the resiliency and robustness of language acquisition abilities in children. PMID- 18448603 TI - Using semantic feature analysis to improve contextual discourse in adults with aphasia. AB - PURPOSE: Semantic feature analysis (SFA) was used to determine whether training contextually related words would improve the discourse of individuals with nonfluent aphasia in preselected contexts. METHOD: A modified multiple-probes across-behaviors design was used to train target words using SFA in 3 adults with nonfluent aphasia. Pretreatment, posttreatment, and follow-up sessions obtained language samples for the preselected contexts. Contexts included 4 story retellings and 4 procedure explanations. RESULTS: All participants improved naming ability for treated words. No generalization to untrained items was found. Within discourse samples, participants increased number of target words produced from pretreatment to posttreatment sessions but did not increase lexical diversity across samples. Participants maintained performance on standardized measures from the beginning to the end of the study. CONCLUSIONS: Results support and extend previous research by indicating that SFA improves confrontational naming ability and may benefit word retrieval in discourse production of closed set contexts. PMID- 18448604 TI - Comparisons of audio and audiovisual measures of stuttering frequency and severity in preschool-age children. AB - PURPOSE: To determine whether measures of stuttering frequency and measures of overall stuttering severity in preschoolers differ when made from audio-only recordings compared with audiovisual recordings. METHOD: Four blinded speech language pathologists who had extensive experience with preschoolers who stutter measured stuttering frequency and rated overall severity from audio-only and audiovisual recordings of 36 preschool children who were stuttering. Stuttering frequency (percentage of syllables stuttered [%SS]) was based on counts of perceptually unambiguous stutterings, made in real time, and overall severity was measured using a 9-point rating scale. RESULTS: Stuttering frequency was statistically significantly lower by around 20% when made from audio-only recordings. This was found to be directly attributable to differences in the counts of stuttered syllables, rather than to differences in the total numbers of syllables spoken. No significant differences were found between recording modalities for the ratings of overall severity. Correlations between %SS scores in the 2 modalities and severity rating scores in the 2 modalities were high, indicating that observers agreed on data trends across speech samples. CONCLUSIONS: Measures of %SS made from audio-only recordings may underestimate stuttering frequency in preschoolers. Although audio-only %SS measures may underestimate stuttering frequency at the start of a clinical trial to a clinically significant extent, posttreatment scores at or below 1.0%SS are likely to underestimate by 0.2%SS or less, which is clinically insignificant. PMID- 18448605 TI - The role of color cues in facilitating accurate and rapid location of aided symbols by children with and without down syndrome. AB - PURPOSE: This research examined how the color distribution of symbols within a visual aided augmentative and alternative communication array influenced the speed and accuracy with which participants with and without Down syndrome located a target picture symbol. METHOD: Eight typically developing children below the age of 4 years, 8 typically developing children over the age of 4 years, and 10 children with Down syndrome participated. Participants were asked to find a target line drawing among an array of 12. Line drawings represented either foods (e.g., grapes, cherries), clothing (e.g., a red shirt, a yellow shirt), or activities (e.g., soccer, swimming). In one condition, symbols that shared a color were clustered together, creating a subgroup within which to search. In another condition, symbols that shared a color were distributed across the display, allowing each to appear individually. Dependent measures were accuracy and speed of finding the target symbol. RESULTS: Clustering same-color symbols facilitated the speed of locating the target for all participants, and facilitated search accuracy in the younger preschool children and participants with Down syndrome. These effects held when targets were foods, clothing, or activities. CONCLUSION: Clinicians should consider the internal color of visual symbols when constructing aided symbol displays, at least for children with Down syndrome. Further research is needed on a number of dimensions, however, including visual processing in other etiological categories, the role of background color, and the relation of color to other stimulus dimensions. PMID- 18448606 TI - Comparison of personal versus fictional narratives of children with language impairment. AB - PURPOSE: Personal narratives are common in children's conversations, recommended as the appropriate genre for early writing by educators, and part of many high stakes tests, possibly because they tend to be better formed than fictional narratives. However, current practice in the field of speech-language pathology employs fictional narratives in assessment, intervention, and study of children with impaired language development. This article explored performance on personal versus fictional narratives by children with language impairment (LI), hypothesizing that performance on the former would be better and a minimal relationship between performances in the 2 genres. METHOD: Twenty-seven children age 7;0-9;9 (years;months) with LI orally produced personal and fictional narratives (responses to a wordless picture book). Narratives were analyzed by raters blind to experimental hypotheses using high-point analysis and an analysis derived from scoring of a high-stakes composition for 4th grade. RESULTS: High point ratings of personal significantly exceeded those of fictional narratives. Disproportionate fictional stories did not meet minimal narrative criteria. However, more personal narratives than would be expected by chance did. The analyses were significantly correlated. Quality of a child's performance of personal was minimally related to that of fictional narratives. CONCLUSIONS: Clinicians may want to consider functional aspects of personal narratives. PMID- 18448607 TI - Blockade of NGF and trk receptors inhibits increased peripheral mechanical sensitivity accompanying cystitis in rats. AB - Visceral inflammation, including that arising from bladder inflammation, reduces the threshold to sensation of innocuous or noxious stimuli applied to peripheral structures (referred hyperalgesia). Cystitis may induce transient or persistent plastic changes mediated by neurotrophins, particularly nerve growth factor (NGF), which contribute to increased nociceptive input. In this study, acute or subacute cystitis was induced in female rats by one or three (at 72-h intervals) 400-microl intravesical instillations of 1 mM acrolein. Sensitivity of the hindpaws to mechanical and thermal stimuli was determined before and 4, 24, 48, 72, and 96 h after treatment. Other groups of rats were treated with intravesical or intrathecal k252a [a nonspecific antagonist of tyrosine kinase (trk) receptors, including trkA, the high-affinity receptor for NGF] before the first or third acrolein instillation. Some rats were intraperitoneally injected with specific NGF-neutralizing antiserum or normal serum before acrolein instillation. Acute and subacute cystitis induced mechanical, but not thermal, referred hyperalgesia that was attenuated by intravesical pretreatment with k252a. Systemic treatment with NGF-neutralizing antiserum before instillation of acrolein suppressed subsequent mechanical referred hyperalgesia. Expression of NGF was increased within the bladder by acute or subacute cystitis and in L6/S1 dorsal root ganglia by subacute cystitis. These results suggest that the bladder derived NGF acting via trk receptors at least partially mediates peripheral sensitization to mechanical stimuli associated with acute and subacute acrolein induced cystitis. PMID- 18448609 TI - Electrophysiological properties and expression of the delayed rectifier potassium (ERG) channels in the heart of thermally acclimated rainbow trout. AB - In ectotherms, compensatory changes in ion channel number and activity are needed to maintain proper cardiac function at variable temperatures. The rapid component of the delayed rectifier K+ current (IKr) is important for repolarization of cardiac action potential and, therefore, crucial for regulation of cellular excitability and heart rate. To examine temperature plasticity of cardiac IKr, we cloned the ether-a-go-go-related gene (ERG) channel and measured its electrophysiological properties in thermally acclimated rainbow trout (Oncorhynchus mykiss; omERG). The present findings demonstrate a complete thermal compensation in the whole cell conductance of the atrial IKr in rainbow trout acclimated to 4 degrees C (cold acclimation) and 18 degrees C (warm acclimation). In situ hybridization indicates that transcripts of the omERG channel are present throughout the muscular tissue of the heart, and quantitative PCR shows increased expression of the omERG in cold-acclimated trout compared with warm-acclimated trout. In both acclimation groups, omERG expression is higher in atrium than ventricle. In addition, the omERG has some functional features that support IKr activity at low temperatures. Voltage dependence of steady-state activation is completely resistant to temperature changes, and steady-state inactivation and activation kinetics are little affected by temperatures below 11 degrees C. Collectively, these findings suggest that high density of cardiac IKr is achieved by cold-induced increase in the number of functional omERG channels and inherent insensitivity of the omERG to temperature below 11 degrees C. These adaptations are probably important in maintaining high heart rates and proper excitability and contractility of trout cardiac myocytes in the cold. PMID- 18448608 TI - Exposure to inhaled particulate matter impairs cardiac function in senescent mice. AB - Daily exposure to particulate matter (PM) is known to adversely affect cardiac function and is also known to be exaggerated with senescence. This study tests the hypothesis that cardiac function is uniquely altered by PM exposure in senescent mice. A mechanism for PM-induced cardiac effects is also postulated by examining the activity of nitric oxide synthase (NOS) and the generation of reactive oxygen species (ROS) in heart tissue. Echocardiography is performed in awake 18- and 28-mo-old mice at baseline and immediately following 3-h exposures to either filtered air or carbon black (CB; approximately 400 microg/m3) on 4 days. At 28 mo, left ventricular diameter at end-systole and end-diastole is significantly (P < 0.05) elevated, and fractional shortening is significantly reduced (49 +/- 3% vs. 56 +/- 3%) with CB exposure. In vivo hemodynamic measurements at 28 mo also demonstrate significant (P < 0.05) reductions in ejection fraction and increases in right ventricular and pulmonary vascular pressures following CB exposure. Functional changes at 28 mo are associated with increased ROS production as suggested by enhanced luminol activity. This elevated ROS production with aging and CB exposure is attributable to NOS uncoupling. Measurements of natriuretic peptide (atrial and brain) transcription and matrix metalloproteinase (MMP2 and MMP9) activity in heart tissue are significantly (P < 0.05) amplified with senescence and exposure to CB, pointing to increased cardiac stress and remodeling. These results demonstrate that acute PM exposure reduces cardiac contractility in senescent mice, and this decline in function is associated with increased ROS production linked to NOS uncoupling. PMID- 18448610 TI - An imprinted gene network that controls mammalian somatic growth is down regulated during postnatal growth deceleration in multiple organs. AB - In mammals, somatic growth is rapid in early postnatal life but decelerates with age and eventually halts, thus determining the adult body size of the species. This growth deceleration, which reflects declining proliferation, occurs simultaneously in multiple organs yet appears not to be coordinated by a systemic mechanism. We, therefore, hypothesized that growth deceleration results from a growth-limiting genetic program that is common to multiple tissues. Here, we identified a set of 11 imprinted genes that show down-regulation of mRNA expression with age in multiple organs. For these genes, Igf2, H19, Plagl1, Mest, Peg3, Dlk1, Gtl2, Grb10, Ndn, Cdkn1c, and SLC38a4, the declines show a temporal pattern similar to the decline in growth rate. All 11 genes have been implicated in the control of cell proliferation or somatic growth. Thus, our findings suggest that the declining expression of these genes contributes to coordinate growth deceleration in multiple tissues. We next hypothesized that the coordinate decline in expression of these imprinted genes is caused by altered methylation and consequent silencing of the expressed allele. Contrary to this hypothesis, the methylation status of the promoter regions of Mest, Peg3, and Plagl1 did not change with age. Our findings suggest that a set of growth-regulating imprinted genes is expressed at high levels in multiple tissues in early postnatal life, contributing to rapid somatic growth, but that these genes are subsequently downregulated in multiple tissues simultaneously, contributing to coordinate growth deceleration and cessation, thus imposing a fundamental limit on adult body size. PMID- 18448611 TI - Cannabinoid-1 receptor antagonists reduce caloric intake by decreasing palatable diet selection in a novel dessert protocol in female rats. AB - Although many feeding protocols induce obesity, few use multiple foods to analyze diet selection within a single group of animals. To this end, we describe a protocol using time-limited access to a dessert that induces hyperphagia and body weight gain while allowing simple analysis of diet selection. Female retired breeder Sprague-Dawley rats were provided with ad libitum access to standard moist chow (1.67 kcal/g) and daily 8-h nocturnal access to either a sugar gel (SG; 0.31 kcal/g) or sugar fat whip (SFW; 7.35 kcal/g) for 15 days, and food intake and body weight were measured daily. Rats given SFW reduced moist chow intake but not enough to compensate for the large amount of calories consumed from SFW, and thus gained weight. We use this SFW overconsumption protocol to investigate the hypothesis that cannabinoid (CB)1 receptor antagonists reduce caloric intake by selectively decreasing consumption of palatable foods. In two experiments, female retired breeder Sprague-Dawley rats were injected with either Rimonabant (1 mg/kg ip) or vehicle (equal parts polyethylene glycol and saline, 1 ml/kg ip) for 7 days, or one of three doses of AM251 (0.3, 1.0, or 3.0 mg/kg ip), or vehicle for 15 days; food intake and body weight were measured daily. Both Rimonabant and AM251 decreased 24-h caloric intake, but the reduction was specific to a decrease in SFW consumption. This supports the hypothesis that these CB1 receptor antagonists impact feeding by modulating the perception of palatability. PMID- 18448612 TI - A warmer ambient temperature increases the passage of interleukin-1beta into the brains of old rats. AB - We have demonstrated that after intraperitoneal lipopolysaccharide (LPS) injection, old rats mount fevers similar to those of young rats at an ambient temperature (Ta) of 31 degrees C, but not at 21 degrees C. The same is true for intraperitoneal or intravenous IL-1beta administration. The underlying mechanism responsible for blunted fever in old rats may be a deficiency in communication between the periphery and the brain. Possibly, peripheral cytokine actions are altered in old rats, such that the signal that reaches the brain is diminished. Here, we hypothesized that at standard laboratory temperatures, not enough IL 1beta is reaching the brain for fever to occur and that a warmer Ta would increase the influx of IL-1beta into the brain, enabling old rats to generate fever. Young (3-5 mo) and old (23-29 mo) Long-Evans rats were maintained for 3 days at either Ta 21 or 31 degrees C prior to intravenous injection with radiolabeled IL-1beta to measure passage across the blood-brain barrier. Young rats showed similar influx of IL-1beta into the brain at the two Tas, but old rats showed significant influx only at the warmer Ta. These data suggest that the lack of fever at a cool Ta may be due to a reduced influx of IL-1beta into the brain. PMID- 18448613 TI - Single muscle fiber adaptations to resistance training in old (>80 yr) men: evidence for limited skeletal muscle plasticity. AB - The purpose of this study was to investigate whole muscle and single muscle fiber adaptations in very old men in response to progressive resistance training (PRT). Six healthy independently living old men (82 +/- 1 yr; range 80-86 yr, 74 +/- 4 kg) resistance-trained the knee extensors (3 sets, 10 repetitions) at approximately 70% one repetition maximum 3 days/wk for 12 wk. Whole thigh muscle cross-sectional area (CSA) was assessed before and after PRT using computed tomography (CT). Muscle biopsies were obtained from the vastus lateralis before and after the PRT program. Isolated myosin heavy chain (MHC) I and IIa single muscle fibers (n = 267; 142 pre; 125 post) were studied for diameter, peak tension, shortening velocity, and power. An additional set of isolated single muscle fibers (n = 2,215; 1,202 pre; 1,013 post) was used to identify MHC distribution. One repetition maximum knee extensor strength increased (P < 0.05) 23 +/- 4 kg (56 +/- 4 to 79 +/- 7 kg; 41%). Muscle CSA increased (P < 0.05) 3 +/- 1 cm2 (120 +/- 7 to 123 +/- 7 cm2; 2.5%). Single muscle fiber contractile function and MHC distribution were unaltered with PRT. These data indicate limited muscle plasticity at the single-muscle fiber level with a resistance training program among the very old. The minor increases in whole muscle CSA coupled with the static nature of the myocellular profile indicate that the strength gains were primarily neurological. These data contrast typical muscle responses to resistance training in young ( approximately 20 yr) and old ( approximately 70 yr) humans and indicate that the physiological regulation of muscle remodeling is adversely modified in the oldest old. PMID- 18448614 TI - Inflammation is associated with a decrease of lipogenic factors in omental fat in women. AB - Obesity is characterized by systemic low-grade inflammation in which adipose tissue, especially the omental depot, is thought to play a key role. We have previously shown that inflammation impairs 3T3-L1 preadipocyte cell line differentiation. To explore whether this interaction also takes place in vivo, the expression of several genes related to inflammation and adipocyte differentiation was assessed in human samples. Paired adipose tissue biopsies (from omental and subcutaneous depots) were obtained from 24 women: 6 lean normoglycemic and 18 obese volunteers with different glycemic states (normoglycemic, glucose-intolerant, or type 2 diabetic). The expression levels of CD14, IL-18, leptin, adiponectin, sterol regulatory element binding transcription factor 1 (SREBP1), peroxisome proliferator-activated receptor gamma (PPARgamma), pre-B-cell colony enhancing factor 1 (PBEF1) (or visfatin), glycerol-3-phosphate dehydrogenase 1 (soluble) (GPD1), lipoprotein lipase (LPL), fatty acid binding protein 4, adipocyte (FABP4), and hypoxia-inducible factor 1alpha were determined by quantitative real-time PCR. CD14 and IL-18 were overexpressed in omental adipose tissue compared with the subcutaneous depot, irrespective of the subject's obesity or diabetes status. A significant decrease of LPL, GPD1, and leptin expression was observed in omental tissue, and an inverse correlation between expression of CD14 and IL-18 and that of PPARgamma, LPL, and FABP4 was observed. The underexpression of omental lipogenic markers was more accentuated in the presence of glucose intolerance. Furthermore, adiponectin and SREBP1 expression was also significantly decreased in omental tissue of type 2 diabetic patients. PBEF1 and HIF1alpha expression remained comparable in all samples. Therefore, in humans, inflammation is increased in the omental depot, as evidenced by CD14 and IL-18 expression. In this localization, the inflammatory state is associated with a decreased expression of lipogenic markers, which is more pronounced in diabetic subjects. PMID- 18448616 TI - Baroreflex control of lumbar and renal sympathetic nerve activity in conscious rats. AB - This study compared the baroreflex control of lumbar and renal sympathetic nerve activity (SNA) in conscious rats. Arterial pressure (AP) and lumbar and renal SNA were simultaneously recorded in six freely behaving rats. Pharmacological estimates of lumbar and renal sympathetic baroreflex sensitivity (BRS) were obtained by means of the sequential intravenous administration of sodium nitroprusside and phenylephrine. Sympathetic BRS was significantly (P < 0.05) lower for lumbar [3.0 +/- 0.4 normalized units (NU)/mmHg] than for renal (7.6 +/- 0.6 NU/mmHg) SNA. During a 219-min baseline period, spontaneous lumbar and renal BRS were continuously assessed by computing the gain of the transfer function relating AP and SNA at heart rate frequency over consecutive 61.4-s periods. The transfer gain was considered only when coherence between AP and SNA significantly differed from zero, which was verified in 99 +/- 1 and 96 +/- 3% of cases for lumbar and renal SNA, respectively. When averaged over the entire baseline period, spontaneous BRS was significantly (P < 0.05) lower for lumbar (1.3 +/- 0.2 NU/mmHg) than for renal (2.3 +/- 0.3 NU/mmHg) SNA. For both SNAs, spontaneous BRS showed marked fluctuations (variation coefficients were 26 +/- 2 and 28 +/- 2% for lumbar and renal SNA, respectively). These fluctuations were positively correlated in five of six rats (R = 0.44 +/- 0.06; n = 204 +/- 8; P < 0.0001). We conclude that in conscious rats, the baroreflex control of lumbar and renal SNA shows quantitative differences but is modulated in a mostly coordinated way. PMID- 18448615 TI - Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries. AB - Hyperhomocysteinemia (HHcy) impairs endothelium-dependent vasodilation by increasing reactive oxygen species, thereby reducing nitric oxide (NO.) bioavailability. It is unclear whether reduced expression or function of the enzyme that produces NO., endothelial nitric oxide synthase (eNOS), also contributes. It is also unclear whether resistance vessels that utilize both NO.and non-NO.vasodilatory mechanisms, undergo alteration of non-NO.mechanisms in this condition. We tested these hypotheses in male C57BL/6 mice with chronic HHcy induced by 6-wk high methionine/low-B vitamin feeding (Hcy: 89.2 +/- 49.0 microM) compared with age-matched controls (Hcy: 6.6 +/- 1.9 microM), using first-order mesenteric arteries. Dilation to ACh (10(-9)-10(-4) M) was measured in isolated, cannulated, and pressurized (75 mmHg) arteries with and without N(G)-nitro-l arginine methyl ester (l-NAME) (10(-4) M) and/or indomethacin (10(-5) M) to test endothelium-dependent dilation and non-NO.-dependent dilation, respectively. The time course of dilation to ACh (10(-4) M) was examined to compare the initial transient dilation due to non-NO., non-prostacyclin mechanism and the sustained dilation due to NO.. These experiments indicated that endothelium-dependent dilation was attenuated (P < 0.05) in HHcy arteries due to downregulation of only NO.-dependent dilation. Western blot analysis indicated significantly less (P < 0.05) basal eNOS and phospho-S1179-eNOS/eNOS in mesenteric arteries from HHcy mice but no difference in phospho-T495-eNOS/eNOS. S1179 eNOS phosphorylation was also significantly less in these arteries when stimulated with ACh ex vivo or in situ. Real-time PCR indicated no difference in eNOS mRNA levels. In conclusion, chronic diet-induced HHcy in mice impairs eNOS protein expression and phosphorylation at S1179, coincident with impaired NO.-dependent dilation, which implicates dysfunction in eNOS post-transcriptional regulation in the impaired endothelium-dependent vasodilation and microvascular disease that is common with HHcy. PMID- 18448617 TI - Effects of age and oral disease on systemic inflammatory and immune parameters in nonhuman primates. AB - This report evaluated systemic inflammatory and immune biomarkers in a cohort of Macaca mulatta (rhesus monkeys) maintained as a large family social unit, including an age range from <1 year to >24 years. We hypothesized that the systemic host responses would be affected by the age, gender, and clinical oral presentation of the population, each contributing to inflammatory and immune responses that would reflect chronic oral infections. The results demonstrated that the prevalence and severity of periodontitis, including missing teeth, increased significantly with age. Generally, minimal differences in clinical parameters were noted between the genders. Systemic inflammatory mediators, including acute-phase reactants, prostaglandin E(2) (PGE(2)), cytokines/chemokines, and selected matrix metalloproteinases (MMP), demonstrated significant differences among the various age groups of animals. Levels of many of these were increased with age, although PGE(2), RANTES, bactericidal permeability-inducing factor (BPI), MMP-1, and MMP-9 levels were significantly increased in the young group ( approximately 1 to 3 years old) relative to those for the older animals. We observed that in the adult and aged animals, levels of the systemic inflammatory mediators related to gingival inflammation and periodontal tissue destruction were significantly elevated. Serum antibody levels in response to a battery of periodontal pathogens were generally lower in the young animals, <50% of those in the adults, and were significantly related to aging in the cohort. The levels of antibodies, particularly those to Porphorymonas gingivalis, Fusobacterium nucleatum, and Tannerella forsythia, were most significantly elevated in animals with periodontal disease, irrespective of the age of the animal. These results provide a broad description of oral health and host responses in a large cohort of nonhuman primates from very young animals to the aged of this species. The findings afford a base of data with which to examine the ontogeny of host responses at mucosal sites, such as the gingival tissues. PMID- 18448618 TI - Correlation of cellular immune responses with protection against culture confirmed influenza virus in young children. AB - The highly sensitive gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot (ELISPOT) assay permits the investigation of the role of cell-mediated immunity (CMI) in the protection of young children against influenza. Preliminary studies of young children confirmed that the IFN-gamma ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to <36 months, an intranasal dose of 10(7) fluorescent focus units (FFU) of a live attenuated influenza virus vaccine (CAIV-T) elicited substantial CMI responses. A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination. The role of CMI in actual protection against community-acquired, culture-confirmed clinical influenza by CAIV-T was investigated in a large randomized, double-blind, placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to <36 months in the Philippines and Thailand. The estimated protection curve indicated that the majority of infants and young children with >or=100 spot-forming cells/10(6) peripheral blood mononuclear cells were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development. The ELISPOT assay for IFN-gamma is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza, especially those used for children. PMID- 18448619 TI - Development and characterization of an equine infectious anemia virus Env pseudotyped reporter virus. AB - We developed a replication-defective reporter virus pseudotyped with the envelope glycoprotein of equine infectious anemia virus (EIAV). The in vitro host range and neutralization phenotype of EIAV Env-pseudotyped virus were similar to those of replication-competent virus. An EIAV Env pseudovirus will improve antigenic characterization of viral variants and evaluation of lentivirus vaccines. PMID- 18448620 TI - Effects of delays in peripheral blood processing, including cryopreservation, on detection of CD31 expression on naive CD4 T cells. AB - Delayed processing of peripheral blood or peripheral blood mononuclear cell isolation and cryopreservation can lead to the detection of somewhat higher levels of CD31 expression on naive CD4 T cells by flow cytometry. These observations should be considered in the planning of multicenter clinical trials and in the interpretation of the results of functional studies. PMID- 18448621 TI - Evaluation of a multicolor, single-tube technique to enumerate lymphocyte subpopulations. AB - To evaluate the fully automated FACSCanto software, we compared lymphocyte subpopulation counts obtained using three-color FACSCalibur-CELLQuest and six color FACSCanto-FACSCanto software techniques. High correlations were observed between data obtained with these techniques. Our study indicated that FACSCanto clinical software is accurate and sensitive in single-platform lymphocyte immunophenotyping. PMID- 18448622 TI - Evaluation of seven tests for diagnosis of human brucellosis in an area where the disease is endemic. AB - The results of seven serologic tests for diagnosis of human brucellosis were evaluated. The titrated Rose Bengal test, microagglutination test, microtiter adapted Coombs test, and immunocapture-agglutination test (Brucellacapt) were positive for all sera from patients with acute brucellosis. The immunoglobulin G (IgG), IgM, and IgA commercial enzyme immunoassays (ELISAs) failed to show specific antibodies in 3 patients, 10 patients, and 1 patient, respectively. The sensitivity of ELISA is not higher than that of conventional tests. PMID- 18448623 TI - Human serum contains a protease that protects against cytotoxic activity of Bacillus anthracis lethal toxin in vitro. AB - The role of innate immunity in the host response to Bacillus anthracis is poorly understood. We found that normal human serum contains an antitoxin mechanism that is capable of protecting macrophages in vitro from B. anthracis lethal toxin mediated killing. This protective activity was limited to defined amounts of toxin and was lost by heat treatment or serum dilution. Some person-to-person variation in the protective activity of serum was noted, especially with higher concentrations of lethal toxin. A similar protective activity was found in murine serum, though human serum consistently neutralized more toxin than did murine serum. The protective activities of both murine and human sera correlated with cleavage of the protective antigen into two fragments with approximate molecular sizes of 20 and 50 kDa that were recognized by the monoclonal antibodies 7.5G and 10F4, respectively. This pattern of fragmentation is consistent with cleavage at multiple sites, including the furin-susceptible site. Cleavage was abolished by heat treatment and calcium chelation. These findings highlight a potential role for serum proteases in protection against the lethal toxin of B. anthracis. PMID- 18448624 TI - Memory T cells specific for novel human papillomavirus type 16 (HPV16) E6 epitopes in women whose HPV16 infection has become undetectable. AB - Human papillomavirus (HPV)-specific T-cell response to the HPV type 16 (HPV16) E6 protein has been shown to be associated with successful viral clearance. The patterns of CD8 T-cell epitopes within HPV16 E6 protein were previously studied in two women with HPV16 clearance. The goal of this study was to characterize these epitopes in terms of their minimal and optimal amino acid sequences and the human leukocyte antigen (HLA) restriction molecules. The presence of the epitope specific memory T cells after viral clearance was also examined. In subject A, the dominant epitope was characterized to be E6 75-83 (KFYSKISEY), restricted by the HLA-B62 molecule, while that of subject B was E6 133-142 (HNIRGRWTGR), restricted by the HLA-A6801 molecule. Homologous epitopes were identified in five other high-risk HPV types for both of these epitopes, but they were not recognized by respective T-cell clone cells. An enzyme-linked immunospot assay or tetramer analysis was performed on peripheral blood mononuclear cells from blood samples collected after viral clearance but prior to isolation of the T-cell clones. The presence of epitope-specific memory T cells was demonstrated. These data suggest that HPV-specific memory T cells were generated in vivo and that they may remain in circulation many months, if not years, after viral clearance. Our findings broaden the spectrum of the CD8 T-cell epitopes of the HPV16 E6 protein. The characterization of novel T-cell epitopes and long-lasting epitope specific memory T cells may be useful for the development of a potential epitope based vaccine. PMID- 18448625 TI - YMCA program for childhood obesity: a case series. AB - Family-based behavioral interventions for treatment of childhood obesity have rarely been tested for effectiveness in community settings. The aim of the study was to evaluate the effectiveness of a community-based program for obese children designed to stabilize or reduce body weight. Obese children from our pediatric practice who were active in the program were evaluated. Weight gain during the time of the study was compared with mean weight gain for a group of obese-matched controls who did not participate in the program. Mean weight gain for subjects was 0.28 kg/mo compared with a weight gain for controls of 0.62 kg/mo. Between the first and last visits, 43% (15/35) of the subjects experienced clinically significant differences in weight gain compared with controls. Eight patients lost weight. A YMCA weight management program, which included group counseling, nutrition education, physical activity, and gift card incentives, resulted in favorable changes in overweight children. PMID- 18448626 TI - Impact of changes in infant death classification on the diagnosis of sudden infant death syndrome. AB - This study evaluates the hypothesis that a decline in sudden infant death syndrome in Minnesota is associated with increases in other categories of sudden unexpected infant death. Matched birth and death certificates, autopsy reports, and home visit questionnaires were reviewed for 722 sudden unexpected infant deaths that occurred from January 1, 1996 through December 31, 2002. Descriptive data and cause of death were recorded. Cause of death was compared for 2 periods: early (1996-1998) and late (2000-2002). The age of the infant at death, sex, race, and infant death rates were similar between the 2 periods ( P = .637). Sudden infant death syndrome declined by 50.1% (P < .001). Overlay deaths increased 235.5% (P < .01). Asphyxia related deaths increased 259.6% (P < .001). Injury-related deaths increased 840.0% (P < .001). A decline in sudden infant death syndrome in Minnesota was associated with increased deaths in categories that are asphyxial in nature and are potentially preventable. PMID- 18448627 TI - Ouabain-induced stimulation of sodium-hydrogen exchange in rat optic nerve astrocytes. AB - Sodium-dependent transporters are inhibited indirectly by the Na-K-ATPase inhibitor ouabain. Here we report stimulation of sodium-hydrogen exchange (NHE) in ouabain-treated cells. BCECF was used to measure cytoplasmic pH in cultured rat optic nerve astrocytes. Ammonium chloride was applied to acid load the cells. On removal of ammonium chloride, cytoplasmic pH fell abruptly, then gradually recovered toward baseline. Ouabain (1 microM) did not change cell sodium content, but the rate of pH recovery increased by 68%. Ouabain speeded pH recovery both in the presence and absence of bicarbonate. In bicarbonate-free medium, dimethylamiloride, an NHE inhibitor, eliminated the effect of 1 microM ouabain on pH recovery. Western blot analysis showed an NHE1 immunoreactive band but not NHE2, NHE3, or NHE4. Immunoprecipitation studies showed phosphorylation of NHE1 in cells treated with 1 microM ouabain. Ouabain evoked an increase of cAMP, and the effect of 1 microM ouabain on pH recovery was abolished by H-89, a protein kinase A inhibitor. 8-Bromoadenosine-cAMP increased the pH recovery rate, and this recovery was not further increased by ouabain. Although 1 microM ouabain did not alter cytoplasmic calcium concentration, it stimulated calcium entry after store depletion, a response abolished by 2-APB. Ouabain-induced stimulation of pH recovery was suppressed by inhibitors of capacitative calcium entry, SKF-96365, and 2-APB, as well as the cytoplasmic calcium chelator BAPTA. The cAMP increase in ouabain-treated cells was abolished by BAPTA and 2-APB. Taken together, the results are consistent with increased capacitative calcium entry and subsequent cAMP-PKA-dependent stimulation of NHE1 in ouabain-treated cells. PMID- 18448628 TI - Rat aquaporin-5 4.3-kb 5'-flanking region differentially regulates expression in salivary gland and lung in vivo. AB - We previously cloned a 4.3-kb genomic fragment encompassing 5'-flanking regulatory elements of rat aquaporin-5 (Aqp5) that demonstrated preferential transcriptional activity in lung and salivary cells in vitro. To investigate the ability of Aqp5 regulatory elements to direct transgene expression in vivo, transgenic (TG) mice and rats were generated in which the 4.3-kb Aqp5 fragment directed the expression of enhanced green fluorescent protein (EGFP). RT-PCR revealed relative promoter specificity for the lung and salivary glands in TG mice. Immunofluorescence microscopy showed strong EGFP expression in salivary acinar cells but not in lung type I (AT1) cells, both known sites of endogenous AQP5 expression. Similar results were obtained in TG rats generated by lentiviral transgenesis. EGFP mRNA was detected in both salivary glands and lung. Robust EGFP fluorescence was observed in frozen sections of the rat salivary gland but not in the lung or other tested tissues. The percentage of EGFP-positive acinar cells was increased in parotid and submandibular glands of TG rats receiving a chronic injection of the beta-adrenergic receptor agonist isoproterenol. EGFP positive cells in the lung that were also reactive with the AT1-cell specific monoclonal antibody VIIIB2 were identified by flow cytometry. These findings demonstrate that the 4.3-kb Aqp5 promoter/enhancer directs strong cell-specific transgene expression in salivary gland and low-level AT1 cell-specific expression in the lung. While these Aqp5 regulatory elements should be useful for functional studies in salivary glands, additional upstream or intronic cis-active elements are likely required for robust expression in the lung. PMID- 18448629 TI - Transmembrane IV of the high-affinity sodium-glucose cotransporter participates in sugar binding. AB - Investigation of the structure/function relationships of the sodium-glucose transporter (SGLT1) is crucial to understanding the cotransporter mechanism. In the present study, we used cysteine-scanning mutagenesis and chemical modification by methanethiosulfonate (MTS) derivatives to test whether predicted transmembrane IV participates in sugar binding. Five charged and polar residues (K139, Q142, T156, K157, and D161) and two glucose/galactose malabsorption missense mutations (I147 and S159) were replaced with cysteine. Mutants I147C, T156C, and K157C exhibited sufficient expression to be studied in detail using the two-electrode voltage-clamp method in Xenopus laevis oocytes and COS-7 cells. I147C was similar in function to wild-type and was not studied further. Mutation of lysine-157 to cysteine (K157C) causes loss of phloridzin and alpha-methyl-D glucopyranoside (alphaMG) binding. These functions are restored by chemical modification with positively charged (2-aminoethyl) methanethiosulfonate hydrobromide (MTSEA). Mutation of threonine-156 to cysteine (T156C) reduces the affinity of alphaMG and phloridzin for T156C by approximately 5-fold and approximately 20-fold, respectively. In addition, phloridzin protects cysteine 156 in T156C from alkylation by MTSEA. Therefore, the presence of a positive charge or a polar residue at 157 and 156, respectively, affects sugar binding and sugar-induced Na(+) currents. PMID- 18448630 TI - Ubiquitination regulates the plasma membrane expression of renal UT-A urea transporters. AB - The renal UT-A urea transporters UT-A1, UT-A2, and UT-A3 are known to play an important role in the urinary concentrating mechanism. The control of the cellular localization of UT-A transporters is therefore vital to overall renal function. In the present study, we have investigated the effect of ubiquitination on UT-A plasma membrane expression in Madin-Darby canine kidney (MDCK) cell lines expressing each of the three renal UT-A transporters. Inhibition of the ubiquitin proteasome pathway caused an increase in basal transepithelial urea flux across MDCK-rat (r)UT-A1 and MDCK-mouse (m)UT-A2 monolayers (P < 0.01, n = 3, ANOVA) and also increased dimethyl urea-sensitive, arginine vasopressin-stimulated urea flux (P < 0.05, n = 3, ANOVA). Inhibition of the ubiquitin-proteasome pathway also increased basolateral urea flux in MDCK-mUT-A3 monolayers (P < 0.01, n = 4, ANOVA) in a concentration-dependent manner. These increases in urea flux corresponded to a significant increase in UT-A transporter expression in the plasma membrane (P < 0.05, n = 3, ANOVA). Further analysis of the MDCK-mUT-A3 cell line confirmed that vasopressin specifically increased UT-A3 expression in the plasma membrane (P < 0.05, n = 3, ANOVA). However, preliminary data suggested that vasopressin produces this effect through an alternative route to that of the ubiquitin-proteasome pathway. In conclusion, our study suggests that ubiquitination regulates the plasma membrane expression of all three major UT-A urea transporters, but that this is not the mechanism primarily used by vasopressin to produce its physiological effects. PMID- 18448631 TI - Phosphatidylinositol 4,5-bisphosphate hydrolysis mediates histamine-induced KCNQ/M current inhibition. AB - The M-type potassium channel, of which its molecular basis is constituted by KCNQ2-5 homo- or heteromultimers, plays a key role in regulating neuronal excitability and is modulated by many G protein-coupled receptors. In this study, we demonstrate that histamine inhibits KCNQ2/Q3 currents in human embryonic kidney (HEK)293 cells via phosphatidylinositol 4,5-bisphosphate (PIP(2)) hydrolysis mediated by stimulation of H(1) receptor and phospholipase C (PLC). Histamine inhibited KCNQ2/Q3 currents in HEK293 cells coexpressing H(1) receptor, and this effect was totally abolished by H(1) receptor antagonist mepyramine but not altered by H(2) receptor antagonist cimetidine. The inhibition of KCNQ currents was significantly attenuated by a PLC inhibitor U-73122 but not affected by depletion of internal Ca(2+) stores or intracellular Ca(2+) concentration ([Ca(2+)](i)) buffering via pipette dialyzing BAPTA. Moreover, histamine also concentration dependently inhibited M current in rat superior cervical ganglion (SCG) neurons by a similar mechanism. The inhibitory effect of histamine on KCNQ2/Q3 currents was entirely reversible but became irreversible when the resynthesis of PIP(2) was impaired with phosphatidylinsitol-4-kinase inhibitors. Histamine was capable of producing a reversible translocation of the PIP(2) fluorescence probe PLC(delta1)-PH-GFP from membrane to cytosol in HEK293 cells by activation of H(1) receptor and PLC. We concluded that the inhibition of KCNQ/M currents by histamine in HEK293 cells and SCG neurons is due to the consumption of membrane PIP(2) by PLC. PMID- 18448632 TI - Attaching values to actions: action and outcome encoding in the primate caudate nucleus. PMID- 18448633 TI - "Il piccolo principe est alle": processing of language switches in auditory sentence comprehension. PMID- 18448634 TI - Why we like to drink: a functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol. AB - People typically drink alcohol to induce euphoria or reduce anxiety, and they frequently drink in social settings, yet the effect of alcohol on human brain circuits involved in reward and emotion has been explored only sparingly. We administered alcohol intravenously to social drinkers while brain response to visual threatening and nonthreatening facial stimuli was measured using functional magnetic resonance imaging (fMRI). Alcohol robustly activated striatal reward circuits while attenuating response to fearful stimuli in visual and limbic regions. Self-ratings of intoxication correlated with striatal activation, suggesting that activation in this area may contribute to subjective experience of pleasure and reward during intoxication. These results show that the acute pharmacological rewarding and anxiolytic effects of alcohol can be measured with fMRI. PMID- 18448635 TI - Dendritic design implements algorithm for synaptic extraction of sensory information. AB - While sensory information is encoded by firing patterns of individual sensory neurons, it is also represented by spatiotemporal patterns of activity in populations of the neurons. Postsynaptic interneurons decode the population response and extract specific sensory information. This extraction of information represented by presynaptic activities is a process critical to defining the input output function of postsynaptic neuron. To understand the "algorithm" for the extraction, we examined directional sensitivities of presynaptic and postsynaptic Ca(2+) responses in dendrites of two types of wind-sensitive interneurons (INs) with different dendritic geometries in the cricket cercal sensory system. In IN 10-3, whose dendrites arborize with various electrotonic distances to the spike initiating zone (SIZ), the directional sensitivity of dendritic Ca(2+) responses corresponded to those indicated by Ca(2+) signals in presynaptic afferents arborizing on that dendrite. The directional tuning properties of individual dendrites varied from each other, and the directional sensitivity of the nearest dendrite to the SIZ dominates the tuning properties of the spiking response. In IN 10-2 with dendrites isometric to the SIZ, directional tuning properties of different dendrites were similar to each other, and each response property could be explained by the directional profile of the spatial overlap between that dendrite and Ca(2+)-elevated presynaptic terminals. For IN 10-2, the directional sensitivities extracted by the different dendritic-branches would contribute equally to the overall tuning. It is possible that the differences in the distribution of synaptic weights because of the dendritic geometry are related to the algorithm for extraction of sensory information in the postsynaptic interneurons. PMID- 18448636 TI - The neurogenesis-controlling factor, Pax6, inhibits proliferation and promotes maturation in murine astrocytes. AB - Astrocytes serve various important functions in the CNS, but the molecular mechanisms of their generation and maturation are still enigmatic. Here, we show that Pax6, a key transcription factor that controls neurogenesis, also regulates proliferation, differentiation, and migration of astrocytes in the CNS. We first reveal that Pax6 is expressed in astrocytes during development as well as postnatally in the wild-type mouse. Astrocytes derived from Pax6 homozygous mutants (Sey/Sey) mice exhibited aberrant proliferation together with immature differentiation, both in vivo and in vitro, with higher migration potential in scratch-wound assays in vitro. Furthermore, a larger population of Sey/Sey astrocytes expresses neural stem cell markers such as nestin, Sox2, and prominin 1. These phenotypes of Pax6-deficient astrocytes putatively occur via higher Akt activity. Thus, the breakdown of Pax6 function induces the retention of neural stem-like characteristics and inhibits astrocyte maturation. PMID- 18448637 TI - Long-range axonal calcium sweep induces axon retraction. AB - Axon guidance molecules trigger a cascade of local signal in growth cones and evoke various morphologic responses, including axon attraction, repulsion, elongation, and retraction. However, little is known about whether subcellular compartments, other than axonal growth cones, control axon outgrowth. We found that in isolated dentate granule cells, local application of glutamate to the somatodendritic areas, but not the axon itself, induced rapid axon retraction, during which a calcium wave propagated from the somata to the axon terminals. The calcium wave and axon retraction were both inhibited by blockade of voltage sensitive calcium channels and intracellular calcium dynamics. A combination of perisomatic application of calcium ionophore and depolarizing current injection induced axonal calcium sweep and axon retraction. Thus, perisomatic environments can modulate axon behavior through long-range intracellular communication. PMID- 18448638 TI - Mitogen-activated protein kinase is a functional component of the autonomous circadian system in the suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) is the master circadian pacemaker driving behavioral and physiological rhythms in mammals. Circadian activation of mitogen activated protein kinase [MAPK; also known as ERK (extracellular signal-regulated kinase)] is observed in vivo in the SCN under constant darkness, although the biological significance of this remains unclear. To elucidate this question, we first examined whether MAPK was autonomously activated in ex vivo SCN slices. Moreover, we investigated the effect of MAPK inhibition on circadian clock gene expression and neuronal firing rhythms using SCN-slice culture systems. We show herein that MAPK is autonomously activated in the SCN, and our data demonstrate that inhibition of the MAPK activity results in dampened rhythms and reduced basal levels in circadian clock gene expression at the SCN single-neuron level. Furthermore, MAPK inhibition attenuates autonomous circadian neuronal firing rhythms in the SCN. Thus, our data suggest that light-independent MAPK activity contributes to the robustness of the SCN autonomous circadian system. PMID- 18448639 TI - Silent synapses in developing rat nucleus tractus solitarii have AMPA receptors. AB - NMDA-only synapses, called silent synapses, are thought to be the initial step in synapse formation in several systems. However, the underlying mechanism and the role in circuit construction are still a matter of dispute. Using combined morphological and electrophysiological approaches, we searched for silent synapses at the level of the nucleus tractus solitarii (NTS), a brainstem structure that is a gateway for many visceral sensory afferent fibers. Silent synapses were detected at birth by using electrophysiological recordings and minimal stimulation protocols. However, anatomical experiments indicated that nearly all, if not all, NTS synapses had AMPA receptors. Based on EPSC fluctuation measurements and differential blockade by low-affinity competitive and noncompetitive glutamate antagonists, we then demonstrated that NTS silent synapses were better explained by glutamate spillover from neighboring fibers and/or slow dynamic of fusion pore opening. Glutamate spillover at immature NTS synapses may favor crosstalk between active synapses during development when glutamate transporters are weakly expressed and contribute to synaptic processing as well as autonomic circuit formation. PMID- 18448640 TI - GABAergic depolarization of the axon initial segment in cortical principal neurons is caused by the Na-K-2Cl cotransporter NKCC1. AB - GABAergic terminals of axo-axonic cells (AACs) are exclusively located on the axon initial segment (AIS) of cortical principal neurons, and they are generally thought to exert a powerful inhibitory action. However, recent work (Szabadics et al., 2006) indicates that this input from AACs can be depolarizing and even excitatory. Here, we used local photolysis of caged GABA to measure reversal potentials (E(GABA)) of GABA(A) receptor-mediated currents and to estimate the local chloride concentration in the AIS compared with other cellular compartments in dentate granule cells and neocortical pyramidal neurons. We found a robust axo somato-dendritic gradient in which the E(GABA) values from the AIS to the soma and dendrites become progressively more negative. Data from NKCC1(-/-) and bumetanide-exposed neurons indicated that the depolarizing E(GABA) at the AIS is set by chloride uptake mediated by the Na-K-2Cl cotransporter NKCC1. Our findings demonstrate that spatially distinct interneuronal inputs can induce postsynaptic voltage responses with different amplitudes and polarities as governed by the subcellular distributions of plasmalemmal chloride transporters. PMID- 18448641 TI - Purkinje-cell-restricted restoration of Kv3.3 function restores complex spikes and rescues motor coordination in Kcnc3 mutants. AB - The fast-activating/deactivating voltage-gated potassium channel Kv3.3 (Kcnc3) is expressed in various neuronal cell types involved in motor function, including cerebellar Purkinje cells. Spinocerebellar ataxia type 13 (SCA13) patients carrying dominant-negative mutations in Kcnc3 and Kcnc3-null mutant mice both display motor incoordination, suggested in mice by increased lateral deviation while ambulating and slips on a narrow beam. Motor skill learning, however, is spared. Mice lacking Kcnc3 also exhibit muscle twitches. In addition to broadened spikes, recordings of Kcnc3-null Purkinje cells revealed fewer spikelets in complex spikes and a lower intraburst frequency. Targeted reexpression of Kv3.3 channels exclusively in Purkinje cells in Kcnc3-null mice as well as in mice also heterozygous for Kv3.1 sufficed to restore simple spike brevity along with normal complex spikes and to rescue specifically coordination. Therefore, spike parameters requiring Kv3.3 function in Purkinje cells are involved in the ataxic null phenotype and motor coordination, but not motor learning. PMID- 18448642 TI - An endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone across the sleep-wake cycle. AB - Skeletal muscle tone is modulated in a stereotypical pattern across the sleep wake cycle. Abnormalities in this modulation contribute to most of the major sleep disorders; therefore, characterizing the neurochemical substrate responsible for transmitting a sleep-wake drive to somatic motoneurons needs to be determined. Glutamate is an excitatory neurotransmitter that modulates motoneuron excitability; however, its role in regulating motoneuron excitability and muscle tone during natural sleep-wake behaviors is unknown. Therefore, we used reverse-microdialysis, electrophysiology, pharmacological, and histological methods to determine how changes in glutamatergic neurotransmission within the trigeminal motor pool contribute to the sleep-wake pattern of masseter muscle tone in behaving rats. We found that blockade of non-NMDA and NMDA glutamate receptors (via CNQX and d-AP-5) on trigeminal motoneurons reduced waking masseter tone to sleeping levels, indicating that masseter tone is maximal during alert waking because motoneurons are activated by an endogenous glutamatergic drive. This wake-related drive is switched off in non-rapid eye movement (NREM) sleep, and this contributes to the suppression of muscle tone during this state. We also show that a functional glutamatergic drive generates the muscle twitches that characterize phasic rapid-eye movement (REM) sleep. However, loss of a waking glutamatergic drive is not sufficient for triggering the motor atonia that characterizes REM sleep because potent activation of either AMPA or NMDA receptors on trigeminal motoneurons was unable to reverse REM atonia. We conclude that an endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone during wakefulness, NREM sleep, and phasic REM sleep but not during tonic REM sleep. PMID- 18448643 TI - CD36/fatty acid translocase, an inflammatory mediator, is involved in hyperlipidemia-induced exacerbation in ischemic brain injury. AB - Hyperlipidemia with accompanying increase in peripheral inflammation is a risk factor for stroke. The effect of excess lipids on stroke-induced injury and the mechanism by which lipid-mediated inflammatory responses contribute to stroke are not known. We investigated these uncertainties by subjecting normal and hyperlipidemic mice to transient middle cerebral artery occlusion, followed by measurement of stroke severity and inflammatory response. Infarct size, swelling, and lipid contents were significantly increased in the high-fat fed ApoE knock out mice, as was the expression of the inflammatory mediators CD36 and monocyte chemoattractant protein 1 (MCP-1) in the brain and periphery. Furthermore, the hyperlipidemic mice exhibited numerous foam cells, a probable cause of increased swelling and postischemic inflammation, in the peri-infarct area. Genetic deletion of cd36 in the hyperlipidemic condition reduced proinflammatory chemokine/receptor and cytokines (MCP-1, CC chemokine receptor 2, and interleukins 1beta and 6), in the brain 6 h after ischemia. The reduced proinflammatory response also resulted in smaller ischemic injury, less swelling, and fewer foam cells at 3 d after ischemia. The results show that hyperlipidemia induced inflammation is a negative factor for stroke outcomes and indicate that downregulating CD36 may be an effective therapeutic strategy for reducing the impact of stroke in hyperlipidemic subjects. PMID- 18448644 TI - Anticipatory activity in anterior cingulate cortex can be independent of conflict and error likelihood. AB - Previous studies have found no agreement on whether anticipatory activity in the anterior cingulate cortex (ACC) reflects upcoming conflict, error likelihood, or actual control adjustments. Using event-related functional magnetic resonance imaging, we investigated the nature of preparatory activity in the ACC. Informative cues told the participants whether an upcoming target would or would not involve conflict in a Stroop-like task. Uninformative cues provided no such information. Behavioral responses were faster after informative than after uninformative cues, indicating cue-based adjustments in control. ACC activity was larger after informative than uninformative cues, as would be expected if the ACC is involved in anticipatory control. Importantly, this activation in the ACC was observed for informative cues even when the information conveyed by the cue was that the upcoming target evokes no response conflict and has low error likelihood. This finding demonstrates that the ACC is involved in anticipatory control processes independent of upcoming response conflict or error likelihood. Moreover, the response of the ACC to the target stimuli was critically dependent on whether the cue was informative or not. ACC activity differed among target conditions after uninformative cues only, indicating ACC involvement in actual control adjustments. Together, these findings argue strongly for a role of the ACC in anticipatory control independent of anticipated conflict and error likelihood, and also show that such control can eliminate conflict-related ACC activity during target processing. Models of frontal cortex conflict-detection and conflict-resolution mechanisms require modification to include consideration of these anticipatory control properties of the ACC. PMID- 18448645 TI - Firing rate dynamics in the hippocampus induced by trajectory learning. AB - The hippocampus is essential for spatial navigation, which may involve sequential learning. However, how the hippocampus encodes new sequences in familiar environments is unknown. To study the impact of novel spatial sequences on the activity of hippocampal neurons, we monitored hippocampal ensembles while rats learned to switch from two familiar trajectories to a new one in a familiar environment. Here, we show that this novel spatial experience induces two types of changes in firing rates, but not locations of hippocampal place cells. First, place-cell firing rates on the two familiar trajectories start to change before the actual behavioral switch to the new trajectory. Second, repeated exposure on the new trajectory is associated with an increased dependence of place-cell firing rates on immediate past locations. The result suggests that sequence encoding in the hippocampus may involve integration of information about the recent past into current state. PMID- 18448646 TI - Activation of the amyloid cascade in apolipoprotein E4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. AB - The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, is associated histopathologically with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated by cross-talk interactions with amyloid beta peptide (Abeta), which accentuate the pathological effects of the amyloid cascade. The mechanisms underlying the Abeta-mediated pathological effects of apoE4 are unknown. We have shown recently that inhibition of the Abeta-degrading enzyme neprilysin in brains of wild-type apoE3 and apoE4 mice results in rapid and similar elevations in their total brain Abeta levels. However, the nucleation and aggregation of Abeta in these mice were markedly affected by the apoE genotype and were specifically enhanced in the apoE4 mice. We presently used the neprilysin inhibition paradigm to analyze the neuropathological and cognitive effects that are induced by apoE4 after activation of the amyloid cascade. This revealed that apoE4 stimulates isoform specifically the degeneration of hippocampal CA1 neurons and of entorhinal and septal neurons, which is accompanied by the accumulation of intracellular Abeta and apoE and with lysosomal activation. Furthermore, these neuropathological effects are associated isoform specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. These findings provide the first in vivo evidence regarding the cellular mechanisms underlying the pathological cross talk between apoE4 and Abeta, as well as a novel model system of neurodegeneration in vivo that is uniquely suitable for studying the early stages of the amyloid cascade and the effects thereon of apoE4. PMID- 18448647 TI - Connexin 43 hemichannels are permeable to ATP. AB - Astrocytes are electrically nonexcitable cells that communicate by means of Ca(2+) signaling. Long-distance intercellular Ca(2+) waves are initiated by release of ATP and activation of purinergic receptors on nearby cells. Previous studies have implicated connexin 43 (Cx43) in ATP release, but definitive proof that ATP exits through Cx43 hemichannels does not exist. Here, through several alternative approaches, we show that ATP anions can permeate through Cx43 hemichannels. First, openings of Cx43 hemichannels were detected in both cell attached and inside-out patch recordings in C6 cells expressing Cx43, but not in C6 cells expressing Cx43-eGFP (enhanced green fluorescent protein) or a C terminus truncation mutant of Cx43. Second, Cx43 hemichannel openings were inhibited by three structurally different gap-junction channel blockers, but not by the P2X(7) blocker Brilliant blue G. Third, bioluminescence imaging of ATP combined with single-channel recording in the inside-out patch configuration showed that ATP efflux coincided with channel openings and was absent when the Cx43 hemichannel was closed. Fourth, ion replacement experiments confirmed that Cx43 hemichannels are permeable to ATP. In summary, these observations provide the first direct evidence for efflux of ATP through Cx43 hemichannels. Furthermore, a putative Cx43 hemichannel with characteristics identical to the Cx43 hemichannel in C6 cells was identified in the membrane of hippocampal astrocytes in acutely prepared slices. PMID- 18448648 TI - Zic deficiency in the cortical marginal zone and meninges results in cortical lamination defects resembling those in type II lissencephaly. AB - The formation of the highly organized cortical structure depends on the production and correct placement of the appropriate number and types of neurons. The Zic family of zinc-finger transcription factors plays essential roles in regulating the proliferation and differentiation of neuronal progenitors in the medial forebrain and the cerebellum. Examination of the expression of Zic genes demonstrated that Zic1, Zic2, and Zic3 were expressed by the progenitor cells in the septum and cortical hem, the sites of generation of the Cajal-Retzius (CR) cells. Immunohistochemical studies have revealed that Zic proteins were abundantly expressed in the meningeal cells and that the majority of the CR cells distributed in the medial and dorsal cortex also expressed Zic proteins in the mid-late embryonic and postnatal cortical marginal zones. During embryonic cortical development, Zic1/Zic3 double-mutant and hypomorphic Zic2 mutant mice showed a reduction in the number of CR cells in the rostral cortex, whereas the cell number remained unaffected in the caudal cortex. These mutants also showed mislocalization of the CR cells and cortical lamination defects, resembling the changes noted in type II (cobblestone) lissencephaly, throughout the brain. In the Zic1/3 mutant, reduced proliferation of the meningeal cells was observed before the thinner and disrupted organization of the pial basement membrane (BM) with reduced expression of the BM components and the meningeal cell-derived secretory factor. These defects correlated with the changes in the end feet morphology of the radial glial cells. These findings indicate that the Zic genes play critical roles in cortical development through regulating the proliferation of meningeal cells and the pial BM assembly. PMID- 18448649 TI - Perceptuo-motor interactions during prehension movements. AB - Adaptive behavior relies on the integration of perceptual and motor processes. In this study, we aimed at characterizing the cerebral processes underlying perceptuo-motor interactions evoked during prehension movements in healthy humans, as measured by means of functional magnetic resonance imaging. We manipulated the viewing conditions (binocular or monocular) during planning of a prehension movement, while parametrically varying the slant of the grasped object. This design manipulates the relative relevance and availability of different depth cues necessary for accurate planning of the prehension movement, biasing visual information processing toward either the dorsal visual stream (binocular vision) or the ventral visual stream (monocular vision). Two critical nodes of the dorsomedial visuomotor stream [V6A (anterior visual area 6) and PMd (dorsal premotor cortex)] increased their activity with increasing object slant, regardless of viewing conditions. In contrast, areas in both the dorsolateral visuomotor stream [anterior intraparietal area (AIP) and ventral premotor cortex (PMv)] and in the ventral visual stream [lateral-occipital tactile-visual area (LOtv)] showed differential slant-related responses, with activity increasing when monocular viewing conditions and increasing slant required the processing of pictorial depth cues. These conditions also increased the functional coupling of AIP with both LOtv and PMv. These findings support the view that the dorsomedial stream is automatically involved in processing visuospatial parameters for grasping, regardless of viewing conditions or object characteristics. In contrast, the dorsolateral stream appears to adapt motor behavior to the current conditions by integrating perceptual information processed in the ventral stream into the prehension plan. PMID- 18448650 TI - Ca-stimulated type 8 adenylyl cyclase is required for rapid acquisition of novel spatial information and for working/episodic-like memory. AB - Ca-stimulated adenylyl cyclases (ACs) transduce neuronal stimulation-evoked increase in calcium to the production of cAMP, which impinges on the regulation of many aspects of neuronal function. Type 1 and type 8 AC (AC1 and AC8) are the only ACs that are directly stimulated by Ca. Although AC1 function was implicated in regulating reference spatial memory, the function of AC8 in memory formation is not known. Because of the different biochemical properties of AC1 and AC8, these two enzymes may have distinct functions. For example, AC1 activity is regulated by both Ca and G-proteins. In contrast, AC8 is a pure Ca sensor. It is neither stimulated by G(s) nor inhibited by G(i). Recent studies also suggested that AC1 and AC8 were differentially concentrated at different subcellular domains, implicating that Ca-stimulated signaling might be compartmentalized. In this study, we used AC8 knock-out (KO) mice and found behavioral deficits in memory retention for temporal dissociative passive avoidance and object recognition memory. When examined by Morris water maze, AC8 KO mice showed normal reference memory. However, the acquisition of newer spatial information was defective in AC8 KO mice. Furthermore, AC8 KO mice were severely impaired in hippocampus-dependent episodic-like memory when examined by the delayed matching to-place task. Because AC8 is preferentially localized at the presynaptic active zone, our results suggest a novel role of presynaptic cAMP signaling in memory acquisition and retention, as well as distinct mechanisms underlying reference and working/episodic-like memory. PMID- 18448651 TI - Reduced odor responses from antennal neurons of G(q)alpha, phospholipase Cbeta, and rdgA mutants in Drosophila support a role for a phospholipid intermediate in insect olfactory transduction. AB - Mechanisms by which G-protein-coupled odorant receptors transduce information in insects still need elucidation. We show that mutations in the Drosophila gene for G(q)alpha (dgq) significantly reduce both the amplitude of the field potentials recorded from the whole antenna in responses to odorants as well as the frequency of evoked responses of individual sensory neurons. This requirement for G(q)alpha is for adult function and not during antennal development. Conversely, brief expression of a dominant-active form of G(q)alpha in adults leads to enhanced odor responses. To understand signaling downstream of G(q)alpha in olfactory sensory neurons, genetic interactions of dgq were tested with mutants in genes known to affect phospholipid signaling. dgq mutant phenotypes were further enhanced by mutants in a PLCbeta (phospholipase Cbeta) gene, plc21C. Interestingly although, the olfactory phenotype of mutant alleles of diacylglycerol kinase (rdgA) was rescued by dgq mutant alleles. Our results suggest that G(q)alpha-mediated olfactory transduction in Drosophila requires a phospholipid second messenger the levels of which are regulated by a cycle of phosphatidylinositol 1,4-bisphosphate breakdown and regeneration. PMID- 18448652 TI - Structural insights into aberrant topological patterns of large-scale cortical networks in Alzheimer's disease. AB - Recent research on Alzheimer's disease (AD) has shown that cognitive and memory decline in this disease is accompanied by disrupted changes in the coordination of large-scale brain functional networks. However, alterations in coordinated patterns of structural brain networks in AD are still poorly understood. Here, we used cortical thickness measurement from magnetic resonance imaging to investigate large-scale structural brain networks in 92 AD patients and 97 normal controls. Brain networks were constructed by thresholding cortical thickness correlation matrices of 54 regions and analyzed using graph theoretical approaches. Compared with controls, AD patients showed decreased cortical thickness intercorrelations between the bilateral parietal regions and increased intercorrelations in several selective regions involving the lateral temporal and parietal cortex as well as the cingulate and medial frontal cortex regions. Specially, AD patients showed abnormal small-world architecture in the structural cortical networks (increased clustering and shortest paths linking individual regions), implying a less optimal topological organization in AD. Moreover, AD patients were associated with reduced nodal centrality predominantly in the temporal and parietal heteromodal association cortex regions and increased nodal centrality in the occipital cortex regions. Finally, the brain networks of AD were about equally as robust to random failures as those of controls, but more vulnerable against targeted attacks, presumably because of the effects of pathological topological organization. Our findings suggest that the coordinated patterns of cortical morphology are widely altered in AD patients, thus providing structural evidence for disrupted integrity in large-scale brain networks that underlie cognition. This work has implications for our understanding of how functional deficits in patients are associated with their underlying structural (morphological) basis. PMID- 18448653 TI - A discontinuous tonotopic organization in the inferior colliculus of the rat. AB - Audible frequencies of sound are encoded in a continuous manner along the length of the cochlea, and frequency is transmitted to the brain as a representation of place on the basilar membrane. The resulting tonotopic map has been assumed to be a continuous smooth progression from low to high frequency throughout the central auditory system. Here, physiological and anatomical data show that best frequency is represented in a discontinuous manner in the inferior colliculus, the major auditory structure of the midbrain. Multiunit maps demonstrate a distinct stepwise organization in the order of best frequency progression. Furthermore, independent data from single neurons show that best frequencies at octave intervals of approximately one-third are more prevalent than others. These data suggest that, in the inferior colliculus, there is a defined space of tissue devoted to a given frequency, and input within this frequency band may be pooled for higher-level processing. PMID- 18448654 TI - Embryonically expressed GABA and glutamate drive electrical activity regulating neurotransmitter specification. AB - Neurotransmitter signaling in the mature nervous system is well understood, but the functions of transmitters in the immature nervous system are less clear. Although transmitters released during embryogenesis regulate neuronal proliferation and migration, little is known about their role in regulating early neuronal differentiation. Here, we show that GABA and glutamate drive calcium dependent embryonic electrical activity that regulates transmitter specification. The number of neurons expressing different transmitters changes when GABA or glutamate signaling is blocked chronically, either using morpholinos to knock down transmitter-synthetic enzymes or applying pharmacological receptor antagonists during a sensitive period of development. We find that calcium spikes are triggered by metabotropic GABA and glutamate receptors, which engage protein kinases A and C. The results reveal a novel role for embryonically expressed neurotransmitters. PMID- 18448655 TI - Thromboxane receptor activation mediates isoprostane-induced increases in amyloid pathology in Tg2576 mice. AB - Alzheimer's disease (AD) amyloid plaques are composed of amyloid-beta (Abeta) peptides produced from proteolytic cleavage of amyloid precursor protein (APP). Isoprostanes, markers of in vivo oxidative stress, are elevated in AD patients and in the Tg2576 mouse model of AD-like Abeta brain pathology. To determine whether isoprostanes increase Abeta production, we delivered isoprostane iPF(2alpha)-III into the brains of Tg2576 mice. Although treated mice showed increased brain Abeta levels and plaque-like deposits, this was blocked by a thromboxane (TP) receptor antagonist, suggesting that TP receptor activation mediates the effects of iPF(2alpha)-III on Abeta. This hypothesis was supported by cell culture studies that showed that TP receptor activation increased Abeta and secreted APP ectodomains. This increase was a result of increased APP mRNA stability leading to elevated APP mRNA and protein levels. The increased APP provides more substrate for alpha and beta secretase proteolytic cleavages, thereby increasing Abeta generation and amyloid plaque deposition. To test the effectiveness of targeting the TP receptor for AD therapy, Tg2576 mice underwent long-term treatment with S18886, an orally available TP receptor antagonist. S18886 treatment reduced amyloid plaques, insoluble Abeta, and APP levels, thereby implicating TP receptor signaling as a novel target for AD therapy. PMID- 18448656 TI - Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex. AB - In the subthalamic nucleus (STN) of Parkinson's disease (PD) patients, a pronounced synchronization of oscillatory activity at beta frequencies (15-30 Hz) accompanies movement difficulties. Abnormal beta oscillations and motor symptoms are concomitantly and acutely suppressed by dopaminergic therapies, suggesting that these inappropriate rhythms might also emerge acutely from disrupted dopamine transmission. The neural basis of these abnormal beta oscillations is unclear, and how they might compromise information processing, or how they arise, is unknown. Using a 6-hydroxydopamine-lesioned rodent model of PD, we demonstrate that beta oscillations are inappropriately exaggerated, compared with controls, in a brain-state-dependent manner after chronic dopamine loss. Exaggerated beta oscillations are expressed at the levels of single neurons and small neuronal ensembles, and are focally present and spatially distributed within STN. They are also expressed in synchronous population activities, as evinced by oscillatory local field potentials, in STN and cortex. Excessively synchronized beta oscillations reduce the information coding capacity of STN neuronal ensembles, which may contribute to parkinsonian motor impairment. Acute disruption of dopamine transmission in control animals with antagonists of D(1)/D(2) receptors did not exaggerate STN or cortical beta oscillations. Moreover, beta oscillations were not exaggerated until several days after 6-hydroxydopamine injections. Thus, contrary to predictions, abnormally amplified beta oscillations in cortico-STN circuits do not result simply from an acute absence of dopamine receptor stimulation, but are instead delayed sequelae of chronic dopamine depletion. Targeting the plastic processes underlying the delayed emergence of pathological beta oscillations after continuing dopaminergic dysfunction may offer considerable therapeutic promise. PMID- 18448657 TI - Vision triggers an experience-dependent sensitive period at the retinogeniculate synapse. AB - In the mammalian visual system, sensory experience is widely thought to sculpt cortical circuits during a precise critical period. In contrast, subcortical regions, such as the thalamus, were thought to develop at earlier ages in a vision-independent manner. Recent studies at the retinogeniculate synapse, however, have demonstrated an influence of vision on the formation of synaptic circuits in the thalamus. In mice, dark rearing from birth does not alter normal developmental maturation of the connection between retina and thalamus. However, deprivation 20 d after birth [postnatal day 20 (p20)] resulted in dramatic weakening of synaptic strength and an increase in the number of retinal inputs that innervate a thalamic relay neuron. Here, by quantifying changes in synaptic strength and connectivity in response to different time windows of deprivation, we find that several days of vision after eye opening is necessary for triggering experience-dependent plasticity. Shorter periods of visual experience do not permit similar experience-dependent synaptic reorganization. Furthermore, changes in connectivity are rapidly reversible simply by restoring normal vision. However, similar plasticity did not occur when shifting the onset of deprivation to p25. Although synapses still weakened, recruitment of additional retinal inputs no longer occurred. Therefore, synaptic circuits in the visual thalamus are unexpectedly malleable during a late developmental period, after the time when normal synapse elimination and pruning has occurred. This thalamic sensitive period overlaps temporally with experience-dependent changes in the cortex, suggesting that subcortical plasticity may influence cortical responses to sensory experience. PMID- 18448658 TI - Working memory and the organization of brain systems. AB - Working memory has historically been viewed as an active maintenance process that is independent of long-term memory and independent of the medial temporal lobe. However, impaired performance across brief time intervals has sometimes been described in amnesic patients with medial temporal lobe damage. These findings raise a fundamental question about how to know when performance depends on working memory and when the capacity for working memory has been exceeded and performance depends on long-term memory. We describe a method for identifying working memory independently of patient performance. We compared patients with medial temporal lobe damage to controls who were given either distraction or no distraction between study and test. In four experiments, we found concordance between the performance of patients and the effect of distraction on controls. The patients were impaired on tasks in which distraction had minimal effect on control performance, and the patients were intact on tasks in which distraction disrupted control performance. We suggest that the patients were impaired when the task minimally depended on working memory (and instead depended substantially on long-term memory), and they performed well when the task depended substantially on working memory. These findings support the conclusion that working memory (active maintenance) is intact after medial temporal lobe damage. PMID- 18448659 TI - The effects of visual stimulation and selective visual attention on rhythmic neuronal synchronization in macaque area V4. AB - Selective attention lends relevant sensory input priority access to higher-level brain areas and ultimately to behavior. Recent studies have suggested that those neurons in visual areas that are activated by an attended stimulus engage in enhanced gamma-band (30-70 Hz) synchronization compared with neurons activated by a distracter. Such precise synchronization could enhance the postsynaptic impact of cells carrying behaviorally relevant information. Previous studies have used the local field potential (LFP) power spectrum or spike-LFP coherence (SFC) to indirectly estimate spike synchronization. Here, we directly demonstrate zero phase gamma-band coherence among spike trains of V4 neurons. This synchronization was particularly evident during visual stimulation and enhanced by selective attention, thus confirming the pattern inferred from LFP power and SFC. We therefore investigated the time course of LFP gamma-band power and found rapid dynamics consistent with interactions of top-down spatial and feature attention with bottom-up saliency. In addition to the modulation of synchronization during visual stimulation, selective attention significantly changed the prestimulus pattern of synchronization. Attention inside the receptive field of the recorded neuronal population enhanced gamma-band synchronization and strongly reduced alpha-band (9-11 Hz) synchronization in the prestimulus period. These results lend further support for a functional role of rhythmic neuronal synchronization in attentional stimulus selection. PMID- 18448660 TI - Frequency facilitation at mossy fiber-CA3 synapses of freely behaving rats is regulated by adenosine A1 receptors. AB - Frequency facilitation, elicited by low-frequency stimulation (LFS) is a specific property of mossy fiber-CA3 synapses. Although it has been widely described in vitro, no evidence as yet exists as to whether this phenomenon occurs in vivo. Here, we show that, in freely behaving rats, frequency facilitation at mossy fiber-CA3 synapses consistently occurs in response to LFS (1 Hz). Extracellular adenosine regulates presynaptic neurotransmitter release via action on adenosine A1 receptors and contributes to frequency facilitation in vitro. We investigated whether adenosine A1 receptors mediate frequency facilitation in freely behaving animals. The adenosine A1 receptor antagonists, DPCPX (8-cyclopentyl-1,3 dipropylxanthine) and phenylxanthine, markedly enhanced mossy fiber synaptic transmission and significantly occluded frequency facilitation. Evoked responses were suppressed by application of the group II metabotropic glutamate receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), in line with the known sensitivity of mossy fiber-CA3 synapses to this agent. By comparison, neither frequency facilitation, effects of the adenosine A1 antagonists, nor effects of DCG-IV were evident at either perforant path-dentate gyrus synapses or commissural/associational CA3 synapses in vivo. These data support that frequency facilitation is an intrinsic property of information storage processes at mossy fiber-CA3 synapses in the intact animal and that frequency facilitation in vivo may be mediated by regulation of the adenosine A1 receptor. PMID- 18448661 TI - Recent advances in the renin-angiotensin system: angiotensin-converting enzyme 2 and (pro)renin receptor. PMID- 18448662 TI - The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. AB - During several months of 2002, severe acute respiratory syndrome (SARS) caused by SARS-coronavirus (SARS-CoV) spread rapidly from China throughout the world, causing more than 800 deaths due to the development of acute respiratory distress syndrome (ARDS), which is the severe form of acute lung injury (ALI). Interestingly, a novel homologue of angiotensin-converting enzyme, termed angiotensin-converting enzyme 2 (ACE2), has been identified as a receptor for SARS-CoV. Angiotensin-converting enzyme and ACE2 share homology in their catalytic domain and provide different key functions in the renin-angiotensin system (RAS). Angiotensin-converting enzyme cleaves angiotensin I to generate angiotensin II, which is a key effector peptide of the system and exerts multiple biological functions, whereas ACE2 reduces angiotensin II levels. Importantly, our recent studies using ACE2 knockout mice have demonstrated that ACE2 protects murine lungs from ARDS. Furthermore, SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo, which can be attenuated by blocking the renin-angiotensin pathway, suggesting that the activation of the pulmonary RAS influences the pathogenesis of ALI/ARDS and SARS. PMID- 18448663 TI - Angiotensin-(1-7) has a dual role on growth-promoting signalling pathways in rat heart in vivo by stimulating STAT3 and STAT5a/b phosphorylation and inhibiting angiotensin II-stimulated ERK1/2 and Rho kinase activity. AB - Angiotensin (ANG) II contributes to cardiac remodelling by inducing the activation of several signalling molecules, including ERK1/2, Rho kinase and members of the STAT family of proteins. Angiotensin-(1-7) is produced in the heart and inhibits the proliferative actions of ANG II, although the mechanisms of this inhibition are poorly understood. Accordingly, in the present study we examined whether ANG-(1-7) affects the ANG II-mediated activation of ERK1/2 and Rho kinase, STAT3 and STAT5a/b in rat heart in vivo. We hypothesized that ANG-(1 7) inhibits these growth-promoting pathways, counterbalancing the trophic action of ANG II. Solutions of normal saline (0.9% NaCl) containing ANG II (8 pmol kg( 1)) plus ANG-(1-7) in increasing doses (from 0.08 to 800 pmol kg(-1)) were administered via the inferior vena cava to anaesthetized male Sprague-Dawley rats. After 5 min, hearts were removed and ERK1/2, Rho kinase, STAT3 and STAT5a/b phosphorylation was determined by Western blotting using phosphospecific antibodies. Angiotensin II stimulated ERK1/2 and Rho kinase phosphorylation (2.3 +/- 0.2- and 2.1 +/- 0.2-fold increase over basal values, respectively), while ANG-(1-7) was without effect. The ANG II-mediated phosphorylation of ERK1/2 and Rho kinase was prevented in a dose-dependent manner by ANG-(1-7) and disappeared in the presence of the Mas receptor antagonist d-Ala7-ANG-(1-7). Both ANG II and ANG-(1-7) increased STAT3 and STAT5a/b phosphorylation to a similar extent (130 140% increase). The ANG-(1-7)-stimulated STAT phosphorylation was blocked by the AT(1) receptor antagonist losartan and not by d-Ala7-ANG-(1-7). Our results show a dual action of ANG-(1-7), that is, a stimulatory effect on STAT3 and 5a/b phosphorylation through AT(1) receptors and a blocking action on ANG II stimulated ERK1/2 and Rho kinase phosphorylation through Mas receptor activation. The latter effect could be representative of a mechanism for a protective role of ANG-(1-7) in the heart by counteracting the effects of locally generated ANG II. PMID- 18448664 TI - Selective increase of angiotensin(1-7) and its receptor in hearts of spontaneously hypertensive rats subjected to physical training. AB - In the present study we investigated the effects of physical training on plasma and cardiac angiotensin(1-7) [Ang(1-7)] levels. In addition, possible changes in expression of the Ang(1-7) Mas receptor in the heart were also evaluated. Normotensive Wistar rats and spontaneously hypertensive rats (SHR) were subjected to an 8 week period of 5% overload swimming training. Blood pressure was determined by a tail-cuff system. Heart and left ventricle weights and cardiomyocyte diameter were analysed to evaluate cardiac hypertrophy. Radioimmunoassay was used to measure angiotensin levels. Expression of Mas was determined by semi-quantitative polymerase chain reaction, immunofluorescence and Western blotting. Physical training induced cardiac hypertrophy in Wistar rats and SHR. A significant decrease of plasma angiotensin II (Ang II) levels in both strains was also observed. Strikingly, trained SHR, but not trained Wistar rats, showed a twofold increase in left ventricular Ang(1-7) levels. No significant changes were observed in plasma Ang(1-7) and left ventricular Ang II concentrations in either strain. Furthermore, Mas mRNA and protein expression in left ventricle were substantially increased in trained SHR. The physical training protocol used did not change blood pressure in either strain. These results suggest that the beneficial effects induced by swimming training in hypertensive rats might include an augmentation of Ang(1-7) and its receptor in the heart. PMID- 18448665 TI - Golgi-resident small GTPase Rab33B interacts with Atg16L and modulates autophagosome formation. AB - Macroautophagy is a mechanism of degradation of cytoplasmic components in all eukaryotic cells. In macroautophagy, cytoplasmic components are wrapped by double membrane structures called autophagosomes, whose formation involves unique membrane dynamics, i.e., de novo formation of a double-membrane sac called the isolation membrane and its elongation. However, the precise regulatory mechanism of isolation membrane formation and elongation remains unknown. In this study, we showed that Golgi-resident small GTPase Rab33B (and Rab33A) specifically interacts with Atg16L, an essential factor in isolation membrane formation, in a guanosine triphosphate-dependent manner. Expression of a GTPase-deficient mutant Rab33B (Rab33B-Q92L) induced the lipidation of LC3, which is an essential process in autophagosome formation, even under nutrient-rich conditions, and attenuated macroautophagy, as judged by the degradation of p62/sequestosome 1. In addition, overexpression of the Rab33B binding domain of Atg16L suppressed autophagosome formation. Our findings suggest that Rab33 modulates autophagosome formation through interaction with Atg16L. PMID- 18448666 TI - A Raft-derived, Pak1-regulated entry participates in alpha2beta1 integrin dependent sorting to caveosomes. AB - We have previously shown that a human picornavirus echovirus 1 (EV1) is transported to caveosomes during 2 h together with its receptor alpha2beta1 integrin. Here, we show that the majority of early uptake does not occur through caveolae. alpha2beta1 integrin, clustered by antibodies or by EV1 binding, is initially internalized from lipid rafts into tubulovesicular structures. These vesicles accumulate fluid-phase markers but do not initially colocalize with caveolin-1 or internalized simian virus 40 (SV40). Furthermore, the internalized endosomes do not contain glycosylphosphatidylinositol (GPI)-anchored proteins or flotillin 1, suggesting that clustered alpha2beta1 integrin does not enter the GPI-anchored protein enriched endosomal compartment or flotillin pathways, respectively. Endosomes mature further into larger multivesicular bodies between 15 min to 2 h and concomitantly recruit caveolin-1 or SV40 inside. Cell entry is regulated by p21-activated kinase (Pak)1, Rac1, phosphatidylinositol 3-kinase, phospholipase C, and actin but not by dynamin 2 in SAOS-alpha2beta1 cells. An amiloride analog, 5-(N-ethyl-N-isopropanyl) amiloride, blocks infection, causes integrin accumulation in early tubulovesicular structures, and prevents their structural maturation into multivesicular structures. Our results together suggest that alpha2beta1 integrin clustering defines its own entry pathway that is Pak1 dependent but clathrin and caveolin independent and that is able to sort cargo to caveosomes. PMID- 18448667 TI - Access to ribosomal protein Rpl25p by the signal recognition particle is required for efficient cotranslational translocation. AB - Targeting of proteins to the endoplasmic reticulum (ER) occurs cotranslationally necessitating the interaction of the signal recognition particle (SRP) and the translocon with the ribosome. Biochemical and structural studies implicate ribosomal protein Rpl25p as a major ribosome interaction site for both these factors. Here we characterize an RPL25GFP fusion, which behaves as a dominant mutant leading to defects in co- but not posttranslational translocation in vivo. In these cells, ribosomes still interact with ER membrane and the translocon, but are defective in binding SRP. Overexpression of SRP can restore ribosome binding of SRP, but only partially rescues growth and translocation defects. Our results indicate that Rpl25p plays a critical role in the recruitment of SRP to the ribosome. PMID- 18448668 TI - Interaction between Epsin/Yap180 adaptors and the scaffolds Ede1/Pan1 is required for endocytosis. AB - The spatial and temporal regulation of the interactions among the approximately 60 proteins required for endocytosis is under active investigation in many laboratories. We have identified the interaction between monomeric clathrin adaptors and endocytic scaffold proteins as a critical prerequisite for the recruitment and/or spatiotemporal dynamics of endocytic proteins at early and late stages of internalization. Quadruple deletion yeast cells (DeltaDeltaDeltaDelta) lacking four putative adaptors, Ent1/2 and Yap1801/2 (homologues of epsin and AP180/CALM proteins), with a plasmid encoding Ent1 or Yap1802 mutants, have defects in endocytosis and growth at 37 degrees C. Live cell imaging revealed that the dynamics of the early- and late-acting scaffold proteins Ede1 and Pan1, respectively, depend upon adaptor interactions mediated by adaptor asparagine-proline-phenylalanine motifs binding to scaffold Eps15 homology domains. These results suggest that adaptor/scaffold interactions regulate transitions from early to late events and that clathrin adaptor/scaffold protein interaction is essential for clathrin-mediated endocytosis. PMID- 18448670 TI - Nucleophosmin is a binding partner of nucleostemin in human osteosarcoma cells. AB - Nucleostemin (NS) is expressed in the nucleoli of adult and embryonic stem cells and in many tumors and tumor-derived cell lines. In coimmunoprecipitation experiments, nucleostemin is recovered with the tumor suppressor p53, and more recently we have demonstrated that nucleostemin exerts its role in cell cycle progression via a p53-dependent pathway. Here, we report that in human osteosarcoma cells, nucleostemin interacts with nucleophosmin, a nucleolar protein believed to possess oncogenic potential. Nucleostemin (NS) and nucleophosmin (NPM) displayed an extremely high degree of colocalization in the granular component of the nucleolus during interphase, and both proteins associated with prenucleolar bodies in late mitosis before the reformation of nucleoli. Coimmunoprecipitation experiments revealed that NS and NPM co-reside in complexes, and yeast two-hybrid experiments confirmed that they are interactive proteins, revealing the NPM-interactive region to be the 46-amino acid N-terminal domain of NS. In bimolecular fluorescence complementation studies, bright nucleolar signals were observed, indicating that these two proteins directly interact in the nucleolus in vivo. These results support the notion that cell cycle regulatory proteins congress and interact in the nucleolus, adding to the emerging concept that this nuclear domain has functions beyond ribosome production. PMID- 18448669 TI - Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: puncta and distal caps. AB - The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca(2+) influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca(2+) channel components to existing and newly forming immunological synapses. PMID- 18448671 TI - Interactions among Ytm1, Erb1, and Nop7 required for assembly of the Nop7 subcomplex in yeast preribosomes. AB - In Saccharomyces cerevisiae, more than 180 assembly factors associate with preribosomes to enable folding of pre-rRNA, recruitment of ribosomal proteins, and processing of pre-rRNAs to produce mature ribosomes. To examine the molecular architecture of preribosomes and to connect this structure to functions of each assembly factor, assembly subcomplexes have been purified from preribosomal particles. The Nop7-subcomplex contains three assembly factors: Nop7, Erb1, and Ytm1, each of which is necessary for conversion of 27SA(3) pre-rRNA to 27SB(S) pre-rRNA. However, interactions among these three proteins and mechanisms of their recruitment and function in pre-rRNPs are poorly understood. Here we show that Ytm1, Erb1, and Nop7 assemble into preribosomes in an interdependent manner. We identified which domains within Ytm1, Erb1, and Nop7 are necessary for their interaction with each other and are sufficient for recruitment of each protein into preribosomes. Dominant negative effects on growth and ribosome biogenesis caused by overexpressing truncated Ytm1, Erb1, or Nop7 constructs, and recessive phenotypes of the truncated proteins revealed not only interaction domains but also other domains potentially important for each protein to function in ribosome biogenesis. Our data suggest a model for the architecture of the Nop7-subcomplex and provide potential functions of domains of each protein. PMID- 18448672 TI - Perspectives on a community-based course for public health students. AB - In recent years, there has been an increase in collaborations between universities and local community agencies. During the 2005-2006 academic year, the Department of Behavioral and Community Health Sciences at the University of Pittsburgh Graduate School of Public Health began a community-university partnership with Hosanna House Inc., a local community service center. The initial phase of this partnership included holding a departmental community development course at the community service center. Information from student journals, course evaluations, and key informant interviews were used to describe the attitudes and perspectives of the students, course instructor, and key informants toward this experience. Overall, this experience positively affected the personal and professional development of the students and was well received by faculty and staff within the academic department and community service center. The authors anticipate that this information will promote and serve as a reference for similar community-university partnerships at other schools of public health. PMID- 18448673 TI - Why conservation planning needs socioeconomic data. PMID- 18448674 TI - Structural basis for NKG2A/CD94 recognition of HLA-E. AB - The NKG2x/CD94 (x = A, C, E) natural killer-cell receptors perform an important role in immunosurveillance by binding to HLA-E complexes that exclusively present peptides derived from MHC class I leader sequences, thereby monitoring MHC class I expression. We have determined the crystal structure of the NKG2A/CD94/HLA-E complex at 4.4-A resolution, revealing two critical aspects of this interaction. First, the C-terminal region of the peptide, which displays the most variability among class I leader sequences, interacts entirely with CD94, the invariant component of these receptors. Second, residues 167-170 of NKG2A/C account for the approximately 6-fold-higher affinity of the inhibitory NKG2A/CD94 receptor compared to its activating NKG2C/CD94 counterpart. These residues do not contact HLA-E or peptide directly but instead form part of the heterodimer interface with CD94. An evolutionary analysis across primates reveals that whereas CD94 is evolving under purifying selection, both NKG2A and NKG2C are evolving under positive selection. Specifically, residues at the CD94 interface have evolved under positive selection, suggesting that the evolution of these genes is driven by an interaction with pathogen-derived ligands. Consistent with this possibility, we show that NKG2C/CD94, but not NKG2A/CD94, weakly but specifically binds to the CMV MHC-homologue UL18. Thus, the evolution of the NKG2x/CD94 family of receptors has likely been shaped both by the need to bind the invariant HLA-E ligand and the need to avoid subversion by pathogen-derived decoys. PMID- 18448675 TI - Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice. AB - Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that plays an important role in integrin-mediated signal transduction. To explore the role and mechanisms of FAK in cardiac development, we inactivated FAK in embryonic cardiomyocytes by crossing the floxed FAK mice with myosin light chain-2a (MLC2a) Cre mice, which expressed Cre as early as embryonic day 9.5 in the heart. The majority of conditional FAK knockout mice generated from MLC2a-Cre (CFKO-2a) died in the embryonic stage with thin ventricular wall and ventricular septal defects. A small fraction of CFKO-2a mice survived to adulthood with spontaneous eccentric right ventricle hypertrophy. Transmission electron microscopy analysis displayed swelling in the rough endoplasmic reticulum in CFKO-2a embryonic cardiomyocytes. We found that decreased cell proliferation, but not increased cell apoptosis or differentiation, is the reason for the thin ventricular wall in CFKO-2a mice. Microarray analysis suggests that myocyte enhancer factor 2a (MEF2a) can be regulated by FAK and that inactivation of FAK in the embryonic heart compromised MEF2a expression. Last, we found that Src, but not PI3K, is important in mediating signal transduction for the regulation of MEF2a by FAK. Together, these results identified the role and mechanisms of FAK in embryonic cardiac development. PMID- 18448676 TI - High blood pressure arising from a defect in vascular function. AB - Hypertension, a major cardiovascular risk factor and cause of mortality worldwide, is thought to arise from primary renal abnormalities. However, the etiology of most cases of hypertension remains unexplained. Vascular tone, an important determinant of blood pressure, is regulated by nitric oxide, which causes vascular relaxation by increasing intracellular cGMP and activating cGMP dependent protein kinase I (PKGI). Here we show that mice with a selective mutation in the N-terminal protein interaction domain of PKGIalpha display inherited vascular smooth muscle cell abnormalities of contraction, abnormal relaxation of large and resistance blood vessels, and increased systemic blood pressure. Renal function studies and responses to changes in dietary sodium in the PKGIalpha mutant mice are normal. These data reveal that PKGIalpha is required for normal VSMC physiology and support the idea that high blood pressure can arise from a primary abnormality of vascular smooth muscle cell contractile regulation, suggesting a new approach to the diagnosis and therapy of hypertension and cardiovascular diseases. PMID- 18448678 TI - ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a. AB - ATP-dependent chromatin remodeling complexes are a notable group of epigenetic modifiers that use the energy of ATP hydrolysis to change the structure of chromatin, thereby altering its accessibility to nuclear factors. BAF250a (ARID1a) is a unique and defining subunit of the BAF chromatin remodeling complex with the potential to facilitate chromosome alterations critical during development. Our studies show that ablation of BAF250a in early mouse embryos results in developmental arrest (about embryonic day 6.5) and absence of the mesodermal layer, indicating its critical role in early germ-layer formation. Moreover, BAF250a deficiency compromises ES cell pluripotency, severely inhibits self-renewal, and promotes differentiation into primitive endoderm-like cells under normal feeder-free culture conditions. Interestingly, this phenotype can be partially rescued by the presence of embryonic fibroblast cells. DNA microarray, immunostaining, and RNA analyses revealed that BAF250a-mediated chromatin remodeling contributes to the proper expression of numerous genes involved in ES cell self-renewal, including Sox2, Utf1, and Oct4. Furthermore, the pluripotency defects in BAF250a mutant ES cells appear to be cell lineage-specific. For example, embryoid body-based analyses demonstrated that BAF250a-ablated stem cells are defective in differentiating into fully functional mesoderm-derived cardiomyocytes and adipocytes but are capable of differentiating into ectoderm derived neurons. Our results suggest that BAF250a is a key component of the gene regulatory machinery in ES cells controlling self-renewal, differentiation, and cell lineage decisions. PMID- 18448677 TI - Insulin signaling and FOXO regulate the overwintering diapause of the mosquito Culex pipiens. AB - The short day lengths of late summer program the mosquito Culex pipiens to enter a reproductive diapause characterized by an arrest in ovarian development and the sequestration of huge fat reserves. We suggest that insulin signaling and FOXO (forkhead transcription factor), a downstream molecule in the insulin signaling pathway, mediate the diapause response. When we used RNAi to knock down expression of the insulin receptor in nondiapausing mosquitoes (those reared under long day lengths) the primary follicles were arrested in a stage comparable to diapause. The mosquitoes could be rescued from this developmental arrest with an application of juvenile hormone, an endocrine trigger known to terminate diapause in this species. When dsRNA directed against FOXO was injected into mosquitoes programmed for diapause (reared under short day lengths) fat storage was dramatically reduced and the mosquito's lifespan was shortened, results suggesting that a shutdown of insulin signaling prompts activation of the downstream gene FOXO, leading to the diapause phenotype. Thus, the results are consistent with a role for insulin signaling in the short-day response that ultimately leads to a cessation of juvenile hormone production. The similarity of this response to that observed in the diapause of Drosophila melanogaster and in dauer formation of Caenorhabditis elegans suggests a conserved mechanism regulating dormancy in insects and nematodes. PMID- 18448679 TI - Single-molecule nonequilibrium periodic Mg2+-concentration jump experiments reveal details of the early folding pathways of a large RNA. AB - The evolution of RNA conformation with Mg(2+) concentration ([Mg(2+)]) is typically determined from equilibrium titration measurements or nonequilibrium single [Mg(2+)]-jump measurements. We study the folding of single RNA molecules in response to a series of periodic [Mg(2+)] jumps. The 260-residue catalytic domain of RNase P RNA from Bacillus stearothermophilus is immobilized in a microfluidic flow chamber, and the RNA conformational changes are probed by fluorescence resonance energy transfer (FRET). The kinetics of population redistribution after a [Mg(2+)] jump and the observed connectivity of FRET states reveal details of the folding pathway that complement and transcend information from equilibrium or single-jump measurements. FRET trajectories for jumps from [Mg(2+)] = 0.01 to 0.1 mM exhibit two-state behavior whereas jumps from 0.01 mM to 0.4 mM exhibit two-state unfolding but multistate folding behavior. RNA molecules in the low and high FRET states before the [Mg(2+)] increase are observed to undergo dynamics in two distinct regions of the free energy landscape separated by a high barrier. We describe the RNA structural changes involved in crossing this barrier as a "hidden" degree of freedom because the changes do not alter the detected FRET value but do alter the observed dynamics. The associated memory prevents the populations from achieving their equilibrium values at the end of the 5- to 10-sec [Mg(2+)] interval, thereby creating a nonequilibrium steady-state condition. The capability of interrogating nonequilibrium steady state RNA conformations and the adjustable period of [Mg(2+)]-jump cycles makes it possible to probe regions of the free energy landscape that are infrequently sampled in equilibrium or single-jump measurements. PMID- 18448681 TI - Selfishness as second-order altruism. AB - Selfishness is seldom considered a group-beneficial strategy. In the typical evolutionary formulation, altruism benefits the group, selfishness undermines altruism, and the purpose of the model is to identify mechanisms, such as kinship or reciprocity, that enable altruism to evolve. Recent models have explored punishment as an important mechanism favoring the evolution of altruism, but punishment can be costly to the punisher, making it a form of second-order altruism. This model identifies a strategy called "selfish punisher" that involves behaving selfishly in first-order interactions and altruistically in second-order interactions by punishing other selfish individuals. Selfish punishers cause selfishness to be a self-limiting strategy, enabling altruists to coexist in a stable equilibrium. This polymorphism can be regarded as a division of labor, or mutualism, in which the benefits obtained by first-order selfishness help to "pay" for second-order altruism. PMID- 18448680 TI - Host and invader impact of transfer of the clc genomic island into Pseudomonas aeruginosa PAO1. AB - Genomic islands, large potentially mobile regions of bacterial chromosomes, are a major contributor to bacteria evolution. Here, we investigated the fitness cost and phenotypic differences between the bacterium Pseudomonas aeruginosa PAO1 and a derivative carrying one integrated copy of the clc element, a 103-kb genomic island [and integrative and conjugative element (ICE)] originating in Pseudomonas sp. strain B13 and a close relative of genomic islands found in clinical and environmental isolates of P. aeruginosa. By using a combination of whole genome transcriptome profiling, phenotypic arrays, competition experiments, and biofilm formation studies, only few differences became apparent, such as reduced biofilm growth and fourfold stationary phase repression of genes involved in acetoin metabolism in PAO1 containing the clc element. In contrast, PAO1 carrying the clc element acquired the capacity to grow on 3-chlorobenzoate and 2-aminophenol as sole carbon and energy substrates. No fitness loss >1% was detectable in competition experiments between PAO1 and PAO1 carrying the clc element. The genes from the clc element were not silent in PAO1, and excision was observed, although transfer of clc from PAO1 to other recipient bacteria was reduced by two orders of magnitude. Our results indicate that newly acquired mobile DNA not necessarily invoke an important fitness cost on their host. Absence of immediate detriment to the host may have contributed to the wide distribution of genomic islands like clc in bacterial genomes. PMID- 18448682 TI - Folding of a donor-acceptor polyrotaxane by using noncovalent bonding interactions. AB - Mechanically interlocked compounds, such as bistable catenanes and bistable rotaxanes, have been used to bring about actuation in nanoelectromechanical systems (NEMS) and molecular electronic devices (MEDs). The elaboration of the structural features of such rotaxanes into macromolecular materials might allow the utilization of molecular motion to impact their bulk properties. We report here the synthesis and characterization of polymers that contain pi electron donating 1,5-dioxynaphthalene (DNP) units encircled by cyclobis(paraquat-p phenylene) (CBPQT(4+)), a pi electron-accepting tetracationic cyclophane, synthesized by using the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The polyrotaxanes adopt a well defined "folded" secondary structure by virtue of the judicious design of two DNP-containing monomers with different binding affinities for CBPQT(4+). This efficient approach to the preparation of polyrotaxanes, taken alongside the initial investigations of their chemical properties, sets the stage for the preparation of a previously undescribed class of macromolecular architectures. PMID- 18448683 TI - Noncanonical role of Hox14 revealed by its expression patterns in lamprey and shark. AB - Hox genes are arranged in uninterrupted clusters in vertebrate genomes, and the nested patterns of their expression define spatial identities in multiple embryonic tissues. The ancestral Hox cluster of vertebrates has long been thought to consist of, maximally, 13 Hox genes. However, recently, Hox14 genes were discovered in three chordate lineages, the coelacanth, cartilaginous fishes, and amphioxus, but their expression patterns have not yet been analyzed. We isolated Hox14 cDNAs from the Japanese lamprey and cloudy catshark. These genes were not expressed in the central nervous systems, somites, or fin buds/folds but were expressed in a restricted cell population surrounding the hindgut. The lack of Hox14 expression in most of the embryonic axial elements, where nested Hox expressions define spatial identities, suggests a decoupling of Hox14 genes' regulation from the ancestral regulatory mechanism. The relaxation of preexisting constraint for collinear expression may have permitted the secondary losses of this Hox member in the tetrapod and teleost lineages. PMID- 18448684 TI - Biogenesis of extracellular microfibrils: Multimerization of the fibrillin-1 C terminus into bead-like structures enables self-assembly. AB - Microfibrils are essential elements in elastic and nonelastic tissues contributing to homeostasis and growth factor regulation. Fibrillins form the core of these multicomponent assemblies. Various human genetic disorders, the fibrillinopathies, arise from mutations in fibrillins and are frequently associated with aberrant microfibril assembly. These disorders include Marfan syndrome, Weill-Marchesani syndrome, Beals syndrome, and others. Although homotypic and heterotypic fibrillin self-interactions are considered to provide critical initial steps, the detailed mechanisms for microfibril assembly are unknown. We show here that the C-terminal recombinant half of fibrillin-1 assembles into disulfide-bonded multimeric globular structures with peripheral arms and a dense core. These globules are similar to the beaded structures observed in microfibrils isolated from tissues. Only these C-terminal fibrillin-1 multimers interacted strongly with the fibrillin-1 N terminus, whereas the monomers showed very little self-interaction activity. The multimers strongly inhibited microfibril formation in cell culture, providing evidence that these recombinant assemblies can also interact with endogenous fibrillin-1. The C terminal self-interaction site was fine-mapped to the last three calcium-binding EGF domains in fibrillin-1. These results suggest a new mechanism for microfibril formation where fibrillin-1 first oligomerizes via its C terminus before the partially or fully assembled bead-like structures can further interact with other beads via the fibrillin-1 N termini. PMID- 18448685 TI - Parent caregiving choices of middle-generation Blacks and Whites in the United States. AB - OBJECTIVE: This study compares how middle-generation caregivers and non caregivers differ by race and explores racial differences in activities of daily living (ADL), instrumental activities of daily living (IADL), and financial assistance that middle-generation caregivers provide for their parents. METHOD: Using 2000 Health and Retirement Study data, racially stratified descriptive analyses and logistic regression models for ADL, IADL, and financial assistance are presented. RESULTS: Parental need and race influence support, with similar patterns of Black and White ADL support, but racial differences in IADL and financial support. Having more children motivates Whites to increase IADL support and reduce financial support; more children decreases Blacks' IADL support. Sibling caregiver networks influence IADL and financial support in ways that vary by race. The number employed is a key determinant for Blacks for all support, but only influences White ADL support. DISCUSSION: The findings of this article indicate the importance of sample stratification by race and that employment or other subsidies may aid the expansion of caregiving by middle-generation adults. PMID- 18448686 TI - In the company of wolves: the physical, social, and psychological benefits of dog ownership. AB - OBJECTIVE: The increase in aging populations has implications for the provision of health and social services. A preventative approach is taken to address this problem by examining a mechanism that can enhance physical health and reduce minor ailments. METHODS: Participants in 10 focus groups discussed physical, psychological, and social benefits associated with human-dog interactions. METHOD: RESULTS: Interaction between humans and dogs is a mechanism that can enhance the physical and psychological health of elderly citizens and promote a social support network between dog owners. In turn, dependence and impact on health and social services are alleviated. DISCUSSION: The social and community consequences of promoting dog ownership in the elderly are addressed, and it is concluded that the benefits of dog ownership should be promoted among the elderly and acknowledged by relevant agencies. PMID- 18448687 TI - Educational differentials in life expectancy with cognitive impairment among the elderly in the United States. AB - OBJECTIVE: This article provides estimates of education differentials in life expectancy with and without cognitive impairment for the noninstitutionalized population aged 70 years and older in the United States. METHOD: Life expectancy with cognitive impairment was calculated using multistate models, allowing transitions between cognitively intact and cognitively impaired states and from each of these states to death and allowing transition rates to vary across age and education. Four waves of the Assets and Health Dynamics of the Oldest Old survey were used. RESULTS: Those with low levels of education are more likely to become cognitively impaired and do so at an earlier age. After age 70, persons with low educational levels can expect to live 11.6 years, and persons with high education 14.1 years, without cognitive impairment. Length of life with cognitive impairment differs by education (1.6 years and 1.0 years at age 70, respectively) but differs little by age. DISCUSSION: Although those with higher education have lower rates of both cognitive impairment and mortality, those who do become cognitively impaired appear to be in poorer health, leading to a reduced probability of improved cognition and increased probability of mortality relative to those with lower educational levels. PMID- 18448688 TI - Optimization of a laboratory-developed test utilizing roche analyte-specific reagents for detection of Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycin-resistant Enterococcus species. AB - Nasal and perianal swab specimens were tested for detection of Staphylococcus aureus and vancomycin-resistant Enterococcus species (VRE) using a laboratory developed real-time PCR test and microbiological cultures. The real-time PCR and culture results for S. aureus were similar. PCR had adequate sensitivity, but culture was more specific for the detection of VRE. PMID- 18448689 TI - Tuberculosis diagnosis and multidrug resistance testing by direct sputum culture in selective broth without decontamination or centrifugation. AB - Tuberculosis culture usually requires sputum decontamination and centrifugation to prevent cultures from being overgrown by contaminating bacteria and fungi. However, decontamination destroys many tuberculous bacilli, and centrifugation often is not possible in resource-poor settings. We therefore assessed the performance of Mycobacterium tuberculosis culture with unprocessed samples plated directly by using tuberculosis-selective media and compared this procedure to conventional culture using centrifuge decontamination. Quadruplicate aliquots of strain H37RV were cultured in 7H9 broth with and without selective antimicrobials and after centrifuge decontamination. The subsequent comparison was made with 715 sputum samples. Split paired sputum samples were cultured conventionally with centrifuge decontamination and by direct culture in tuberculosis-selective media containing antibiotics. Centrifuge decontamination reduced tuberculosis H37RV colonies by 78% (P < 0.001), whereas direct culture in tuberculosis-selective media had no inhibitory effect. Similarly, in sputum cultures that were not overgrown by contaminants, conventional culture yielded fewer tuberculosis colonies than direct culture (P < 0.001). However, the sensitivity of conventional culture was greater than that of direct culture, because samples were less affected by contamination. Thus, of the 340 sputum samples that were tuberculosis culture positive, conventional culture detected 97%, whereas direct culture detected 81% (P < 0.001). Conventional and direct cultures both took a median of 8.0 days to diagnose tuberculosis (P = 0.8). In those direct cultures that detected drug resistance or susceptibility, there was a 97% agreement with the results of conventional culture (Kappa agreement statistic, 0.84; P < 0.001). Direct culture is a simple, low-technology, and rapid technique for diagnosing tuberculosis and determining drug susceptibility. Compared to that of conventional culture, direct culture has reduced sensitivity because of bacterial overgrowth, but in basic laboratories this deficit may be outweighed by the ease of use. PMID- 18448690 TI - Detection of pathogenic protozoa in the diagnostic laboratory: result reproducibility, specimen pooling, and competency assessment. AB - Stool microscopy as performed in clinical parasitology laboratories is a complex procedure with subjective interpretation. Quality assurance (QA) programs often emphasize proficiency testing as an assessment tool. We describe a result reproducibility assessment tool, which can form part of a broader QA program, and which is based on the blinded resubmission of selected clinical samples, using concordance between the reports of the initial and resubmitted specimen as an indicator. Specimens preserved in sodium acetate-acetic acid-formalin can be stored for several months for use in such a program. The presence of multiple protozoa in one specimen does not affect concordance. Some dilution of specimens occurs in this process, and this may explain poor concordance when specimens with low protozoal concentrations are resubmitted. Evaluation of this tool in a large parasitology laboratory revealed concordance rates for pathogenic protozoa (Entamoeba histolytica/Entamoeba dispar, Giardia lamblia, and Dientamoeba fragilis) of about 80%, which may be considered for use as a benchmark value. We also used this tool to demonstrate that when pairs of specimens from one patient are pooled to create a single specimen, concordance between the results of the individual and pooled specimens is high. PMID- 18448691 TI - Detection of caspofungin resistance in Candida spp. by Etest. AB - The caspofungin susceptibilities of 28 Candida sp. clinical isolates, including 8 caspofungin-resistant isolates characterized by mutations in the Fks1 protein, were determined by the Etest in RPMI and AM3 media. Good discrimination between wild-type and mutant isolates was obtained. These results suggest that the Etest is valuable for the detection of caspofungin resistance in Candida spp. PMID- 18448692 TI - Method To Detect Only Live Bacteria during PCR Amplification. AB - Ethidium monoazide (EMA) is a DNA cross-linking agent and eukaryotic topoisomerase II poison. We previously reported that the treatment of EMA with visible light irradiation (EMA + Light) directly cleaved chromosomal DNA of Escherichia coli (T. Soejima, K. Iida, T. Qin, H. Taniai, M. Seki, A. Takade, and S. Yoshida, Microbiol. Immunol. 51:763-775, 2007). Herein, we report that EMA + Light randomly cleaved chromosomal DNA of heat-treated, but not live, Listeria monocytogenes cells within 10 min of treatment. When PCR amplified DNA that was 894 bp in size, PCR final products from 10(8) heat-treated L. monocytogenes were completely suppressed by EMA + Light. When target DNA was short (113 bp), like the hly gene of L. monocytogenes, DNA amplification was not completely suppressed by EMA + Light only. Thus, we used DNA gyrase/topoisomerase IV and mammalian topoisomerase poisons (here abbreviated as T-poisons) together with EMA + Light. T-poisons could penetrate heat-treated, but not live, L. monocytogenes cells within 30 min to cleave chromosomal DNA by poisoning activity. The PCR product of the hly gene from 10(8) heat-treated L. monocytogenes cells was inhibited by a combination of EMA + Light and T-poisons (EMA + Light + T-poisons), but those from live bacteria were not suppressed. As a model for clinical application to bacteremia, we tried to discriminate live and antibiotic-treated L. monocytogenes cells present in human blood. EMA + Light + T-poisons completely suppressed the PCR product from 10(3) to 10(7) antibiotic-treated L. monocytogenes cells but could detect 10(2) live bacteria. Considering the prevention and control of food poisoning, this method was applied to discriminate live and heat-treated L. monocytogenes cells spiked into pasteurized milk. EMA + Light + T-poisons inhibited the PCR product from 10(3) to 10(7) heat-treated cells but could detect 10(1) live L. monocytogenes cells. Our method is useful in clinical as well as food hygiene tests. PMID- 18448693 TI - Rapid screening for carriage of methicillin-resistant Staphylococcus aureus by PCR and associated costs. AB - PCR tests for the rapid and valid detection of methicillin-resistant Staphylococcus aureus (MRSA) are now available. We evaluated the costs associated with contact screening for MRSA carriage in a tertiary-care hospital with low MRSA endemicity. Between 1 October 2005 and 28 February 2006, 232 patients were screened during 258 screening episodes (644 samples) for MRSA carriage by GenoType MRSA Direct (Hain Lifescience GmbH, Nehren, Germany). Conventional culture confirmed all PCR results. According to in-house algorithms, 34 of 258 screening episodes (14.7%) would have qualified for preemptive contact isolation, but such isolation was not done upon negative PCR results. MRSA carriage was detected in 4 (1.5%) of 258 screening episodes (i.e., in four patients), of which none qualified for preemptive contact isolation. The use of PCR for all 258 screening episodes added costs (in Swiss francs [CHF]) of CHF 104,328.00 and saved CHF 38,528.00 (for preemptive isolation). The restriction of PCR screening to the 34 episodes that qualified for preemptive contact isolation and screening all others by culture would have lowered costs for PCR to only CHF 11,988.00, a savings of CHF 38,528.00. Therefore, PCR tests are valuable for the rapid detection of MRSA carriers, but high costs require the careful evaluation of their use. In patient populations with low MRSA endemicity, the broad use of PCR probably is not cost-effective. PMID- 18448694 TI - First clinical report of pandemic Vibrio parahaemolyticus O3:K6 infection in Italy. PMID- 18448695 TI - Occult hepatitis C virus infection revisited with ultrasensitive real-time PCR assay. AB - Occult hepatitis C infection is regarded as a new entity that should be considered when diagnosing patients with a liver disease of unknown origin. Using an ultrasensitive real-time PCR assay, we demonstrated that occult hepatitis C virus (HCV) infection cannot be found in peripheral blood mononuclear cells of patients with cryptogenic liver diseases, HCV--associated systemic vasculitis, or connective tissue diseases. The significance of such occult infection must be elucidated. PMID- 18448697 TI - Lyme disease in Oregon. AB - The incidence of Lyme disease in Oregon is calculated from cases reported to the Oregon State Health Division. We reviewed the exposure history of reported cases of Lyme disease and performed field surveys for infected Ixodes pacificus ticks. The incidence of Lyme disease correlated with the distribution of infected I. pacificus ticks. PMID- 18448696 TI - Classification of Cryptosporidium species from patients with sporadic cryptosporidiosis by use of sequence-based multilocus analysis following mutation scanning. AB - In the present study, we analyzed genetic variation in Cryptosporidium species from humans (n = 62) with clinical cryptosporidiosis in South Australia. Sequence variation was assessed in regions within the small subunit of nuclear rRNA (p SSU), the 70-kDa heat shock protein (p-hsp70), and the 60-kDa glycoprotein (p gp60) genes by employing single-strand conformation polymorphism analysis and sequencing. Based on the analyses of p-SSU and p-hsp70, Cryptosporidium hominis (n = 38) and Cryptosporidium parvum (n = 24) were identified. The analysis of p gp60 revealed eight distinct subgenotypes, classified as C. hominis IaA17R1 (n = 3), IbA9G3R2 (n = 14), IbA10G2R2 (n = 20), and IfA12G1R1 (n = 1), as well as C. parvum IIaA18G3R1 (n = 15), IIaA20G3R1 (n = 6), IIaA22G4R1 (n = 2), and IIcA5G3R2 (n = 1). Subgenotypes IaA17R1 and IIaA22G4R1 are new. Of the six other subgenotypes, IbA10G2R2, IIaA18G3R1, IIaA20G3R1, and IIcA5G3R2 were reported previously from the state of Victoria. This is the fourth record in Australia of C. parvum subgenotype IIaA18G3R1 from humans, which, to date, has been isolated only from cattle in other countries. This subgenotype might be a significant contributor to sporadic human cryptosporidiosis and may indicate a greater zoonotic contribution to the infection of humans in the area of study. Comparative analyses revealed, for the first time, the differences in the genetic makeup of Cryptosporidium populations between two relatively close, major metropolitan cities. PMID- 18448698 TI - Comparison of PCR, immunofluorescence assay, and pathogen isolation for diagnosis of q fever in humans with spontaneous abortions. AB - Coxiella burnetii, an obligate intracellular parasite with a worldwide distribution, is the causative agent of Q fever in humans. We tested a total of 368 samples (placental bits, genital swabs, fecal swabs, and urine and serum samples) collected from women (n = 74) with spontaneous abortions for C. burnetii by a PCR assay targeting IS1111, the repetitive transposon-like region of C. burnetii (trans-PCR); real-time PCR; an indirect immunofluorescence assay (IFA); and the isolation of the pathogen. The IFA showed seropositivity for 25.68% of the women with spontaneous abortions, whereas trans-PCR and real-time PCR each detected the pathogen in 21.62% of cases. Overall, 25.68% of the subjects were positive by one or more assays. Real-time PCR showed a slightly higher level of sensitivity than trans-PCR. With the IFA as the reference, the two PCR assays showed a higher level of sensitivity (84.21%) than pathogen isolation (26.31%), while both the PCR assays and pathogen isolation were specific (100%). The detection of high numbers of C. burnetii cells in clinical samples and the frequent association of the pathogen with cases of spontaneous abortions observed in this study revealed that Q fever remains underdiagnosed and that the prevalence in India is underestimated. PMID- 18448699 TI - Multiplex PCR and oligonucleotide microarray for detection of single-nucleotide polymorphisms associated with Plasmodium falciparum drug resistance. AB - Drug resistance in Plasmodium falciparum is a serious public health threat in the countries where this organism is endemic. Since resistance has been associated with specific single-nucleotide polymorphisms (SNPs) in parasite genes, molecular markers are becoming useful surrogates for monitoring the emergence and dispersion of drug resistance. In this study, a multiplex PCR (mPCR) and oligonucleotide microarray method was developed for the detection of these SNPs in genes encoding chloroquine resistance transporter (Pfcrt), multidrug resistance 1 (Pfmdr1), dihydrofolate reductase (Pfdhfr), dihydropteroate synthetase (Pfdhps), and ATPase 6 (PfATPase6) of P. falciparum. The results show that DNA microarray technology, combined with mPCR, is a promising and time saving tool that supports conventional detection methods, allowing sensitive, accurate, simultaneous analysis of the SNPs associated with drug resistance in P. falciparum. PMID- 18448700 TI - The half-cycle correction explained: two alternative pedagogical approaches. AB - Students of Markov decision models are often taught to add a half-cycle's worth of incremental utility to the cumulative total for each health state. The reason for this "half-cycle correction'' is often illustrated by a graph of the proportion of the hypothetical Markov cohort remaining in a given state. The ideal graph is shown as a smooth, declining, curve that represents the transition of patients randomly throughout each cycle. On the same graph, the effect of the accounting of state membership at the end of each cycle in discrete, computer based approximations of the ideal Markov process is shown. Students are able to clearly see that the cumulative incremental utility in the discrete case underestimates the desired quantity. Likewise, they find the concept of shifting the ideal curve to the right by one-half cycle to reduce the latter discrepancy to be intuitive. However, students often find the approximate equivalence of shifting the ideal state membership curve and adding a half-cycle's worth of incremental utility to the total for the state at the beginning of a discrete Markov process to be a difficult cognitive leap. This article describes 2 pedagogical devices, algebraic and intuitive/visual approaches, that may assist the instructor of Markov theory to convey the latter concept. Elements of adult learning theory are discussed, which may help the instructor to choose which approach to employ. Implementation of the half-cycle correction in commonly used decision-analytic software is also discussed. PMID- 18448701 TI - The half-life of truth: what are appropriate time horizons for research decisions? AB - PURPOSE: To evaluate alternative approaches taken to estimate the population that could benefit from research and to demonstrate that explicitly modeling future change leads to more appropriate estimates of the expected value of information (EVI). METHODS: Existing approaches to estimating the population typically focus on the time horizon for decisions, employing seemingly arbitrary estimates of the appropriate horizon. These approaches implicitly use the time horizon as a proxy for future changes in technologies, prices, and information. Different approaches to quantifying the time horizon are explored, in the context of a stylized model, to demonstrate the impact of uncertainty in this estimate on EVI. An alternative approach is developed that explicitly models future changes in technologies, prices, and information and that demonstrates the impact on EVI estimates. RESULTS: Explicitly modeling future changes means that the EVI for the decision problem may increase or decrease over time, but the EVI for the group of parameters that can be evaluated by current research tends to decline. The finite and infinite time horizons for the decision problem represent special cases (e.g., price shock or no changes, respectively). This type of analysis can be used to inform policy decisions relating to the timing of research. CONCLUSIONS: The value of information depends on future changes in technologies, prices, and evidence. Finite time horizons for decision problems can be seen as a proxy for the complex and uncertain process of future change. A more explicit approach to modeling these changes could provide a more appropriate basis for calculating EVI, but this raises a number of significant methodological and technical challenges. PMID- 18448702 TI - Family practitioners' diagnostic decision-making processes regarding patients with respiratory tract infections: an observational study. AB - BACKGROUND: The influence of patient characteristics on family practitioners' (FPs') diagnostic decision making has mainly been investigated using indirect methods such as vignettes or questionnaires. Direct observation-borrowed from social and cultural anthropology-may be an alternative method for describing FPs' real-life behavior and may help in gaining insight into how FPs diagnose respiratory tract infections, which are frequent in primary care. OBJECTIVE: To clarify FPs' diagnostic processes when treating patients suffering from symptoms of respiratory tract infection. METHODS: This direct observation study was performed in 30 family practices using a checklist for patient complaints, history taking, physical examination, and diagnoses. The influence of patients' symptoms and complaints on the FPs' physical examination and diagnosis was calculated by logistic regression analyses. Dummy variables based on combinations of symptoms and complaints were constructed and tested against saturated (full) and backward regression models. RESULTS: In total, 273 patients (median age 37 years, 51% women) were included. The median number of symptoms described was 4 per patient, and most information was provided at the patients' own initiative. Multiple logistic regression analysis showed a strong association between patients' complaints and the physical examination. Frequent diagnoses were upper respiratory tract infection (URTI)/common cold (43%), bronchitis (26%), sinusitis (12%), and tonsillitis (11%). There were no significant statistical differences between "simple heuristic'' models and saturated regression models in the diagnoses of bronchitis, sinusitis, and tonsillitis, indicating that simple heuristics are probably used by the FPs, whereas "URTI/common cold'' was better explained by the full model. CONCLUSION: FPs tended to make their diagnosis based on a few patient symptoms and a limited physical examination. Simple heuristic models were almost as powerful in explaining most diagnoses as saturated models. Direct observation allowed for the study of decision making under real conditions, yielding both quantitative data and "qualitative'' information about the FPs' performance. It is important for investigators to be aware of the specific disadvantages of the method (e.g., a possible observer effect). PMID- 18448703 TI - Application of high-throughput isothermal denaturation to assess protein stability and screen for ligands. AB - Many diseases in humans are caused by mutations that decrease the stability of specific proteins or increase their susceptibility to aggregation. Consequently, the availability of high-throughput methods for assessing protein stability and aggregation properties under physiological conditions (e.g., 37 degrees C) is necessary to analyze physicochemical properties under conditions that are closer to in vivo models. Therefore, the authors have explored the use of isothermal denaturation (ITD) in a 384-well format to evaluate the reproducibility of the method in assessing the stability of proteins at temperatures below the melting temperature and detecting the binding of ligands. Under the conditions tested, the authors were able to assess the stability of citrate synthase and malate dehydrogenase at different constant temperatures and detect the binding of oxaloacetate and nicotinamide adenine dinucleotide to these 2 enzymes, respectively, using the 384-well format. The ITD experiments detected ligand binding to these proteins at about 4 times lower concentration compared with techniques that measure changes in melting temperature. The data show that ITD can be applied to screen libraries of a relatively large number of compounds or detect small stability differences between protein variants. PMID- 18448705 TI - Should we force the obese to diet? PMID- 18448704 TI - Two strategies for gene regulation by promoter nucleosomes. AB - Chromatin structure is central for the regulation of gene expression, but its genome-wide organization is only beginning to be understood. Here, we examine the connection between patterns of nucleosome occupancy and the capacity to modulate gene expression upon changing conditions, i.e., transcriptional plasticity. By analyzing genome-wide data of nucleosome positioning in yeast, we find that the presence of nucleosomes close to the transcription start site is associated with high transcriptional plasticity, while nucleosomes at more distant upstream positions are negatively correlated with transcriptional plasticity. Based on this, we identify two typical promoter structures associated with low or high plasticity, respectively. The first class is characterized by a relatively large nucleosome-free region close to the start site coupled with well-positioned nucleosomes further upstream, whereas the second class displays a more evenly distributed and dynamic nucleosome positioning, with high occupancy close to the start site. The two classes are further distinguished by multiple promoter features, including histone turnover, binding site locations, H2A.Z occupancy, expression noise, and expression diversity. Analysis of nucleosome positioning in human promoters reproduces the main observations. Our results suggest two distinct strategies for gene regulation by chromatin, which are selectively employed by different genes. PMID- 18448706 TI - Clinical ethicists' perspectives on organisational ethics in healthcare organisations. AB - BACKGROUND: Demand for organisational ethics capacity is growing in health organisations, particularly among managers. The role of clinical ethicists in, and perspective on, organisational ethics has not been well described or documented in the literature. OBJECTIVE: To describe clinical ethicists' perspectives on organisational ethics issues in their hospitals, their institutional role in relation to organisational ethics, and their perceived effectiveness in helping to address organisational ethics issues. DESIGN AND SETTING: Qualitative case study involving semi-structured interviews with 18 clinical ethicists across 13 health organisations in Toronto, Canada. RESULTS: From the clinical ethicists' perspective, the most pressing organisational ethics issues in their organisations are: resource allocation, staff moral distress linked to the organisation's moral climate, conflicts of interest, and clinical issues with a significant organisational dimension. Clinical ethicists were consulted in particular on issues related to staff moral distress and clinical issues with an organisational dimension. Some ethicists described being increasingly consulted on resource allocation, conflicts of interest, and other corporate decisions. Many clinical ethicists felt they lacked sufficient knowledge and understanding of organisational decision-making processes, training in organisational ethics, and access to organisational ethics tools to deal effectively with the increasing demand for organisational ethics support. CONCLUSION: Growing demand for organisational ethics expertise in healthcare institutions is reshaping the role of clinical ethicists. Effectiveness in organisational ethics entails a re-evaluation of clinical ethics training to include capacity building in organisational ethics and organisational decision making processes as a complement to traditional clinical ethics education. PMID- 18448707 TI - Mexican heroism. PMID- 18448708 TI - Is truth a supreme value? AB - Is truth a supreme value? At times, we doctors have to contend with a complex dilemma in which we face the value of truth on the one hand and conflict with another value on the other. Is it sometimes permissible and even necessary not to report the truth in favour of another, more important value? This is a description of an experience in which a doctor had to handle such an issue when a pregnant Muslim woman asked for a document that she wasn't pregnant when in fact she was, in order to avert the possibility of being murdered to preserve the honour of the family. The doctor decided that the value of life was more important than the value of truth. PMID- 18448709 TI - The potential impact of decision role and patient age on end-of-life treatment decision making. AB - BACKGROUND: Recent research demonstrates that people sometimes make different medical decisions for others than they would make for themselves. This finding is particularly relevant to end-of-life decisions, which are often made by surrogates and require a trade-off between prolonging life and maintaining quality of life. We examine the impact of decision role, patient age, decision maker age and multiple individual differences on these treatment decisions. METHODS: Participants read a scenario about a terminally ill cancer patient faced with a choice between an aggressive chemotherapy regimen that will extend life by two years and palliative treatments to control discomfort for one remaining month. Participants were randomly assigned to one of three decision roles (patient, physician, or an abstract other) and the scenario randomly varied whether the patient was described as 25 or 65-years old. RESULTS: When deciding for a 65-year old patient, approximately 60% of participants selected aggressive chemotherapy regardless of decision role. When deciding for a 25-year old patient, however, participants were more likely to select chemotherapy for a patient (physician role) or another person (abstract other) than for themselves (70%, 67%, and 59%, respectively). In addition, confidence that powerful others (eg, physicians) control one's health, as well as respondents' age and race, consistently predicted treatment choices. CONCLUSIONS: Patient age appears to influence medical decisions made for others but not those that we make for ourselves. These findings may help to explain the discord that often occurs when younger cancer patients refuse life-extending treatments. PMID- 18448710 TI - Clinical prioritisations of healthcare for the aged--professional roles. AB - BACKGROUND: Although fair distribution of healthcare services for older patients is an important challenge, qualitative research exploring clinicians' considerations in clinical prioritisation within this field is scarce. OBJECTIVES: To explore how clinicians understand their professional role in clinical prioritisations in healthcare services for old patients. DESIGN: A semi structured interview-guide was employed to interview 45 clinicians working with older patients. The interviews were analysed qualitatively using hermeneutical content analysis. PARTICIPANTS: 20 physicians and 25 nurses working in public hospitals and nursing homes in different parts of Norway. RESULTS AND INTERPRETATIONS: The clinicians struggle with not being able to attend to the comprehensive needs of older patients, and being unfaithful to professional ideals and expectations. There is a tendency towards lowering the standards and narrowing the role of the clinician. This is done in order to secure the vital needs of the patient, but is at the expense of good practice and holistic role modelling. Increased specialisation, advances and increase in medical interventions, economical incentives, organisational structures, and biomedical paradigms, may all contribute to a narrowing of the clinicians' role. CONCLUSION: Distributing healthcare services in a fair way is generally not described as integral to the clinicians' role in clinical prioritisations. If considerations of justice are not included in clinicians' role, it is likely that others will shape major parts of their roles and responsibilities in clinical prioritisations. Fair distribution of healthcare services for older patients is possible only if clinicians accept responsibility in these questions. PMID- 18448711 TI - The practicalities of terminally ill patients signing their own DNR orders--a study in Taiwan. AB - OBJECTIVES: To investigate the current situation of completing the informed consent for do-not-resuscitate (DNR) orders among the competent patients with terminal illness and the ethical dilemmas related to it. PARTICIPANTS: This study enrolled 152 competent patients with terminal cancer, who were involved in the initial consultations for hospice care. ANALYSIS: Comparisons of means, analyses of variance, Student's t test, chi(2) test and multiple logistic regression models. RESULTS: After the consultations, 117 (77.0%) of the 152 patients provided informed consent for hospice care and DNR orders. These included 21 patients (17.9%) who signed the consent by themselves, and 96 (82.1%) whose consent sheet was signed only by family members. The reasons why patients were not involved in the discussions toward the consent (n = 82) included poor physical or psychological condition (44.9%), concerns of the consultant hospice team (37.2%), and the family's refusal (28.2%). On a multivariate analysis, patients' awareness of their poor prognosis (odds ratio = 4.07, 95% confidence interval = 2.05 to 8.07) and their understanding of hospice care (2.27, 1.33 to 3.89) were two independent factors (p < 0.01) that influenced their participation in the discussions or their personal signature in the informed consent. CONCLUSION: The family-oriented culture in Asian countries may violate the principles of the Patient Self-Determination Act and the requirements of the Hospice Care Law in Taiwan, which inevitably poses an ethical dilemma. Earlier truth-telling and continuing education of the public by hospice care workers will be helpful in solving such ethical dilemmas. PMID- 18448712 TI - The Ashley treatment: a step too far, or not far enough? AB - This "current controversies" contribution describes the recent case of a severely disabled six year old girl who has been subjected to a range of medical interventions at the request of her parents and with the permission of a hospital clinical ethics committee. The interventions prescribed have become known as "the Ashley treatment" and involve the performance of invasive medical procedures (eg, hysterectomy) and oestrogen treatment. A central aim of the treatment is to restrict the growth of the child and thus make it easier for her parents to care for her at home. The paper below discusses the main objections to the treatment. It concludes that the most serious concern raised by the case is that it may set a worrying precedent if the moral principle employed in justification of the treatment is applied again to endorse it in similar circumstances. Finally, it raises the possibility that that same moral principle may even be invoked to justify more radical interventions than those that were actually performed in the Ashley treatment. PMID- 18448713 TI - An assessment of the process of informed consent at the University Hospital of the West Indies. AB - OBJECTIVE: To assess the adequacy of the process of informed consent for surgical patients at the University Hospital of the West Indies. METHOD: The study is a prospective, cross-sectional, descriptive study. 210 patients at the University Hospital of the West Indies were interviewed using a standardised investigator administered questionnaire, developed by the authors, after obtaining witnessed, informed consent for participation in the study. Data were analysed using SPSS V.12 for Windows. RESULTS: Of the patients, 39.4% were male. Of the surgical procedures, 68.6% were scheduled, 7.6% urgent and 23.8% emergency, 35.2% were minor and 64.8% major. Information imparted/received was acceptable in 40% of cases, good in 24% and inadequate (unacceptable) in 36% of cases. Almost all (97.6%) patients stated that they understood why an operation was planned and 93.3% thought that they had given informed consent. Most (95.2%) thought that they had free choice and made up their own mind. A quarter (25.2%) of all patients were told that it was mandatory for them to sign the form. There was a discussion of possible side effects and complications in 56.7% of patients. CONCLUSIONS: This study clearly indicates that surgical patients at the University Hospital of the West Indies feel that they have given informed consent. However, it also suggests that more information should be given to patients for consent to be truly informed. PMID- 18448714 TI - Patients' preferences for receiving clinical information and participating in decision-making in Iran. AB - INTRODUCTION: This study, the first of its kind in Iran, was to assess Iranian patients' preferences for receiving information and participating in decision making and to evaluate their satisfaction with how medical information is given to them and with their participation in decision-making at present. METHOD AND MATERIALS: 299 of 312 eligible patients admitted to general internal medicine or surgery wards from May to December 2006 were interviewed according to a structured questionnaire. The questionnaire contained questions about patients' preferences regarding four domains of information and their participation in decision-making. Patients' responses were measured on a visual analogue scale graded from 1 to 10. RESULTS: The mean (SD) score for desire to receive information was 8.88 out of 10 (1.5) and for participation in medical decision making was 7.75 out of 10 (3). The desire to receive information was greater in women than men (9.0 (1.5) vs 7.8 (1.4), p = 0.025). It was also correlated with their education (r = 0.2, p = 0.001) and their estimation of the severity of their own disease (r = 0.13, p = 0.027). The score for preference to participate in decision-making was higher in women than in men (7.95 (2.8) and 7.0 (3.2), respectively; beta = 0.8, p = 0.022) and was negatively correlated with education (r = -0.14, p = 0.015). DISCUSSION: This study shows that Iranian patients are highly interested in receiving information about their condition and participating in clinical decision-making. No predictive variable for such attitudes was found; therefore, the only way for the physician to recognise patients' desire is to ask them explicitly. PMID- 18448715 TI - To what extent should older patients be included in decisions regarding their resuscitation status? AB - As medical technology continues to advance and we develop the expertise to keep people alive in states undreamt of even 20 years ago, there is increasing interest in the ethics of providing, or declining to provide, life-sustaining treatment. One such issue, highly contentious in clinical practice as well as in the media (and, through them, the public), is the use of do-not-attempt resuscitation orders. The main group of patients affected by these orders is older people. This article explores some of the arguments regarding who should make the decision to implement such an order, with particular reference to older people and the unique issues they face in relation to resuscitation. The author concludes by arguing that official guidelines, while representing an ideal, are not easily applied in a typical acute setting where decisions regarding resuscitation are most commonly made, and makes suggestions as to how they may be implemented more successfully. PMID- 18448716 TI - The quality of bioethics debate: implications for clinical ethics committees. AB - Bioethicists have recently expressed concern over a lack of quality control within the field. This apprehension focuses on bioethics expanding in ways that obscure its distinctive ethical remit and the specialist reasoning skills it requires. This thesis about the quality and conduct of bioethics may have particular relevance for clinical ethics. As one of the youngest offshoots of bioethics, the field focuses on the ethical issues that arise specifically in a clinical context. However, non-ethics specialists are increasingly involved in this field. This means that clinical ethics could be especially vulnerable to the quality control concerns articulated within bioethics. The growing public profile of clinical ethics means that concerns over quality in this area warrant specific attention by those concerned with declining standards in bioethics and those working in clinical ethics. PMID- 18448717 TI - Genomics and equal opportunity ethics. AB - Genomics provides information on genetic susceptibility to diseases and new possibilities for interventions which can fundamentally alter the design of fair health policies. The aim of this paper is to explore implications of genomics from the perspective of equal opportunity ethics. The ideal of equal opportunity requires that individuals are held responsible for some, but not all, factors that affect their health. Informational problems, however, often make it difficult to implement the ideal of equal opportunity in the context of healthcare. In this paper, examples are considered of how new genetic information may affect the way individual responsibility for choice is assigned. It is also argued that genomics may result in relocation of the responsibility cut by providing both new information and new technology. Finally, how genomics may affect healthcare policies and the market for health insurance is discussed. PMID- 18448718 TI - The perceived role of Islam in immigrant Muslim medical practice within the USA: an exploratory qualitative study. AB - BACKGROUND: Islam and Muslims are underrepresented in the medical literature and the influence of physician's cultural beliefs and religious values upon the clinical encounter has been understudied. OBJECTIVE: To elicit the perceived influence of Islam upon the practice patterns of immigrant Muslim physicians in the USA. DESIGN: Ten face-to-face, in-depth, semistructured interviews with Muslim physicians from various backgrounds and specialties trained outside the USA and practising within the the country. Data were analysed according to the conventions of qualitative research using a modified grounded-theory approach. RESULTS: There were a variety of views on the role of Islam in medical practice. Several themes emerged from our interviews: (1) a trend to view Islam as enhancing virtuous professional behaviour; (2) the perception of Islam as influencing the scope of medical practice through setting boundaries on career choices, defining acceptable medical procedures and shaping social interactions with physician peers; (3) a perceived need for Islamic religious experts within Islamic medical ethical deliberation. LIMITATIONS: This is a pilot study intended to yield themes and hypotheses for further investigation and is not meant to fully characterise Muslim physicians at large. CONCLUSIONS: Immigrant Muslim physicians practising within the USA perceive Islam to play a variable role within their clinical practice, from influencing interpersonal relations and character development to affecting specialty choice and procedures performed. Areas of ethical challenges identified include catering to populations with lifestyles at odds with Islamic teachings, end-of-life care and maintaining a faith identity within the culture of medicine. Further study of the interplay between Islam and Muslim medical practice and the manner and degree to which Islamic values and law inform ethical decision-making is needed. PMID- 18448719 TI - Minors and informed consent in carrier testing: a survey of European clinical geneticists. AB - PURPOSE: A study was made of attitudes of clinical geneticists regarding the age at which minors should be allowed to undergo a carrier test and the reasons they provide to explain their answer. METHODS: European clinical institutions where genetic counselling is offered to patients were contacted. 177 (63%) of the 287 eligible respondents answered a questionnaire. RESULTS: Clinical geneticists were significantly more in favour of providing a carrier test to a younger person if the request was made together with the parents than if the adolescent requested the test personally. Although a large fraction of respondents (16%-30%) were "neither unwilling nor willing" to provide a carrier test to a 16-year-old adolescent who requested the test personally, for most disorders slightly more clinical geneticists were "very willing" or "willing". CONCLUSION: Age is not the only decisive element when considering the participation of adolescents in decisions affecting their health. The clinical geneticists referred to cognitive, emotional and sexual maturity and the support of parents as crucial elements in their comments regarding when to tell children about their genetic risk or to allow adolescents to request a carrier test. PMID- 18448720 TI - The medical student global health experience: professionalism and ethical implications. AB - Medical student and resident participation in global health experiences (GHEs) has significantly increased over the last decade. In response to growing student interest and the proven impact of such experiences on the education and career decisions of resident physicians, many medical schools have begun to establish programmes dedicated to global health education. For the innumerable benefits of GHEs, it is important to note that medical students have the potential to do more harm than good in these settings when they exceed their actual capabilities as physicians-in-training. While medical training programmes are beginning to provide students with the knowledge to put their GHEs in context, they must remember that they also bear the responsibility of training their students in a framework to approach these experiences in a principled and professional way. It is necessary that these institutions provide adequate and formalised preparation for both clinical and ethical challenges of working in resource-poor settings. This paper outlines potential benefits and risks of GHEs and delineates recommendations to some of the current issues. PMID- 18448721 TI - Human rights and bioethics. AB - In the first part of this article we survey the concept of human rights from a philosophical perspective and especially in relation to the "right to healthcare". It is argued that regardless of meta-ethical debates on the nature of rights, the ethos and language of moral deliberation associated with human rights is indispensable to any ethics that places the victim and the sufferer in its centre. In the second part we discuss the rise of the "right to privacy", particularly in the USA, as an attempt to make the element of personal free will dominate over the element of basic human interest within the structure of rights and when different rights seem to conflict. We conclude by discussing the relationship of human rights with moral values beyond the realm of rights, mainly human dignity, free will, human rationality and response to basic human needs. PMID- 18448722 TI - The views of cancer patients on patient rights in the context of information and autonomy. AB - OBJECTIVES: The aim of this study is to evaluate the views of cancer patients on patient rights in the context of the right to information and autonomy according to articles related to the issue in the "Patient Rights Regulation". METHODS: The research was conducted among cancer patients in the medical oncology department of a research and practice hospital using a random sampling method between June and September 2005. Data were collected during face-to-face interviews using a questionnaire. RESULTS: There was a high rate of positive response to the items that the patients have the right to be informed (86.5%), that the physician should inform the patient on the diagnosis and the treatment (92.3%) and that the physician is obliged to inform the patient (76.9%). Only 43.3% of the patients stated that the patient has the right to refuse the treatment recommended by the physician. The participants mostly agreed that the patient should participate in decisions about the treatment and that patient consent should be given (78.8%). CONCLUSIONS: There are extensive efforts in Turkey towards making patient rights a significant supportive component of health services. For patient rights to become a natural part of medical practice it is necessary to give priority to education of both patients and physicians about patient rights and to lay emphasis on an ethical approach in the patient-physician relationship. PMID- 18448723 TI - Payment for research participation: a coercive offer? AB - Payment for research participation has raised ethical concerns, especially with respect to its potential for coercion. We argue that characterising payment for research participation as coercive is misguided, because offers of benefit cannot constitute coercion. In this article we analyse the concept of coercion, refute mistaken conceptions of coercion and explain why the offer of payment for research participation is never coercive but in some cases may produce undue inducement. PMID- 18448724 TI - Status of healthcare studies submitted to UK research ethics committees for approval in 2004-5. AB - BACKGROUND: In view of the increasing complexity of research ethics committee (REC) applications and thus the time and expense involved in completing the forms, continual monitoring of outcome of clinical research studies for which ethics applications have been submitted is essential in determining whether resources are being effectively used, or alternatively whether significant numbers of research proposals are abandoned because of lack of funding or manpower. Previously published surveys for which data are available examined outcome of studies receiving REC approval 10 or more years ago. METHODS: A prospective questionnaire-based survey sent out in July 2006 to all 506 principal investigators who submitted research ethics applications to nine Greater Manchester RECs between April 2004 and March 2005. Data on the outcome of REC applications, and the status of the research study were collected and analysed. RESULTS: 288 of the 506 (57%) questionnaires were returned. 97% of REC applications were approved, and 87% of studies were in progress or had been completed 1-2 years after approval had been granted. Researchers employed by universities (51%), healthcare (43%) and the pharmaceutical industry (6%) had similar rates of success in initiating research studies. CONCLUSIONS: This survey suggests that most research studies submitted to RECs in Manchester, UK are approved and initiated. PMID- 18448725 TI - The religious beliefs of students and the teaching of medical ethics: a comment on Brassington. AB - It has recently been suggested by Brassington that, when students in classes in medical ethics announce that some view that they wish to express is related to their religious convictions, the teacher is obliged to question them explicitly about the suggested link. Here, a different conclusion is reached. The view is upheld that, although the strategy recommended by Brassington is permissible and might sometimes be desirable, it is not obligatory nor is it, in general, likely to be optimal. PMID- 18448726 TI - Learning a way through ethical problems: Swedish nurses' and doctors' experiences from one model of ethics rounds. AB - OBJECTIVE: To evaluate one ethics rounds model by describing nurses' and doctors' experiences of the rounds. METHODS: Philosopher-ethicist-led interprofessional team ethics rounds concerning dialysis patient care problems were applied at three Swedish hospitals. The philosophers were instructed to promote mutual understanding and stimulate ethical reflection, without giving any recommendations or solutions. Interviews with seven doctors and 11 nurses were conducted regarding their experiences from the rounds, which were then analysed using content analysis. FINDINGS: The goal of the rounds was partly fulfilled. Participants described both positive and negative experiences. Good rounds included stimulation to broadened thinking, a sense of connecting, strengthened confidence to act, insight into moral responsibility and emotional relief. Negative experiences were associated with a sense of unconcern and alienation, as well as frustration with the lack of solutions and a sense of resignation that change is not possible. The findings suggest that the ethics rounds above all met the need of a forum for crossing over professional boundaries. The philosophers seemed to play an important role in structuring and stimulating reasoned arguments. The nurses' expectation that solutions to the ethical problems would be sought despite explicit instructions to the contrary was conspicuous. CONCLUSION: When assisting healthcare professionals to learn a way through ethical problems in patient care, a balance should be found between ethical analyses, conflict resolution and problem solving. A model based on the findings is presented. PMID- 18448727 TI - Interprofessional ethics rounds concerning dialysis patients: staff's ethical reflections before and after rounds. AB - OBJECTIVE: To evaluate whether ethics rounds stimulated ethical reflection. METHODS: Philosopher-ethicist-led interprofessional team ethics rounds concerning dialysis patient care problems were applied at three Swedish hospitals. The philosophers were instructed to stimulate ethical reflection and promote mutual understanding between professions but not to offer solutions. Questionnaires directly before and after rounds were answered by 194 respondents. The analyses were primarily content analysis with Boyd's framework but were also statistical in nature. FINDINGS: Seventy-six per cent of the respondents reported a moderate to high rating regarding new insights on ethical problem identification, but the ethics rounds did not seem to stimulate the ethical reflection that the respondents had expected (p < 0.001). Dominant new insights did not seem to fit into traditional normative ethics but were instead interpreted as hermeneutic ethics. This was illustrated in the extended perspective on the patient and increased awareness of relations to other professions. Regarding insights into how to solve ethical problems, the request for further interprofessional dialogue dominated both before and after rounds. CONCLUSION: The findings show the need for interprofessional reflective ethical practice but a balance between ethical reflection and problem solving is suggested if known patients are discussed. Further research is needed to explore the most effective leadership for reflective ethical practice. PMID- 18448728 TI - Should fertility doctors and clinical embryologists be involved in the recruitment, counselling and reimbursement of egg donors? PMID- 18448729 TI - Analysis of extrema of heartbeat time series in exercise test. AB - The heartbeat time series of the electrocardiogram recorded during exercise test clearly reflects the physiological control mechanism of the autonomic nervous system on heart rate. This series shows both decreasing and increasing trends and variability of the variance. We analyse the series of intervals between two consecutive extrema, i.e. the durations of accelerations or decelerations of heart rate. We compute the distribution of the length of these intervals and their mean in a model of stationary independent variables, where they are independent of the variables' distribution. We use the mean length as discriminant statistics to compare stress and recovery phases. Data analysis performed over the heartbeat series of 14 healthy subjects shows significant difference between stress and recovery. PMID- 18448730 TI - Cosmetic therapies in obstetrics and gynecology practice: putting a toe in the water? PMID- 18448731 TI - The impact of pelvic floor dysfunction on sexuality: how should we counsel our patients? PMID- 18448733 TI - Sexual function 6 months after first delivery. AB - OBJECTIVE: To explore the association of anal sphincter laceration and sexual function 6 months postpartum in the Childbirth and Pelvic Symptoms (CAPS) cohort. METHODS: The primary CAPS study, a prospective cohort study, was designed to estimate the postpartum prevalence and incidence of urinary and fecal incontinence. Three cohorts of new mothers (vaginal delivery with a third- or fourth-degree anal sphincter tear, vaginal delivery without a third- or fourth degree anal sphincter tear, and cesarean delivery without labor) were compared at 6 months postpartum. Sexual function was assessed with the Pelvic Organ Prolapse/Urinary Incontinence/Sexual Function Short Form Questionnaire (PISQ-12). Urinary and fecal incontinence were assessed using the Medical Epidemiological and Social Aspects of Aging questionnaire and the Fecal Incontinence Severity Index, which is embedded within the Modified Manchester Health Questionnaire. RESULTS: Most women (459 [90%]) of those with partners reported sexual activity at the 6-month visit. Fewer women whose delivery was complicated by anal sphincter laceration reported sexual activity when compared with those who delivered vaginally without sphincter laceration (88 compared with 94%, P=.028). The mean PISQ-12 score (39+/-4) did not differ between delivery groups (P=.92). Pain (responses of "sometimes," "usually," or "always") during sex affected one of three sexually active women (164 [36%]). CONCLUSION: At 6 months postpartum, primiparous women who delivered with anal sphincter laceration are less likely to report sexual activity. LEVEL OF EVIDENCE: II. PMID- 18448734 TI - Female sexual function and pelvic floor disorders. AB - OBJECTIVE: To investigate the hypothesis that pelvic floor disorders are associated with female sexual problems, independently of other related factors. METHODS: The study population included 301 adult women seeking outpatient gynecologic and urogynecologic care. Pelvic floor disorders were assessed with the Pelvic Floor Disorders Inventory-20 (PFDI-20) and the pelvic organ prolapse quantification examination. Sexual function was assessed with the Personal Experiences Questionnaire. Using ordinal regression analysis, we identified characteristics and conditions associated with decreased libido, infrequent orgasm, decreased arousal, and dyspareunia. RESULTS: Sexual function was poorer among 78 women (26%) without a current sexual partner than among 223 with a partner (P<.01). Among the 223 with a current partner, women with a high Pelvic Floor Disorders Inventory score were significantly more likely to report decreased arousal (P<.01), infrequent orgasm (P<.01), and increased dyspareunia (P<.01). A similar pattern was observed for the urinary, colorectal-anal, and prolapse scales of the Pelvic Floor Disorders Inventory, although some associations were marginally significant. Stage III-IV prolapse was significantly associated with infrequent orgasm (P=.02), but other sexual complaints were not more common with increasing prolapse stage. CONCLUSION: Pelvic floor symptoms are significantly associated with reduced sexual arousal, infrequent orgasm, and dyspareunia. We conclude that sexual function is worse in women with symptomatic prolapse but not in women with asymptomatic prolapse. LEVEL OF EVIDENCE: II. PMID- 18448735 TI - Decreasing the incidence of anal sphincter tears during delivery. AB - OBJECTIVE: To estimate if an interventional program causes a decrease in the frequency of anal sphincter ruptures. METHODS: A total of 12,369 vaginal deliveries between 2002 and March 2007 were enrolled in the interventional cohort study. Slowing the delivery of the infant's head and instructing the mother not to push while the head is delivered was the intervention. Data were analyzed in relation to occurrence of anal sphincter tears. RESULTS: The proportion of parturients with anal sphincter tears decreased significantly during the study period from 4.03% (285 of 7,069) to 1.17% (42 of 3,577) (P<.001). A similar decrease was observed for instrumental deliveries (from 16.26% to 4.90%; P<.001) and noninstrumental deliveries (from 2.70% to 0.72%; P<.001). Although the number of patients with fourth-degree anal sphincter ruptures from 2002 through 2004 was 10, 13, and 11 per year, respectively, there was just one fourth-degree anal sphincter rupture during the whole study period of 18 months (P<.001). The number of episiotomies increased from 13.9% (980 of 7,069) in the years 2002-2004, to 23.1% during the first 9 months of the intervention (416 of 1,776; P<.001), but decreased to 21.1% (381 of 1,801) during the last 9 months of the intervention. CONCLUSION: As a result of this intervention the number of anal sphincter ruptures was reduced from 4.03% to 1.17%. LEVEL OF EVIDENCE: II. PMID- 18448736 TI - The natural history of clinically unrecognized anal sphincter tears over 10 years after first vaginal delivery. AB - OBJECTIVE: To estimate the influence of clinically unrecognized anal sphincter injuries detected by endoanal ultrasonography 3 months after first vaginal delivery on symptoms of anal incontinence over the subsequent 10-year period. METHODS: One-hundred fifty-six consecutive primigravid women were recruited, anal endosonography performed, and bowel habit predelivery characterized by means of a validated 24-point questionnaire. After excluding four women with a clinically recognized sphincter tear after delivery and 18 who delivered by cesarean, these procedures were repeated 3 months postpartum. The questionnaire was repeated at 5 and 10 years to estimate continence change over the decade after delivery. Logistic regression was used to examine the effect of clinically unrecognized sphincter tears on continence. RESULTS: After delivery, continence deteriorated from baseline in 37 (28%) women, eight of whom had anal sphincter tears. Continence did not deteriorate in 97 women, six of whom had anal sphincter tears. At 10 years, 59 (55%) of 107 contactable women had continence scores greater than zero, 23 of whom had deteriorated from baseline. There was a significant relationship between a sphincter tear that was symptomatic after delivery and continence deterioration sustained at 5 and 10 years (odds ratio 2.8 for change in continence score). However, no relationship was found over 10 years for those women who sustained a sphincter tear but whose continence did not deteriorate postpartum. CONCLUSION: Ultrasonographic anal sphincter defects without postpartum incontinence are not associated with deterioration in continence over the following decade. LEVEL OF EVIDENCE: II. PMID- 18448738 TI - Cesarean delivery on maternal request in southeast China. AB - OBJECTIVE: To estimate the incidence of overall cesarean delivery and cesarean delivery on maternal request in southeast China in the past decade. METHODS: We used data from a population-based maternal and child health surveillance system, which covers 21 cities and counties in two provinces in southeast China. We examined the rate of cesarean delivery and cesarean delivery on maternal request in 1.1 million singleton births from 1994 to early 2006. Cesarean delivery on maternal request was defined as a prelabor cesarean delivery for a singleton gestation without contraindications for vaginal delivery at 38 weeks of gestation or later. RESULTS: During the 13-year study period, the percentage of women who had high school or higher education increased from 13% to 46%. The overall cesarean rate increased from 22% in 1994 to 60% in 2003 and moderated to 56% in 2006. The corresponding rates of cesarean delivery on maternal request (per 100 all deliveries) were 0.8%, 22%, and 20%, respectively. The rates varied enormously among cities and counties. In some areas, cesarean delivery on maternal request accounted for half of all cesarean births. The patterns of rate change were diverse and uneven, and the pattern of risk factors changed substantially between 1994 and 2006. Nulliparity, higher education, older maternal age, having been delivered at provincial or county hospitals, and women's occupations were previously associated with rate of cesarean delivery on maternal request. The rate of cesarean delivery on maternal request no longer varies by age, hospital level, or occupation. CONCLUSION: The rate of cesarean delivery increased dramatically in southeast China in the past decade. Cesarean delivery on maternal request was the predominant contributor to the increase. LEVEL OF EVIDENCE: III. PMID- 18448737 TI - Individualized norms of optimal fetal growth: fetal growth potential. AB - OBJECTIVE: To demonstrate that individualized optimal fetal growth norms, accounting for physiologic and pathologic determinants of fetal growth, better identify normal and abnormal outcomes of pregnancy than existing methods. METHODS: In a prospective cohort of 38,033 singleton pregnancies, we identified 9,818 women with a completely normal outcome of pregnancy and characterized the physiologic factors affecting birth weight using multivariable regression. We used those physiologic factors to individually predict optimal growth trajectory and its variation, growth potential, for each fetus in the entire cohort. By comparing actual birth weight with growth potential, population, ultrasound, and customized norms, we calculated for each fetus achieved percentiles, by each norm. We then compared proportions of pregnancies classified as normally grown, between 10th and 90th percentile, or aberrantly grown, outside this interval, by growth potential and traditional norms, in 14,229 complicated pregnancies, 1,518 pregnancies with diabetes or hypertensive disorders, and 1,347 pregnancies with neonatal complications. RESULTS: Nineteen physiologic factors, associated with maternal characteristics and early placental function, were identified. Growth potential norms correctly classified significantly more pregnancies than population, ultrasound, or customized norms in complicated pregnancies (26.4% compared with 18.3%, 18.7%, 22.8%, respectively, all P<.05), pregnancies with diabetes or hypertensive disorders (37.3% compared with 23.0%, 28.0%, 34.0%, respectively, all P<.05) and neonatal complications (33.3% compared with 19.7%, 24.9%, 29.8%, respectively, all P<.05). CONCLUSION: Growth potential norms based on the physiologic determinants of birth weight are a better discriminator of aberrations of fetal growth than traditional norms. LEVEL OF EVIDENCE: II. PMID- 18448739 TI - Bilirubin/albumin ratios in fetal blood and in amniotic fluid in rhesus immunization. AB - OBJECTIVE: To test the hypothesis that unconjugated bilirubin is equally distributed over the albumin molecules present in fetal blood and amniotic fluid in Rhesus (Rh) immunization. METHODS: Molar concentrations of unconjugated bilirubin and albumin were measured in fetal blood and amniotic fluid samples, obtained before the first intrauterine transfusion in 30 nonhydropic, anti-D alloimmunized fetuses, with gestational ages ranging from 20 to 35 weeks. RESULTS: Bilirubin concentration in amniotic fluid was best predicted by a combination of bilirubin concentration in fetal blood (P<.001), albumin concentration in fetal blood (P=.008), and albumin concentration in amniotic fluid (P<.001) (adjusted R2=0.91). The bilirubin/albumin ratios in fetal blood were linearly correlated with the bilirubin/albumin ratios in amniotic fluid (R2=0.75, P<.001). However, the bilirubin/albumin ratios in fetal blood were always higher than the bilirubin/albumin ratios in amniotic fluid (regression coefficient 1.4, 95% confidence interval 1.1-1.7). In our population, a bilirubin/albumin ratio in amniotic fluid of 0.10 or greater had a better sensitivity and specificity to predict severe anemia (Z hemoglobin -5 standard deviations or less) than the Queenan 4 or the Liley 2c line. CONCLUSION: The relation between fetal hemolysis and amniotic fluid bilirubin concentration is based on the linear correlation between bilirubin/albumin ratios in fetal blood and in amniotic fluid. The slope in Queenan's and Liley's chart follows that of the albumin concentration in amniotic fluid during gestation. LEVEL OF EVIDENCE: III. PMID- 18448740 TI - Maternal morbidity rates in a managed care population. AB - OBJECTIVE: To identify and estimate prevalence rates of maternal morbidities by pregnancy outcome and selected covariates during the antepartum, intrapartum, and postpartum periods in a defined population of pregnant women. METHODS: We used electronic data systems of a large, vertically integrated, group-model health maintenance organization (HMO) to develop an algorithm that searched International Classification of Diseases, 9th Revision, Clinical Modification, codes for 38 predetermined groups of pregnancy-related complications among women enrollees of this HMO between January 1, 1998, and December 31, 2001. RESULTS: We identified 24,481 pregnancies among 21,011 women. Although prevalence and type of morbidity varied by pregnancy outcome, overall, 50% of women had at least one complication. The most common complications were anemia (9.3%), urinary tract infections (9.0%), mental health conditions (9.0%), hypertensive disorders (8.5%), and pelvic and perineal trauma (7.0%). CONCLUSION: A range of mild-to severe pregnancy complications were identified using linked inpatient and outpatient databases. The most common complications we found usually do not require hospitalization so would be missed in studies that use only hospitalization data. Our data allowed examination of a broad scope of conditions and severity. These findings increase our understanding of the extent of maternal morbidity. LEVEL OF EVIDENCE: II. PMID- 18448741 TI - Missed opportunities for chlamydia screening of young women in the United States. AB - OBJECTIVE: To identify missed opportunities for chlamydia screening in ambulatory care offices. METHODS: We analyzed data from the 2005 National Ambulatory Medical Care Survey to estimate the number of visits to obstetrician-gynecologists and primary care physicians (family and general practitioners, internists, and pediatricians) for preventive care, pelvic examinations, Pap tests, and urinalyses for nonpregnant women aged 15-25 years, and the proportion of these visits at which chlamydia tests were not performed. RESULTS: Obstetrician gynecologists provided care for nonpregnant women aged 15-25 years at 6.3 million office visits during 2005, and primary care physicians at 20.9 million visits. Although obstetrician-gynecologists conducted only 23.1% of visits made by young women, they conducted 68.8% of visits with pelvic examinations and 71.1% of visits with Pap tests. Primary care physicians conducted 77.5% of visits with urinalyses. Obstetrician-gynecologists did not perform a chlamydia test at 3.2 of 3.8 million (82.1%) visits with pelvic examinations and at 1.8 of 2.3 million (77.3%) visits with Pap tests. Primary care physicians did not perform a chlamydia test at 2.9 of 3.0 million (99.1%) visits with urinalyses. CONCLUSION: There are many missed opportunities for chlamydia testing of young women in ambulatory care visits - during pelvic examinations, Pap tests, and urinalyses. Effective and simple interventions are needed to increase targeted chlamydia screening of women by physicians. LEVEL OF EVIDENCE: III. PMID- 18448742 TI - Rates of human papillomavirus vaccination, attitudes about vaccination, and human papillomavirus prevalence in young women. AB - OBJECTIVE: To estimate rates of human papillomavirus (HPV) vaccination, factors associated with intention and belief in one's ability (self-efficacy) to receive the vaccine, and prevalence of vaccine-type HPV during the first year after an HPV-6, HPV-11, HPV-16, HPV-18 vaccine was licensed. METHODS: Sexually experienced females 13-26 years of age (N=409) were recruited from three primary care clinics, completed a questionnaire, and underwent cervicovaginal HPV DNA testing. Outcome measures were HPV vaccination, intention and belief in one's ability to receive the HPV vaccine in the next year, and prevalence of vaccine-type HPV. Factors independently associated with intention and belief in one's ability to receive the HPV vaccine were determined by logistic regression. RESULTS: Five percent of participants had received at least one HPV vaccine dose, 66% intended to receive the vaccine, 65% were confident they could find the time to get vaccinated, 54% believed that they could receive all three shots, and 42% believed that they could afford vaccination. Sixty-eight percent of women were HPV-positive: 9% for HPV-6, 3% for HPV-11, 17% for HPV-16, and 12% for HPV-18. Factors independently associated with intention included believing that influential people would approve of vaccination, higher perceived severity of cervical cancer or genital warts, fewer safety barriers, and pregnancy history. Factors associated with a high belief in one's ability to receive the vaccine included perceived severity of HPV, sexually transmitted disease history, insurance coverage, and fewer practical barriers to vaccination. CONCLUSION: Interventions that aim to increase intention and belief in one's ability to receive HPV vaccines, which may lead to higher vaccination rates, should address personal beliefs about vaccination as well as systemic barriers to vaccination. LEVEL OF EVIDENCE: III. PMID- 18448743 TI - Dengue infection in pregnancy: prevalence, vertical transmission, and pregnancy outcome. AB - OBJECTIVE: To estimate prevalence rate of recent dengue infection in parturients, as well as the vertical transmission rate, and to compare pregnancy outcomes among infected women. METHOD: A prospective cohort study was performed. Maternal and paired umbilical cord bloods were taken at delivery. A brief questionnaire on febrile illness and dengue in pregnancy was completed by participants. The samples were sent to a World Health Organization Collaborating Center for Arbovirus Reference and Research. Maternal sera were tested with a dengue specific immunoglobulin M (IgM) capture test. The paired umbilical cord serum was tested to determine when the maternal sample was positive. Dengue reverse transcriptase polymerase chain reaction (PCR) was performed on all dengue IgM positive sera. Pregnancy outcome was extracted from delivery records. RESULTS: A total of 2,958 parturients were enrolled, and 2,531 paired maternal-umbilical cord blood samples were available for testing. Dengue-specific IgM was positive in 63 of 2,531 (2.5%, 95% confidence interval [CI] 1.9-3.2%) maternal samples. Only 1 of 64 (1.6%, 95% CI 0.0-9.5%) of the paired umbilical cord sera was IgM positive. All reverse transcriptase PCR tests were negative. Fifty-six of 63 (88.9%) of dengue IgM-positive women did not report a febrile illness in pregnancy. Apart from a higher mean age in dengue IgM-positive women of 30.6+/ 5.2 compared with 29.2+/-4.9 years (P=.025) compared with dengue IgM-negative women, all other characteristics were similar. Rates of preterm birth, mode of delivery, postpartum hemorrhage, low birth weight, and neonatal outcomes were not different. CONCLUSION: Recent dengue infection was demonstrated in 2.5% of parturients, with a vertical transmission rate of 1.6%. Pregnancy outcome of recently infected women was not different. LEVEL OF EVIDENCE: II. PMID- 18448744 TI - Association of preterm birth with sustained postnatal inflammatory response. AB - OBJECTIVE: To investigate fetal or neonatal inflammatory patterns based on 25 inflammatory markers in neonatal dried blood spots samples from infants born preterm and term, collected several days after birth. METHODS: Dried blood spots samples from 160 neonates were analyzed for 25 inflammatory markers using multiplex technology: 26 neonates born very preterm (before 32 weeks of gestation), drawn at a mean 6 days (95% confidence interval [CI], 5-7 days) after birth; 52 born preterm (32-36 weeks of gestation), drawn at mean 5 days (95% CI, 5-6 days) after birth; and 82 born at term (at or after 37 weeks of gestation), drawn at mean 5 days (95% CI, 5-5 days) after birth. Markers statistically significantly associated with preterm birth were analyzed in a multivariable model together with maternal and neonatal risk factors for preterm birth. RESULTS: Elevated levels of interleukin (IL)-1beta, IL-6, soluble IL-6ralpha, IL 8, matrix metalloproteinase-9, and transforming growth factor-beta1 and decreased levels of IL-18, brain-derived neurotrophic factor, and C-reactive protein were associated with preterm birth. Maternal risk factors could explain only an increase of IL-1beta, whereas neonatal factors could explain several of the elevated and decreased inflammatory markers in the dried blood spots samples from the infants born preterm compared with the infants born at term. CONCLUSION: The differences in levels of inflammatory markers in dried blood spots samples from infants born preterm compared with infants born at term supports the hypothesis that inflammation of fetal origin might be a cause of preterm birth. LEVEL OF EVIDENCE: II. PMID- 18448745 TI - CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial. AB - OBJECTIVE: To evaluate whether 3-month administration of CDB-2914, a selective progesterone receptor modulator, reduces leiomyoma size and symptoms. METHODS: Premenopausal women with symptomatic uterine leiomyomata were randomly assigned to CDB-2914 at 10 mg (T1) or 20 mg (T2) daily or to placebo (PLC) for 3 cycles or 90-102 days if no menses occurred. The primary outcome was leiomyoma volume change determined by magnetic resonance imaging at study entry and within 2 weeks of hysterectomy. Secondary outcomes included the proportion of amenorrhea, change in hemoglobin and hematocrit, ovulation inhibition, and quality-of-life assessment. RESULTS: Twenty-two patients were allocated, and 18 completed the trial. Age and body mass index were similar among groups. Leiomyoma volume was significantly reduced with CDB-2914 administration (PLC 6%; CDB-2914 -29%; P=.01), decreasing 36% and 21% in the T1 and T2 groups, respectively. During treatment, hemoglobin was unchanged, and the median estradiol was greater than 50 pg/mL in all groups. CDB-2914 eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles: CDB-2914, 20%; PLC, 83%; P=.001). CDB-2914 improved the concern scores of the uterine leiomyoma symptom quality-of-life subscale (P=.04). One CDB-2914 woman developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. CONCLUSION: Compared with PLC, CDB-2914 significantly reduced leiomyoma volume after three cycles, or 90-102 days. CDB-2914 treatment resulted in improvements in the concern subscale of the Uterine Fibroid Symptom Quality of Life assessment. In this small study, CDB-2914 was well-tolerated without serious adverse events. Thus, there may be a role for CDB-2914 in the treatment of leiomyomata. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,www.clinicaltrials.gov, NCT00290251 LEVEL OF EVIDENCE: I. PMID- 18448746 TI - Explained compared with unexplained fever in postoperative myomectomy and hysterectomy patients. AB - OBJECTIVE: To confirm that fever with localized findings is less prevalent among febrile postoperative myomectomy patients than it is among hysterectomy patients. METHODS: Hospital records of 341 hysterectomy patients and 250 myomectomy patients were reviewed. Rate of overall febrile morbidity, proportion of fever with localized findings, proportion of febrile patients worked-up, and other perioperative parameters were recorded. Fever was prospectively defined both inclusively (temperature at least 38.0 degrees C occurring at least 4 hours postoperatively) and in standard fashion (temperature at least 38.0 degrees C after 24 hours postoperatively). A localized fever required a positive laboratory, radiologic, or clinical finding. Chi-square, Student t test, and multivariable logistic regression were used. RESULTS: The proportion of patients who developed postoperative fever after at least 4 hours was identical between myomectomy and hysterectomy patients (39.2% compared with 39.3%, P=.98). However, the proportion of febrile myomectomy patients with localized findings was significantly lower than hysterectomy patients (14.3% compared with 31.3%, P=.003). Likewise, when comparing respective rates of overall and localized fever after at least 24 hours postoperatively, similar results were obtained. Multivariable analysis confirmed the lower likelihood of localized findings among febrile postoperative myomectomy patients compared with hysterectomy patients (odds ratio of localized fever 0.30, 95% confidence interval 0.12-0.75, P=.01). Additionally, obesity raised the likelihood of localized findings in each group by 6% per unit of body mass index (odds ratio 1.06, 95% confidence interval 1.01 1.10, P=.03). CONCLUSION: Overall postoperative fever rates are similar, but myomectomy is independently associated with fewer localized fevers than hysterectomy. Given the relatively low likelihood of localized fever, clinicians may consider simplifying the fever workup of postoperative myomectomy patients. LEVEL OF EVIDENCE: II. PMID- 18448747 TI - High prevalence of concomitant anogenital lichen sclerosus and extragenital psoriasis in adult women. AB - OBJECTIVE: To analyze the prevalence of lichen sclerosus and psoriasis in gynecologic patients. METHODS: The prevalence of lichen sclerosus and psoriasis individually, as well as the prevalence of both diseases in the same patient, was evaluated among 2,800 women attending a primary care gynecology practice for annual routine gynecologic examinations. The incidence of lichen sclerosus (new diagnosis of lichen sclerosus per year/population at risk) was calculated for the last 5 years. RESULTS: Two hundred (7.1%) women had a biopsy-proven anogenital lichen sclerosus, and 57 women (2%) had an extragenital psoriasis vulgaris. Fifteen women had both diseases (0.5%). The prevalence of psoriasis in lichen sclerosus patients was 7.5% (15 of 200; 95% confidence interval 4.3-12.1%) compared with 1.6% (42 of 2,600) in the non-lichen sclerosus patient group. Lichen sclerosus was diagnosed in 13 of 15 psoriasis patients at an average of 19.5 years after the diagnosis of psoriasis at the age of 48 years (range 30-70 years). The incidence rates of lichen sclerosus for the last 5 years were 0.5% in 2002, 0.7% in 2003 and 2004, 1.9% in 2005, and 1.8% in 2006. CONCLUSION: The prevalence of psoriasis in lichen sclerosus patients (7.5%) is higher than in the general population and among the non-lichen sclerosus patients in this practice (1.6%). This association may result from a similar immune dysregulation in these women. LEVEL OF EVIDENCE: II. PMID- 18448748 TI - Vaginal descent and pelvic floor symptoms in postmenopausal women: a longitudinal study. AB - OBJECTIVE: To determine whether vaginal descent changes are associated with pelvic floor symptoms in postmenopausal women. METHODS: This 4-year prospective study included 260 postmenopausal women with an intact uterus enrolled at one Women's Health Initiative (WHI) clinical trial site. All completed at least two annual pelvic organ prolapse quantification (POP-Q) examinations and symptom questionnaires (30 bladder, bowel, and prolapse symptom items, modified from the Pelvic Floor Distress Inventory). Symptoms were grouped, and group scores categorized into two or three evenly distributed levels. Year 4 data collection was incomplete because the overall WHI study halted. Generalized logistic linear models and generalized estimating equation methods were used to measure associations between vaginal descent and a symptom or symptom score, controlling for time, age, and body mass index (BMI). RESULTS: Mean age was 68+/-5 years, BMI 30+/-6 kg/m(2), and median parity 4. Ninety-five percent of women had POP-Q stages I-II prolapse. Increasing maximal vaginal descent was associated with "see/feel a bulge" and "sensation of protrusion or bulging," and with obstructive bladder, prolapse, and obstructive bowel scores. Increasing apical descent (POP-Q point C) was associated with "see/feel a bulge," increasing anterior descent (POP Q point Ba) with bladder pain and obstructive bladder scores, and increasing posterior descent (POP-Q point Bp) with the bowel incontinence score. CONCLUSION: Although previous work showed that most pelvic floor symptoms correlated poorly with levels of early prolapse, longitudinal analysis suggests that vaginal descent progression over time is positively associated with various bladder, bowel, and prolapse symptoms in postmenopausal women with stages I-II prolapse. LEVEL OF EVIDENCE: II. PMID- 18448749 TI - A simple clinical maneuver to reduce laparoscopy-induced shoulder pain: a randomized controlled trial. AB - OBJECTIVE: To estimate the efficacy of a simple clinical maneuver that facilitates removal of residual abdominal carbon dioxide (CO2) after laparoscopic surgery to reduce shoulder pain. METHODS: A total of 116 female outpatients who were scheduled for elective gynecologic laparoscopic surgery were randomly allocated to either the current standard (control group) or to additional efforts to remove residual CO2 at the end of surgery. In the control group, CO2 was removed by passive deflation of the abdominal cavity through the cannula. In the intervention group, CO2 was removed by means of Trendelenburg position (30 degrees) and a pulmonary recruitment maneuver consisting of five manual inflations of the lung. Postoperative shoulder pain was assessed before discharge and 12, 24, 36, and 48 hours later using a visual analog scale (VAS, 0-100). In addition, positional characteristics of the shoulder pain and incidence of postdischarge nausea and vomiting were recorded until 48 hours after discharge. RESULTS: Pain scores in the control and intervention groups were 30.3+/-4.5 compared with 15.6+/-3.0, 25.7+/-4.7 compared with 10.8+/-2.4, and 21.7+/-4.3 compared with 9.1+/-2.5 at 12, 24 and 36 hours after discharge, respectively (all P<.05). The intervention reduced positional pain from 63% to 31% (P<.05) and the incidence of postoperative nausea and vomiting from 56.5% to 20.4% (P<.001). CONCLUSION: This simple clinical maneuver at the end of surgery reduced shoulder pain as well as postoperative nausea and vomiting after laparoscopic surgery by more than half. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, ClinicalTrials.gov, NCT00575237 LEVEL OF EVIDENCE: I. PMID- 18448751 TI - Relationship of time since childbirth and other pregnancy factors to premenopausal breast cancer prognosis. AB - OBJECTIVE: To investigate the influence of time since childbirth and other pregnancy factors on the prognosis of premenopausal breast cancer. METHODS: Women who delivered an infant in Nova Scotia, Canada, between 1980 and 2001 were identified from a provincial perinatal database and linked to the Nova Scotia Cancer Registry to determine primary breast cancer diagnoses among women aged younger than 50 years. Relative risks and Cox proportional hazards ratios were calculated to quantify the relationship of time from childbirth to diagnosis and other pregnancy factors to the extent of disease at diagnosis and on survival after breast cancer diagnosis. RESULTS: Of the 123,323 women who delivered an infant during the study period, 716 women were diagnosed with invasive breast cancer. Women with less than 5 years between their last delivery and diagnosis were more likely to be diagnosed with later-stage disease and had poorer survival even after adjusting for stage of disease (less than 2 years, adjusted hazards ratio 2.1, 95% confidence interval 1.2-3.9; 2-4 years, hazards ratio 1.6, 95% confidence interval 0.9-2.8) compared with women with 5 years or more. For every 13 women with less than 2 years between delivery and diagnosis, one excess death will occur, compared with women with 5 or more years between delivery and diagnosis. CONCLUSION: A time interval of less than 2 years (and 2-4 years) between childbirth and breast cancer diagnosis worsens the prognosis in a dose response fashion. Clinicians should be aware of these findings when examining women in the first 5 years after a delivery. LEVEL OF EVIDENCE: II. PMID- 18448750 TI - Lynch syndrome in women less than 50 years of age with endometrial cancer. AB - OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6-19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III. PMID- 18448752 TI - Selective serotonin reuptake inhibitors for premenstrual syndrome and premenstrual dysphoric disorder: a meta-analysis. AB - OBJECTIVE: To systematically review evidence of the treatment benefits of selective serotonin reuptake inhibitors (SSRIs) for symptoms related to severe premenstrual syndrome (PMS) and premenstrual dysphoric disorder. DATA SOURCES: We conducted electronic database searches of MEDLINE, Web of Science, Cochrane Library, Embase, PsycINFO, and Cinahl through March 2007, and hand-searched reference lists and pertinent journals. METHODS OF STUDY SELECTION: Studies included in the review were double-blind, randomized, controlled trials comparing an SSRI with placebo that reported a change in a validated score of premenstrual symptomatology. Studies had to report follow-up for any duration longer than one menstrual cycle among premenopausal women who met clinical diagnostic criteria for PMS or premenstrual dysphoric disorder. From 2,132 citations identified, we pooled results from 29 studies (in 19 citations) using random-effects meta analyses and present results as odds ratios (ORs). TABULATION, INTEGRATION, AND RESULTS: Our meta- analysis, which included 2,964 women, demonstrates that SSRIs are effective for treating PMS and premenstrual dysphoric disorder (OR 0.40, 95% confidence interval [CI] 0.31-0.51). Intermittent dosing regimens were found to be less effective (OR 0.55, 95% CI 0.45-0.68) than continuous dosing regimens (OR 0.28, 95% CI 0.18-0.42). No SSRI was demonstrably better than another. The choice of outcome measurement instrument was associated with effect size estimates. The overall effect size is smaller than reported previously. CONCLUSION: Selective serotonin reuptake inhibitors were found to be effective in treating premenstrual symptoms, with continuous dosing regimens favored for effectiveness. PMID- 18448753 TI - Preoperative evaluation of the gynecologic patient: considerations for improved outcomes. AB - The preoperative evaluation serves several purposes for the gynecologist. Patients with previously undiagnosed, or incompletely managed, medical concerns are identified and appropriate treatment initiated. In women with known medical concerns, the surgeon can anticipate problems and plan for appropriate postoperative care. In certain cases, the preoperative evaluation identifies medical conditions that are unstable enough to adversely affect the postoperative outcome, and appropriate referral for medical management can be made. One of the most important aspects of the evaluation is the identification of women at high risk for cardiovascular complications. A stepwise approach is useful to identify those women who may proceed to surgery and those who need further testing. Much of the preoperative evaluation of the woman with pulmonary disease can be done during the history and physical examination without additional testing. Deep venous thrombosis is a significant concern in gynecologic surgery; appropriate identification of the woman at risk is important, with initiation of prophylaxis occurring shortly after the surgery concludes. Many women undergoing gynecologic surgery have diabetes. Careful management of diabetes in the perioperative period has become more germane, with evidence of improved outcomes as tight control is achieved. Much of the preoperative evaluation falls easily into the purview of the gynecologist, with advice presented as to when medical consultation should be considered. PMID- 18448754 TI - Physician reentry: a concept whose time has come. AB - Three retrainees were accepted into an innovative program designed to refresh skills to return physicians to the obstetrics and gynecology workforce after a voluntary leave of absence. The program was constructed in such a way that it did not affect existing training opportunities for medical students and residents. A protocol for application and acceptance was developed that incorporated an admissions committee and a fellowship director. The need for such retraining programs and considerations in structuring, including candidate selection, faculty involvement and support, needs assessment and curriculum development, and a protocol for administration are presented. It is hoped that other training programs with experienced educators and a surplus of clinical cases will use our model to establish their own physician reentry programs, returning these valuable members of the physician workforce to practice. PMID- 18448755 TI - Ob-gyn special delivery. PMID- 18448757 TI - Probiotics for prevention of necrotizing enterocolitis in preterm infants. PMID- 18448758 TI - BRCA screening. PMID- 18448759 TI - Doripenem (doribax)--a new parenteral carbapenem. PMID- 18448760 TI - SSRIs and osteoporosis. PMID- 18448761 TI - A once-yearly IV bisphosphonate for osteoporosis. PMID- 18448762 TI - Major changes in endocarditis prophylaxis for dental, GI and GU procedures. PMID- 18448763 TI - Optimal catheter placement during sonohysterography: a randomized controlled trial comparing cervical to uterine placement. PMID- 18448764 TI - Estimation of birth weight by two-dimensional ultrasonography. PMID- 18448767 TI - ACOG Practice Bulletin No. 93: diagnosis and management of vulvar skin disorders. PMID- 18448768 TI - ACOG Committee Opinion No. 405: ovarian tissue and oocyte cryopreservation. PMID- 18448769 TI - ACOG Committee Opinion No. 406: coping with the stress of medical professional liability litigation. PMID- 18448770 TI - ACOG Committee Opinion No. 407: low bone mass (osteopenia) and fracture risk. PMID- 18448771 TI - Understanding fatigue in major depressive disorder and other medical disorders. AB - BACKGROUND: Although fatigue is a common symptom that occurs in many psychiatric and other medical disorders, the pathophysiological mechanisms of fatigue are still unclear. OBJECTIVE: The goal of this review is to assess the state of knowledge about fatigue in depression and other disorders and identify new avenues for research in the study of fatigue. METHOD: The author reviewed some 50 articles in the field. CONCLUSION: An approach that emphasizes the similarities between fatigue and depression may improve the understanding of these complex syndromes. As more is learned about the neuropathology of the heterogeneous syndrome of depression, the etiology of many of the symptoms domains associated with depression, including fatigue, may become clearer. PMID- 18448772 TI - Treating the physical symptoms of depression with second-generation antidepressants: a systematic review and metaanalysis. AB - BACKGROUND: Approximately two-thirds of patients with depression experience physical pain symptoms. Coexisting pain complicates the treatment of depression and is associated with worse depression outcomes. OBJECTIVE: The authors reviewed the effect of newer antidepressants on pain in patients with depression. METHOD: The authors searched systematically for trials of second-generation antidepressants that enrolled depression patients and reported pain outcomes, pooling changes on the pain visual-analog scale (VAS), using random-effects models. RESULTS: Eight trials were eligible. Pooled analysis of head-to-head trials showed no difference in VAS between duloxetine and paroxetine. Both drugs were superior to placebo. CONCLUSION: The authors found insufficient evidence to support the choice of one second-generation antidepressant over another in patients with pain accompanying depression. PMID- 18448774 TI - The safety of ECT in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Electroconvulsive therapy (ECT) involves the administration of general anesthesia and assisted ventilation while the patient is apneic. OBJECTIVE: Care must be taken to screen for significant pulmonary dysfunction before treatment. Very little has been written about the safety and management strategy of ECT patients with chronic obstructive pulmonary disease (COPD). METHOD: In this retrospective chart review, authors describe their experience with patients in recent years who had this disorder and were treated with ECT. RESULTS: Authors list recommendations for the pre-ECT work up and anesthetic management during and after the treatments. CONCLUSION: Recent guidelines recommend administration of patients' prescribed inhalers on the morning of ECT treatment. Also, caution is recommended when using ECT in patients taking theophylline because this drug has been associated with prolonged seizures and status epilepticus in these patients. PMID- 18448773 TI - A prospective examination of antidepressant use and its correlates in patients with acute coronary syndrome. AB - BACKGROUND: Depression has been implicated in the occurrence of recurrent coronary events and cardiac or all-cause mortality in acute coronary syndrome (ACS) patients. OBJECTIVE: The authors describe the frequency and type of antidepressant use and its correlates 18 months after ACS hospital discharge. METHOD: A sample of 661 ACS inpatients, recruited from three hospitals, completed a sociodemographic survey and the Hospital Anxiety and Depression Scale (HADS), and clinical data were extracted from charts. A mailed survey 9 months and 18 months post-discharge assessed self-reported antidepressant use, and the HADS was re-administered. RESULTS: Approximately 9% of participants reported antidepressant use both 9 and 18 months post-hospitalization, with 77% concordance in usage over time. Participants most frequently reported using selective serotonin reuptake inhibitors and least often tricyclics. Logistic regression revealed that antidepressant users were more likely to be anxious and have more comorbidity, and were less likely to work full-time, whereas number of medications, age, and marital status were not related. CONCLUSION: Patients with comorbid physical and mental conditions who are unemployed may be more likely to receive an antidepressant because of greater depression symptoms or greater exposure to healthcare providers, which increases the potential for symptom recognition and treatment. PMID- 18448775 TI - Normalizing attributions may contribute to non-help-seeking behavior in people with fibromyalgia syndrome. AB - BACKGROUND: Causal attributions of bodily perceptions indicate the possibility of some degree of control over events. Therefore, attributions are important to support the social significance of experience and confer meaning. OBJECTIVE: The aim of this study is to investigate whether non-patients with fibromyalgia (FMS) use more normalizing attributions than healthy control subjects and help-seeking patients. METHOD: Thirty-seven FMS patients attending tertiary care were compared with 38 non-patients and 34 healthy controls on mean anxiety, depression, attribution style, and alexithymia scores. RESULTS: Mean normalizing scores were greatest in the non-patient group, followed by the healthy-control group, and smallest in the tertiary-care attending group. Non-patients are using more normalizing explanations than the FMS patients and the healthy-control subjects. CONCLUSION: Thus, normalization may negatively influence help-seeking behavior and contribute to non-help-seeking behavior. PMID- 18448776 TI - Depression after diagnosis of advanced non-small cell lung cancer and survival: a pilot study. AB - BACKGROUND: Major depressive disorder is estimated to occur in 10%-25% of people with cancer, and it has been inconsistently linked to increased mortality. OBJECTIVE: This pilot study investigates the association of depression and survival in advanced non-small cell lung cancer (NSCLC) patients. METHOD: Forty three recently-diagnosed advanced NSCLC patients completed the Hospital Anxiety and Depression Scale and were followed prospectively. RESULTS: Patients with depression had poorer survival. Median survival was four times shorter than those without depression. Controlling for baseline performance status, depression predicted 6-month mortality, but was not significant for overall survival. CONCLUSION: Although depression after advanced-NSCLC diagnosis was associated with poorer survival at 6 months, this association was not present for overall survival; however, further research with larger samples should be pursued. PMID- 18448777 TI - The effect of pegylated interferon-alpha2b and ribavirin on posttraumatic stress disorder symptoms. AB - BACKGROUND: Patients with chronic psychiatric diagnoses have a prevalence of chronic hepatitis C (HCV) approximately 11 times higher than the general American population. Posttraumatic stress disorder (PTSD) is particularly common among HCV patients. OBJECTIVE: The authors describe the effect of treatment with pegylated interferon-alpha(2b) (IFN) and ribavirin for patients with HCV on their posttraumatic stress disorder (PTSD) symptoms. METHOD: Sixteen patients with HCV and combat-related PTSD were followed for 24 weeks and assessed with self-report measures of PTSD, hostility, and depression. RESULTS: Depression and Resentment scores significantly increased in five patients treated with IFN and ribavirin, but no significant differences were found in PTSD scores when compared with 11 control patients. CONCLUSION: The results suggest that patients with PTSD and HCV can be safely treated with anti-viral therapies when they are given appropriate psychiatric care. PMID- 18448778 TI - Cardiovascular symptoms in coronary-artery disease patients are strongly correlated with emotional distress. AB - BACKGROUND: The relationship of cardiovascular events and cardiovascular symptoms is unclear, and physical symptoms, including most cardiovascular symptoms, are known to be influenced by emotional distress. OBJECTIVE: Authors examined the relative strength of association of multiple measures of emotional distress and accepted cardiac risk factors with five common cardiac symptoms (chest pain, fatigue, palpitations, presyncope, and dyspnea). METHOD: The authors tested the association of multiple cardiovascular symptoms with various measures of emotional distress (i.e., the scales of the Symptom Checklist-90-Revised) and the putative risk factors for disease status in 109 patients with documented coronary artery disease. RESULTS: Measures of emotional distress were stronger correlates of patient-rated distress due to the symptoms than were traditional risk factors. CONCLUSION: Treatment of emotional distress may be a viable strategy for symptom control in cardiovascular disease. PMID- 18448779 TI - Comorbid somatic symptoms and functional status in patients with fibromyalgia and chronic fatigue syndrome: sensory amplification as a common mechanism. AB - BACKGROUND: Somatic symptoms are common in conditions such as fibromyalgia (FM) and chronic fatigue syndrome (CFS). OBJECTIVE: Authors investigated a potential shared pathologic mechanism: a generalized perceptual abnormality where there is heightened responsiveness to varied sensory stimulation, including pain. METHOD: A composite measure of sensory sensitivity was created and compared with measures of somatic symptoms, comorbid psychological disturbances, and self-reported physical functioning in 38 patients with FM and/or CFS. RESULTS: Sensory amplification influenced physical functioning indirectly through pain intensity, and physical symptoms and fatigue also independently contributed to physical functioning. CONCLUSION: Sensory amplification may be an underlying pathophysiologic mechanism in these disorders that is relatively independent of depression and depressive symptoms. PMID- 18448780 TI - Determinants of quality of life in Marfan syndrome. AB - BACKGROUND: Marfan syndrome (MFS) is a rare, heritable disorder that affects connective tissue. Men and women are equally affected. Clinical manifestations involve multiple sites, especially bones and ligaments and heart and blood vessels. OBJECTIVE: Authors sought to investigate quality of life (QoL) in MFS patients, assessing positive and negative sociodemographic factors and self perceived well-being and functional status. METHOD: Thirty-six patients affected by MFS were interviewed and were administered the SF-36 psychometric questionnaire. RESULTS: Subjects affected by MFS reported an impaired quality of life in the psychological domain but not in the physical domain, as compared with a healthy population. Being male and older was significantly associated with a poorer perceived mental QoL. CONCLUSION: The authors found that MFS negatively influences QoL, increases psychological distress, and may be a possible risk for some psychiatric disorders. PMID- 18448781 TI - Too much too soon? Refeeding syndrome as an iatrogenic cause of delirium. AB - BACKGROUND: Delirium is a significant and costly complication of medical hospitalization, and it has been shown to be a significant predictor of morbidity and mortality. It is often noted as a symptom in reported cases of refeeding syndrome, which is a potentially fatal complication in the treatment of patients suffering from malnutrition. OBJECTIVE: A case of delirium due to refeeding syndrome in a 61-year-old man is presented to help clinicians recognize this entity. The pathophysiology of refeeding syndrome and its possible role as an as yet poorly-identified iatrogenic cause of delirium are discussed. METHOD: A diagnosis of delirium due to refeeding syndrome was made, and a nutrition consult was requested. Per nutrition recommendations, the patient was placed on a restricted calorie regimen, with aggressive supplementation of magnesium and phosphate. RESULTS: With his new dietary regimen, his mental status gradually improved, with complete resolution of his delirium by the 8th hospital day. He suffered no further episodes of confusion or disorientation. CONCLUSION: The relationship between refeeding syndrome and delirium may be of particular significance in the elderly, since malnutrition, medical hospitalization, and delirium are prevalent phenomena in this population. PMID- 18448782 TI - A patient with acute traumatic quadriplegia who requested a DNR order. PMID- 18448783 TI - Elevated clozapine serum level after treatment with amiodarone. PMID- 18448784 TI - A preliminary attempt to personalize risperidone dosing using drug-drug interactions and genetics: part I. AB - BACKGROUND: Personalized prescription is described even in lay journals, but there has been no attempt to propose personalizing dosing for any specific psychiatric drug. OBJECTIVE: Any attempt to develop personalized dosing needs to be anchored in our understanding of the pharmacological response of each drug in each person's environment, particularly drug-drug interactions (DDIs) and how genetic make-up influences drug response. METHOD: Risperidone (R) is used as an example. R's pharmacologic response is reviewed in detail by focusing on our current knowledge of its pharmacodynamic and pharmacokinetic actions. The influences of the environment and genetics on these two actions are reviewed. RESULTS: R's antipsychotic action is probably mainly explained by the blocking of dopamine receptors, particularly D(2) receptors. There are polymorphic variations of this gene (DRD(2)), but it is not clear that they have clinical relevance in predicting adverse drug reactions (ADRs) or antipsychotic response. CONCLUSION: Previous exposure to antipsychotics increases the need for higher R dosing, but the mechanism for this tolerance is not well understood. Other brain receptors, such as other dopamine, serotonin, and adrenergic receptors may explain some of these ADRs. Some polymorphic variations in these receptors have been described, but they cannot yet be used to personalize R dosing. PMID- 18448785 TI - Electroconvulsive therapy for severe major depressive disorder after orthotopic liver transplantation. PMID- 18448786 TI - Neuroleptic use in a patient with a prolonged QTc interval. PMID- 18448787 TI - Delirium with psychotic features possibly associated with mesotherapy. PMID- 18448788 TI - The 9th International Symposium on the Maillard Reaction. Preface. PMID- 18448789 TI - Receptor for advanced glycation end products: fundamental roles in the inflammatory response: winding the way to the pathogenesis of endothelial dysfunction and atherosclerosis. AB - The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the immune-inflammatory response and in atherosclerosis. Multiple studies have elucidated that ligand-RAGE interaction on cells, such as monocytes, macrophages, and endothelial cells, mediates cellular migration and upregulation of proinflammatory and prothrombotic molecules. In addition, recent studies reveal definitive rules for RAGE in effective T lymphocyte priming in vivo. RAGE ligand AGEs may be formed in diverse settings; although AGEs are especially generated in hyperglycemia, their production in settings characterized by oxidative stress and inflammation suggests that these species, in part via RAGE, may contribute to the pathogenesis of atherosclerosis. In murine models of atherosclerosis, vascular inflammation is a key factor and one which is augmented, in parallel with even further increases in RAGE ligands, in diabetic macrovessels. The findings that antagonism and genetic disruption of RAGE in atherosclerosis-susceptible mice strikingly reduces vascular inflammation and atherosclerotic lesion area and complexity link RAGE intimately to these processes and suggest that RAGE is a logical target for therapeutic intervention in aberrant inflammatory mechanisms and in atherosclerosis. PMID- 18448791 TI - Determination of N epsilon-(carboxymethyl)lysine in foods and related systems. AB - The sensitive and specific determination of advanced glycation end products (AGEs) is of considerable interest because these compounds have been associated with pro-oxidative and proinflammatory effects in vivo. AGEs form when carbonyl compounds, such as glucose and its oxidation products, glyoxal and methylglyoxal, react with the epsilon-amino group of lysine and the guanidino group of arginine to give structures including N epsilon-(carboxymethyl)lysine (CML), N epsilon (carboxyethyl)lysine, and hydroimidazolones. CML is frequently used as a marker for AGEs in general. It exists in both the free or peptide-bound forms. Analysis of CML involves its extraction from the food (including protein hydrolysis to release any peptide-bound adduct) and determination by immunochemical or instrumental means. Various factors must be considered at each step of the analysis. Extraction, hydrolysis, and sample clean-up are all less straight forward for food samples, compared to plasma and tissue. The immunochemical and instrumental methods all have their advantages and disadvantages, and no perfect method exists. Currently, different procedures are being used in different laboratories, and there is an urgent need to compare, improve, and validate methods. PMID- 18448790 TI - Central nervous system regulation of energy metabolism: ghrelin versus leptin. AB - In this brief review, we introduce some major themes in the regulation of energy, lipid, and glucose metabolism by the central nervous system (CNS). Rather than comprehensively discussing the field, we instead will discuss some of the key findings made regarding the interaction of the hormones ghrelin and leptin with the CNS. PMID- 18448792 TI - Food anoxia and the formation of either flavor or toxic compounds by amino acid degradation initiated by oxidized lipids. AB - Amino acid degradation plays an important role in the formation of both flavors and toxic compounds during food processing. These reactions are produced, to a significant extent, as a consequence of the Maillard reaction among amino acids and carbohydrates. However, recent studies have shown that lipids also take part in these reactions. This article reviews the current knowledge of the contribution of lipids to both flavor and toxic-compound formation by amino acid degradation, describing the formation of Strecker aldehydes and the conversion of amino acids into their vinylogous derivatives as a consequence of lipid-amino acid reactions. Current data suggest that amino acids can be converted into either Strecker aldehydes or vinylogous derivatives by many lipid derivatives, which exhibit diverse reactivities for both reactions. Reaction conditions, including the presence of oxygen, also play a major role in the Strecker aldehyde/vinylogous derivative ratio obtained. Nevertheless, the high number of lipid derivatives involved, the different alternative pathways, and the existence of both positive and negative synergisms between lipids and carbohydrates make it hard to predict the effect of reaction conditions in the Strecker aldehyde/vinylogous derivative ratio obtained in complex food systems. PMID- 18448793 TI - Post-schiff base chemistry of the Maillard reaction: mechanism of imine isomerization. AB - Schiff bases play a critical role, not only in initiating the Maillard reaction, but also in its propagation. Little attention has been paid so far to the ability of these imines to undergo isomerization and thus contribute to the diversity of Maillard reaction products. In this study, imine isomerization through 5 oxazolidinone formation was explored in a phenylalanine/glyceraldehyde model system, and spectroscopic evidence was provided for its formation by taking advantage of the strong carbonyl absorption band centered at 1784 cm(-1). The importance of 5-oxazolidinone formation lies in its ability to decarboxylate to azomethine ylide and subsequently form two isomeric imines, each capable of producing distinct Maillard products. Evidence for the formation of such ylides was also provided through their ability to undergo 1,3-dipolar cycloaddition with dipolarophiles. PMID- 18448794 TI - Receptor for advanced glycation end product expression in experimental diabetic retinopathy. AB - The advanced glycation end product (AGE)-receptor for AGE (RAGE) pathway is involved in the pathogenesis of diabetic microvascular damage. The special distribution of RAGE and its engagement has an impact on the development of diabetic retinopathy. In the present study, we used immunofluorescence and confocal laser microscopy to study RAGE expression with special emphasis on Muller glia in Sprague Dawley rats. RAGE expression was low in nondiabetic retinae and was found in ganglion cells and Muller cell end feet. In diabetic retinae, upregulated RAGE was predominantly expressed in retinal glia. Since Muller cells are important in the regulation of important features of early retinal vascular damage, such as vascular permeability, homeostasis, and response to stress, RAGE appears to be a central modulator in diabetic retinopathy. PMID- 18448795 TI - Advanced glycation end product homeostasis: exogenous oxidants and innate defenses. AB - Increased oxidative stress (OS) underlies many chronic diseases prevalent in aging. Data in humans confirm the hypothesis that advanced glycation end products (AGEs) and other oxidants derived from the diet may be major contributors to increased OS in normal adults as well as those with diabetes mellitus or kidney failure. Mice fed a diet with a lowered (approximately 50%) content of AGEs or a typical calorie-restricted (CR) diet, accumulated a smaller amount of AGEs, maintained normal levels of AGE receptor-1 (AGER1), and did not have increased oxidant stress or cardiac or kidney fibrosis with aging. However, the findings in mice fed a CR diet with an increased content of AGEs resembled those in mice fed a nonrestricted diet that had the usual higher content of AGEs. Thus, there was an inverse correlation between the dietary AGE content, the AGER1 to receptor for AGE (RAGE) ratio, OS, organ damage, and life span. In both humans and mice, there was an inverse correlation between the AGER1 to RAGE ratio and the levels of OS. PMID- 18448796 TI - Advanced glycation as a basis for understanding retinal aging and noninvasive risk prediction. AB - The retina is exquisitely sensitive to age-related processes, and, in many cases, these can precipitate progressive and profound loss of vision. Many asymptomatic abnormalities that accrue in the outer retina as we get older can serve as a sinister preamble to age-related macular degeneration (AMD). This condition remains the leading cause of irreversible blindness in industrialized countries, but its precise pathogenesis has yet to be completely elucidated. Over recent years, increasing evidence has suggested that the accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs in the outer retina could play a significant role in the initiation and progression of AMD. The current review outlines this evidence and indicates how products of Maillard chemistry could be used as robust markers for outer retinal aging and susceptibility to AMD. The utility of Raman spectroscopy to measure AGE adducts in human tissues is presented. The methodology reinforces the association between AGE formation and retinal aging and provides exciting possibilities for assessing these pathogenic agents in the living eye and, perhaps, for providing a valuable index for AMD susceptibility. PMID- 18448797 TI - Methylglyoxal: its presence in beverages and potential scavengers. AB - Nonenzymic glycation, also known as the Maillard reaction, is a complex series of reactions between reducing sugars and amino compounds. Previous studies have demonstrated that reactive dicarbonyl compounds (e.g., methylglyoxal [MG] and glyoxal [GO]), formed as intermediate products of the Maillard reaction, irreversibly and progressively modify proteins over time and yield advanced glycation end products (AGEs), which are thought to contribute to the development of diabetes mellitus and its complications. Several studies have shown that higher levels of MG are present in diabetic patients' plasma than in healthy people's plasma. Thus, decreasing the levels of MG and GO will be an effective approach to reduce the formation of AGEs and the development of diabetic complications. Here, we briefly describe our effort in searching for non- or less toxic trapping agents of reactive dicarbonyl species from dietary sources. In addition, we have discovered that commercial beverages contain extremely high levels of MG. The potential hazardous effects of dietary MG on humans remain to be explored. PMID- 18448798 TI - The RAGE pathway: activation and perpetuation in the pathogenesis of diabetic neuropathy. AB - The molecular mechanisms underlying loss of pain perception in diabetic neuropathy are poorly understood. Experimental diabetic neuropathy models recently provided evidence that engagement of the receptor for advanced glycation end products (RAGE) and RAGE-dependent sustained activation of the proinflammatory transcription factor nuclear factor kappa B might significantly contribute to reduced nociception. Most importantly, diabetes-induced loss of pain perception is largely prevented in RAGE-deficient mice compared to RAGE bearing wild-type mice. Identifying RAGE-dependent inflammation as one pathomechanism underlying neuronal dysfunction might provide the basis for new therapeutic approaches. PMID- 18448799 TI - The role of the amadori product in the complications of diabetes. AB - Strong evidence has emerged in recent years in support of an association between advanced glycation and the complications of diabetes, whereby both glycoxidation products and oxoaldehydes have been implicated. In contrast, except for the fact that skin collagen-linked fructosamine (Amadori product) is a strong predictor of the risk of progression of microvascular disease in humans, Amadori products have not been associated with complications in most animal experiments. Below we develop the hypothesis that glucose-derived advanced glycation end products (AGEs), such as glucosepane, may inflict sustained damage to the extracellular matrix in diabetes and contribute to tissue stiffening and accelerated sclerosis in arteries, kidneys, and other organs as supported by immunochemical studies using a glucosepane antibody. We also hypothesize that many more structures derived from Amadori products with nucleophiles, such as primary amines and thiols, are expected. The selective prevention of Amadori-derived AGEs using deglycating enzymes would be desirable. However, x-ray diffraction studies of Amadoriase I crystals show that the active site of the enzyme is deeply embedded, explaining why this approach is unlikely to succeed in vivo. Preliminary experiments with nucleophiles show that aminoguanidine and other compounds block glucosepane in vitro. PMID- 18448800 TI - Mitigation strategies to reduce acrylamide formation in fried potato products. AB - Potato products contain high amounts of acrylamide, which sometimes exceeds the concentration of 1 mg/L. However, many strategies for acrylamide reduction in potato products are possible. In this work, the different approaches for reducing acrylamide formation have been reviewed, keeping in mind that in the application of strategies for acrylamide formation, the main criteria to be maintained are the overall organoleptic and nutritional qualities of the final product. PMID- 18448801 TI - Therapeutic interruption of advanced glycation in diabetic nephropathy: do all roads lead to Rome? AB - A major common feature of the chemically disparate compounds that inhibit advanced glycation end product (AGE) accumulation or signaling is their ability to show end-organ protection in experimental models of diabetes complications. The mechanisms by which these AGE- lowering therapies confer their benefits remain unsolved. Is it the reduction in tissue AGE levels per se or the inhibition of downstream signal transduction (as has been described with the soluble receptor for AGE)? Possible modes of action that need to be investigated include the ability of some of these agents to stimulate antioxidant defenses, to lower cholesterol and other lipid levels, and to inhibit low-grade inflammation. To understand these novel mechanisms, further examination of the advanced glycation pathway and, in particular, the diverse action of these agents in ameliorating the development of diabetic complications is needed. PMID- 18448802 TI - The other side of the Maillard reaction. AB - The Maillard reaction plays an important role in eye lens aging and cataract formation. Methylglyoxal (MGO) is a metabolic dicarbonyl compound present in the lens. It reacts with arginine residues in lens proteins to form advanced glycation end products (AGEs), such as hydroimidazolones and argpyrimidine. alpha Crystallin, comprising alphaA- and alphaB-crystallin, is a major protein of the lens and it functions as a chaperone protein. We have found that upon reaction with MGO, human alphaA-crystallin becomes a more effective chaperone. Modification of specific arginine residues to AGEs appears to be the reason. Mutation of these arginine residues to alanine mirrors the effect of MGO, suggesting neutralization of the positive charge on arginine residues as a cause for improved chaperone function. Reaction with MGO also blocks the loss of the chaperone function of alphaA-crystallin caused by nonenzymatic glycation by ascorbate and ribose. These findings suggest that low levels of MGO might help the lens remain transparent during aging. PMID- 18448803 TI - Dicarbonyls stimulate cellular protection systems in primary rat hepatocytes and show anti-inflammatory properties. AB - Advanced glycation endproducts (AGEs) and their precursor dicarbonyls are generally perceived as having adverse health effects. They are also considered to be initiators and promoters of disease and aging. However, proof for a causal relationship is lacking. On the other hand, it is known that AGEs and melanoidins possess beneficial properties, such as antioxidant and metal-chelating activities. Furthermore, some AGEs may stimulate the cellular detoxification system, generally known as the phase II drug metabolizing system. We show here that several reactive dicarbonyl intermediates have the capability to stimulate the cellular phase II detoxification systems in both a reporter cell line and primary rat hepatocytes. In addition, we demonstrate that dicarbonyls can attenuate the inflammatory signaling induced by tumor necrosis factor-alpha in a reporter cell system. PMID- 18448804 TI - N-terminal glycation of proteins and peptides in foods and in vivo: evaluation of N-(2-furoylmethyl)valine in acid hydrolyzates of human hemoglobin. AB - Specific determination of N-(2-furoylmethyl)valine (FM-Val) together with furosine in acid hydrolyzates of human hemoglobin of healthy volunteers (n = 6) and diabetic patients (n = 14) by means of reversed-phase HPLC with electrospray ionization-time-of-flight mass spectroscopy is reported. Whereas FM-Val is formed during acid hydrolysis of the N-terminal hemoglobin adduct N-fructosylvaline, furosine results from acid degradation of lysine residues glycated at the epsilon amino group. Quantification was based on the use of synthesized isotopomers, namely N-[2-(13C6)furoylmethyl]valine and N-epsilon-[2-(13C6)furoylmethyl]lysine, thus enabling interference-free detection and calibration. Taking the conversion factors into account, the amount of N-terminally bound N-fructosylvaline in human hemoglobin was between 518 and 774 pmol/mg protein for healthy volunteers and between 586 and 1426 pmol/mg protein for diabetic patients. Derivatization at the side chain of peptide-bound lysine residues to N-epsilon-fructosyllysine was from 1156 to 1753 pmol/mg protein for healthy controls and from 1191 to 2409 pmol/mg protein for diabetics. For these patients, the amount of N-fructosylvaline showed good correlation with the values for HbA(1c). The significantly higher relative extent of glycation at the N terminus compared to side-chain glycation points to a specific and intraindividual capacity for enzymatic deglycation in human erythrocytes, which can be assessed using the proposed method. PMID- 18448805 TI - The dicarbonyl proteome: proteins susceptible to dicarbonyl glycation at functional sites in health, aging, and disease. AB - Reactive, physiological, dicarbonyl, glycating agents, glyoxal and methylglyoxal, are arginine-directed glycating agents forming mainly hydroimidazolone residues. Arginine residues have high-frequency occurrence in sites of protein-protein, enzyme substrate and protein-nucleotide binding sites. There is emerging evidence that functionally important arginine residues in proteins are often activated toward dicarbonyl glycation--leading to functional impairment. When uncontrolled, this is associated with aging, degenerative diseases, and metabolic disorders where dicarbonyl glycation may be viewed as damage to the proteome. The glyoxalase system, particularly glyoxalase 1, is the vanguard against dicarbonyl glycation in physiological systems. Functional regulation of glyoxalase 1 suggests a role for dicarbonyl glycation in cell signaling. Although extents of modification are usually low, the dicarbonyl proteome is a critical feature of the impact of glycation on physiological function--particularly in mitochondrial dysfunction, vascular disease, and potentially in disorders of lipoprotein metabolism. PMID- 18448806 TI - Peroxyl radicals are essential reagents in the oxidation steps of the Maillard reaction leading to generation of advanced glycation end products. AB - Polyunsaturated fatty acids (PUFAs) are incorporated in all membranes of mammalian and plant cells and are extremely sensitive to oxygen. This property is used in nature to respond to any changes in cell membrane structure. In the first step of a response, lipid hydroperoxide molecules are generated. An increasing impact switches the enzymatic reaction to a nonenzymatic one by generation of lipid peroxyl radicals, which attack sugars by oxidation. In the course of these reactions, hydrogen peroxyl radicals are generated, resembling lipid peroxyl radicals in their reactivity. The reactions induced by these radicals are not under genetic control, they attack nearly all types of biological molecules (such as proteins, lipids, and sugars), and are responsible for the deleterious cell alterations in aging and age-related diseases (such as diabetes, Alzheimer's disease, or atherosclerosis) and probably also in autoimmune diseases, which involve sugars at the cell membranes. Lipid peroxidation processes are induced by heating fats, meat, and other nutritional products. The oxidation products generated by consumption of heated food cause damage of mammalian cells. The deleterious reactions can be partly reduced by consumption of plants and/or algae. These contain, among other well-known antioxidants, furan fatty acids, which are important scavengers of peroxyl radicals. PMID- 18448807 TI - Application of mass spectrometry for the detection of glycation and oxidation products in milk proteins. AB - Protein mass spectometry techniques, such as electrospray ionization mass spectrometry or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), are effective methods to screen for protein modifications derived from the Maillard reaction. The analysis of the intact proteins reveals the major modification, most commonly the Amadori product, whereas partial enzymatic hydrolysis prior to mass spectrometry additionally allows the detection of minor adducts. Therefore, a mass spectrometric method was developed for the analysis of whey protein modifications occurring during heat treatment. The two main whey proteins, alpha-lactalbumin and beta-lactoglobulin, were incubated with lactose in a milk model and modifications were recorded using MALDI-TOF-MS. The analysis of the intact proteins revealed protein species with 0 4 lactulosyl residues. Partial enzymatic hydrolysis with endoproteinase AspN prior to mass spectrometric analysis enabled the detection of further modifications and their localization in the amino acid sequence. Detected modifications were lactulosyllysine, N epsilon-(carboxymethyl)lysine, lysine aldehyde, methionine sulfoxide, cyclization of N-terminal glutamic acid to a pyrrolidone, and oxidation of cysteine or tryptophan. Protein modifications in heated milk and commercially available dairy products can be analyzed after the separation of the milk proteins using one-dimensional SDS-PAGE. PMID- 18448808 TI - Inhibition of advanced glycation end products: an implicit goal in clinical medicine for the treatment of diabetic nephropathy? AB - Several factors have been incriminated in the genesis of diabetic nephropathy. To elucidate their interplay, we have used a hypertensive, obese, diabetic rat model with nephropathy (SHR/NDmcr-cp) that mimics human type 2 diabetes. This model is characterized by hypertension, obesity with the metabolic syndrome, diabetes with insulin resistance, and intrarenal advanced glycation end product (AGE) accumulation. In order to achieve renoprotection, which was evaluated by histology and albuminuria, various therapeutic approaches were used: caloric restriction, antihypertensive agents (angiotensin II receptor blocker [ARB] and calcium channel blocker), lipid- (bezafibrate) or glucose-lowering (insulin and pioglitazone) agents, and cobalt chloride (a hypoxia-inducible factor activator). Altogether, renoprotection is not necessarily associated with blood pressure or glycemic control. By contrast, it is almost always associated with decreased AGE formation, with the exception of insulin, which induces hyperinsulinemia, eventually leading to an overproduction of transforming growth factor-beta. AGE formation is reduced directly by in vitro active compounds (e.g., ARBs) or indirectly by in vitro inactive compounds (e.g., pioglitazone and cobalt). In the latter cases, AGE reduction may reflect a decreased oxidative stress as it is concomitant with a marked reduction of oxidative stress markers. It remains to be seen whether the renoprotection offered by these various approaches may be additive. PMID- 18448809 TI - Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia. Neuritic amyloid plaques and concomitant chronic inflammation are prominent pathological features of AD. beta-amyloid peptide (Abeta), the major component of plaques, and advanced glycation end products (AGEs), post-translational protein modifications, are key activators of plaque-associated inflammation. Abeta, AGEs, S100b, and amphoterin bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-kappaB)-regulated cytokines. RAGE-mediated inflammation caused by glial cells and subsequent changes in neuronal glucose metabolism are likely to be important contributors to neurodegeneration in AD. As long as the neuronal damage is reversible, drugs interfering with the Abeta and AGE-RAGE pathways might be interesting novel therapeutics for the treatment of AD. PMID- 18448810 TI - Isolation and partial characterization of four fluorophores formed by nonenzymatic browning of methylglyoxal and glutamine-derived ammonia. AB - An aqueous solution of L-glutamine (50 mmol/L) and methylglyoxal (100 mmol/L) was incubated at 120 degrees C for 3 h in a 200 mmol/L phosphate buffer (pH 7.4). Four major fluorophores were revealed on the HPLC chromatogram. The same four fluorophores were obtained from the heating of a mixture of ammonia and methylglyoxal. After purification and concentration, they were structurally characterized by electrospray ionization mass spectrometry (ESI-MS) using the high resolution and tandem mass spectrometry capabilities of a quadrupole time-of flight MS. The accurate mass measurement of their [M+H]+ ions, the MS fragment patterns, and the presence of one to two nitrogen indicate the formation of fluorophores with molecular formulas of C7H7NO3, C8H9NO3, C12H14N2O4, and C12H14N2O5. These results show that, in an aqueous solution, free glutamine undergoes a rapid degradation, leading to the formation of ammonia which reacts with methylglyoxal to form fluorescent heterocyclic Maillard products. PMID- 18448811 TI - Pentosidine effects on human osteoblasts in vitro. AB - Osteoporosis, a multifactorial and progressive skeletal metabolic disease, is characterized by low-mass density and structural deterioration of bone micro architecture that leads to enhanced bone fragility and increased susceptibility to fractures. Recently, it has been proposed that age-related bone loss could be correlated with the glycoxidative process. The aim of the present study was to investigate the in vitro effects of pentosidine, a glycoxidative end product, on human osteoblasts (HOb). The mineralization rate, the specific bone markers (alkaline phosphatase [ALP], collagen Ialpha1 [COL Ialpha1], osteocalcin [BGP]), and the human receptor for advanced glycation end products (RAGE) gene expression have been evaluated. Pentosidine incubation of HOb caused a significant decrease in ALP, Col Ialpha1, and RAGE mRNA levels, but only the RAGE gene expression decreased with no dose dependency. Moreover, pentosidine incubation of osteoblasts hampered the formation of bone nodules. No effect was observed on BGP gene expression under all experimental conditions. Our data gives further support to a detrimental effect of AGEs on bone that leads to functional alterations of osteoblasts. This study addresses a crucial role of protein glycoxidation in the bone mineralization process. AGEs formation and accumulation in bone may be one of the first pathogenetic steps of bone remodeling in aging and in age-related diseases, leading to enhanced bone mass loss. PMID- 18448812 TI - Strategy for the study of the health impact of dietary Maillard products in clinical studies: the example of the ICARE clinical study on healthy adults. AB - The study of the health impact of dietary Maillard products (MPs) in realistic clinical studies requires the design of nutritionally equivalent diets with high and low levels of MPs. This difficult challenge may be achieved by setting the high-MP diet at the regular daily level, where the common use of grilling, frying, and roasting processes allows significant amounts of carboxymethyllysine, hydroxymethylfurfural and acrylamide to be formed. In such conditions, we show that major lipid degradation does not occur, nor does degradation of vitamin E or thiamine. Based on this finding, the low-MP diet; must be constructed accordingly, by replacing all high-temperature techniques with steam cooking or the absence of cooking. The cooking fat must be replaced with similar raw fat as seasoning in the low-MP diet, the high caloric density resulting from water loss in the high-MP diet must be compensated by higher food quantities offered in the low-MP diet, and the vitamin loss in fruit and vegetables resulting from high temperatures in the high-MP diet can be circumvented by increasing the corresponding portion size. In the ICARE study, equilibrated diets were proposed, fulfilling all nutritional needs, but with a 3- to 45-fold difference in MP concentrations. Individual quantification of nutritional and MP intakes will ensure the nutritional equivalence of the two diets and allow for quantification of the specific impact of ingested MPs. PMID- 18448813 TI - Plasma concentration and urinary excretion of N epsilon-(carboxymethyl)lysine in breast milk- and formula-fed infants. AB - Industrial processing of infant formulas (IFs) induces the formation of Maillard products, namely N epsilon-(carboxymethyl)lysine (CML). CML content is expected to be several times higher in IFs than in fresh human breast milk. To elucidate whether CML is absorbed from IFs into the bloodstream, CML concentration in the plasma and urine were analyzed in 6-month-old infants (34 breast fed and 25 fed exclusively with IFs) and in 56 samples of human breast milk and 16 commercial IFs. We found that IFs contain higher amounts of CML compared to mother's milk (median: 70-fold; range: 28- to 389-fold), and CML content was higher in hydrolyzed IFs than in nonhydrolyzed IFs (P < 0.03). Plasma CML levels were 46% higher (P < 0.01) and urinary excretion of CML was 60-fold higher (P < 0.001) in the formula-fed infants than in the breast-fed group. Infants fed with hydrolyzed IFs displayed significantly higher plasma CML levels than those on nonhydrolyzed formulations. We conclude that CML from IFs is absorbed into the circulatory system and is rapidly excreted in the urine. PMID- 18448814 TI - Acrolein induces inflammatory response underlying endothelial dysfunction: a risk factor for atherosclerosis. AB - Endothelial dysfunction by proinflammatory stimuli represents an important link between risk factors and the pathologic mechanisms underlying atherosclerosis. Thus, control of the inflammatory status of endothelial cells is crucial to limiting the disease. Tobacco smoking induces inflammatory reactions and promotes atherosclerosis; however, the mechanism that links cigarette smoking to an increased incidence of atherosclerosis is poorly understood. Our study demonstrates that acrolein, a known toxin in tobacco smoke, elevates oxidative stress via inactivation of thioredoxin reductase and stimulates expression of cyclooxygenase-2 through activation of the protein kinase C, p38 mitogen activated protein kinase, and cAMP response element-binding protein pathway in endothelial cells. Our finding suggests that acrolein may play a role in the progression of atherosclerosis. PMID- 18448815 TI - Oxidative stress and advanced glycation in diabetic nephropathy. AB - Nephropathy remains a significant cause of morbidity and mortality in the diabetic population and is the leading cause of end-stage renal failure in the Western World. As a result of the diabetic milieu, increased generation of reactive oxygen species (ROS) is thought to play a key role in the progression of diabetic nephropathy. Recent experimental studies have suggested that the receptor for advanced glycation end products (RAGE), which is central to the advanced glycation pathway, may mediate renal structural and functional damage via oxidative stress. This review focuses on how RAGE and subsequent ROS generation play a deleterious role in the diabetic kidney, promoting cross-talk among signaling pathways, ultimately leading to renal dysfunction. PMID- 18448816 TI - Vitamin C-mediated Maillard reaction in the lens probed in a transgenic-mouse model. AB - Aging human lens crystallins are progressively modified by yellow glycation, oxidation, and cross-linked carbonyl compounds that have deleterious properties on protein structure and stability. In order to test the hypothesis that some of these compounds originate from oxidized vitamin C, we have overexpressed the human vitamin C transporter 2 (hSCVT2) in the mouse lens. We find that levels of ascorbic and dehydroascorbic acid are highly elevated compared to the wild type and that the lenses have accumulated yellow color and advanced Maillard reaction products identical with those of the human lens. Treatment of the mice with nucleophilic inhibitors can slow down the process, opening new avenues for the pharmacological prevention of senile cataractogenesis. PMID- 18448817 TI - Aging, diabetes, and renal failure catalyze the oxidation of lysyl residues to 2 aminoadipic acid in human skin collagen: evidence for metal-catalyzed oxidation mediated by alpha-dicarbonyls. AB - The epsilon-amino group of lysyl residues oxidatively deaminates in the presence of alpha-dicarbonyl sugars and redox-active metals forming alpha-aminoadipic acid delta-semialdehyde (allysine; Suyama's hypothesis), which can further oxidize into 2-aminoadipic acid. Here we show that 2-aminoadipic acid is significantly (P < 0.05) correlated with 6-hydroxynorleucine, carboxyethyllysine (CEL), and carboxymethyllysine (CML) in human skin collagen. Since CEL and CML can originate from carbohydrate and lipid by oxidative decomposition and alpha-dicarbonyl formation, these results provide support for Suyama's hypothesis. Allysine, in turn, is readily converted by oxidation into 2-aminoadipic acid, which accumulates to high levels in skin (i.e., > 2 nmol/mg collagen). PMID- 18448818 TI - alpha-Dicarbonyl compounds--key intermediates for the formation of carbohydrate based melanoidins. AB - The Maillard reaction of carbohydrates and amino acids is the chemical basis for flavor and color formation in many processed foods. Dicarbonyl compounds, such as 1-, 3-deoxyosones and 1,4-dideoxyosones, as well as short-chain dicarbonyls, such as methylgyoxal or glyoxal, are key compounds of the Maillard browning reaction. The alpha-dicarbonyls are also starting materials for polymerization reactions which lead to formation of carbohydrate-based melanoidins. With regard to the dicarbonyl compound, different possible chemical structures of melanoidins will be discussed. The analysis by size-exclusion chromatography revealed that those colored compounds differ in their molecular size and are directly associated with reactions having specific alpha-dicarbonyl compounds. PMID- 18448819 TI - Approaches to wine aroma: C1 transfer during the reaction between diacetyl and cysteine. AB - The model reaction of cysteine and diacetyl under winemaking conditions resulted in the identification of over 40 products. Of these, 12 were also identified in wine samples. Several products of the model system contained unexpected structures that do not fit the four-carbon skeletal pattern of diacetyl. Possible synthetic routes to one of these products, trimethylpyrazine, are presented. PMID- 18448820 TI - Antioxidant activity and chemical properties of crude and fractionated Maillard reaction products derived from four sugar-amino acid Maillard reaction model systems. AB - Antioxidant activity of Maillard reaction products (MRPs) derived from four sugar amino acid Maillard reaction model systems (glucose [Glc] or ribose [Rib] reacted with glycine [Gly] and L-lysine [Lys]) were examined in terms of chemical properties and molecular weight fractionation of reaction products. Rib-amino acid model systems produced MRPs with higher antioxidant activity than Glc-amino acid model MRPs (P < 0.05, Rib-Lys > Rib-Gly > Glc-Lys > Glc-Gly). In the same sugar or same amino acid model systems, antioxidant activity of MRPs was negatively related to the final pH, fluorescent intensity, and the content of dicarbonyl compounds. Antioxidant activity positively related to the production of late-stage browning MRPs. Fraction I from the Glc-Lys model system separated by gel filtration chromatography had the highest oxygen radical absorbance capacity (ORAC) value (1736 micromol Trolox/g MRP). Fraction IV from the Rib-Lys model system had a higher ORAC value compared to Fraction III. This result indicated that high molecular weight MRPs do not necessarily have higher antioxidant activity compared to low molecular weight MRPs. PMID- 18448821 TI - Advanced glycation endproducts in chronic heart failure. AB - Advanced glycation endproducts (AGEs) have been proposed as factors involved in the development and progression of chronic heart failure (CHF). Cross-linking by AGEs results in vascular and myocardial stiffening, which are hallmarks in the pathogenesis of CHF. Additionally, stimulation of receptors by AGEs may affect endothelial function and myocardial calcium uptake and may perpetuate coronary sclerosis in CHF. CHF is common in conditions with AGE accumulation, such as diabetes and renal failure. This review describes in detail the interrelation of plasma AGEs, renal function, and the severity and prognosis in clinical CHF patients with mild to moderate loss of renal function. This association is compared with the relation between tissue AGE accumulation (marked by skin autofluorescence) and diastolic dysfunction in renal failure. The evidence reviewed here provides support for the assumed role of AGEs in determining the severity and prognosis of CHF, but also highlights the differences in this relation between plasma and tissue AGEs and between patients with and without advanced renal failure. Ongoing clinical intervention trials to reduce AGE accumulation in patients with CHF may elucidate the causal role of AGEs in the development and course of CHF. PMID- 18448822 TI - Origin and yields of acetic acid in pentose-based Maillard reaction systems. AB - The formation of acetic acid from pentoses was studied in aqueous buffered systems (90-120 degrees C, pH 6.0-8.0) containing equimolar concentrations of 13C labeled xylose and glycine. Acetic acid was quantified by gas chromatography-mass spectroscopy using an isotope dilution assay. Acetic acid was mainly formed from the C-1/C-2 carbon atoms of xylose (77-87%), while small amounts were also formed from the C-4/C-5 atoms of the pentose sugar (9-15%). Temperature and pH had only a small effect on the relative contribution of the sugar carbon atoms to acetic acid. These results support beta-dicarbonyl cleavage of 1-deoxypento-2,4-diulose as a major pathway leading to acetic acid in pentose-based Maillard reaction systems under food processing conditions. Acetic acid was confirmed as a major degradation product of pentoses at the early stage of the Maillard reaction, yielding 16 mol% and 28 mol% at pH 6.0 and pH 8.0, respectively. PMID- 18448823 TI - The peptide-catalyzed Maillard reaction: characterization of 13C reductones. AB - The reaction pathways of amino acids and reducing sugars are now fully understood. The focus in the last few years, however, has turned to the reaction of peptides and proteins with reducing sugars. We have investigated the reaction of gamma-aminobutanoic acid, the heptapeptide Nalpha-Acetyl-Lys-Lys-beta-Ala-Lys beta-Ala-Lys-Gly, and the model protein beta-casein in Maillard reactions with 1 13C arabinose. Characterization of 13C-labeled acetic acid and norfuraneol by gas chromatography-mass spectrometry and nuclear magnetic resonance revealed new formation pathways. The results demonstrate significant differences in the labeling pattern of the products depending on the amine used, indicating different formation pathways of acetic acid and norfuraneol. PMID- 18448824 TI - Model studies on protein glycation: influence of cysteine on the reactivity of arginine and lysine residues toward glyoxal. AB - Mixtures of N alpha-hippurylarginin, N alpha-hippuryllysine, and glyoxal were incubated in the absence and presence of N alpha-acetylcysteine in order to assess the individual reactivity of these nucleophilic amino acid residues. The incubations were performed under atmospheric and high hydrostatic pressure (400 MPa), and, at the same time, beta-casein was reacted with glyoxal. The results showed that arginine is the main partner for glyoxal in the absence of cysteine, whereas a lysine derivatization was not apparent. In the presence of cysteine, however, arginine was almost completely protected from the reaction, whereas a noticeable formation of lysine derivatives, mainly carboxymethyllysine, was observed. Based on these findings, a reaction mechanism is proposed to explain the influence of cysteine on the reaction. PMID- 18448825 TI - Analysis of amadori peptides enriched by boronic acid affinity chromatography. AB - Glycation of peptides and proteins by D-glucose is a universal, nonenzymatic reaction with important implications for the pathogenesis and diagnosis of many diseases, including diabetes mellitus. Whereas some modification sites have been identified in serum albumin and hemoglobin, a general approach to map glycation sites for nonabundant proteins present in complex mixtures, such as serum, is still missing. Here, we describe a universal enrichment procedure for glycated peptides using boronic acid affinity chromatography in the first dimension followed by reversed-phase chromatography, coupled either online to electrospray ionization mass spectrometry (ESI-MS) or offline to matrix-assisted laser desorption/ionization (MALDI) MS. This two-dimensional approach was optimized for high recoveries and low cross reactivities. For bovine serum albumin, a total of 31 Amadori peptides were identified in a tryptic digest corresponding to 26 different glycation sites. PMID- 18448826 TI - Induction of heat shock proteins and the proteasome system by casein-N epsilon (carboxymethyl)lysine and N epsilon-(carboxymethyl)lysine in Caco-2 cells. AB - Repeated mild heat shock treatment has been shown to have anti-aging effects on cellular mechanisms in vitro. Among these, the age-associated accumulation of advanced glycation end products (AGEs), such as N(epsilon)-(carboxymethyl)lysine (CML), has been demonstrated to be effectively prevented in glyoxal-exposed human skin fibroblasts following mild heat shock treatment. The biochemical mechanism responsible for this inhibition is not yet known. However, the involvement of heat shock proteins (HSPs) and the misfolded proteins degrading the ubiquitin proteasome system have been hypothesized. As AGE-modified proteins are likely to be conformationally modified, we investigated whether treatment of human intestinal cells with casein-linked CML or nonprotein-linked CML affects the expression of HSPs and the ubiquitin-proteasome system by using matrix-assisted laser desorption/ionization-time-of-flight tandem mass spectroscopy (after protein separation by two-dimensional gel electrophoresis) and by Western blotting. Compared to nontreated control cells, expression of HSP90, HSP60, HSP70 chaperones, and the proteasome S26 ATPase subunit 2 were significantly upregulated in casein-CML and in CML-treated cells. Exposure of Caco-2 cells to beta-amyloid, a nonglycation product, revealed similar results. In conclusion, the results indicate that CML and casein-linked CML activate the expression of HSPs as well as the proteasome system, which are involved in the degradation of misfolded and possibly glycated proteins. Whether this mechanism is based on binding to cell surface receptors, such as the receptor for AGE, has to be clarified in future studies. PMID- 18448827 TI - Reversal of hyperglycemia-induced angiogenesis deficit of human endothelial cells by overexpression of glyoxalase 1 in vitro. AB - Dicarbonyl glycation of RGD and GFOGER sites in type IV collagen has been associated with decreased angiogenesis. In this study, we investigated whether overexpression of glyoxalase 1 to decrease dicarbonyl glycation would prevent the angiogenesis deficit induced by hyperglycemia in vitro. Transfection of human microvascular endothelial cells resulted in a four-fold increase in glyoxalase 1 activity compared with controls. Incubation of human microvascular endothelial cells in model hyperglycemia produced a 32% decrease in formation of tube structures that was prevented by glyoxalase 1 overexpression. We conclude that increased protection against dicarbonyl glycation of endothelial cell protein protects hyperglycemia-induced angiogenesis deficit. PMID- 18448828 TI - Pathophysiological role of the glyoxalase system in renal hypoxic injury. AB - Methylglyoxal (MG), a reactive dicarbonyl compound mainly produced by metabolic pathways, such as glycolysis, binds to proteins or nucleic acids and forms advanced glycation end products. MG is efficiently metabolized by the glyoxalase system where MG is converted by glyoxalase I (GLO I) to S-D-lactoylglutathione. Although the glyoxalase system has been shown to play a pathological role in various diseases, including diabetic complications, its detailed pathophysiological function remains to be elucidated. We are interested in renal hypoxic diseases, but very little information is available regarding the association between the glyoxalase system and renal hypoxic diseases. Therefore, we investigated the biological role of GLO I in renal hypoxic diseases by using the rat ischemia/reperfusion (I/R) injury model. I/R induced the reduction of renal GLO I activity associated with morphological changes and renal dysfunction. Interestingly, the rats that overexpress human GLO I (GLO I Tg rats) showed amelioration of these manifestations in renal I/R (e.g., improvement of the tubulointerstitial injury and renal function). Accumulation of renal MG adducts, carboxyethyllysine, induced by I/R also decreased in GLO I Tg rats compared to wild-type rats. These results demonstrate that GLO I has renoprotective effects in I/R injury via reduction of protein modification by MG. PMID- 18448829 TI - Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde 3-phosphate dehydrogenase in diabetes. AB - S-(2-succinyl)cysteine (2SC) is a chemical modification of proteins formed by a Michael addition reaction between the Krebs cycle intermediate, fumarate, and thiol groups in protein--a process known as succination of protein. Succination causes irreversible inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in vitro. GAPDH was immunoprecipitated from muscle of diabetic rats, then analyzed by ultra-performance liquid chromatography-electrospray ionization-mass spectroscopy. Succination of GAPDH was increased in muscle of diabetic rats, and the extent of succination correlated strongly with the decrease in specific activity of the enzyme. We propose that 2SC is a biomarker of mitochondrial and oxidative stress in diabetes and that succination of GAPDH and other thiol proteins may provide the chemical link between glucotoxicity and the pathogenesis of diabetic complications. PMID- 18448830 TI - Dietary advanced glycation endproducts and oxidative stress: in vivo effects on endothelial function and adipokines. AB - Advanced glycation endproducts (AGEs) and oxidative stress (OS) contribute to the development and progression of diabetic complications. We have reported that dietary AGEs and OS induce acute endothelial dysfunction in vivo, but little is known about their effects on adipokines. Twenty inpatients with type 2 diabetes mellitus (mean age: 55.9; range: 32-71 years), received a standard diabetes diet for 6 days. On days 4 and 6, the acute effects of a high-AGE (HAGE) or a low-AGE (LAGE) meal (15.100 vs. 2.750 kU AGE) were studied in a randomized, cross-over, investigator-blinded design. Measurements were performed after an overnight fast, at baseline (B) and at 2, 4, and 6 h after the HAGE or LAGE meals. Both meals had the same ingredients and differed only by the cooking method. Two h following HAGE, a significant decrease from baseline occurred in adiponectin (-10%*double dagger vs. +0%) and leptin (-22%*double dagger vs. -13%*), and a significant increase occurred in vascular cell adhesion molecule 1 (+19%*double dagger vs. 5%) and thiobarbituric acid reactive substances (+23%*double dagger vs. +6%). These changes did not occur, or occurred to a lesser extent, following LAGE. At 4 h following HAGE, an increase in methylglyoxal (+20%double dagger vs. -5%) and E selectin (+54%*double dagger vs. -3%) occurred. Urinary AGEs increased only after HAGE (+51%*double dagger vs. -2%; values presented as HAGE vs. LAGE; *P < 0.05 vs. baseline, double daggerP < 0.05 vs. LAGE). The postprandial excursions in glucose, insulin, and triglycerides were similar between both meals. A meal rich in AGEs induces acute endothelial and adipocyte dysfunction. These effects were prevented by changing the cooking method. PMID- 18448831 TI - Preparation of nucleotide advanced glycation endproducts--imidazopurinone adducts formed by glycation of deoxyguanosine with glyoxal and methylglyoxal. AB - An analytical procedure was developed for nucleotide advanced glycation endproducts formed by the reaction of glyoxal and methylglyoxal with deoxyguanosine under physiological conditions. For this, the imidazopurinone derivatives, 3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin 9(8)one (dG-G) and 3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6-methylimidazo [2,3-b]purine-9(8)one (dG-MG), were prepared. Authentic standard and stable isotope-substituted standard adducts were prepared and an isotopic dilution analysis assay methodology was developed using liquid chromatography with tandem mass spectrometry and optimized DNA extraction and nuclease digestion procedures. Analysis of dG-G, dG-MG, and the oxidative marker 8-hydroxydeoxyguanosine in the DNA of cultured human cells and mononuclear leukocytes showed that nucleotide advanced glycation endproducts are major markers of DNA damage in human cells. PMID- 18448832 TI - Maillard products as biomarkers in cancer. AB - Because tumors exert increased glycolysis rates, a high intracellular carbonyl stress with the formation of Maillard products may evolve. Therefore, we studied the presence of N epsilon-(carboxymethyl)lysine (CML) modification in breast cancer tissues from 20 patients and found significant cytoplasmatic staining in tumor cells that was independent of the tumor stage, tumor type, and microanatomic localization. Studying breast cancer cell lines, we also found strong cytoplasmatic CML staining that was again independent of their invasive or metastatic behavior. Our results reveal that tumor cells show a strong cytoplasmatic immunoreactivity to CML without evident association with breast carcinoma type, differentiation, tumor stage, or intratumoral localization. We conclude that CML formation is a general tumor cell-associated process. PMID- 18448833 TI - Glycation of plasma lipoprotein lipid membrane and screening for lipid glycation inhibitor. AB - We recently reported that phosphatidylethanolamine (PE)-linked Amadori product (Amadori-PE) increased abnormally in diabetic plasma. However, the glycation mechanism of human plasma low-density lipoprotein (LDL) is still unclear. Moreover, lipid glycation inhibitors have yet to be discovered. In this study, we compared the glycation kinetics of LDL lipid and LDL protein in vitro and screened lipid glycation inhibitors. LDL-PE was converted to Amadori-PE followed by LDL protein (apoB) glycation. Pyridoxal 5'-phosphate could easily react with PE before the glucose-PE reaction, and the PE-pyridoxal 5'-phosphate adduct was detected in human red blood cells. Pyridoxal 5'-phosphate can be used in diabetes prevention. PMID- 18448834 TI - Analysis of amadori-glycated phosphatidylethanolamine in the plasma of healthy subjects and diabetic patients by liquid chromatography-tandem mass spectrometry. AB - Peroxidized phospholipid-mediated cytotoxity, the abnormal increase in the levels of phosphatidylcholine hydroperoxide (PCOOH) found in the plasma of type 2 diabetic patients, is involved in the pathophysiology of many diseases. PCOOH accumulation may be related to Amadori-glycated phosphatidylethanolamine (deoxy-D fructosyl PE, or Amadori-PE) because Amadori-PE causes oxidative stress. However, the occurrence of lipid glycation products, including Amadori-PE, in vivo remains unclear. We developed a method to analyze Amadori-PE by using quadrupole/linear ion-trap mass spectrometry, the Applied Biosystems 4000 Q TRAP. We found that pyridoxals could easily be condensed with PE before the glucose-PE reaction occurred. The PE-pyridoxal 5'-phosphate adduct was detectable in human red blood cells, and the increased plasma Amadori-PE concentration in streptozotocin induced diabetic rats was decreased by dietary supplementation with pyridoxal 5' phosphate. Therefore, it is likely that pyridoxal 5'-phosphate acts as a lipid glycation inhibitor in vivo, and this may contribute to diabetes prevention. PMID- 18448835 TI - Evaluating the extent of protein damage in dairy products: simultaneous determination of early and advanced glycation-induced lysine modifications. AB - An isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to determine lysine (Lys), N(epsilon)-fructosyllysine (FL), N epsilon-carboxymethyllysine (CML), and pyrraline (Pyr) in dairy products. The presented approach entails protein cleavage via enzymatic digestion to liberate the aforementioned compounds, which were then quantified using a stable isotope dilution assay. LC-MS/MS analysis was performed by positive electrospray ionization recording two transition reactions per analyte in selected reaction monitoring mode. The CML and Lys values obtained with enzymatic digestion were compared to those acquired with acid hydrolysis HCl (6 mol/L), and the two proteolysis methods yielded comparable quantifications. Allowing for the fact that the investigated compounds are formed during different stages of the glycation process, the method is able to reveal the progress of protein glycation in dairy products. PMID- 18448836 TI - A novel yellow pigment, furpipate, derived from lysine and furfural. AB - Furfural is an important intermediate compound of the Maillard reaction of pentose or ascorbic acid. We examined the browning of furfural and lysine by heating these compounds in solution and found two yellow compounds. The first, furpipate, is a novel pipecolic acid derivative and was (Z)-3-(2 furylmethylidene)-3H, 4H, 5H, 6H-pyridine-2-carboxylic acid. The second was decarboxylated-furpipate. Furpipate shows absorption maxima at 370 nm and 310 nm under acidic and alkaline conditions, respectively. This compound was the major colored compound of the heated solution containing lysine and furfural. PMID- 18448837 TI - Time-dependent component-specific regulation of gastric acid secretion-related proteins by roasted coffee constituents. AB - Consumption of coffee beverages has been reported to cause gastric irritation in some consumers as a result of increased gastric acid secretion. In the complex mechanisms of gastric acid secretion, the activity and expression of the H+,K+ ATPase is regulated by transmitters, such as histamine, acetylcholine, gastrin, somatostatin, and their corresponding receptors. Here, we report the effect of three coffee constituents, chlorogenic acid, caffeine, and N-methyl pyridinium ions, on the expression of the histamine receptor H2, the acetylcholine receptor M3, the gastrin receptor, the somatostatin receptor, and the H+,K+-ATPase. Human gastric cancer cells were exposed to chlorogenic acid, caffeine, or N-methyl pyridinium in their coffee brew-representative concentrations as well as to physiological stimulators of gastric acid secretion. Gene expression levels of receptor proteins and those of the H+,K+-ATPase were measured at different time points by real-time PCR. Expression of prosecretory receptors significantly increased between one and one-half to twofold after treatment with chlorogenic acid or caffeine compared to control cells at the same time point. Chlorogenic acid and caffeine also increased the H+,K+-ATPase gene expression twofold higher compared to control cells. In contrast, N-methyl pyridinium downregulated the expression of the prosecretory gastrin receptor significantly, by -27%. In conclusion, chlorogenic acid, caffeine, and N-methyl pyridinium impair the expression of gastric acid secretion-related proteins in a time-dependent manner. Future work will be aimed at the elucidation of the cooperative interplay of individual components using recombinates of single coffee constituents. PMID- 18448838 TI - Modification of vimentin: a general mechanism of nonenzymatic glycation in human skin. AB - In a recent study, we were able to show that the intermediate filament protein vimentin aggregates in human dermal fibroblasts because of modification by the advanced glycation endproduct carboxymethyllysine (CML). In this work, we investigated the formation of intracellular CML in relation to the concentration of glucose in the culture medium. The natural degradation product of glucose, methylglyoxal, was able to induce the aggregation of vimentin. This dicarbonyl leads to the formation of the modifications MG-H1 and carboxyethyllysine (CEL) as a result of the reaction with arginine and lysine residues of proteins. Furthermore, we found that the protein vimentin was modified, not only by CML and CEL, but also by pentosidine and pyrraline. These findings underline the special position of vimentin as a preferential target of the Maillard reaction in human skin. PMID- 18448839 TI - Gastrin-releasing peptide (GRP) in the ovine uterus: regulation by interferon tau and progesterone. AB - Gastrin-releasing peptide (GRP) is abundantly expressed by endometrial glands of the ovine uterus and processed into different bioactive peptides, including GRP1 27, GRP18-27, and a C-terminus, that affect cell proliferation and migration. However, little information is available concerning the hormonal regulation of endometrial GRP and expression of GRP receptors in the ovine endometrium and conceptus. These studies determined the effects of pregnancy, progesterone (P4), interferon tau (IFNT), placental lactogen (CSH1), and growth hormone (GH) on expression of GRP in the endometrium and GRP receptors (GRPR, NMBR, BRS3) in the endometrium, conceptus, and placenta. In pregnant ewes, GRP mRNA and protein were first detected predominantly in endometrial glands after Day 10 and were abundant from Days 18 through 120 of gestation. Treatment with IFNT and progesterone but not CSH1 or GH stimulated GRP expression in the endometrial glands. Western blot analyses identified proGRP in uterine luminal fluid and allantoic fluid from Day 80 unilateral pregnant ewes but not in uterine luminal fluid of either cyclic or early pregnant ewes. GRPR mRNA was very low in the Day 18 conceptus and undetectable in the endometrium and placenta; NMBR and BRS3 mRNAs were undetectable in ovine uteroplacental tissues. Collectively, the present studies validate GRP as a novel IFNT-stimulated gene in the glands of the ovine uterus, revealed that IFNT induction of GRP is dependent on P4, and found that exposure of the ovine uterus to P4 for 20 days induces GRP expression in endometrial glands. PMID- 18448841 TI - Testis-specific novel transcripts in chicken: in situ localization and expression pattern profiling during sexual development. AB - Tissue-specific novel transcripts expressed during sexual development were examined by RT-PCR, quantitative RT-PCR (qRT-PCR), and in situ hybridization to provide data for chicken genomics. Public databases for transcript data have been constructed with known and unknown sequences of various tissues from different animals. However, the expression patterns and functions of the transcripts are less known. From the The Institute for Genomics Research Gallus gallus library, we examined 291 tentative consensus (TC) sequences that assembled 100% with transcripts by RT-PCR during male and female sexual development from Embryonic Day 6 to 25 wk of age. We found 85 TC sequences that were specific to testicular development; of these, 43 TC sequences were exclusively upregulated in 25-wk-old testis. Another 52 TC sequences were not specific to one tissue, but occurred in the testis and ovary at different developmental ages. Twelve testis-specific TC sequences upregulated in 25-wk-old testis were randomly selected and further examined with qRT-PCR. For precise localization, these 12 testis-specific TC sequences were examined by in situ hybridization with 25-wk-old adult testis. Six TC sequences were strongly expressed in secondary spermatocytes and haploid spermatids until spermatozoa release. Another six TC sequences were differentially expressed in the adluminal compartment of seminiferous tubules. Among the testis-specific TC sequences, TC120901 is a known gene, phospholipase C, zeta (PLCZ1). Our data provide potential insight into gene expression and genomic information on novel transcripts that are important to avian reproduction. PMID- 18448840 TI - Age-dependent loss of sperm production in mice via impaired lysophosphatidic acid signaling. AB - Approximately half of all infertility cases can be attributed to male reproductive dysfunction for which low sperm count is a major contributing factor. The current study identified receptor-mediated lysophosphatidic acid (LPA) signaling as a new molecular component influencing male fertility. LPA is a small signaling phospholipid, the effects of which are mediated through at least five G protein-coupled receptors, named LPA 1-5. LPA1/2/3, but not LPA4/5, show high expression in mouse testis. Mice deficient in LPA1/2/3 showed a testosterone independent reduction of mating activity and sperm production, with an increased prevalence of azoospermia in aging animals. A significant increase of germ cell apoptosis also was observed in testes. Germ cell apoptosis led to a reduction in germ cell proliferation. These data demonstrate a novel in vivo function for LPA signaling as a germ cell survival factor during spermatogenesis. PMID- 18448842 TI - Involvement of the KIT/KITL signaling pathway in 4-vinylcyclohexene diepoxide induced ovarian follicle loss in rats. AB - Repeated daily dosing of rats with the occupational chemical 4-vinylcyclohexene diepoxide (VCD) depletes the ovary of primordial and primary follicles through an increase in the natural process of atresia. Additionally, in vitro exposure of Postnatal Day 4 (PND 4) rat ovaries to VCD causes similar follicular depletion. This study was designed to investigate survival signaling pathways that may be associated with VCD-induced ovotoxicity in small preantral follicles. Female Fischer 344 rats (PND 28) were dosed daily (80 mg/kg/day VCD i.p.; 12 days in vivo), and PND 4 ovaries were cultured (VCD 20 or 30 microM; 8 days in vitro). Microarray analysis identified a subset of 14 genes whose expression was increased or decreased by VCD in both experiments (i.e., via both exposure routes). Particularly, the analysis showed that relative to controls, VCD did not affect mRNA expression of growth and differentiation factor 9 (Gdf9), whereas there were decreases in mRNA encoding bone morphogenic protein receptor 1a (Bmpr1a) and Kit. To confirm findings from microarray, the genes Gdf9, Bmpr1a, and Kit were further examined. When growth factors associated with these pathways were added to ovarian cultures during VCD exposure, GDF9 and BMP4 had no effect on VCD-induced ovotoxicity; however, KITL attenuated this follicle loss. Additionally, there was a decrease in Kit and an increase in Kitl expression (mRNA and protein) following VCD exposure, relative to control. These results support that VCD compromises KIT/KITL signaling, which is critical for follicular survival in primordial and primary follicles. PMID- 18448843 TI - The equatorial subsegment in mammalian spermatozoa is enriched in tyrosine phosphorylated proteins. AB - The equatorial subsegment (EqSS) was originally identified by atomic force microscopy as a discrete region within the equatorial segment of Artiodactyl spermatozoa. In this investigation, we show that the EqSS is enriched in tyrosine phosphorylated proteins and present preliminary evidence for its presence in mouse and rat spermatozoa. The anti-phosphotyrosine monoclonal antibody (McAb) 4G10 bound strongly and discretely to the EqSS of permeabilized boar, ram, and bull spermatozoa. It also bound to a small patch on the posterior acrosomal region of permeabilized mouse and rat spermatozoa, suggesting that the EqSS is not restricted to the order Artiodactyla. An anti-HSPA1A (formerly Hsp70) antibody recognized the EqSS in boar spermatozoa. Immunogold labeling with McAb 4G10 localized the tyrosine phosphorylated proteins to the outer acrosomal membrane. This was verified by freeze-fracture electron microscopy, which identified the EqSS in three overlying membranes, the plasma membrane, outer acrosomal membrane, and inner acrosomal membrane. In all five species, tyrosine phosphorylated proteins became restricted to the EqSS during sperm maturation in the epididymis. The major tyrosine phosphorylated proteins in the EqSS of boar and ram spermatozoa were identified by mass spectrometry as orthologs of human SPACA1 (formerly SAMP32). Immunofluorescence with a specific polyclonal antibody localized SPACA1 to the equatorial segment in boar spermatozoa. We speculate that the EqSS is an organizing center for assembly of multimolecular complexes that initiate fusion competence in this area of the plasma membrane following the acrosome reaction. PMID- 18448844 TI - Intrafollicular steroids and anti-mullerian hormone during normal and cystic ovarian follicular development in the cow. AB - Development of follicular cysts is a frequent ovarian dysfunction in cattle. Functional changes that precede cyst formation are unknown, but a role for anti Mullerian hormone (AMH) in the development of follicular cysts has been suggested in humans. This study aimed to characterize intrafollicular steroids and AMH during follicular growth in a strain of beef cows exhibiting a high incidence of occurrence of follicular cysts. Normal follicular growth and cyst development were assessed by ovarian ultrasonography scanning during the 8 days before slaughtering. Experimental regression of cysts was followed by rapid growth of follicles that reached the size of cysts within 3-5 days. These young cysts exhibited higher intrafollicular concentrations of testosterone, estradiol 17beta, and progesterone than large early dominant follicles did in normal ovaries, but they exhibited similar concentrations of AMH. Later-stage cysts were characterized by hypertrophy of theca interna cells, high intrafollicular progesterone concentration, and high steroidogenic acute regulatory protein mRNA expression in granulosa cells. Progesterone and AMH concentrations in the largest follicles (> or =10 mm) and cysts were negatively correlated (r = -0.45, P < 0.01). Smaller follicles (<10 mm) exhibited higher intrafollicular testosterone and estradiol-17beta concentrations in ovaries with cysts compared to normal ovaries. During follicular growth, AMH concentration dropped in follicles larger than 5 mm in diameter and in a similar way in ovaries with and without cysts. In conclusion, enhanced growth and steroidogenesis in antral follicles <10 mm preceded cyst formation in cow ovaries. Intrafollicular AMH was not a marker of cystic development in the cow, but low AMH concentrations in cysts were associated with luteinization. PMID- 18448845 TI - The ovary of the gestating South American plains vizcacha (Lagostomus maximus): suppressed apoptosis and corpora lutea persistence. AB - The South American plains vizcacha, Lagostomus maximus, displays an exceptional ovulation rate of up to 800 eggs per cycle, the highest rate recorded for a mammal. Massive polyovulation arises from the overexpression of the apoptosis inhibiting BCL2 gene leading to a suppression of apoptotic pathways responsible for follicular atresia in mammals. We analyzed the ovarian histology, ovarian apoptosis, and apoptosis-related protein expression with special emphasis in corpora lutea throughout the 5-mo-long gestation period, at parturition day and early postpartum, in L. maximus. Corpora lutea were abundant throughout gestation with no sign of structural regression even at the end of gestation. Both immunohistochemistry and Western blot analysis showed strong signals for apoptosis-inhibiting BCL2 protein, whereas the proapoptotic BAX protein was just detected in isolated luteal cells in gestating females and postpartum females. Apoptosis-associated DNA fragmentation detected by TUNEL was very scarce and occasional and correlated with BAX detection in luteal cells. Marked expression of progesterone and alpha-estrogen receptors in luteal cells was found at early, mid-, and late gestation as well as at parturition day and early postpartum samples. Additionally, serum level of progesterone increased markedly to reach maximal values at late gestation and decreasing at parturition to levels found at early gestation, suggesting that corpora lutea remained functional throughout gestation. These results point out that the unusual ovarian environment of L. maximus in which germ cell demise is abolished through antiapoptotic BCL2 gene overexpression also preserves structural integrity and functionality of corpora lutea during the whole gestation. Overexpression of antiapoptotic BCL2 gene may represent a strategy for an essential need of ovary and corpora lutea in order to maintain pregnancy until term. PMID- 18448846 TI - Mild cognitive impairment: challenging issues. PMID- 18448847 TI - Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis. AB - The relationships between total serum cholesterol (TC) and dementia and between TC and cognitive decline were investigated in a systematic review of 18 prospective studies. Follow-ups ranged from 3 to 29 years, and included a total of 14,331 participants evaluated for Alzheimer disease (AD), 9,458 participants evaluated for Vascular dementia (VaD), 1,893 participants evaluated for cognitive decline, and 4,793 participants evaluated for cognitive impairment. Compatible results were pooled using meta-analysis. Consistent associations between high midlife TC and increased risk of AD, and high midlife TC and increased risk of any dementia were found. There was no evidence supporting an association between late-life TC and AD, or between late-life TC and any dementia. No study reported a significant association between TC (measured in midlife or late-life) and VaD. An association between high midlife TC and cognitive impairment was found but there was only weak evidence for an association between TC and cognitive decline. Two of seven studies reporting data on the interaction between TC and apolipoprotein e4-allele had significant effects. Results suggest the effect of TC on dementia risk occurs in midlife but not late-life, and that there may be different cardiovascular risk factor profiles for AD and VaD. Results from additional studies involving long-term follow-up of midlife samples will allow for clarification of the association between age, TC and risk of specific types of dementia. These data are required to inform recommendations of modulation of cholesterol to reduce or delay dementia risk. PMID- 18448848 TI - Terminal-decline effects for select cognitive tasks after controlling for preclinical dementia. AB - OBJECTIVE: In a previous study, the authors found no accelerated decline in close proximity to death for a measure of global cognitive functioning, after excluding persons in a preclinical phase of dementia. However, specific cognitive tasks might be more sensitive to terminal-decline effects. The purpose of this study was to explore possible terminal-decline effects for a range of cognitive tasks after controlling for preclinical dementia. DESIGN: Community-based cohort study. SETTING: The Kungsholmen district of Stockholm. PARTICIPANTS: A total of 585 persons (75+ years) were repeatedly assessed over an 11-year period. Level and change in cognitive performance were compared for three groups: persons in close proximity to death, persons in a preclinical phase of dementia, and persons who remained alive and nondemented throughout the study. MEASUREMENTS: Tasks assessing primary and episodic memory, verbal ability, and visuospatial skill. RESULTS: Compared with an analysis where all dead subjects were included in the impending-death group, removing the preclinical dementia cases resulted in markedly attenuated mortality-related effects. However, the impending-death group still declined at a faster rate relative to the comparison group on Digit Span forward, word recognition, and category fluency. Notably, these were tasks for which the comparison group showed no significant decline. CONCLUSIONS: A considerable proportion of the terminal-decline effect is accounted for by the impact of preclinical dementia. However, for tasks that are relatively resistant to age-related change, such effects might be detected independently of preclinical dementia. PMID- 18448850 TI - Clinical criteria for the diagnosis of Alzheimer disease: still good after all these years. AB - OBJECTIVE: To examine the impact of newer neuropathological techniques on the power of National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association criteria for Alzheimer disease (AD) to detect AD at later postmortem study. DESIGN: We examined clinical and postmortem diagnoses of persons evaluated postmortem with thioflavin-S staining for plaques and tangles and immunohistochemical staining techniques for alpha synuclein, uhiquitin, and tau protein. SETTING: Alzheimer Disease Center. PARTICIPANTS: Clinically evaluated persons for whom tissue diagnosis was available. RESULTS: Of 313 evaluees, 166 met criteria for probable AD. An additional 59 subjects had clinical diagnoses that included AD, e.g., possible AD, Lewy body variant of AD, AD and Parkinsonism, and mixed AD and vascular dementia. Of the 166 probable AD cases, 147 of 166 (88.6%) met pathologic criteria for AD. When all five AD groups were combined, 194 of 225 subjects (86.2%) met pathologic criteria for AD. There were five cases diagnosed pathologically as tangle-only dementia, which was considered a variant of AD. A pathologic diagnosis of Lewy body variant of AD was made in 56 (17.9%) of cases, including 44 of 313 (14.1%) cases diagnosed as probable or possible AD. Pure dementia with Lewy bodies was seen in 13 (4.2%). There were 9 (2.9%) cases of mixed AD and vascular dementia, and 37 (11.4%) cases of frontotemporal dementia. CONCLUSIONS: McKhann et al. criteria for probable and possible AD are valid for AD but do not exclude additional Lewy body pathology. PMID- 18448849 TI - Cognitive discrepancies versus APOE genotype as predictors of cognitive decline in normal-functioning elderly individuals: a longitudinal study. AB - OBJECTIVES: Cognitive-discrepancy analysis has been shown to be a useful technique for detecting subtle cognitive deficits in normal-functioning elderly individuals who are genetically at-risk for Alzheimer disease (AD). However, studies that have used cognitive-discrepancy measures to date have used retrospective or cross-sectional designs, and the utility of this approach to predict cognitive decline has not been examined in a prospective investigation. DESIGN: Longitudinal study. SETTING: San Diego, CA, Veterans Administration Hospital. PARTICIPANTS: Twenty-four normal-functioning elderly individuals participated in the study, with 16 subjects exhibiting no change in their Dementia Rating Scale (DRS) scores over an 1-year period (Stable Group), and 8 subjects exhibiting a decline in DRS scores over the 1-year period (Decline group). MEASUREMENTS: A cognitive-discrepancy measure isolating cognitive switching was computed that contrasted performance on a new higher-level task of executive functioning (a Stroop/Switching measure) relative to a composite measure of lower-level Stroop conditions. RESULTS: a) In the year before their cognitive changes, the Decline group exhibited a significantly larger cognitive discrepancy (Stroop/Switching versus lower-level Stroop conditions) score compared with a control (Stable) group; and b) the cognitive-discrepancy measure was superior to APOE genotype in predicting DRS decline. CONCLUSION: Cognitive discrepancy analysis isolating a component executive function ability not only seems to be a useful tool for identifying individuals at risk for cognitive deficits, but also shows promise in predicting individuals who may show subtle cognitive decline over time. PMID- 18448851 TI - Outcomes and predictors of late-life depression trajectories in older primary care patients. AB - OBJECTIVES: The naturalistic outcomes of depression in older primary care patients have been poorly characterized. The authors sought to identify depressive trajectories over 2 years and to examine specified outcome predictors. DESIGN: Two-year observational cohort study. SETTING: University-based and independent practice primary care practices in greater Rochester. PARTICIPANTS: All patients aged >65 years presenting for care on selected recruitment days were eligible to participate. Of 392 subjects enrolled, 316 (80.6%) completed study measures over a 2-year follow-up. MEASUREMENTS: Depression trajectories were derived by applying longitudinal cluster analysis to weekly depression status from the Longitudinal Interval Follow-up Evaluation. RESULTS: The authors identified six distinct trajectory clusters that followed clinically intuitive patterns. Although subjects initially nondepressed or in the subsyndromal to minor depression range had a range of possible outcomes over 2 years, the cluster initially near the major depression level remained at that level over time. Consistent predictors of depression trajectory were baseline depressive symptom severity, medical burden, and psychiatric functional status; for some clusters, previous history of depression and perceived social support also had prognostic significance. CONCLUSION: The "real-world" outcomes of patients with more severe depressive symptoms are strikingly poor. Given the diverse outcomes of those with subsyndromal to mild forms of minor depression, clinicians might focus treatments on those at highest risk of poor outcome, i.e., those with greater depressive symptoms and medical burden and lower psychiatric functioning and social support. Preventive interventions research might focus on developing treatments to mitigate potentially modifiable risks such as deficits in social support. PMID- 18448852 TI - Mild cognitive impairment and everyday function: evidence of reduced speed in performing instrumental activities of daily living. AB - OBJECTIVE: Mild cognitive impairment (MCI) may involve subtle functional losses that are not detected with typical self- or informant-report assessments of daily function. Information about the nature of functional difficulties in MCI can be used to augment common clinical assessment procedures, and aspects of function that are affected in MCI can serve as meaningful endpoints for intervention trials. DESIGN: Cross-sectional case and comparison group study. SETTING: University medical center. PARTICIPANTS: Fifty participants with MCI and 59 cognitively normal participants. MEASUREMENTS: The authors compared the groups on dimensions of both speed and accuracy in performing instrumental activities of daily living (IADLs), using a standardized Timed IADL measure that evaluates five functional domains commonly encountered in everyday life (telephone use, locating nutrition information on food labels, financial abilities, grocery shopping, medication management). RESULTS: Across Timed IADL domains, MCI participants demonstrated accuracy comparable with cognitively normal participants but took significantly longer to complete the functional activities, controlling for depressive symptoms (p< 0.001). Slower performance was demonstrated in each discrete domain except financial abilities. CONCLUSION: These results suggest that slower speed of task performance is an important component and perhaps an early marker of functional change in MCI that would not be detected using traditional measurements of daily function. Future research should address the question of whether performance-based functional measures, as well as simple queries regarding whether functional activities take longer than usual to complete, may improve the prediction of future cognitive decline and disease progression among those individuals in whom MCI represents impending dementia. PMID- 18448853 TI - The impact of depressive symptoms and chronic diseases on active life expectancy in older Americans. AB - OBJECTIVES: The authors prospectively examined whether depressive symptoms (DS) in older adults negatively affected active live expectancy (ALE), or remaining years free of disability, and mortality, independently and in the presence of chronic diseases, and after stratification by gender. DESIGN: Prospective cohort study, first three waves (1993-1998) of the Asset and Health Dynamics Among the Oldest Old. SETTING: DATA COLLECTION: University of Michigan; analysis: University of South Florida. PARTICIPANTS: Nationally representative sample of community-dwelling adults age 70 and older (N = 7,381). MEASUREMENTS: DS (Center for Epidemiological Studies Depression, 8-item version), self-reported cancer, diabetes, heart disease, or stroke, difficulty with activities of daily living, death, and estimates of total, active, and disabled life expectancy. RESULTS: DS reduced ALE by 6.5 years for young-old men (age 70), 3.2 years for old-old men (age 85), 4.2 years for young-old women, and 2.2 years for old-old women, and these effects remained significant at all ages and across gender even after controlling for chronic disease, the one exception being DS and cancer in old-old women. DS also reduced total life expectancy significantly, although controlling for some chronic diseases (particularly cancer and stroke) eliminated the effect of DS across age and gender groups. CONCLUSION: Depressive symptoms represent a serious and distinct threat to independent functioning in older adults. Whether experienced alone, or in combination with chronic diseases, depressive symptoms shorten ALE substantially. Timely diagnosis and treatment of depressive symptoms in older adults may delay the onset of disability and improve the quality of life. PMID- 18448854 TI - Research rumors as urban legends. PMID- 18448855 TI - Quality of life of older adults in Canada and Norway: examining the Iowa model. AB - In this study, Glick and Tripp-Reimer's (1996) Iowa model for gerontological nursing serves as a guiding framework for a descriptive exploratory study of quality of life (QOL) of older adults. Using secondary data, the authors explored whether the effects of health appraisal, morbidities, social support transitions (SST), and the environment on QOL would be partly mediated by cognitive developmental transitions (CDT). Data sets were available from studies with random samples of community-dwelling older adults from Canada (n = 202) and Norway (n = 490). The partly and fully mediated effects found suggest positive CDT in older age might be significantly enhanced by the presence of intimate ties, positive perceptions of one's health limitations, and residence in a healthy, safe, and resource-rich physical environment. These findings represent a novel attempt at testing complex linkages between aspects of elder, environment, and nursing concepts within the Iowa model warranting further research. PMID- 18448856 TI - International translation of health behavior research innovations: part 1. Introduction. PMID- 18448857 TI - Cultural adaptation process for international dissemination of the strengthening families program. AB - The Strengthening Families Program (SFP) is an evidence-based family skills training intervention developed and found efficacious for substance abuse prevention by U.S researchers in the 1980s. In the 1990s, a cultural adaptation process was developed to transport SFP for effectiveness trials with diverse populations (African, Hispanic, Asian, Pacific Islander, and Native American). Since 2003, SFP has been culturally adapted for use in 17 countries. This article reviews the SFP theory and research and a recommended cultural adaptation process. Challenges in international dissemination of evidence-based programs (EBPs) are discussed based on the results of U.N. and U.S. governmental initiatives to transport EBP family interventions to developing countries. The technology transfer and quality assurance system are described, including the language translation and cultural adaptation process for materials development, staff training, and on-site and online Web-based supervision and technical assistance and evaluation services to assure quality implementation and process evaluation feedback for improvements. PMID- 18448858 TI - Frequent consulting and multiple morbidity: a qualitative comparison of 'high' and 'low' consulters of GPs. AB - BACKGROUND: Frequent consulting is associated with multiple and complex social and health conditions. It is not known how the impact of multiple conditions, the ability to self-manage and patient perception of the GP consultation combines to influence consulting frequency. OBJECTIVE: To investigate reasons for frequent consultation among people with multiple morbidity but contrasting consulting rates. METHODS: Qualitative study with in-depth interviews in the west of Scotland. Participants were 23 men and women aged about 50 years with four or more chronic illnesses; 11 reported consulting seven or more times in the last year [the frequent consulters (FCs)] and 12, three or fewer times [the less frequent consulters (LFCs)]. The main outcome measures were the participants' accounts of their symptoms, self-management strategies and reasons for consulting a GP. RESULTS: All participants used multiple self-management strategies. FCs described: more disruptive symptoms, which were resistant to self-management strategies; less access to fewer treatments and resources and more medical monitoring, for unstable conditions and drug regimens. The LFCs reported: less severe and more containable symptoms; accessing more efficacious self-management strategies and infrequent GP monitoring for stable conditions and routine drug regimens. All participants conveyed consulting as a 'last resort'. However, the GP was seen as 'ally', for the FCs, and as 'innocent bystander', for the LFCs. CONCLUSIONS: This qualitative investigation into the combined significance of multiple morbidities and self-management on the GP consultation suggests that current models of self-management might have limited potential to reduce utilization rates among this vulnerable group. Severity of symptoms, stability of condition and complexity of drug regimens combine to influence the availability of effective resources and influence frequency of GP consultations. PMID- 18448859 TI - Omega-3/omega-6 fatty acids for attention deficit hyperactivity disorder: a randomized placebo-controlled trial in children and adolescents. AB - OBJECTIVE: The aim of the study was to assess omega 3/6 fatty acids (eye q) in attention deficit hyperactivity disorder (ADHD). METHOD: The study included a randomized, 3-month, omega 3/6 placebo-controlled, one-way crossover trial with 75 children and adolescents (8-18 years), followed by 3 months with omega 3/6 for all. Investigator-rated ADHD Rating Scale-IV and Clinical Global Impression (CGI) scale were outcome measures. RESULTS: A majority did not respond to omega 3/6 treatment. However, a subgroup of 26% responded with more than 25% reduction of ADHD symptoms and a drop of CGI scores to the near-normal range. After 6 months, 47% of all showed such improvement. Responders tended to have ADHD inattentive subtype and comorbid neurodevelopmental disorders. CONCLUSION: A subgroup of children and adolescents with ADHD, characterized by inattention and associated neurodevelopmental disorders, treated with omega 3/6 fatty acids for 6 months responded with meaningful reduction of ADHD symptoms. PMID- 18448860 TI - Test and product review: Freer, P. (2003). Play Attention interactive learning tool. Asheville, NC: Unique Logic and Technology Inc. PMID- 18448861 TI - Long-term, open-label safety and efficacy of atomoxetine in adults with ADHD: final report of a 4-year study. AB - OBJECTIVE: Previously, data from 97 weeks of open-label atomoxetine treatment of adults with attention-deficit/hyperactivity disorder (ADHD) were reported. This final report of that study presents results from over 4 years of treatment. METHOD: Results were derived from the study of 384 patients (125 patients remaining in the open-label trial since the interim report), receiving up to 221 weeks of treatment. Primary efficacy measure was the Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) Total ADHD Symptom score. Adverse events and vital signs were assessed. RESULTS: CAARS-Inv:SV Total ADHD Symptom scores decreased 30.2% (p < .001) during treatment. Similar, significant decreases were noted for the secondary efficacy measures, including the Sheehan Disability Scale Total score, which improved 25.3% (p < .001). Adverse events consisted primarily of pharmacologically (noradrenergic) expected effects. CONCLUSIONS: Results of this open-label study support the long-term efficacy, safety, and tolerability of atomoxetine for the treatment of adult ADHD. PMID- 18448862 TI - Child sexual abuse and adult romantic adjustment: comparison of single- and multiple-indicator measures. AB - This study compared the usefulness of single- and multiple-indicator strategies in a model examining the role of child sexual abuse (CSA) to predict later marital satisfaction through attachment and psychological distress. The sample included 1,092 women and men from a nonclinical population in cohabiting or marital relationships. The single-item measure assessed the presence or absence of CSA. The multiple-indicator measure included items relating to level of force, relationship with perpetrator, number of abusive experiences, and nature of assault. Structural equation modeling indicated that, for research purposes, a dichotomized item provided as much information as a complex measure to predict the relationship between sexual abuse and marital adjustment through attachment representations and psychological distress. However, when analyses were conducted strictly within the CSA victims group, no correlation was found between abuse severity and psychosocial measures. The present results show that in a community sample, CSA may be an important risk factor that develops couple difficulties, regardless of the severity of the trauma. PMID- 18448863 TI - Influence of lipid-soluble gating modifier toxins on sodium influx in neocortical neurons. AB - The electrical signals of neurons are fundamentally dependent on voltage-gated sodium channels (VGSCs), which are responsible for the rising phase of the action potential. An array of naturally occurring and synthetic neurotoxins have been identified that modify the gating properties of VGSCs. Using murine neocortical neurons in primary culture, we have compared the ability of VGSC gating modifiers to evoke Na+ influx. Intracellular sodium concentration ([Na+](i)) was monitored using the Na+-sensitive fluorescent dye, sodium-binding benzofuran isophthalate. All sodium channel gating modifier compounds tested produced a rapid and concentration-dependent elevation in neuronal [Na+](i). The increment in [Na+](i) exceeded 40 mM at high concentrations of brevetoxins, batrachotoxin, and the novel lipopeptide, antillatoxin. The maximal increments in neuronal [Na+](i) produced by neurotoxin site 2 alkaloids, veratridine and aconitine, and the pyrethroid deltamethrin were somewhat lower with maximal [Na+](i) increments of less than 40 mM. The rank order of efficacy of sodium channel gating modifiers was brevetoxin (PbTx)-1 > PbTx-desoxydioxolane > batrachotoxin > antillatoxin > PbTx-2 = PbTx-3 > PbTx-3alpha-naphthoate > veratridine > deltamethrin > aconitine > gambierol. These data demonstrate that the ability of sodium channel gating modifiers to act as partial agonists is shared by compounds acting at both neurotoxin sites 2 and 5. The concentration-dependent increases in [Na+](i) produced by PbTx-2, antillatoxin, veratridine, deltamethrin, aconitine, and gambierol were all abrogated by tetrodotoxin, indicating that VGSCs represent the sole pathway of Na+ entry after exposure to gating modifier neurotoxins. PMID- 18448864 TI - Modeling corticosteroid effects in a rat model of rheumatoid arthritis II: mechanistic pharmacodynamic model for dexamethasone effects in Lewis rats with collagen-induced arthritis. AB - A mechanism-based model for pharmacodynamic effects of dexamethasone (DEX) was incorporated into our model for arthritis disease progression in the rat to aid in identification of the primary factors responsible for edema and bone loss. Collagen-induced arthritis was produced in male Lewis rats after injection of type II porcine collagen. DEX was given subcutaneously in single doses of 0.225 or 2.25 mg/kg or 7-day multiple doses of 0.045 or 0.225 mg/kg at 21 days postdisease induction. Effects on disease progression were measured by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST), and tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Lumbar and femur BMD was determined by PIXImus II dual-energy X-ray absorptiometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were assayed by quantitative real-time polymerase chain reaction. Indirect response models, drug interaction models, transduction processes, and the fifth-generation model of corticosteroid dynamics were integrated and applied using S-ADAPT software to describe how dexamethasone binding to GR can regulate diverse processes. Cytokine mRNA, GR mRNA, plasma CST, and paw edema were suppressed after DEX administration. TNF-alpha mRNA expression and BMD seemed to increase immediately after dosing but were ultimately reduced. Model parameters indicated that IL-6 and IL-1beta were most sensitive to inhibition by DEX. TNF-alpha seemed to primarily influence edema, whereas IL-6 contributed the most to bone loss. Lower doses of corticosteroids may be sufficient to suppress the cytokines most relevant to bone erosion. PMID- 18448865 TI - Modeling corticosteroid effects in a rat model of rheumatoid arthritis I: mechanistic disease progression model for the time course of collagen-induced arthritis in Lewis rats. AB - A mechanism-based model was developed to describe the time course of arthritis progression in the rat. Arthritis was induced in male Lewis rats with type II porcine collagen into the base of the tail. Disease progression was monitored by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST) concentrations, and tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Bone mineral density was determined by PIXImus II dual energy X-ray densitometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were determined by quantitative real-time polymerase chain reaction. Disease progression models were constructed from transduction and indirect response models and applied using S-ADAPT software. A delay in the onset of increased paw TNF-alpha and IL-6 mRNA concentrations was successfully characterized by simple transduction. This rise was closely followed by an up-regulation of GR mRNA and CST concentrations. Paw swelling and body weight responses peaked approximately 21 days after induction, whereas bone mineral density changes were greatest at 23 days after induction. After peak response, the time course in IL-1beta, IL-6 mRNA, and paw edema slowly declined toward a disease steady state. Model parameters indicate TNF-alpha and IL-1beta mRNA most significantly induce paw edema, whereas IL-6 mRNA exerted the most influence on BMD. The model for bone mineral density captures rates of turnover of cancellous and cortical bone and the fraction of each in the different regions analyzed. This small systems model integrates and quantitates multiple factors contributing to arthritis in rats. PMID- 18448866 TI - Topical implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. AB - Mesenchymal stem cells (MSCs) are attractive cell sources in regenerative medicine. We examined the effects of topical MSCs implantation on an experimental model of inflammatory bowel disease. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in vitro, were characterized by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and differentiation assays. Experimental colitis was induced by intraluminal instillation of 2,4,6-trinitrobonzene sulfonic acid (TNBS) in the colons of male rats. The putative MSCs and unselected fresh bone marrow cells were injected into the colonic submucosa surrounding the area exposed to TNBS. The healing process of the injury was examined macroscopically and immunohistologically. Multipotent MSCs positive for CD29 and CD90, and negative for CD31 and CD34, were implanted into colon tissue surrounding the lesion; a majority of the engrafted cells were positive for vimentin. The implantation significantly accelerated healing of the damaged mucosa compared with vehicle-injected controls. The MSCs expressed vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1 in vitro and after the implantation. In conclusion, we found that MSCs were successfully topically implanted in the colon and that they were associated with accelerated healing of TNBS-induced colitis. The beneficial effects of the MSCs might be mediated, at least in part, by their ability to differentiate into colonic interstitial cells and by their ability to provide VEGF and TGF-beta1 to the injured area. PMID- 18448867 TI - Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. AB - Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT)1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. In this study, we demonstrated that i.v. or intrathecal administration of GlyT1 inhibitors, cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4 tetrahydronaphthalen-2-yl methyl)amino methylcarboxylic acid (ORG25935) or sarcosine, and GlyT2 inhibitors, 4-benzyloxy-3,5-dimethoxy-N-[1 (dimethylaminocyclopently)-methyl]benzamide (ORG25543) and (O-[(2-benzyloxyphenyl 3-fluorophenyl)methyl]-L-serine) (ALX1393), or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The antiallodynia effect is mediated through spinal glycine receptor alpha3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. However, these manipulations to stimulate glycinergic neuronal activity were without effect during the 4 days after nerve injury, whereas manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days after surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain. PMID- 18448868 TI - SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia. AB - Waldenstrom macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow at the time of diagnosis, implying continuous homing of WM cells into the marrow. The mechanisms by which trafficking of the malignant cells into the bone marrow has not been previously elucidated. In this study, we show that WM cells express high levels of chemokine and adhesion receptors, including CXCR4 and VLA-4. We showed that CXCR4 was essential for the migration and trans endothelial migration of WM cells under static and dynamic shear flow conditions, with significant inhibition of migration using CXCR4 knockdown or the CXCR4 inhibitor AMD3100. Similarly, CXCR4 or VLA-4 inhibition led to significant inhibition of adhesion to fibronectin, stromal cells, and endothelial cells. Decreased adhesion of WM cells to stromal cells by AMD3100 led to increased sensitivity of these cells to cytotoxicity by bortezomib. To further investigate the mechanisms of CXCR4-dependent adhesion, we showed that CXCR4 and VLA-4 directly interact in response to SDF-1, we further investigated downstream signaling pathways regulating migration and adhesion in WM. Together, these studies demonstrate that the CXCR4/SDF-1 axis interacts with VLA-4 in regulating migration and adhesion of WM cells in the bone marrow microenvironment. PMID- 18448869 TI - An aberrant protein complex in CSF as a biomarker of Alzheimer disease. AB - OBJECTIVE: To determine if an aberrant protein complex consisting of prostaglandin-d-synthase (PDS) and transthyretin (TTR) in CSF differentiates between subjects with Alzheimer disease (AD) and normal control (NC) subjects. METHODS: Western blot analysis and a unique sandwich ELISA were used to quantify levels of complexed PDS/TTR in ventricular CSF of subjects with autopsy-verified diagnoses and in lumbar CSF of living subjects with mild to moderate probable AD and age-matched NC subjects. Ventricular CSF was obtained from short postmortem interval autopsies of 7 NC subjects (4 men/3 women), 12 diseased control (DC) subjects (7 men/5 women), 4 subjects with mild cognitive impairment (MCI) (2 men/2 women), and 8 subjects with late-stage AD (LAD) (4 men/4 women). Lumbar CSF was obtained from 15 subjects with probable AD (5 men/10 women) and 14 age matched NC subjects (10 men/4 women) and was analyzed in a double-blind fashion. RESULTS: A significant increase in complexed PDS/TTR in ventricular CSF was found in MCI and LAD subjects but not DC subjects compared with NC subjects. Double blind analysis of complexed PDS/TTR in lumbar CSF showed a significant sixfold increase in levels of the PDS/TTR complex in living probable AD subjects compared with age-matched NC subjects and a 100% sensitivity and 93% specificity in the identification of subjects with AD. CONCLUSION: After further study of larger numbers of patients, quantifying prostaglandin-d-synthase/transthyretin complex in CSF may be useful in the diagnosis of Alzheimer disease, possibly in the early stages of the disease. PMID- 18448870 TI - Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. AB - BACKGROUND: Pregnancy registries for women taking anticonvulsant drugs have been developed to determine more efficiently the fetal risks of each drug. A total of 722 drug-exposed pregnancies are needed to identify a sevenfold increase in the rate of occurrence of a specific abnormality, such as spina bifida, with a frequency of 1 in 1,000. METHODS: The infants with major malformations born to the 791 women who had taken lamotrigine as monotherapy and had enrolled in the North American AED Pregnancy Registry were identified. Medical records were obtained from the affected infants' doctors. A total of 107 of the 791 infants or pregnancies were excluded. RESULTS: A total of 16 (2.3%) of 684 infants exposed to lamotrigine had major malformations that were identified at birth. Five infants (7.3/1,000) had oral clefts: isolated cleft palate (3), isolated cleft lip (1), and cleft lip and palate (1). The rate among the lamotrigine-exposed infants showed a 10.4-fold increase (95% CI: 4.3-24.9) in comparison to 206,224 unexposed infants surveyed at birth at Brigham and Women's Hospital in Boston, where the prevalence of isolated oral clefts was 0.7/1,000. A comparison was made also to 1,623 infants exposed to lamotrigine, as monotherapy, who had enrolled in five other registries. There were four infants with oral clefts: prevalence 2.5/1,000 (RR: 3.8, 95% CI: 1.4-10.0). CONCLUSIONS: The infant exposed in the first trimester of pregnancy to the anticonvulsant drug lamotrigine has an increased risk to have an isolated cleft palate or cleft lip deformity. PMID- 18448871 TI - Diffusion tensor imaging of the pyramidal tracts in infants with motor dysfunction. AB - OBJECTIVE: To determine if diffusion tensor imaging (DTI) metrics of the pyramidal tracts correlate with motor outcome in infants presenting with motor dysfunction. METHODS: DTI tractography of the pyramidal tracts was performed in 21 patients with clinical motor dysfunction who were less than 30 months of age and in 22 age-matched controls. We plotted tract-specific DTI metrics (fractional anisotropy, parallel diffusivity, transverse diffusivity, and mean diffusivity) against age for the controls and generated normative curves. For each patient, we calculated the deviation from the normative curves. Patients returned for a neurodevelopmental evaluation when they were over 36 months of age, and motor outcome measures were performed. We analyzed the association between normative deviation in DTI metrics and motor outcome measures using linear and logistic regression models. RESULTS: Normative deviation in fractional anisotropy and transverse diffusivity were significantly correlated with all measures of motor outcome. Lower fractional anisotropy and higher transverse diffusivity compared to controls were associated with worse motor outcome. Furthermore, children who were eventually diagnosed with permanent motor dysfunction had lower fractional anisotropy and higher transverse diffusivity compared with those whose motor dysfunction normalized. CONCLUSIONS: Diffusion tensor imaging metrics correlate with motor outcome in infants presenting with motor dysfunction. The identification of a quantitative imaging marker that can be applied to infants at the time of clinical presentation has implications for the evaluation of early motor dysfunction. PMID- 18448872 TI - VBM anticipates the rate of progression of Alzheimer disease: a 3-year longitudinal study. AB - OBJECTIVE: To determine whether regional atrophy or neuropsychological factors can predict the rate of decline in patients with mild Alzheimer disease (AD). BACKGROUND: Despite important implications for planning the care and treatment strategy, few prognostic factors of severe AD progression are known. METHODS: Twenty-three patients with mild AD were followed up every 6 months over the course of 3 years. At baseline, patients with AD and 18 controls underwent a neuropsychological battery and a brain MRI. At the end of the 3 years, patients with AD were dichotomized into slow decliners (SLD) or fast decliners (FD) groups on the basis of their decline in Mini-Mental State Examination score over time. We compared baseline cognitive performance and imaging data using voxel-based morphometry (VBM). RESULTS: SLD and FD groups did not differ in age, gender, level of education, mean estimated duration of illness, and standard neuropsychological data at inclusion, except for the Attentional Battery of the Cambridge Neuropsychological Tests Automated Battery (speed processing in shifting condition). VBM comparison between SLD and FD groups demonstrated more gray matter tissue loss in the FD group in the medial occipitoparietal areas, especially in the precuneus, the lingual gyrus, the cuneus, and the surrounding cortex of the parieto-occipital sulcus bilaterally. CONCLUSION: Voxel-based morphometry analysis demonstrated that patients who will have a faster decline at 3 years already had a more extensive cortical atrophy than SLD patients, especially in the medial occipitoparietal areas, which was not yet detected by clinical and neuropsychological assessment. PMID- 18448873 TI - Monte Carlo dose calculation of segmental IMRT delivery to a moving phantom using dynamic MLC and gating log files. AB - Respiratory gating is emerging as a tool to limit the effect of motion for liver and lung tumors. In order to study the impact of target motion and gated intensity modulated radiation therapy (IMRT) delivery, a computer program was developed to simulate segmental IMRT delivery to a moving phantom. Two distinct plans were delivered to a rigid-motion phantom with a film insert in place under four conditions: static, sinusoidal motion, gated sinusoidal motion with a duty cycle of 25% and gated sinusoidal motion with duty cycle of 50% under motion conditions of a typical patient (A = 1 cm, T = 4 s). The MLC controller log files and gating log files were retained to perform a retrospective Monte Carlo dose calculation of the plans. Comparison of the 2D planar dose distributions between simulation and measurement demonstrated that our technique had at least 94% of the points passing gamma criteria of 3% for dose difference and 3 mm as the distance to agreement. This note demonstrates that the use of dynamic multi-leaf collimator and respiratory monitoring system log files together with a fast Monte Carlo dose calculation algorithm is an accurate and efficient way to study the dosimetric effect of motion for gated or non-gated IMRT delivery on a rigidly moving body. PMID- 18448874 TI - The impact of different dose-response parameters on biologically optimized IMRT in breast cancer. AB - The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I-II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P(+)), the biologically effective uniform dose (D), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P(+) between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven beam plan, the differences in P(+) are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose-response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients. However, the jump from generalized to individualized radiation therapy may significantly increase the therapeutic window for patients with extreme radio sensitivity or radioresistance, provided that these are identified. Even for radiosensitive patients a simple treatment technique is sufficient to maximize the outcome, since no significant benefits were obtained with a more complex technique using seven intensity-modulated beams portals. PMID- 18448875 TI - Response of the alanine/ESR dosimetry system to MV X-rays relative to (60)Co radiation. AB - The measurand relevant in dosimetry for radiation therapy is the absorbed dose to water, D(W). The Physikalisch-Technische Bundesanstalt (PTB) has established a secondary standard for D(W) for high-energy photon and electron radiation based on electron spin resonance (ESR) of the amino acid alanine. Since the calibration is usually performed using (60)Co radiation while a huge part of the external radiation therapy is done with high-energy x-rays from linear accelerators, determination of the response is an important issue. The results presented in this paper are the most accurate ones available today with uncertainties assigned to the relative response for 8 MV and 16 MV of the order of 0.3%. The experimental results are compared to Monte Carlo simulations using the EGSnrc software package. In the appendix, it is demonstrated how mean values from repetitive irradiations and their uncertainties are obtained in a consistent way using Bayesian statistics, even in the presence of at first sight inconsistent data. It is important to note that the formulae derived to obtain the final results follow from first principles, without recurring to ad hoc solutions or simple recipes and are valid for all kinds of repetitive measurements. PMID- 18448876 TI - Strain reduction of the extensor carpi radialis brevis tendon proximal origin following the application of a forearm support band. AB - STUDY DESIGN: Experimental laboratory design. OBJECTIVES: To measure the strain at the proximal origin of the extensor carpi radialis brevis (ECRB), and to determine the influence of a forearm support band. BACKGROUND: A forearm support band is often used with the intent to decrease stresses around the origin of the wrist extensors. However, the influence of the location of the band has not been studied. METHODS AND MEASURES: The forearm support band was applied on 8 cadaver arms (mean +/- SD age, 78.4 +/- 10.3 years) and 2 experimental conditions were performed. First, strain measurements were made without applying tension to the distal ECRB tendon, then strain measurements were made with a traction force of 21.5 N being applied to the distal ECRB tendon. Strain of the proximal origin of the ECRB, 1.0 cm distal from the lateral epicondyle, was recorded using a strain gauge. The band was mounted on the forearm at distances equal to 80%, 70%, 60%, 50%, 40%, 30%, and 20% of the forearm length as measured from the wrist. Testing order was randomized. Tension applied to the band was 19.6 N. RESULTS: When no tension was applied to the ECRB, there was no statistically significant difference (P>.05) in strain values at the ECRB origin by mounting the band at any of the forearm positions. In the tension condition, the average (SD) strain with no band was 2.40% (1.40%). The average strain value of 0.85% (0.65%), when the band was mounted 80% of the forearm length proximal to the wrist, was statistically smaller than that obtained without the band (P<.05). CONCLUSIONS: The strain on the ECRB origin was less when the forearm support band was applied 80% proximal from the wrist joint. LEVEL OF EVIDENCE: Therapy, level 5. PMID- 18448877 TI - Feedforward responses of transversus abdominis are directionally specific and act asymmetrically: implications for core stability theories. AB - STUDY DESIGN: Experimental laboratory study supplemented with a repeated case study. OBJECTIVE: To examine bilateral muscle activity of the deep abdominals in response to rapid arm raising, specifically to examine the laterality and directional specificity of feedforward responses of the transversus abdominis (TrA). BACKGROUND: Based on the feedforward responses of trunk muscles during rapid arm movements, authors have concluded that the deep trunk muscles have different control mechanisms compared to the more superficial muscles. It has been proposed that deep trunk muscles such as TrA contribute substantially to the stability of the lumbar spine and that this is achieved through simultaneous bilateral feedforward activation. These inferences are based on unilateral fine wire electromyographic (EMG) data and there are limited investigations of bilateral responses of the TrA during unilateral arm raising. METHODS AND MEASURES: Bilateral fine-wire and surface EMG data from the anterior deltoid, TrA, obliquus internus (OI), obliquus externus, biceps femoris, erector spinae, and rectus abdominis during repeated arm raises were recorded at 2 kHz. EMG signal linear envelopes were synchronized to the onset of the anterior deltoid. A feedforward window was defined as the period up to 50 ms after the onset of the anterior deltoid, and paired onsets for bilateral muscles were plotted for both left and right arm movements. RESULTS: Trunk muscles from the group data demonstrated differences between sides (laterality), which were systematically altered when alternate arms were raised (directional specificity). This was clearly evident for the TrA but less obvious for the erector spinae. The ipsilateral biceps femoris and obliquus externus, and contralateral OI and TrA, were activated earlier than the alternate side for both right and left arm movements. This was a consistent pattern over a 7-year period for the case study. Data for the rectus abdominis derived from the case study demonstrated little laterality or directionally specific response. CONCLUSION: This is the first study to show that the feedforward activity of the TrA is specific to the direction of arm movement and not bilaterally symmetrical. The asymmetry of TrA activity during arm raising suggests that the interpretation of the role of TrA as a bilateral stabilizer during anticipatory postural adjustments needs to be revised. Future research needs to examine muscle synergies associated with the asymmetrical function of the TrA and the underlying mechanism associated with low load stability training. LEVEL OF EVIDENCE: Therapy, level 5. PMID- 18448878 TI - Total knee arthroplasty: muscle impairments, functional limitations, and recommended rehabilitation approaches. AB - The number of total knee arthroplasty (TKA) surgeries performed each year is predicted to steadily increase. Following TKA surgery, self-reported pain and function improve, though individuals are often plagued with quadriceps muscle impairments and functional limitations. Postoperative rehabilitation approaches either are not incorporated or incompletely address the muscular and functional deficits that persist following surgery. While the reason for quadriceps weakness is not well understood in this patient population, it has been suggested that a combination of muscle atrophy and neuromuscular activation deficits contribute to residual strength impairments. Failure to adequately address the chronic muscle impairments has the potential to limit the long-term functional gains that may be possible following TKA. Postoperative rehabilitation addressing quadriceps strength should mitigate these impairments and ultimately result in improved functional outcomes. The purpose of this paper is to describe these quadriceps muscle impairments and discuss how these impairments can contribute to the related functional limitations following TKA. We will also describe the current concepts in TKA rehabilitation and provide recommendations and clinical guidelines based on the current available evidence. LEVEL OF EVIDENCE: Therapy, level 5. PMID- 18448879 TI - The effect of skin thickness and time in the absorption of dexamethasone in human tendons using iontophoresis. AB - STUDY DESIGN: Experimental laboratory study. OBJECTIVES: To measure the transmission of dexamethasone sodium phosphate (DEX-P) using iontophoresis as a function of skinfold tissue thickness and time elapsed between treatment and tissue extraction. BACKGROUND: Iontophoresis is a modality used in physical therapy with the intent to drive medications through the skin to underlying tissues using a direct electrical current. DEX-P is the most commonly used medication with iontophoresis and is used to treat a variety of connective tissue conditions. METHODS AND MEASURES: Sixteen adults undergoing anterior cruciate ligament reconstructive surgery using the semitendinosis/gracilis autograft received a 40-mA-min dose of iontophoresis with 0.4% DEX-P superficial to a slip of the distal semitendinosis tendon prior to surgery. The tendon slip was extracted within 4 hours. Time between treatment and tissue extraction and skinfold thickness were measured. Analysis was performed on the slip of the semitendinosis using high-performance liquid chromatography mass spectrum. RESULTS: Of the 16 subjects (10 female, 6 male; mean age, 33 years), 7 had measurable amounts of DEX-P in the tendon slip (4 female, 3 male; mean age, 34 years). The average concentration in the 16 subjects was 2.9 ng/g of tendon tissue. There was no correlation between DEX-P absorbed and skinfold thickness (r = -0.08, P = .79) or time elapsed (r = 0.25, P = .38). In a subset of the 7 individuals that showed measurable levels of DEX-P absorbed, the average concentration of DEX-P was 6.6 ng/g of tendon tissue, and there was a relationship between DEX-P concentrations and time elapsed that did not reach statistical significance (r = 0.71, P = .11). CONCLUSIONS: Iontophoresis appears to facilitate the transmission of dexamethasone to connective tissues in humans with skinfold thickness up to at least 30 mm. The absorption of the dexamethasone seemed to continue to occur for up to 4 hours after delivery. It is not clear why DEX-P was measured in only 7 of the 16 subjects. LEVEL OF EVIDENCE: Therapy, level 5. PMID- 18448880 TI - The relationship between passive ankle plantar flexion joint torque and gastrocnemius muscle and achilles tendon stiffness: implications for flexibility. AB - STUDY DESIGN: Experimental laboratory study. OBJECTIVES: We tested the hypothesis that the muscle fibers and the connective tendinous structures, combined in series, provide the resistance to passive joint movement at the ankle. We also determined the relative association between passive joint torque and each of these 2 elements. BACKGROUND: The reason for individual variation in joint flexibility or tightness is not clearly understood, but the influence of musculotendinous stiffness has been inferred. METHODS AND MEASURES: Each of the subjects (6 women and 6 men) was seated with the right knee extended and right ankle positioned at a 30 degrees , 20 degrees , 10 degrees , 0 degrees , -10 degrees , -20 degrees , and -30 degrees (0, neutral position, positive values reflecting plantar flexion) angle while passive plantar flexion torque was measured. The distal muscle-tendon junction of the medial gastrocnemius was visualized by ultrasonography, and its positional change was defined as muscle belly length change. The whole muscle-tendon unit length change was estimated from joint angle changes, from which Achilles tendon length change was estimated. RESULTS: Both the muscle belly and tendon were significantly elongated as the ankle was dorsiflexed (at 0 degrees the mean +/- SD muscle belly elongation was 10.3% +/- 1.8 %, and the tendon elongation was 2.8% +/- 1.2 %, of the initial length at 30 degrees of ankle plantar flexion), from which stiffness indices were determined both for muscle belly and tendon. The passive torque at 0 degrees , 10 degrees , -20 degrees , and -30 degrees was significantly correlated with the stiffness indices of the Achilles tendon (at 0 degrees , r2 = 0.70 and 0.62 for overall and specific stiffness, respectively; P<.05). A tendon stiffness index, separately obtained from tendon lengthening during maximal isometric contraction, was also correlated with passive ankle plantar flexion torque at 0 degrees , -10 degrees , -20 degrees , and -30 degrees (at 0 degrees , r2 = 0.76; P<.05). The specific stiffness index of the muscle belly was correlated (r2 = 0.47, P<.05) with the passive ankle plantar flexion torque at 0 degrees , but its overall stiffness index was not (r2 = 0.32, P>.05). CONCLUSION: Results suggest that extensibility of the muscle-tendon unit of the Achilles tendon for the most part is related to passive ankle plantar flexion joint torque. PMID- 18448881 TI - Humeral resurfacing hemiarthroplasty with meniscal allograft in a young patient with glenohumeral osteoarthritis. AB - STUDY DESIGN: Case report. BACKGROUND: Management of glenohumeral joint osteoarthritis in young, active patients is challenging due to the significant functional limitations and progression of the disease, coupled with the limited lifespan of prosthetic implants presently in use. The purpose of this report is to present the detailed rehabilitation program and outcome of a patient who suffered an initial glenohumeral dislocation and, following multiple surgical interventions, required shoulder hemiarthroplasty and biologic glenoid resurfacing to return to function. CASE DESCRIPTION: An objectively based rehabilitation protocol was used for this patient following shoulder hemiarthroplasty. Data collected included passive and active range of motion, isometric rotational strength, and functional outcome scores to include the Single Assessment Numeric Evaluation (SANE) and American Shoulder Elbow Surgeons (ASES) outcome measures. OUTCOMES: Progressive improvements in active and passive range of motion were documented at numerous points during postoperative rehabilitation, including 1 and 2 years postoperatively. The patient's initial functional outcome scores improved from 2/100 to 90/100 in the SANE and from 17/100 to 85/100 for the ASES rating scales. At 2 years postsurgery the SANE score was 60/100 and ASES 68/100. DISCUSSION: Early postoperative range of motion exercises performed in a range protecting the subscapularis, coupled with a progressive program of rotator cuff and scapular strengthening exercises, resulted in decreased pain, improved range of motion, and return to work in a limited capacity following hemiarthroplasty with biologic glenoid resurfacing. Further research in series of patients following this procedure will help to establish optimal treatment guidelines and prognosis for young active patients with severe glenohumeral joint osteoarthritis. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 18448883 TI - On the path to sustainable publishing. PMID- 18448882 TI - Effects of dynamic head tilts on sensory organization test performance: a comparison between college-age athletes and nonathletes. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVE: To compare postural performance measures of athletes with those of nonathletes when completing the standard Sensory Organization Test (SOT) and a modified SOT that included dynamic head tilts (DHT-SOT). BACKGROUND: Authors of recently published research have suggested that modifications to the SOT protocol (eg, introduction of pitch and roll head tilts) may enhance the test's sensitivity when assessing postural stability in individuals with higher balance capabilities or with well compensated sensory deficits. METHODS AND MEASURES: Nineteen athletes and 19 nonathletes (group) completed both the SOT and DHT-SOT (protocol). During the SOT, participants stood upright as steadily as possible for 20 seconds during each of 6 different sensory conditions. As a variation of the SOT, the DHT-SOT incorporated active pitch and roll head tilts into the SOT protocol. Four 2-way mixed-model analyses of variance (with protocol as the repeated factor) were performed to determine if the composite equilibrium score or the visual, vestibular, or somatosensory ratio scores differed between the 2 groups across the 2 testing protocols. RESULTS: Significant group-by-protocol interaction effects were present for both the composite equilibrium score and visual ratio. Follow-up simple main-effects analyses indicated that these measures did not differ between groups for the SOT protocol but were significantly different on the DHT-SOT. CONCLUSIONS: The addition of dynamic head tilts to the SOT protocol resulted in subtle differences in balance function between athletes and nonathletes. Athletes demonstrated an increased ability to adapt to sensory disruptions during the DHT-SOT. Therapists should consider including active pitch and roll head tilts to the SOT when evaluating individuals with higher balance function or to detect subtle deficits in balance function. LEVEL OF EVIDENCE: Diagnosis, level 3b. PMID- 18448884 TI - Subcutaneous abscess in a patient referred to physical therapy following spinal epidural injection for lumbar radiculopathy. PMID- 18448885 TI - Investing in the research process: Nursing Health Services Research Unit - University of Toronto site. AB - Linda O'Brien-Pallas, RN, PhD, FCAHS is a Professor in the Faculties of Nursing and Medicine at the University of Toronto and Director, Co-Founder and Co Principal Investigator of the Nursing Health Services Research Unit (University of Toronto site). Dr. O'Brien-Pallas is acknowledged globally for her pioneering and innovative research in health human resources modelling, quality of work life for nurses and nursing workload measurement. The rigour of her research has been praised by respected researchers at international conferences, and her expertise is sought by governments and stakeholders at all levels in Canada and throughout the world. She is frequently called upon by the World Health Organization and the International Council of Nurses to provide high-level consultation on matters including midwifery and health human resources planning. Dr. O'Brien-Pallas has provided leadership to many boards and committees and is a co-founder of the Dorothy M. Wylie Nursing Leadership Institute, which received the 2003 Ted Freedman Award for Innovation in Education. She has received numerous awards for her research and innovative contributions to nursing, including the Canadian Nurses Association's prestigious Jeanne Mance Award in 2006. PMID- 18448886 TI - Evolution. PMID- 18448887 TI - Luddite or luminary? PMID- 18448888 TI - Building leadership capacity through peer career coaching: a case study. AB - Today's demanding healthcare environment requires resiliency, creativity and innovation in delivery of patient care and service. Hospitals must create a workplace where staff are supported to develop professionally as knowledge workers. In 2003, University Health Network (UHN) partnered with donnerwheeler, career planning and development consultants, to provide a program for its 2,700 registered nurses. One component of this project, a peer coaching program called Coach Mastery, is profiled in this case study, which describes how it was implemented and the successes, challenges and outcomes in building internal leadership capacity and supporting staff development through career planning and development. PMID- 18448889 TI - Post-doctoral training in nursing: a consideration of opportunities and strategies. AB - Launching one's career as an independent researcher can be a difficult task, especially without formal training or mentorship beyond doctoral studies. Post doctoral training offers opportunities to further develop, refine and broaden one's repertoire of research skills. The purpose of this paper is to introduce practical strategies for nurses considering post-doctoral training. Strategies addressed include selecting a post-doctoral supervisor, investigating funding sources and getting the most out of the post-doctoral experience. Suggestions are included for supervisors who wish to provide an exceptional post-doctoral learning experience. PMID- 18448890 TI - Nursing scope of practice: descriptions and challenges. AB - The nursing workforce is faced with shortages of near crisis proportions, yet little is understood about the optimal utilization of various categories of nurses - Licensed Practical Nurses (LPNs), Registered Nurses (RNs) and Registered Psychiatric Nurses (RPNs). The primary purpose in this study was to elicit the perceptions of nurses (RNs, LPNs, and RPNs) of what "working to full scope of practice" meant to them. Participants included acute care nurses in three health regions in western Canada. A key finding from the study was the fact that nurses most often discussed scope of practice by reference to the tasks they perform, rather than the roles they play in healthcare delivery. Assessment and coordination of care were two components of nursing work that most differentiated the three nursing roles. Nonetheless, insufficient role differentiation among nurses and between nurses and other healthcare professionals leaves some nurses feeling devalued and not respected for their contribution to healthcare delivery. PMID- 18448891 TI - Nursing workforce utilization: an examination of facilitators and barriers on scope of practice. AB - Several reports have highlighted the need to address underutilization of health human resources, but barriers to and facilitators of role optimization for nurses are poorly understood. The purpose in this study was to understand the perceptions of nurses - Licensed Practical Nurses (LPNs), Registered Nurses (RNs) and Registered Psychiatric Nurses (RPNs) - of the extent to which they can work to full scope of practice and identify barriers and facilitators in optimizing their roles. As part of a mixed-methods study, semi-structured interviews were conducted with 167 acute care nurses (RNs, LPNs, RPNs and nurse managers) in three western Canadian health regions. Approximately 48% of all nurses interviewed felt they were working to full scope, at least some of the time. Barriers to working to full scope included heavy workload, high patient acuity, lack of time, poor communication and ineffective teamwork. Identified facilitators were working as a team, management and leadership support and support for continuing education. Barriers need to be addressed in light of nursing shortages, as these are closely related to job satisfaction and directly affect the retention and recruitment of all groups of nurses. Policies and strategies based on these findings must be developed to ensure that nurses can work to their full scope of practice. PMID- 18448893 TI - Toward a sound philosophy of premedical education. PMID- 18448894 TI - Perspective: united we stand, divided we fall: the case for a single primary care specialty in the United States. AB - Primary care as an academic discipline and key component of the U.S. health care system faces a threatened future, despite numerous studies in the United States and cross-nationally that substantiate its health-promoting benefits. The United States remains the only Western industrialized nation that delivers primary care through three major disciplines rather than as a single specialty. This fragmented model may contribute to the fact that the United States does not have a primary-care-based health care system and that the U.S. population demonstrates poorer health outcomes than do those countries whose health systems are based on primary care and managed by a single primary care specialty. Fragmentation also creates confusion about primary care's identity, diminishes its influence because it does not speak with a common voice, and creates competition for academic and professional status, resources, curricular priority, research and training program funding, patients, and reimbursement. A large, single-specialty body of primary physicians could eliminate much duplication and competition and demonstrate greater political influence with academia, government agencies, insurers, and corporate America. A single specialty that incorporates the strengths of the three primary care disciplines would expand the clinical scope of primary care and could serve as a potent enabling force to lead health system reform. It would also produce measurable benefits for medical student and graduate medical education, health system design and service delivery, and primary care research. The author outlines a plan of action, involving all stakeholders, to initiate and achieve the single-specialty goal. PMID- 18448895 TI - The impact of increasing medical school class size on clinical clerkships: a national survey of internal medicine clerkship directors. AB - PURPOSE: To determine the impact of increasing medical school class size on the internal medicine clerkship. METHOD: In 2006, the Clerkship Directors in Internal Medicine surveyed its 110 institutional members to discover whether their medical school class size had increased (or would increase) and the impact of increasing class size on number of students per teaching site, number of clerkship sites needed, and resources needed. Respondents rated their agreement or disagreement with statements about increasing class size, and they provided free-text responses. Analyses included descriptive statistics and qualitative analysis. RESULTS: Response rate was 76% (83/110). In the three years preceding the survey, one medical school decreased class size; 43% increased by a mean of 14 students per year (10%). Most respondents (51%) expected class size to increase by a mean of 17 students per year (12%) through 2009; none expected class size to decrease. Increasing class size by 15% would mean adding 3.7 (standard deviation = 2.2) students per inpatient site, 2.9 (2.9) new inpatient sites, 3.0 (2.2) students per ambulatory site, and 4.9 (5.5) ambulatory sites. Respondents disagreed with the questionnaire statements that they would have more resources, teachers, and protected time; they agreed with statements that recruiting teachers would be harder as class size increases. Free-text responses to the challenges of increasing class size revealed two themes: strain on resources (space, time, faculty), and the impact on the educational experience. CONCLUSIONS: Internal medicine clerkship directors believe increasing medical school class size will dramatically increase resources needed during clerkships and may adversely impact education. PMID- 18448896 TI - Perspective: the case for subspecialty clinical learning in early medical education-moving from case-based to patient-based learning. AB - The subspecialty departments are greatly underutilized for teaching during the first two years of medical school. While second-year students are spending most of their time behind closed doors in the laboratory, lectures, and small groups, the clinical environment is teeming with actual patients whose cases are often directly analogous to the material being learned. Moreover, even in today's environment of increased emphasis on quality of medical care and medical education reform, many U.S. medical students still lack essential exposure to common technologies, tests, and procedures performed within several subspecialties. To remedy this situation, the authors propose that educators develop a system of subspecialty clinical learning for first- and/or second-year students correlated to the classroom study of the pathophysiology of the various organ systems. For example, the second-year cardiology course could be augmented with self-directed, patient-centered learning assignments in the cardiac unit, the pathology lab, the echo lab, and other areas. The authors explain the several advantages of comprehensive subspecialty clinical learning (e.g., it will help prepare physicians to practice distributed care, aid development of competencies within the behavioral and social sciences, foster students' professional development, and encourage creative approaches to issues of health care quality). The authors acknowledge the multiple difficulties of implementing such an approach, and present evidence supporting their argument that with the appropriate vision and leadership, such a living curriculum is important and achievable. PMID- 18448897 TI - Preparing medical students for clerkships: a descriptive analysis of transition courses. AB - Students have reported several challenging aspects of the transition to clerkships, such as applying clinical knowledge, learning experientially, using clinical skills, adjusting to clinical settings, and understanding roles. In an effort to address some of these challenges, a number of medical schools have added transition courses to their curricula, but little information about these courses has been published. The authors draw on findings from a study of the design and content of 30 transition courses offered in U.S. medical schools, to examine various approaches and provide a framework to guide the design of transition courses. Most courses (83%) were between one day and one week long. The authors identified three primary course themes: presentation of new information and skills, review and application of content covered in the preclerkship curriculum, and student well-being. All courses presented new information and skills, and more than half of the courses (53%) addressed all three themes. The most common curricular topics were technical/procedural skills, safety precautions, orientation to clinical settings, review of clinical skills, and stress management. Hands-on experience was the most frequently used instructional approach. Few courses had explicit goals and objectives, and evaluation of students was rare. Transition courses can address some of the needs and challenges associated with early clerkship experiences. These courses should explicitly target areas of need that are described in the literature as well as those identified within one's own institution. They should include clear objectives, learning activities tailored to the areas of need and objectives, and student and course evaluations. PMID- 18448899 TI - What makes a good clinical teacher in medicine? A review of the literature. AB - PURPOSE: The authors perform a review of the literature pertinent to the question, "What makes a good clinical teacher in medicine?" METHOD: After framing the question, based on discussions of their own experiences with clinical teachers, the authors performed a search of the literature pertinent to the question, "What are the qualities of a good clinical teacher in medicine?" Between July and December, 2006, they reviewed titles from Index Medicus (1909 1966), PubMed (1966 to the present), PubMed Related Articles, and referenced articles. The initial selections were chosen by scanning pre-1966 Index Medicus title lists and post-1966 abstracts. Chosen articles were then read in their entirety, and those which described specific characteristics of clinical teachers were selected for inclusion. Qualitative analysis was used to identify themes. RESULTS: From 4,914 titles, 68 articles were selected for analysis-26 published before 1966, and 42 published after 1966. Four hundred eighty descriptors were identified and grouped into 49 themes, which were clustered into three main categories: physician, teacher, and human characteristics. Echoing the authors' intuitive descriptions, noncognitive characteristics dominated the descriptions and themes. CONCLUSIONS: Excellent clinical teaching, although multifactorial, transcends ordinary teaching and is characterized by inspiring, supporting, actively involving, and communicating with students. Faculty development programs and future research should focus on development of the noncognitive attributes of clinical teachers, as well as the knowledge and skills associated with effective teaching. PMID- 18448900 TI - Longitudinal pedagogy: a successful response to the fragmentation of the third year medical student clerkship experience. AB - A longitudinal clerkship was designed at Harvard Medical School (HMS) in 2004 2005 to emphasize continuity, empathy, learner-centeredness, and patient-centered care. In 2005-2006, the curriculum was piloted with eight students who voluntarily enrolled in the third-year curriculum, which focused on longitudinal mentorship and feedback, interdisciplinary care, integration of clinical and basic science, and humanism in patient care. Eighteen traditional curriculum (TC) students at HMS who were comparable at baseline served as a comparison group. SHELF exams and OSCE performance, monthly and end-of-year surveys, and focus groups provided comparisons between pilot and TC students on their performance, perceptions, attitudes, and satisfaction. Pilot students performed as well as or better than their peers in standardized measures of clinical aptitude. They demonstrated statistically significant greater preservation of patient-centered attitudes compared with declining values for TC students. Pilot students rated the atmosphere of learning, effective integration of basic and clinical sciences, mentorship, feedback, clerkship satisfaction, and end-of-year patient-care preparedness significantly higher than TC students. The authors conclude that implementation of a longitudinal third-year curriculum, with only modest alterations in existing clinical training frameworks, is feasible and effective in meeting its stated goals. "Exposing" the hidden curriculum through specific longitudinal activities may prevent degradation of student attitudes about patient-centered care. Minimizing the disjointed nature of clinical training during a critical time in students' training by providing a cohesive longitudinal curriculum in parallel to clinical clerkships, led by faculty with consistent contact with students, can have positive effects on both professional performance and satisfaction. PMID- 18448902 TI - Burnout in medical school deans: an uncommon problem. AB - PURPOSE: To assess the burnout level among U.S. and Canadian medical school deans and to study how burnout relates to certain characteristics including hours worked, effectiveness, and support from family and colleagues. METHOD: Questionnaires were sent in September 2006 to 100 deans who had served at least one year. The questionnaire included 13 questions from the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), which measures three subcomponents of burnout: emotional exhaustion, depersonalization, and personal accomplishment. RESULTS: The response rate was 90%. The median age of participants was 60; the median length of service at the current institution was four years; the median number of hours worked per week was 70.0. Deans most frequently identified school budget deficits, loss of funding, and departure of key faculty as stressors. Whereas only 11% reported being dissatisfied with their positions, 33% reported it was likely they would step down within the next two years. The predominant pattern of MBI-HSS subscale scores in participating deans was moderate emotional exhaustion, moderate depersonalization, and high personal accomplishment. Only 2% of respondents satisfied all three subscale scores for high burnout. Emotional exhaustion was significantly directly associated with work week length and number of weekend days worked and was inversely associated with spousal support, length of service, and age. CONCLUSIONS: Despite having an "extreme" job, only 2% of deans exhibited high levels of burnout. A high sense of control and self efficacy, a supportive family, increasing length of service, and increasing age may be factors which reduce burnout in deans. PMID- 18448903 TI - Qualities of the medical school dean: insights from the literature. AB - PURPOSE: To review the literature and resources for professional development of medical school executives in order to identify the characteristics proposed as relevant to medical school deanship. METHOD: In 2006, the authors conducted a PubMed search using the key words leadership, dean, medical school, and academic medical center to identify relevant publications since 1995. Articles were excluded that that did not address the roles and responsibilities of the North American medical school dean. Articles gleaned through review of materials from relevant executive development programs and interviews with leaders involved in these programs were added. RESULTS: Both management skills (e.g., institutional assessment, strategic planning, financial stewardship, recruitment and retention of talent) and leadership skills (e.g., visioning, maximizing values, building constituency) are commonly cited as important deans of contemporary medical schools. Key content knowledge (e.g., academic medical center governance, expectations of clinicians and scientists, process of medical education) and certain attitudes (e.g., commitment to the success of others, appreciation of institutional culture) are also noted to be valuable qualities for medical school deans. CONCLUSIONS: The literature review identifies a number of areas of knowledge and skill consistently affirmed by scholars as important to success for medical school deans. These characteristics can provide a basic foundation for needs assessment and professional development activities of academic medical executives preparing for and entering medical school deanships, and they can also provide insight to those charged with selecting their next dean. PMID- 18448905 TI - Medicine and the arts. Visitation by John Stone. Commentary. PMID- 18448904 TI - Evaluating a leadership program: a comparative, longitudinal study to assess the impact of the Executive Leadership in Academic Medicine (ELAM) Program for Women. AB - PURPOSE: The Hedwig van Ameringen Executive Leadership in Academic Medicine (ELAM) program provides an external yearlong development program for senior women faculty in U.S. and Canadian medical schools. This study aims to determine the extent to which program participants, compared with women from two comparison groups, aspire to leadership, demonstrate mastery of leadership competencies, and attain leadership positions. METHOD: A pre-/posttest methodology and longitudinal structure were used to evaluate the impact of ELAM participation. Participants from two ELAM cohorts were compared with women who applied but were not accepted into the ELAM program (NON) and women from the Association of American Medical Colleges (AAMC) Faculty Roster. The AAMC group was a baseline for midcareer faculty; the NON group allowed comparison for leadership aspiration. Baseline data were collected in 2002, with follow-up data collected in 2006. Sixteen leadership indicators were considered: administrative leadership attainment (four indicators), full professor academic rank (one), leadership competencies and readiness (eight), and leadership aspirations and education (three). RESULTS: For 15 of the indicators, ELAM participants scored higher than AAMC and NON groups, and for one indicator they scored higher than only the AAMC group (aspiration to leadership outside academic health centers). The differences were statistically significant for 12 indicators and were distributed across the categories. These included seven of the leadership competencies, three of the administrative leadership attainment indicators, and two of the leadership aspirations and education indicators. CONCLUSIONS: These findings support the hypothesis that the ELAM program has a beneficial impact on ELAM fellows in terms of leadership behaviors and career progression. PMID- 18448907 TI - Perspective: the unintended consequences of training residents in dysfunctional outpatient settings. AB - In the past 25 years, academic leaders and accreditation bodies in internal medicine and pediatrics have made multiple efforts to increase residents' exposure to ambulatory primary care medicine, to bring hospital-based residency training more in line with the career paths of graduates. Current proposals continue the trend of increasing ambulatory exposure through providing more clinical hours in the outpatient setting as a pedagogic strategy to improve residents' practical skills in providing quality care in outpatient settings. Resident clinics, however, are often understaffed and dysfunctional. Under these circumstances, the work environment encourages some residents to learn only that providing high-quality primary care is a frustrating and unrewarding form of labor. Leaders in medicine have used innovative organizational strategies to improve residents' outpatient experiences. Model primary care residency programs and clinics have been created. The diffusion of model primary care clinical practices and structures is, however, limited by the strain of generating sufficient clinical revenue to run an academic medical center efficiently and reliably in the current environment. Increased outpatient exposure, without attention to the quality of practice settings, is potentially counterproductive, generating an unintended consequence that is the opposite of the goals of policy: it may reinforce residents' interest in subspecialty practice. PMID- 18448909 TI - The leaky pipeline: factors associated with early decline in interest in premedical studies among underrepresented minority undergraduate students. AB - PURPOSE: To determine the causes among underrepresented racial and ethnic minority groups (URM) of a decline in interest during the undergraduate years in pursuing a career in medicine. METHOD: From fall 2002 through 2007, the authors conducted a longitudinal study of 362 incoming Stanford freshmen (23% URM) who indicated on a freshman survey that they hoped to become physicians. Using a 10 point scale of interest, the authors measured the change in students' levels of interest in continuing premedical studies between the beginning of freshman year and the end of sophomore year. Follow-up interviews were conducted with 68 participants, approximately half of whom had experienced decreases in interest in continuing as premeds, and half of whom who had experienced increases in interest. RESULTS: URM students showed a larger decline in interest than did non URM students; women showed a larger decline than did men, independent of race or ethnicity. The authors found no association between scholastic ability as measured by SAT scores and changes in level of interest. The principal reason given by students for their loss of interest in continuing as premeds was a negative experience in one or more chemistry courses. Students also identified problems in the university's undergraduate advising system as a contributor. CONCLUSIONS: Largely because of negative experiences with chemistry classes, URM students and women show a disproportionate decline in interest in continuing in premedical studies, with the result that fewer apply to medical school. PMID- 18448910 TI - Addressing medical school diversity through an undergraduate partnership at Texas A&M Health Science Center: a blueprint for success. AB - Imperative to increasing diversity in the physician workforce is increasing the pool of qualified underrepresented minority applicants to medical schools. With this goal in mind, the Texas A&M Health Science Center College of Medicine (A&M College of Medicine) has partnered with Prairie View A&M University (PVAMU), a historically black college and university that is a component of the Texas A&M university system, to develop the undergraduate medical academy (UMA). The UMA was established by legislative mandate in 2003 and is a state-funded program. The authors describe the development of partnership between the A&M College of Medicine and PVAMU, focusing on the key attributes that have been identified for success. The administrative structure of the UMA ensures that the presidents of the two institutions collaborate to address issues of program oversight and facilitates a direct relationship between the dean and associate dean for academic affairs of A&M College of Medicine and the director of the UMA to define the program objectives and structure. The authors delineate the admission process to the UMA, as well as the academic requirements of the program. Students attend lecture series during the academic year and participate in summer programs on the A&M College of Medicine campus in addition to receiving intensive academic counseling and opportunities for tutoring in several subjects. The authors also describe the initial success in medical school admissions for UMA students. This partnership provides a model blueprint that can be adopted and adapted by other medical schools focused on increasing diversity in medicine. PMID- 18448911 TI - Perspective: after a century of criticizing premedical education, are we missing the point? AB - Ever since Abraham Flexner formalized the idea of premedical education in 1910, medical educators have argued about how best to prepare students for medical school. This back-and-forth about the premedical years has focused almost exclusively on the range and content of the required course work; noticeably absent from the debate is consideration of the ways in which the experience of the premedical years-including the curricular and noncurricular demands placed on students-shape the moral education of the next generation of physicians. The authors review the century-long conversation about premedical education, highlighting the themes of that discussion and the important aspects of being a "premed" that have not been a part of the conversation. From their systematic review of college and university Web sites designed for premedical students and from comments collected from a symposium on the premedical years, the authors describe how life as a premedical student, and not just curricular content, teaches important lessons about what it means to be a professional. The authors also report important disparities in attitudes about premedical education; for example, premedical advisors regard the "sifting process" of premedical education as a "journey of discovery," whereas students describe their premedical years as a competition. The authors' work suggests a new approach to premedical education, an approach that combines the coursework needed to succeed in medical school with formal opportunities to reflect on both the positive and pernicious effects of the premedical years. PMID- 18448912 TI - It's okay not to know. PMID- 18448913 TI - Perspective: fostering biomedical literacy among America's youth: how medical simulation reshapes the strategy. AB - Medicine is a uniquely powerful platform for teaching science and ethics, technology and humanity, life and death. Yet, society has historically limited medical education to a select few, and only after an advanced course of premedical studies. In an era when biomedical literacy is increasingly viewed as a national imperative, the authors hypothesized that advanced instruction in medicine could be intellectually transformative among a broad range of young people. Using high-fidelity patient simulators, a group of college and high school students was immersed in a weeklong course designed to replicate the practice of modern medicine. On the basis of the students' reported experiences, the authors feel that patient simulation can foster forceful interest in the life sciences at an early age. Such efforts could catalyze a significant expansion of interest in biomedical science among students nationwide. PMID- 18448914 TI - Albert Einstein College of Medicine. PMID- 18448916 TI - From acute renal failure to acute kidney injury: emerging concepts. PMID- 18448917 TI - Trust one who has gone through it. PMID- 18448918 TI - What is the score with mortality predictions in acute lung injury? PMID- 18448920 TI - The interleukin-6 gene and critical illness: is inflammatory gene variation the key to personalized medicine in the intensive care unit? PMID- 18448919 TI - Can B-type natriuretic peptide liberate us from the task of mechanical ventilation weaning? PMID- 18448921 TI - Should sedation be standardized in the intensive care unit? PMID- 18448922 TI - Between critical illness and hospital discharge: prolonged acute mechanical ventilation. PMID- 18448923 TI - Genes and sepsis: how tight is the fit? PMID- 18448924 TI - Lost in (knowledge) translation: "All breakthrough, no follow through"? PMID- 18448925 TI - Delayed gastric emptying in critical illness: is enhanced enterogastric inhibition with cholecystokinin and peptide YY involved? PMID- 18448926 TI - Does sugar cause clotting? Intensive insulin treatment and activation of coagulation. PMID- 18448927 TI - Corticosteroids and septic shock: a new episode of a never-ceasing story? PMID- 18448928 TI - Enhanced and earlier detection of bacteremia and fungemia by multiplex polymerase chain reaction: how much enhanced, how much earlier, and at what cost? PMID- 18448929 TI - The transfusion of pre storage leukoreduced packed red blood cells to injured patients. PMID- 18448930 TI - Continuous infusion of beta-lactams in the intensive care unit--best way to hit the target? PMID- 18448931 TI - Continuous renal replacement therapy-induced alkalosis in intensive care unit patients: the questions start here. PMID- 18448932 TI - Moving toward preventive therapy in acute lung injury. PMID- 18448933 TI - Life after intensive care--it's life... but not as we know it! PMID- 18448934 TI - Pyrexia of uncertain overtones. PMID- 18448935 TI - Hydroxyethyl starch: under the microscope. PMID- 18448936 TI - Novel molecular strategy to prevent pulmonary edema. PMID- 18448937 TI - The insulin, glucose, ischemia, and inflammation conundrum. PMID- 18448938 TI - Teasing and skinning muscles in sepsis research. PMID- 18448939 TI - Hypothermia hype: is it worth it? PMID- 18448940 TI - Flow or no flow: that is the question! PMID- 18448941 TI - Strategies to reduce neuronal cell death in bacterial meningitis. PMID- 18448942 TI - E-CPR... is there E-nough E-vidence to reach a "tipping point" for rapid deployment? PMID- 18448943 TI - Atrial fibrillation in the critically ill: common sense for a common problem. PMID- 18448944 TI - What do families know? A question of interpretation. PMID- 18448945 TI - Calcitonin peptides--the mediators in sepsis or just another fairy tale? PMID- 18448947 TI - When does a point of view become an intellectual conflict of interest? PMID- 18448948 TI - Does orthogonal polarization spectral imaging really visualize the "micro" vasculature? Yes it does! PMID- 18448949 TI - Acid-base balance. PMID- 18448951 TI - The effect of positive expiratory pressure and tracheal tube cuff type on pulmonary aspiration. PMID- 18448953 TI - Pressure support ventilation: a significant confounding factor in the determination of the rapid shallow breathing index. PMID- 18448957 TI - Delayed oxygenation assessment in patients with severe community-acquired pneumonia. PMID- 18448958 TI - Hydroxyethyl starch 130/0.4: safe in cardiac surgery? PMID- 18448959 TI - Empiric antibiotic therapy for suspected ventilator-associated pneumonia. PMID- 18448961 TI - Normobaric hyperoxia--a further treatment option following traumatic brain injury? PMID- 18448964 TI - Recently identified factors predisposing children to infectious diseases. AB - PURPOSE OF REVIEW: To identify articles published between January 2006 and January 2008 that have significantly enhanced our understanding of why some children are prone to severe or recurrent infectious diseases. RECENT FINDINGS: Significant inroads into the genetic basis of immune disorders leading to severe and recurrent infections in children have been made over the last few years. We now understand the specific susceptibility to herpes simplex virus encephalitis, the underlying cause of hyper IgE and Hermansky-Pudlak type 2 syndromes, as well as further explanations for the genotypic/phenotypic variations in severe combined immunodeficiency, common variable immunodeficiency and congenital neutropenia syndromes. Virulence factors for Staphylococcus aureus and Plasmodium falciparum have also been identified, and disease pathophysiology of respiratory syncytial virus related bronchiolitis and of acute pyelonephritis are better understood. SUMMARY: Progress in this area continues to be rapid. Clinicians now have the knowledge and techniques to explain why many children develop infectious diseases. PMID- 18448965 TI - Diagnostic tests in neonatal sepsis. AB - PURPOSE OF REVIEW: The present review examines the major developments in early detection of neonatal sepsis, with an emphasis on the utility of diagnostic laboratory markers in clinical practice. RECENT FINDINGS: Measures of acute phase proteins, cytokines, cell surface antigens, and bacterial genomes have been used alone or in combination to improve diagnosis of neonatal sepsis. Most studies evaluating laboratory diagnostic markers are retrospective cohorts or single center experience with relatively small sample size. Interpretation of these studies is confounded by inconsistent definitions of sepsis, heterogeneous sample populations, and different thresholds for diagnostic markers. Furthermore, many diagnostic markers are not available for routine care, they require specialized analytical procedures, and are expensive to perform. SUMMARY: A better understanding of the neonatal inflammatory response to sepsis and identification of sensitive and specific markers of inflammation or rapid microbe-specific diagnostic tests would assist in the early detection of neonatal sepsis and in safely withholding antibiotics for patients in whom sepsis is unlikely. PMID- 18448966 TI - Healthcare-associated infections in neonates. AB - PURPOSE OF REVIEW: To identify important findings in the recent literature related to healthcare-associated infections in neonatal care. RECENT FINDINGS: Bloodstream infection remains the leading healthcare-associated infection in the neonatal unit, but multimodal interventions have been shown to successfully reduce this life-threatening complication. Emerging pathogens such as methicillin resistant Staphylococcus aureus, extended-spectrum-beta-lactamase-producing Gram negative organisms and pan-resistant Acinetobacter baumannii or Serratia marcescens complicate the use of standard antibiotic treatment and are a particular concern in this setting because of the limitation in antibiotic classes among neonates. Community-acquired methicillin-resistant S. aureus infections are increasing in frequency and are particularly worrisome. Fluconazole prophylaxis offers a simple solution for the prevention of invasive Candida infection and has been already widely adopted. Although there is evidence for its efficacy, there is still some debate about the pros and cons of azole prophylaxis in the prevention of invasive Candida infections. Furthermore, its use in low-prevalence settings remains highly questionable. The introduction of restrictive guidelines limiting the use of antibiotics in early-onset neonatal infections has proved to be safe and efficient and may also reduce the incidence of late-onset infection. Outbreaks remain an ongoing concern in neonatal care and are increasingly complicated by emerging multiresistant pathogens. SUMMARY: Healthcare-associated infections remain a permanent challenge among neonates. PMID- 18448967 TI - Effectiveness of impregnated central venous catheters for catheter related blood stream infection: a systematic review. AB - PURPOSE OF REVIEW: Clinicians need information on the relative effectiveness of different types of impregnated central venous catheter for serious infection and their relative costs and adverse effects in order to decide which type, if any, to use. RECENT FINDINGS: We systematically reviewed 37 randomized controlled trials involving 11 586 patients. Only seven studies were classified as good on all measures of study quality. Compared with standard catheters, significant and substantial reductions in catheter-related blood stream infection were found for heparin-coated and antibiotic-impregnated central venous catheters. We found no statistically significant benefits of antiseptic central venous catheters, coated with chlorhexidine and silver sulphadiazine, or sliver-impregnated central venous catheters, compared with standard catheters. The few 'head-to-head' comparisons confirmed the benefits of antibiotic impregnation compared with chlorhexidine and silver sulphadiazine or silver impregnation, but no significant difference was found for heparin-coated compared with silver-impregnated central venous catheters. No studies reported serious adverse events, but there is some evidence of antibiotic resistance from in-vitro studies. No impregnated central venous catheter exists for neonates weighing less than 3 kg, and few studies have been undertaken in larger children. SUMMARY: The most promising options for reducing catheter-related blood stream infection are heparin-coated or antibiotic impregnated central venous catheters. Large, high-quality randomized controlled trials are needed to evaluate which of these methods is most effective for reducing clinically important consequences of catheter-associated infection. PMID- 18448968 TI - Fungal prophylaxis in very low birth weight neonates: nystatin, fluconazole or nothing? AB - PURPOSE OF REVIEW: To examine recent evidence on the efficacy of antifungal prophylaxis to prevent neonatal systemic fungal infection. The review also aims to examine other relevant data, including the incidence of fungal infection, adverse effects of antifungal therapy and avoidable risk factors. RECENT FINDINGS: There is strong evidence that systemic fluconazole prophylaxis reduces the incidence of systemic fungal infections, with a trend towards reduction in mortality. However, the preprophylaxis incidence of fungal infection has been very high in the published studies. Fluconazole use is sometimes associated with cholestasis and there are theoretical concerns as well that prophylactic fluconazole will select for fluconazole-resistant organisms and nonalbicans Candida infections. There is reasonable evidence that oral nystatin is effective in preventing fungal infections and at the same time it is inexpensive and well tolerated. The reported incidence of systemic fungal infections is much lower in the UK than in the USA and Italy. SUMMARY: Oral nystatin prophylaxis is inexpensive, effective and nontoxic and should be used routinely for babies of birth weight less than 1500 g. Systemic fluconazole, which is more toxic and may select for resistant fungi, is probably only indicated when the rate of fungal infection remains high despite introducing measures targeting known risk factors for fungal infection. These measures include introducing enteral feeds early, reducing the duration of parenteral feeding, and reducing the use of broad spectrum antibiotics, particularly cephalosporins. Future studies of prophylactic fluconazole should use oral nystatin, not placebo, as the comparator. PMID- 18448970 TI - Acute haematogenous osteomyelitis in children: is there any evidence for how long we should treat? AB - PURPOSE OF REVIEW: Despite diagnostic and therapeutic advances, acute haematogenous osteomyelitis in children continues to cause significant morbidity and disease burden. The molecular epidemiology of causal organisms has wide geographic variation, but regardless of cause children often require several weeks of inpatient parenteral antibiotic therapy. This review focuses on antibiotic treatment and length of antibiotic therapy. RECENT FINDINGS: Currently there is no international and little local consensus regarding the route or duration for antibiotic treatment of acute haematogenous osteomyelitis in children. Although there are encouraging data from review papers and case series, no randomized controlled trial has been conducted to show good evidence for shorter courses of parenteral antibiotic treatment. Prospective studies show effective treatment for a wide variety of antibiotic agents, but there are few comparative studies. Overall treatment for 4-6 weeks is considered standard therapy, but the laboratory or clinical parameters that would determine the decision to switch to oral therapy remain undefined. SUMMARY: Evidence-based data about the route and duration of intravenous antibiotic treatment for acute haematogenous osteomyelitis in children are still limited to observational and retrospective studies. A randomized controlled trial will provide much needed data. PMID- 18448969 TI - Emerging aspects of rabies infection: with a special emphasis on children. AB - PURPOSE OF REVIEW: Increased awareness of the long-neglected rabies virus could promote the highly effective methods of preventing human deaths. Rabies and rabies-related lyssaviruses have recently been appearing in unexpected places, sometimes with dire consequences. Although rabies of canine origin remains 100% fatal in human beings, should the surprising recovery of a single unvaccinated child influence treatment now? RECENT FINDINGS: Evidence of rabies-related lyssavirus infection of bats is increasing across continents and with new virus types. Human rabies has been misdiagnosed as cerebral malaria, or even drug abuse. Organ transplant recipients have been infected. The first unvaccinated patient, a teenager, bitten by a bat, recovered from rabies encephalitis, but why might this be? Highly effective control and prevention of infection is possible. Preexposure prophylaxis for schoolchildren could now become routine. Improved economical intradermal postexposure vaccine regimens could increase the availability of affordable treatment in developing countries. Controlling dog rabies could prevent 95% of human deaths, but education and resources are lacking. SUMMARY: The risks and problems of rabies and other lyssaviruses vary greatly across the world. Knowledge of epidemiology and prevention could save the lives of victims of animal bites and promote efforts to control and even eliminate dog rabies. PMID- 18448971 TI - Kawasaki disease: an overview. AB - PURPOSE OF REVIEW: Kawasaki disease is an acute, self-limited vasculitis of childhood. The increasing frequency of the disease as well as the deficiency of specific diagnostic means renders its diagnosis and treatment an area of intense investigation. The purpose of this review is to summarize all the known features of Kawasaki disease and also give an insight to the latest findings. RECENT FINDINGS: Kawasaki disease is one of the leading causes of acquired heart disease in children while its cause remains essentially unknown. Viruses, bacterial conventional as well as superantigens, and genetic polymorphisms have been implicated in the etiology of the disease. Markers of inflammation, such as CCL2 and CCXCL10, contribute to the pathology and the diagnosis of Kawasaki disease. Intravenous administration of immunoglobulin remains the mainstay of therapy for Kawasaki disease. Nevertheless, forms of the disease refractory to intravenous administration of immunoglobulin therapy may respond to aspirin, corticosteroids, cyclophosphamide, and/or plasmapheresis. SUMMARY: The present review covers evidence regarding the history of Kawasaki disease, the epidemiology, etiology, pathology, genetic influences, and long-term sequela. It also includes an evaluation of contemporary diagnostic techniques and optimal therapeutic approaches with an emphasis on recent publications. PMID- 18448972 TI - Multiple sclerosis: immunopathogenesis and controversies in defining the cause. AB - PURPOSE OF REVIEW: Multiple sclerosis is a major cause of neurological disability in Western societies. The most important reason for the limited success obtained in the treatment and prevention so far is most likely related to the limited knowledge about its cause and pathogenesis. This paper discusses recent progress and controversies in the understanding of the pathogenesis and cause of multiple sclerosis. RECENT FINDINGS: Both T helper cells type 1 (Th1 cells), Th17 cells, cytotoxic T cells, B cells and regulatory T cells are involved in the inflammatory process. Axonal loss seems to be driven by inflammation during the early stages of disease but may become independent of inflammation at later stages. The target antigen of the immune response has not been identified. Weak genetic association has been established in two cytokine receptors, whereas increasing female: male ratio support the importance of environmental risk factors. A substantial proportion of intrathecal B cells are infected with Epstein-Barr virus. SUMMARY: Multiple sclerosis is a complex disease and calls for integrated efforts from immunology, epidemiology, neuroscience and genetics. In particular, the immunological implications of environmental risk factors such as vitamin D desufficiency, smoking and Epstein-Barr virus infection need to be explored. PMID- 18448973 TI - Mycobacterial interaction with innate receptors: TLRs, C-type lectins, and NLRs. AB - PURPOSE OF REVIEW: The recent discovery of novel classes of receptors, including toll-like receptors and nucleotide-binding oligomerization domain (NOD)-like receptors is challenging the crucial role of the innate immune system in the recognition of Mycobacterium tuberculosis. The present review is to focus on the roles and mechanisms of specific pattern-recognition receptor-microbial interaction for the host defense against mycobacterial infections. RECENT FINDINGS: Toll-like receptors, key players in innate immunity, are now known to be important for the initiation and coordination of host responses to Mycobacterium tuberculosis. The interaction of Mycobacterium tuberculosis with toll-like receptors triggers intracellular signaling cascades that culminate in a proinflammatory response, but can also trigger signals that dampen the innate immune response. Other membrane-bound pattern-recognition receptors, including the mannose receptor, DC-SIGN, and Dectin-1, contribute to the propagation of Mycobacterium tuberculosis inflammatory signals, and Nod-like receptors (cytosolic pattern-recognition receptors) also act in modulating host recognition of Mycobacterium tuberculosis. Interactions between toll-like receptors and other pattern-recognition receptors are also evident in responses to Mycobacterium tuberculosis, as are possible mechanisms for coordination of innate and adaptive immunity. SUMMARY: The complexity of Mycobacterium tuberculosis-pattern recognition receptor interactions and their effects on host cell responses suggest key roles for innate immunity in controlling Mycobacterium tuberculosis, and the possibility of developing novel therapeutics for tuberculosis that target Mycobacterium tuberculosis-regulated innate immunity pathways. PMID- 18448974 TI - Current concepts in immunoregulation and pathology of human Chagas disease. AB - PURPOSE OF REVIEW: Chagas disease is a complex ailment caused by infection with Trypanosoma cruzi. It afflicts millions in Latin America. Years of studies have focused on the development of pathology in Chagas disease and recent studies have helped us understand the cellular mechanisms behind differential clinical evolution of Chagas disease. RECENT FINDINGS: We discuss recent findings concerning the cellular immune response in human Chagas disease focusing on immunoregulation and the development of pathology. We seek to put several findings into the context of a disease that initially controls an extreme and patent infection, and later progresses to a chronic phase marked by the presence (cardiac and digestive forms), or not (indeterminate form), of associated pathology. SUMMARY: Several theories exist to explain differential clinical evolution of Chagas disease. A coherent understanding of these theories will certainly aid in determining what combination of them approximates the true development of chagasic pathology. For achieving the goal of developing a successful therapy or intervention, it is critical that no theory be excluded at this point, but. Rather, rather that a thoughtful analysis and assimilation of the best components of each system into a central theory that best fits the reality of human Chagas disease is desirable. PMID- 18448975 TI - Mechanisms of shock in hantavirus pulmonary syndrome. AB - PURPOSE OF REVIEW: Despite abundant literature on hantavirus, few reports have focused on the shock in hantavirus pulmonary syndrome. This review approaches recent advances that allow us to better understand the pathogenesis of hantavirus pulmonary syndrome shock. RECENT FINDINGS: Hantavirus pulmonary syndrome has been studied in a hamster model that mimics human shock and respiratory failure. In vitro experiments show that pathogenic hantaviruses are able to inhibit antiviral responses, and that cytotoxicity of hantavirus-specific T cells enhances the permeability of infected endothelial cells. The idea that the primary cardiac lesion of shock is mostly functional has been shaken by the report of a typical myocarditis in hearts from human hantavirus pulmonary syndrome fatal cases. The involvement of regulatory T cells on hantavirus persistence in its rodent reservoir suggests that these cells could protect from severe hantavirus pulmonary syndrome and shock. SUMMARY: Hantavirus pulmonary syndrome shock is probably related to an exacerbated immune response of CD8+ T cells producing cytotoxicity on infected endothelial cells, presence of myocarditis and myocardial depression induced by nitric oxide. The virulence elements in G1 glycoprotein could also contribute to shock. Active suppression of immune T regulatory cells is probably involved in hantavirus pulmonary syndrome pathogenesis. These are all new aspects of hantavirus pulmonary syndrome pathogenesis that stimulate further studies to elucidate mechanisms of shock and to develop effective treatment strategies. PMID- 18448976 TI - Hepatitis B: modern concepts in pathogenesis--APOBEC3 cytidine deaminases as effectors in innate immunity against the hepatitis B virus. AB - PURPOSE OF REVIEW: APOBEC3 editing enzymes inhibit retroviruses by cytidine deamination in minus-strand cDNA, leading to G to A hypermutated proviruses, and by less well characterized inhibition of retroviral replication independently of catalysis. This review focuses on the effects of APOBEC3 enzymes on the pararetrovirus hepatitis B virus. RECENT FINDINGS: The cytidine deaminases APOBEC3B, APOBEC3C, APOBEC3F and APOBEC3G deaminate cytidine residues in hepatitis-B-virus minus-strand cDNA, resulting in G to A hypermutated genomes in the serum of hepatitis-B-virus-infected patients. APOBEC3B, APOBEC3F and APOBEC3G directly inhibit hepatitis-B-virus reverse transcription independently of deaminase activity. In human liver, APOBEC3B, APOBEC3F and APOBEC3G are expressed to low levels, but in human primary hepatocytes stimulated with interferon-alpha, APOBEC3G is induced to levels sufficient for hepatitis-B-virus inhibition. APOBEC3B inhibits hepatitis-B-virus gene transcription, and APOBEC3B and APOBEC3G preferentially mutate the hepatitis-B-virus x gene leading to the truncated hepatitis-B-virus x variants in hepatitis-B-virus-associated liver cancer. SUMMARY: The interferon-inducible APOBEC3G and the other APOBEC3s restrict hepatitis B virus by cytidine deamination in hepatitis-B-virus minus-strand cDNA and by direct inhibition of hepatitis-B-virus reverse transcriptase. The nuclear localized APOBEC3B is implicated in liver cancer development. To what extent these enzymes contribute to noncytolytic clearance of hepatitis B virus in vivo remains to be defined, yet the APOBEC3 cytidine deaminases are likely to play a role in these processes. PMID- 18448977 TI - The function and biological role of toll-like receptors in infectious diseases: an update. AB - PURPOSE OF REVIEW: The present review summarizes exciting new findings and reports recent advances in the understanding of the role of toll-like receptors in health and disease. It intends to provide a rough survey on topics discussed by researchers in the field and to stimulate discussion on new aspects of the complex processes involved in innate host defence. RECENT FINDINGS: Novel findings have been reported on the many aspects of toll-like receptors biology, namely the receptor structure and the molecular process of ligand recognition, receptor assembly, cellular localization and trafficking, downstream signaling and the regulatory factors involved, genetic polymorphisms within receptor genes and their linkage to human diseases, and the functional role of toll-like receptors in immune defence and host-microbe homeostasis. SUMMARY: Recent advances have allowed a more detailed picture not only of the processes involved in microbial recognition and host defence but also revealed unexpected insights into the cause of inflammatory processes and the close interrelationship between the vertebrate host and the microbially colonized environment. PMID- 18448978 TI - Shigellosis: the current status of vaccine development. AB - PURPOSE OF REVIEW: Shigellosis, a major form of bacillary dysentery, is caused by infection with Shigella organisms. In poor countries, Shigella-caused dysentery is endemic and causes an estimated 163 million illness episodes annually and more than one million deaths. Although several strategies have been used to develop vaccines targeting shigellosis, none has been licensed for use outside China. Owing to the wide range of Shigella serotypes and subtypes, there is a need for a multivalent vaccine representing prevalent species and serotypes. RECENT FINDINGS: Vaccine development has been limited by the lack of a suitable animal model for vaccine testing. This review discusses the most advanced strategies for Shigella vaccine development including live attenuated, conjugate, broad spectrum, and proteosome-based vaccines and describes current animal models under study. SUMMARY: The greatest barrier to the use of vaccine against shigellosis in developing areas is poor immune responses to oral vaccines in children who have minimal maternal antibodies. Clinical studies of promising shigellosis vaccine candidates are urgently needed after confirmation of safety, immunogenicity, and protection in volunteer challenge models. PMID- 18448979 TI - Bibliography. Current world literature. Pediatric and neonatal infection. PMID- 18448980 TI - Minimum 1-year follow-up for patients with vertical shear sacroiliac joint dislocations treated with iliosacral screws: does joint ankylosis or anatomic reduction contribute to functional outcome? AB - OBJECTIVE: To prospectively analyze a homogenous group of trauma patients with pure sacroiliac (SI) joint dislocations treated with iliosacral screws (ISS), with specific attention to functional outcome and its correlation with the presence or absence of SI joint ankylosis and quality of reduction. DESIGN: Retrospective chart and radiographic review of initial injury and treatment, with prospective long-term evaluation of radiographs, computed tomography (CT) scans, and functional assessments. SETTING: Level One Regional Trauma Center. PATIENTS: Twenty-three patients who were skeletally mature with traumatic vertical shear pelvic injuries associated with a pure SI joint dislocation. INTERVENTION: Treatment consisted of closed or open reduction in the supine or prone position and insertion of a single ISS placed percutaneously for the fixation of the posterior ring injury. MAIN OUTCOME MEASUREMENT: Each patient was evaluated for functional outcome using version 2 of the Short-Form 36 (SF-36v2), the short version of the Musculoskeletal Functional Assessment (sMFA), the Iowa Pelvic Scoring System, and the Majeed Pelvic Scoring System. Additionally, at the follow up visit, each patient received plain radiographs of the pelvis and CT scanning of the pelvis. RESULTS: Minimum follow-up was 1 year postindex procedure (13-120 months). In this subset of patients with pure SI dislocations treated with ISS alone, anatomic reduction was the only predictor of a more favorable functional outcome (P = 0.04). Specifically, SI joint ankylosis did not affect functional outcome in these patients. CONCLUSIONS: Based on the results of this study, in the treatment of vertically displaced, pure SI joint dislocations, an anatomic reduction (whether closed or open), followed by ISS fixation should be the goal because this appears to be the only predictor of a more favorable functional outcome in patients with this injury. Complete SI joint ankylosis appears to have no effect, either positive or negative, on functional outcome in these patients. PMID- 18448981 TI - A prospective study evaluating incision placement and wound healing for tibial plafond fractures. AB - OBJECTIVES: To report the soft tissue complications after fixation of tibial plafond fractures to test the validity of the recommendation that a 7-cm skin bridge represents the minimum safe distance between surgical incisions. DESIGN: Prospective observational cohort. SETTING: Level 1 Trauma Center. PATIENTS: A total 42 patients with 46 tibial plafond fractures. INTERVENTION: All injuries had a minimum of 2 surgical approaches for operative management of the tibial plafond and associated fibula fracture (if applicable). Two low-energy injuries had single-stage open reduction internal fixation of the tibia and fibula, and the remaining high- energy fractures had a 2-staged approach to management. MAIN OUTCOME MEASUREMENTS: The surgical approaches used, length of the incisions, distance between the incisions, and overlap between the incisions were recorded. Wound healing was assessed in the outpatient clinic over a 3-month period. RESULTS: Two surgical approaches were used in 32 fractures, and 3 approaches were used in 14 fractures. The mean width of the skin bridge was 5.9 cm. The majority of the skin bridges were 5.0 to 5.9 cm (n = 25) or 6.0 to 6.9 cm (n = 16). Only 17% of the skin bridges were greater than 7.0 cm. Soft tissue complications occurred in 4 (9%) of 46 fractures. Healing of 2 anterolateral incisions was complicated by eschars that ultimately resolved with local wound care. One posterolateral fibular incision failed to heal until the fibular plate was removed. One patient required subsequent surgical procedures for infection. CONCLUSIONS: Despite a measured skin bridge of less than 7 cm in 83% of instances, the soft tissue complication rate was low in this group of tibial plafond fractures. With careful attention to soft tissue management and surgical timing, incisions for tibial plafond fractures may be placed less than 7 cm apart, allowing the surgeon to optimize exposures on the basis of injury pattern. PMID- 18448983 TI - Radiographic and clinical comparisons of distal tibia shaft fractures (4 to 11 cm proximal to the plafond): plating versus intramedullary nailing. AB - OBJECTIVE: The purposes of this study were to review distal tibia shaft fractures treated with a plate or a nail and to assess the clinical and radiographic results, complication rates, and the need for secondary procedures. DESIGN: Retrospective review. SETTING: Two Level I trauma centers. PATIENT/PARTICIPANTS: We retrospectively reviewed 111 patients with 113 extra-articular distal tibia fractures between 4 and 11 cm proximal to the plafond. Seventy-six were treated with an intramedullary nail and 37 were treated with a medial plate. Twenty-nine (27%) of the concomitant fibula fractures were fixed. MAIN OUTCOME MEASUREMENTS: Complications and secondary procedures were evaluated in 111 patients after a mean of 24 months (range, 12-84 months). RESULTS: A total of 111 patients with 113 fractures of the distal tibia were reviewed. Their mean age was 39.1 years, 69% were men, and 30% had open fractures. Four patients underwent additional procedures for soft tissue coverage. None of these had infection. Five patients (4.4%) developed osteomyelitis: four after intramedullary nailing (5.3%) and one after plating (2.7%). Nine patients (12%) had delayed union or nonunion after nailing. One patient (2.7%) had a nonunion after plating (P = 0.10). Nonunion was more common after concurrent fixation of the fibula (14% versus 2.6%, P = 0.04). Angular malalignment of > or =5 degrees occurred in 22 patients with nails (29%) and 2 with plates (5.4%, P = 0.003). Eight patients had malunions of > or =10 degrees. Valgus was the most common deformity (n = 16). Malunion was more common after open fracture (38%, P = 0.006) but was not related to fibula fixation. Painful hardware was removed in six patients (7.9%) with nails and in two patients (5.4%) with plates. CONCLUSIONS: Distal tibia fractures may be treated successfully with plates or nails. Delayed union, malunion, and secondary procedures were more frequent after nailing. Randomized prospective assessment may further clarify these issues and provide information about costs associated with these fractures. PMID- 18448984 TI - Biomechanical strength of the Peri-Loc proximal tibial plate: a comparison of all locked versus hybrid locked/nonlocked screw configurations. AB - OBJECTIVE: The purpose of this study was to compare the biomechanical properties of a contoured locking plate instrumented with either an all-locked or hybrid locked/nonlocked screw construct in a proximal metaphyseal fracture of the tibia (AO 41-A3.2). METHODS: A standardized proximal metaphyseal wedge osteotomy (AO 41 A3.2) was created in five pairs of cadaveric tibia. Each pair was randomly instrumented with either an all-locked or combination locked/nonlocked screw construct using a locked contoured periarticular plate (Peri-Loc periarticular locked plating system, Smith & Nephew, Memphis, TN). Vertical subsidence (irreversible deformation) and deflection (reversible deformation) in each pair were analyzed and compared. Load to failure, defined by complete fracture gap closure, was also determined. RESULTS: There was no statistically significant difference in vertical subsidence (P = 0.19) or deflection (P = 0.19) of the proximal tibia between the all-locked and combination locked/nonlocked screw construct with increasing levels of cyclical axial load from 200 to 1200 N. Failure occurred at a mean value of 2160 N in the locked group and 1760 N in the hybrid group (P = 0.19); the failure mode was plate bending in all specimens. CONCLUSIONS: The results indicate that the use of compression screws with locked screws in this particular construct allows a similar amount of irreversible and reversible deformation in response to an axial load when compared to an all locked screw construct. This suggests that there is no statistically significant difference in the stability in fixation between the two methods, allowing the surgeon the freedom to choose the appropriate screw combination unique to each fracture. PMID- 18448985 TI - Treatment of posterior cruciate ligament tibial avulsion fractures through a modified open posterior approach: operative technique and 12- to 48-month outcomes. AB - OBJECTIVES: To report clinical and functional outcomes following fixation of tibial posterior cruciate ligament (PCL) avulsion fractures through a modified open posterior approach when combined with a rehabilitation program emphasizing early range of motion. DESIGN: Retrospective case series. SETTING: Level I trauma center. PATIENTS: From March 4, 2000 to May 8, 2003, there were 16 cases of PCL tibial avulsion injuries presented to our institution, with 10 patients available for follow up at 12 to 48 months (mean 28 months). INTERVENTION: Fixation of tibial PCL avulsion fractures was with a lag screw and washer placed through a modified open posterior approach. Range of motion was begun on postoperative day 1. MAIN OUTCOME MEASUREMENTS: Clinical stability, range of motion, gastrocnemius muscle strength, radiographic appearance, and each patient's overall health related quality of life (using the musculoskeletal functional assessment tool) were evaluated at final follow up. RESULTS: The average musculoskeletal functional assessment score was 14. (Musculoskeletal functional assessment scores range from 0-100, with higher scores indicating poorer function.) All patients achieved union of their fracture and had clinically stable knees at the latest follow-up. Flexion difference greater than 10 degrees (P = 0.16), extension difference greater than 2 degrees (P = 0.38), and heel raise difference more than 8 repetitions (P = 0.23) were not demonstrated in comparison to the normal side. CONCLUSIONS: Treatment of tibial PCL avulsion fractures, which includes fixation through a modified open posterior approach and early postoperative range of motion, results in healing of the fracture, good functional outcomes, stability to posterior draw testing, and does not lead to gastrocnemius weakness or significant range of motion deficits at 12 to 48 months postoperatively. PMID- 18448986 TI - Long-term outcome of operatively treated fracture-dislocations of the olecranon. AB - OBJECTIVES: To report the long-term results of operative treatment of anterior and posterior olecranon fracture-dislocations and compare them with the results recorded fewer than 2 years after surgery. DESIGN: Retrospective case series with long-term evaluation. SETTING: Level I trauma center. PATIENTS AND PARTICIPANTS: Ten patients with anterior olecranon fracture-dislocation and ten patients with posterior olecranon fracture-dislocation were evaluated after an average of 18 years (range, 11 to 28 years) after injury. Fifteen patients had an early follow up available at an average 14 months (range, 6 to 24 months) after surgery. The average age at injury was 30 years (range, 14 to 53 years). INTERVENTION: Treatment included plate and screw fixation (11 patients), tension band wiring (8 patients), and radiocapitellar transfixation (1 patient). Six patients had additional elbow surgery before the final evaluation. MAIN OUTCOME MEASUREMENTS: Flexion arc, arthrosis, Mayo Elbow Performance Index (MEPI), Disability of Arm Shoulder and Hand questionnaire (DASH). RESULTS: The mean arc of elbow flexion was 105 degrees (range, 15 to 140 degrees) at 1 year and 122 degrees (range 10 to 145 degrees; P = 0.01) at final evaluation. Radiographic arthrosis was observed in 14 patients (70%): severe in 3, moderate in 2, and mild in 9 patients. Five patients (25%) had ulnar nerve dysfunction at the final evaluation. The MEPI was excellent in 13 patients, good in 4, fair in 2, and poor in 1. The mean DASH score was 9 points (range, 0 to 53 points). CONCLUSION: The initial results of operative treatment of fracture-dislocations of the olecranon are durable over time. PMID- 18448987 TI - A biomechanical comparison of plate configuration in distal humerus fractures. AB - OBJECTIVES: Our aim was to test the hypothesis that two plates placed parallel to each other are stronger and stiffer than plates placed perpendicular to each other for fixation of a distal humerus fracture model. METHODS: We created an artificial distal humeral fracture model by osteotomizing two groups of identical epoxy resin humera. Screw and plate constructs were built to mimic osteosynthesis. In the first group, 3.5-mm reconstruction plates were placed parallel to each other along each of the medial and lateral supracondylar ridges. In the second group, 3.5-mm reconstruction plates were placed perpendicular to each other with a medial supracondylar ridge plate and a posterolateral plate. Stiffness and strength data of the two constructs were obtained by testing to failure with sagittal plane bending forces. RESULTS: The parallel plate group (n = 7) had a mean stiffness of 214.9 +/- 43.3 N/mm and a mean strength of 304.4 +/- 63.5 N. The perpendicular plate group (n = 8) had a mean stiffness of 138.3 +/- 44.6 N/mm and a mean strength of 214.9 +/- 43.3 N. These differences were significant (Student's t test, P < 0.05). CONCLUSIONS: As theoretically expected, a parallel plate configuration is significantly stronger and stiffer than a perpendicular plate configuration when subjected to sagittal bending forces in a distal humerus fracture model. PMID- 18448988 TI - Biomechanical comparison of a 2 and 3 proximal screw-configured antegrade piriformis intramedullary nail with a trochanteric reconstruction nail in an unstable subtrochanteric fracture model. AB - OBJECTIVE: The objective of this study was to test the stiffness and ultimate load to failure of new intramedullary (IM) nail proximal screw configurations as compared to a trochanteric reconstruction nail. METHODS: Twenty-one synthetic composite femurs were mounted on a Material Testing System and tested in axial compression 5 times. The femurs had an 1 of 2 IM nail types inserted with 1 of 3 proximal screw configurations: a 3-screw configuration with 2 transverse screws and a screw angled into the femoral neck; a 2-screw design with a single transverse screw and a single screw angled into the femoral neck; 2 parallel screws angled into the femoral neck. There were 7 specimens in each group. An unstable fracture (OTA/AO 32-C3.2) was created. and the stiffness of these constructs was tested in compression 5 times. Each construct was then loaded to failure in compression. RESULTS: The 3-screw construct provided more axial stiffness (214 N/mm +/- 75) than either the 2-screw construct (123 N/mm +/- 32) or the trochanteric reconstruction nail (127 N/mm +/- 21) (P = 0.017 and 0.035 for 3-screw vs. 2-screw and recon respectively, P = 0.45 for 2-screw vs. recon). Load-to-failure testing demonstrated similarity among the different screw configurations (3-screw = 2230 N +/- 265, 2-screw = 2283 N +/- 260, Reconstruction nail = 2121 N +/- 156) (P = 1.0 all groups). CONCLUSIONS: The proximal 3-screw configuration provided more stiffness than either the 2-screw configuration or trochanteric reconstruction nail. The 2-screw configuration performed equally to a standard trochanteric reconstruction nail in stiffness testing. The ultimate loads to failure for the 3 tested constructs were not significantly different. PMID- 18448989 TI - Platelet gel supplementation in long bone nonunions treated by external fixation. AB - OBJECTIVE: The aim of the present study was to evaluate the use of previously frozen, thawed platelet gel supplementation to accelerate the healing of long bone nonunions treated by external fixation. DESIGN: Prospective case series with historical controls. SETTING: University Hospital. PATIENTS: Twenty patients affected by tibial, humeral, or forearm atrophic nonunions were treated by percutaneous stabilization with unilateral external fixators and injection of autologous platelet gel. The healing time was compared to the result obtained in a historical control group treated without platelet gel supplementation. MAIN OUTCOME MEASUREMENTS: Consolidation rate and radiographic healing time of nonunions in the 2 groups were assessed by independent blinded observers. The nonunion was judged to be healed when bridging callus formation on both radiographic views was observed on at least 3 of 4 cortices. RESULTS: The healing rate of nonunion was 90% (18/20) in platelet gel cases and 85% (17/20) in controls, respectively (P = 0.633). The mean time until radiographic consolidation in nonunions supplemented with platelet gel (147 +/- 63 days) was not different to the result in the control group (153 +/- 61 days; P = 0.784). Analyzing the mean healing time for separate segments, no differences were noted between study and control group-that is, tibia: 112 +/- 43 and 130 +/- 5 days, respectively (P = 0.382); humerus, 225 +/- 36 and 202 +/- 70 days, respectively (P = 0.530). CONCLUSION: The present study failed to show the clinical usefulness of isolated percutaneous platelet gel supplementation in long bone nonunions treated by external fixation; however, caution should be exercised in interpreting this result because the actual numbers are small and the statistical power is limited. PMID- 18448990 TI - Low-energy femoral shaft fractures associated with alendronate use. AB - OBJECTIVE: Increasing evidence suggests long-term alendronate use may overly suppress bone metabolism, limiting repair of microdamage and creating risk for insufficiency fractures. The purpose of this study is to demonstrate an association between alendronate use and a specific pattern of low-energy femoral shaft fracture. DESIGN, SETTING, AND PATIENTS: A retrospective review was performed of patients with femoral shaft fractures admitted to a Level 1 trauma center between January 2002 and March 2007. Seventy low-energy fractures were identified. MAIN OUTCOME MEASURE: The medical records were reviewed, and the incidence and duration of alendronate use were recorded. The incidence of a specific femoral shaft fracture in those patients taking alendronate compared with those not being treated was determined. RESULTS: There were 59 females and 11 males. The average age was 74.7 years. Twenty-five (36%) were being treated with alendronate. None of the patients had used or were using other bisphosphonates. Nineteen (76%) of these 25 patients demonstrated a simple, transverse fracture with a unicortical beak in an area of cortical hypertrophy. This fracture pattern was seen in only 1 patient (2%) not being treated with alendronate. Alendronate use was a significant risk factor for the fracture pattern (odds ratio [OR]) 139.33, 95% CI [19.0-939.4], P < 0.0001). This pattern was 98% specific to alendronate users. The average duration of alendronate use in those with the pattern was significantly longer than those who did not exhibit the pattern but were taking alendronate, 6.9 years versus 2.5 years of use, respectively (P = 0.002). Only 1 patient with the fracture pattern had been taking alendronate for less than 4 years. CONCLUSIONS: Low-energy fractures of the femoral shaft with a simple, transverse pattern and hypertrophy of the diaphyseal cortex are associated with alendronate use. This may result from propagation of a stress fracture whose repair is retarded by diminished osteoclast activity and impaired microdamage repair resulting from its prolonged use. PMID- 18448991 TI - Reconstruction of lateral trochlear defect with radial head autograft. AB - A novel procedure has been developed to address severe fractures of the lateral trochlea and capitellum when open reduction and internal fixation is not practical and patient factors preclude the use of total elbow arthroplasty. We present 3 patients in whom an ipsilateral radial head autograft was used to reconstruct the lateral trochlea, restoring both function and stability of the elbow. PMID- 18448992 TI - Posteromedial supine approach for reduction and fixation of medial and bicondylar tibial plateau fractures. AB - Traditionally, both high- and low-energy tibial plateau fractures are classified on the basis of the anteroposterior (AP) plain radiograph. Several fracture types exist that are not included in currently used classification schemes, including posteromedial shear and coronal plane fractures. These fracture types can appear as isolated fracture lines or as a part of a bicondylar plateau fracture. The purpose of this study is to describe a posteromedial supine surgical approach and antiglide plating of the posteromedial fragment, either as a single approach for a unicondylar posteromedial fracture or in combination with a second lateral approach for bicondylar fractures. We have used this technique in 27 patients that had posteromedial shear fractures on preoperative computed tomography (CT) scans, in the setting of a Level I trauma center. Ten were isolated medial plateau fractures, and 17 had bicondylar fractures. Radiographic analysis was done for all patients, and clinical outcomes were available in 19 out of 27 patients through phone interviews and chart reviews. Mean follow-up was 3.5 years (range 1-12 years). Seventy-five percent of patients had anatomic or good reductions. The average Oxford knee score was 19.9 +/- 5.4 (12-29). Average range of motion was 0 to 120 (0-90 to 0-130). The articular malreduction (>5-mm gap or step-off) rate was 4%, and there were no wound complications. Posteromedial shear fractures of the tibial plateau are not uncommon. This pattern is assessable using the preoperative CT scan. A supine posteromedial approach with antiglide plating provides a good clinical solution for these complex injuries. PMID- 18448993 TI - Ipsilateral anterior then irreducible posterior hip dislocation without fracture: a case report. AB - Anterior hip dislocations and posterior hip dislocations are injuries that commonly result from high-energy trauma. Different mechanisms of injury and forces are typically required for anterior and posterior hip dislocations. We present the case of a patient who sustained an injury that initially resulted in an anterior hip dislocation. After reduction and without experiencing further significant trauma, the patient dislocated posteriorly while being transferred from a stretcher to a table in radiology some 14 hours later. To our knowledge, there have been no such presentations in the literature. PMID- 18448994 TI - Bridge plating of the wrist for temporary stabilization of concomitant radiocarpal, intercarpal, and carpometacarpal injuries: a report of two cases. AB - Concomitant injuries of the radiocarpal, intercarpal, and carpometacarpal joints are rare and usually result from very high-energy trauma. The skeletal injury is often accompanied by severe soft tissue trauma. Repair of the radiocarpal and intercarpal ligaments needs to be augmented with immobilization. Traditional methods of immobilization, such as casts and external fixators have limitations. We describe our experience in 2 patients using a technique in which a wrist arthrodesis plate is temporarily placed from the radius to metacarpal to span the carpus and protect the radiocarpal and intercarpal repairs. The plate is removed after 3 months. PMID- 18448995 TI - Measuring the outcomes of lung cancer treatment. PMID- 18448996 TI - The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition. AB - PURPOSE: To identify, in the international staging database of the International Association for the Study of Lung Cancer, those prognostic factors that were significant and independent of clinical stage. MATERIAL AND METHODS: From the data submitted to the staging data base concerning 100,869 patients, cases were selected for which all the following variables were available: clinical stage, age, gender, performance status (PS), and histologic cell types. For non-small cell lung cancer (NSCLC), 12,428 patients were assessable, and for SCLC, 6609 patients were available for this study. Methods used were Cox regression analyses and recursive partitioning and amalgamation analyses. RESULTS: PS appeared to be a very important prognostic factor for survival in addition to clinical stage. Age and gender were other independent significant variables; For NSCLC and SCLC separately, recursive partitioning and amalgamation allowed the identification of four groups of patients with differing prognoses. In advanced NSCLC (stage IIIB / IV), some routine laboratory tests (mainly white blood cells and hypercalcaemia) were also found to be significant prognostic variables. In SCLC, albumin was an independent biologic prognostic factor. CONCLUSION: In addition to stage, PS and, to a lesser extent, age and gender seem to be important prognostic factors for survival in lung cancer. Although this data was obtained from the largest series ever used for such an analysis in lung cancer, these prognostic factors and models require confirmation in the prospective study already planned by the International Association for the Study of Lung Cancer Lung Cancer Staging Project. PMID- 18448997 TI - Epidermal growth factor receptor mutations in multicentric lung adenocarcinomas and atypical adenomatous hyperplasias. AB - BACKGROUND: The mechanisms of generation and progression of multicentric lung adenocarcinoma (AD), bronchioloalveolar carcinoma (BAC), and atypical adenomatous hyperplasia (AAH) in the peripheral lung is not well known. In this study, we analyzed epidermal growth factor receptor (EGFR) mutations in the cases of multicentric AD, BAC, and AAH to reveal the role of EGFR mutation in their generations and progressions. METHOD: Ninety-seven AAH, BAC, or AD lesions less than 3 cm in size in 26 patients were surgically resected. Of these, EGFR mutations of the nodules with the highest and the second highest grade of histologic malignancy were examined in each patient by using the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp method. RESULTS: EGFR mutations could be examined in 48 nodules in the 26 patients. The EGFR mutations were found more frequently in lesions with higher histologic malignancy, ie, 9 of 10 ADs (90%), 16 of 28 BACs (57%), and one of 10 AAHs (10%). In 22 patients who could be examined of EGFR mutations for the two lesions in each patient, only two patients (9%) had the same mutation patterns between the two lesions, whereas 15 patients (68%) had the different statuses and the remaining five (23%) had no mutations. CONCLUSION: Our data demonstrated that EGFR mutations seem to contribute to the acquisition of malignant potential in the AAH-AD sequence and occur independently in each lesion and in the cases of multicentric AD, BAC, and AAH. PMID- 18448998 TI - Detection of EGFR gene mutations using the wash fluid of CT-guided biopsy needle in NSCLC patients. AB - INTRODUCTION: In this study, we examined whether epidermal growth factor receptor (EGFR) mutations were detectable using a polymerase chain reaction-based assay and wash fluid of computed tomography (CT)-guided lung biopsy needles. METHODS: DNA was extracted from wash fluid of CT-guided biopsy needles of 53 lung tumors (as diagnosed according to the results of the CT-guided biopsies). EGFR mutations, specifically exon19 deletions and exon21 L858R mutations, were examined using a mutant-enriched polymerase chain reaction assay. We also examined the presence of EGFR mutations in 26 surgically resected tumor specimens and compared the results with those obtained for the corresponding wash fluid samples. RESULTS: The amount of DNA obtained for the wash fluid of the CT-guided biopsy needles ranged from 35 to 2360 ng. There were no significant differences in the amount of extracted DNA according to the tumor characteristics, including tumor size and the percentage of ground glass opacity. Thirty-four of the 53 lung tumor samples were histologically diagnosed as non-small cell lung cancer (NSCLC). Exon19 deletions and exon21 L858R mutations in EGFR were detected in 4 (12%) and 13 (38%) of 34 NSCLC cases, respectively. No EGFR mutations were found in the non-NSCLC cases. The EGFR mutation status in the wash fluid samples was consistent with those obtained for all 26 corresponding surgical specimens. CONCLUSION: Our results indicate that EGFR mutations can be detected using wash fluid of CT-guided biopsy needles. In this manner, the DNA genotype can be determined even in extremely small clinical specimens using highly sensitive assays. PMID- 18448999 TI - Impact of HER2 gene and protein status on the treatment outcome of cisplatin based chemoradiotherapy for locally advanced non-small cell lung cancer. AB - BACKGROUND: It has not been fully evaluated whether both HER2 gene copy number and HER2 protein expression are related to the outcome of chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The aim of this study was to evaluate their relationships. METHODS: HER2 gene copy number determined by fluorescence in situ hybridization (FISH) and HER2 protein expression determined by immunohistochemistry (IHC) were assessed in 68 patients with LA-NSCLC enrolled in our previous phase II trials of concurrent cisplatin based chemoradiotherapy, and a multivariate analysis was conducted for response and survival. RESULTS: HER2-IHC-positive tumors were detected in 23 patients (34%), and the median ratio of HER2 to chromosome 17 copy number was 0.93 (range, 0.55-2.00). The HER2-FISH results were marginally correlated with the IHC results (p = 0.0715). When the median ratio in the FISH analysis was used as a cut-off level for its positivity, there was no association between either HER2-FISH or IHC status and objective response to chemoradiotherapy. Contrary, a multivariate analysis revealed HER2-FISH result but not IHC result was an independent poor prognostic factor for both overall survival and progression-free survival (hazard ratio = 2.568, 95% confidence interval [CI] = 1.117-5.903, p = 0.0264 and hazard ratio = 2.283, 95% CI = 1.005-5.189, p = 0.0487, respectively). CONCLUSIONS: Patients with HER2 FISH-positive LA-NSCLC had a poorer outcome even when treated with cisplatin-based chemoradiotherapy, despite the strong need for validation assessment of these observations. Development of more effective treatment for these high-risk patients is needed to improve their poor prognosis. PMID- 18449000 TI - Lung cancer with localized ground-glass attenuation represents early-stage adenocarcinoma in nonsmokers. AB - BACKGROUND: Studies of lung cancer showing localized ground-glass attenuation (GGA) on thin-section computed tomography (TSCT) have been limited to resected stage IA adenocarcinomas. This study aimed to clarify the features of localized GGA cancer as a distinct clinicoradiological entity through a survey of lung cancers of all types. METHODS: From 2000 through 2002, 492 patients with newly diagnosed stage I-IV lung cancer underwent TSCT at a single institution. The tumors were semiquantitatively classified into four groups on the basis of GGA area as a percentage of the whole tumor shadow (GGA ratio) on TSCT images: 100%, 99-50%, 49-1%, and 0%. The relationship between clinicopathological data and the GGA ratio, predictors of the presence of GGA, survival data, and prognostic factors were evaluated retrospectively. RESULTS: All localized GGA cancers were adenocarcinomas (p < 0.05). A GGA component was not found in patients with advanced cancer (p < 0.05). GGA cancer was related to nonsmoking status (Odds ratio 6.17, p < 0.05). A threshold tumor size of 30 mm in GGA cancer (hazard ratio, 2.86; p < 0.01) and the GGA ratio (hazard ratio, 4.17; p < 0.01) were independent prognostic factors. Survival rates were higher in patients with a GGA ratio > or = 50% and stage IB lung cancer than in patients with a GGA ratio < 50% and stage IA lung cancer. CONCLUSION: Localized GGA cancer, with presurgical prognostic factors of tumor size and GGA ratio, represents early-stage lung adenocarcinoma in nonsmokers. PMID- 18449001 TI - Improved treatment and survival for lung cancer patients in South-East Scotland. AB - INTRODUCTION: Lung cancer survival in Scotland has historically been poor but many changes to the lung cancer services have been introduced and this study was conducted to investigate the impact of these changes on treatment and survival. METHODS: Data obtained from the Scottish Cancer Registry, South-East Scotland Cancer Network audit and Edinburgh Cancer Centre database were used to conduct a comparison of the management and outcomes of lung cancer patients from South-East Scotland diagnosed in 1995 and in 2002. RESULTS: Data on 971 patients diagnosed in 2002 and 927 in 1995 were analyzed and demonstrated that though the use of treatment overall had not changed (62% in 2002 versus 63% in 1995) the use of potentially curative radiotherapy (15 versus 5% chi p < 0.001) and chemotherapy for non-small cell lung cancer (18 versus 7% chi p < 0.001) had increased, but not resection rates (11 versus 10%). The use of palliative radiotherapy declined (38% versus 31% chi p < 0.001). Patients diagnosed in 2002 had an adjusted hazard of death of 0.7 (95% confidence interval, 0.6-0.8) compared with 1995, with median survival from date of diagnosis of 5.2 versus 4.1 month and 2 year overall survival 15 versus 11% (log rank p = 0.004). Localized disease and younger age were also associated with a reduced hazard of death. CONCLUSIONS: Patients diagnosed with lung cancer in Scotland in 2002 had a reduced hazard of death and improved survival compared with 1995. It is hypothesized that this was due in part to improvements in service organization and increased use of treatments likely to increase survival. PMID- 18449002 TI - Trimodality treatment of malignant pleural mesothelioma. AB - INTRODUCTION: Multimodality treatment has achieved significant success in local control and treatment of early-stage malignant pleural mesothelioma patients. However, its favorable effect on survival is questionable. METHODS: We have instituted a trimodality treatment protocol consisting of extrapleural pneumonectomy, adjuvant high-dose (54 Gy) hemithoracic irradiation, and platin based chemotherapy in a multi-institutional setting. Preoperative pulmonary function tests, echocardiogram, chest computed tomography, and magnetic resonance imaging scans were performed in all patients. Twenty patients have been treated with this protocol during 2003-2007. Seventeen had a history of environmental asbestos/erionite exposure. Clinical stages were T1-3N0-2. RESULTS: Median age was 56 (41-70, 8 female). There was one postoperative mortality (% 5) due to ARDS. Morbidity occurred in 11 patients (% 55). Histology was epithelial in 17, mixed in 2, and sarcomatoid in 1. Sixteen patients underwent extrapleural pneumonectomy. Microscopic margin positivity was present in 14 patients with macroscopic complete resection. Twelve patients completed all three treatments. Median follow-up was 16 months (1-43). Overall median survival was 17 months (24% at 2 years). Eight patients had extrapleural lymph node involvement (internal mammary [n = 3], subcarinal [n = 2], pulmonary ligament [n = 1], diaphragmatic [n = 1], subaortic [n = 1]). There was better survival in patients without lymph node metastasis (24 versus 13 months median survival, p = 0.052). Currently, 7 patients are alive, 6 without recurrence, and 2 patients at 40 and 45 months. CONCLUSIONS: Trimodality treatment in malignant pleural mesothelioma seems to prolong survival in patients without lymph node metastasis. Novel techniques are needed for preoperative assessment of extrapleural lymph nodes. PMID- 18449003 TI - Pooled analysis of elderly patients with non-small cell lung cancer treated with front line docetaxel/gemcitabine regimen: the Hellenic Oncology Research Group experience. AB - INTRODUCTION: Thirty to 40% of patients with non-small cell lung cancer (NSCLC) are older than 70 years and rarely are enrolled in clinical trials. Moreover, in clinical practice, > 75% of patients older than 65 years with metastatic NSCLC never receive any kind of chemotherapy. PURPOSE: To retrospectively evaluate the impact of age on efficacy and toxicity of chemotherapy regimens in patients with advanced NSCLC treated with the docetaxel-gemcitabine combination. PATIENTS AND METHODS: Pooled data from six clinical trials of the Hellenic Oncology Research Group were analyzed. According to their age, patients were divided into two groups: those with age < 70 years and those with > or = 70 years. RESULTS: A total of 858 patients were included in this analysis. Six hundred sixty-six (77.6%) patients were younger than 70 years, whereas 192 (22.4%) patients where > or = 70-year-old. Overall response rate was 30.3% and 30.2% for patients < 70 years and > or = 70 years, respectively (p = 0.974). The median time to tumor progression was 4.1 and 4.5 months for patients < 70 years and > or = 70 years, respectively (p = 0.948). Median overall survival was 9.9 and 9.2 months for patients < 70 and > or = 70, respectively (p = 0.117). The multivariate analysis revealed performance status (PS) (p = 0.0001) and stage (p = 0.0001) as independent factors with significant impact on the hazard of death. Chemotherapy was well tolerated, but the incidence of grade III/IV mucositis was significantly higher in elderly patients (0.2% versus 1.5% for patients < 70 versus > or = 70 years, respectively; p = 0.011). CONCLUSION: The docetaxel/gemcitabine regimen has a comparable efficacy and tolerance in young (< 70 years) and elderly (> or = 70 years) patients. PMID- 18449004 TI - Efficacy and safety of oxaliplatin and gemcitabine with bevacizumab in advanced non-small cell lung cancer. AB - INTRODUCTION: We conducted a multicenter phase II study to evaluate the efficacy and safety of oxaliplatin and gemcitabine with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients with chemotherapy naive, nonsquamous, stage IIIB or IV NSCLC received gemcitabine 1000 mg/m on days 1 and 8, oxaliplatin 130 mg/m on day 1, and bevacizumab 15 mg/kg on day 1 every 21 days for 4 cycles. Patients with stable disease or response received maintenance bevacizumab every 3 weeks until progression. Primary end point was median time to progression (TTP). RESULTS: Nineteen of 44 eligible patients had partial response in the intent-to-treat analysis for an objective response rate of 43% (95% confidence interval [CI], 26.3-60.1%); 16 patients had stable disease for a disease control rate of 80% (95% CI, 72.0-87.0%). Median TTP was 5.5 months (95% CI, 3.8-6.9 months), which approached that seen in phase III studies. Median survival was 13.7 months (95% CI, 7.3-21.8 months). The most common grade 3 or 4 adverse events were hypertension (11%), neutropenia (9%), diarrhea (7%), dyspnea (7%), and thromboembolic events (7%). Pulmonary hemorrhage was not observed. CONCLUSIONS: The results of this phase II study suggest that oxaliplatin and gemcitabine with bevacizumab was active and reasonably well tolerated. Median TTP approached that in phase III studies. This combination represents another treatment option for advanced NSCLC. PMID- 18449006 TI - Phase I trial of nanoparticle albumin-bound paclitaxel in combination with gemcitabine in patients with thoracic malignancies. AB - BACKGROUND: Nab-paclitaxel has a different toxicity profile than solvent-based paclitaxel including a lower rate of severe neutropenia. This trial was designed to determine the maximum tolerated dose and dose limiting toxicities (DLT) of nab paclitaxel in combination with gemcitabine. METHODS: Patients were required to have a performance status of 0 to 1, < or = three prior cytotoxic chemotherapy regimens, and preserved renal, hepatic, and bone marrow function. Patients received gemcitabine 1000 mg/m on days 1, 8 in all cohorts, and nab-paclitaxel at doses of 260, 300, 340 mg/m every 21 days depending on the treatment cohort (1 cycle = 21 days). DLT were assessed after the first cycle, and doses were escalated in cohorts of 3 to 6 patients. RESULTS: Eighteen patients were consented and 15 patients are evaluable [median age 62 years (range, 35-75); median number of prior treatments 3 (range, 1-4); tumor types: non-small cell lung cancer (NSCLC) (n = 8), small cell lung cancer (SCLC) (n = 6), and esophageal cancer (n = 1)]. At a nab-paclitaxel dose of 300 mg/m, 1 of 6 pts experienced a DLT (omission of day 8 gemcitabine due to absolute neutrophil count < 500), and at an nab-paclitaxel dose of 340 mg/m 2 of 3 patients experienced a DLT (1 pt grade 3 rash and pruritus; 1 pt grade 3 fatigue and anorexia). Responses were observed in NSCLC and SCLC. CONCLUSIONS: The maximum tolerated dose of nab-paclitaxel is 300 mg/m in combination with gemcitabine 1000 mg/m on days 1, 8 every 21 days. This combination demonstrated activity in previously treated NSCLC and SCLC patients. PMID- 18449007 TI - Tissue heterogeneity of EGFR mutation in lung adenocarcinoma. AB - Tissue heterogeneity of EGFR gene mutation was studied in 10 formalin-fixed paraffin-embedded (FFPE) samples from four cases that demonstrated EGFR mutations in snap-frozen samples. EGFR mutations identical to those in frozen sample were demonstrated in 8 of 10 FFPE samples by direct sequencing and in 9 of 10 by fragment length analysis, but an exon-19 deletion mutation could not be identified in one FFPE sample analyzed by both techniques, despite multiple repeated assays. This suggests that some tumors may demonstrate intratumoral heterogeneity for the occurrence of EGFR mutation. PMID- 18449005 TI - Bortezomib, paclitaxel, and carboplatin as a first-line regimen for patients with metastatic esophageal, gastric, and gastroesophageal cancer: phase II results from the North Central Cancer Treatment Group (N044B). AB - PURPOSE: This study was undertaken to explore the response rate of a first-line, three-drug regimen that consisted of bortezomib, paclitaxel, and carboplatin in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, or gastric cardia. PATIENTS AND METHODS: Patients with the above diagnosis and acceptable organ function were treated intravenously on a 21-day cycle with the following: bortezomib 1.2 mg/m on days 1, 4, and 8; paclitaxel 175 mg/m on day 2; and carboplatin with an area under the curve of 6 on day 2. Patients received indefinite treatment unless they manifested tumor progression or severe adverse events. All were monitored for tumor response as well as other clinical outcomes. RESULTS: The cohort included 35 eligible patients with a median age of 59 years (range, 36-78) and an Eastern Cooperative Oncology Group performance score of 0, 1, and 2 in 60%, 34%, and 6% of patients, respectively. Although this regimen was well tolerated, the tumor response rate was lower than that anticipated at 23% (95% confidence interval: 10%, 40%), thereby prompting premature study closure. There were no complete responses. The median survival for the cohort was 8.9 months (95% confidence interval: 5.9, 12.8). CONCLUSION: As prescribed in this trial and for this indication, this regimen does not merit further testing. PMID- 18449008 TI - B-cell non-Hodgkin lymphoma presenting as an endobronchial polypoid mass. PMID- 18449009 TI - Epithelioid sarcoma metastatic to the lung as pulmonary cysts without other metastatic manifestation. PMID- 18449010 TI - Prognostic value of posttreatment [18F] fluorodeoxyglucose uptake of primary non small cell lung carcinoma treated with radiation therapy with or without chemotherapy: a brief review. AB - In patients treated with radiation therapy for non-small cell lung carcinoma, positron emission tomography and computed tomography are commonly used to assess response to treatment. Seven rather small single-institution series have documented the ability of posttreatment positron emission tomography to predict local control and survival through measurements of [F] fluorodeoxyglucose uptake. The ability to make prognostic assessments using this information would be a major clinical breakthrough by allowing early alterations in patient management. Here, we review the current literature on the prognostic value of posttreatment [F] fluorodeoxyglucose uptake in patients treated with radiation therapy with or without chemotherapy for non-small cell lung carcinoma. PMID- 18449011 TI - Good vibrations and the power of positron thinking: positron emission tomography and endoscopic ultrasound in staging of mesothelioma-two case reports. PMID- 18449012 TI - Lack of FDG uptake in small cell carcinoma associated with ANNA-1 positive paraneoplastic autonomic neuropathy. AB - A 76-year-old smoker presented with profound weight loss due to gastrointestinal dysmotility associated with high levels of the paraneoplastic antibody ANNA-1. Serial computed tomography scans showed regressing subcarinal adenopathy, and positron emission tomography imaging showed mild fluorodeoxy-d-glucose uptake in subcarinal nodes, suggestive of benign disease. Diagnosis of small cell carcinoma was established by biopsy of mediastinal nodes. This case highlights the importance of a thorough search for malignancy in patients with high levels of circulating autoantibodies and suggests that benign-appearing imaging studies be interpreted with caution in patients with paraneoplastic autoimmune syndromes. PMID- 18449013 TI - Summary report 7th Annual Targeted Therapies of the Treatment of Lung Cancer. PMID- 18449014 TI - Gefitinib-associated Propionibacterium acnes pleural empyema. PMID- 18449015 TI - Pulmonary epithelioid haemangioendothelioma and bevacizumab. PMID- 18449017 TI - In reference to quantitative analysis of syndecan-1 expression in dysplasia and squamous cell carcinoma of the oral cavity. PMID- 18449018 TI - In reference to classification and management of tracheoesophageal and tracheopharyngeal fistulas after laryngectomy. PMID- 18449022 TI - In reference to visualization of endolymphatic hydrops in patients with Meniere's disease. PMID- 18449023 TI - Advances in facial rejuvenation: Botulinum toxin A. Hyaluronic acid dermal fillers, and combination therapies--consensus recomendations. Editor's Foreword. PMID- 18449026 TI - Advances in facial rejuvenation: botulinum toxin type a, hyaluronic acid dermal fillers, and combination therapies--consensus recommendations. AB - BACKGROUND: Facial aesthetics and rejuvenation are evolving rapidly due to changes in products, procedures, and patient demographics. Clinicians can benefit from ongoing guidance on products, tailoring treatments to individual patients, treating multiple facial areas, and using combinations of products and ways to optimize outcomes. METHODS: A multidisciplinary group of aesthetic treatment experts convened to review the properties and uses of botulinum toxin type A (BoNTA) and hyaluronic acid fillers and to update consensus recommendations for facial rejuvenation using these two types of products. The group considered paradigm shifts in facial aesthetics; optimal techniques for using BoNTA and hyaluronic acid fillers alone and in combination; the influence of patient sex, ethnicity, cultural ideals, and skin color on treatment; general techniques; patient education and counseling; and emerging trends and needs in facial rejuvenation. RESULTS: The group provided specific recommendations by facial area, focusing on relaxing musculature, restoring volume, and recontouring using BoNTA and hyaluronic acid fillers alone and in combination. For the upper face, BoNTA remains the cornerstone of treatment, with hyaluronic acid fillers used to augment results. These fillers are central to the midface because of the need to restore volume. BoNTA and hyaluronic acid in combination can improve outcomes in the lower face. CONCLUSIONS: Optimal outcomes in facial aesthetics require in depth knowledge of facial aging and anatomy, an appreciation that rejuvenation is a three-dimensional process involving muscle control, volume restoration, and recontouring, and thorough knowledge of properties and techniques specific to each product in the armamentarium. PMID- 18449029 TI - Fluoroquinolones versus beta-lactam based regimens for the treatment of osteomyelitis: a meta-analysis of randomized controlled trials. AB - STUDY DESIGN: A meta-analysis of randomized control trials. OBJECTIVE: To compare fluoroquinolones to beta-lactams for the treatment of osteomyelitis. SUMMARY OF BACKGROUND DATA: Treatment of osteomyelitis remains a real challenge in medicine necessitating the use of broad-spectrum antibiotics, because of the variety of the pathogens causing the infection and the fact that the infected bone may become necrotic and avascular, preventing systemic antibiotics from adequately penetrating to the infection site. METHODS: A literature search was performed by 2 reviewers independently (PubMed database and the Cochrane Central Register of Controlled Trials). RESULTS: We identified 7 studies eligible for inclusion in our meta-analysis; ciprofloxacin, ofloxacin, and pefloxacin were used in 3, 3, and 1 study, respectively, while various beta-lactams (mainly in the intravenous form) were used as comparators. There was no difference in treatment success for osteomyelitis between fluoroquinolones and beta-lactams [194 patients, fixed effect model (FEM), odds ratio (OR) = 0.99, 95% confidence interval (CI) 0.51 1.91], bacteriological success (201 isolates, FEM, OR = 0.88, 95% CI = 0.45 1.70), superinfections (173 patients, FEM, OR = 1.75, 95% CI = 0.63-4.90), relapses (153 patients, FEM, OR = 1.23, 95% CI = 0.46-3.31), or adverse events (170 patients, FEM, OR = 0.47, 95% CI = 0.21-1.06). CONCLUSION: Fluoroquinolones are as effective as beta-lactams for the treatment of osteomyelitis and can be considered as a useful alternative in the physician's armamentarium. The value of fluoroquinolones for the treatment of osteomyelitis lies in the fact that they can be administered in an outpatient setting. However, they should be used with caution, so as to preserve their activity against increasingly resistant bacteria. PMID- 18449030 TI - Prognostic value of somatosensory-evoked potentials in the surgical management of cervical spondylotic myelopathy. AB - STUDY DESIGN: Preoperative somatosensory-evoked potentials (SEPs) were retrospectively analyzed and classified, and compared with surgical outcome. OBJECTIVE: To evaluate the value of the preoperative SEP waveform in predicting the clinical outcome after surgical management of cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: SEPs have played an important role in spinal surgery. However, the value of SEPs in predicting the outcome of surgery for CSM remains controversial. METHODS: This study enrolled 76 CSM patients who underwent surgical intervention. Median nerve SEPs were recorded before surgery. The Japanese Orthopedic Association (JOA) scoring system was used to evaluate the neurologic function before surgery and at postoperative follow-up at 1, 3, 6, 12, and 24 months. Patients were divided into 5 groups according to the classification of their preoperative SEP waveforms. Group I patients had normal SEPs, group IIa had normal latency and abnormal amplitude, group IIb had abnormal latency and normal amplitude, group III had abnormal latency and amplitude, and group IV had immeasurable waveforms. The myelopathic disability scores and surgical outcomes in different groups were compared by the Kruskal-Wallis test. RESULTS: The SEP classification was found to be significantly associated with the JOA score (Pearson's chi test, chi = 53.9, P < 0.05). There were no significant differences in JOA score recovery at different follow-up times within any SEP group. At 24 months after surgery, there was no significant difference in the recovery ratio between groups I and IIa, or between groups IIb and III (Kruskal Wallis test, P > 0.05). However, the recovery ratio was significantly higher in groups I and IIa than in all the other groups (Kruskal-Wallis test, P < 0.05), and in groups IIb and III than in group IV (Kruskal-Wallis test, P < 0.05). CONCLUSION: SEP classification correlates well with CSM disability and postoperative recovery ratio. Median nerve SEP recordings would be a valuable and practical tool for the diagnosis and prognosis of myelopathy. PMID- 18449031 TI - Clinical magnification error in lateral spinal digital radiographs. AB - STUDY DESIGN: Observational. OBJECTIVE: The objectives of this study were to determine the range of clinical magnification error in lateral spinal digital radiographs, and to determine the effect of body mass index (BMI) on this error. SUMMARY OF BACKGROUND DATA: The magnification error in plain radiographs is often estimated at 15% to 30%. The variability of this error in digital spinal radiographs has not been assessed. METHODS: An analysis of 250 patients with digital radiographs and computed tomography (CT)/magnetic resonance images (MRIs) was performed. Digital imaging software was used to measure the anteroposterior vertebral body dimensions at C2, C5, L1, and L4. Magnification values were determined in comparison to CT/MRI. CT measurements were also compared with MRI. BMI for each patient was obtained by chart review. RESULTS: The mean magnification at the cervical spine (C2 and C5 combined) was 1.22 +/- 0.01, with a range of 1.06 to 1.57 (n = 198, STDEV = 0.08); at the lumbar spine (L1 and L4 combined) it was 1.31 +/- 0.01, with a range of 1.09 to 1.63 (n = 300, STDEV = 0.08). The difference between the mean anteroposterior vertebral body dimensions as measured on CT and MRI was < 0.1 mm (n = 135, P < 0.2514, paired t test). There was a significant positive correlation between BMI and magnification at both the cervical and lumbar spines by linear regression (Cervical: n = 99; P = 0.0019; Lumbar: n = 150; P < 0.0001). There was a significant difference in magnification between nonobese and obese patients at both the cervical and lumbar levels. Cervical: 1.19 +/- 0.01 magnification for nonobese (n = 144), versus 1.26 +/- 0.01 for obese (n = 39) (P < 0.0001). Lumbar: 1.28 +/- 0.01 (n = 208), versus 1.38 +/- 0.01 (n = 78) (P < 0.0001), respectively. CONCLUSION: Linear clinical measurements obtained on digital radiographs are subject to significant magnification errors at both the cervical and lumbar spines. This error correlates to the patient's BMI. Consequently, clinical decision-making that is based on linear measurements obtained from radiographs that do not account for this error is invalid. In a scenario where this measurement is crucial (e.g., dynamic radiographs), this error can be corrected by comparison to morphometric data from a CT/MRI. PMID- 18449032 TI - Polymethylmethacrylate augmentation of pedicle screw for osteoporotic spinal surgery: a novel technique. AB - STUDY DESIGN: A retrospective study to evaluate the clinical results of patients with osteoporosis and various spinal diseases treated surgically with polymethylmethacrylate (PMMA) augmented pedicle screw. OBJECTIVE: To report a novel technique using PMMA for pedicle screw augmentation in osteoporotic spinal surgery. SUMMARY OF BACKGROUND DATA: Many studies have proved that the stiffness and strength of pedicle screw fixation can be significantly increased when the pedicle screw is augmented with various cements. However, most of those studies were experimental. Clinical reports using those materials for pedicle screw augmentation are rare and a practical and reliable technique for primary pedicle screw augmentation with cement has not yet been established. METHODS: Forty-one patients [23 female, 18 male, mean age 75.1 (50-90) years] with osteoporosis and various spinal diseases underwent spinal decompression and instrumentation with PMMA augmentation of pedicle screw. Pre-and postoperative scores for visual analogue scale for pain and Oswestry disability index questionnaire were analyzed. The screw migration, which is the distance from the screw tip to the anterior cortex and upper endplate of vertebra, was also evaluated immediately after the operation and at the mean 22.3 months final follow-up. RESULTS.: Totally 291 of 300 screws were augmented with PMMA. There was neither neurologic deterioration nor symptomatic cement leakage after surgery. The mean visual analogue scale pain score of these patients improved from 9.2 to 1.5 (P < 0.01) and the functional Oswestry disability index score improved from 77.5% to 44.2% (P < 0.01). Kyphotic deformity was improved from average 23.2 degrees to 11.9 degrees after surgery, and to 14.9 degrees at final follow-up (P < 0.01). The average loss of kyphosis correction was 3 degrees. There was no significant screw migration when the screws distances just after operation and at the final follow up were compared (P > 0.01). CONCLUSION: The presented technique of PMMA for augmentation of pedicle screw is a safe, reliable, and practical technique for osteoporotic patients who also had various spinal diseases and need spinal instrumentation. PMID- 18449033 TI - Surgical management of severely displaced pediatric seat-belt fracture dislocations of the lumbar spine associated with occlusion of the abdominal aorta and avulsion of the cauda equina: a report of two cases. AB - STUDY DESIGN: Case report. OBJECTIVE: To present 2 cases of fracture-dislocations of the lumbar spine associated with injury to the aorta and avulsion of the cauda equina and present recommendations regarding urgent management of these injuries. SUMMARY OF BACKGROUND DATA: The "seat-belt syndrome" was first described by Garrett and Braunstein in 1962 to describe intraabdominal visceral injuries with fractures of the lumbar spine. Although this syndrome has been described in previously, there have been no reported cases of pediatric patients with significant injury to the abdominal aorta. METHODS: We present 2 seat-belt injuries occurring within a 4 month period at a pediatric trauma center with significantly displaced lumbar fracture-dislocation, abdominal aortic occlusion, and complete neurologic injury. RESULTS: Rigid fixation of the spinal fracture dislocation in both cases was delayed since these patients were deemed to be hemodynamically unstable. Aggressive mobilization, wound care, and pulmonary toilet were possible after stabilization of the spine. Despite this, 1 patient eventually died. CONCLUSION: These cases need to be managed according to principles established in the treatment of extremity fractures with vascular and neurologic injuries. That is, early rigid fixation of the fracture to protect the vascular repair. PMID- 18449034 TI - Inferior vena cava syndrome following percutaneous vertebroplasty with polymethylmethacrylate. AB - STUDY DESIGN: A case of inferior vena cava syndrome following percutaneous vertebroplasty is described herein. OBJECTIVE: To alert clinicians to the potential occurrence of inferior vena cava syndrome following percutaneous vertebroplasty. SUMMARY OF BACKGROUND DATA: Vertebroplasty is a less invasive treatment solution for the osteoporotic compression fracture. There complications of the cement leakage would appear to have been rather infrequent. We report a case of inferior vena cava syndrome related to the cement leakage. METHODS: A 59 year-old woman underwent percutaneous vertebroplasty for painful T11, L1, L2, and L3 compression fractures, under general anesthesia at a community hospital. A contralateral transpedicular approach was made in order to inject polymethylmethacrylate resin into the fractured vertebra. RESULTS: Just subsequent to surgery, this patient developed dyspnea, arthralgia, myalgia, and progressive right lower-limb pain, redness, and swelling., conservative treatment being then undertaken, albeit in vain. One week after the attempted remediation of this patient's condition, she was transferred to our hospital for further management. After admission, radiography of the patient's lumbar spine (lateral view) revealed multiple cement leakage in the area of the posterior longitudinal ligament and also in the anterior paravertebral area. The abdominal and pelvic CT scan and venography revealed vertebroplasty cement leakage into the lumbar vein, the left renal vein, and the inferior vena cava. Thrombosis at the left common iliac vein and left femoral vein were noted with extension into the inferior part of the inferior vena cava. Intravenous heparin was then administered to our patient for the ensuing 20 days, at which time heparin was replaced by warfarin, in order to attempt to prevent progressive venous thrombosis. The patient's leg edema appeared to improve 10 weeks subsequent to her surgery, she then being able to perambulate using a rigid walker. CONCLUSION: This case illustrates the need for clinicians to be critically aware of the potential occurrence of inferior vena cava syndrome among patients who have undergone percutaneous vertebroplasty, especially when multiple levels of vertebra are injected as part of the vertebroplasty procedure. PMID- 18449036 TI - Rationale behind the current state-of-the-art treatment of scoliosis (in the pedicle screw era). PMID- 18449037 TI - Prospective pulmonary function comparison of anterior spinal fusion in adolescent idiopathic scoliosis: thoracotomy versus thoracoabdominal approach. AB - STUDY DESIGN: Prospective clinical study of a retrospective database. OBJECTIVE: To compare the prospective pulmonary function changes following anterior spinal instrumentation and fusion through an open thoracotomy with the same procedure through a thoracoabdominal approach at 2 years follow-up. SUMMARY OF BACKGROUND DATA: Open anterior spinal instrumentation and fusion for adolescent idiopathic scoliosis (AIS) has been known to decrease pulmonary function after surgery. However, the differential effect of an open thoracotomy versus thoracoabdominal approach on pulmonary function in AIS is unknown. METHODS: Sixty-four AIS patients who underwent an anterior spinal instrumentation and fusion through an open thoracotomy (TC group) for a major main thoracic scoliosis were compared with 55 patients who underwent the same procedure through a thoracoabdominal approach (TA group) for a major thoracolumbar/lumbar (TL/L) scoliosis using pulmonary function tests assessing forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) before surgery and 2 years after surgery. The TC group was divided into 2 groups, TC group with thoracoplasty (1-5 ribs, n = 35) and TC group without thoracoplasty (n = 29). RESULTS: Preoperative and 2 year postoperative absolute FVC in the TC group averaged 3.05L and 2.74L, respectively (0.31L decrease, P < 0.0001) versus 3.27L and 3.21L, respectively (0.06L decrease, P = 0.15) in the TA group. The TC group demonstrated a significantly larger decrease in absolute FVC at 2 years postoperative (P < 0.0001). Preoperative and 2-year postoperative absolute FEV1 in the TC group averaged 2.56L and 2.35L, respectively (0.21L decrease, P < 0.0001) versus 2.82L and 2.81L, respectively (0.02L decrease, P = 0.67) in the TA group. The TC group demonstrated a significantly larger decrease in absolute FEV1 at 2 years postoperative (P = 0.001). TC patients with thoracoplasty (n = 35) demonstrated a similar average decrease (0.34L) of absolute FVC at 2 years postoperative compared with those without thoracoplasty (0.26L, P = 0.49) and a similar average decrease of absolute FEV1 at 2 years postoperative (0.23L vs. 0.19L without thoracoplasty, P = 0.76). CONCLUSION: An open thoracotomy approach for treating a main thoracic curve demonstrated a significant decrease in the absolute pulmonary function tests values at 2 years postoperative while the thoracoabdominal approach for treating a TL/L curve did not. PMID- 18449038 TI - Thoracoplasty in thoracic adolescent idiopathic scoliosis. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To evaluate the effect and outcome of thoracoplasty in conjunction with pedicle screw instrumentation in the treatment of thoracic adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Some spine surgeons recently think more correction of hump deformity using pedicle screws without thoracoplasty. Although thoracoplasty has been conventional treatment of rib hump, there are few papers about the results of pedicle screw instrumentation and concomitant thoracoplasty. METHODS: Eighty seven patients with thoracic AIS (mean age, 14.4 years) treated by pedicle screw instrumentation were retrospectively analyzed after a minimum follow-up of 2 years. Patients were divided into 3 groups; N-T group (no thoracoplasty with iliac bone graft, n = 37), T+N-DVR [thoracoplasty without direct vertebral rotation (DVR), n = 20] and T+DVR group (thoracoplasty with DVR, n = 30). In the T (T+N-DVR and T+DVR) group, 4 to 8 ribs were resected and used for bone graft. Patients were evaluated for deformity correction, balance, pulmonary function, height and angle of rib hump, clinical outcomes (SRS-30), and complications. RESULTS: In the N-T group, the thoracic curve was corrected from 53 degrees to 16 degrees (69% correction), in the T+N-DVR group from 55 degrees to 18 degrees (69%) and in the T+DVR group from 54 degrees to 10 degrees (81%). There was no difference in postoperative spinal balance and pulmonary function among the 3 groups. The correction rates of hump height and angle were 35% and 38% in the N-T group, respectively, 57% and 58% in the T+N-DVR, and 70% and 72% in the T+DVR. The T group showed significantly better correction of rib hump and self-image score in the SRS-30 questionnaire than the N-T group. There were 8 iliac donor site problems in the N-T group and 3 hemothorax in the T group, which had no adverse effect in the final result. CONCLUSION: Thoracoplasty showed significantly better rib hump correction, satisfactory clinical outcomes without pulmonary function compromise, or iliac bone graft site morbidity in the treatment of thoracic AIS with pedicle screw instrumentation. PMID- 18449039 TI - Spontaneous lumbar curve correction in selective thoracic fusions of idiopathic scoliosis: a comparison of anterior and posterior approaches. AB - STUDY DESIGN: A retrospective evaluation of adolescent idiopathic scoliosis (AIS) patients treated with selective thoracic instrumentation and fusion. OBJECTIVE: To evaluate the predictors and the effect of surgical approach (anterior versus posterior) on spontaneous lumbar curve correction (SLCC) after selective thoracic fusion in patients with structural thoracic and compensatory lumbar curves. SUMMARY OF BACKGROUND DATA: Spontaneous coronal correction of the unfused lumbar curve has been described previously; however controversy continues regarding the effect of surgical approach on SLCC. METHODS: One hundred thirty-two anterior and 44 posterior selective thoracic fusions instrumented distally to T11, T12, or L1 were identified from a multicenter AIS database. A 2-way ANOVA was used to compare SLCC with regards to surgical approach and the lowest instrumented vertebra (LIV). A Pearson's correlation analysis was utilized to identify radiographic variables associated with SLCC. A secondary analysis of surgical approach was then performed on 28 pairs of patients matching the factors that correlated positively with SLCC. RESULTS: The average SLCC for the anterior approach (44% +/- 19%) was less than that for the posterior approach (49% +/- 19%; P = 0.07), and was found to increase significantly with a more distal LIV (P = 0.03). Pearson's correlation analysis revealed the strongest correlations between SLCC and preoperative lumbar curve flexibility (r = 0.20) and 2-year postoperative thoracic curve percent correction (r = 0.47). A secondary analysis of SLCC in paired curves matched by LIV, lumbar curve flexibility and thoracic percent correction revealed no difference between anterior (48%) and posterior (49%) approaches (P = 0.75). CONCLUSION: Anterior and posterior instrumented fusions performed selectively on the appropriate curves result in equal SLCC when matched by LIV, flexibility of the lumbar curve, and percent thoracic curve correction achieved. This suggests that the observed phenomenon of SLCC after selective thoracic fusion in AIS is independent of surgical approach and can be reliably achieved with either technique. PMID- 18449040 TI - Juvenile idiopathic scoliosis: the effectiveness of part-time bracing. AB - STUDY DESIGN: A retrospective review of 34 patients with juvenile idiopathic scoliosis (JIS) treated with a nighttime bending brace. OBJECTIVE: To determine the effectiveness of part-time bracing in JIS. SUMMARY OF BACKGROUND DATA: Although previous bracing studies have focused on adolescent idiopathic scoliosis, no authors have dealt specifically with part-time bracing for JIS. METHODS: Twenty-three patients included in the study met the following criteria: curves greater than 20 degrees and Risser zero at initiation of bracing, brace wear more than 12 months, completion of the bracing program and Risser sign greater than or equal to 4 at final follow-up. Patients were analyzed according to 3 groups: (1) success (progression equal or less than 5 degrees), (2) progression more than 5 degrees (but not requiring surgery and achieving curve stabilization at skeletal maturity), and (3) surgery (curve progressing to greater than 45 degrees ) with failure of bracing treatment during skeletal immaturity. RESULTS: Seven boys and 16 girls with a total of 37 curves were analyzed. The average age at referral and initiation of bracing was 8.3 and 10.3 years, respectively. Average curve magnitude at time of bracing was 30 degrees. Length of bracing averaged 3.7 years with follow-up after brace discontinuation of 2.5 years. Nine patients met the criteria for success, with 7 patients progressing and 7 patients eventually requiring spinal fusion. Of the 37 curves, 19 (51%) were successfully managed in the brace. The magnitude of curvature at initiation of bracing did not relate to a successful outcome, whereas success did correlate with higher radiographic in-brace correction. Given the longer course of treatment for JIS patients, part-time bracing offers potential psychosocial and compliance benefits. CONCLUSION: Part-time bracing in JIS is successful and is better than the natural history. PMID- 18449041 TI - Fusion rates after thoracoscopic release and bone graft substitutes in idiopathic scoliosis. AB - STUDY DESIGN: A retrospective assessment of fusion rates using either morselized allograft bone or demineralized bone matrix (DBM) following video-assisted thoracoscopic surgery (VATS) in idiopathic scoliosis. OBJECTIVE: To compare fusion rates between allograft bone and demineralized bone matrix (Grafton DBM Flex) following VATS using on standard standing lateral spine radiographs. SUMMARY OF BACKGROUND DATA: Both VATS and bone graft substitutes are accepted surgical techniques. However, their concomitant use in spinal deformity surgery has not been previously reported. Bone graft substitute has the advantage of decreasing operative time, blood loss, and donor site morbidity associated with autografts. METHODS: Anterior thoracic discectomies were performed using VATS. Forty patients with 1 year or more follow-up were evaluated-12 with morselized allograft bone (Allograft group) and 28 with folded Grafton DBM Flex (DBM group). Factors analyzed included age, number of anterior levels fused, operative time, anterior perioperative blood loss, curve correction, and fusion rates. Clinical and radiographic evaluations were performed before surgery and at month, 1 year, and at most recent follow-up. Interbody fusion was assessed on standing lateral radiographs using the Newton et al 4-level grading scale. RESULTS: There were no significant differences in age at surgery, number of anterior vertebral levels fused, anterior operative time per level, anterior intraoperative blood loss, chest tube drainage and duration, or total perioperative anterior blood loss between the 2 groups. Percent curve correction from before surgery to the most recent follow-up were very similar in both Allograft (68%) and DBM groups (67%). At most recent assessment, 60 of 73 disc spaces (82%) in the Allograft group and 100 of 109 disc spaces (92%) in the DBM group were rated as radiographically fused (Newton et al Grade I and II). There was no significant difference between the 2 groups (P = 0.088). No patients were observed to have crankshaft, pseudoarthrosis or hardware failure. There were no complications related to the bone graft material used. CONCLUSION: Demineralized bone matrix (Grafton DBM Flex) seem to be an effective bone graft substitute in thoracoscopic surgery for idiopathic scoliosis. PMID- 18449042 TI - Comparison of radiographic outcomes for the treatment of scoliotic curves greater than 100 degrees: wires versus hooks versus screws. AB - STUDY DESIGN: A retrospective comparative study. OBJECTIVE: To compare the efficacy and safety of several different anchors in the apical levels of scoliotic curves > or = 100 degrees using radiographic outcomes and clinical complications. SUMMARY OF BACKGROUND DATA: To the best of our knowledge, no reports have compared various anchors at the apical level for correction of scoliosis curves > or = 100 degrees. METHODS: Sixty-eight scoliosis patients (44 neuromuscular, 21 idiopathic, and 3 congenital) with major curves > or = 100 degrees (mean, 112.7 degrees; range, 100 degrees -159 degrees ) who underwent segmental spinal instrumentation and fusion with different anchors in the apical level were analyzed. All patients had a minimum 2-year follow-up (mean, 4.0 years; range, 2.0-10.5) and were divided into Group W (sublaminar wires n = 26), Group H (hooks n = 18), Group A (anterior vertebral screws n = 7), and Group PS (pedicle screws n = 17) based on the type of apical anchor used. Radiographic parameters and complications were investigated. RESULTS: The 4 groups did not demonstrate any significant differences in gender, age at surgery, preoperative major Cobb angle, or curve flexibility (all P > 0.05). However, the PS group demonstrated a shorter follow-up period compared with the other 3 groups (P < 0.05). The PS group demonstrated the greatest correction rate, smallest loss of correction (P < 0.05), and greatest amount of correction of the apical vertebral translation (P < 0.0005) at ultimate follow-up. There were 4 cases (5.9%) of pseudarthrosis (3 in Group W, 1 in Group H; P > 0.05), 6 cases (8.8%) of implant failure (4 in Group W, 2 in Group H; P > 0.05). Despite one (1.5%) intraoperative neurologic complication (differences among groups, P > 0.05), there was no permanent neurologic deficit. CONCLUSION: All 4 constructs were able to achieve and maintain acceptable correction safely without permanent neurologic deficit and all demonstrated acceptable implant failure rate. Pedicle screw constructs in the apical levels demonstrated the best coronal correction, smallest loss of correction, and greatest amount of apical vertebral translation correction of the major Cobb angle compared with the other constructs without neurologic complications. PMID- 18449043 TI - Loss of spinal cord monitoring signals in children during thoracic kyphosis correction with spinal osteotomy: why does it occur and what should you do? AB - STUDY DESIGN: A retrospective review of pediatric kyphosis patients undergoing a spinal cord-level osteotomy for correction. OBJECTIVE: To evaluate the prevalence, etiology, timing, and intervention related to loss of spinal cord monitoring data during surgical correction of pediatric kyphosis in the spinal cord region. SUMMARY OF BACKGROUND DATA: Although much has been written regarding the risks inherent to scoliosis surgery, there is less literature available regarding the neurologic outcomes of pediatric kyphosis surgery. As more surgeons contemplate posterior-only kyphosis correction with spinal cord-level osteotomies, the importance of maintaining spinal cord neurologic function is paramount. METHODS: Forty-two patients with pediatric kyphosis undergoing a posterior-only spinal reconstruction with a spinal cord level osteotomy or posterior-based vertebral column resection performed were reviewed. Patients were categorized by diagnosis, type and incidence of osteotomies, and loss of neurogenic mixed-evoked potential (NMEP) data. Interventions required to regain data and postoperative neurologic outcomes were also reviewed. RESULTS: Of the 42 patients, 9 (21.4%) demonstrated a complete loss of NMEP data sometime during surgery while concomitant somatosensory sensory-evoked potentials (SSEP) remained within acceptable limits of baseline values. All 9 patients had intraoperative intervention including: blood pressure elevation (n = 1), release of corrective forces (n = 2), blood pressure elevation and correction release (n = 3), malalignment/subluxation adjustment (n = 1), further bony decompression (n = 1), or restoration of anterior column height via a titanium cage along with further posterior decompression (n = 1). In all cases, SSEPs were unchanged and NMEPs returned varying from 8 to 20 minutes after loss, with all patients having a normal wake-up test intraoperatively and a normal neurologic examination after surgery. CONCLUSION: Intraoperative multimodality monitoring with some form of motor tract assessment is a fundamental component of kyphosis correction surgery in the spinal cord region in order to create a safer, optimal environment and to minimize neurologic deficit. The surgeon must be able to trust the information monitoring provides and act on it accordingly. PMID- 18449044 TI - Transcranial motor-evoked potentials combined with response recording through compound muscle action potential as the sole modality of spinal cord monitoring in spinal deformity surgery. AB - STUDY DESIGN: This study is a prospective review of all spinal cord monitoring procedures in our unit from 1999 to 2004 in patients undergoing spinal deformity correction surgery. OBJECTIVE: To report the sensitivity and specificity of transcranial motor-evoked potentials (MEP) and compound muscle action potential (CMAP) monitoring as the sole modality in spinal deformity correction surgery. SUMMARY OF BACKGROUND DATA: Combined spinal cord monitoring with somatosensory evoked potentials and MEP has been widely used. The use of CMAP as the only modality has not been widely used and its efficacy has not been fully elucidated. METHODS: The intraoperative monitoring outcomes were compared with patient's postoperative clinical outcomes. The sensitivity and specificity were calculated and determined for our monitoring protocol. RESULTS: Transcranial MEPs were measured in 144 patients in 172 procedures. In 2 patients (3 procedures), we were unable to record any CMAPs. There were 15 intraoperative monitoring changes. There were no new postoperative neurological deficits. CONCLUSION: The monitoring criteria are sufficiently strict to achieve a sensitivity of 1.0 and a specificity of 0.97. Monitoring of CMAPs alone has been adequate to avoid clinical neurological deficits. PMID- 18449045 TI - Adolescent idiopathic scoliosis patients report increased pain at five years compared with two years after surgical treatment. AB - STUDY DESIGN: A multicenter study of changes in Scoliosis Research Society (SRS) outcome measures after surgical treatment of adolescent idiopathic scoliosis (AIS). OBJECTIVE: To evaluate changes in patient determined outcome measures between 2 and 5 years after AIS surgery. SUMMARY OF BACKGROUND DATA: Current surgical procedures have been shown to improve subjective measures in patients with AIS. At 2-year follow-up, AIS patients reported significant improvement in all 4 preoperative domains of the SRS questionnaire. In addition, the major Cobb angle was shown to be negatively correlated with preoperative scores in the pain, general self-image, and general function domains. Five-year SRS scores have not been evaluated previously. METHODS: A multicenter, prospectively generated database was used to obtain perioperative, radiographic, and SRS-24 outcomes data. The inclusion criteria were: a diagnosis of AIS, surgical treatment (anterior, posterior, or combined), a comprehensive set of radiographic measures, and completed preoperative, 2-year, and 5-year SRS questionnaires. Repeated measures analysis of variance was used to compare changes in patient responses for each of the 7 outcome domains. Univariate analysis of variance was used to compare the change in pain score at 5 years to the level of the lowest instrumented vertebrae and surgical approach. A correlation analysis was used to determine the association between changes in any of the radiographic variables and changes in SRS scores. The data were checked for normality and equal variances, and the level of significance was set at P < 0.01. RESULTS: Forty-nine patients (42 women, 7 men; 14.2 +/- 2.1 year old; 5.4 +/- 0.6 years follow-up) met the inclusion criteria for this study. Thirty-seven of 49 (76%) of these patients underwent an open or thoracoscopic anterior procedure. SRS-24 scores improved significantly in 3 of the 4 preoperative domains at the 2-year visit. At 5 years postop, a statistically significant decrease in the pain score (4.2 +/- 0.6 to 3.9 +/- 0.9, P = 0.003) and a trend toward worsening scores in 4 other domains was observed; however, Patient Satisfaction scores remained unchanged. Lowest instrumented vertebrae and surgical approach could not be correlated to changes in the pain score. In addition, no correlation was found between changes in any of the 21 radiographic measures evaluated and changes in SRS scores. CONCLUSION: There was a statistically significant increase in reported pain from 2 to 5 years after surgical treatment; however, the etiology of worsening pain scores could not be elucidated. Given continued patient satisfaction, the clinical relevance of this small reduction remains unknown. Nevertheless, this observation deserves further evaluation and must be considered in relation to the natural history of this disease. PMID- 18449046 TI - Perioperative outcomes and complications related to teaching residents and fellows in scoliosis surgery. AB - STUDY DESIGN: Single-surgeon retrospective case series of 303 consecutive operative patients with idiopathic scoliosis (IS). OBJECTIVE: The purpose of this study is to evaluate the perioperative outcomes in patients undergoing surgery for IS as a function of the experience level of the surgical assistant. SUMMARY OF BACKGROUND DATA: The experience level of the surgical assistant, who is often a resident or fellow, has never before been evaluated as an independent factor in predicting perioperative outcomes and morbidity in scoliosis surgery. We hypothesize that there is no difference in perioperative outcomes with varying experience level of the surgical assistant. METHODS: We evaluated the clinical, radiographic, and operative records from 303 consecutive operative patients from consecutive patients with IS. Group I was comprised of residents or spine fellows as assistants (teaching service, n = 175), and Group II consisted of junior or senior attendings as assistants (private practice service, n = 128). Multivariable linear regression was used to evaluate the relationship between experience level of the assistant and curve correction, operative time, estimated blood loss (EBL), complications, transfusions, and length of stay. RESULTS: In the posterior spinal fusion group (PSF, n = 164), there were no statistically significant differences in operative times between Groups I and II. Group I operative time was significantly increased, however, in patients undergoing anterior spinal surgery (ASF, P = 0.01), video-assisted thoracoscopic surgery (P = 0.0004), and combined anterior/posterior surgeries (ASF/PSF, P = 0.0063). There were no differences in EBL in ASF, video-assisted thoracoscopic surgery, or PSF surgeries, however, Group I had significantly higher EBL in the ASF/PSF group (P = 0.0016). No group differences were detected with respect to curve correction, transfusion rates, length of stay, or early complication rates. CONCLUSION: The experience level of surgical assistant had little bearing on perioperative morbidity or radiographic outcomes in scoliosis surgery. Marginally increased operative times and EBL, without an increase in transfusions or complications, is an acceptably safe tradeoff for educating orthopedic residents and fellows. PMID- 18449047 TI - Postoperative ketorolac does not predispose to pseudoarthrosis following posterior spinal fusion and instrumentation for adolescent idiopathic scoliosis. AB - STUDY DESIGN: A retrospective review comparing patients who had postoperative ketorolac and those who did not following posterior spinal fusion and instrumentation (PSFI) for adolescent idiopathic scoliosis (AIS). OBJECTIVE: To analyze the effect of postoperative ketorolac on the incidence of pseudoarthrosis in postoperative AIS patients. SUMMARY OF BACKGROUND DATA: Ketorolac (Toradol, Roche Laboratories, Nutley, NJ) is a nonsteroidal antiinflammatory drug that is an effective adjunct to manage postoperative pain. It has been previously demonstrated to inhibit spinal fusion in adult patients undergoing a L4 to sacral fusion. To our knowledge, there are no large studies analyzing this effect following PSFI for AIS. METHODS: An IRB-approved retrospective medical record review was performed from 1994 to 2000 of patients undergoing a PSFI for AIS at a single institution. Segmental spinal instrumentation (Texas Scottish Rite Hospital) and iliac crest bone graft were used in both groups. Demographic and operative data were recorded. Patients were divided into those who had postoperative ketorolac (K group) and those who did not (NK group). Patients who had a surgically confirmed pseudoarthrosis were identified and the K group and NK group were statistically compared. RESULTS: There were 161 patients in the NK group and 158 in the K group. There were no differences with respect to age (14.4 vs. 14.2 years), gender (83.9% vs. 84.8% females), levels fused (9.8 vs. 9.7), or preoperative curve magnitude (57.9 degrees vs. 58.9 degrees ). In the K group, the number of doses of ketorolac administered was 6.7 for an average of 26.7 mg for a duration of 46 hours after surgery. Patients in the K group were more likely to have Motrin (average 5.8 doses) compared with the NK group (average 0.7 doses) (P < 0.01). No patient in the K group had a history of cigarette smoking compared with 2 patients in the NK group, both of whom went on to solid arthrodesis. The overall incidence of pseudoarthrosis was 2.5% for all patients. There was no difference in the incidence of pseudoarthrosis comparing the K (1.9%) and the NK group (3.1%)(P = 0.7). When the single rod posterior implants were excluded, there was no difference between the K (0.7%) and NK groups (1.8%) (P = 0.58). CONCLUSION: Ketorolac does not increase the incidence of developing a pseudoarthrosis when used as an adjunct for postoperative analgesia following a PSFI for AIS using segmental spinal instrumentation and iliac crest bone graft. The differences seen here compared with adults may be due to the greater healing potential in these young patients. We recommend utilization of ketorolac after surgery to supplement pain management when necessary. PMID- 18449048 TI - Surgical treatment of adult scoliosis: is anterior apical release and fusion necessary for the lumbar curve? AB - STUDY DESIGN: A retrospective study. OBJECTIVES: To analyze radiographic and functional outcomes after posterior segmental spinal instrumentation and fusion (PSSIF) with and without an anterior apical release of the lumbar curve in adult scoliosis patients. SUMMARY OF BACKGROUND DATA: No comparison study on PSSIF of adult lumbar scoliosis with apical release versus without has been published. METHODS: Forty-eight adult patients with lumbar scoliosis (average age at surgery 49.6 years, average follow-up 3.7 years) who underwent PSSIF were analyzed with respect to radiographic change, perioperative and postoperative complications, and Scoliosis Research Society (SRS) outcome scores. Twenty-three patients underwent an anterior apical release of the lumbar curve via a thoracoabdominal approach followed by PSSIF (Group I). The remaining 25 patients underwent a PSSIF of the lumbar curve followed by anterior column support at the lumbosacral region through an anterior paramedian retroperitoneal or posterior transforaminal approach (Group II). RESULTS: Before surgery, Group I showed a somewhat larger lumbar major Cobb angle (63.2 degrees vs. 55.9 degrees , P = 0.07), and both groups demonstrated significant differences in lumbar curve flexibility (26.9% vs. 37.2%, P = 0.02) and thoracolumbar kyphosis (27.0 degrees vs. 15.0 degrees , P = 0.03). After surgery, at the ultimate follow-up, there were no significant differences in major Cobb angle, C7 plumbline to the center sacral vertical line (P = 0.17), C7 plumbline to the posterior superior endplate of S1 (P = 0.44), and sagittal Cobb angles at the proximal junction (P = 0.57), T10-L2 (P = 0.24) and T12-S1 (P = 0.51). There were 4 pseudarthroses in Group I and one in Group II (P = 0.02). Postoperative total normalized SRS outcome scores at ultimate follow-up were significantly higher in Group II (69% vs. 79%, P = 0.01). CONCLUSION: Posterior segmental spinal instrumentation and fusion without anterior apical release of lumbar curves in adult scoliosis demonstrated better total SRS outcome scores and no differences in radiographic parameters without differences in clinical complications. However, the use of BMP in some of these patients (44%) may have also contributed to these differences. PMID- 18449049 TI - Surgical correction of scoliosis in pediatric patients with cerebral palsy using the unit rod instrumentation. AB - STUDY DESIGN: Retrospective clinical and radiographic consecutive case series of 2 surgeons. OBJECTIVE: The purpose of this study was to present a large consecutive series of patients with cerebral palsy who were treated with the Unit rod instrumentation at a single institution. The goal was to report the incidence of surgical complications, degree of deformity correction, reoperation rate, prevalence of pseudarthrosis, and the caretakers' perceived outcome. SUMMARY OF BACKGROUND DATA: Children with cerebral palsy frequently develop scoliosis that requires surgical correction. Segmental instrumentation has been the primary mode of treatment. There are no reported large series with long-term follow up. METHODS: This study was a retrospective review of 287 children treated with the Unit rod instrumentation. This instrumentation with fusion included the whole spine (between C7 and T3 into the pelvis) with 242 posterior-only and 45 anterior posterior procedures. Of this group, 241 patients were observed for more than 2 years. This review focused on the rate of complications and radiographic outcome of the treatment. Parent and caretaker interviews were conducted to define perceived functional outcome after surgery. RESULTS: Scoliosis was corrected from a mean of 76 degrees to 25 degrees (68%). Pelvic obliquity was corrected from a mean of 17 degrees to 5 degrees (71%). In posterior-only procedures the average blood loss was 2.8 L, ICU stay was 4.9 days, and the hospital stay was 19.6 days. In combined procedures, the average blood loss was 3.4 L, ICU stay was 6.7 days, and the hospital stay was 24.5 days. Major complications included 3 perioperative deaths, 18 deep wound infections [12 early deep infections in a total of 287 patients (4.2%); 6 late deep infections in a total of 236 patients (2.5%)], and 2 patients with septicemia who recovered after prolonged antibiotic management. Caretakers' survey reported a 96% satisfaction rate. CONCLUSION: The Unit rod instrumentation is a common standard technique and the primary instrumentation system for the treatment of pediatric patients with cerebral palsy and neuromuscular scoliosis because it is simple to use, it is considerably less expensive than most other systems, and can achieve good deformity correction with a low loss of correction, as well as a low prevalence of associated complications and a low reoperation rate. PMID- 18449050 TI - Free-hand pedicle screw placement during revision spinal surgery: analysis of 552 screws. AB - STUDY DESIGN: : A retrospective study. OBJECTIVE: : To evaluate the safety of free-hand pedicle screw placement during revision surgery at levels with a solid posterior fusion mass and/or identified pseudarthroses of the thoracic and lumbosacral spine. SUMMARY OF BACKGROUND DATA: : Placement of pedicle screws into previous fusion masses or pseudarthrosis levels of the spine is challenging because of the loss of anatomic landmarks. We are aware of no study focusing on screw placement without any type of radiographic or navigational assistance. METHODS: : Thirty-seven patients underwent revision spinal surgery with posterior spinal instrumentation and fusion using 552 transpedicular screws by a single surgeon from 1994 to 2003. Among 552 screws, 184 were inserted into virgin levels, 60 were inserted into the vertebral body through previous screw holes, 208 were inserted into fusion masses, and 100 were inserted into pseudarthrosis levels. We used the quadrangulation method to gain pedicle access in a prior fusion mass after diligent exposure of any and all visible anatomic landmarks. All screws were analyzed using radiographs, intraoperative monitoring data, and clinical outcomes. RESULTS: : There were 29 women and 8 men. The mean age of patients at the time of surgery was 38 + 6 years (range, 8-75 years). Six screws were removed intraoperatively according to the triggered electromyography criteria and 4 of them were repositioned after checking the integrity of the pedicle by a careful probing technique (1.09%). Six screws were removed after checking the intraoperative radiographs and 5 screws were misplaced, as noted, in postoperative radiographs (1.99%). Two patients underwent revision surgery at 3 days and 6 weeks after initial surgery, respectively, for root decompression at the osteotomy site although screw positions were correct. CONCLUSION: : The free hand technique of thoracic and lumbosacral pedicle screw placement in revision spinal surgery is reliable and safe when using the quadrangulation method of gaining pedicle access in a prior fusion mass or at pseudarthrosis levels. PMID- 18449051 TI - A central hook-rod construct for osteotomy closure: a technical note. AB - STUDY DESIGN: A retrospective consecutive case series. OBJECTIVE: To illustrate a new surgical technique for closing osteotomies in fixed sagittal imbalance patients, and to evaluate the radiographic outcomes and complications. SUMMARY OF BACKGROUND DATA: During an osteotomy site closure, various techniques were used, most of which involve patient positioning, rod cantilevering, extending the fixation points, allowing less correction, and compressing through pedicle fixation points. Most of these techniques place added stress on the spinal pedicle screw fixation points, which may lead to screw loosening and eventual fixation failure. We used a central compression hook-rod construct for osteotomy closure to avoid adding compression force to the pedicle screws. METHODS: Twenty three consecutive patients in whom fixed sagittal imbalance was treated with a lumbar pedicle subtraction osteotomy or multilevel Smith-Petersen Osteotomies (SPO) using a central compression hook-rod construct for osteotomy closure were analyzed. Compression hooks were inserted into the fusion mass above and below the osteotomy site and centrally attached to a short rod. Compression forces were applied to securely close the osteotomy site. The mean age was 49.0 years (range, 33-75 years). Diagnoses included 11 scoliosis, 10 degenerative sagittal imbalance, and 2 ankylosing spondylitis patients. All but 2 cases were revisions. Sixteen patients had a pedicle subtraction osteotomy, and 7 had multilevel SPOs. A radiographic and clinical analysis was performed to evaluate the efficacy and possible complications of this technique. RESULTS: Overall, lumbar lordosis increased an average of 31 degrees (range, 11 degrees -68 degrees ) and local lordosis through the osteotomy site increased by an average of 28 degrees (range, 3 degrees -47 degrees ). The C7 sagittal plumbline improved an average of 109 mm (range, 11-240 mm). In all cases, the osteotomy closures were performed without screw loosening or loss of correction intraoperatively. There were no hook-rod construct failures, but one transient root paresis, which might be related to this method. There was no pseudarthroses or significant correction loss after surgery. CONCLUSION: A central hook-rod construct is a safe, quick, controlled, and effective method for spinal osteotomy site closure. It may add strength to the overall construct and avoids the placement of direct compression force on the main pedicle screw fixation points that may lead to screw loosening during the osteotomy site closure, and ultimately to fixation failure. PMID- 18449052 TI - Re: Sasso R, Heller J, Hacker B, Smucker J. Artificial disc versus fusion. A prospective, randomized study with 2-years follow-up on 99 patients. Spine 2007;32:2933-40. PMID- 18449054 TI - Re: Celik SE, Kara A. Does shaving the incision site increase the infection rate after spinal surgery? Spine 2007;32:1575-7. PMID- 18449055 TI - Re: Kim N, Delport E, Cucuzzella T, Marley J, Pruitt C. Is sedation indicated before spinal injections? Spine 2007;32:E748-E52. PMID- 18449059 TI - Human papillomavirus DNA detected in breast milk. AB - Human papillomavirus (HPV) testing of 223 breast milk samples 3 days postpartum was performed with polymerase chain reaction, hybridization, and sequencing. HPV 16-DNA was detected in 4.0% of the samples. HPV carriage in the breast milk was not correlated with mother's oral or cervical HPV-status or the demographic data. Oral HPV-infection of the spouse at month 6 and 12 postpartum was statistically significantly associated with HPV carriage in the breast milk. PMID- 18449060 TI - Interventions using foreign material to treat congenital heart disease in children increase the risk for infective endocarditis. AB - BACKGROUND: Congenital heart disease (CHD) is a risk factor for infective endocarditis (IE). We aimed to assess the impact of cardiac interventions on the frequency and microbial profile of IE in children with CHD. METHODS: Episodes of IE were analyzed in children aged < or =18 years with CHD between 1995 and 2005 with respect to cardiac surgery or catheter interventions with or without implantation of foreign material. RESULTS: Diagnosis of IE was made in 14 (0.36%) of 3826 children with CHD including native IE in 6 and postinterventional IE in 8 patients. During the period 3029 cardiac interventions (1944 surgeries; 1085 catheters) were performed; foreign material was implanted in 1360 interventions (1139 surgeries; 221 catheters) including all 8 patients with postinterventional IE. Cardiac intervention by itself did not change the risk for IE compared with no intervention. The risk of IE after implantation of foreign material was higher than following intervention without implantation (odds ratio, 21.0; 95% confidence interval, 1.2-365; P < 0.05). Pacemaker implantation was associated with the highest risk for IE (odds ratio, 11.0; 95% confidence interval, 2.6 46.5; P < 0.001). Staphylococci were the most frequently isolated organisms in foreign material-associated IE. CONCLUSIONS: Cardiac intervention in children with CHD does not increase the risk for IE. Postinterventional IE in children with CHD is strongly linked to implantation of foreign material, especially of pacemaker. PMID- 18449058 TI - Maternal smoking and oral clefts: the role of detoxification pathway genes. AB - BACKGROUND: There is evidence for an effect of cigarette smoking on risk of oral clefts. There are also hypothetical pathways for a biologic effect involving toxic chemicals in cigarette smoke. METHODS: We performed a combined case-control and family-triad study of babies born with oral clefts in Norway in the period 1996 to 2001, with 88% participation among cases (n = 573) and 76% participation among controls (n = 763). Mothers completed a questionnaire 4 months after birth of the baby. DNA was collected from parents and children, and assayed for genes related to detoxification of compounds of cigarette smoke (NAT1, NAT2, CYP1A1, GSTP1, GSTT1, and GSTM1). RESULTS: For isolated cleft lip (with or without cleft palate) there was a dose-response effect of smoking in the first trimester. The odds ratio rose from 1.6 (95% confidence interval = 1.0-2.5) for passive smoking to 1.9 (0.9-4.0) for mothers who smoked more than 10 cigarettes per day. There was little evidence of an association with cleft palate. Genetic analyses used both case-control and family-triad data. In case-triads we found an association between a NAT2 haplotype and isolated cleft lip (relative risk of 1.6 with 1 copy of the allele and 2.5 with 2 copies), but with little evidence of interaction with smoking. Other genes did not show associations, and previously described interactions with smoking were not confirmed. CONCLUSION: First-trimester smoking was clearly associated with risk of cleft lip. This effect was not modified by variants of genes related to detoxification of compounds of cigarette smoke. PMID- 18449061 TI - Importance of a thorough examination. AB - Scrub typhus is a common cause of febrile illness among children from rural regions in tropical countries. We described 2 cases of scrub typhus with an eschar localized in the genitalia that was missed during the routine medical examination of a febrile child. PMID- 18449062 TI - Correlation between respiratory syncytial virus (RSV) test data and hospitalization of children for RSV lower respiratory tract illness in Florida. AB - BACKGROUND: Florida experiences year-round outbreaks of respiratory syncytial virus (RSV), but it is unknown if there is a correlation between RSV virology data and disease-related hospitalizations. We analyzed RSV surveillance and hospitalization data for the state of Florida to determine if there is an association between seasonal virology data and the incidence of International Classification of Diseases, 9th revision, clinical modification (ICD-9-CM) coded hospitalizations for RSV lower respiratory tract illness. METHODS: We conducted a retrospective analysis for each of 5 regions of Florida for 4 years (2001-2004) of monthly RSV surveillance data presented on the Florida Department of Health website and hospitalization data provided by the Agency for Health Care Administration. RSV was considered present when > or =10% of laboratory tests were positive in a given month and the duration of seasons was determined by the number of consecutive months threshold values were exceeded. Hospitalizations in children 24 months of age and younger were defined as RSV related if any of the following RSV-specific ICD-9-CM codes appeared on the discharge summary: 079.6 RSV; 466.11 acute bronchiolitis caused by RSV; and 480.1 pneumonia caused by RSV. RESULTS: RSV circulated year-round statewide and seasons ranged from 7-8 months in the southwest, northwest, and north regions of Florida to 11-12 months in the central and southeast regions, respectively. More than 23,000 children younger than 24 months of age were hospitalized throughout the state for an RSV-related illness during the 4-year period, with almost 20,000 (86%) of the admissions in infants less than 12 months of age. There were 23 hospitalizations yearly per 1000 births and more than 90% of discharges occurred during the defined RSV seasons. CONCLUSIONS: To our knowledge, this is the first study to demonstrate a positive correlation between RSV test data and hospitalizations both statewide and for individual regions within Florida. It would be prudent for clinicians to obtain results of local RSV virology data to guide decisions on timing of prophylaxis to prevent RSV hospitalizations. PMID- 18449063 TI - A randomized comparative study of levofloxacin versus amoxicillin/clavulanate for treatment of infants and young children with recurrent or persistent acute otitis media. AB - BACKGROUND: The need for alternative antimicrobial therapy for recurrent and persistent acute otitis media (AOM) in children has raised interest in assessing the efficacy and safety of fluoroquinolones for treatment of these infections. METHODS: In an evaluator-blinded, active-comparator, noninferiority, multicenter study, children (6 months to <5 years) were randomized 1:1 to receive levofloxacin (10 mg/kg twice daily) or amoxicillin/clavulanate (14:1; amoxicillin 45 mg/kg twice daily) for 10 days, with evaluations 4-6 days of therapy (visit 2), 2-5 days after completing therapy (visit 3), and 10-17 days after last dose (visit 4). Primary outcome was clinical cure at visit 3 based on resolution of clinical signs and symptoms of AOM. RESULTS: A total of 1650 children were randomized and 1305 were clinically evaluable at visit 3 (630 levofloxacin, 675 comparator). Clinical cure rates were 72.4% (456 of 630) in levofloxacin-treated and 69.9% (472 of 675) in amoxicillin/clavulanate-treated children. Cure rates were also similar for levofloxacin and comparator for each age group (< or =24 months: 68.9% versus 66.2%; >24 months: 76.9% versus 75.1%; respectively). Cure rates at visit 4 were 74.9% and 73.8% in levofloxacin and amoxicillin/clavulanate groups, respectively. The upper limits of the confidence intervals were less than the noninferiority margin of 10% indicating that levofloxacin treatment is noninferior to comparator treatment overall and in both infants (6 months to 2 years) and children 2-5 years. No differences between treatment groups regarding the frequency or type of adverse events were apparent. CONCLUSIONS: Levofloxacin was not inferior to amoxicillin/clavulanate for the treatment of recurrent and/or persistent AOM in infants and children. PMID- 18449064 TI - A randomized controlled trial of the impact of chlorhexidine skin cleansing on bacterial colonization of hospital-born infants in Nepal. AB - BACKGROUND: Chlorhexidine skin cleansing might substantially reduce neonatal infection and mortality in developing countries. Few data exist on the impact of chlorhexidine cleansing on skin colonization of infants during the first day of life or on the absorption potential of chlorhexidine during newborn skin cleansing. METHODS: Hospital-born newborns in Kathmandu, Nepal were randomly allocated to full-body skin cleansing with 0.25%, 0.50%, or 1.00% chlorhexidine solution. Skin swabs were collected from the axilla, inguinal, and peri-umbilical areas before cleansing (baseline), and at 2 and 24 hours after treatment. Skin flora was quantified and organisms identified. In a subsample, heel prick blood was collected 24 hours after the cleansing and percutaneous absorption of chlorhexidine was assessed. RESULTS: Among 286 enrolled newborns, no adverse effects on skin were reported and body temperature was minimally reduced (mean reduction, 0.33 degrees C). In all groups, positive skin culture rates were significantly reduced at 2 hours but generally not at 24 hours; greater reductions were observed with higher concentrations of chlorhexidine. Effect at 24 hours was highest in the 1.00% group (37% lower positive skin culture rate). For 15 of 75 infants with heel pricks, chlorhexidine was detected at trace concentrations (<8 ng/mL, n = 14; 25.8 ng/mL, n = 1). CONCLUSIONS: Chlorhexidine skin cleansing seemed safe and reduced skin flora in newborns in a dose-dependent manner 2 hours after treatment. Greater residual effect at the highest concentration (1%) might provide broader benefit and may simplify combined maternal and neonatal regimens by matching the concentration used for vaginal cleansing during labor. PMID- 18449065 TI - Rates of tympanic membrane closure in double-tympanocentesis studies. AB - BACKGROUND: Data on the outcome of tympanic membrane (TM) closure after tympanocentesis in acute otitis media (AOM) patients is limited. OBJECTIVES: To analyze the dynamics of TM perforation closure after 1 or 2 tympanocentesis procedures performed at diagnosis and during AOM treatment. PATIENTS AND METHODS: Study population included 113 children enrolled in 4 double-tympanocentesis studies. Only the files of patients whose first and second examination were performed by the same 2 otorhinolaryngologists were analyzed. Middle ear fluid (MEF) was cultured on day 1 and days 4-6, the latter only in initially culture positive patients. Patients were also examined on days 11-14 and followed until days 22-28. RESULTS: Ninety-three (82%) patients underwent tympanocentesis on days 4-6; 103 (91%) and 95 (84%) were evaluable on days 11-14 and 22-28, respectively. One hundred seventy-three ears underwent tympanocentesis on day 1 and 139 on days 4-6. Ninety-seven (86%) patients had positive MEF cultures. One hundred fifty-three (88%) tympanocentesis procedures performed at enrollment were closed on days 4-6. No differences were recorded in the closure rates as function of patient age, previous AOM history, MEF culture positivity, pathogens isolated at enrollment, and pathogen eradication on days 4-6. The 20 eardrums still open on days 4-6 were closed on days 11-14. Eleven (9%) of the evaluable ears tapped on days 4-6 were not closed on days 11-14 and 9 of 10 were closed on days 22-28. CONCLUSIONS: TM perforation closed in most cases within a few days regardless of patient and disease characteristics, and 2 consecutive tympanocentesis procedures performed at short-time intervals are associated with good TM closure rates. PMID- 18449066 TI - Role of human herpesvirus 6 infection in young Brazilian children with rash illnesses. AB - BACKGROUND: Human herpesvirus type 6 (HHV-6) has been shown to infect almost all children by 4 years of age. Primary infection causes an undifferentiated febrile illness, with approximately 30% of children exhibiting the classic clinical manifestations of exanthem subitum. Even with typical clinical presentation, exanthem subitum is frequently misdiagnosed as measles or rubella. Our aim was to describe the frequency and clinical manifestations of HHV-6 infection in children less than 4 years of age enrolled in a study designed to define the etiology of rash diseases. PATIENTS AND METHODS: The study was conducted between January 1998 and December 2006 at a general hospital and a large primary health care unit from Niteroi, Rio de Janeiro, Brazil. Sera from 223 children, in whom measles, rubella, dengue fever, and parvovirus B19 infections were excluded, were studied for anti-HHV-6 antibodies using an indirect immunofluorescence test. Demographic and clinical data of those patients were described. RESULTS: Ninety-seven (43.5%) of the children had evidence of primary HHV-6 infection. The age of onset peaked at 6-11 months and 75% of the HHV-6 infection occurred in children between 6 and 17 months. Only 21% of the HHV-6 cases had a typical roseola-like illness and 73% and 46%, respectively, fulfilled the clinical criteria of measles and rubella suspected case. CONCLUSIONS: Our study confirms the importance of HHV-6 infection in young children and highlights the difficulties of diagnosing a rash illness on clinical grounds alone. PMID- 18449067 TI - Resolution of human immunodeficiency virus type 1 infection-related severe pulmonary hypertension in a very low-birth-weight infant. AB - Pulmonary arterial hypertension (PAH) affects approximately 0.5% of human immunodeficiency virus (HIV)-infected adults with poor prognosis. The effectiveness of highly active antiretroviral therapy for treatment of HIV related PAH (HIV-PAH) remains controversial. Little is known about the incidence, clinical course, and therapy options for PAH in HIV-1-infected pediatric patients. Here, we report the case of a preterm infant with HIV-related life threatening PAH, which resolved after initiation of highly active antiretroviral therapy. PMID- 18449068 TI - Chlamydia positivity in American Indian/Alaska Native women screened in family planning clinics, 1997-2004. AB - BACKGROUND: Previous studies demonstrated high levels of Chlamydia trachomatis (CT) infections within American Indian/Alaskan Native (AI/AN) populations but there are few analyses of CT prevalence in these populations over time. METHODS: We analyzed data from 7374 visits at which diagnostic tests for CT were collected in AI/AN women aged 15 to 24 years seen at family planning clinics associated with the Region X Infertility Prevention Project. Trends in population characteristics and test positivity were examined and compared with non-AI/AN women tested in the same setting and time period. Chlamydia positivity was adjusted for changes in diagnostic test type. Multivariable logistic regression was used to identify characteristics associated with infection. RESULTS: Adjusted CT positivity in AI/AN women rose from 7.8% to 11.0%, which was 1.5 to 2.2 times the non-AI/AN population levels over the study period (absolute difference 2.8% 6.6%). Differences persisted after correction for test type and age. Temporal changes in positivity among AI/AN women were associated with a rise in reported risk behaviors and decline in age of the population being tested. Risk factors associated with positivity among AI/AN women were younger age, > or =1 behavioral risks, > or =1 clinical findings, partner with chlamydia, chlamydia in past year, and pregnancy related visit. CONCLUSIONS: AI/AN women had consistently higher levels of chlamydia positivity than non-Native women, even after adjustment for age and diagnostic test. Further investigation of risks for chlamydia, related outcomes, access to screening, sexual networks, and enhanced surveillance would be beneficial for improving health in this vulnerable population. PMID- 18449069 TI - Laboratory aspects of screening men for Chlamydia trachomatis in the new millennium. AB - OBJECTIVE: To describe and review the methods for laboratory diagnosis of Chlamydia trachomatis in men. BACKGROUND: Men provide a reservoir for continued transmission of C. trachomatis to women, thus representing a population for potential targeted screening. Although there are no formal recommendations by professional organizations for screening men for chlamydia, guidance has been provided by the Centers for Disease Control and Prevention for sites wishing to screen men, who are primarily asymptomatic. METHODS: Review of the published literature for diagnostic laboratory tests for C. trachomatis in men. RESULTS: The laboratory test of choice for screening men is a nucleic acid amplification test (NAAT), and the specimen of choice is first-catch urine. The NAAT has sufficient sensitivity and specificity, and urine provides a noninvasive specimen; together, this combination provides the achievement of sensitivities of >90% to 97% and high specificity (99%). Populations of men, such as those in detention, Job Corps training, emergency departments, the military, and high schools can offer accessible target populations for easily implemented chlamydia screening. CONCLUSION: Screening more men with NAAT assays may provide the possibility of reducing the overall burden of chlamydia in both men and women. PMID- 18449070 TI - HIV testing in adolescents and young adults receiving STI testing in an urban primary care setting. PMID- 18449071 TI - Genotyping of urogenital Chlamydia trachomatis in Regional New South Wales, Australia. PMID- 18449072 TI - Chlamydia trachomatis positivity rates among men tested in selected venues in the United States: a review of the recent literature. AB - The cost-effectiveness of screening men for Chlamydia trachomatis depends in part on the prevalence of chlamydia in the screened population and the ease with which screening programs can be implemented. Screening in venues with high rates of chlamydia positivity among men may therefore be an important adjunct to chlamydia control. To evaluate the recent US literature on chlamydia positivity in chlamydia screening programs among asymptomatic men in nonsexually transmitted disease clinic settings, we reviewed published articles between 1995 and June 2007, using PubMed as the primary search tool. Articles were abstracted and positivity rates summarized by type of venue, race/ethnicity, age group, and US region. The overall median positivity rate was 5.1%. The highest rates were observed among men tested in juvenile (7.9%) and adult (6.8%) detention facilities, among blacks (6.7%), the 15 to 19 years old (6.1%) and 20 to 24 years old (6.5%) age groups, and among men screened in the southern United States (6.4%). Chlamydia rates among men are high in certain venues, particularly correctional settings, but also depend on the demographic composition of the target population and location. Programs considering male chlamydia screening programs should conduct pilot programs to assess chlamydia positivity as well as feasibility and cost in target venues. PMID- 18449073 TI - Implementing Chlamydia screening programs in juvenile correctional settings: the california experience. AB - OBJECTIVES: To present strategies, methods, and tools for implementing a chlamydia screening program across diverse county juvenile justice systems in California, and to present screening and treatment outcomes of this program. METHODS: Requirements for juvenile hall participants in a chlamydia screening program were described as well as the administrative structure of program implementation. An assessment of screening using administrative data was conducted. Facilitators and barriers to implementation were identified through interviews with local program coordinators and/or institutional medical and correctional staff. RESULTS: Screening projects were implemented in January 2003 in 15 counties (18 juvenile halls) throughout the state. Among institutions with relevant data, the proportion of female detainees screened for chlamydia rose from 35% preprogram implementation to 66% in 2006. CONCLUSIONS: High screening levels with high case yields and treatment rates in the juvenile correctional setting can be accomplished and sustained, despite many barriers, if effective collaboration between public health and correctional entities is established. PMID- 18449074 TI - [The influenza epidemic plan, do you know about it?]. PMID- 18449075 TI - [The contribution of positron emission tomography in pleural disease]. AB - INTRODUCTION: Positron emission tomography (PET) has a clear role in oncology, particularly in thoracic disease. In the light of our experience and a revue of the literature we define precisely the role of metabolic imaging in the diagnosis of pleural pathology. BACKGROUND: In particular PET allows characterisation of malignant pleural disease and provides prognostic information in mesothelioma. Metabolic imaging provides clinical information for the staging of pulmonary cancer, in the search for a primary tumour in metastatic pleurisy and also in the follow up of chronic or recurrent pleural pathology. CONCLUSIONS: It is justified, therefore, that PET joins the diagnostic armamentarium of pleural pathology, solid or liquid. PMID- 18449076 TI - [Epidemiology of and risk factors for invasive aspergillosis in nonneutropenic patients]. AB - INTRODUCTION: Invasive aspergillosis is a major cause of mortality among patients with hematological malignancies and undergoing bone marrow transplantation. Whereas diagnosis and therapeutic strategies are evaluated for neutropenic patients, only limited data among nonneutropenic patients are available. STATE OF THE ART: Beside classical chronic pulmonary aspergillosis, an increased incidence of acute invasive aspergillosis is reported for nonneutropenic patients, such as patients suffering from chronic respiratory diseases or systemic diseases treated with corticosteroid therapy, and solid organ transplant recipients. PERSPECTIVES: A better knowledge of pathophysiology and epidemiology of invasive aspergillosis is needed to adapt the disease classification for nonneutropenic patients. Beside, the performance of diagnostic tools must be evaluated specifically in this population. CONCLUSIONS: Invasive aspergillosis is underdiagnosed in nonneutropenic patients which may simultaneously be colonized by Aspergillus and receive immunosuppressive therapy. It remains a life-threatening disease as severe as in neutropenic patients, at least partially related to a delayed diagnostic. PMID- 18449077 TI - [Volatile Organic Compounds (VOC): definition, classification and properties]. AB - The term volatile organic compounds includes a wide variety of chemical substances with the common feature of being carbon compounds that are volatile at ambient temperature. They can be classified into different families defined by their chemical formulae, each of which possesses common properties, although there may be major differences in terms of toxicity. For that reason the effects of VOC on health have to be considered both in an individual way and also from a global viewpoint on account of their common toxic properties and the role they play in the formation of environmental photo-oxidative pollutants, both outdoors and indoors. PMID- 18449078 TI - [A methodology for the evaluation of the health related and environmental characteristics of building products]. AB - A global methodology for the evaluation of the environmental and health-related characteristics of building products is presented. This methodology is based on environmental product declaration according to the NF P 01-010 standard for the environmental part and on specific tests for the characterization of the potential health-related impact of building products (emissions of volatile organic compounds and formaldehyde in indoor air, odour emissions, aptitude for growth of micro-organisms: moulds and bacteria, natural radioactive emissions). This methodology can be used either by: *Manufacturers for the communication on the environmental and health-related properties of their building products, *End users, consumers, retailers, building owners and architects wishing to introduce environmental and health-related criteria in their selection procedure of building products, e.g. for "green building" construction. PMID- 18449079 TI - [Late onset, non-infectious pulmonary complications after haematological stem cell transplantation]. AB - INTRODUCTION: Non infectious pulmonary complications which frequently occur in the late follow-up of haemopoietic stem cell transplant (HSCT) recipients account for an increase in mortality and morbidity. Different histological entities have been described among which bronchiolitis obliterans is the most common. BACKGROUND: Because of the absence of prospective epidemiological studies and the difficulties in obtaining surgical lung biopsies from these frail patients little is known about these conditions. Although their pathogenesis is poorly understood they probably result from a chronic pulmonary graft versus host disease (GVHD). The introduction of or increase in systemic immunosuppressive treatment, usually indicated for controlling extra-thoracic manifestations of GVHD, may lead to the resolution of an organising pneumonia but is usually ineffective in the treatment of bronchiolitis obliterans. VIEWPOINTS: Current prospective cohort studies together with randomised prospective studies evaluating more targeted treatments should help determine the frequency, the risk factors and the precise characteristics of the different entities of late non-infectious pulmonary diseases following HSCT and should also improve their management. Furthermore, the recent demonstration of lung abnormalities in animal models of chronic GVHD, similar to those observed in humans, should allow a better understanding of the pathogenesis. CONCLUSION: The prevalence of these diseases is increasing throughout the world. More precise analysis, the identification of risk factors and study of the pathophysiological mechanisms involved should allow better understanding and management than at present. PMID- 18449080 TI - [What is the therapeutic response to corticosteroid in smokers with asthma?]. AB - Inhaled corticosteroid is the first choice antiinflammatory therapy for chronic asthma. International guidelines are based upon data obtained in the non-smokers with asthma. The objective of this review is to highlight the interaction between cigarette smoking and metabolism of steroids and to consider the consequences of such an interaction on clinical and respiratory function. The mechanisms of corticosteroid resistance induced by cigarette smoking results of overexpression of glucocorticoid receptor beta, increased activation of pro-inflammatory transcription factors (nuclear factor-kappaB) and cytokines (IL-4, IL-8, TNF alpha) or reduced histone deacetylase activity. Compared with non smokers with asthma, inhaled corticosteroids in smokers with asthma does not improve asthma control, lung function and bronchial obstruction. Active smoking impairs the efficacy of short-term oral corticosteroid treatment. Smoking cessation is the highest priority in smokers with asthma. PMID- 18449081 TI - [Occupational respiratory cancers]. AB - Lung cancer and pleural mesothelioma are the most common occupational cancers. Recent epidemiological studies have estimated that the fraction attributable to occupational factors varies from 13 to 29% for lung cancer in men and is about 85% for pleural mesothelioma in men. Previous occupational exposure to asbestos is the most common occupational exposure in these cancers. Mesothelioma immediately leads the clinician to look for past asbestos exposure. In contrast, the search for an occupational exposure that should be routine in all cases of lung cancer, is generally more difficult because of the number of occupational aetiological factors and the absence of criteria that allow distinction of an occupational cancer from a tobacco related one. Therefore attention should be paid to the identification of occupational exposure in order to set up primary prevention programmes to prevent exposure still present in the working environment and, on the other hand, to identify the subjects entitled to the acknowledgement of occupational disease and/or to obtain the compensation available to asbestos victims. PMID- 18449082 TI - [Inhaled insulin: a model for pulmonary systemic absorption?]. AB - European Union has recently approved a form of insulin intended to be inhaled. This innovative presentation has the potential to partially or completely replace the injections and thus facilitate starting insulin therapy which is considered with apprehension and too often differed. On this occasion, we reviewed the issues raised by this pulmonary route for systemic absorption (anatomical and cytological limits, cellular mechanisms, relevant physical parameters, facilitating chemical cofactors, role of tobacco smoking and of common respiratory diseases). The pharmacokinetics of inhaled and injectable insulins are comparable, apart from an appreciably faster absorption of the former and both show the same intra-individual variability. The total biodisponibility is definitely lower with the inhaled way but it is notably increased in smokers. These characteristics can vary according to the inhalation system used. A frequent induced cough, the increase in circulating anti-insulin antibodies and a potentially higher cost are not really determining obstacles. The indications will have to be clearly specified and the long-term inocuity of long term inhalation of such a mitogene especially in children and former smokers remains to be formally proven. PMID- 18449083 TI - [The organisation of intensive care in a situation of pandemic avian influenza]. AB - The development of an epidemic of avian influenza will have a major impact on the organisation and structure of the facilities for treatment. This paper, the product of collaboration between the six learned societies concerned, analyses the impact of a possible pandemic on the various aspects of management of patients requiring intensive care. It describes the organisation of hospital pathways for flu and non-flu patients with, in particular, the necessary actions in terms of separation of care facilities, the triage of patients and the cancellation of non-urgent activities. It analyses the preconditions necessary for the efficient functioning of intensive care and the predictable limiting factors. It underlines the importance of training of medical and paramedical personnel. Finally, it tackles the specific problems of paediatric intensive care: organisation, capacity for admissions and training. PMID- 18449084 TI - [Occupational thoracic cancers]. PMID- 18449085 TI - [Occupational lung cancers: incidence and risk factors]. PMID- 18449086 TI - [Lung cancers attributed to occupational exposure]. PMID- 18449087 TI - [Evaluation of occupational exposure]. PMID- 18449088 TI - [Medical surveillance after occupational exposure to carcinogens]. PMID- 18449089 TI - [Medical and social aspects of occupational thoracic cancer]. PMID- 18449090 TI - [Mineral analysis and thoracic cancer]. PMID- 18449091 TI - [Role of tumor markers in the diagnosis of occupational thoracic cancer]. PMID- 18449092 TI - [Exercise tests: essential tools for the evaluation of cardio-respiratory function in children]. PMID- 18449093 TI - [Impact of low socioeconomic status on the demography and co-morbidities of asthma]. AB - OBJECTIVES: Asthma is a frequent and serious chronic respiratory disease which is sometimes fatal. It involves all ages and all social subclasses. The goal of our study was to determine the demography of asthma in a low socio-economic community in Lebanon and to describe its association with various epidemiologic factors. MATERIALS AND METHODS: The computerized data of 44.814 patients of a nongovernmental organization (Hariri Foundation), in Lebanon were reviewed. Asthmatic patients diagnosed by a health professional on the basis of medical criteria during the period from January 2003 to June 2005 were included in the analysis. The socio-economic characteristics of this population were retrieved and their geographical distributions were depicted. The study focused on the association of asthma with cutaneous and ocular allergies, depression, obesity and alcohol consumption. RESULTS: The majority of asthmatic patients (75%) belonged to a low socio-economic environment with a salary lower than $200 per month. 31% were illiterate. 583 (1.3%) of patients on the database were asthmatic. The rate in children was higher (2.08%) than in adults (1.09%). The majority of asthma occurred among subjects from Bekaa valley and South Lebanon. Asthma was associated more strongly with being an ex-smoker (OR 4.37; 95% CI 2.38, 8.02) than being a current smoker (OR 1.44; 95% CI 1.11, 1.87). A significant and strong association was found with depression (OR 25.6; 95% CI 3.32, 197.6), obesity (OR 4.09, 95% CI 1.31, 12.73) and with regular alcohol consumption (OR 11.78; 95% CI 1.55, 89.44). CONCLUSION: This study describes the association of asthma in this population with low socio-economic status. By defining the demographic characteristics of the asthma population the Ministry of Health and the medical organizations concerned should be better able to manage the condition. This study confirms, in a Lebanese population, the epidemiological associations described in other populations around the world. PMID- 18449094 TI - [Factors predicting mortality during an outbreak of Legionnaire's disease in the north of France]. AB - Between November 2003 and January 2004 in the North of France a large outbreak of legionnaire's disease affected 85 patients. The clinical, biological and radiological characteristics of the patients were investigated to determine factors associated with mortality. Two populations were defined and compared: patients who died within 28 days and those who survived. Eighty-five patients were included in this study. The median age was 75 years. The median fever was 39.3 +/- 0.1 degrees. Fifteen patients (17.6%) had at least 3 underlying co morbidities. Cough, dyspnoea, confusion and diarrhoea were found in respectively 46, 68, 47, and 15% of the patients. The median of urea was 0.7 +/- 0.05 g/L, creatinine 16 +/- 1.5 mg/L, CRP 332 +/- 15 mg/L. On the chest X-ray, lung infiltrates were present in 64% and multilobar in 40%. The overall mortality rate was 21%. In univariate analysis, diabetes mellitus, dyspnoea, urea>0.90 g/l and CRP>350 mg/l were predictive factors of mortality. In multivariate analysis, diabetes mellitus, urea>0.90 g/l, and bilateral infiltrates on chest X ray were retained as independent risk factors for death. PMID- 18449095 TI - [Age and management decisions in patients with primary lung cancer]. AB - INTRODUCTION: Therapeutic decisions are difficult in elderly patients because of the heterogeneity of this population. Our objective was to evaluate the role of age in the management of patients suffering from primary lung cancer seen in the department of respiratory diseases of the Limoges regional teaching hospital between 2002 and 2004. METHODS: A cross sectional study analysed the management of 363 patients suffering from primary lung cancer. The patients were divided into two groups according to their age (less than seventy or seventy and over). A comparison was made between the management of the two groups. RESULTS: The comparisons according to age produced evidence of reduced activity, greater dependence, an increased Charlson score, less frequently administered radiotherapy and chemotherapy, and more frequent symptomatic treatment in the elderly group (p<0.001). CONCLUSIONS: The geriatric assessment of patients suffering from primary lung cancer should make allowance for the physiological age of the patient and adapt the management to ensure the best quality of life. PMID- 18449096 TI - [Exercise alveolar hypoventilation in long-term survivors of bronchopulmonary dysplasia]. AB - BACKGROUND: We aimed to confirm that children who have survived bronchopulmonary dysplasia (BPD) display lower ventilation during exercise than healthy children, and to determine whether alveolar hypoventilation associated with exercise induced hypoxemia occurred in these children. METHODS: Twenty children with BPD (birth weight 1441+/-523 g [mean +/- SD], gestational age 31+2.3 weeks), aged 7 to 14 years, and 18 matched healthy children, born at term, performed resting pulmonary function and cardiopulmonary incremental exercise tests. Arterialized capillary blood gases were measured at rest and at maximal exercise in the BPD group. RESULTS: The BPD group showed moderate expiratory airflow limitation and hyperinflation. Maximal oxygen uptake and ventilatory threshold were similar in the two groups. The BPD group displayed ventilatory limitation on exercise, with greater use of the ventilatory reserve (p<0.01), lower maximal ventilation (p<0.01), tidal volume (p=0.01). Changes in ventilation (p<0.0001) and tidal volume (p=0.003) during exercise were significantly smaller in the BPD group than in controls, at similar submaximal workloads. At peak exercise, we observed hypoxemia in 12 BPD children (60%). In the subgroup with hypoxemia, a significant increase in PaCO2 (p=0.01) was measured at peak exercise, showing alveolar hypoventilation sustained by the lower tidal volume. CONCLUSIONS: Despite normal maximal aerobic performance, BPD children showed ventilatory limitation on exercise, frequently with hypoxemia and alveolar hypoventilation. Despite an improvement in their pulmonary condition, continued follow-up by cardiopulmonary exercise testing, is strongly recommended. PMID- 18449097 TI - [Are narghile smokers different from cigarette smokers?]. AB - BACKGROUND: The extent of smoking related health and economic problems is causing increasing alarm throughout the world. In the last few years a great number of subjects, especially in the developing world, have been smoking narghile and epidemiological studies on narghile smoking are an essential subject for investigation. The objectives of this study are to describe the social and cultural characteristics of narghile smokers in Lebanon compared to tobacco smokers. MATERIALS AND METHODS: Our sample is based on the data of 37579 subjects who consulted a non-governmental organisation (NGO), the Hariri Foundation, between 2003 and 2005. This NGO comprises 22 specialised centres distributed throughout Lebanon. The following data concerning exclusive narghile and cigarette smokers were collected: age, sex, the type and duration of tobacco addiction and the level of education. RESULTS: 13776 subjects (36.6% of the sample) were smokers of whom 88% smoked mostly cigarettes. 1529 subjects (11.1%) smoked narghile exclusively, a prevalence of 4.06%. The narghile smokers were younger than the cigarette smokers with a mean age of 36.2+/-8.63 years compared to 45.52+/-1.87 years. The majority of narghile smokers were women (56.57%) giving a male/female ratio of 0.77. A large number of narghile smokers were recent consumers with an exposure of less than 5 years. They differed from the cigarette smokers of whom the majority (72.2%) had smoked for more than 10 years. The proportion of illiterate subjects was greater among the narghile smokers (36.2%) than the cigarette smokers (24.2%). CONCLUSION: The consumption of tobacco is a real and frequent problem in Lebanon. The consumption of narghile is scourge that is gaining popularity, notably among women and the young. This problem is becoming a public health issue that needs to be taken into account within the framework of an anti-smoking policy in Lebanon. PMID- 18449098 TI - [Septicemia, bilateral community acquired pneumonia and empyema due to Burkholderia pseudomallei (mellioidosis) with a favorable outcome following prolonged specific antibiotic therapy]. AB - INTRODUCTION: Melioidosis is an infectious disease due to Burkholderia pseudomallei (Bp). It is regarded as endemic in southeast Asia and northern Australia. The septicaemic form is a severe illness with a high mortality. The tsunami in 2004 has renewed its current importance. CASE REPORT: A 57 year old man was admitted to hospital with a 2 week history of fever, productive cough and progressive weight loss. On admission he was in septic shock and respiratory failures secondary to a left lower lobe community acquired pneumonia. This progressed to a left sided empyema. Bp was isolated from blood cultures and the pleural pus. Initial intensive therapy with ceftazidime and cotrimoxazole for 4 weeks, followed by cotrimoxazole alone for 20 weeks, led to complete recovery with little residual radiological abnormality. Follow up gave no evidence of relapse but revealed an operable, squamous cell, bronchial carcinoma. CONCLUSION: Melliodosis seems to be an emerging disease in New Caledonia with 10 cases identified since 1999. A favourable climate and possibly an animal reservoir might explain sporadic cases in this region. It is important for the medical profession to be aware of this disease in order to ensure the rapid and correct management of patients whose life is at risk. PMID- 18449099 TI - [Difficulties in the management of localised pulmonary Goodpasture's syndrome]. AB - INTRODUCTION: The diagnosis of the pulmonary forms of Goodpasture's syndrome is not easy and requires a renal biopsy when no anti-glomerular basement membrane antibodies are detected, since the disease can lead to spontaneous massive intra alveolar haemorrhage that can be fatal. Treatment for the pulmonary-renal form combining corticosteroids, cyclophosphamide and plasmapheresis should be applied to the pulmonary form to control haemorrhage and prevent relapse. CASE REPORT: We report the case of a patient suffering from the localised pulmonary form of Goodpasture's syndrome in whom the diagnosis was delayed due to a negative indirect immunofluorescent antibody bioassay. After a serious early relapse remission was achieved with comprehensive treatment and a tobacco withdrawal programme. CONCLUSION: If there is no delay in diagnosis and comprehensive treatment is given, the prognosis for these patients is good with a recovery rate of 80 to 90%. PMID- 18449100 TI - [Late respiratory function complications following burns]. AB - INTRODUCTION: Twenty five per cent of thermal injuries are associated with secondary respiratory events linked to several mechanisms. In the acute phase of the accident oedema of the airways, the fume inhalation syndrome and ARDS are the most common causes responsible for death in 60% of cases. Late respiratory complications are little known and neglected. They comprise obstructive ventilatory defects due to the inhalation syndrome and restrictive defects secondary to ARDS or to dermal injury. CASE REPORT: We report the case of a female patient, extensively burnt 2 years previously, admitted to hospital with severe acute respiratory failure complicating COPD. The presence of both restrictive and obstructive defects led to the suggestion of alternative underlying mechanisms such as the pulmonary consequences of ARDS and extensive dermal scars. The latter were responsible for an armour like thickening of the skin of the thorax compatible with the restrictive defect. CONCLUSIONS: These functional abnormalities and the potential severity of acute respiratory failure are indications for regular pulmonary follow-up of patients with severe circumferential scarring of the thorax who are at high risk for respiratory complications. PMID- 18449101 TI - [Difficult weaning due to tracheal compression by an esophageal bezoar]. AB - INTRODUCTION: Bezoars result from the aggregation of ingested materials (food, drugs, hair) that accumulate at a certain anatomic level in the gastrointestinal tract. It is a rare condition, which is favoured by a reduction in intestinal motility, or by a primary abnormality reducing the patency of gastrointestinal tract. CASE REPORT: We present a case when acute respiratory symptoms revealed an oesophageal bezoar. The patient presented with compression of the posterior tracheal wall by an oesophageal bezoar. The diagnosis was confirmed by oesophageal endoscopy. Treatment consisted in endoscopy-guided fragmentation and removal of the bezoar followed by topical lavage. CONCLUSION: Oesophageal bezoars may account for compression of the posterior tracheal wall causing acute respiratory failure or difficult weaning from the ventilator. The close anatomic proximity between the gastrointestinal and respiratory tract may explain the impact of oesophageal bezoars on the respiratory tract. PMID- 18449102 TI - [Congenital cystic adenomatoid malformation of the lung. Report of 3 cases with late presentation]. AB - Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare congenital developmental abnormality, representing about 25% of all congenital lung lesions. In many cases, respiratory distress occurs during the neonatal period, and in about 80- 85% of patients, CCAM is diagnosed before the age of two years due to respiratory infection. It is very rare that presentation is delayed until adulthood. We report three cases of CCAM presenting in adults. The diagnosis was based on clinical and radiological findings in one case and two patients were not diagnosed until surgery. The lesion was present in the right lung in two and in left lung in one patient. All patients underwent surgical resection. The result of histopathological examination confirmed CCAM Stocker type 1, without malignancy. The post operative follow up showed an excellent recovery. Clinicians and pathologists need to be aware of the fact that CCAM can be present for the first time in adolescents or in adults. The clinical diagnosis is suggested by radiographic findings and is confirmed at pathology as surgery is generally indicated. PMID- 18449103 TI - [An unusual complication of thoracostomy]. AB - INTRODUCTION: Post pneumonectomy infection is a well-described surgical complication. Treatment usually involves thoracostomy and requires local treatments. We report here an unusual complication of this situation. CASE REPORT: A 62 year old man had a pneumonectomy for non-small cell lung cancer. Following this he required a thoracostomy to treat a thoracic empyema and this was treated with local anti-septic agents. Subsequently he developed asthenia and a diagnosis of hyperthyroidism was made secondary to local disinfectant treatment with iodine agents. CONCLUSIONS: We describe an original case of thyroxicosis occurring in a patient following treatment for post-pneumonectomy empyema. We would recommend monitoring thyroid function in this context. PMID- 18449104 TI - [Cyst of the right hemithorax]. PMID- 18449105 TI - [Atypical presentation of bilateral cysts]. PMID- 18449106 TI - [Research training in Pneumology, scholarships 2007]. PMID- 18449108 TI - Prevalence of oral soft tissue lesions in an elderly venezuelan population. AB - AIM: The purpose of the present study was to determine the prevalence of the oral soft tissue lesions in patients referred to the geriatric unit "Dr. Joaquin Quintero", National Institute of Gerontology. STUDY DESIGN: 340 patients were clinically evaluated, of these 266 were institutionalized and 74 were seen at the outpatient clinic, age ranging 60 to 104 years. 212 were females and 128 males. The statistical analysis was done using the SPSS software (11.0) to a significant level of 5% (p<0.05). RESULTS: Fifty seven percent of the studied population presented one or more oral lesions, associated to prosthetic use, trauma and tobacco consumption. Females were more affected than males. The lesions were more frequently observed between 60 to 74 years of the institutionalized group of patients of these, 34% exhibited only one oral lesion. Few cases presented up to 4 oral lesions. The most common alterations observed were: denture stomatitis, oral leukoplakia, hemangioma, oral melanotic macule, traumatic fibroma, inflammatory fibrous hyperplasia and angular cheilitis. CONCLUSIONS: The findings observed in this population are important to be considered when clinically evaluating oral soft tissue in elderly. Close follow up and systematic evaluation is required in this population. PMID- 18449109 TI - Immunohistochemical analysis of the patterns of p53 and PCNA expression in odontogenic cystic lesions. AB - OBJECTIVE: the role of p53 expression in odontogenic lesions has not been fully determined, but has been associated with cell proliferation. The purpose of this study was to analyze p53 and proliferating cell nuclear antigen (PCNA) expression in 4 different odontogenic lesions. DESIGN: expression of p53 and PCNA was analyzed in radicular and dentigerous cysts, odontogenic keratocysts, and calcifying odontogenic cysts (Gorlin cysts) using monoclonal antibodies for detection of p53 and PCNA. RESULTS: PCNA expression was significantly greater in the basal layer of radicular cysts and in the suprabasal layer of odontogenic keratocysts; the percentage of p53 positive cells was significantly greater in the suprabasal layer of odontogenic keratocysts. CONCLUSIONS: The patterns of p53 and PCNA expression in dentigerous and radicular cysts were similar although the two lesions are of different origin. In odontogenic keratocysts and Gorlin cysts, results indicate a different pattern of tumor growth. PMID- 18449110 TI - Oral lesions in HIV infected individuals from Ribeirao Preto, Brazil. AB - OBJECTIVES: The aim of this study was to diagnosis oral lesions related to HIV infection in individuals followed in the General Hospital of the School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil. The presence of oral lesions was correlated with gender, age, smoking habit, levels of CD4 lymphocytes, HIV load, time of HIV seropositivity, AIDS condition, use of removable dental prosthesis, and use of HAART. MATERIALS AND METHODS: 340 HIV infected individuals were selected for this study, all participants of the study were examined by only one practiced dentist which performed anamnesis, peribuccal and oral examination. RESULTS: Oral lesions were observed in 113 of 340 (33.2%) HIV infected individuals. These oral lesions included: oral candidiasis (17.7%) of pseudomembranous (10.8%) and of erythematous types (6.9%), angular cheilitis (13.9%), hairy leukoplakia (11.8%), and oral ulcers (2.1%). Oral candidiasis lesions were more frequently observed in women (p.033). Smoking addict participants presented a high frequency of tongue hairy leukoplakia (p.038) and a reduced frequency of oral ulcers (p.018). Hairy leukoplakia and pseudomembranous candidiasis were inversely correlated to CD4+L levels and directly correlated with HIV load, behaving as immune depression markers. Hairy leukoplakia and pseudomembranous candidiasis also showed an inverse correlation with HAART use (p<.0001). Patients using mobile dental prosthesis presented a high frequency of erythematous candidiasis (p.003). CONCLUSION: The inverse correlation with CD4+L level and the direct correlation with HIV load suggest that oral lesions could be used as alternative clinical markers for poor immune condition in HIV infected individuals. PMID- 18449111 TI - Sensitivity of direct immunofluorescence in oral diseases. Study of 125 cases. AB - Direct immunofluorescence (DIF) is widely used for the diagnosis of bullous diseases and other autoimmune pathologies such as oral lichen planus. There is no evidence in the literature on how the following variants influence the detection rate of DIF: intraoral site chosen for the biopsy, perilesional locus or distant site from the clinical lesion, number of biopsies and instrument used. OBJECTIVES: to determine if the following variants influenced the sensitivity (detection rate): intraoral site chosen for the biopsy, perilesional or distant site from the clinical lesion, number of biopsies and instrument used (punch or scalpel). MATERIAL AND METHODS: A retrospective study was done at the Catedra de Patologia y Clinica Bucodental II at the Facultad de Odontologia, Universidad de Buenos Aires; 136 clinical medical histories were revised for the period March 2000 - March 2005 corresponding to patients with clinical diagnosis of OLP and bullous diseases (vulgar pemphigus, bullous pemphigoid and cicatricial pemphigoid). RESULTS: DIF detection rate was 65.8% in patients with OLP, 66.7% in cicatricial pemphigoid patients, in bullous pemphigoid 55.6%, in pemphigus vulgaris 100%, and in those cases in which certain diagnosis could not be obtained, the DIF positivity rate was 45.5% (Pearson chi(2) (4)= 21.5398 Pr= 0.000). There was no statistically significant difference between the different sites of biopsy (Fisher exact test: 0.825). DIF detection rate in perilesional biopsies was 66.1% and in those distant from the site of clinical lesion was 64.7% (Pearson chi(2) v1)= 0.0073 Pr= 0.932. When the number of biopsies were incremented, DIF detection rate also incremented (Pearson chi(2) = 8.7247 Pr= 0.003). The biopsies taken with punch had a higher detection rate than those taken with scalpel (39.1% versus 71.7%) (Pearson chi(2) = 49.0522 Pr= 0.000). CONCLUSION: While not statistically significant, the tendency outlined in this study indicates there are intraoral regions in which the detection rate of the DIF technique is higher than others: mouth floor, hard palate, superior labial mucosa, ventral face of tongue. This finding could allow a choice of accessible locations and easy operator manipulation, even in distant places from the clinical lesion. Perilesional biopsies have a detection rate similar to those taken distant from the clinical lesion, and those taken with punch have a higher sensitivity rate than those taken with scalpel (both differences were statistically significant). PMID- 18449112 TI - Salivary concentration of TNFalpha, IL1 alpha, IL6, and IL8 in oral squamous cell carcinoma. AB - OBJECTIVES: The aim of this study was to compare the concentration of tumor necrosis factor alpha, interleukin 1 alpha, 6, and 8 in the saliva of oral squamous cell carcinoma patients with control group. STUDY DESIGN: In this study 18 subjects were involved, nine patients with oral squamous cell carcinomas and nine age-sex-matched healthy individuals that were matched for gingival conditions too. Active dental abscesses, collagen vascular diseases, and infectious diseases during one month before saliva sampling were considered as exclusion criteria. Unstimulated whole saliva was collected and after processing the samples were analyzed by Enzyme Linked Immune Assay. RESULTS: The concentration of salivary interleukin 6 in oral squamous cell carcinoma patients was higher than control group and it was statistically significant (p < 0.05). The concentration of salivary tumor necrosis factor alpha, interleukin 1 alpha and 8 in case group was higher than control group but it was not statistically significant (p > 0.05). CONCLUSIONS: These results shows that more studies are needed to accept the utility of these cytokines in predicting or diagnosis of oral squamous cell carcinoma or evaluation of treatment. PMID- 18449113 TI - Cardiovascular diseases in dental practice. Practical considerations. AB - Coronary heart disease is the principal cause of death in the industrialized world. Its most serious expression, acute myocardial infarction, causes 7.2 million deaths each year worldwide, and it is estimated that 20% of all people will suffer heart failure in the course of their lifetime. The control of risk cardiovascular factors, including arterial hypertension, obesity and diabetes mellitus is the best way to prevent such diseases. The most frequent and serious cardiovascular emergencies that can manifest during dental treatment are chest pain (as a symptom of underlying disease) and acute lung edema. Due to the high prevalence and seriousness of these problems, the dental surgeon must be aware of them and should be able to act quickly and effectively in the case of an acute cardiovascular event. In patients with a history of cardiovascular disease, attention must center on the control of pain, the reduction of stress, and the use or avoidance of a vasoconstrictor in dental anesthesia. In turn, caution is required in relation to the antiplatelet, anticoagulant and antihypertensive medication typically used by such patients. PMID- 18449114 TI - Evaluating periodontal conditions in patients with von Willebrand's disease in Hospital Universitario de Maracaibo (University Hospital, Maracaibo)-Venezuela. AB - OBJECTIVE: To evaluate the periodontal conditions of patients with von Willebrand's Disease (vWD who went for dental examination in the "Area of attention to patients with systemic disease" of the University Hospital in Maracaibo, Venezuela. DESIGN OF THE STUDY: 40 patients (28 female and 12 male), with ages ranging from 10 to 72 years, who regularly attended dental control, were evaluated along with a control group of patients with no hemorrhagic alterations. Periodontal conditions were evaluated using the Loe and Silness Gingival Index (GI) and Greene and Vermillon's Simplified Oral Hygiene Index (SOHI). The results were analyzed using averages, Standard Deviation, Student's T test and the Chi(2) test, with P<0.0005. RESULTS: 92.5% of the patients had Type 1 vWD and 7.5% had Type 2 or 3. Periodontal Indices: GI (0.70+/-0.40, slight) and SOHI (1,70+/-0,80, acceptable). Comparison with the control group showed that there were statistically significant differences in the SOHI (P = 0.02). CONCLUSIONS: Periodontal conditions in patients with vWD regularly attending for dental control were within acceptable parameters. Education of the patient with regard to prevention and opportune treatment is of utmost importance, thereby avoiding the oral hemorrhagic complications produced by the periodontal disease. Of equal importance is multidisciplinary teamwork. PMID- 18449115 TI - Study of available bone for interforaminal implant treatment using cone-beam computed tomography. AB - OBJECTIVES: To analyze the availability of bone in the interforaminal region and to demonstrate the variation in diagnosis between panoramic x-ray and cone-beam computed tomography (CBCT). MATERIAL AND METHODS: In 50 patients and in 5 areas of each, a series of parameters concerning available bone were measured on both the panoramic and the CT images. RESULTS: Panoramic images underestimate the vertical and horizontal measurements when compared with CBCT. Regarding implant treatment, the interforaminal region presents the same remaining bone height throughout its full extent, the correlation between one side of the midline and the other was highly significant for all the parameters studied, and 20% of the sample showed some buccal and/or lingual concavity. CONCLUSION: Cone-beam CT is an advantageous system for interforaminal implant treatment planning, especially since the reported radiation dose is minimal and geometric accuracy is very high. PMID- 18449116 TI - Lateral periodontal cysts: a retrospective study of 11 cases. AB - OBJECTIVE: To describe the clinical, radiological and histopathological features of lateral periodontal cysts among patients diagnosed in different centers (Vall d'Hebron General Hospital, Granollers General Hospital, the Teknon Medical Center, and the Master of Oral Surgery and Implantology of the University of Barcelona Dental School; Barcelona, Spain). STUDY DESIGN: A retrospective observational study was made of 11 lateral periodontal cysts, all of which were diagnosed following a thorough clinical examination, radiological study and posterior histological study. RESULTS: The mean patient age was 37 years, and males predominated over females. The mean lesion size was 1.25 cm. A single relapse was recorded 7 years after removal of the initial lesion. All the cysts were surgically removed. DISCUSSION AND CONCLUSIONS: Lateral periodontal cysts are very infrequent, and are characterized by the preserved vitality of the adjacent teeth. Identification of the lesion is initially based on the clinical findings, though histological study is required to confirm the diagnosis. The treatment of choice is the surgical removal, though occasional relapses have been documented. PMID- 18449117 TI - Osteochemonecrosis of the jaws due to bisphosphonate treatments. Update. AB - Bisphosphonates (BP),were initially used in industry and later as a drug due to their great affinity to osseous tissue, because of their powerful antiresorptive effect as a treatment in various osteopathies, such as osteoporosis, Paget disease or hypercalcemia associated with some malignant tumors, as myeloma or breast cancer. They are administered orally or intravenously, and although well tolerated, the most frequent side effects are gastrointestinal, in addition to osteonecrosis when they are administered via endovenous. The aim of this work has been to evaluate the existing publications in accredited scientific literature on biphosphonates and their action mechanism and the relationship with the appearance of osteonecrosis of the jaws. Although the mechanism by which osteonecrosis of the jaws develops is not known exactly, there seems to be influence by osteoclast inhibiton, antiangiogenic action, an inhibitory effect on the cellular cycle by the keratinocytes, as well as, reinforcement of the chemiotoxic action in oncological patients treated with other drugs. Clinically, it ranges from a non-specificity of symptoms to lesions such as osteomyelitis with necrosis and osseous sequesters that may be accompanied by fetor ex oris, with the appearance of many Actinomyces contaminated lesions. As for published antecedents on osteonecrosis due to bisphosphonate treatment found until 2006: 46.5% had a previous diagnosis of multiple myeloma; 38.8% were patients with metastatic breast cancer; 6.2% patients of metastatic prostate cancer; 4.1% suffered from osteoporosis; 3.5% from other metastatic diseases and 0.8% had Paget disease. The drugs that seem to have the highest incidence of osteochemionecrosis are: zoledronate, pamidronate, alendronate, risendronate and ibandronate, from the greatest to the least. Additionally, the risk of osteonecrosis being produced is accumulative and may reach 21% in the third year of intravenous bisphosphonate use. PMID- 18449118 TI - Evidence concerning the medical management of caries. AB - Caries is an infectious, chronic and cumulative disease. It seriously affects quality of life and creates considerable expense for individuals and communities. The disease can be managed by acting on biofilm formation and maturation, by modifying the kinetics of apatite solution or with a combination of the two processes. This can be achieved by mechanical and chemical control of plaque, appropriate use of fluorides, controlling diet and salivary flow, when possible. Many of these factors depend on the patient's co-operation. Decisions concerning treatment are influenced by two questions: the scientific evidence for the different alternatives available and each patient's individual caries risk. The use of different fluoride regimes, depending on the individual risk, remains the most scientifically proven method for avoiding the appearance of new lesions and curbing the speed at which existing ones progress. Chemical control of plaque using chlorhexidine is indicated for patients at high microbiological risk; it is more effective at controlling caries when used in combination with fluorides. Fissure sealing is an effective means of controlling occlusal caries of the molars when the patient's caries risk and the eruptive age of the tooth are taken into account. PMID- 18449119 TI - Pediatric dental care in a tertiary public hospital. Four years of experience in the Service of Stomatology of Valencia University General Hospital (Valencia, Spain). AB - A study is made of the experience gained with the Child Oral Care Program (Plan de Atencion Dental Infantil, PADI) in the Service of Stomatology of Valencia University General Hospital (Valencia, Spain) after four years in operation (July 2003 - July 2007). STUDY DESIGN: The sample comprised 2626 children between 5-14 years of age, pertaining to department 9 of the Valencian public health system. A clinical history was compiled in each case, a radiological study was made, and a treatment plan was elaborated including fillings, extractions, and control visits. RESULTS: Of the 2626 designated children, 2369 visited our Service - mostly referred from the Preventive Dental Care Units. A total of 5784 fillings were carried out (93.3% with silver amalgam, 5.6% with composites and the rest as provisional fillings). The permanent first molars were the teeth with the largest number of fillings (70.2% of the total). These were followed in order of frequency by the second molars (19.1%). As regards composite resin fillings, most involved the upper central incisors, followed by the upper lateral incisors. A total of 644 extractions were performed, corresponding to 110 permanent teeth and 534 temporary teeth. In the case of the permanent dentition, the first molars were the most commonly removed teeth. In the temporary dentition, the most frequently removed teeth were the second molars. CONCLUSIONS: The response of the population to this program has been very good, and reinforces the preventive measures already in place, with the provision of restorative treatments to improve the oral and dental health of the pediatric population, and yielding good results in terms of the program quality indicators. The Service of Stomatology (Valencia University General Hospital) is able to address the demand and offers the public health network integrated and continuous patient care. PMID- 18449120 TI - Crystal-associated synovitis- ultrasonographic feature and clinical correlation. AB - The aim of this paper is to describe the ultrasonographic findings in rheumatologic pathology due to crystal deposition. There are four main types of crystals involved: monosodium urate, calcium pyrophosphate dihydrate, basic calcium phosphate (hydroxyapatite), and calcium oxalate. In gout the joint fluid is anechoic only at the first gouty attack; afterwards the synovium begins to proliferate. Double contuour sign, a focal or diffuse enhancement of the superficial margin of the articular cartilage is a specific finding. Bursitis has chronic features from the beginning. The ultrasonographic aspect of tophi depends on their age and size (at first small, hypoechoic and homogenous nodules, then echoic with hyperechoic edges and finally pseudotumoral, inhomogeneous). The depositions in the superficial layer are hyperechoic, well delimited only in the absence of inflammatory reaction. The depositions at the entheseal level are leading to the gouty enthesopathy. In knee involvement irregularities of the anterior surface of patella are found. In chondrocalcinosis the most important ultrasonographic signs are the thin hyperechoic band, parallel to the surface of the hyaline cartilage and the punctuated pattern of the fibrocartilage. In hydroxyapatite associated disease, calcifications are frequent in the shoulder or in the great trochanter of the hip, with aspects depending of the calcification phase. Milwakee shoulder is an advanced form of this pathology, associated with rotator cuff arthropathy. Oxalate crystal deposition disease is seen rarely, in patients with primary hyperoxaluria and in patients with end-stage renal disease. Therefore ultrasonography is useful in characterize the articular and juxta articular alterations in crystal related diseases. PMID- 18449121 TI - Arthroscopic evaluation of ultrasonography and magnetic resonance imaging for diagnosis of rotator cuff tear. AB - BACKGROUND: Rotator cuff tear--diagnosis; comparison of MRI, ultrasonographic and arthroscopic findings. MATERIALS AND METHODS: Retrospective study--20 patients treated for shoulder pain due to rotator cuff tear, initially conservatively and after more than 6 months by arthroscopic shoulder surgery. Comparison of intraoperative findings with preoperative US and MRI images. RESULTS: Sensitivity of USG--1.0, specificity 0.9. Sensitivity of MRI--0.92, specificity 1.0. DISCUSSION: Clinical examination and physical tests are not fully reliable diagnostic tools in patients with shoulder pain, because symptoms of different conditions overlap. Using ultrasound to visualize the shoulder area has some advantages to other imaging techniques such as CT scan or MRI, and has a very good sensitivity and good specificity. Many authors agree that MRI is one of the most effective methods for the diagnosis of rotator cuff tear. CONCLUSIONS: Ultrasound and magnetic resonance imaging are both very sensitive techniques for diagnosis of rotator cuff abnormalities. Ultrasonography can be used as a primary method owing to its fast procedure and affordable cost.
PMID- 18449122 TI - Evaluation of risk factors in developmental dysplasia of the hip in children from multiple pregnancies: results of hip ultrasonography using Graf's method. AB - BACKGROUND: The risk factors for developmental dysplasia of the hip (DDH) in infants from unifetal pregnancies are commonly known. Many of these factors also apply to multiple pregnancies. The aim of this paper was to evaluate the influence of selected, widely recognized DDH risk factors in unifetal pregnancy on the development of hip joints in infants from multiple pregnancies. The following risk factors were examined: family history of DDH, breech presentation, duration of pregnancy, birth weight and sex. MATERIAL AND METHODS: The study included 200 newborns (400 hip joints) from multiple pregnancies. Ultrasound screening was performed using the Graf method during the first five postnatal days. RESULTS: No cases of hip joint dysplasia requiring treatment were reported in the study group. The analysis of correlations between hip joint type according to Graf and the evaluated risk factors revealed the following results: type IIa hips were reported in 26 (6.91%) infants with a family history of DDH, one infant (1.22%) who demonstrated a breech presentation, 23 prematurely born infants (8.93%) and 28 infants with a mean birth weight of 2402 g. The correlations were not statistically significant. Type IIa hips were reported in 21 female infants (10.82%), which constituted a statistically significant correlation (p < or = 0.05). CONCLUSIONS: Among the examined risk factors only the sex of the infant turned out to be significant for the development of hip joints in babies from multiple pregnancies. Type IIa hip joints were more common in female infants.No statistically significant correlations were found between Graf hip types and family history of DDH, breech presentation of the fetus, pregnancy duration under 38 weeks or the infant's birth weight. PMID- 18449123 TI - Potential value of contrast-enhanced gray-scale ultrasonography in diagnosis of acute muscle injury--preliminary results. AB - BACKGROUND: Ultrasonography performed shortly after a direct or indirect muscle trauma may be confusing. The extent of a muscular tear can be difficult to assess because of oedema, intramuscular haematomas and red infarct. The aim of this study was to find out if it is possible to assess the extent of muscular lesions shortly (6 to 48 hours) after a trauma with improved accuracy using contrast enhanced gray-scale ultrasonography. MATERIALS AND METHODS: Ultrasonograp[hic examinations were carried out in 7 male football players 8 to 48 hours following a direct (4) and indirect (3) trauma, and one female dancer with an indirect muscle trauma. Standard B-mode US examinations and gray-scale contrast-enhanced US after administration of Sonovue (Altana Pharma, Konstanz, Germany) were performed in all patients to evaluate the margins and size of the posttraumatic lesions. In contrast-enhanced studies, the size of the structural lesion in the muscle and space that might correspond to the muscle tear were measured. RESULTS: In all 8 cases, the borders of the muscular lesions were better delineated following administration of the contrast agent as a poorly and irregularly enhanced or non-enhancing areas. In 3 cases of direct and 2 cases of indirect trauma, the lesions were bigger in the contrast-enhanced study, and in one case of direct trauma and 2 indirect lesions, they were smaller following contrast enhancement. CONCLUSION: These preliminary results indicate that gray-scale contrast-enhanced US of muscle can be helpful in the assessment of the extent of muscular trauma in dubious cases during the early post-injury period. PMID- 18449124 TI - Potential value of three-dimensional ultrasonography in diagnosing muscle injuries in comparison to two-dimensional examination--preliminary results. AB - BACKGROUND: Two-dimensional ultrasonography (2D-US) has become a widely used and accepted diagnostic tool in musculoskeletal disorders. Its utility in the evaluation of muscle injury and pathology is generally recognised. In contrast, the place and role of three-dimensional US imaging (3D-US) in the diagnostic work up of musculoskeletal conditions are still not recognised even though 3D-US is a well-established technique in, for example, obstetrics. The aim of this study was to find out if it is possible to assess lesions of muscles more accurately and with more detail using the 3D technique in comparison to 2D imaging. MATERIAL AND METHODS: The study involved 14 patients aged 16-39 years (mean age 24.8 yrs) with muscle injuries and 2 volunteers to determine the best technique of performing the examination and acquiring images that can best visualise the structure of muscles. The 2D and 3D images were compared with respect to visualisation of lesions and their size. It was also investigated whether the additional third "Z" plane could furnish relevant information regarding the visible lesion. RESULTS: The results of evaluation of features and size of the lesions in the muscles were very similar and reliable with both modalities. For small lesions, measurements of their size differed slightly. The differences were bigger for bigger lesions. Additional information leading to re-classification of the type of the lesion or more precise delineation of its margins was obtained in 6 of the 14 cases (42.8%). The duration of a 3D study was usually longer with bigger lesions. The 3D-reconstructed model helped in better visualising and understanding the anatomical relations of the injured muscle with surrounding tissues. Recording data as volume scans made possible later re-assessment of images and their independent verification by a consultant at any desired time. CONCLUSIONS: 1. 3D US imaging is as reliable and accurate as the 2D technique in the assessment of muscle injuries. In some cases, especially with smaller lesions, the borders and type of the lesion are better visualized with the additional third plane. Additional information regarding the location of the lesions in the frontal plane can be obtained with 3D imaging. It is more difficult to assess whole lesions of greater size requiring two or more volume scans. The acquisition of volume data enables the reading of images at any desired time and also makes it possible to ask a consultant to verify the findings.

PMID- 18449125 TI - A comparison of the effect of autogenous vs. frozen homogenous grafts on the healing of non-union of forearm bones. AB - BACKGROUND: A large percentage of autogenous and homogenous grafts are resorbed and replaced by the recipient's own tissue. It is generally believed that autogenous grafts are superior to homogenous ones. The aim of our study was to compare the effectiveness of autografts and allografts in achieving the healing of a non-union of forearm bones. MATERIAL AND METHODS: Between 1976 and 2005, 56 patients with 68 non-unions of forearm bone shafts were operated on. The study group consisted of 45 male and 11 female patients aged 8 to 85. The patients were operated on using methods requiring autogenous cancellous bone chips or homogenous frozen grafts. Autografts were used in 47 patients, and allografts were applied in the treatment of 21 non-unions. The effectiveness and speed of achieving a bone union with both types of grafts were subsequently compared. RESULTS: The percentage and time of bone union were similar between autogenous and homogenous grafts. The differences are not statistically significant. CONCLUSION: No statistically significant differences in the effectiveness and time to bone union were found between recipients of autogenous vs. homogenous grafts. The use of homogenous frozen grafts seems justified when the mechanical advantages of the graft are not essential. It also allows for avoiding additional mutilation to healthy parts of the body. PMID- 18449126 TI - Restoration of hand function and ability to perform activities of daily living following surgery for carpal tunnel syndrome. AB - BACKGROUND: The aim of the study was to assess treatment efficacy in patients following surgery for carpal tunnel syndrome and compare hand function with patients' subjective evaluation and their ability to carry out activities of daily living. MATERIAL AND METHODS: The study involved patients undergoing rehabilitation at the Malopolska Region Hand Rehabilitation Centre at L. Rydygier Specialized Hospital in Cracow and at the Hand Rehabilitation Unit at the Scanmed Medical Centre in Cracow. The patients were admitted to the Centre after surgical release of the transverse ligament of the wrist. Fifty hands (40 patients) were evaluated and treated. The rehabilitation programme was customised for each patient, and included patient education, a programme of home-based exercises and physiotherapeutic treatment in our centres. The patients were evaluated twice: before starting rehabilitation and at the end of the treatment. Hand function was evaluated using Swanson's method, the Alderson-McGall Hand Function Questionnaire and the Nine Hole Peg Test. Patients were also asked to provide a subjective evaluation of the typical signs and symptoms of CTS. RESULTS: The study showed improvement in all tests and a high level of correlation between various evaluations of hand function and patients' subjective feelings. CONCLUSIONS: The time at which post-operative rehabilitation was started significantly affected the outcomes of rehabilitation in the study group. There was a significant correlation between hand function impairment and subjective feelings of the patients vs. their quality of daily living. PMID- 18449127 TI - Assessment of functional abilities of patients with contraindications to operative treatment of femoral neck fractures. AB - BACKGROUND: Major obstacles to operative treatment of elderly patients with femoral neck fractures frequently encountered in clinical practice include poor overall health, lack of consent to have an operation, and general medical or anaesthesiological contraindications. In such cases, conservative treatment is the only possibility. This aims at maximally improving the patient's functional status, an approach best termed "movement-oriented patient management". MATERIAL AND METHODS: The study population consisted of 51 patients (31 F, 20 M) with femoral neck fractures in whom surgery was contraindicated. The patients took part in a movement-oriented management programme. The study consisted in evaluating movement abilities, self-care and locomotion of the patients using the Harris and Lazansky scales. Patients were evaluated twice: at discharge from hospital and at three months after discharge. RESULTS: In patients assessed using the Lazansky score, Evaluation 1 revealed 88% poor results and 12% satisfactory results, compared to 63% poor results and 37% satisfactory results at evaluation 2. Harris scores did not differ between Evaluations 1 and 2, with 100% of the patients achieving the lowest scores. CONCLUSIONS: 1) The study population of patients with femoral neck fractures in whom surgery was contraindicated did not demonstrate a definite improvement or deterioration of their functional status following "movement-oriented management"; 2) "movement-oriented management" cannot be regarded as having any effect on change in functional status, which should therefore be improved using a more beneficial method of treatment. PMID- 18449128 TI - Does osteoarthritis further compromise the postural stability of women with osteoporosis? AB - BACKGROUND: It is known that women with osteoporosis display only slight deficits in postural control. However, a condition that often co-exists with OP is osteoarthritis (OA), which has been shown to significantly compromise balance. To establish reasonable inclusion criteria for balance assessment of women with OP and investigate if specific treatment regimens are necessary for those subjects, it is important to evaluate the differences in postural control and postural strategies between the two groups. MATERIAL AND METHOD: We compared postural sway in quiet standing measured by the parameters of the center-of-pressure (COP) signals, recorded on a force plate, of 30 women with osteoporosis and 27 women with coexisting mild osteoarthritis. RESULTS: Our results indicated that the latter subjects had higher COP sway in the sagittal compared with the frontal plane, while the former subjects had similar sway in both planes. Subjects with both conditions relied more on vision to preserve postural stability compared with subjects with osteoporosis alone, and they also appeared to compensate further with a higher frequency of their body oscillations. CONCLUSIONS: 1. Even mild symptoms of osteoarthritis may affect balance and misrepresent the observed postural behavior in stabilographic studies. 2. The indications for the treatment regimens of. PMID- 18449129 TI - Bilateral stress fracture of distal fibula and tibia--case report. AB - The article presents a very rare case of bilateral distal tibial and fibular stress fractures in a 58-year-old white male. Excessive work load was undoubtedly the direct cause of the fractures as the patient's job involved carrying heavy (about 7 kg) packs of newspapers up stairs for 4 hours every night, with the distance covered amounting to approximately 80 floors. The available literature does not contain descriptions of similar bilateral distal tibial and fibular fractures in an otherwise healthy professionally active male patient. Supplementing the case description is a review of the epidemiology, signs, symptoms, diagnosis and methods of treatment of tibial and fibular stress fractures. PMID- 18449130 TI - Bone mineral density in cystic fibrosis patients under the age of 18 years. AB - AIM: The increase in life expectancy of cystic fibrosis (CF) patients has brought about a rise in new clinical problems in these patients, such as a decrease in bone mineral density (BMD). The cause of diminished BMD in CF is multi-factorial. METHODS: The aim of this cross-sectional study, conducted on 39 CF patients under the age of 18 years, was to evaluate the degree of bone mineralization and the prevalence of low BMD in these patients during a follow-up at the Cystic Fibrosis Regional Center of Tuscany, using a dual energy X-ray absorptiometry (DXA) scan, and to then study the factors correlated with low BMD. RESULTS: Areas BMD values (g/cm2) and Z-score values were determined. Eighteen patients (46%) out of the our sample had decreased BMD, while 21 patients (54%) had normal values. A statistically significant association was found between BMD Z-score values and pancreatic insufficiency, BMI<5th percentile and DeltaF508 homozygosis. Subjects treated with oral steroid therapy had a 3.9 times greater risk of developing osteoporosis compared to non-treated subjects (95% C.I.: 1.07-22.6; R.R. 4.9). An association was found between BMD Z-score values and FEV1 values (r=0.29; P=0.06), physical activity total score values (r=0.22; P=0.19) and the Chrispin Norman chest radiographic score (r=-0.31; P=0.06). CONCLUSION: Early identification of reduced bone mass values would permit early intervention to prevent the development of osteoporosis. Maintaining pulmonary function, guaranteeing optimal nutritional status, following an adequate program of physical activity and controlling steroid intake could maintain BMD over time. PMID- 18449131 TI - Does prolonged breastfeeding reduce the risk for childhood leukemia and lymphomas? AB - AIM: Prolonged breastfeeding was shown to reduce the risk of childhood acute leukemia. The aim of the study was to investigate the protective effect of longer breastfeeding on the risk of lymphoid malignancies in children and its dependent socio-economic factors. METHODS: The study group comprised of 169 patients with acute lymphocytic leukemia (ALL), Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL), age =or<15 years, and 169 healthy controls, matched to patients by age and sex. Mothers of all study subjects provided information via telephone about the history of breastfeeding and parameters seen as proxies for viral infection. RESULTS: The mean age+/-SD of cases was 5.44+/- 3.29 years and of control subjects 5.51+/-3.62 years. The male/female ratio was 1.73. Overall, the mean number of months of breastfeeding in the male patients and controls was 9.1 (95% confidence interval [CI] 7.9-10.4) and 12.1 (95% CI 11.0-13.4), respectively (P<0.001), and in the female patients and controls 8.4 (95% CI 6.9-10.1) and 11.5 (95% CI 10.0-13.0), respectively (P<0.01). In 103 ALL patients, a shorter period of breastfeeding (0-6 months duration), was associated with increased odds ratio (OR) for males (OR=3.1, 95% CI 1.4-6.8) and females (OR=2.2, 95% CI 0.8-6.32) as compared to breastfeeding longer than 6 months. In 103 ALL patients, 32 HL and 34 NHL patients, there were no statistically significant differences in the duration of breastfeeding between the male and female patients and their respective controls. In multivariate analysis, statistically significant risk factors for the development of childhood lymphoid malignancy were: a shorter duration of breastfeeding, lower age and level of education of mother and higher income, larger size of accommodation and birth order in the family. CONCLUSION: The current study confirmed that a longer duration of breastfeeding has protective effect against ALL and HL. Additional factors found to be associated with an elevated risk of lymphoid malignancy were low age and low education of mother. All these factors can be related to an increased risk of early childhood infections. PMID- 18449132 TI - [Fluticasone in the therapy of asthmatic children: short-term effects on growth]. AB - AIM: Inhaled corticosteroids (ICS), for years used in the therapy of low-moderate bronchial asthma, reduce the rate of asthmatic attack with improved pulmonary functioning and quality of life. Clinical trials have been addressed mainly to study the efficacy rather than the safety of drugs, so that the side effects of these drugs have not yet been accurately defined. Clinical experience shows that growth delay appears in the first months of therapy with ICS. The aim of the study was to evaluate the influence of the therapy with spacer-administered inhaled corticosteroid on short-term auxological development in prepubertal children. METHODS: In a group of children with low asthma, height and weight have been evaluated before and after six months of inhaled therapy with dipropionate fluticasone at a dose of 100 microg per day. RESULTS: Twenty-five patients (19 males and 6 females; age 5.5+/-1.6 years; range: 2.6-7.8 years) showed a regular growth during the six months of therapy (mean height 0.8 standard deviation score [SDS] before therapy and 0.8 SDS after therapy), while 21 (17 males and 4 females; age 10.0+/-1.5 years; range 8.0-12.7 years) showed an increment of growth rate (mean height from 0.5 SDS to 0.7 SDS, respectively). CONCLUSION: Spacer-administered low dose fluticasone does not negatively influence short-term growth rate, regardless of the age of the patients. PMID- 18449133 TI - Causes of accidents in pediatric patients: what has changed through ages. AB - AIM: Accidents are the main cause of death and disability in children and adolescents aged 1-15 years and cause more than one sixth of all infant admissions to hospital. In Italy, about 400 children and adolescents are involved in domestic accidents and more than 200 in road accidents. The aim of the study was to determine the number and type of accidents involving children and adolescents in the area of Siena and to compare present results with those obtained 20 years ago in order to assess the effectiveness of preventive measures evolving in the period. METHODS: Two groups of patients were admitted to the hospital of Siena for accidents between 1980-1985 and 2000-2006; age, gender, type of accident, frequency distribution in the study period and age of highest frequency of accidents were analysed. RESULTS: The most frequent cause of admission to hospital in the earlier period was limb trauma with and without fracture, whereas in the later period it was head injury without fracture followed by limb trauma with and without fracture, and fracture of the skull, spine and trunk in boys and girls. Some variation in the course of the years was observed in both study period, however a constant, gradual reduction in admissions is evident. CONCLUSION: Comparison of these data with those collected 20 years earlier revealed a general reduction in the number of hospital admissions. This encouraging result suggests that what has been done so far is effective and should be continued, and that it is also worthwhile taking measures to further reduce the toll of accidents. PMID- 18449134 TI - Mechanical ventilatory support in preterm infants. AB - A large proportion of premature infants presents with acute respiratory failure after birth and require mechanical ventilatory support. In addition to conventional mechanical ventilation, an increasing number of these infants are currently supported by newer modes including synchronized, volume targeted and noninvasive mechanical ventilation. While these new modes have improved weaning from mechanical ventilation they have not had a consistent impact on respiratory outcome or other morbidities. This is a review of the different modes of invasive and noninvasive mechanical ventilation used to support premature infants with respiratory failure. PMID- 18449135 TI - Management of respiratory failure in the preterm infant. AB - Respiratory failure is common in the preterm infant. Support of the infant with oxygen, positive pressure, and assisted ventilation are among the commonest interventions required in neonatal care. This article is an overview of many features of respiratory care of the preterm infant, including the goals of therapy, continuous positive airways pressure (CPAP), non-invasive ventilation, various modes of ''conventional'' ventilation, high frequency ventilation and inhaled nitric oxide use. The proven benefits and limitations of various interventions are discussed, and areas requiring further investigation are highlighted. Although it is clear that respiratory support is life-saving, there is a lack of good evidence to choose one mode of support over another. Many prospective trials have been performed which, in general, have failed to demonstrate a significant additional benefit of any newer mode of ventilation over conventional time-cycled pressure limited ventilation. Many of the currently available modes of respiratory support have never been subjected to adequate study. Newer modes of respiratory support including such innovations as volume targeted ventilation, pressure support ventilation, and inhaled nitric oxide use in the preterm, require further investigation prior to their adoption for routine clinical use. PMID- 18449136 TI - Gastroesophageal reflux in infants: can a simple left side positioning strategy help this diagnostic and therapeutic conundrum? AB - Gastroesophageal reflux (GER) is a very common condition that interrupts feeding and sleep routine in up to 30% of newborn infants. ''GER disease'' affects 3-5% of newborns and is defined when more serious complications are associated with GER. The diagnosis and treatment of GER disease in infants is fraught with difficulty due to the wide range of clinical presentations and the lack of diagnostic modalities and appropriate diagnostic criteria. These issues lead to failure to accurately diagnose reflux disease, or alternatively, over-diagnosis of reflux disease leading to the prescription of unnecessary and costly acid suppression therapies and surgical interventions. When faced with a newborn infant with GER, medical professionals prefer to offer parents a non pharmacological therapy and/or some ''common sense'' advice rather than a drug. To date the only non-pharmacological intervention proven to reduce reflux is the positioning of infants on their left side after feeding. Despite this clear evidence, a left side positioning strategy has yet to be accepted by the wider medical community due to the current lack of appropriate evidence-based guidelines. This review will evaluate the basis left-side positioning as a simple, non-pharmacological approach to the treatment of GER related symptoms in preterm and term infants 0-6 months of age. PMID- 18449137 TI - Depression and suicidal behavior in alcohol abusing adolescents: possible role of selenium deficiency. AB - Depression and suicidal behavior in adolescents are frequently comorbid with alcohol and drug abuse. Alcohol abuse may lead to the deficiency of micronutrients including selenium, an essential trace element. In addition, dietary intake of selenium in some geographic areas is low. The combination of these two factors may result in significant selenium deficiency. Selenium plays an important role in brain function. Selenium is a potent protective agent for neurons through the expression of selenoproteins. Studies suggest that low selenium status is associated with depressed mood, anxiety, and cognitive decline. A tremendous amount of structural and functional brain development takes place during the teenage years. Many of the changes that take place during the second decade of life are novel and do not simply represent the remnants of childhood plasticity. Considerable evidence suggests that alcohol affects brain function and behavior differently during adolescence than during adulthood. Adolescents are more vulnerable to the long-term effects of alcohol abuse. The adolescent brain may be especially sensitive to a harmful combination of alcohol abuse and selenium deficiency. This combination may contribute to depression and suicidal behavior in adolescents. Recent research opens new avenues for the potential development of selenium containing compounds as preventive or therapeutic agents in psychiatric and neurological conditions. Healthy nutrition and possibly mineral supplementations should be a part of the treatment plan of adolescents with alcohol use disorders especially when alcohol misuse is comorbid with depression. PMID- 18449138 TI - Noninvasive ventilation in infants and children. AB - Noninvasive ventilation provides respiratory support without airway invasion. It is defined by interface between the ventilator and the patient rather than any specific technique. It has the advantage for allowing the patients a greater degree of autonomy, control and comfort in that they can talk, eat and drink while receiving ventilatory support. There is also a trend of less need for sedation. In addition, nosocomial ventilator associated infections may be diminished. Noninvasive ventilation has been used in the management of adults with acute respiratory failure for decades, however it is only in the last few years that the benefits in children had been recognized and accepted. Technical difficulties with noninvasive ventilation in children such as poor mask fitting, inadequate ventilation because of leaks, and eye irritation and nasal dryness due to high flow have been recognized and are being addressed to varying degrees. Recent attention to mask, helmet and strapping device designs, and proper positioning have improved patient compliance and acceptance. However even with these modifications, the use of noninvasive ventilation is limited in patients with congenital facial anomalies which preclude a tight fitting mask. It is also difficult to apply in conditions when there is a potential infection such as facial trauma or burns. In this manuscript, the authors discuss the role of noninvasive ventilation in infants and children. PMID- 18449139 TI - [The essential fatty acids omega-6 and omega-3: from their discovery to their use in therapy]. AB - In 1929 Burr and Burr discovered the essential fatty acids omega-6 and omega-3. Since then, researchers have shown a growing interest in unsaturated essential fatty acids as they form the framework for the organism's cell membranes, particularly the neurones in the brain, are involved in the energy-transformation process, regulate the information flows between cells. Polyunsaturated fatty acids are also precursors of ''hormonal'' molecules, often with opposing effects, prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipossines, resolvines, protectines that regulate immunity, platelet aggregation, inflammation, etc. They showed that raised levels of polyunsaturated fatty acids omega-3 in tissue correlate with a reduced incidence of degenerative cardiovascular disease, some mental illnesses such as depression, and neuro degenerative diseases such as Alzheimer's. The balance between omega-3 and omega 6 acids allows the cell membranes to develop with exactly the right flexibility and fluidity, to carry messages between neurones, that is a determining factor in physical and mental well-being and has a profound influence on all the body's inflammatory responses. The results of a number of scientific studies suggest that omega-3 acids contribute to measuring and restricting inflammatory symptoms, whereas omega-6 acids (and saturated fats) give free range to inflammatory responses and amplify allergic reactions. Today in the Western countries, the ratio of omega-3 acids to omega-6 in the diet is weighted 1:10 in favour of omega 6 to up to 1:25 in some areas, while for proper functioning a 4:1 ratio of omega 6 acids to omega-3 acids is generally considered the optimum. In addition, the type of diet followed in the Western countries is very rich in saturated fats like butter and animal fats, but because of an excessive supply of these less noble fats, the cell membranes lose flexibility and this can affect the way they work. An appropriate supplement can be an efficient, effective and often necessary way to meet the body's needs, enhance its daily functions and promote health and longevity. PMID- 18449140 TI - [Future perspectives in the therapy of asthma in children]. AB - Asthma therapy recognizes three fundamental key points: primary prevention, secondary prevention, including the control of inflammatory mechanisms and related symptoms, and tertiary prevention, consisting in the treatment of the early phases leading to airway remodelling. As for primary prevention in infants at ''high risk'' exclusive breastfeeding for at least 3-6 months and the prevention of allergen exposure, respiratory infections and tobacco smoking are recommended. Recent findings suggest a possible protective role of diet (i.e. the intake of vegetables and vitamins and the pre-probiotics). About secondary prevention, the efficacy of drugs suggested by international guidelines (GINA or ARIA) such as antihistamines, leukotriene modifiers and inhaled corticosteroids, it is well known; such drugs can be variably used in different associations, in accordance with the clinical features of the single patient. Among the new therapeutic perspectives, a special attention should be paid to anti-IgE monoclonal antibodies and other humanized monoclonal antibodies targeting and neutralizing inflammatory cytokines; chimeric allergens blocking mast cell receptors; recombinant interleukins with ''anti-inflammatory'' or ''anti allergic'' properties; in vitro expansion of T lymphocytes with regulatory functions (Treg), and their possible therapeutic approach. Moreover, new experimental observations have identified the role of molecules derived from engineering technologies able to control allergic inflammation. As for prevention and treatment of allergic symptoms, specific immunotherapy has a relevant role, moreover in the paediatric area: it finds progressively greater consensus in terms of both efficacy and safety and is finally recognized in the latest GINA and ARIA guidelines. Tertiary prevention, which concerns the so called ''airway remodeling'', includes new therapeutic approaches such as montelukast, which can control fibroblasts proliferation and their transformation in myofibroblasts, and phosphodiesterase inhibitors. Finally, the use of peptide and non-peptide antagonists of Bradykinin B2 receptors seems to be of great interest. PMID- 18449141 TI - Floating-Harbor syndrome: case report. AB - Floating-Harbor syndrome is a rare disorder which is clinically characterized by short stature, retarded speech development, delayed bone ages, triangular face, bulbous nose and thin lips. We described two cases with Floating-Harbor syndrome and briefly reviewed the relevant literature. PMID- 18449142 TI - Intrauterine fistulation of perforated Meckel's diverticulum to the surface of the sac of an intact exomphalos minor. AB - The presence of Meckel's diverticulum in the exomphalos sac is a well known entity but the intrauterine perforation of the diverticulum is very rare. We report a case of intrauterine fistulation of Meckel's diverticulum to the surface of the intact sac of an exomphalos minor. PMID- 18449143 TI - Case report of congenital fistula of the penile urethra. AB - Isolated congenital fistula of the penile urethra is extremely rare. A case of congenital urethral fistula with an intact glandular urethra without chordee is reported with a discussion of the possible etiology and management. PMID- 18449144 TI - [NF1 and gliomas: the importance of the MRI]. PMID- 18449145 TI - Hyperimmunoglobulin syndrome in a patient applying with meningitis diagnosis. PMID- 18449146 TI - Effects of static dosimetric leaf gap on MLC-based small-beam dose distribution for intensity-modulated radiosurgery. AB - The aim of the present study was to evaluate the effect of various specific dosimetric leaf gaps on the multileaf collimator (MLC)-based small-beam dose distribution. The dosimetric static leaf gap was determined by comparing the profiles of small MLC-based beams with those of small collimated fields (square fields of 1, 2, 3, and 4 cm). The results showed that an approximately 2-mm gap was optimal with the Millennium 120-leaf MLC (Varian Medical Systems, Palo Alto, CA) and a Varian 21EX 6-MV photon beam. We also investigated how much the leaf gap affects the planning results and the actual dose distribution. A doughnut shaped planning target volume (PTV, 6.1 cm3) and inner organ at risk (OAR, 0.3 cm3) were delineated for delicate intensity-modulated radiosurgery test planning. The applied leaf gaps were 0, 1, and 2 mm. The measured dose distributions were compared with the dose distribution in the treatment planning system. The maximum dose differences at inside PTV, outside PTV, and inner OAR were, respectively, 22.3%, 20.2%, and 35.2% for the 0-mm leaf gap; 17.8%, 22.8%, and 30.8% for the 1 mm leaf gap; and 5.5%, 8.5%, and 6.3% for the 2-mm leaf gap. In a human head phantom (model 605: CIRS, Norfolk, VA) study, large dose differences of 1.3% 12.7% were noted for the measurements made using the MLC files generated by the three different leaf gaps. The planned results were similar, and measurements showed a large dose difference associated with the various leaf gaps. These results strongly suggest that plans generated by a commercial inverse planning system commissioned using general collimated field data will probably demonstrate discrepancies between the planned treatments and the measured results. PMID- 18449147 TI - A device for precision positioning and alignment of room lasers to diminish their contribution to patient setup errors. AB - This report presents an analysis of patient setup errors resulting from inaccurately positioned wall lasers. It suggests that laser beams should agree within 0.2 degree or better with the machine axes that they are delineating. For typical simulator and treatment rooms having wall-to-isocenter distances of 3 m, this requirement is satisfied when the beam-emitting aperture is mounted within about 1.0 cm from the intersection of the respective machine axis with the wall. To achieve the required precision, we developed and clinically tested a simple, inexpensive tool, the Laser Placer (LP). The essential component of the LP is a cube with mirror surfaces that is aligned with the machine axes using built-in spirit levels and the light field and cross hairs of the collimator. Wall, ceiling, and sagittal lasers are installed and aligned according to reflections of their beams by the cube, and reference lines provided by the LP. Measurements showed that, even in new accelerator installations performed by highly experienced technicians, wall lasers are often mounted off target by more than 1.5 cm. Such inaccuracies can contribute systematic errors of 2 mm or more to the random setup errors attributable to interfraction movement in patient anatomy. To keep setup errors to a minimum, medical physicists should check beam orthogonality in addition to beam congruence at isocenter as recommended by the TG-40 quality assurance protocol from the American Association of Physicists in Medicine. PMID- 18449148 TI - Measurement of craniocaudal catheter displacement between fractions in computed tomography-based high dose rate brachytherapy of prostate cancer. AB - The objective of this work is to measure the cranio-caudal displacement of catheters occurring between consecutive fractions of transrectal ultrasound (TRUS) guided high dose rate (HDR) prostate brachytherapy. Ten consecutive patients were treated with 2 fractions of 9.5 Gy TRUS guided HDR brachytherapy using dental putty for the fixation of catheters. For each patient, a CT scan with 3 mm slice thickness was acquired before each of the two fractions. Two different references were employed to measure the catheter displacement between fractions: the ischial bone as a bony marker (BM) and the center of two gold markers (COGM) implanted in the prostate. The catheter displacement was calculated by multiplying the thickness of CT slice with the difference in number of CT slices between the reference slice and the slice containing the tip of a catheter. The average (range) magnitude of caudal catheter displacement was 2.7 mm (-6.0 to 13.5 mm) for BM method and 5.4 mm (-3.75 to 18.0 mm) for COGM method, respectively. The measurement data obtained from BM and COGM methods verified that both prostate movement and catheter displacement occurred independently between fractions. The most anterior and medial two catheters (catheter position 8 and 12) had the greatest tendency to be displaced in the caudal direction because they were located at the most distant position from the fulcrum, susceptible to the rotation of the dental putty in lateral plane due to the movement of patient legs between fractions. In conclusion, the use of both BM and COGM methods can demonstrate the prostate and catheter movement relative to the BM between fractions. We found a pattern of catheter displacement using our technique. Based on our finding further improvement of our results may be possible by modification of our current technique. PMID- 18449149 TI - Quantitative evaluation of a cone-beam computed tomography-planning computed tomography deformable image registration method for adaptive radiation therapy. AB - Deformable (non-rigid) registration is an essential tool in both adaptive radiation therapy and image-guided radiation therapy to account for soft-tissue changes during the course of treatment. The evaluation method most commonly used to assess the accuracy of deformable image registration is qualitative human evaluation. Here,we propose a method for systematically measuring the accuracy of an algorithm in recovering artificially introduced deformations in cases of rigid geometry, and we use that method to quantify the ability of a modified basis spline (B-Spline) registration algorithm to recover artificially introduced deformations. The evaluation method is entirely computer-driven and eliminates biased interpretation associated with human evaluation; it can be applied to any chosen method of image registration. Our method involves using planning computed tomography (PCT) images acquired with a conventional CT simulator and cone-beam computed tomography (CBCT) images acquired daily by a linear accelerator-mounted kilovoltage image system in the treatment delivery room. The deformation that occurs between the PCT and daily CBCT images is obtained using a modified version of the B-Spline deformable model designed to overcome the low soft-tissue contrast and the artifacts and distortions observed in CBCT images. Clinical CBCT images and contours of phantom and central nervous system cases were deformed (warped) with known random deformations. In registering the deformed with the non deformed image sets, we tracked the algorithm's ability to recover the original, non-deformed set. Registration error was measured as the mean and maximum difference between the original and the registered surface contours from outlined structures. Using this approach, two sets of tests can be devised. To measure the residual error related to the optimizer's convergence performance, the warped CBCT image is registered to the unwarped version of itself, eliminating unknown factors such as noise and positioning errors. To study additional errors introduced by artifacts and noise in the CBCT image, the warped CBCT image is registered to the original PCT image. Using a B-Spline deformable image registration algorithm, mean residual error introduced by the algorithm's performance on noise-free images was less than 1 mm, with a maximum of 2 mm. The chosen deformable image registration model was capable of accommodating significant variability in structures over time, because the artificially introduced deformation magnitude did not significantly influence the residual error. On the second type of test, noise and artifacts reduced registration accuracy to a mean of 1.33 mm and a maximum of 4.86 mm.The accuracy of deformable image registration can be easily and consistently measured by evaluating the algorithm's ability to recover artificially introduced deformations in rigid cases in which the true solution is known a priori. The method is completely automated, applicable to any chosen registration algorithm, and does not require user interaction of any kind. PMID- 18449150 TI - Using an onboard kilovoltage imager to measure setup deviation in intensity modulated radiation therapy for head-and-neck patients. AB - The purpose of the present study was to use a kilovoltage imaging device to measure interfractional and intrafractional setup deviations in patients with head-and-neck or brain cancers receiving intensity-modulated radiotherapy (IMRT) treatment. Before and after IMRT treatment, approximately 3 times weekly, 7 patients were imaged using the Varian On-Board Imager (OBI: Varian Medical Systems, Palo Alto, CA), a kilovoltage imaging device permanently mounted on the gantry of a Varian 21EX LINAC (Varian Medical Systems). Because of commissioning of the remote couch correction of the OBI during the study, online setup corrections were performed on 2 patients. For the other 5 patients, weekly corrections were made based on a sliding average of the measured data. From these data, we determined the interfractional setup deviation (defined as the shift from the original setup position suggested by the daily image), the residual error associated with the weekly correction protocol, and the intrafractional setup deviation, defined as the difference between the post-treatment and pretreatment images. We also used our own image registration software to determine interfractional and intrafractional rotational deviations from the images based on the template-matching method. In addition, we evaluated the influence of inter-observer variation on our results, and whether the use of various registration techniques introduced differences. Finally, translational data were compared with rotational data to search for correlations. Translational setup errors from all data were 0.0 +/- 0.2 cm, -0.1 +/- 0.3 cm, and -0.2 +/- 0.3 cm in the right-left (RL), anterior-posterior (AP), and superior-inferior (SI) directions respectively. Residual error for the 5 patients with a weekly correction protocol was -0.1 +/- 0.2 cm (RL), 0.0 +/- 0.3 cm (AP), and 0.0 +/- 0.2 cm (SI). Intrafractional translation errors were small, amounting to 0.0 +/- 0.1 cm, -0.1 +/- 0.2 cm, and 0.0 +/- 0.1 cm in the RL, AP, and SI directions respectively. In the sagittal and coronal views respectively, interfractional rotational errors were -1.1 +/- 1.7 degrees and -0.5 +/- 0.9 degrees, and intrafractional rotational errors were 0.3 +/- 0.6 degrees and 0.2 +/- 0.5 degrees. No significant correlation was seen between translational and rotational data. The OBI image data were used to study setup error in the head-and-neck patients. Nonzero systematic errors were seen in the interfractional translational and rotational data, but not in the intrafractional data, indicating that the mask is better at maintaining head position than at reproducing it. PMID- 18449151 TI - Forward-planning intensity-modulated radiotherapy technique for prostate cancer. AB - In this study, we present an intensity-modulated radiotherapy technique based on forward planning dose calculations to provide a concave dose distribution to the prostate and seminal vesicles by means of modified dynamic arc therapy (M-DAT). Dynamic arcs (350 degrees) conforming to the beam's eye view of the prostate and seminal vesicles while shielding the rectum, combined with two lateral oblique conformal fields (15 degrees with respect to laterals) fitting the prostate only,were applied to deliver doses of 78 Gy and 61.23 Gy in 39 fractions to the prostate and seminal vesicles respectively. Dynamic wedges (45 degrees of thick end, anteriorly oriented) were used with conformal beams to adjust the dose homogeneity to the prostate, although in some cases, hard wedges (30 degrees of thick part,inferiorly oriented) were used with arcs to adjust the dose coverage to the seminal vesicles. The M-DAT was applied to 10 patients in supine and 10 patients in prone positioning to determine the proper patient positioning for optimum protection of the rectum. The M-DAT was compared with the simplified intensity-modulated arc therapy (SIMAT) technique, composed of three phases of bilateral dynamic arcs. The mean rectal dose in M-DAT for prone patients was 22.5 +/- 5.1 Gy; in M-DAT and SIMAT for supine patients, it was 30.2 +/- 5.1 Gy and 39.4 +/- 6.0 Gy respectively. The doses to 15%, 25%, 35%, and 50% of the rectum volume in M-DAT for prone patients were 44.5 +/- 10.2 Gy, 33.0 +/- 8.2 Gy, 25.3 +/- 6.4 Gy, and 16.3 +/- 5.6 Gy respectively. These values were lower than those in M-DAT and in SIMAT for supine patients by 7.7%, 18.2%, 22.4%, and 28.5% and by 25.0%, 32.1%, 34.9%, and 41.9% of the prescribed dose (78 Gy) respectively. Ion chamber measurements showed good agreement of the calculated and measured isocentric dose (maximum deviation of 3.5%). Accuracy of the dose distribution calculation was evaluated by film dosimetry using a gamma index, allowing 3% dose variation and 4 mm distance to agreement as the individual acceptance criteria in prostate and seminal vesicle levels alike for all supine and prone patients. We found that fewer than 10% of the pixels in the dose distribution of the calculated area of10 x 10-cm failed the acceptance criteria. These pixels were observed mainly in the low-dose regions, particularly at the level of the seminal vesicles. In conclusion, the single-phase M-DAT technique with patients in the prone position was found to provide the intended coverage of the prescribed doses to the prostate and seminal vesicles with improved protection for the rectum. Accordingly, M-DAT has replaced non-modulated conformal radiotherapy or SIMAT as the standard treatment for prostate cancer in our department. PMID- 18449152 TI - Clinical and dosimetric experience with MammoSite-based brachytherapy under the RTOG 0413 protocol. AB - MammoSite balloon brachytherapy is a relatively new technique for partial breast irradiation. The present paper focuses on the treatment planning, dosimetry, and quality assurance aspects of that treatment, based on the Radiation Therapy Oncology Group 0413 randomized prospective trial (RTOG 0413) protocol. We investigate the usefulness of evaluating implants for treatment appropriateness according to the full set of RTOG criteria as compared with the manufacturer's guidelines. We describe our methods to improve MammoSite balloon implants that would otherwise not comply with the protocol. The initially acquired computed tomography (CT) images are evaluated for tissue conformance, balloon surface-to skin distance, and balloon symmetry. If the implant fails to meet the foregoing criteria, corrective action such as delay in the CT scan, balloon manipulation, or fluid volume adjustment is taken, and the patient is re-scanned. If the corrective action appears to be successful, three dimensional treatment planning and dose-volume histogram analysis is performed to evaluate the geometric and dosimetric parameters with regard to the RTOG 0413 protocol. The evaluated parameters include, volume ratio of the lumpectomy cavity to the ipsilateral breast, target volume coverage, tissue-balloon conformance, balloon symmetry, minimal balloon surface-to-skin distance, maximum skin dose, and normal breast tissue dose-volume parameters V150 and V200. Among our implants, 21.7% did not initially meet the RTOG 0413 acceptance criteria. Asymmetry and poor conformance values reduce the target volume coverage, and so an implant with moderate conformance and asymmetry can be within the manufacturer's guidelines, but still not meet the RTOG criteria. Our intervention corrected all but one of the implants that failed to meet the criteria. Manipulating the cavity and adjusting the balloon volume may salvage an implant and meet the strict geometric and dosimetric criteria imposed by the RTOG 0413 protocol. PMID- 18449153 TI - Three-dimensional quantitative dose reduction analysis in MammoSite balloon by Monte Carlo calculations. AB - Current treatment planning systems (TPSs) for partial breast irradiation using the MammoSite brachytherapy applicator (Cytyc Corporation, Marlborough, MA) often neglect the effect of inhomogeneity, leading to potential inaccuracies in dose distributions. Previous publications either have studied only a planar dose perturbation along the bisector of the source or have paid little attention to the anisotropy effect of the system. In the present study, we investigated the attenuation-corrected radial dose and anisotropy functions in a form parallel to the updated American Association of Physicists in Medicine TG-43 formalism. This work quantitatively delineates the inaccuracies in dose distributions in three dimensional space. Monte Carlo N-particle transport code simulations in coupled photon-electron transport were used to quantify the changes in dose deposition and distribution caused by the increased attenuation coefficient of iodine-based contrast solution. The source geometry was that of the VariSource wire model VS2000 (Varian Medical Systems, Palo Alto, CA). The concentration of the iodine based solution was varied from 5% to 25% by volume, a range recommended by the balloon's manufacturer. Balloon diameters of 4, 5, and 6 cm were simulated. Dose rates at the typical prescription line (1 cm away from the balloon surface) were determined for various polar angles. The computations showed that the dose rate reduction throughout the entire region of interest ranged from 0.64% for the smallest balloon diameter and contrast concentration to 6.17% for the largest balloon diameter and contrast concentration. The corrected radial dose function has a predominant influence on dose reduction, but the corrected anisotropy functions explain only the effect at the MammoSite system poles. By applying the corrected radial dose and anisotropy functions to TPSs, the attenuation effect can be reduced to the minimum. PMID- 18449154 TI - Verification procedure for isocentric alignment of proton beams. AB - We present a technique--based on the Lutz, Winston, and Maleki test used in stereotactic linear accelerator radiosurgery--for verifying whether proton beams are being delivered within the required spatial coincidence with the gantry mechanical isocenter. Our procedure uses a proton beam that is collimated by a circular aperture at its central axis and is then intercepted by a small steel sphere rigidly supported by the patient couch. A laser tracker measurement system and a correction algorithm for couch position assures precise positioning of the steel sphere at the mechanical isocenter of the gantry. A film-based radiation dosimetry technique, chosen for the good spatial resolution it achieves, records the proton dose distribution for optical image analysis. The optical image obtained presents a circular high-dose region surrounding a lower-dose area corresponding to the proton beam absorption by the steel sphere, thereby providing a measure of the beam alignment with the mechanical isocenter. We found the self-developing Gafchromic EBT film (International Specialty Products, Wayne, NJ) and commercial Epson 10000 XL flatbed scanner (Epson America, Long Beach, CA) to be accurate and efficient tools. The positions of the gantry mechanical and proton beam isocenters, as recorded on film, were clearly identifiable within the scanning resolution used for routine alignment testing (0.17 mm per pixel). The mean displacement of the collimated proton beam from the gantry mechanical isocenter was 0.22 +/- 0.1 mm for the gantry positions tested, which was well within the maximum deviation of 0.50 mm accepted at the Proton Therapy Center in Houston. PMID- 18449155 TI - The use of LiF (TLD-100) as an out-of-field dosimeter. AB - The commonly used thermoluminescent dosimeter TLD-100 (Harshaw Chemical Company, Solon, OH) responds not only to photons and electrons, but also to neutrons that are produced during high-energy therapies. As a result, TLD-100 measurements outside of the treatment field are suspect when high-energy radiation is used. Although alternatives such as TLD-700 do not respond to neutrons, specialty dosimeters of this kind are expensive and are not routinely used in most clinics. In the current study, we examined the accuracy of TLD-100 in measuring the out-of field photon dose as a function of treatment energy. To determine the accuracy of TLD-100 as compared with TLD-700, TLD-100 was irradiated outside of the treatment field by medical accelerators operated at 6, 10, 15, and 18 MV. In an effort to eliminate the response of TLD-100 to neutrons, TLD capsules were encased in varying thicknesses of cadmium foil (0.25 - 0.75 mm) before being irradiated at 18 MV. The out-of-field TLD-100 was found to be accurate at 6 MV and 10 MV, but to be substantially over-responsive at 15 MV and 18 MV (by up to 1063% relative to TLD-700). By wrapping the TLD-100 in up to 0.75 mm of cadmium, it was possible to drastically reduce (down to 39% on average) the over-response of the TLD-100; however, total removal of the over-responsiveness was not possible. Although TLD 100 is well suited for measuring out-of-field dose at energies as high as 10 MV, at higher energies (15 MV or greater), this dosimeter over-responds substantially and should not be used. Although encasing the TLD in cadmium minimized over response to a degree, the reduction was not sufficient to make TLD-100 viable for measuring out-of-field dose at high treatment energies. PMID- 18449156 TI - Quality assurance device for four-dimensional IMRT or SBRT and respiratory gating using patient-specific intrafraction motion kernels. AB - Emerging technologies such as four-dimensional computed tomography (4D CT) and implanted beacons are expected to allow clinicians to accurately model intrafraction motion and to quantitatively estimate internal target volumes (ITVs) for radiation therapy involving moving targets. In the case of intensity modulated (IMRT) and stereotactic body radiation therapy (SBRT) delivery, clinicians must consider the interplay between the temporal nature of the modulation and the target motion within the ITV. A need exists for a 4D IMRT/SBRT quality assurance (QA) device that can incorporate and analyze customized intrafraction motion as it relates to dose delivery and respiratory gating. We built a 4D IMRT/SBRT prototype device and entered (X, Y, Z)(T) coordinates representing a motion kernel into a software application that 1. transformed the kernel into beam-specific two-dimensional (2D) motion "projections," 2. previewed the motion in real time, and 3. drove a recision X-Y motorized device that had, atop it, a mounted planar IMRT QA measurement device. The detectors that intersected the target in the beam's-eye-view of any single phase of the breathing cycle (a small subset of all the detectors) were defined as "target detectors" to be analyzed for dose uniformity between multiple fractions. Data regarding the use of this device to quantify dose variation fraction-to-fraction resulting from target motion (for several delivery modalities and with and without gating) have been recently published. A combined software and hardware solution for patient-customized 4D IMRT/SBRT QA is an effective tool for assessing IMRT delivery under conditions of intrafraction motion. The 4D IMRT QA device accurately reproduced the projected motion kernels for all beam's-eye-view motion kernels. This device has been proved to, effectively quantify the degradation in dose uniformity resulting from a moving target within a static planning target volume, and, integrate with a commercial respiratory gating system to ensure that the system is working effectively. Such a device is discussed as a potential tool to optimize the gating duty cycle to maximize delivery efficiency while minimizing dose variability. PMID- 18449157 TI - Monte Carlo determination of radiation-induced cancer risks for prostate patients undergoing intensity- modulated radiation therapy. AB - The application of intensity-modulated radiation therapy (IMRT) has enabled the delivery of high doses to the target volume while sparing the surrounding normal tissues. The drawbacks of intensity modulation, as implemented using a computer controlled multileaf collimator (MLC), are the larger number of monitor units (MUs) and longer beam-on time as compared with conventional radiotherapy. Additionally, IMRT uses more beam directions--typically 5-- 9 for prostate treatment--to achieve highly conformal dose and normal-tissue sparing. In the present work, we study radiation-induced cancer risks attributable to IMRT delivery using MLC for prostate patients. Whole-body computed tomography scans were used in our study to calculate (according to report no. 116 from the National Council on Radiation Protection and Measurements) the effective dose equivalent received by individual organs. We used EGS4 and MCSIM to compute the dose for IMRT and three-dimensional conformal radiotherapy. The effects of collimator rotation, distance from the treatment field, and scatter and leakage contribution to the whole-body dose were investigated. We calculated the whole body dose equivalent to estimate the increase in the risk of secondary malignancies. Our results showed an overall doubling in the risk of secondary malignancies from the application of IMRT as compared with conventional radiotherapy. This increase in the risk of secondary malignancies is not necessarily related to a relative increase in MUs. The whole-body dose equivalent was also affected by collimator rotation, field size, and the energy of the photon beam. Smaller field sizes of low energy photon beams (that is, 6 MV) with the MLC axis along the lateral axis of the patient resulted in the lowest whole body dose. Our results can be used to evaluate the risk of secondary malignancies for prostate IMRT patients. PMID- 18449158 TI - Determination of depth and field size dependence of multileaf collimator transmission in intensity-modulated radiation therapy beams. AB - Intensity-modulated radiation therapy (IMRT) plans for the treatment of large and complex volumes may contain a relatively large contribution from multileaf collimator (MLC) transmission. In such cases, comprehensive characterization of direct and scatter MLC transmission is important. We designed a set of tests (open beam, closed static MLC, and dynamic MLC gap) to determine dosimetric MLC properties as a function of field size and depth at the central axis. We developed a generalized model of MLC transmission to account for direct MLC transmission, MLC scatter, beam hardening, and leaf-end transmission (dosimetric gap). The model is consistent with the beam model used in IMRT optimization. We tested the model for extreme asymmetric fields relevant for large targets and for split IMRT fields. We applied our MLC scatter estimation formula to clinically relevant cases and showed that MLC scatter is contributing an undesired background dose. This contribution is relatively large, especially in low-dose regions. (For instance, a uniform extra dose may dramatically increase normallung toxicity in thorax treatment.) For complex IMRT of large-volume targets, we found direct MLC transmission dose to be as high as 30%, and MLC scatter, up to 10% within the target volume for the selected cases. We identified that the dose discrepancies between the IMRT planning system [Eclipse (Varian Medical Systems, Palo Alto, CA)] and ionization chamber measurements (inside and outside of the field) are attributable to an inadequate model of MLC transmission in the planning system (constant-value model). In the present study, we measured MLC transmission properties for Varian 6EX (6 MV) and 21EXs (6 and 10 MV) linear accelerators; however, the experimental method and theoretical model are more general. PMID- 18449159 TI - Development of an optimum photon beam model for head and-neck intensity-modulated radiotherapy. AB - Intensity-modulated radiotherapy (IMRT) for complex sites such as tumors of the head and neck requires a level of accuracy in dose calculation beyond that currently used for conformal treatment planning. Recent advances in treatment planning systems have aimed to improve the dose calculation accuracy by improving the modeling of machine characteristics such as interleaf leakage, tongue and groove, and rounded multileaf collimator (MLC) leaf ends. What is uncertain is the extent to which these model parameters improve the agreement between dose calculation and measurements for IMRT treatments. We used Pinnacle version 7.4f (Philips Medical Systems, Andover, MA) to carry out optimization of additional photon-beam model parameters for both an Elekta Precise (Elekta, Stockholm, Sweden) and a Varian (Varian Medical Systems, Palo Alto, CA) linear accelerator (LINAC). One additional parameter was added to the beam models in turn, and associated models were commissioned to investigate the dosimetric impact of each model parameter on 5 clinical head-and-neck IMRT plans. The magnitude and location of differences between the models was determined from gamma analysis of the calculated planar dose maps. A final model that incorporated all of the changes was then commissioned. For the Elekta Precise, the impact of all the changes was determined using a gamma analysis as compared with measured films. Cumulative differences of up to more than 3%/3 mm were observed when dose distributions with and without all of the model changes were compared. Individually, for both LINACs, the addition of modeling for the rounded MLC leaf ends caused the most dramatic change to the calculation of the dose distribution, generating a difference of 3%/3 mm in up to 5% of pixels for the 5 patient plans sampled. The effect of tongue-and-groove modeling was more significant for the Varian LINAC (at 1%/1 mm, mean of 25% of pixels as compared with 5% of pixels with the Elekta Precise LINAC). The combined changes to the Elekta model were found to improve agreement with measurement. Current commercially available treatment planning systems offer accuracy sufficient for clinical implementation of head-and-neck IMRT. For this treatment site, the ability to accurately model the rounded MLC leaf ends has the greatest affect on the similarity of the calculated dose distribution to measurements. In addition, for the Varian LINAC, modeling of the tongue-and-groove effect was also advantageous. PMID- 18449161 TI - Clinical assessment and characterization of a dual tube kilovoltage X-ray localization system in the radiotherapy treatment room. AB - INTRODUCTION: Although flat-panel based X-ray imaging has been well tested in diagnostic radiology, its use as an image-guided-radiotherapy (IGRT) system in a treatment room is new and requires systematic assessment. MATERIALS AND METHODS: BrainLab Novalis IGRT system was used for this study. It consists of two floor mounted kV X-ray tubes projecting obliquely into two flat-panel detectors mounted on the ceiling. The system automatically fuses the 2D localization images with 3D simulation CT image to provide positioning guidance. The following characteristics of the system were studied: (1) Coincidence of the isocenters between the IGRT and Linac; (2) Image quality; (3) Exposure; (4) Linearity, uniformity and repeatability. RESULTS: (1) Localization accuracy and coincidence of the isocenters between the IGRT and Linac was better than 1-mm. (2) The spatial resolution was quantified using the relative modulation-transfer-function with f50=0.7-0.9 lp/mm. The variation of contrast-noise-ratio with technical settings was measured. (3) The maximal exposure of an image was less than 95 mR. An empirical relation between the exposure and the X-ray technical setting was derived. (4) The linearity, uniformity and repeatability of the system generally meet the requirements. CONCLUSION: The system can be safely and reliably used as a target localization device. PMID- 18449162 TI - Study of the uncertainty in the determination of the absorbed dose to water during external beam radiotherapy calibration. AB - To achieve a good clinical outcome in radiotherapy treatment, a certain accuracy in the dose delivered to the patient is required. Therefore, it is necessary to keep the uncertainty in each of the steps of the process inside some acceptable values, which implies a global uncertainty as low as possible. This work is focused on the uncertainty evaluation of absorbed dose to water in the routine calibration for clinical beams, in the range of energies used in external radiotherapy. With this aim, different uncertainty components (corrected electrometer reading, calibration factor, beam quality correction factor and reference conditions) associated to beam calibration have been considered. Results show a typical uncertainty in the determination of absorbed dose to water during beam calibration around 1.3% for photon beams and 1.5% for electron beams (k=1 in both cases) when the N(D,w) formalism is used and is theoretically calculated. These values may be different depending on the uncertainty provided by the standards laboratory for calibration factor, which is shown in the work. If the total application of the N(D,w) formalism, that is to say, specific calibrations of each chamber in the user's beam qualities, is taken into account the uncertainty in this step of the process could be placed close to 1.0%. Furthermore, the possibility of an uncertainty reduction with the absorbed dose to water formalism adoption against the air kerma one is discussed. PMID- 18449163 TI - Is daily CT image guidance necessary for nasal cavity and nasopharyngeal radiotherapy: an investigation based on helical tomotherapy. AB - In order to analyze the magnitude of set up errors corrected by Helical TomoTherapy Mega-Voltage CT on a daily or weekly basis and their impact on the delivered dose to the tumor and organs at risk (OAR), the setup errors of 6 nasal cavity and 4 nasopharyngeal cancer patients who were treated with Helical Tomotherapy for 25-33 fractions were retrospectively analyzed. Each patient had MVCT guided repositioning for all fractions of treatment. The new dose volume histogram (DVH) and equivalent uniform dose (EUD) for planning target volume (PTV) and OARs were calculated for hypothetical situations where no imaging guidance (IG) or once weekly image guidance (WIG) took place. The mean total set up error if treated without daily IG was 3.6+/-1.0 mm, which can be reduced to 1.7+/-0.6 mm if a WIG was performed. The geometrical uncertainties from the absence of image guidance resulted in a reduction of mean PTV EUD dose by 2.1+/ 1.0 %, which can be reduced to 1.4+/-1.0 % with WIG. The EUD of OARs increased 1.8+/-2.0 Gy or 0.8+/-1.3 Gy without or with WIG respectively. Without daily IG, the mean patient position uncertainty has relatively small impacts on the mean PTV and OAR dosimetry, which can be further reduced approximately by half using a WIG. On the other hand, because of the large variance, with low probability, substantial deviation from the original planned dosimetry may occur without IG. Therefore, daily MVCT is preferred as an important safety measure in the IMRT. PMID- 18449164 TI - Development of a geometry-based respiratory motion-simulating patient model for radiation treatment dosimetry. AB - Temporal and spatial anatomical changes caused by respiration during radiation treatment delivery can lead to discrepancies between the prescribed and actually received radiation doses. This paper presents a study to construct a respiratory motion-simulating, four-dimensional (4D) patient anatomical and dosimetry model for the study of dosimetric effects of organ motion on various radiation treatment plans and delivery strategies. A 3D VIP-Man (VIsible Photographic Man) model has been reconstructed using the Non-Uniform Rational B-Splines (NURBS) method to reflect the deformation of organs during respiration by manipulating surface control points as time-dependent equations. The 4D model is applied to dose simulation using the Monte Carlo code EGS4 (Electron Gamma Shower, version 4). Two delivery scenarios in radiation therapy were simulated: "gating" treatment and 4D "image-guided" treatment. For each delivery scenario, one conformal plan and one Intensity Modulated Radiation Therapy (IMRT) plan were developed. A lesion in the left lung was modeled to investigate the impact of respiratory motion on radiation dose distributions. Based on target dose volume histograms (DVHs), it is demonstrated that it is important to use accurate "gating" to improve the dose distribution. The results also suggest that, during a 4D "image-guided" treatment delivery, monitoring of patient breathing pattern is critical. This study demonstrates the potential of using "standard" motion simulating patient model for 4D treatment planning and motion management. PMID- 18449165 TI - Verifying monitor unit calculations for tangential whole breast fields in 3 dimensional planning. AB - An essential component of quality assurance in radiation therapy is verifying the accuracy of monitor unit calculations. For tangential breast fields, monitor unit differences between primary calculations and second checks are usually larger than considered acceptable at other anatomical sites. A simple model to reconcile the differences between sophisticated and simple algorithms is presented, based on estimating the the volume irradiated by the field, replacing the breast contour with a rectangular block having an equal volume but a new field width which provides almost equivalent scatter to the prescription point. This analysis can also assist the treatment planning physicist in selecting a tolerance window for verifying monitor unit calculations for tangential breast fields. PMID- 18449166 TI - Use of three-dimensional (3D) optical flow method in mapping 3D anatomic structure and tumor contours across four-dimensional computed tomography data. AB - A 3-dimensional (3D) optical flow program that includes a multi-resolution feature has been developed and applied to 3D anatomical structure and gross tumor volume (GTV) contour mapping for 4-dimensional (4D) CT data. The study includes contour mapping for 3 real patient CT data sets, and also for a thoracic phantom in which the displacement for each voxel is known. Of the real patient CT data sets, one set has been used to map contours of lung and GTV over all the respiration phases, while the others were studied using only the end inspiration and end expiration phases, in which the displacement between the phases were the largest. Including the residual motion in the 4D CT data and motion table shaking, the optical flow calculation agrees to within 1 mm with the known displacement. Excluding those errors that are not introduced by optical flow algorithm, the agreement can be within 0.1 mm with a displacement magnitude of 24 mm. The mapped contours of lungs, liver, esophagus, GTV, etc. in real patient 4D CT images were acceptable to clinicians. The 3D optical flow program is a good tool for anatomical structure and tumor volume contour mapping across 4D CT scans. PMID- 18449167 TI - Effect of output variation with dose rate on the Virtual Wedge factor. AB - Siemens Virtual Wedge factor may drift significantly due to increase in output as dose rate decreases. This variation of output is caused by defective sample and hold boards in the dosimetry circuit due to radiation damage. In this note, we present a simple model based on the principle of Virtual Wedge operation and the measured output variation with dose rate to quantitatively describe Virtual Wedge factor drift as a function of field size and wedge angle. Our results support the recommendation that VWF be measured for large field sizes (e.g., 20 ' 20 cm2) and large wedge angles (e.g., 60 degrees) as a part of routine quality assurance. PMID- 18449168 TI - Experimental evaluation of the accuracy of skin dose calculation for a commercial treatment planning system. AB - This work investigates the accuracy of skin dose calculations using the Eclipse treatment planning system. Skin dose was measured using micro-MOSFETs for a range of irradiation conditions (open fields, physical wedges, dynamic wedges, different SSDs) for 6MV and 10MV beams, and compared with the mean dose calculated to a 2mm thick "skin" structure for semi-cylindrical phantoms (representative of a neck or breast). Agreement between the calculated and measured skin dose values was better than +/-20% for 95% of all measured points (both 6MV and 10MV x-ray spectra). For a fixed geometry, the TPS correctly calculated relative changes in dose, showing that minimization of skin dose in IMRT will be effective in Eclipse. PMID- 18449170 TI - Histopathology and surgical anatomy of patients with primary hyperparathyroidism and calcium phosphate stones. AB - Using a combination of intra-operative digital photography and micro-biopsy we measured renal cortical and papillary changes in five patients with primary hyperparathyroidism and abundant calcium phosphate kidney stones. Major tissue changes were variable papillary flattening and retraction, dilation of the ducts of Bellini, and plugging with apatite deposits of the inner medullary collecting ducts and ducts of Bellini. Some of the papillae in two of the patients contained plentiful large interstitial deposits of Randall's plaque and where the deposits were most plentiful we found overgrowth of the attached stones. Hence, this disease combines features previously described in brushite stone formers- dilation, plugging of ducts and papillary deformity--with the interstitial plaque and stone overgrowth characteristic of routine idiopathic calcium oxalate stone formers, suggesting that these two patterns can coexist in a single patient. PMID- 18449171 TI - Activation of Erk1/2 and Akt following unilateral ureteral obstruction. AB - Chronic unilateral ureteral obstruction is a well characterized model of renal injury leading to tubulointerstitial fibrosis and distinct patterns of cell proliferation and apoptosis in the obstructed kidney. In this study we assessed the contribution of the mitogen activated protein kinase (MAPK)-ERK1/2 and the phosphatidylinositol 3 kinase (PI3K)-Akt pathways to early renal changes following unilateral obstruction. Increased activation of small Ras GTPase and its downstream effectors ERK1/2 and Akt was detected in ligated kidneys. The use of specific pharmacological inhibitors to either ERK1/2 or Akt activation led to decreased levels of fibroblast-myofibroblast markers in the interstitium while inhibition of PI3K reduced the number of proliferating cells and the amount of interstitial extracellular matrix deposition. Treatment with an ERK1/2 inhibitor diminished the number of apoptotic tubule and interstitial cells. Our results suggest a role for the MAPK-ERK1/2 and PI3K-Akt systems in early changes induced by ureteral obstruction and that inhibition of these signaling pathways may provide a novel approach to prevent progression of renal fibrosis. PMID- 18449172 TI - Leukocyte chemotactic factor 2: A novel renal amyloid protein. AB - Renal amyloid deposits can often be seen in primary amyloidosis (immunoglobulin light chain disease) or in secondary forms such as reactive amyloidosis as well as in several hereditary forms where a variety of mutant proteins 'precipitate' as amyloid plaques. However, in rare cases, amyloidosis may be identified by renal biopsy, but no definitive diagnosis could be made. We have isolated amyloid fibrils from such a case in which the patient presented with nephrotic syndrome and subsequent azotemia requiring hemodialysis. Evaluation for amyloid deposition in other organ systems was negative and immunohistochemical analysis of the kidney deposits for known contributing proteins was unrevealing. Biochemical analysis of the fibrils identified a new amyloid subunit protein, leukocyte chemotactic factor 2, originally identified as a possible chemotactic and growth factor. A monoclonal antibody to this protein reacted specifically with the amyloid deposits in the glomeruli and interstitium by immunohistochemistry. This study emphasizes the importance of biochemical characterization of amyloid present in renal biopsies. PMID- 18449173 TI - Chronic course of a hemolytic uremic syndrome caused by a deficiency of factor H related proteins (CFHR1 and CFHR3). PMID- 18449176 TI - When proton pumps go sour: Urinary acidification and kidney stones. AB - H(+)-ATPases mediate urinary acidification along the collecting duct, and mutations in their B1 and a4 subunits result in distal renal tubular acidosis. The pathomechanisms by which these mutations affect pump activity are only poorly understood. Common polymorphisms may impair pump activity and may link the pump to a higher risk for alkaline urine and the development of kidney stones. PMID- 18449174 TI - Hyperphosphatemia of chronic kidney disease. AB - Observational studies have determined hyperphosphatemia to be a cardiovascular risk factor in chronic kidney disease. Mechanistic studies have elucidated that hyperphosphatemia is a direct stimulus to vascular calcification, which is one cause of morbid cardiovascular events contributing to the excess mortality of chronic kidney disease. This review describes the pathobiology of hyperphosphatemia that develops as a consequence of positive phosphate balance in chronic kidney disease and the mechanisms by which hyperphosphatemia acts on neointimal vascular cells that are stimulated to mineralize in chronic kidney disease. The characterization of hyperphosphatemia of chronic kidney disease as a distinct syndrome in clinical medicine with unique disordered skeletal remodeling, heterotopic mineralization and cardiovascular morbidity is presented. PMID- 18449177 TI - IgA1 glycosylation in IgA nephropathy: as sweet as it can be. AB - Abnormally O-glycosylated IgA1 is likely to be involved in the pathogenesis of IgA nephropathy (IgAN). Buck et al. show that the enzyme activity and gene expression of specific glycosyltransferases, in purified B cells isolated from peripheral blood and bone marrow, is not reduced in IgAN patients. As only a small fraction of IgA in IgAN patients is abnormally glycosylated, it is probable that a more detailed molecular analysis at the single cell level is required to unravel the cause of this abnormality. PMID- 18449178 TI - The dynamics of kidney donation: viewpoints from the donor, the recipients, and the transplant team. AB - Living kidney transplantation has become increasingly widespread to reduce organ shortage. Very few studies have prospectively investigated the donor's long-term risks. Living donation is a complex medical decision in which different actors are involved. This therapeutic option needs educational programs for potential donors, recipients, and transplant professionals to make them aware of the possible risks and benefits. It is important to fully exploit living-donor kidney transplantation. PMID- 18449181 TI - The Case: an unknown toxin. PMID- 18449182 TI - Reversible advanced ischemic hand atrophy due to arteriovenous fistula steal. PMID- 18449184 TI - From anesthetic mechanisms research to drug discovery. AB - The ability to render patients insensible and amnesic to remarkably invasive procedures that are uncomfortable to watch, let alone experience, has been rightly designated as one of the greatest medical discoveries of all time. General anesthesia, introduced formally in the mid-nineteenth century, is now delivered to approximately 40 million patients every year in the United States alone. Given its central role in health care, it is indeed extraordinary how poorly we understand anesthesia and anesthetics. In fact, definitions are at best operational and convey little understanding of the underlying neurobiology, while the hypothetical mechanisms are surprisingly superficial. Worse, there is growing concern that the anesthetic drugs in current use, especially the inhaled anesthetics, have durable adverse effects on cognition. PMID- 18449185 TI - Model-based approach and signal detection theory to evaluate the performance of recruitment centers in clinical trials with antidepressant drugs. AB - The objective of this study was to characterize the performance of each recruitment center in multicenter clinical trials and to provide criteria to discriminate between informative and noninformative centers using the signal detection approach. Data were derived from the GlaxoSmithKline Clinical Trial database on paroxetine and bupropion, totaling 4,016 subjects with major depressive disorders (MDDs) across nine trials. The probability of observing clinically relevant difference of active treatment from placebo was estimated in each center as a function of the placebo Hamilton Depression Rating Scale (HAMD 17) scores at baseline and at week 8. The center's performance was defined using the posterior probability (PP) of detecting a signal of a treatment effect. Only 60% of the centers were classified as informative. In these centers, the signal of treatment effect increased by approximately 80%. The signal detection approach appears to be a useful methodology to rank the performance of recruitment centers and to classify each center as informative or not in respect of detection of clinically relevant signals of efficacy. A further analysis indicated that a minimal sample of four subjects is required in order to predict the typical placebo response in each center. PMID- 18449186 TI - Trends in obesity and its distribution: data from the Northern Sweden MONICA Survey, 1986-2004. AB - OBJECTIVE: Obesity, especially abdominal, is a risk factor for many diseases. This study explored trends in the prevalence of general and abdominal obesity, 1986-2004, in northern Sweden. METHODS AND PROCEDURES: Cross-sectional population surveys were performed in 1986, 1990, 1994, 1999, and 2004; 250 men and 250 women aged 25-34, 35-44, 45-54, and 55-64 years (from 1994, also 65-74 years) were randomly selected; the overall participation rate was 77%. Anthropometric data were used. RESULTS: Weight and BMI increased in all men, most significantly in men aged 25-64 years (P<0.0005). Weight increased in women aged 25-64 years (P<0.005) and BMI in women aged 25-44 years (P<0.005). Prevalence of obesity (BMI>or=30) increased significantly in men aged 25-44 and 55-74 years (P<0.005; for men 65-74 years old, P<0.05) and in women aged 25-44 years (P<0.005). Waist circumference decreased significantly between 1986 and 1990 in all women (P<0.005) and in men aged 55-64 years (P<0.05). After 1990 waist circumference increased, most markedly so in women; by 2004 circumference measurements for women, and for men aged 55-64 years, were equal to those of 1986, while for men aged 25-54 years they were higher. Prevalence of abdominal obesity has increased since 1990, most markedly so in women aged 45-64 years (P<0.0005). DISCUSSION: The rapid increase in both general and central obesity raises concern for the future; increasing abdominal obesity in women is particularly alarming. PMID- 18449187 TI - Maternal obesity: a problem for both mother and child. PMID- 18449188 TI - RNA toxicity is a component of ataxin-3 degeneration in Drosophila. AB - Polyglutamine (polyQ) diseases are a class of dominantly inherited neurodegenerative disorders caused by the expansion of a CAG repeat encoding glutamine within the coding region of the respective genes. The molecular and cellular pathways underlying polyQ-induced neurodegeneration are the focus of much research, and it is widely considered that toxic activities of the protein, resulting from the abnormally long polyQ tract, cause pathogenesis. Here we provide evidence for a pathogenic role of the CAG repeat RNA in polyQ toxicity using Drosophila. In a Drosophila screen for modifiers of polyQ degeneration induced by the spinocerebellar ataxia type 3 (SCA3) protein ataxin-3, we isolated an upregulation allele of muscleblind (mbl), a gene implicated in the RNA toxicity of CUG expansion diseases. Further analysis indicated that there may be a toxic role of the RNA in polyQ-induced degeneration. We tested the role of the RNA by altering the CAG repeat sequence to an interrupted CAACAG repeat within the polyQ-encoding region; this dramatically mitigated toxicity. In addition, expression of an untranslated CAG repeat of pathogenic length conferred neuronal degeneration. These studies reveal a role for the RNA in polyQ toxicity, highlighting common components in RNA-based and polyQ-protein-based trinucleotide repeat expansion diseases. PMID- 18449189 TI - The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. AB - Lysosomes are the stomachs of the cell-terminal organelles on the endocytic pathway where internalized macromolecules are degraded. Containing a wide range of hydrolytic enzymes, lysosomes depend on maintaining acidic luminal pH values for efficient function. Although acidification is mediated by a V-type proton ATPase, a parallel anion pathway is essential to allow bulk proton transport. The molecular identity of this anion transporter remains unknown. Recent results of knockout experiments raise the possibility that ClC-7, a member of the CLC family of anion channels and transporters, is a contributor to this pathway in an osteoclast lysosome-like compartment, with loss of ClC-7 function causing osteopetrosis. Several mammalian members of the CLC family have been characterized in detail; some (including ClC-0, ClC-1 and ClC-2) function as Cl- conducting ion channels, whereas others act as Cl-/H+antiporters (ClC-4 and ClC 5). However, previous attempts at heterologous expression of ClC-7 have failed to yield evidence of functional protein, so it is unclear whether ClC-7 has an important function in lysosomal biology, and also whether this protein functions as a Cl- channel, a Cl-/H+ antiporter, or as something else entirely. Here we directly demonstrate an anion transport pathway in lysosomes that has the defining characteristics of a CLC Cl-/H+ antiporter and show that this transporter is the predominant route for Cl- through the lysosomal membrane. Furthermore, knockdown of ClC-7 expression by short interfering RNA can essentially ablate this lysosomal Cl-/H+ antiport activity and can strongly diminish the ability of lysosomes to acidify in vivo, demonstrating that ClC-7 is a Cl-/H+ antiporter, that it constitutes the major Cl- permeability of lysosomes, and that it is important in lysosomal acidification. PMID- 18449190 TI - Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation. AB - Numerous post-translational modifications of histones have been described in organisms ranging from yeast to humans. Growing evidence for dynamic regulation of these modifications, position- and modification-specific protein interactions, and biochemical crosstalk between modifications has strengthened the 'histone code' hypothesis, in which histone modifications are integral to choreographing the expression of the genome. One such modification, ubiquitylation of histone H2B (uH2B) on lysine 120 (K120) in humans, and lysine 123 in yeast, has been correlated with enhanced methylation of lysine 79 (K79) of histone H3 (refs 5-8), by K79-specific methyltransferase Dot1 (KMT4). However, the specific function of uH2B in this crosstalk pathway is not understood. Here we demonstrate, using chemically ubiquitylated H2B, a direct stimulation of hDot1L-mediated intranucleosomal methylation of H3 K79. Two traceless orthogonal expressed protein ligation (EPL) reactions were used to ubiquitylate H2B site-specifically. This strategy, using a photolytic ligation auxiliary and a desulphurization reaction, should be generally applicable to the chemical ubiquitylation of other proteins. Reconstitution of our uH2B into chemically defined nucleosomes, followed by biochemical analysis, revealed that uH2B directly activates methylation of H3 K79 by hDot1L. This effect is mediated through the catalytic domain of hDot1L, most likely through allosteric mechanisms. Furthermore, asymmetric incorporation of uH2B into dinucleosomes showed that the enhancement of methylation was limited to nucleosomes bearing uH2B. This work demonstrates a direct biochemical crosstalk between two modifications on separate histone proteins within a nucleosome. PMID- 18449191 TI - A novel route for ATP acquisition by the remnant mitochondria of Encephalitozoon cuniculi. AB - Mitochondria use transport proteins of the eukaryotic mitochondrial carrier family (MCF) to mediate the exchange of diverse substrates, including ATP, with the host cell cytosol. According to classical endosymbiosis theory, insertion of a host-nuclear-encoded MCF transporter into the protomitochondrion was the key step that allowed the host cell to harvest ATP from the enslaved endosymbiont. Notably the genome of the microsporidian Encephalitozoon cuniculi has lost all of its genes for MCF proteins. This raises the question of how the recently discovered microsporidian remnant mitochondrion, called a mitosome, acquires ATP to support protein import and other predicted ATP-dependent activities. The E. cuniculi genome does contain four genes for an unrelated type of nucleotide transporter used by plastids and bacterial intracellular parasites, such as Rickettsia and Chlamydia, to import ATP from the cytosol of their eukaryotic host cells. The inference is that E. cuniculi also uses these proteins to steal ATP from its eukaryotic host to sustain its lifestyle as an obligate intracellular parasite. Here we show that, consistent with this hypothesis, all four E. cuniculi transporters can transport ATP, and three of them are expressed on the surface of the parasite when it is living inside host cells. The fourth transporter co-locates with mitochondrial Hsp70 to the E. cuniculi mitosome. Thus, uniquely among eukaryotes, the traditional relationship between mitochondrion and host has been subverted in E. cuniculi, by reductive evolution and analogous gene replacement. Instead of the mitosome providing the parasite cytosol with ATP, the parasite cytosol now seems to provide ATP for the organelle. PMID- 18449192 TI - 3.88 A structure of cytoplasmic polyhedrosis virus by cryo-electron microscopy. AB - Cytoplasmic polyhedrosis virus (CPV) is unique within the Reoviridae family in having a turreted single-layer capsid contained within polyhedrin inclusion bodies, yet being fully capable of cell entry and endogenous RNA transcription. Biochemical data have shown that the amino-terminal 79 residues of the CPV turret protein (TP) is sufficient to bring CPV or engineered proteins into the polyhedrin matrix for micro-encapsulation. Here we report the three-dimensional structure of CPV at 3.88 A resolution using single-particle cryo-electron microscopy. Our map clearly shows the turns and deep grooves of alpha-helices, the strand separation in beta-sheets, and densities for loops and many bulky side chains; thus permitting atomic model-building effort from cryo-electron microscopy maps. We observed a helix-to-beta-hairpin conformational change between the two conformational states of the capsid shell protein in the region directly interacting with genomic RNA. We have also discovered a messenger RNA release hole coupled with the mRNA capping machinery unique to CPV. Furthermore, we have identified the polyhedrin-binding domain, a structure that has potential in nanobiotechnology applications. PMID- 18449193 TI - Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. AB - Phosphoinositide 3-kinases (PI3Ks) signal downstream of multiple cell-surface receptor types. Class IA PI3K isoforms couple to tyrosine kinases and consist of a p110 catalytic subunit (p110alpha, p110beta or p110delta), constitutively bound to one of five distinct p85 regulatory subunits. PI3Ks have been implicated in angiogenesis, but little is known about potential selectivity among the PI3K isoforms and their mechanism of action in endothelial cells during angiogenesis in vivo. Here we show that only p110alpha activity is essential for vascular development. Ubiquitous or endothelial cell-specific inactivation of p110alpha led to embryonic lethality at mid-gestation because of severe defects in angiogenic sprouting and vascular remodelling. p110alpha exerts this critical endothelial cell-autonomous function by regulating endothelial cell migration through the small GTPase RhoA. p110alpha activity is particularly high in endothelial cells and preferentially induced by tyrosine kinase ligands (such as vascular endothelial growth factor (VEGF)-A). In contrast, p110beta in endothelial cells signals downstream of G-protein-coupled receptor (GPCR) ligands such as SDF-1alpha, whereas p110delta is expressed at low level and contributes only minimally to PI3K activity in endothelial cells. These results provide the first in vivo evidence for p110-isoform selectivity in endothelial PI3K signalling during angiogenesis. PMID- 18449194 TI - Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. AB - Pre-existing neutralizing antibody provides the first line of defence against pathogens in general. For influenza virus, annual vaccinations are given to maintain protective levels of antibody against the currently circulating strains. Here we report that after booster vaccination there was a rapid and robust influenza-specific IgG+ antibody-secreting plasma cell (ASC) response that peaked at approximately day 7 and accounted for up to 6% of peripheral blood B cells. These ASCs could be distinguished from influenza-specific IgG+ memory B cells that peaked 14-21 days after vaccination and averaged 1% of all B cells. Importantly, as much as 80% of ASCs purified at the peak of the response were influenza specific. This ASC response was characterized by a highly restricted B cell receptor (BCR) repertoire that in some donors was dominated by only a few B cell clones. This pauci-clonal response, however, showed extensive intraclonal diversification from accumulated somatic mutations. We used the immunoglobulin variable regions isolated from sorted single ASCs to produce over 50 human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains with high affinity. This strategy demonstrates that we can generate multiple high affinity mAbs from humans within a month after vaccination. The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine. However, we found that most of the influenza virus-specific mAbs showed the highest affinity for the current vaccine strain. Thus, OAS does not seem to be a common occurrence in normal, healthy adults receiving influenza vaccination. PMID- 18449195 TI - Single-stranded DNA-binding protein hSSB1 is critical for genomic stability. AB - Single-strand DNA (ssDNA)-binding proteins (SSBs) are ubiquitous and essential for a wide variety of DNA metabolic processes, including DNA replication, recombination, DNA damage detection and repair. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating nucleases, helicases and strand-exchange proteins, activating transcription and mediating protein-protein interactions. In eukaryotes, the major SSB, replication protein A (RPA), is a heterotrimer. Here we describe a second human SSB (hSSB1), with a domain organization closer to the archaeal SSB than to RPA. Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. Upon induction of DNA damage, hSSB1 accumulates in the nucleus and forms distinct foci independent of cell-cycle phase. These foci co localize with other known repair proteins. In contrast to RPA, hSSB1 does not localize to replication foci in S-phase cells and hSSB1 deficiency does not influence S-phase progression. Depletion of hSSB1 abrogates the cellular response to DSBs, including activation of ATM and phosphorylation of ATM targets after ionizing radiation. Cells deficient in hSSB1 exhibit increased radiosensitivity, defective checkpoint activation and enhanced genomic instability coupled with a diminished capacity for DNA repair. These findings establish that hSSB1 influences diverse endpoints in the cellular DNA damage response. PMID- 18449197 TI - Chemical compass model of avian magnetoreception. AB - Approximately 50 species, including birds, mammals, reptiles, amphibians, fish, crustaceans and insects, are known to use the Earth's magnetic field for orientation and navigation. Birds in particular have been intensively studied, but the biophysical mechanisms that underlie the avian magnetic compass are still poorly understood. One proposal, based on magnetically sensitive free radical reactions, is gaining support despite the fact that no chemical reaction in vitro has been shown to respond to magnetic fields as weak as the Earth's ( approximately 50 muT) or to be sensitive to the direction of such a field. Here we use spectroscopic observation of a carotenoid-porphyrin-fullerene model system to demonstrate that the lifetime of a photochemically formed radical pair is changed by application of < or =50 microT magnetic fields, and to measure the anisotropic chemical response that is essential for its operation as a chemical compass sensor. These experiments establish the feasibility of chemical magnetoreception and give insight into the structural and dynamic design features required for optimal detection of the direction of the Earth's magnetic field. PMID- 18449196 TI - Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. AB - Half a century ago, the apical ectodermal ridge (AER) at the distal tip of the tetrapod limb bud was shown to produce signals necessary for development along the proximal-distal (P-D) axis, but how these signals influence limb patterning is still much debated. Fibroblast growth factor (FGF) gene family members are key AER-derived signals, with Fgf4, Fgf8, Fgf9 and Fgf17 expressed specifically in the mouse AER. Here we demonstrate that mouse limbs lacking Fgf4, Fgf9 and Fgf17 have normal skeletal pattern, indicating that Fgf8 is sufficient among AER-FGFs to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype; however, when we also removed different combinations of the other AER-FGF genes, we obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate P-D-patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the long-standing hypothesis that AER-FGF signalling is permissive rather than instructive for limb patterning. We discuss how a two-signal model for P-D patterning can be integrated with the concept of early specification to explain the genetic data presented here. PMID- 18449199 TI - IL12B polymorphisms are linked but not associated with Plasmodium falciparum parasitemia: a familial study in Burkina Faso. AB - Chromosome 5q31-q33 has been linked to Plasmodium falciparum parasitemia in several independent studies. This chromosomal region contains numerous immunoregulatory genes. Among these, IL12B that encodes the p40 subunit of interleukin-12 (IL-12) appeared to be a promising functional candidate gene, and IL12Bpro, a promoter polymorphism, was associated with mortality from severe malaria in children. In this study, we characterized genetic variation in IL12B in 215 individuals belonging to 34 families and evaluated linkage and association of parasitemia with IL12B polymorphisms and haplotypes. We searched for IL12B polymorphisms in the coding regions and the corresponding intron-exon borders. We also examined IL12Bpro and IL12B 3'untranslated region (UTR) polymorphisms, which are thought to influence the production of IL-12. We showed a high level of conservation of IL12B-coding regions and identified five polymorphisms in introns and the two polymorphisms in the promoter and the 3'UTR regions. Although IL12B polymorphisms were linked to parasitemia, there was association of parasitemia with neither polymorphisms nor haplotypes. We cannot exclude that an unknown IL12B cis-regulatory element polymorphism affects both IL-12 production and parasitemia. However, our results suggest that genetic variation in IL12B does not explain differences in parasitemia in individuals living in an endemic area. PMID- 18449200 TI - Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves' disease. AB - Graves' disease (GD) and Hashimoto's thyroiditis (HT) represent the commonest forms of autoimmune thyroid disease (AITD) each presenting with distinct clinical features. Progress has been made in determining association of HLA class II DRB1, DQB1 and DQA1 loci with GD demonstrating a predisposing effect for DR3 (DRB1(*)03 DQB1(*)02-DQA1(*)05) and a protective effect for DR7 (DRB1(*)07-DQB1(*)02 DQA1(*)02). Small data sets have hindered progress in determining HLA class II associations with HT. The aim of this study was to investigate DRB1-DQB1-DQA1 in the largest UK Caucasian HT case control cohort to date comprising 640 HT patients and 621 controls. A strong association between HT and DR4 (DRB1(*)04 DQB1(*)03-DQA1(*)03) was detected (P=6.79 x 10(-7), OR=1.98 (95% CI=1.51-2.59)); however, only borderline association of DR3 was found (P=0.050). Protective effects were also detected for DR13 (DRB1(*)13-DQB1(*)06-DQA1(*)01) (P=0.001, OR=0.61 (95% CI=0.45-0.83)) and DR7 (P=0.013, OR=0.70 (95% CI=0.53-0.93)). Analysis of our unique cohort of subjects with well characterized AITD has demonstrated clear differences in association within the HLA class II region between HT and GD. Although HT and GD share a number of common genetic markers this study supports the suggestion that differences in HLA class II genotype may, in part, contribute to the different immunopathological processes and clinical presentation of these related diseases. PMID- 18449201 TI - High plasma aldosterone and low renin predict blood pressure increase and hypertension in middle-aged Caucasian populations. AB - Plasma aldosterone and renin levels have been associated with blood pressure increase and 3-4 year incidence of hypertension in a middle-aged North American community in Framingham. To confirm these findings in a different population, a nested case-control study was performed in a national sample of 1984 French non hypertensive volunteers aged 45-64 year and followed for 5 years. Cases and controls (individuals becoming hypertensive or remaining non-hypertensive on follow-up) were individually matched on sex, diastolic and systolic pressures at baseline. Multivariable regression models show that plasma aldosterone and renin are respectively positively and negatively associated with the increase in systolic pressure (P=0.01 and 0.001) and the risk of hypertension (22% increase and 16% decrease per s.d. increment in the log, P=0.04 and 0.07). These associations are mostly observed in the lowest tertiles of dietary sodium and potassium intakes where plasma aldosterone is positively associated with the increase in systolic pressure (P=0.01 and 0.08) and the risk of hypertension (59 and 69% increase per s.d. increment in the log, P=0.02 and 0.01), whereas plasma renin is negatively associated with the increase in systolic pressure (P=0.0004 and 0.004) and the risk of hypertension (31 and 28% decrease per s.d. increment in the log, P=0.03 and 0.05). These results reinforce the hypothesis that high plasma aldosterone and low plasma renin levels precede blood pressure increase and the occurrence of hypertension in middle-aged Caucasian populations. PMID- 18449202 TI - Genomic typing for patient-specific human leukocyte antigen-alleles is an efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell transplantation from alternative donors. PMID- 18449203 TI - In-vivo detectable antibodies directed against the oncofetal antigen/immature laminin receptor can recognize and control myeloma cells--clinical implications. PMID- 18449205 TI - Successful treatment of multicentric Castleman's disease with combined immunochemotherapy in an AIDS patient with multiorgan failure. PMID- 18449204 TI - Telomerase inhibitor GRN163L inhibits myeloma cell growth in vitro and in vivo. AB - Human telomerase, the reverse transcriptase which extends the life span of a cell by adding telomeric repeats to chromosome ends, is expressed in most cancer cells but not in the majority of normal somatic cells. Inhibition of telomerase therefore holds great promise as anticancer therapy. We have synthesized a novel telomerase inhibitor GRN163L, a lipid-attached phosphoramidate oligonucleotide complementary to template region of the RNA subunit of telomerase. Here, we report that GRN163L is efficiently taken up by human myeloma cells without any need of transfection and is resistant to nucleolytic degradation. The exposure of myeloma cells to GRN163L led to an effective inhibition of telomerase activity, reduction of telomere length and apoptotic cell death after a lag period of 2-3 weeks. Mismatch control oligonucleotides had no effect on growth of myeloma cells. The in vivo efficacy of GRN163L was confirmed in two murine models of human multiple myeloma. In three independent experiments, significant reduction in tumor cell growth and better survival than control mice was observed. Furthermore, GRN163L-induced myeloma cell death could be significantly enhanced by Hsp90 inhibitor 17AAG. These data provide the preclinical rationale for clinical evaluation of GRN163L in myeloma and in combination with 17AAG. PMID- 18449206 TI - Corticosteroids in the prevention of graft-vs-host disease after allogeneic myeloablative stem cell transplantation: a systematic review and meta-analysis. PMID- 18449207 TI - The most frequent t(14;19)(q32;q13)-positive B-cell malignancy corresponds to an aggressive subgroup of atypical chronic lymphocytic leukemia. PMID- 18449208 TI - Aberrant expression of Notch1 interferes with the B-lymphoid phenotype of neoplastic B cells in classical Hodgkin lymphoma. AB - Plasticity of committed mouse B cells has been demonstrated by inactivation of the B-cell commitment transcription factor PAX5, resulting in loss of the B-cell phenotype and differentiation into various hematopoietic lineages. Furthermore, mature mouse B cells could be reprogrammed into macrophages by overexpression of myeloid-specific transcription factors. Here, we report that aberrant activity of the transmembrane receptor, Notch1, interferes with the B-lymphoid phenotype of mature human germinal center-derived B cells in Hodgkin lymphoma, so called Hodgkin and Reed-Sternberg cells. They have lost the B-cell phenotype despite their mature B-cell origin. Notch1 remodels the B-cell transcription factor network by antagonizing the key transcription factors E2A and early B-cell factor (EBF). Through this mechanism, B lineage-specific genes were suppressed and B lineage-inappropriate genes were induced. We provide evidence that absence of the Notch inhibitor Deltex1 contributes to deregulated Notch activity in Hodgkin and Reed-Sternberg cells. These data suggest that Notch activation interferes with dedifferentiation of neoplastic B cells in Hodgkin lymphoma. PMID- 18449209 TI - Skin pathology induced by snake venom metalloproteinase: acute damage, revascularization, and re-epithelization in a mouse ear model. AB - Viperid snakebite envenomation induces blistering and dermonecrosis. The pathological alterations induced by a snake venom metalloproteinase in the skin were investigated in a mouse ear model. Metalloproteinase BaP1, from Bothrops asper, induced rapid edema, hemorrhage, and blistering; the latter two effects were abrogated by preincubation with the metalloproteinase inhibitor batimastat. Neutrophils did not play a role in the pathology, as depletion of these cells resulted in a similar histological picture. Blisters are likely to result from the direct proteolytic activity of BaP1 of proteins at the dermal-epidermal junction, probably at the lamina lucida, as revealed by immunostaining for type IV collagen and laminin. Widespread apoptosis of keratinocytes was detected by the TUNEL assay, whereas no apoptosis of capillary endothelial cells was observed. BaP1 induced a drastic reduction in the microvessel density, revealed by immunostaining for the endothelial marker vascular endothelial growth factor receptor-2. This was followed by a rapid angiogenic response, leading to a partial revascularization. Skin damage was followed by inflammation and granulation tissue formation. Then, a successful re-epithelization process occurred, and the skin of the ear regained its normal structure by 2 weeks. Venom metalloproteinase-induced skin damage reproduces the pathological changes described in snakebitten patients. PMID- 18449210 TI - Infrared radiation-induced matrix metalloproteinase in human skin: implications for protection. AB - Human skin is exposed to infrared radiation (IR) from natural and artificial sources. In previous studies, near IR radiation (IRA; 760-1,440 nm) was shown to elicit a retrograde mitochondrial signaling response leading to induction of matrix metalloproteinase-1 (MMP-1) expression. These studies, however, have exclusively employed cultured human skin fibroblasts ex vivo. Here, we have assessed the in vivo relevance of these observations by exposing healthy human skin in vivo to physiologically relevant doses of IRA. Eighty percent of the tested individuals responded to IRA radiation by upregulating of MMP-1 expression. Specifically, IRA irradiation caused increased expression of MMP-1 in the dermis, but not in the epidermis. Raman spectroscopy revealed that IRA radiation also caused a significant decrease in the antioxidant content of human skin. In vitro studies had previously shown that IRA-induced MMP-1 expression was mediated through an oxidative stress response, which originates from the mitochondrial electron transport chain. We now report that incubation of cultured human dermal fibroblasts or treatment of human skin with specific antioxidants prevented IRA radiation-induced MMP-1 expression in vitro and in vivo. Thus, IRA irradiation most likely promotes premature skin aging and topical application of appropriate antioxidants represents an effective photoprotective strategy. PMID- 18449211 TI - Fibroblast dysfunction is a key factor in the non-healing of chronic venous leg ulcers. AB - Chronic age-related degenerative disorders, including the formation of chronic leg wounds, may occur due to aging of the stromal tissues and ensuing dysfunctional cellular responses. This study investigated the impact of environmental-driven cellular aging on wound healing by conducting a comprehensive analysis of chronic wound fibroblast (CWF) behavior in comparison with patient-matched healthy skin normal fibroblasts (NF). The dysfunctional wound healing abilities of CWF correlated with a significantly reduced proliferative life span and early onset of senescence compared with NF. However, pair-wise comparisons of telomere dynamics between NF and CWF indicated that the induction of senescence in CWF was telomere-independent. Microarray and functional analysis suggested that CWFs have a decreased ability to withstand oxidative stress, which may explain why these cells prematurely senescence. Microarray analysis revealed lower expression levels of several CXC chemokine genes (CXCL-1, -2, -3, -5, -6, -12) in CWF compared with NF (confirmed by ELISA). Functionally, this was related to impaired neutrophil chemotaxis in response to CWF-conditioned medium. Although the persistence of non-healing wounds is, in part, due to prolonged chronic inflammation and bacterial infection, our investigations show that premature fibroblast aging and an inability to correctly express a stromal address code are also implicated in the disease chronicity. PMID- 18449212 TI - Regulated osteopontin expression by dendritic cells decisively affects their migratory capacity. PMID- 18449213 TI - Traffic-related air pollution, climate, and prevalence of eczema in Taiwanese school children. AB - The prevalence of childhood eczema is increasing in many countries. Epidemiological studies, however, say little of its association to outdoor air pollution and climate factors. We conducted a nationwide survey of middle-school students in Taiwan from 1995 to 1996. The 12-month prevalence of eczema was compared with air monitoring station data of temperature, relative humidity, and criteria air pollutants. A total of 317,926 children attended schools located within 2 km of 55 stations. Prevalence rates of recurrent eczema were 2.4 and 2.3% in boys and girls, respectively, with prevalence rates of flexural eczema 1.7% in both sexes. After adjustment for possible confounders, flexural eczema was found to be associated with traffic-related air pollutants, including nitrogen oxides and carbon monoxide. Recurrent eczema was associated with traffic related air pollution only in girls. There were no associations for the highest monthly means of temperature, whereas the annual means and the lowest monthly means of temperature were negatively related to flexural eczema, but only in girls. The lowest monthly mean relative humidity was positively related to eczema. The results suggest that air pollution and climatic factors, which showed stronger associations in girls than boys, may affect the prevalence of childhood eczema. PMID- 18449214 TI - Effect of corneodesmosome degradation on the intercellular delamination of human stratum corneum. PMID- 18449215 TI - Oxidative stress-inducible lentiviral vectors for gene therapy. AB - Oxidative stress is important in several pathologies, including cardiovascular diseases such as atherosclerosis and cardiac ischemia-reperfusion injury. An important mechanism for adaptation to oxidative stress is induction of genes through the antioxidant response element (ARE), which regulates the expression of antioxidant and cytoprotective genes via the transcription factor Nrf2 (nuclear factor E2-related factor 2). As Nrf2-regulated genes are induced during oxidant stress occurring, for example, in reperfusion after ischemia, we took a novel approach to exploit ARE for the development of oxidative stress-inducible gene therapy vectors. To this end, one, two or three ARE-containing regions from human NAD(P)H:quinone oxidoreductase-1, glutamate-cysteine ligase modifier subunit and mouse heme oxygenase-1 were cloned into a vector expressing luciferase under a minimal SV40 promoter. The construct, which was the most responsive to ARE inducing agents, was chosen for further studies in which a lentiviral vector was produced for an efficient transfer to endothelial cells. Heme oxygenase-1 (HO-1), which has well-characterized anti-inflammatory properties, was used as the therapeutic transgene. In human endothelial cells, ARE-driven HO-1 overexpression inhibited nuclear factor-kappaB activation and subsequent vascular cell adhesion molecule-1 expression induced by tumor necrosis factor-alpha. We conclude that the ARE element is a promising alternative for the development of oxidative stress-inducible gene therapy vectors. PMID- 18449217 TI - Community proteogenomics highlights microbial strain-variant protein expression within activated sludge performing enhanced biological phosphorus removal. AB - Enhanced biological phosphorus removal (EBPR) selects for polyphosphate accumulating microorganisms to achieve phosphate removal from wastewater. We used high-resolution community proteomics to identify key metabolic pathways in 'Candidatus Accumulibacter phosphatis' (A. phosphatis)-mediated EBPR and to evaluate the contributions of co-existing strains within the dominant population. Overall, 702 proteins from the A. phosphatis population were identified. Results highlight the importance of denitrification, fatty acid cycling and the glyoxylate bypass in EBPR. Strong similarity in protein profiles under anaerobic and aerobic conditions was uncovered (only 3% of A. phosphatis-associated proteins exhibited statistically significant abundance differences). By comprehensive genome-wide alignment of 13,930 orthologous proteins, we uncovered substantial differences in protein abundance for enzyme variants involved in both core-metabolism and EBPR-specific pathways among the A. phosphatis population. These findings suggest an essential role for genetic diversity in maintaining the stable performance of EBPR systems and, hence, demonstrate the power of integrated cultivation-independent genomics and proteomics for the analysis of complex biotechnological systems. PMID- 18449216 TI - Efficient entry inhibition of human and nonhuman primate immunodeficiency virus by cell surface-expressed gp41-derived peptides. AB - Membrane-anchored C-peptides (for example, maC46) derived from human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41 effectively inhibit HIV-1 entry in cell lines and primary human CD4+ cells in vitro. Here we evaluated this gene therapy approach in animal models of AIDS. We adapted the HIV gp41-derived maC46 vector construct for use in rhesus monkeys. Simian immunodeficiency virus (SIV and SHIV) sequence-adapted maC46 peptides, and the original HIV-1-derived maC46 expressed on the surface of established cell lines blocked entry of HIV-1, SIVmac251 and SHIV89.6P. Furthermore, primary rhesus monkey CD4+ T cells expressing HIV sequence-based maC46 peptides were also protected from SIV entry. Depletion of CD8+ T cells from PBMCs enhanced the yield of maC46-transduced CD4+ T cells. Supplementation with interleukin-2 (IL-2) increased transduction efficiency, whereas IL-7 and/or IL-15 provided no additional benefit. Phenotypic analysis showed that maC46-transduced and expanded cells were predominantly central memory CD4+ T cells that expressed low levels of CCR5 and slightly elevated levels of CD62L, beta7-integrin and CXCR4. These findings show that maC46-based cell surface-expressed peptides can efficiently inhibit primate immunodeficiency virus infection, and therefore serve as the basis for evaluation of this gene therapy approach in an animal model for AIDS. PMID- 18449219 TI - Evaluation of three polymerase chain reaction techniques for detection of Brucella DNA in peripheral human blood. AB - Brucellosis is a widespread zoonosis. Currently the diagnosis of this zoonosis is based on microbiological and serological laboratory tests. Polymerase chain reaction (PCR) has been used to detect DNA from Brucella. Different target genes, primer pairs, PCR techniques, and extraction procedures have previously been published for Brucella detection. But only a few of these primers have been used in human samples, and only one study has been carried out to compare sensitivity between them. In the present study, 3 sets of primers and 3 different PCR protocols amplifying 3 different regions of the Brucella genome were compared for detection of Brucella DNA in a peripheral-blood PCR assay to conclude which is most suitable for the clinical diagnostic laboratory. These 3 pairs of primers amplify 3 different fragments included in (i) a gene encoding a 31 kDa Brucella abortus antigen (B4/B5), (ii) a sequence 16S rRNA of B. abortus (F4/R2), and (iii) a gene encoding an outer membrane protein (omp-2) (JPF/JPR). Some modifications on the reported techniques were applied during the present work to improve the outcome. The results showed that the B4/B5 primer pair had the highest sensitivity for detection of positive samples (98%), the JPF/JPR primer pair detected 88.4% of positive samples, whereas F4/R2 primer pair was the least sensitive, being able to detect only 53.1% of positive samples. The specificity of the 3 techniques was 100%. The B4/B5 primer pair was also able to detect the smallest number of bacteria (700 cfu/mL), whereas JPF/JPR was able to detect 7 x 105 cfu/mL and F4/R2 was able to detect 7 x 107 cfu/mL. It is thus concluded that using the B4/B5 primer PCR with the suggested modifications is a robust assay, which meets the sensitivity requirements to be used for testing of human blood samples for brucellosis in the diagnostic laboratory. PMID- 18449218 TI - Characterization of putative membrane protein genes of the 'Candidatus Phytoplasma asteris', chrysanthemum yellows isolate. AB - To characterize potentially important surface-exposed proteins of the phytoplasma causing chrysanthemum yellows (CY), new primers were designed based on the conserved regions of 3 membrane protein genes of the completely sequenced onion yellows and aster yellows witches' broom phytoplasmas and were used to amplify CY DNA. The CY genes secY, amp, and artI, encoding the protein translocase subunit SecY, the antigenic membrane protein Amp and the arginine transporter ArtI, respectively, were cloned and completely sequenced. Alignment of CY-specific secY sequences with the corresponding genes of other phytoplasmas confirmed the 16S rDNA-based classification, while amp sequences were highly variable within the 'Candidatus Phytoplasma asteris'. Five CY partial sequences were cloned into the pRSetC expression vector, and 3 of the encoded protein fragments (Amp 64/651, Amp 64/224, ArtI 131/512) were expressed as fusion antigens for the production of CY specific polyclonal antibodies (A416 against Amp 64/224; A407 against ArtI 131/512). A416 recognized, in Western blots, the full-length Amp from CY-infected plants (periwinkle, daisy) and insect vectors (Euscelidius variegatus, Macrosteles quadripunctulatus). A416 also reacted to European aster yellows, to primula yellows phytoplasmas, to northern Italian strains of 'Ca. Phytoplasma asteris' from lettuce and gladiolus, but it did not react to American aster yellows phytoplasma. PMID- 18449221 TI - Evaluation of two wild types of Pleurotus ostreatus (MCC07 and MCC20) isolated from nature for their ability to decolorize Benazol Black ZN textile dye in comparison to some commercial types of white rot fungi: Pleurotus ostreatus, Pleurotus djamor, and Pleurotus citrinopileatus. AB - Biological decolorization of Benazol Black ZN, a reactive azo-type textile dyestuff, was comparatively studied using 3 different commercial-type white rot fungi strains (Pleurotus ostreatus, Pleurotus cornucopiae var. citrinopileatus, Pleurotus djamor, and 2 wild types of P. ostreatus (MCC07 and MCC20) isolated from the nature. The initial dye concentrations in the medium were 500 and 1000 mg.L-1. All the organisms studied decolorized Benazol Black ZN to varying degrees. At low dye concentration, both commercial and wild type of P. ostreatus resulted in the best decolorization, conversely, wild-type P. ostreatus (MCC07) was found to be much more robust against increasing dye concentration and provided the best decolorization efficiency at high dye concentration. PMID- 18449220 TI - Seasonal variation in communities of ammonia-oxidizing bacteria based on polymerase chain reaction - denaturing gradient gel electrophoresis in a biofilm reactor for drinking water pretreatment. AB - The diversity and variation of total and active ammonia-oxidizing bacteria in a full-scale aerated submerged biofilm reactor for drinking water pretreatment were characterized by clone libraries and denaturing gradient gel electrophoresis (DGGE) analysis of 16S rRNA and its gene during a whole year. Sequences obtained from clone libraries affiliated with the Nitrosomonas oligotropha lineage and the Nitrosomonas communis lineage. An uncultured subgroup of Nitrosomonas communis lineage was also detected. Seasonal variations in both total and active ammonia oxidizing bacteria communities were observed in the DGGE profiles, but an RNA based analysis reflected more obvious dynamic changes in ammonia-oxidizer community than a DNA-based approach. Statistical study based on canonical correspondence analysis showed that a community shift of active ammonia oxidizers was significantly influenced by temperature and pH, but no significant correlation was found between environmental variables and total ammonia-oxidizer community shift. PMID- 18449222 TI - Aspergillus flavus aflatoxin occurrence and expression of aflatoxin biosynthesis genes in soil. AB - The carcinogen aflatoxin B1 (AFB1) produced by Aspergillus flavus is a major food safety concern in crops. However, information on AFB1 occurrence in soil and crop residue is scarce. A series of experiments investigated the occurrence of AFB1 in soil and corn residues and ascertained the ecology of A. flavus in a Dundee silt loam soil. Samples of untilled soil (0-2 cm) and residues were collected in March 2007 from plots previously planted with a corn isoline containing the Bacillus thuringiensis (Bt) endotoxin gene or the parental non-Bt isoline. AFB1 levels were significantly different in various corn residues. The highest AFB1 levels were observed in cobs containing grain, with 145 and 275 ng.g-1 in Bt and non-Bt, respectively (P > or = F = 0.001). Aflatoxin levels averaged 3.3 and 9.6 ng.g-1 in leaves and (or) stalks and cobs without grain, respectively. All soils had AFB1 ranging from 0.6 to 5.5 ng.g-1 with similar levels in plots from Bt and non Bt corn. Based on cultural methods, soil contained from log10 3.1 to 4.5 A. flavus cfu.g-1 with about 60% of isolates producing aflatoxin. Laboratory experiments demonstrated that AFB1 is rapidly degraded in soil at 28 degrees C (half-life < or = 5 days). The potential of the soil A. flavus to produce aflatoxins was confirmed by molecular methods. Transcription of 5 aflatoxin biosynthesis genes, including aflD, aflG, aflP, aflR, and aflS, were detected by reverse transcription - polymerase chain reaction analysis in soil. Although AFB1 appears to be transient in soils, it is clear that AFB1 is produced in surface soil in the presence of corn residues, as indicated by A. flavus cfu levels, AFB1 detection, and expression of aflatoxin biosynthetic genes. PMID- 18449223 TI - Characterization of formulated microbial products by denaturing gradient gel electrophoresis, total cellular fatty acid analysis, and DNA microarray analysis. AB - Two commercial products, Biotize and Cycle, containing bacteria as an active ingredient were characterized for species identification and batch-to-batch variation by denaturing gradient gel electrophoresis (DGGE), total cellular fatty acid analysis (FAA), and a taxonomic DNA microarray. DGGE was useful at assessing the stability of consortia in different batches, and cluster analysis differentiated each batch even when only slight differences in species composition were observed. DGGE, FAA, and DNA microarray results indicated little batch-to-batch variation in Biotize and some batch variation in Cycle. The 3 methods agreed well with species identification in Biotize but generated conflicting results in the species composition of Cycle. This multi-method approach was useful in determining if the observed bacterial species present in the products matched the expected species composition. PMID- 18449224 TI - Safety evaluation of two bacterial strains used in Asian probiotic products. AB - Probiotics, known for their prophylactic and therapeutic properties, are routinely used by the medical community in various regions of the world. In some Asian countries, these products are controlled as pharmaceutical substances and must adhere to strict regulatory guidelines. However, outside of Europe where the European Food Safety Authority has recently adopted a Qualified Presumption of Safety approach for probiotics used in food and feed, current safety requirements do not necessitate screening for the presence of virulence and other risk factors, which may result in the inadvertent use of probiotic strains harboring harmful genes. A safety evaluation was conducted on Enterococcus faecium R0026 and Bacillus subtilis R0179 used in several commercial probiotic products marketed in Asia. Molecular techniques were used to verify the identity of each strain and antibiotic resistance profiles were determined towards clinically relevant antibiotics. Strains were subsequently screened for the presence of enterotoxins and virulence factors and were subjected to 28 days of repeated high dose oral toxicity testing in rats. No risk factors or aberrant activities were identified using such a detailed approach. Thus, both microbes were deemed to pose low risk to the consumer and, therefore, safe for use as probiotics. PMID- 18449225 TI - Flavonoid-responsive nodY-lacZ expression in three phylogenetically different Bradyrhizobium groups. AB - Previously, restriction fragment length polymorphism analysis using the nodD1YABC gene probe showed the genetic diversity of common nodD1ABC gene regions of Bradyrhizobium japonicum, Bradyrhizobium elkanii, and the Thai soybean Bradyrhizobium. The nodD1 sequences of representative strains of the 3 groups differed phylogenetically, suggesting that responses of NodD1 proteins of the 3 Bradyrhizobium groups to diverse flavonoids may differ. To confirm this hypothesis, 6 representative strains were chosen from the 3 Bradyrhizobium groups. Six reporter strains were constructed, all carrying the pZB32 plasmid, which contains a nod box and the nodY-lacZ fusion of B. japonicum USDA 110. Differences in nodY-lacZ expression among the strains in response to 37 flavonoid compounds at various concentrations were evaluated. Of those compounds, prunetin (4',5-dihydroxy-7-methoxyisoflavone) and esculetin (6,7-dihydroxycoumarin) were identified as Bradyrhizobium group-specific nod gene inducers. Esculetin showed nod gene induction activities unique to Thai Bradyrhizobium strains. The levels of nodY-lacZ induction among B. japonicum and Thai Bradyrhizobium strains increased with increasing concentration of prunetin, whereas, those in B. elkanii strains did not. PMID- 18449226 TI - Characterization of the Serratia marcescens SdeCDE multidrug efflux pump studied via gene knockout mutagenesis. AB - Serratia marcescens is an important nosocomial agent having high antibiotic resistance. A major mechanism for S. marcescens antibiotic resistance is active efflux. To ascertain the substrate specificity of the S. marcescens SdeCDE efflux pump, we constructed pump gene deletion mutants. sdeCDE knockout strains showed no change in antibiotic susceptibility in comparison with the parental strains for any of the substrates, with the exception of novobiocin. In addition, novobiocin was the only antibiotic to be accumulated by sdeCDE-deficient strains. Based on the substrates used in our study, we conclude that SdeCDE is a Resistance-Nodulation-Cell Division family pump with limited substrate specificity. PMID- 18449227 TI - Characterization of plant growth-promoting Bacillus edaphicus NBT and its effect on lead uptake by Indian mustard in a lead-amended soil. AB - The plant growth promotion characteristics of a heavy-metal-resistant strain of Bacillus edaphicus NBT was characterized. The strain was also evaluated for promoting plant growth and lead (Pb) uptake of Brassica juncea L. Czern (Indian mustard) in soil artificially contaminated with 0, 400, and 800 mg Pb.kg-1 soil. Atomic absorption spectrometer analysis demonstrated that strain NBT could release water-soluble Pb from lead carbonate in the solution. Strain NBT had the capacity to produce indole acetic acid, siderophores, and 1-aminocyclopropane-1 carboxylate deaminase. Low and high Pb treatments significantly decreased the growth of Indian mustard. Inoculation with strain NBT was found to increase root dry mass (ranging from 16% to 22%) and above-ground tissue dry mass (ranging from 24% to 30%) of Indian mustard in the Pb-amended soil. Strain NBT was able to mobilize Pb efficiently in plants in Pb-amended soil. In the soil treated with 400 and 800 mg Pb.kg-1 soil, the increase in Pb uptake varied from 18% to 46% in live bacterium-inoculated Indian mustard plants compared with dead bacterium inoculated control. The strain was also able to colonize and develop in the rhizosphere soil of Indian mustard after root inoculation. PMID- 18449228 TI - Heat stability of chaetoglobosins A and C. AB - Chaetomium globosum is commonly found in water-damaged buildings and produces the mycotoxins chaetoglobosin A and chaetoglobosin C (Ch-A and Ch-C, respectively). While attempting to purify Ch-A and Ch-C, we observed that these mycotoxins were broken down after heating. The objective of this study was to determine the temperature and the amount of time necessary to break down Ch-A and Ch-C. We demonstrated that the amounts of Ch-A were significantly reduced when exposed to 75 degrees C for 24 h and 100 degrees C for 90, 120, or 150 min. Under the same conditions, the levels of Ch-C were also lower (although not significantly). At 175 degrees C, no Ch-A was detected after 15 min and Ch-C was significantly reduced after 30 min. Our findings will aid other researchers who work with these mycotoxins in the future. PMID- 18449229 TI - Narrowband multichannel filters and integrated optical filter arrays. AB - We propose and demonstrate three approaches to achieve narrowband multichannel filters. These are multiple heterostructures with defects, guided-mode resonance (GMR) Brewster filters with multiple channels, and integrated narrow bandpass filter arrays. Transmission studies for multiple heterostructures with defects are presented. We show that the enlargement of the forbidden band and multiple channel filtering can be reached simultaneously with these configurations. GMR Brewster filters with multiple channels can be obtained with a single-layer grating. The same properties can be obtained by use of double-layer structures that consist of a homogeneous layer and a grating with equal refractive index. We developed a combinatorial etching technique that has 32 elements on a single substrate with which to fabricate integrated narrow bandpass filters. Single- and double-chamber integrated optical filter arrays were fabricated by use of this etching technique. These narrowband multichannel filters and narrow bandpass filter arrays show good filtering features and can be utilized in many optical applications. PMID- 18449230 TI - Laser damage resistance of hafnia thin films deposited by electron beam deposition, reactive low voltage ion plating, and dual ion beam sputtering. AB - A comparative study is made of the laser damage resistance of hafnia coatings deposited on fused silica substrates with different technologies: electron beam deposition (from Hf or HfO(2) starting material), reactive low voltage ion plating, and dual ion beam sputtering. The laser damage thresholds of these coatings are determined at 1064 and 355 nm using a nanosecond pulsed YAG laser and a one-on-one test procedure. The results are associated with a complete characterization of the samples: refractive index n measured by spectrophotometry, extinction coefficient k measured by photothermal deflection, and roughness measured by atomic force microscopy. PMID- 18449231 TI - Chalcogenide coatings of Ge15Sb20S65 and Te20As30Se50. AB - Chalcogenide coatings are investigated to obtain either optical components for spectral applications or optochemical sensors in the mid-infrared. The deposition of Ge(15)Sb(20)S(65) and Te(20)As(30)Se(50) chalcogenide glasses is performed by two physical techniques: electron-beam and pulsed-laser deposition. The quality of the film is analyzed by scanning electron microscopy, atomic force microscopy, and energy dispersive spectroscopy to characterize the morphology, topography, and chemical composition. The optical properties and optical constants are also determined. A CF(4) dry etching is performed on these films to obtain a channeled optical waveguide. For a passband filter made by electron-beam deposition, cryolite as a low-refractive-index material and chalcogenide glasses as high refractive-index materials are used to favor a large refractive-index contrast. A shift of a centered wavelength of a photosensitive passband filter is controlled by illumination time. PMID- 18449233 TI - Three-dimensional simulation of diffraction and absorption losses in all-fiber multilayer filters. AB - A rigorous modal three-dimensional calculation method is used to analyze the diffraction and absorption losses in Fabry-Perot (FP) multilayer interferential filters between both single-mode input and output fibers. With an ordinary personal computer, this method affords accurate calculation of the absorption losses and the diffraction into the cladding modes of both fibers as well as the reflectance into the input fiber. The calculation results show that absorption losses and diffraction are troublesome for high-finesse FP filters. PMID- 18449232 TI - Estimation of the average residual reflectance of broadband antireflection coatings. AB - We deal with optimal two-material antireflection (AR) coatings for the visible and adjacent spectral regions. It has been shown before that, for a given set of input parameters (refractive indices of the substrate, ambient medium and high- and low-index coating materials, and for a given spectral width of the AR coating), such designs consist of one or more clusters of layers of approximately constant optical thickness and number of layers. We show that, through the analysis of many different optimal coatings, it is possible to derive two parameters for a simple empirical expression that relates the residual average reflectance in the AR region to the number of clusters. These parameters are given for all possible combinations of relative spectral bandwidth equal to 2, 3, and 4; low-index to ambient-medium index ratio equal to 1.38 and 1.45; and high to-low index ratio equal to 1.4, 1.5, and 1.7. The agreement between the numerically and the empirically calculated values of residual average reflectance is excellent. From the information presented the optical thin-film designer can quickly calculate the required number of layers and the overall optical thickness of an AR coating having the desired achievable residual average reflectance. PMID- 18449235 TI - Characterization of low losses in optical thin films and materials. AB - Residual absorption in optical coatings and materials is directly measured by means of the laser-induced deflection (LID) technique. For transmissive coatings a measurement strategy is introduced that allows for the separation of different absorptions of the investigated sample (bulk, coating, surface) by use of only one sample. Laser irradiation yields absorption values between 2 x 10(-3) and 2.9 x 10(-2) for antireflecting and highly reflecting (HR) coatings at 193 nm and 30.6 x 10(-6) for a HR mirror at 527 nm. Use of laser-induced fluorescence at 193 nm excitation reveals trivalent cerium and prasodymium and hydrocarbons in different single layers and coatings. In addition to correlation with absorption data, the influence of a high fluorescence quantum yield on the absorption measurement is discussed. PMID- 18449234 TI - Elastic and plastic relaxation of densified SiO2 films. AB - Ion- and plasma-assisted deposition has been extensively used for the fabrication of high-performance optical films with dense and smooth microstructures that are essential for applications such as low-loss and environmentally stable optics. SiO(2) is a well-known amorphous material suitable for energetic deposition. SiO(2) single layers and SiO(2)-based single-cavity narrow-bandpass filters were prepared by plasma-ion-assisted deposition. The refractive index and film thickness were determined by variable-angle spectroscopic ellipsometry. The high compressive stress of the densified film was correlated to increased packing density. The center wavelength shift of the narrow-bandpass filters as a function of sample-temperature as well as high-temperature annealing was determined via spectral transmission measurement. Structural relaxation of the densified SiO(2) films was observed from the variation of the refractive index and physical thickness for the single layers and the center wavelength shift for the narrow bandpass filters, suggesting elastic and plastic deformation of the densified films corresponding to a reversible and an irreversible center wavelength shift, respectively. PMID- 18449236 TI - Stochastic subwavelength structures on poly(methyl methacrylate) surfaces for antireflection generated by plasma treatment. AB - Subwavelength structures of sufficient height-to-width aspect ratio are adequate for reduction of the Fresnel reflection of surfaces. In the case of low-pressure plasma-treated polymers, the self-organized features are stochastically distributed on the surface area with unequal shapes. Common descriptions use effective medium theory along with a continuously altering volume filling factor that together lead to a lateral homogeneous layer with a depth-dependent refractive index. We use a fixed gradient function for the refractive index for reverse engineering of in situ measured broadband optical data, and we compare the results with nonoptic methods. PMID- 18449237 TI - Monitoring thin films of the fence post design and its advantages for narrow bandpass filters. AB - A fence post design, when viewed on a plot of index of refraction versus film thickness, has thin (usually of equal thickness) high-index posts that stand above a broad low-index ground. Monitoring fence post and related posthole designs offers error compensation and error reduction. There tend to be two or more extrema within the optical monitoring trace of each layer between the fence posts that aid in the calibration and control of film thickness. This also leads to a potentially improved control during deposition of narrow bandpass filters that have been designed with nonquarterwaves at the passband wavelength. PMID- 18449238 TI - Variable narrow-band transmission filters for spectrometry from space. 2. Fabrication process. AB - The optical components described here are variable narrow-band transmission filters, where the transmittance peak varies with the position along the surface of the filter itself. They allow the construction of ultracompact and low-weight spectrometers for space applications. The theoretical behavior of graded filters has been already investigated by the authors, for imaging spectrometry of the Earth surface. The application of graded filters to miniaturized instruments for planetary missions (Mercury) is considered. Experimental results on the fabrication of small-dimension variable transmission filters operating over a wide spectrum, from visible to near infrared, are reported. PMID- 18449239 TI - Optical and structural properties of LaF3 thin films. AB - LaF(3) thin films of different thicknesses were deposited on CaF(2) (111) and silicon substrates at a relatively low substrate temperature of 150 degrees C. Optical (transmittance, reflectance, refractive index, and extinction coefficient) and mechanical (morphology and crystalline structure) properties have been investigated and are discussed. It is shown that LaF(3) thin films deposited on CaF(2) (111) substrates are monocrystalline and have a bulklike dense structure. Furthermore, it is presented that low-loss LaF(3) thin films can be deposited not only by boat evaporation but also by electron beam evaporation. PMID- 18449240 TI - Light intensification modeling of coating inclusions irradiated at 351 and 1053 nm. AB - Electric-field modeling provides insight into the laser damage resistance potential of nodular defects. The laser-induced damage threshold for high reflector coatings is 13x lower at the third harmonic (351 nm) than at the first harmonic (1053 nm) wavelength. Linear and multiphoton absorption increases with decreasing wavelength, leading to a lower-third harmonic laser resistance. Electric-field effects can also be a contributing mechanism to the lower laser resistance with decreasing wavelength. For suitably large inclusions, the nodule behaves as a microlens. The diffraction-limited spot size decreases with wavelength, resulting in an increase in intensity. Comparison of electric-field finite-element simulations illustrates a 3x to 16x greater light intensification at the shorter wavelength. PMID- 18449241 TI - Residual stress in Ta2O5-SiO2 composite thin-film rugate filters prepared by radio frequency ion-beam sputtering. AB - Ta-Si oxide composite thin-film rugate filters were prepared by radio frequency ion-beam sputtering and their residual stress and substrate deflections were measured. The residual stress and substrate deflection of these composite film rugate filters were less than that of notch filters made from a series of discrete quarter-wave layers with alternate high and low indices because of the smooth modulation of composition and no interface structure of the rugate filter. PMID- 18449242 TI - Hybrid approach for rugate filter design. AB - Fourier techniques and direct optimization are applied to the synthesis of complex rugate filters. A hybrid approach is presented. The design strategies are illustrated numerically for different spectral shapes. PMID- 18449243 TI - Optical interference coatings 2007 measurement problem. AB - The 2007 Measurement Problem comprised measurements of the transmission and reflectance spectra and the determination of optical constants for a single oxide layer on fused silica. The angle of incidence was 45 degrees . PMID- 18449244 TI - Analysis of dip coating processing parameters by double optical monitoring. AB - Double optical monitoring is applied to determine the influence of main process parameters on the formation of sulfated zirconia and self-assembled mesoporous silica solgel films by dip coating. In addition, we analyze, for the first time to the best of our knowledge, the influence of withdrawal speed, temperature, and relative humidity on refractive-index and physical thickness variations (uncertainties of +/-0.005 and +/-7 nm) during the process. Results provide insight into controlled production of single and multilayer films from complex fluids by dip coating. PMID- 18449245 TI - Crystal phase transition of HfO2 films evaporated by plasma-ion-assisted deposition. AB - HfO(2) is a well-known high-refractive-index material for optical interference coatings from the infrared down to the ultraviolet (UV). Dense, homogeneous, and stoichiometric HfO(2) film is critical for low-loss UV optics where the spectral region is close to its fundamental absorption edge. We prepare HfO(2) films by plasma-ion-assisted deposition with various amounts of plasma-ion momentum transfer. The correlation between the HfO(2) film structure and the optical properties are evaluated by a variable-angle spectroscopic ellipsometry, indicating inhomogeneous to homogeneous to inhomogeneous film structural evolution with increasing momentum transfer during deposition. The HfO(2) film inhomogeneity, surface roughness, and crystal phase are confirmed by scanning electron microscopy cross-sectional, atomic force microscopy, and x-ray diffraction measurements. The results suggest that the HfO(2) film structural evolution corresponds to crystal phase transition from weak monocline amorphous to strong monocline depending on the amount of plasma-ion momentum transfer during film deposition. PMID- 18449246 TI - History of the development and industrial production of low thermal emissivity coatings for high heat insulating glass units. AB - Low-emissivity (low-E) coatings play a dominate role in high heat insulating multiple glass units with which an essential part of heat energy can be saved in buildings. With such coatings as the main part, and to a lesser part with low thermal conductive filling gases of the units' interspaces, their heat transmittance can be reduced from 6.0 W/m(2)? K for a single glazing--still glazed to a high degree--to 0.4 W/m(2) K for a triple insulating glass unit. This astonishing development is regarded as one of the most important innovations of the flat glass industry in the past century. The roots of low-E coatings in the 1960s, their startup for production in the 1970s, and, most important, further development steps accompanied by, and partly also codesigned actively by the author, are depicted. PMID- 18449247 TI - Preparation of MgF2-SiO2 thin films with a low refractive index by a solgel process. AB - Porous MgF(2)-SiO(2) thin films consisting of MgF(2) particles connected by an amorphous SiO(2) binder are prepared by a solgel process. The films have a low refractive index of 1.26, sufficient strength to withstand wiping by a cloth, and a high environmental resistance. The refractive index of the film can be controlled by changing the processing conditions. Films can be uniformly formed on curved substrates and at relatively low temperatures, such as 100 degrees C. The low refractive index of the film, which cannot be achieved by conventional dry processes, is effective in improving the performance of antireflective coatings. PMID- 18449248 TI - Investigation of tin-based alternatives for cadmium in optoelectronic thin-film materials. AB - Increasing legislation has steadily been introduced throughout the world to restrict the use of heavy metals, particularly cadmium (Cd) and lead (Pb) in high temperature pigments, ceramics, and optoelectronic material applications. Removal of cadmium from thin-film optical and semiconductor device applications has been hampered by the absence of viable alternatives that exhibit similar properties with stability and durability. We describe a range of tin-based compounds that have been deposited and characterized in terms of their optical and mechanical properties and compare them with existing cadmium-based films that currently find widespread use in the optoelectronic and semiconductor industries. PMID- 18449249 TI - Fluoride antireflection coatings deposited at 193 nm. AB - Antireflection coatings for 193 nm composed of low-index (MgF(2) and AlF(3)) and high-index (LaF(3) and GdF(3)) materials are deposited by the resistive heating boat method at a substrate temperature of 300 degrees C. The optical characteristics (reflectance and optical loss), microstructure (morphology and surface roughness), stress, and laser-induced damage threshold (LIDT) of the coatings are investigated and discussed. The related reflection at 193 nm of the four kinds of antireflection coatings is smaller than 0.2% and the optical loss is less than 0.15%. Of the fluoride antireflection coatings, AlF(3)/GdF(3) had the lowest stress value. Antireflection coatings with AlF(3) as the low-index material had higher LIDT values than when MgF(2) was used. PMID- 18449250 TI - OpenFilters: open-source software for the design, optimization, and synthesis of optical filters. AB - The design of optical filters relies on powerful computer-assisted methods. Many of these methods are provided by commercial programs, but, in order to adapt and improve them, or to develop new methods, one needs to create his own software. To help people interested in such a process, we decided to release our in-house software, called OpenFilters, under the GNU General Public License, an open source license. It is programmed in Python and C++, and the graphical user interface is implemented with wxPython. It allows creation of multilayer and graded-index filters and calculation of reflection, transmission, absorption, phase, group delay, group delay dispersion, color, ellipsometric variables, admittance diagram, circle diagram, electric field distribution, and generation of reflection, transmission, and ellipsometric monitoring curves. It also provides the refinement, needle, step, and Fourier transform methods. PMID- 18449251 TI - 2007 topical meeting on optical interference coatings: manufacturing problem. AB - Measurements are described on the experimental filters submitted to the Third Optical Thin Film Manufacturing Problem in which the object was to produce multilayers with a measured colorimetric performance that is as close as possible to that specified. The perceived colors of the coating, when illuminated with randomly polarized light incident at 7 degrees by a source representing average daylight with a correlated color temperature of approximately 6500 K, were to be yellow and blue, respectively, in light reflected from its two surfaces, and the color was to appear white when viewed in transmission mode. Eleven teams from 7 different countries submitted a total of 18 samples. PMID- 18449252 TI - Investigation of MgF2 optical thin films with ultralow refractive indices prepared from autoclaved sols. AB - We have successfully developed a process to form high quality MgF(2) thin films with ultralow refractive indices from autoclaved sols prepared from magnesium acetate and hydrofluoric acid. And we have confirmed that our porous MgF(2) coatings have not only high transmittance in the UV region but also high uniformity of film thickness. They can be uniformly formed on phiv 300 mm substrates as a single coating and as a hybrid coating with sublayers formed by physical vapor deposition. They are expected to be applied to various optics that need high transmittance in the UV region. PMID- 18449253 TI - Cooled infrared filters and dichroics for the James Webb Space Telescope Mid Infrared Instrument. AB - The cooled infrared filters and dichroic beam splitters manufactured for the Mid Infrared Instrument are key optical components for the selection and isolation of wavelengths in the study of astrophysical properties of stars, galaxies, and other planetary objects. We describe the spectral design and manufacture of the precision cooled filter coatings for the spectrometer (7 K) and imager (9 K). Details of the design methods used to achieve the spectral requirements, selection of thin film materials, deposition technique, and testing are presented together with the optical layout of the instrument. PMID- 18449254 TI - Optical modeling of organic solar cells based on CuPc and C60. AB - We have investigated the influence of the poly(3,4-ethylenedioxythiophene)-blend poly(styrene-sulfonate) (PEDOT:PSS) layer on the short-circuit current density (J(sc)) of single planar heterojunction organic solar cells based on a copper phthalocyanine (CuPc)-buckminsterfullerene (C(60)) active layer. Complete optical and electrical modeling of the cell has been performed taking into account optical interferences and exciton diffusion. Comparison of experimental and simulated external quantum efficiency has allowed us to estimate the exciton diffusion length to be 37 nm for the CuPc and 19 nm for the C(60). The dependence of short-circuit current densities versus the thickness of the PEDOT:PSS layer is analyzed and compared with experimental data. It is found that the variation in short-circuit current densities could be explained by optical interferences. PMID- 18449255 TI - From angle-resolved ellipsometry of light scattering to imaging in random media. AB - A procedure is described to allow selective cancellation of polarized scattering within optical substrates and multilayers. It is shown how bulk scattering (respectively surface) can be directly eliminated while the remaining roughness (respectively bulk) signal is still measurable. The same procedure can be applied to isolate a single interface or bulk within a stack or to detect slight departure from perfect correlation within multilayers. Experiments and a procedure for selective imaging in random media are described. PMID- 18449256 TI - Residual stress in obliquely deposited MgF2 thin films. AB - MgF(2) films with a columnar microstructure are obliquely deposited on glass substrates by resistive heating evaporation. The columnar angles of the films increases with the deposition angle. Anisotropic stress does not develop in the films with tilted columns. The residual stresses in the films depend on the deposition and columnar angles in a columnar microstructure. PMID- 18449257 TI - Atomic layer deposition process with TiF4 as a precursor for depositing metal fluoride thin films. AB - A novel atomic layer deposition process for the preparation of fluoride thin films in a temperature range of 225 degrees C-400 degrees C is introduced. The crystallinity, morphology, composition, thicknesses, refractive indices, and transmittance of the films are analyzed. Low impurity levels are obtained at 350 degrees C-400 degrees C with good stoichiometry. Refractive indices of 1.34-1.42 for MgF(2), 1.43 for CaF(2), and 1.57-1.61 for LaF(3) films are obtained. PMID- 18449258 TI - Theoretical analysis of two nonpolarizing beam splitters in asymmetrical glass cubes. AB - The design principle for a nonpolarizing beam splitter based on the Brewster condition in a cube is introduced. Nonpolarizing beam splitters in an asymmetrical glass cube are proposed and theoretically investigated, and applied examples are given. To realize 50% reflectance and 50% transmittance at specified wavelengths for both polarization components with an error of less than 2%, two measurements are taken by adjusting the refractive index of the substrate material and optimizing the thicknesses of each film in the design procedures. The simulated results show that the targets are achieved using the method reported here. PMID- 18449259 TI - Efficiency of polarimetric z probing in optical multilayers. AB - Numerical calculation is performed to validate the principles of a single optical technique devoted to real time probing or imaging of submultilayers within interferential coatings. PMID- 18449261 TI - Sputter deposition of silicon oxynitride gradient and multilayer coatings. AB - The optical properties of silicon oxynitride films deposited by reactive dc magnetron sputtered films have been investigated. In particular the absorption characteristics of silicon nitride thin films in the visible spectrum and their optical bandgap were analyzed with regard to their composition and deposition properties. It can be shown that there is a significant difference between the absorption in the visible spectrum and the optical bandgap for these layers. The influence of unipolar and bipolar pulse modes on the optical layer properties is presented. The extinction coefficient for silicon nitride single layers could be reduced to a value of 2 x 10(-4) at 500 nm without external heating. There is also the dependence of the absorption of silicon oxynitride layers on the discharge voltage. We present the resulting spectra of rugate and edge filters that consist of these layers and offer lower absorption than single layers. PMID- 18449260 TI - Annealing dependence of residual stress and optical properties of TiO2 thin film deposited by different deposition methods. AB - Titanium oxide (TiO(2)) thin films were prepared by different deposition methods. The methods were E-gun evaporation with ion-assisted deposition (IAD), radio frequency (RF) ion-beam sputtering, and direct current (DC) magnetron sputtering. Residual stress was released after annealing the films deposited by RF ion-beam or DC magnetron sputtering but not evaporation, and the extinction coefficient varied significantly. The surface roughness of the evaporated films exceeded that of both sputtered films. At the annealing temperature of 300 degrees C, anatase crystallization occurred in evaporated film but not in the RF ion-beam or DC magnetron-sputtered films. TiO(2) films deposited by sputtering were generally more stable during annealing than those deposited by evaporation. PMID- 18449262 TI - Induced metal-dielectric selective reflecting filter for miniprojectors. AB - Metal-dielectric multiple-band high-reflection coatings are designed as induced filters and fabricated by reactive deposition. Ta(2)O(5) and SiO(2) are used as high- and low-refractive-index layers, and Cr and Al are used as bonding and reflective layers, respectively, for constructing the filters. The metal dielectric coatings are deposited on a light-shaping flexible plastic substrate for use as a screen with high-contrast enhancement performance. This screen was suitable for miniprojectors with red, green, and blue LEDs as light sources. Mechanical properties such as stress, hardness, and adhesive strength of these multilayer films are investigated also. PMID- 18449263 TI - Low temperature deposition of indium tin oxide films by plasma ion-assisted evaporation. AB - Coatings of transparent conductive oxides, especially indium tin oxide (ITO), are important in different fields. So far, application of these materials has been limited to substrates with high thermal stability. We describe an improved coating process for ITO based on plasma ion-assisted evaporation at a substrate temperature below 100 degrees C, which is suitable for organic substrates. In characterizing the thin films, we used the classical Drude theory to calculate the resistivity from optical film properties and compared the data with linear four-point measurements. X-ray diffraction spectroscopy was used to determine the structural properties of the thin films. PMID- 18449264 TI - High-accuracy measurements of the normal specular reflectance. AB - The French Laser Megajoule (LMJ) is designed and constructed by the French Commissariat a l'Energie Atomique (CEA). Its amplifying section needs highly reflective multilayer mirrors for the flash lamps. To monitor and improve the coating process, the reflectors have to be characterized to high accuracy. The described spectrophotometer is designed to measure normal specular reflectance with high repeatability by using a small spot size of 100 mum. Results are compared with ellipsometric measurements. The instrument can also perform spatial characterization to detect coating nonuniformity. PMID- 18449265 TI - High reflectivity multilayer for He-II radiation at 30.4 nm. AB - SiC/Mg and B(4)C/Mo/Si multilayers were designed for He-II radiation at 30.4 nm. These multilayers were prepared by use of a direct current magnetron sputtering system and measured at the National Synchrotron Radiation Laboratory, China. The measured reflectivities were 38.0% for the SiC/Mg multilayer at an incident angle of 12 deg and 32.5% for the B(4)C/Mo/Si multilayer at 5 deg, respectively. A dual function multilayer mirror was also designed by use of the aperiodic SiC/Mg multilayer. Annealing experiments were performed to investigate the thermal stability of the SiC/Mg multilayer. The interface of the SiC/Mg multilayer before and after annealing was studied by electron-induced x-ray emission spectra, which evidences the absence of thermal reaction products at the interfaces after annealing. PMID- 18449266 TI - Measurement of stress in aluminum film coated on a flexible substrate by the shadow moire method. AB - This investigation proposes the use of the shadow moire method (SMM) to measure stress in a thin film that is coated on a flexible substrate. The technique defines the profile of the sample by contour lines without the application of an external force, and the radius of curvature is calculated from these contour lines. The SMM is insensitive to environmental noise and has the same advantages as the interference method, such as being nondestructive and easy to use. For Al film with a thickness of 120 nm coated on a polyimide substrate by a DC magnetron sputtering system (800 W, room temperature), the stress is 0.45 +/- 0.042 GPa. PMID- 18449267 TI - Optical properties and residual stress of YbF3 thin films deposited at different temperatures. AB - The influence of deposition temperature on the optical properties, microstructure, and residual stress of YbF(3) films, deposited by electron-beam evaporation, has been investigated. The increased refractive indices and surface roughness of YbF(3) films indicate that the film density and columnar structure size increase with deposition temperature. At the same time, higher packing density reduces absorption of moisture. The residual stress is related to deposition temperature and to substrate. For the samples deposited on BK7, the residual stress mainly comes from intrinsic stress, however, for those on fused silica, thermal stress is the dominant factor of total residual stress. PMID- 18449268 TI - Optical thin-film reflection filters based on the theory of photonic crystals. AB - Based on the theory of photonic crystals and the framework of a single-channel reflection filter that we presented before, structures of reflection filters with multiple channels are proposed. These structures can overcome some drawbacks of conventional multichannel transmission filters and are much easier to fabricate. We have practically fabricated the reflection filters with two and three channels, and the tested results show approximate agreement with theoretical simulation. Moreover, the superprism effect is also simulated in the single channel reflection filter, the superiorities to transmission filters are discussed, and these analyses may shed some light on new applications of reflection filters in optical communication and other systems. PMID- 18449269 TI - Process for deposition of AlF3 thin films. AB - We fabricated aluminum fluoride (AlF(3)) thin films by pulsed DC magnetron sputtering with various CF(4) flow rates and sputtering powers. Our method is distinct from the conventional deposition process in that we used inexpensive Al (99.99% purity) as the target instead of an expensive fluoride compound. The optical properties and microstructure of the thin films were examined. The optical quality of AlF(3) thin films deposited at a 20 W sputtering power and injected 110 SCCM (SCCM denotes cubic centimeters per minute at standard temperature and pressure) CF(4) flow at room temperature showed improvement with an extinction coefficient of less than 7 x 10(-4) at 193 nm. The deposition of AlF(3) thin films at different substrate temperatures and annealed by UV light was also investigated. PMID- 18449270 TI - Optical properties of plasma ion-assisted deposition silicon coatings: application to the manufacture of blocking filters for the near-infrared region. AB - I report on the preparation and characterization of optical constants of silicon coatings deposited by an electron beam gun with plasma ion-assisted deposition. With the fabrication of long-wave-pass filters the reliability of the optical constants is assured. PMID- 18449271 TI - In situ optical characterization and reengineering of interference coatings. AB - A new optical monitoring system has been developed that allows recording of transmission spectra in the wavelength range between 400 and 920 nm of a growing optical coating during deposition. Several kinds of thin film sample have been prepared by use of a hybrid monitoring strategy that is essentially based on a combination of quartz monitoring and in situ transmission spectra measurements. We demonstrate and discuss the applicability of our system for reengineering procedures of high-low stacks and measurements of small vacuum or thermal shifts of optical coatings. PMID- 18449272 TI - Optical Interference Coatings Design Contest 2007: triple bandpass filter and nonpolarizing beam splitter. AB - A triple bandpass filter (28 solutions received) and a nonpolarizing beam splitter (23 solutions received) were the subjects of the design contest held in conjunction with the 2007 Optical Interference Coatings topical meeting of the Optical Society of America. Fifteen designers participated using a wide spectrum of design approaches and optimization strategies to create the submissions. The results differ significantly, but all meet the contest requirements. Fabien Lemarchand wins both contests by submitting the thinnest (6254 nm) triple bandpass design and the widest (61.7 nm) nonpolarizing beam-splitter design. Michael Trubetskov is in second place, followed by Vladimir Pervak in both contests. The submitted designs are described and evaluated. PMID- 18449273 TI - Graded wavelike two-dimensional photonic crystal made of thin films. AB - A filling-factor-graded wavelike two-dimensional photonic crystal (2DPC) possessing a light-path bending effect that is polarization dependent is theoretically studied by using a qualitative analysis of the isofrequency curves. The numerical simulation results obtained by using the finite-difference time domain method demonstrate that such a graded 2DPC has potential applications in a polarization splitter and a parallel-plane resonant cavity. A new kind of waveguide structure that combines a filling-factor-graded wavelike 2DPC and one dimensional multilayer thin films is also discussed. PMID- 18449274 TI - Optical design of hybrid-type attenuated phase-shift masks for extreme ultraviolet lithography by use of a Fabry-Perot interference filter. AB - We have designed what we believe to be new hybrid-type attenuated phase-shift masks for extreme-ultraviolet optical lithography by use of a Fabry-Perot interference filter. The designs for the attenuated phase-shift masks show a smaller step height for less geometric shadow effects than additive- and subtractive-type attenuated phase-shift masks, a contrast higher than 94% for both deep-ultraviolet and extreme-ultraviolet wavelength regimes, and a 180 degrees phase-shift in the extreme-ultraviolet wavelength regime. PMID- 18449275 TI - Enhancement of adhesion between antireflection coating and cellulose triacetate by surface pretreatment using argon-helium plasma. AB - The adhesion of optical thin films on cellulose triacetate (TAC) was enhanced with surface pretreatment by argon-helium plasma. The optical properties, water contact angle, surface morphology, and thin film adhesion of TAC substrate that had been treated with different plasma gases were also investigated. An antireflection coating adhered well to TAC with an appropriate interface layer. PMID- 18449276 TI - Antireflection coating with UV-protective properties for polycarbonate. AB - Polycarbonate is the chosen material for covers of automotive displays because it combines high transparency with high breaking strength. The requirements for coatings include an improvement of the scratch resistance and antireflection properties as well as high stability for challenging environmental conditions. A coating that involves all required properties has been developed and deposited onto polycarbonate by plasma-ion assisted deposition. PMID- 18449277 TI - Roughness evolution and scatter losses of multilayers for 193 nm optics. AB - Optical scattering arising from interface roughness and interference effects is a dominant loss mechanism of thin film coatings for 193 nm. A procedure is presented where at-wavelength scatter measurements in combination with atomic force microscopy are used as a tool for the in-depth characterization of the origins of scattering. For highly reflective coatings, the influence of the substrate roughness on the growth properties is analyzed. Moreover, the effects of interface roughness and optical thickness deviations on the scattering properties are separated. Furthermore, the procedure was used to investigate scattering properties of coatings at 45 degrees incidence and of coatings applied in immersion fluid that so far could not be accessed by direct measurement. PMID- 18449278 TI - Using fence post designs to speed the atomic layer deposition of optical thin films. AB - Atomic layer deposition (ALD) at this time is much slower than conventional optical thin-film deposition techniques. A more rapid ALD process for SiO(2) has been developed than for other ALD materials. A fence post design for optical thin films has thin layers of high-index posts standing above a broad low-index ground. If a design for ALD can be predominantly composed of SiO(2) layers with thin high-index layers, the deposition times can be correspondingly shortened, and it is shown that the required performance can still be nearly that of more conventional designs with high- and low-index layers of equal thickness. This combination makes the ALD benefits of conformal coating and precise thickness control more practical for optical thin-film applications. PMID- 18449279 TI - Charles Keith Carniglia (1944-2006): in memoriam. AB - Chuck Carniglia was an industrial scientist, an educator, and a friend to all he met. He had an important impact on the optical thin-film community. This article highlights his career and accomplishments. PMID- 18449280 TI - Optical Society of America's 2007 Topical Meeting on Optical Interference Coatings: overview. AB - The Optical Society of America's Topical Meeting on Optical Interference Coatings convenes every three years to survey and capture advancements in the broad area of optical coatings. This meeting serves as a focal point for global technical interchange in the field of optical interference coatings. It includes papers on research, development, and applications of optical coatings, such as fundamental and theoretical contributions in the field as well as practical techniques and applications. PMID- 18449281 TI - Principle and analysis of the moving-optical-wedge interferometer. AB - A new type of interferometer, the moving-optical-wedge interferometer, is presented, and its principle and properties are studied. The novel interferometer consists of one beam splitter, two flat fixed mirrors, two fixed compensating plates, one fixed optical wedge, and one moving optical wedge. The optical path difference (OPD) as a function of the displacement of the moving optical wedge from the zero path difference position is accomplished by the straight reciprocating motion of the moving optical wedge. A large physical shift of the moving optical wedge corresponds to a very short OPD value of the new interferometer if the values of the wedge angle and the refractive index of the two optical wedges are given properly. The new interferometer is not so sensitive to the velocity variation of the moving optical wedge and the mechanical disturbances compared with the Michelson interferometer, and it is very applicable to low-spectral-resolution application for any wavenumber region from the far infrared down to the ultraviolet. PMID- 18449282 TI - Three-dimensional vector holograms in anisotropic photoreactive liquid-crystal composites. AB - In this paper, we describe the principle of the three-dimensional vector holograms formed in anisotropic recording medium. The polarization states of the interference light are three-dimensionally modulated due to both the polarization interference and optical anisotropy in the recording medium. The electric field of the polarized light reorients the director and forms the three-dimensional vector hologram in anisotropic photoreactive liquid-crystal composites. The theoretical consideration reveals the formation mechanism and optical characteristics of the resultant three-dimensional vector holograms. PMID- 18449283 TI - Optical encoder based on a nondiffractive beam. AB - Optical encoders are used in industrial and laboratory motion equipment to measure rotations and linear displacements. We introduce a design of an optical encoder based on a nondiffractive beam. We expect that the invariant profile and radial symmetry of the nondiffractive beam provide the design with remarkable tolerance to mechanical perturbations. We experimentally demonstrate that the proposed design generates a suitable output sinusoidal signal with low harmonic distortion. Moreover, we present a numerical model of the system based on the angular spectrum approximation whose predictions are in excellent agreement with the experimental results. PMID- 18449284 TI - Three-dimensional-two-dimensional mixed display system using integral imaging with an active pinhole array on a liquid crystal panel. AB - A display system that simultaneously displays two-dimensional (2D) and three dimensional (3D) images using a pinhole array on a liquid crystal (LC) panel is proposed. Using the transparent structure of the LC panel, the system can generate or eliminate pinholes electrically and can display a 3D image in a selectable specific area of the display panel, while 2D images are displayed on the rest of the screen. An analysis showing the advantages and limitations of the proposed system is provided. Finally, the proposed principle is proven by experimental results. PMID- 18449285 TI - Radiative transfer codes for atmospheric correction and aerosol retrieval: intercomparison study. AB - Results are summarized for a scientific project devoted to the comparison of four atmospheric radiative transfer codes incorporated into different satellite data processing algorithms, namely, 6SV1.1 (second simulation of a satellite signal in the solar spectrum, vector, version 1.1), RT3 (radiative transfer), MODTRAN (moderate resolution atmospheric transmittance and radiance code), and SHARM (spherical harmonics). The performance of the codes is tested against well-known benchmarks, such as Coulson's tabulated values and a Monte Carlo code. The influence of revealed differences on aerosol optical thickness and surface reflectance retrieval is estimated theoretically by using a simple mathematical approach. All information about the project can be found at http://rtcodes.ltdri.org. PMID- 18449286 TI - Temperature measurements of turbid aqueous solutions using near-infrared spectroscopy. AB - We report a method that uses near-infrared spectroscopy and multivariate analysis to measure the temperature of turbid aqueous solutions. The measurement principle is based on the fact that the peak wavelength of the water absorption band, with its center near 1440 nm, shifts with changes in temperature. This principle was used to measure the temperatures of 1 mm thick samples of aqueous solutions containing Intralipid (2%), which are often used as optical phantoms for biological tissues due to similar scattering characteristics. Temperatures of pure water and aqueous solutions containing glucose (100 mg/ml and 200 mg/ml) were also measured for comparison. For the turbid Intralipid solutions, the absorbance spectrum varied irregularly with time due to the change in scattering characteristics. However, by making use of the difference between the absorbance at 1412 nm and the temperature-independent absorbance at 1440 nm, we obtained SEPs (standard error of prediction) of 0.3 degrees C and 0.2 degrees C by univariate linear regression and partial least squares regression, respectively. These accuracies were almost the same as those for the transparent samples (pure water and glucose solution). PMID- 18449287 TI - Electro-optic sensor from high Q resonance between optical D-fiber and slab waveguide. AB - An electro-optic sensor capable of detecting electric fields with a high degree of sensitivity and linearity is fabricated using optical D-fiber. The slab coupled optical sensor utilizes weak coupling and long evanescent interaction with a lithium niobate waveguide. Transmission dips from mode resonances have a linewidth of 0.12 nm and a Q factor of approximately 13,000. These sharp resonances improve device sensitivity and are achieved due to the unique fabrication process possible with D-shaped fibers. The sensor deviates <0.1% from linearity while monitoring fields between 200 V/m and 20 kV/m and promises high sensitivity to fields well beyond that range. PMID- 18449288 TI - Complete polarization conversion using one crystal with dual transverse Pockels effect. AB - Based on dual transverse Pockels effect, complete polarization conversion can be achieved by using only one electro-optic crystal and its two externally applied voltages. The electro-optic phase retardation and the azimuth angle of the field induced principal dielectric axes of the crystal can be independently and linearly controlled by the amplitude and direction of the applied electric field, and the formulas for this correlation are deduced for arbitrary input and output polarization states. The candidate crystals mainly include the uniaxial crystals of 3 m, 62 m, and 32 symmetry groups, and the cubic crystals of 43 m and 23 symmetry groups. Theoretical analysis demonstrates that one crystal exhibiting both dual transverse Pockels effect and optical activity can also be used for complete polarization converter. The continuous polarization rotation of a linearly polarized light from 0 degrees to 180 degrees has been performed experimentally by use of single lithium niobate crystal with four lateral electrodes. In addition the light beam position-dependent polarization conversion by using a bulk electro-optic crystal is also measured in the experiment. This new type of polarization converter will have potential applications in many fields due to its simple configuration, explicit control logic of polarization conversion, and lower power consumption. PMID- 18449289 TI - In-flight performance and calibration of SPICAV SOIR onboard Venus Express. AB - Solar occultation in the infrared, part of the Spectoscopy for Investigation of Characteristics of the Atmosphere of Venus (SPICAV) instrument onboard Venus Express, combines an echelle grating spectrometer with an acousto-optic tunable filter (AOTF). It performs solar occultation measurements in the IR region at high spectral resolution. The wavelength range probed allows a detailed chemical inventory of Venus's atmosphere above the cloud layer, highlighting the vertical distribution of gases. A general description of the instrument and its in-flight performance is given. Different calibrations and data corrections are investigated, in particular the dark current and thermal background, the nonlinearity and pixel-to-pixel variability of the detector, the sensitivity of the instrument, the AOTF properties, and the spectral calibration and resolution. PMID- 18449290 TI - Fourier transform infrared spectroscopy of size-segregated aerosol deposits on foil substrates. AB - A method based on Fourier transform infrared (FTIR) double-pass transmittance spectroscopy was developed for determining functional group loading in size segregated ambient aerosol deposits. The impactor employed for sample collection utilized rotating stages, which produced uniform particulate matter (PM) deposits on standard Al foil substrates. Each sample was analyzed without extraction using an FTIR spectrometer equipped with a reflectometer accessory. The use of the reflectometer obviated the need for infrared window materials as substrates. (NH(4))(2)SO(4) aerosol generated under laboratory conditions were used to calibrate deposit mass to the band strength of the relatively isolated nu(4) bending mode of SO(2-)(4) centered near 620 cm(-1). Atmospheric PM was sampled during the summer of 2004 in Huntsville, Ala. Sulfate concentrations determined in this initial study correlated well with measurements made by collocated EPA air samplers. PMID- 18449291 TI - Luus-Jaakola optimization procedure for phase-only sampled-fiber Bragg gratings. AB - We describe a Luus-Jaakola (LJ) optimization algorithm approach for the design of wavelength division multiplexing (WDM) optical communication systems by using phase-only sampled-fiber Bragg gratings. The LJ method is used to optimize the phase grating as well as the number of segments which form the grating. The numerical example of WDM is studied. The method is easily applicable and shows promising results with low refractive index modulation. PMID- 18449292 TI - Time-resolved fluorescence polarization dynamics and optical imaging of Cytate: a prostate cancer receptor-targeted contrast agent. AB - Cypate-octreote peptide analogue conjugate (Cytate) was investigated as a prostate cancer receptor-targeted contrast agent. The absorption and fluorescence spectra of Cytate were ranged in the near-infrared "tissue optical window." Time resolved investigation of polarization-dependent fluorescence emitted from Cytate in solution as well as in cancerous and normal prostate tissues was conducted. Polarization preservation characteristics of Cytate in solution and tissues were studied. Fluorescence intensity emitted from the Cytate-stained cancerous prostate tissue was found to be much stronger than that from the Cytate-stained normal prostate tissue, indicating more Cytate uptake in the former tissue type. The polarization anisotropy of Cytate contained in cancerous prostate tissue was found to be larger than that in the normal prostate tissue, indicating a larger degree of polarization preservation in Cytate-stained cancerous tissue. The temporal profiles of fluorescence from Cytate solution and from Cytate-stained prostate tissue were fitted using a time-dependent fluorescence depolarization model. The photoluminescence imaging of Cytate-stained cancerous and normal prostate tissues was accomplished, showing the potential of Cytate as a fluorescence marker for prostate cancer detection. PMID- 18449293 TI - Multiple path interference and differential modal delay reduction using spatial filters in a 4F system. AB - Multiple path interference (MPI) and differential modal delay (DMD) are two major impairments in fiber optic communication systems. MPI can be found in a few mode fibers in which a higher order mode propagates as a weak replica of the signal and interferes with the fundamental mode at the output of the fiber link. DMD in multimode fibers (MMF) leads to intersymbol interference, which limits the bit rate-distance product of the system. A simple method is proposed to reduce MPI and DMD effects using spatial filters in a 4F system. Higher order modes have higher spatial frequency components. Therefore by choosing a proper spatial filter with a suitable bandwidth, a fraction of the unwanted higher order modes can be suppressed, and therefore MPI and DMD effects can be reduced. PMID- 18449294 TI - Analytical model for optimizing the parameters of an external passive Q-switch in a fiber laser. AB - An analytical model is developed for optimizing two key parameters of an external passive Q-switch in a fiber laser from the criterion of the minimum average mode area inside the saturable absorber. One parameter is the optimum focal position that is analytically derived to be a function of the thickness and initial transmission of the saturable absorber. The other parameter is the optimum magnification of the reimaging optics that is analytically derived to be in terms of the numerical aperture and core radius of the laser fiber as well as the thickness and initial transmission of the saturable absorber. To demonstrate the utilization of the present model, an experiment on the subject of the passively Q switched fiber laser is performed and optimized. PMID- 18449295 TI - Adjoint time domain method for fluorescent imaging in turbid media. AB - Application of adjoint time domain methods to the inverse problem in 3D fluorescence imaging is a novel approach. We demonstrate the feasibility of this approach experimentally on the basis of a time gating technique completely in the time domain by using a small number of time windows. The evolution of the fluorescence energy density function inside a highly scattering cylinder was reconstructed together with optical parameters. Reconstructed energy density was used in localizing two fluorescent tubes. Relatively accurate reconstruction demonstrates the effectiveness and the potential of the proposed technique. PMID- 18449296 TI - Temperature-insensitive laser frequency stabilization with magnetic tuning. AB - We have implemented a tunable laser frequency lock with a wide recapture range and low sensitivity to temperature fluctuation, based on electronically power normalized Doppler-broadened absorption spectra. The method requires no frequency modulation. A distributed-feedback diode laser locked to this system exhibits submegahertz stability over many hours. It has been used to magneto-optically trap rubidium atoms for a full day. PMID- 18449297 TI - Analytical solution of the heat equation in a longitudinally pumped cubic solid state laser. AB - Knowledge about the temperature distribution inside solid-state laser crystals is essential for calculation of thermal phase shift, thermal lensing, thermally induced birefringence, and heat-induced crystal bending. Solutions for the temperature distribution for the case of steady-state heat loading have appeared in the literature only for simple cylindrical crystal shapes and are usually based on numerical techniques. For the first time, to our knowledge, a full analytical solution of the heat equation for an anisotropic cubic cross-section solid-state crystal is presented. The crystal is assumed to be longitudinally pumped by a Gaussian pump profile. The pump power attenuation along the crystal and the real cooling mechanisms, such as convection, are considered in detail. A comparison between our analytical solutions and its numerical counterparts shows excellent agreement when just a few terms are employed in the series solutions. PMID- 18449298 TI - Unsupervised clustering approaches to color classification for color-based image code recognition. AB - Color-vision-based applications for mobile phones has become a subject of special interest lately. It would be interesting to investigate an unsupervised, adaptive, and fast algorithm that can classify color components into color clusters. We propose a hierarchical clustering approach using a single-linkage algorithm and a k-means clustering approach to color classification for color based image code recognition in mobile computing environments. We also measured the performance of the proposed algorithms by color channel stretch, which is a simple color-correction method. Experimental results show that the single-linkage method is more robust than previous algorithms used in experiments with varying cameras and print materials. In particular the k-means-based method with color channel stretching has the highest performance and is the most robust under varying environment conditions such as illuminants, cameras, and print materials. PMID- 18449299 TI - High-performance infrared narrow-bandpass filters for the Indian National Satellite System meteorological instrument (INSAT-3D). AB - This paper describes the design and manufacture of a set of precision cooled (210 K) narrow-bandpass filters for the infrared imager and sounder on the Indian Space Research Organisation (ISRO) INSAT-3D meteorological satellite. We discuss the basis for the choice of multilayer coating designs and materials for 21 differing filter channels, together with their temperature-dependence, thin film deposition technologies, substrate metrology, and environmental durability performance. PMID- 18449300 TI - Measurement of the enhanced evanescent fields of integrated waveguides for optical near-field sensing. AB - The sensitivity of an integrated optical sensing device can be enhanced by coating it with a high refractive index layer, while both incoupled intensity and spatial resolution are maintained. The potential for enhanced sensing is demonstrated using titanium indiffused waveguiding structures in LiNbO(3) coated with a TiO(2) film. To the best of our knowledge, it could be measured for the first time that the outcoupled intensity at the surface was enhanced by a factor of 12-15 while keeping the penetration depth of the evanescent field constant of the order of only a few tens of nanometers. The evanescent fields of the guided modes were measured and characterized with a scanning near-field optical microscope and are in accordance with the numerical simulations. PMID- 18449301 TI - Three-dimensional particle tracking with subnanometer resolution using off-focus images. AB - A three-dimensional (3D) particle tracking algorithm based on microscope off focus images is presented in this paper. Subnanometer resolution in all three axes at 400 Hz sampling rate is achieved using a complementary metal-oxide semiconductor (CMOS) camera. At each sampling, the lateral position of the spherical particle is first estimated by the centroid method. The axial position is then estimated by comparing the radius vector, which is converted from the off focus two-dimensional image of the particle with no information loss, with an object-specific model, calibrated automatically prior to each experiment. Estimation bias and variance of the 3D tracking algorithm are characterized through analytical analysis. It leads to an analytical model, enabling prediction of the measurement performance based on calibration data. Finally, experimental results are presented to illustrate the performance of the measurement method in terms of precision and range. The validity of the theoretical analysis is also experimentally confirmed. PMID- 18449302 TI - Application of orthogonal sampling to incomplete data interferometric tomography: numerical simulation and experimental analysis. AB - Orthogonal projection sampling mode was proposed to reconstruct the incomplete data flow field in optical computerized tomography (OCT). With numerical simulation technique, a two-peak plane symmetric flow field was reconstructed in different sampling modes and discussed in simulated results is the reconstructive accuracy with error indexes, such as mean square error (MSE) and peak error (PE). The corresponding experiments were researched with a Fabry-Perot rotary interferometer. The results indicated that the errors were drastically reduced and the precision was improved when orthogonal projection sampling mode was adopted in the reconstruction of the incomplete data field. The MSE obtained with orthogonal sampling mode was decreased 72.81% from that of the sequential projection sampling mode (the difference between the MSE obtained with the orthogonal sampling mode and that with the sequential sampling mode divided by the MSE of the sequential sampling mode) and the PE was decreased by 73.97%. The precision obtained from the experimental results reached 10%, which showed the orthogonal projection sampling could be a practicable sampling mode for the incomplete data field reconstruction in OCT and could provide some guidance for the flow-field measurement and apparatus design in the practical situation. PMID- 18449303 TI - Ellipsoidal and parabolic glass capillaries as condensers for x-ray microscopes. AB - Single-bounce ellipsoidal and paraboloidal glass capillary focusing optics have been fabricated for use as condenser lenses for both synchrotron and tabletop x ray microscopes in the x-ray energy range of 2.5-18 keV. The condenser numerical apertures (NAs) of these devices are designed to match the NA of x-ray zone plate objectives, which gives them a great advantage over zone plate condensers in laboratory microscopes. The fabricated condensers have slope errors as low as 20 murad rms. These capillaries provide a uniform hollow-cone illumination with almost full focusing efficiency, which is much higher than what is available with zone plate condensers. Sub-50 nm resolution at 8 keV x-ray energy was achieved by utilizing this high-efficiency condenser in a laboratory microscope based on a rotating anode generator. PMID- 18449304 TI - Measured and simulated performance of a ceramic micromechanical beam steering device at 94 GHz. AB - We report the first experimental demonstration of a transmission-mode micromechanical beam steering device for use in standoff terahertz imaging and spectroscopy. The device was constructed by laminating laser-cut 96% alumina sheets to form two plates with interlocking rectangular gratings of 762 microm period and was characterized at 94 GHz in a free-space measurement setup with an automated elevation scan. Plate tilts as great as 6 degrees deflected the transmitted beam by 6 degrees for the transverse electric (TE) polarization and by 4 degrees for the transverse magnetic polarization. Finite-difference time domain simulations of the TE performance were in good agreement with the measurements. PMID- 18449305 TI - Measurements of complex refractive indices of metals at several wavelengths by frustrated total internal reflection due to surface plasmon resonance. AB - By employing a modified Otto's configuration for measuring surface plasmon resonance that has been proposed by Bliokh and his coworkers [Appl. Phys. Lett.89, 021908 (2006)APPLAB0003-695110.1063/1.2220540] we have obtained complex refractive indices of metals at several wavelengths. We demonstrate that the configuration has high potential for obtaining dispersion relations of metal conductors in bulk samples as well as in thin films from the visible to the near infrared wavelength region. Furthermore, we show that the configuration enables us to obtain the complex refractive indices of metals or a thickness or refractive index of a dielectric layer on the metal at different points simultaneously. We have constructed a measurement system and carried out basic experiments. The experimental results agreed well with numerically simulated values or published ones. PMID- 18449306 TI - Gas detection by correlation spectroscopy employing a multimode diode laser. AB - A gas sensor based on the gas-correlation technique has been developed using a multimode diode laser (MDL) in a dual-beam detection scheme. Measurement of CO(2) mixed with CO as an interfering gas is successfully demonstrated using a 1570 nm tunable MDL. Despite overlapping absorption spectra and occasional mode hops, the interfering signals can be effectively excluded by a statistical procedure including correlation analysis and outlier identification. The gas concentration is retrieved from several pair-correlated signals by a linear-regression scheme, yielding a reliable and accurate measurement. This demonstrates the utility of the unsophisticated MDLs as novel light sources for gas detection applications. PMID- 18449307 TI - Bootstrap beacon creation for overcoming the effects of beacon anisoplanatism in a laser beam projection system. AB - We address the problem of using adaptive optics to deliver power from an airborne laser platform to a ground target through atmospheric turbulence under conditions of strong scintillation and anisoplanatism. We explore three options for creating a beacon for use in adaptive optics beam control: scattering laser energy from the target, using a single uncompensated Rayleigh beacon, and using a series of compensated Rayleigh beacons. We demonstrate that using a series of compensated Rayleigh beacons distributed along the path provides the best beam compensation. PMID- 18449308 TI - Turbulence-induced channel crosstalk in an orbital angular momentum-multiplexed free-space optical link. AB - A multichannel free-space optical (FSO) communication system based on orbital angular momentum (OAM)-carrying beams is studied. We numerically analyze the effects of atmospheric turbulence on the system and find that turbulence induces attenuation and crosstalk among channels. Based on a model in which the constituent channels are binary symmetric and crosstalk is a Gaussian noise source, we find optimal sets of OAM states at each turbulence condition studied and determine the aggregate capacity of the multichannel system at those conditions. OAM-multiplexed FSO systems that operate in the weak turbulence regime are found to offer good performance. We verify that the aggregate capacity decreases as the turbulence increases. A per-channel bit-error rate evaluation is presented to show the uneven effects of crosstalk on the constituent channels. PMID- 18449309 TI - A sensitive, spatially uniform photodetector for broadband infrared spectrophotometry. AB - We describe the design and performance of a liquid helium-cooled As:Si blocked impurity-band photodetector system intended for spectrophotometry in the thermal infrared (2 to 30 mum) spectral region. The system has been characterized for spectral sensitivity, noise, thermal stability, and spatial uniformity, and optimized for use with a Fourier-transform infrared spectrophotometer source for absolute goniometric reflectance measurements. Its performance is evaluated and compared to more common detector systems used in this spectral region, including room-temperature pyroelectric and liquid-N(2)-cooled photoconductive devices. PMID- 18449310 TI - Holographic image storage and multiple hologram storage in a planar Methyl Red doped liquid crystal film. AB - Holographic images are recorded and the diffraction characteristic of the hologram is investigated in a planar Methyl Red-doped liquid crystal film without an external electric field. Multiple holograms are stored in this film with no external electric field, and peristrophic multiplexing, angular multiplexing, and spatial multiplexing are demonstrated to be suited for the implementation of azo dye doped liquid crystal films among the multiplexing techniques. The diffraction efficiency is theoretically studied for multiple storage. Optical reconstruction for peristrophic multiplexed holograms and angular multiplexed holograms is discussed, which involves the peristrophic rotation angles and the recording angles, respectively. PMID- 18449311 TI - Time exposure performance of Mo-Au Gibbsian segregating alloys for extreme ultraviolet collector optics. AB - Successful implementation of extreme ultraviolet (EUV) lithography depends on research and progress toward minimizing collector optics degradation from intense plasma erosion and debris deposition. Thus studying the surface degradation process and implementing innovative methods, which could enhance the surface chemistry causing the mirrors to suffer less damage, is crucial for this technology development. A Mo-Au Gibbsian segregation (GS) alloy is deposited on Si using a dc dual-magnetron cosputtering system and the damage is investigated as a result of time dependent exposure in an EUV source. A thin Au segregating layer is maintained through segregation during exposure, even though overall erosion in the Mo-Au sample is taking place in the bulk. The reflective material, Mo, underneath the segregating layer is protected by this sacrificial layer, which is lost due to preferential sputtering. In addition to theoretical work, experimental results are presented on the effectiveness of the GS alloys to be used as potential EUV collector optics material. PMID- 18449312 TI - Optical design of a dynamic focus catheter for high-resolution endoscopic optical coherence tomography. AB - The optical system design of a dynamic focus endoscopic probe for optical coherence tomography is reported. The dynamic focus capability is based on a liquid lens technology that provides variable focus by changing its curvatures in response to an electric field variation. The effects of a cylindrical exit window present, in practice, for a catheter were accounted for. Degradation in image quality caused by this window was corrected to get diffraction limited imaging performance. As a result, the dynamically focusing catheter with a lateral resolution ranging from 4 to 6 mum through an approximately 5 mm imaging distance was designed without mechanically refocusing the system. PMID- 18449314 TI - Active feedback scheme for minimization of helicity-dependent instrumental asymmetries. AB - A method for the active feedback reduction of optical instrumental intensity asymmetries is presented. It is based on the fast chopping of two spatially separated beams of light with orthogonal linear polarizations that are recombined and passed through a quarter-wave plate to yield a single beam with rapidly flipping helicity. Active electro-optic feedback has been successfully employed to maintain this asymmetry below 10(-5). PMID- 18449313 TI - Observation of nanoparticle internalization on cellular membranes by using noninterferometric widefield optical profilometry. AB - We demonstrate the observation of gold-nanoparticle internalization in membranes of living cells by using noninterferometric widefield optical profilometry (NIWOP). The NIWOP technique can trace the height of an 80 nm gold particle on the membrane by calibrating the change of light intensity scattered from the particle along the optical axis. On the membrane, the depth resolution based on the scattering signal is similar to that based on the reflection signal, nearly 20 nm. Comparing the heights of the nanoparticle and the nearby cell membranes, we can identify the occurrence of particle internalization. Combining fluorescence microscopy with NIWOP, we also find actin aggregation around the site of the internalization process, which is an indication of endocytosis. PMID- 18449315 TI - Electric field and temperature measurement using ultra wide bandwidth pigtailed electro-optic probes. AB - We present pigtailed electro-optic probes that allow a simultaneous measurement of high frequency electric fields and temperature using a unique laser probe beam. This has been achieved by the development of a novel probe design associated with a fully automated servo-controlled optical bench, initially developed to stabilize the electric field sensor response. The developed electro optic probes present a stable response in outdoors conditions over a time duration exceeding 1 h, a frequency bandwidth from kHz to tens of GHz with a sensitivity of 0.7 Vm(-1)Hz(-(1/2)), and a temperature accuracy of 40 mK. PMID- 18449316 TI - Non-tissue-like features in the time-of-flight distributions of plastic tissue phantoms. AB - We measure high-temporal-resolution time-of-flight distributions of picosecond laser pulses in the visible and near-infrared, scattered in the forward direction by solid and liquid phantoms, and compare them to those obtained by using ex vivo tissues. We demonstrate that time-of-flight distributions from solid phantoms made of Delrin, Nylon, and Teflon are modulated by ripples that are absent in the biological samples and disappear when the temporal and/or angular resolution of the measuring apparatus is decreased. This behavior prevents the use of such materials as tissue phantoms when spatial mode and time selection are required, such as in imaging methods exploiting early arriving photons. PMID- 18449317 TI - Principle of the moving-mirror-pair interferometer and the tilt tolerance of the double moving mirror. AB - A novel type of interferometer, the moving-mirror-pair interferometer, is presented, and its principle and properties are studied. The new interferometer is built with three flat mirrors, which include two flat moving mirrors fixed as a single moving part by a rigid structure and one flat fixed mirror. The optical path difference (OPD) is obtained by the straight reciprocating motion of the double moving mirror, and the OPD value is four times the physical shift value of the double moving mirror. The tilt tolerance of the double moving mirror of the novel interferometer is systematically analyzed by means of modulation depth and phase error. Where the square aperture is concerned, the formulas of the tilt tolerance were derived. Due to the novel interferometer's large OPD value and low cost, it is very applicable to the high-spectral-resolution Fourier-transform spectrometers for any wavenumber region from the far infrared to the ultraviolet. PMID- 18449318 TI - Optimal selection of representative colors for spectral reflectance reconstruction in a multispectral imaging system. AB - In a multispectral color imaging system, the spectral reflectance of the object being imaged always needs to be accurately reconstructed by employing the training samples on specific color charts. Considering that the workload is heavy when all those color samples are used in practical applications, it is important to select only a limited number of the most representative samples. This is possible as the color charts are usually designed to cover the range of commonly imaged colors, and the color samples are redundant for spectral image reconstruction. We propose an eigenvector-based method and a virtual-imaging based method for representative color selection by minimizing the total reflectance root-mean-squares errors. The effectiveness of the proposed methods is confirmed by experimental results when compared with existing techniques. PMID- 18449319 TI - Highly-sensitive and high-resolution all-fiber three-dimensional measurement system. AB - A practical all-fiber three-dimensional measurement system is demonstrated with an incoherent interferometer at the eye-safe wavelength of 1.55 mum. The sensitivity and axial resolution are as high as 102 dB and 1.4 mum from a few meters' distance, respectively. A rotating scanner is developed for axial scanning, and a wide longitudinal scanning range of 54 mm is demonstrated. The high resolution images of a few samples are clearly obtained at the speed of 52 points/s. Moreover, the resolution, sensitivity, speed, and angle dependence are discussed for measurement of a 100 yen Japanese coin. PMID- 18449320 TI - Tomographic imaging of airglow from airborne spectroscopic measurements. AB - A description is given of the methodology based on a single, aircraft-mounted spectroscopic imager to tomographically reconstruct airglow perturbations induced by atmospheric gravity waves. In this configuration, the imager passes under the airglow structure to gather multiple-angle views of the wave structure in a relatively short amount of time. Under the assumption that the airglow structure does not change significantly during the acquisition interval, the data can be tomographically inverted to estimate the 2D (horizontal-vertical) airglow structure. We develop an inversion strategy for this image formation task and illustrate its applicability by inverting time-sequential imaging data taken from different vantage points during the ALOHA-93 campaign to reconstruct atmospheric gravity wave structures. PMID- 18449321 TI - Curvature sensor using a highly birefringent photonic crystal fiber with two asymmetric hole regions in a Sagnac interferometer. AB - A curvature sensor based on a highly birefringent (Hi-Bi) photonic crystal fiber inserted into a Sagnac interferometer is demonstrated. For this purpose, a novel Hi-Bi photonic crystal fiber was designed and fabricated. Half of the microstructured region of the photonic crystal fiber was composed by large diameter holes, while the other half contained small diameter holes. Because of this geometry, the fiber core was shifted from the center and high birefringence appears in the optical fiber. Curvature was applied for three different fiber directions for a range of 0.6-5 m(-1). Temperature and longitudinal strain was also characterized for constant curvature. The configuration showed insensitivity to these two physical parameters. PMID- 18449322 TI - Measurement of photoresist grating profiles based on multiwavelength scatterometry and artificial neural network. AB - We employed a grating profile measurement method, which is based on the combination of multiwavelength scatterometry and artificial neural network, to determine the critical dimensions of submicrometer-period photoresist gratings with wavy sidewall profiles. Six laser beams in three wavelengths and two orthogonal polarizations were adopted for the scatterometry measurement, and the incident angle of each beam was chosen following principles that we propose for achieving high sensitivity. We measured diffraction efficiencies of a large number of photoresist gratings made on glass substrates and high-reflectivity multilayer substrates coated with a chromium thin-film layer, and determined the grating groove parameters using a neural network model. The experimental results are statistically compared with results extracted from scanning electron micrographs. Good agreements between the indirect, neural network predicted results and the direct, scanning electron microscopy results are obtained. PMID- 18449323 TI - Visible and near infrared reflectances measured from laboratory ice clouds. AB - We present laboratory results of the 0.68 microm visible (VIS) and 1.617 microm near infrared (NIR) reflectances typically used for inferring optical depth and ice crystal size from satellite radiometers, from ice clouds generated in a temperature controlled column cloud chamber. Two types of ice crystals were produced in this experiment: small columns and dendrites with mean maximum dimensions of about 17 and 35 microm. Within experimental uncertainty, the measured reflectances from ice clouds at both wavelengths agree reasonably well with the theoretical results computed from the plane-parallel adding-doubling method for radiative transfer using the measured ice particle morphology. We demonstrate that laboratory scattering and reflectance data for thin ice clouds with optical depths less than 0.4 can be used for validation of the thin cirrus optical depth and ice crystal size that have been routinely retrieved from the satellite VIS-NIR two channel pair. PMID- 18449324 TI - Direct effects of manganese compounds on dopamine and its metabolite Dopac: an in vitro study. AB - Following combustion of fuel containing the additive methylcyclopentadienyl manganese-tricarbonyl (MMT), manganese phosphate (MnPO(4)) and manganese sulfate (MnSO(4)) are emitted in the atmosphere. Manganese chloride (MnCl(2)), another Mn(2+) species, is widely used experimentally. Using rat striatal slices, we found that MnPO(4) decreased tissue and media dopamine (DA) and media Dopac (a DA metabolite) levels substantially more than either MnCl(2) or MnSO(4); antioxidants were partially protective. Also, both MnCl(2) and MnPO(4) (more potently) oxidized DA and Dopac even in the absence of tissue in the media, suggesting a direct interaction between Mn and DA/Dopac. Because aminochrome is a major oxidation product of DA, we next determined whether MnPO(4) will be more potent in forming aminochrome than MnCl(2) or MnSO(4) which, indeed, was the case. Thus, a potential additional mechanism for the neurotoxic effects of environmentally-relevant forms of Mn, MnPO(4) in particular, is the generation of reactive DA intermediates. PMID- 18449325 TI - Neuroticism and Affective Priming: Evidence for a Neuroticism-Linked Negative Schema. AB - Neuroticism has been hypothesized to systematically relate to semantic memory networks favoring negative affect, but no studies using affective priming tasks have established this link. The present two studies, involving 145 undergraduate participants, sought to provide initial evidence along these lines. Study 1 used a task in which participants were asked to judge their emotions in the past, whereas Study 2 used a perceptual identification task in which participants merely had to identify the word in question. In both studies, neuroticism was positively correlated with negative affective priming, but not positive affective priming. The studies suggest that neuroticism systematically relates to the inter connectivity of negative affect with semantic memory systems, whether involving the self-concept (Study 1) or not (Study 2). These results are novel and important in understanding individual differences in neuroticism and their affective processing correlates. PMID- 18449326 TI - Advances in Exponential Random Graph (p*) Models Applied to a Large Social Network. AB - Recent advances in statistical network analysis based on the family of exponential random graph (ERG) models have greatly improved our ability to conduct inference on dependence in large social networks (Snijders 2002, Pattison and Robins 2002, Handcock 2002, Handcock 2003, Snijders et al. 2006, Hunter et al. 2005, Goodreau et al. 2005, previous papers this issue). This paper applies advances in both model parameterizations and computational algorithms to an examination of the structure observed in an adolescent friendship network of 1,681 actors from the National Longitudinal Study of Adolescent Health (AddHealth). ERG models of social network structure are fit using the R package statnet, and their adequacy assessed through comparison of model predictions with the observed data for higher-order network statistics.For this friendship network, the commonly used model of Markov dependence leads to the problems of degeneracy discussed by Handcock (2002, 2003). On the other hand, model parameterizations introduced by Snijders et al (2006) and Hunter and Handcock (2006) avoid degeneracy and provide reasonable fit to the data. Degree-only models did a poor job of capturing observed network structure; those that did best included terms both for heterogeneous mixing on exogenous attributes (grade and self-reported race) as well as endogenous clustering. Networks simulated from this model were largely consistent with the observed network on multiple higher order network statistics, including the number of triangles, the size of the largest component, the overall reachability, the distribution of geodesic distances, the degree distribution, and the shared partner distribution. The ability to fit such models to large datasets and to make inference about the underling processes generating the network represents a major advance in the field of statistical network analysis. PMID- 18449327 TI - The effect of additional characters on choice of referring expression: Everyone counts. AB - Two story-telling experiments examine the process of choosing between pronouns and proper names in speaking. Such choices are traditionally attributed to speakers striving to make referring expressions maximally interpretable to addressees. The experiments revealed a novel effect: even when a pronoun would not be ambiguous, the presence of another character in the discourse decreased pronoun use and increased latencies to refer to the most prominent character in the discourse. In other words, speakers were more likely to call Minnie Minnie than shewhen Donald was also present. Even when the referent character appeared alone in the stimulus picture, the presence of another character in the preceding discourse reduced pronouns. Furthermore, pronoun use varied with features associated with the speaker's degree of focus on the preceding discourse (e.g., narrative style and disfluency). We attribute this effect to competition for attentional resources in the speaker's representation of the discourse. PMID- 18449328 TI - Computing a family of skeletons of volumetric models for shape description. AB - Skeletons are important shape descriptors in object representation and recognition. Typically, skeletons of volumetric models are computed using iterative thinning. However, traditional thinning methods often generate skeletons with complex structures that are unsuitable for shape description, and appropriate pruning methods are lacking. In this paper, we present a new method for computing skeletons of volumetric models by alternating thinning and a novel skeleton pruning routine. Our method creates a family of skeletons parameterized by two user-specified numbers that determine respectively the size of curve and surface features on the skeleton. As demonstrated on both real-world models and protein images in bio-medical research, our method generates skeletons with simple and meaningful structures that are particularly suitable for describing cylindrical and plate-like shapes. PMID- 18449329 TI - Who is the skull base surgeon of the future? PMID- 18449330 TI - The role of the le fort I maxillotomy in the management of incompletely resected pituitary macroadenomas. AB - OBJECTIVE: The options available for the treatment of a nonsecreting pituitary macroadenoma that has been incompletely resected include reoperation, fractionated radiation therapy, and radiosurgery. Reoperation in this setting may be hindered by the same obstacles that prevented a complete resection during the initial surgical procedure, and should prompt consideration of an alternate approach or exposure. METHODS: Between January 1998 and December 2003, 10 consecutive patients were referred to the Department of Neurosurgery at the University of Texas Southwestern Medical Center for the evaluation of a nonsecreting pituitary macroadenoma that measured 3 cm or greater in diameter despite having undergone an attempt at a complete resection elsewhere. Each of these patients was reoperated using a Le Fort I maxillotomy to enhance the exposure provided by a traditional transsphenoidal approach. RESULTS: A total or near total (> 95%) resection was achieved in each case. One patient required reoperation for the repositioning of a fat graft to treat a cerebrospinal fluid fistula and one patient experienced a worsening of anterior pituitary function postoperatively. Five patients noted improved vision and no patient experienced further visual loss. Three patients have required subsequent treatment of small foci of recurrent or progressing tumor with stereotactic radiation therapy. No patient has received fractionated radiation therapy. CONCLUSION: The added exposure provided by a Le Fort I maxillotomy facilitates the resection of pituitary macroadenomas that have been incompletely resected by a traditional transnasal, trans-sphenoidal approach. PMID- 18449332 TI - The middle cranial fossa: morphometric study and surgical considerations. AB - The anatomical features of the temporal bone can vary significantly among different individuals. These variations affect the operative view in middle cranial fossa surgery. We performed 18 middle fossa approaches in 9 cadaveric heads, with detailed morphological analysis, to identify unfavorable situations and reliable systems to avoid complications during surgery. We recorded linear, angular measurements and calculated areas. We performed a computed tomography (CT) scan with analysis of the amount of bone to remove in two temporal bones. We found that the location of the internal auditory canal (IAC) is the keystone of bone removal. We also found accuracy in the system suggested by E. and J. L. Garcia-Ibanez for its identification and that there is a smaller surgical window in female patients (statistically significant) that can be predicted on preoperative imaging studies. Our study also confirms significant individual variability in the mutual relationships of different surgical landmarks. We concluded that surgery of the middle fossa requires detailed understanding of the complex temporal bone anatomy. The surgeon has to be aware of extreme variability of the more commonly used anatomical landmarks. The method to identify the position of the IAC described by E. and J. L. Garcia-Ibanez seems to be the simplest and most reliable. When the surgical strategy includes an anterior petrosectomy, interindividual variability can critically affect the working area, particularly in females. The working area can be estimated on preoperative CT scans through the petrous bone. PMID- 18449331 TI - Tumors and pseudotumors of the endolymphatic sac. AB - This article reports on the presentation, diagnosis, management, and treatment outcomes of lesions of the endolymphatic sac in patients treated at a tertiary neurotology referral center. It summarizes survival results in the largest series groups and presents a new diagnostic entity of pseudotumor of the endolymphatic sac. The study includes retrospective review of all patients diagnosed with lesions of the endolymphatic sac within our practice between 1994 and 2005 as well as review of the literature. The primary outcome measure was survival, and the secondary outcome measure was disease-free survival following definitive resection. Postoperative complications were assessed. Survival characteristics of the largest reported case series groups were reviewed. Five cases of endolymphatic sac lesions were identified. Of these, three were true endolymphatic sac tumors and two were inflammatory pseudotumors of the endolymphatic sac. All three of the endolymphatic sac tumors patients survived (100%), and two of the three had disease-free survival (67%). Two of three patients maintained persistent facial paresis postoperatively. Both patients with benign pseudotumors survived (100%). Our study concluded that endolymphatic sac tumors are rare neoplasms of the temporal bone that, although locally aggressive and invasive, have excellent prognosis for survival with complete resection. We report a new entity of pseudotumor of the endolymphatic sac that mimics true sac tumors in every respect on presentation but which is non-neoplastic in origin. PMID- 18449333 TI - Noncontiguous bilateral esthesioneuroblastoma: a case report. AB - Esthesioneuroblastoma is a rare malignant neoplasm arising from the olfactory epithelium. This tumor has a tendency to originate from one side of the nasal cavity or paranasal sinuses with frequent extension into the contralateral nasal cavity through direct invasion. A review of the literature reveals numerous case reports describing esthesioneuroblastoma with unilateral or bilateral involvement; however, there have been no known reports of bilateral noncontiguous (multifocal) esthesioneuroblastoma. We present a unique case of a patient diagnosed with two separate primary esthesioneuroblastomas who was managed with preoperative radiation followed by surgical resection of the tumor. This case illustrates that esthesioneuroblastoma must remain as part of the differential diagnosis for a multifocal, noncontiguous intranasal and paranasal sinus mass. PMID- 18449334 TI - Primary central nervous system lymphoma presenting as bilateral tumors of the internal auditory canal. AB - The increasing incidence of central nervous system (CNS) lymphoma in the general population, especially in young adults with AIDS, should alert the otolaryngologist that in future there will be an even greater incidence of this rare disease. It may be responsible for hearing loss accompanied by other neurological deficits. CNS lymphoma often has a rapidly progressive course. Early diagnosis and rapid therapy are crucial for a better prognosis. We report a case of primary CNS lymphoma involving both internal auditory canals that presented with sudden deafness and disequilibrium accompanied by facial and abducens nerve palsy. PMID- 18449335 TI - Lateral transmaxillosphenoidal approach to the lateral compartment of the cavernous sinus: technical case report. AB - This article outlines the surgical technique and the indications for the lateral transmaxillosphenoidal approach, which is illustrated by an index case. A 27-year old woman presented with a trigeminal sensory deficit caused by a dermoid tumor occupying the lateral compartment of her right cavernous sinus. A lateral transmaxillosphenoidal approach was performed, and the tumor was removed lateral to the intracavernous carotid artery (ICA) and medial to intracavernous cranial nerves. The lateral transmaxillosphenoidal approach is similar to the transmaxillosphenoidal approach used for the removal of pituitary adenomas invading the medial compartment of the cavernous sinus. By opening the lateral wall of the sphenoid sinus just above and laterally to the carotid artery, tumor can be removed medial to the intracavernous cranial nerves and lateral to the ICA. PMID- 18449336 TI - Microsurgical Anatomy of the Cavernous Sinus: Measurements of the Triangles in and around It. AB - OBJECTIVES: Since the pioneering work of Parkinson, several studies have described the microsurgical anatomy and surgical procedures involving the cavernous sinus (CS). A proposed geometric construct has been adopted as nomenclature for the region by many neurosurgeons. However, authors differ in naming and describing some of these triangular spaces. The purpose of this study is to present the anatomy and measure the dimensions of the 10 triangles in and around this region. MATERIALS AND METHODS: Eighteen CS of five cadaveric heads and four skull bases fixed in formalin were dissected using 3 x to 40 x magnification of the surgical microscope. The heads and skull bases were injected with colored silicone and the sides and area of the triangles were measured. Each cadaveric head was placed in a Sugita head-holder and a cranio-orbitozygomatic approach and a combined extra- and intradural approach were performed. The last step was the detachment of the brain from the skull base and measurement of the inferolateral paraclival and inferomedial paraclival triangles. RESULTS: The measurements of the medial border, lateral border, and base of each triangle as well as the standard deviation and area are presented. The posteromedial middle fossa triangle was the largest and the clinoidal triangle the smallest. CONCLUSIONS: The normal anatomy of the CS triangle and its areas are important in the approach of the CS lesions because these spaces are natural corridors through which the lesions can be reached. The same concept must be used for the triangles around this space. Whenever these geometric spaces might be distorted by pathology or surgical maneuvers, the surgeon must have precise knowledge about their normal sizes. PMID- 18449338 TI - Electrodeposited Sol-gels for Electrochemical Sensing of Cr(VI). PMID- 18449337 TI - Peptide Mimetics of Apolipoproteins Improve HDL Function. AB - Over the past decade evidence has accumulated that suggests that the anti inflammatory properties of HDL may be at least as important as the levels of HDL cholesterol. The recent failure of the torcetrapib clinical trails has highlighted the potential differences between HDL-cholesterol levels and HDL function. Agents to improve HDL function including HDL anti-inflammatory properties provide a new therapeutic strategy for ameliorating atherosclerosis and other chronic inflammatory conditions related to dyslipidemia. Seeking guidance from the structure of the apolipoproteins of the plasma lipoproteins has allowed the creation of a series of polypeptides that have interesting functionality with therapeutic implications. In animal models of atherosclerosis, peptide mimetics of apolipoproteins have been shown to improve the anti inflammatory properties of HDL, significantly reduce lesions and improve vascular inflammation and function without necessarily altering HDL-cholesterol levels. Some of these are now entering the clinical arena as interventions in pharmacologic and pharmacodynamic studies. PMID- 18449339 TI - Multiple doping of CsI:Tl crystals and its effect on afterglow. AB - Despite the acknowledged advantages of CsI:Tl in many scintillator applications, a characteristic property that undermines its use in high-speed radiographic and radionuclide imaging is the presence of a strong afterglow component in its scintillation decay. This causes pulse pileup in high count-rate applications, reduced energy resolution in radionuclide imaging, and reconstruction artifacts in computed tomography applications. The research outlined here addresses the specific issue of suppressing the afterglow in CsI:Tl crystals by modifying them with codopants. In previous work we reported that one specific codopant, Eu(2+), was particularly effective in this regard, lowering the normalized intensity of the afterglow in the time range of 10 mus - 100 ms by almost two orders of magnitude compared to conventional material. We also found, however, that the extent of the suppressive effect was significantly influenced by the presence of additional additives, some of which were inadvertently introduced by the very material that provided the primary Eu codopant itself. The effects of these secondary codopants, which include elemental iodine and various oxidic species, are addressed in the present investigation. PMID- 18449340 TI - Laparoscopic liver resection. PMID- 18449341 TI - The medical management of primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease of uncertain etiology characterized by the destruction of the intrahepatic and/or extrahepatic ducts through inflammation and fibrosis. This ultimately leads to biliary complications including cirrhosis, cholangiocarcinoma, and eventually death. Given the uncertainty surrounding the pathogenesis of the disease, a number of different medical therapies have been studied in the treatment of PSC. However, there currently are no effective medical therapies known to halt the progression of disease. The only definitive therapy for PSC is liver transplantation. This review will primarily focus on the medical approaches that have been studied for the treatment of PSC as well as on the management of symptoms commonly associated with the disease. PMID- 18449342 TI - A 13-year-old boy with chronic abdominal pain and vomiting. PMID- 18449343 TI - The ethics of outsourcing surrogate motherhood to India. PMID- 18449344 TI - Liposomal doxorubicin in suspected ovarian carcinoma patient with very low creatinine clearance test value. AB - A 74-year-old woman presented with moderate ascites with diagnostic features of adenocarcinoma of the ovary. She was given 1 course of cisplatin- and paclitaxel based chemotherapy but did not have her creatinine clearance tested, which was consequently found to be very low. She subsequently presented with gross debilitating symptoms and toxicity. However, she tolerated 20 mg/m(2) dose of liposomal doxorubicin every 4 weeks and was a good responder. Only 1 previous study of use of doxorubicin was found in such a low level of creatinine clearance. PMID- 18449345 TI - How to improve patient compliance in dyslipidemia diagnosis and treatment. PMID- 18449346 TI - Patient handoffs, or walking along a narrow mountain ledge. PMID- 18449347 TI - Rapid injections trump slow for minimizing injection pain. PMID- 18449348 TI - Aspirin helps prevent recurring colorectal adenomas--folic acid does not. PMID- 18449349 TI - Issues in creating a US health television network. PMID- 18449350 TI - Poetry and medicine. PMID- 18449351 TI - Acute renal failure secondary to chronic lymphocytic leukemia: a case report. AB - Acute renal insufficiency associated with chronic lymphocytic leukemia (CLL) has a variety of causes. An extremely rare cause of renal dysfunction is dense leukemic infiltrate in the renal interstitium. This report describes a patient with CLL who developed acute renal failure secondary to leukemic infiltration and who had a partial response to chemotherapy. This diagnosis should always be considered when a patient with CLL, regardless of the clinical stage, presents with renal insufficiency because it appears to respond reasonably well to a variety of therapies. The finding of enlarged kidneys on renal ultrasound is suggestive of infiltrative disease, but is not always present. Proteinuria is generally mild. The literature is reviewed. PMID- 18449352 TI - A reader and author respond to "Why is evidence-based medicine the legal standard of practice?". PMID- 18449353 TI - Myocilin variations and familial glaucoma in Taxiarchis, a small Greek village. AB - PURPOSE: To initiate a prospective study of glaucoma in a Greek village reported over 30 years ago to have several large families with primary open-angle glaucoma (POAG). METHODS: A random group of 126 villagers from Taxiarchis, Greece was examined in the village community center. The detailed evaluation included ophthalmic and general history, measurement of blood pressure, intraocular pressure (IOP), and central corneal thickness (CCT) as well as evaluation of the optic nerve status. RESULTS: The incidence of glaucoma approached 18% in this small isolated village. Myocilin variants were present in almost half of the individuals screened with Arg76Lys and Thr377Met being the most common finding (25% and 17%, respectively). Over half of the individuals with the Thr377Met mutation were diagnosed with glaucoma. Two of these patients were homozygous for the Thr377Met mutation. Three individuals with the Arg76Lys polymorphism had glaucoma; however, two of these individuals also had the Thr377Met mutation. Only two patients with pseudoexfoliation were identified. CONCLUSIONS: The incidence of glaucoma and the Thr377Met MYOC mutation in this population is much higher than that reported for other European populations. PMID- 18449355 TI - The function of filensin and phakinin in lens transparency. AB - PURPOSE: Beaded filaments are lens cell-specific intermediate filaments composed of two proteins: filensin and phakinin (CP49). Filensin and phakinin are believed to function in the maintenance of lens transparency. To elucidate the function of filensin and phakinin at the molecular level, we examined the degradation of these two proteins in normal and cataractous rat lenses. METHODS: A hereditary cataract model, the Shumiya cataract rat (SCR), was used for these studies. Anti filensin antibodies were raised against three different regions of the protein, the rod domain, the inner region of the tail domain, and the outer region of the tail domain. Anti-filensin and anti-phakinin antibodies were used to examine the conformation of degradation of filensin and phakinin by western blot analysis and fluorescent immunocytochemistry of cryosectioned lenses. RESULTS: In the normal lens, filensin was processed from a 94 kDa protein to proteins of 50 kDa and 38 kDa. Similarly, phakinin was processed from a 49 kDa protein to one of 40 kDa. The concentrations of filensin and phakinin in the rat lens cortex fluctuated with age and decreased during cataractogenesis. The 50 kDa form of filensin decreased significantly before opacification. In the normal lens, phakinin, the filensin rod domain, and the filensin inner tail domain localized to membrane lining regions in the shallow cortex and to the central region of the cytoplasm in the deep cortex. The COOH-terminal domain of filensin localized to the membrane lining region in the deep cortex. In pre-cataractous lenses, phakinin and the filensin rod domain localized primarily to the membranes lining the shallow cortex region and were distributed throughout the cytoplasm of lens fiber cells in the deep cortex. CONCLUSIONS: The 50 kDa form of filensin is important for the localization of beaded filaments in lens fiber cells and for lens transparency. PMID- 18449354 TI - A proteome map of the zebrafish (Danio rerio) lens reveals similarities between zebrafish and mammalian crystallin expression. AB - PURPOSE: To characterize the crystallin content of the zebrafish lens using two dimensional gel electrophoresis (2-DE). These data will facilitate future investigations of vertebrate lens development, function, and disease. METHODS: Adult zebrafish lens proteins were separated by 2-DE, and the resulting spots were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). The relative proportion of each crystallin was quantified by image analysis, and phosphospecific staining was used to identify phosphorylated alpha-crystallins. The proportion of each crystallin in the soluble and insoluble fraction of the lens was also determined by resolving these lens fractions separately by 2-DE. RESULTS: alpha-, beta-, and gamma-crystallins comprised 7.8, 36.0, and 47.2% of the zebrafish lens, respectively. While the alpha-crystallin content of the zebrafish lens is less than the amounts found in the human lens, the ratio of alphaA:alphaB crystallin is very similar. The phosphorylation pattern of zebrafish alphaA-crystallins was also similar to that of humans. The most abundant gamma-crystallins were the diverse gammaMs, comprising 30.5% of the lens. Intact zebrafish crystallins were generally more common in the soluble fraction with truncated versions more common in the insoluble fraction. CONCLUSIONS: While the total alpha- and gamma-crystallin content of the zebrafish lens differs from that of humans, similarities in alpha crystallin ratios and modifications and a link between crystallin truncation and insolubility suggest that the zebrafish is a suitable model for the vertebrate lens. The proteome map provided here will be of value to future studies of lens development, function, and disease. PMID- 18449356 TI - Comparative expression analysis of aquaporin-5 (AQP5) in keratoconic and healthy corneas. AB - PURPOSE: Keratoconus (KC) is a common progressive corneal disease characterized by excessive stromal thinning, central or paracentral conical protrusion, and disruptions in Bowman's layer. The etiology of KC is largely unknown, and a combination of genetic and environmental factors is believed to play a role in the origin of the disease. Recently, the absence of transcripts of the water channel, aquaporin-5 (AQP5), was demonstrated by reverse-transcription polymerase chain reaction (RT-PCR) in KC tissues and was proposed as a possible marker for KC. In this study, we sought to evaluate AQP5 mRNA and protein expression in KC and non-KC corneal tissues using a combination of techniques. METHODS: A total of 69 samples of corneal tissue were analyzed including 39 corneal buttons from patients with advanced KC, 16 samples of non-KC corneal epithelium belonging to patients who underwent surface refractive surgery, 12 sclerocorneal rims obtained from healthy donor subjects, and two healthy corneal buttons. Determination of AQP5 transcript and protein expression patterns was performed by means of real time RT-PCR, immunohistochemistry, immunocytochemistry, and flow cytometry methods. Cell culture was performed to identify AQP5 protein expression in KC epithelial cells. RESULTS: AQP5 mRNA was expressed with no significant differences between KC and non-KC tissues. Moreover, AQP5 protein expression analysis did not reveal differences in protein levels and/or cell location among KC and non-KC tissues. Interestingly, AQP5 expression continues for up to 21 days in the isolated KC corneal epithelial cells. CONCLUSIONS: Our results do not support a role for AQP5 in KC etiopathogeny or as a disease marker. Genetic background differences or a distinct pathogenetic KC cascade specific to the analyzed population could account for the dissimilarities observed in KC-related AQP5 expression. PMID- 18449357 TI - Sex hormones' regulation of rodent physical activity: a review. AB - There is a large body of emerging literature suggesting that physical activity is regulated to a varying extent by biological factors. Available animal data strongly suggests that there is a differential regulation of physical activity by sex and that the majority of this differential regulation is mediated by estrogen/testosterone pathways with females in many animal species having higher daily activity levels than males. The purpose of this manuscript is to review the mechanisms by which estrogen, progesterone, and testosterone affect the regulation of physical daily activity. This review lays the foundation for future investigations in humans as well as discussions about relative disease risk mediated by differential biological regulation of physical activity by sex. PMID- 18449358 TI - Suicidality in Body Dysmorphic Disorder. AB - Suicidal ideation, suicide attempts, and completed suicide appear common in individuals with body dysmorphic disorder (BDD). Available evidence indicates that approximately 80% of individuals with BDD experience lifetime suicidal ideation and 24% to 28% have attempted suicide. Although data on completed suicide are limited and preliminary, the suicide rate appears markedly high. These findings underscore the importance of recognizing and effectively treating BDD. However, BDD is underrecognized in clinical settings even though it is relatively common and often presents to psychiatrists and other mental health practitioners, dermatologists, surgeons, and other physicians. This article reviews available evidence on suicidality in BDD and discusses how to recognize and diagnose this often secret disorder. Efficacious treatments for BDD, ie, serotonin reuptake inhibitors (SRIs) and cognitive-behavioral therapy, are also discussed. Although data are limited, it appears that SRIs often diminish suicidality in these patients. Additional research is greatly needed on suicidality rates, characteristics, correlates, risk factors, treatment, and prevention of suicidality in BDD. PMID- 18449359 TI - A cytochrome b model, [Fe(TPP)(4-MeHIm)(2)][K(222-cryptand)](2)Cl(2). PMID- 18449360 TI - Neutrophil gelatinase-associated lipocalin: new paths for an old shuttle. AB - Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a lipocalin that is well known for its functions as a shuttle for iron and siderophores, which comprises a critical component of innate immunity to exogenous bacterial infections. However, several lines of recent evidence have added new dimensions of functionality that have attracted the interest of cancer biologists and oncologists. This review will highlight the exciting new paths and roles that are emerging for NGAL in human cancers, in the tissue response to anticancer therapy, and in the acute kidney injuries that commonly complicate the care of patients with cancer. The evidence for NGAL induction and its role in various human cancers will be explored. The current status of NGAL as a predictive non-invasive biomarker of acute kidney injuries will also be examined. PMID- 18449361 TI - BEING EMOTIONAL DURING DECISION MAKING-GOOD OR BAD? AN EMPIRICAL INVESTIGATION. AB - This paper examines the link between affective experience and decision-making performance. In a stock investment simulation, 101 stock investors rated their feelings on an Internet Web site while making investment decisions each day for 20 consecutive business days. Contrary to the popular belief that feelings are generally bad for decision making, we found that individuals who experienced more intense feelings achieved higher decision-making performance. Moreover, individuals who were better able to identify and distinguish among their current feelings achieved higher decision-making performance via their enhanced ability to control the possible biases induced by those feelings. PMID- 18449362 TI - How Does an Amide-N Chemical Shift Tensor Vary in Peptides? AB - This study addresses a void in the existing literature on the amide-(15)N chemical shift anisotropy (CSA) tensor of peptides: a systematic investigation of how the tensor varies in different peptides. Amide-(15)N CSA tensors for several dipeptides are obtained using quantum chemical calculations, as well as for a series of model Ala-X and X-Ala sequences in both alpha-helical and beta-sheet conformations (where X is one of the naturally occurring amino acids). The calculated values show a significant variation in both isolated and extended peptide structures. Hydrogen bonding at both the carbonyl group and the N-H bond of the peptide plane is shown to affect the principal values of the tensor. Calculations on model peptides indicate that the amide-(15)N CSA tensor is dependent on atoms located within a distance of five bonds. Consequently, the tensor of a given peptide residue is unaffected by residues other than those adjacent to it, which implies that the amide-(15)N CSA tensor should be considered in the context of tripeptide sequences. This further suggests that the amide-(15)N CSA tensor of the second residue of a given tripeptide sequence may be extrapolated to the same sequence in any other polypeptide or protein, given the same backbone conformation and intermolecular environment. These conclusions will facilitate future NMR structural studies of proteins. PMID- 18449363 TI - Range Condition and ML-EM Checkerboard Artifacts. AB - The expectation maximization (EM) algorithm for the maximum likelihood (ML) image reconstruction criterion generates severe checkerboard artifacts in the presence of noise. A classical remedy is to impose an a priori constraint for a penalized ML or maximum a posteriori probability solution. The penalty reduces the checkerboard artifacts and also introduces uncertainty because a priori information is usually unknown in clinic. Recent theoretical investigation reveals that the noise can be divided into two components: one is called null space noise and the other is range-space noise. The null-space noise can be numerically estimated using filtered backprojection (FBP) algorithm. By the FBP algorithm, the null-space noise annihilates in the reconstruction while the range space noise propagates into the reconstructed image. The aim of this work is to investigate the relation between the null-space noise and the checkerboard artifacts in the ML-EM reconstruction from noisy projection data. Our study suggests that removing the null-space noise from the projection data could improve the signal-to-noise ratio of the projection data and, therefore, reduce the checkerboard artifacts in the ML-EM reconstructed images. This study reveals an in-depth understanding of the different noise propagations in analytical and iterative image reconstructions, which may be useful to single photon emission computed tomography, where the noise has been a major factor for image degradation. The reduction of the ML-EM checkerboard artifacts by removing the null-space noise avoids the uncertainty of using a priori penalty. PMID- 18449364 TI - Part 2: Reader's and authors' responses to "Integrative medicine: sorting fact from fiction". PMID- 18449365 TI - Physicians pay attention: you aren't testing your patients adequately for kidney disease! PMID- 18449366 TI - A reader and author respond to "Esoteric or exoteric? Music in medicine". PMID- 18449367 TI - A reader responds to "The need for a US health television network". PMID- 18449368 TI - Part 3: A reader responds to "Integrative medicine: sorting fact from fiction". PMID- 18449369 TI - Partial hepatic resection for metastatic colorectal cancer can prolong life. PMID- 18449370 TI - How not to harm your patients when inserting chest tubes. PMID- 18449371 TI - Castle Connolly "top doctors" ratings. PMID- 18449372 TI - Part 2: A reader and author respond to "Why is evidence-based medicine the legal standard of practice?". PMID- 18449373 TI - Part 2: Readers respond to "Science and sensibility: an interview with professor Rolf M. Zinkernagel, Nobel Prize winner for medicine 1996". PMID- 18449374 TI - CME professional? What's that? PMID- 18449375 TI - How helpful are task force statements about "insufficient evidence"? PMID- 18449376 TI - Possible role of cyclooxygenase-2 in schistosomal and non-schistosomal-associated bladder cancer. AB - BACKGROUND AND PURPOSE: Cyclooxygenase (COX) is an angiogenic factor that is strongly related to inflammatory diseases and the development of cancer and metastasis in several cancers. It is overexpressed in a variety of premalignant and malignant conditions, including urinary bladder cancer. Our aim was to investigate and compare the expression of COX-2 enzyme in patients with bladder cancer, chronic cystitis, and normal bladder tissue. The results were correlated to the classic prognostic factors, mainly tumor stage and grade, in a trial to determine the prognostic significance of COX-2 marker. MATERIALS AND METHODS: Seventy-five bladder samples were taken, including 50 cases with bladder cancer (31 were schistosomal-associated and 19 non-schistosomal-associated), 20 samples from cases with chronic cystitis (7 were nonschistosomal and 13 were schistosomal cystitis), and 5 samples from normal bladder tissue taken as control. The specimens were stained by streptavidin-biotin immunohistochemistry protocol, with COX-2 monoclonal antibody. RESULTS: Although no notable expression of COX-2 was observed in the normal bladder, it was slightly expressed in chronic cystitis especially in areas of dysplasia and squamous metaplasia, whereas there was a significant increase in COX-2 (P < .001) with moderate-to-strong granular cytoplasmic expression in all malignant histologic types. The COX-2 reactivity was higher in transitional cell carcinoma (TCC) than in squamous cell carcinoma (SqCC) (P < .01). COX-2 expression was significantly higher in schistosomal associated TCC than in non-schistosomal-associated TCC (P < .01). There was a statistically significant positive correlation between COX-2 expression and tumor grade (P = .0052). COX-2 expression was significantly higher in grade 3 bladder TCC than in grades 1 and 2 bladder TCC (P < .05, P < .01). A correlation between COX-2 expression and progression of bladder TCC also was observed (P = .001). There was a significant difference in COX-2 expression level between the bladder TCCs at different clinical stages (P < .01). CONCLUSION: COX-2 is overexpressed in schistosomal-associated bladder cancer. COX-2 may be of significance to the development and proliferation of bladder TCC, consistent with a potential role for COX-2 inhibitors in the prevention and management of this disease. PMID- 18449377 TI - Nonsense mutation in the CRYBB2 gene causing autosomal dominant progressive polymorphic congenital coronary cataracts. AB - PURPOSE: We sought to identify the genetic defect in a large, five-generation Chinese family with autosomal dominant progressive polymorphic congenital coronary cataracts and to examine the clinical features in detail. METHODS: Clinical and ophthalmologic examinations were conducted on family members. All members were genotyped with microsatellite markers at loci previously associated with cataracts. Two-point LOD scores were calculated using a linkage package after genotyping. A mutation was detected by direct sequencing and verified by denaturing high-performance liquid chromatography (DHPLC). RESULTS: Clinical observations showed that all affected family members had progressive polymorphic coronary cataracts. Linkage analysis was obtained at markers, D22S303 (LOD score [Z]=2.11, recombination fraction [theta]=0.0) and D22S1167 (Z=1.20, theta=0.0). Haplotype analysis indicated that the cataract gene was closely linked with these two markers. Sequencing the betaB-crystallin gene (CRYBB2) revealed a C --> T transition in exon 6, which changed a codon from Gln to a stop codon (P.Q155X). This mutation cosegregated with all affected individuals and was not observed in any unaffected family member or 100 normal, unrelated individuals. CONCLUSIONS: This study identified a mutation in CRYBB2 in a large Chinese family with autosomal dominant progressive polymorphic congenital coronary cataracts. These results provide evidence that CRYBB2 is a pathogenic gene for congenital cataracts; at the same time, congenital cataracts are a clinically and genetically heterogeneous lens condition. PMID- 18449378 TI - Cardiovascular high-risk patients--treat to protect, but whom? AB - Current guidelines for the prevention of coronary heart disease emphasize the importance of global cardiovascular risk, which requires the evaluation and treatment of multiple risk factors. Cardiovascular risk can be stratified with the Framingham algorithm, which produces a numerical score related to the presence of risk factors, such as hypertension, dyslipidemia, and smoking. However, this algorithm is not generally applicable to European countries, particularly for those countries where the risk for cardiovascular disease is low. The SCORE (Systematic COronary Risk Evaluation) project has produced risk charts that are based on cholesterol, blood pressure, and age for low-risk European countries (Belgium, France, Greece, Italy, Luxembourg, Spain, and Switzerland) and high-risk countries. Assessments of end-organ damage can provide further prognostic information, particularly in intermediate-risk patients, but the value of including additional biomarkers in risk stratification remains to be confirmed. Risk for coronary heart disease is high or very high in more than 50% of hypertensive patients. Risk appears to be underestimated in clinical practice, particularly in those patients at highest risk. Major intervention trials with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have shown that these agents reduce the risk for cardiovascular events in patients at all levels of risk, with the greatest benefits seen in those at highest risk. PMID- 18449379 TI - No HOPE without proof: do ARBs meet the standard for cardiovascular protection? AB - Blockade of the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) plays an important role in the protection and prevention of cardiovascular disease. The Heart Outcomes Prevention Evaluation (HOPE) study established the significant effect of ACE inhibition on cardiovascular morbidity and mortality beyond blood pressure control. Smaller studies have demonstrated the efficacy of ARBs. In addition, a recent analysis from the Blood Pressure Lowering Treatment Trialists' Collaboration showed that ARB-based and ACE inhibitor-based treatment regimens were comparable in terms of the odds ratio for stroke and heart failure, independent of blood pressure reduction. There is an emerging body of evidence to suggest that a combination approach to RAS blockade with an ARB and an ACE inhibitor may further improve cardiovascular outcome compared with monotherapy with either agent alone. The large-scale ONgoing Telmisartan Alone or in combination with Ramipril Global Endpoint Trial (ONTARGET), comparing high-dose ramipril (HOPE study dosage) with telmisartan or a combination of the two, should provide important insight into the benefits of RAS blockade intervention. The results of ONTARGET are anticipated to be available in 2008. PMID- 18449380 TI - Cardiac and vascular protection: the potential of ONTARGET. AB - Cardiovascular risk is determined by multiple risk factors. Blockade of the renin angiotensin system is an important approach to the prevention of cardiovascular events. In the largest angiotensin receptor blocker cardiovascular outcome study to date, the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) program will compare the efficacy of therapy with telmisartan and ramipril, in reducing cardiovascular events in patients at high risk (history of coronary artery disease, stroke or transient ischemic attack, peripheral artery disease, or diabetes with evidence of end-organ damage). Recruited patients (n = 31,546) will be followed up for a period of 6 years, and more than 150,000 patient-years of data will be recorded. The primary endpoint is a composite of cardiovascular death, stroke, acute myocardial infarction, and hospitalization for congestive heart failure; secondary endpoints focus on reductions in newly diagnosed heart failure, new-onset type 2 diabetes, cognitive decline, atrial fibrillation, and nephropathy. In addition, an ambulatory blood pressure monitoring substudy will be conducted to assess the effect of treatment on endpoints after adjustment for 24-hour blood pressure values. Other substudies of the treatment effects on erectile dysfunction, blood markers, arterial stiffness, oral glucose tolerance, and the progression of target organ damage are also planned. The results of the ONTARGET program are due in 2008, and the findings are expected to have important clinical implications for the management of patients at high cardiovascular risk. PMID- 18449381 TI - Targeting cardiovascular protection: the concept of dual renin-angiotensin system control. AB - The renin-angiotensin system plays a key role in the regulation of blood pressure, and blockade of this system now forms a central part of strategies to reduce the risk for cardiovascular events in high-risk patients. Both angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to be effective in lowering blood pressure and reducing the risk for cardiovascular events, but both classes of drug have some limitations. Plasma concentrations of angiotensin II increase during ACE-inhibitor therapy in some patients, partly as a result of the production of angiotensin II via non-ACE pathways; furthermore, elevated aldosterone concentrations can occur in a significant proportion of patients. ARBs block the deleterious effects of angiotensin II at angiotensin type 1 receptors irrespective of the origin of the peptide, but the beneficial effects of kinins may be diminished. ARB therapy results in activation of angiotensin type 2 receptors, resulting in potentially beneficial anti-inflammatory, antithrombotic, and antiproliferative effects, but the clinical significance of these effects remains controversial. Some ARBs, particularly telmisartan, have been shown to act as partial agonists of peroxisome proliferator-activated receptor gamma, thereby increasing insulin sensitivity. Combination therapy with ACE inhibitors and ARBs offers the potential for effective blood pressure control, decreased aldosterone production, enhanced kinin activity, and increased insulin sensitivity. The potential clinical benefits of this approach in high-risk patients are currently being investigated in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), which is comparing therapy using a combination of telmisartan plus ramipril with the use of each drug in monotherapy. PMID- 18449382 TI - Prospects for renovascular protection by more aggressive renin-angiotensin system control. AB - Risk factors such as hypertension or diabetes result in a continuum of renal damage. Without intervention, initial subclinical endothelial damage progresses to incipient disease, identified by microalbuminuria. Glomerular filtration rate declines, macroalbuminuria develops, and eventually end-stage renal disease (ESRD) emerges. Because of the interrelationship between cardiovascular and renal disease and their common pathophysiologies involving angiotensin II, many patients die of cardiovascular disease before renal replacement therapy is needed. Blood pressure control is key to renoprotection, but blood pressure independent mechanisms are also implicated. Targeting the renin-angiotensin system (RAS) using angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) is a logical approach to managing all at risk patients. In advanced nephropathy, therapy aims at retarding progression to ESRD. For incipient nephropathy, ideal therapy should bring about microalbuminuria regression. In patients at risk of renal damage, preventing early target-organ damage is essential. Although evidence of ACE inhibitor benefit is limited, data show that ARBs provide renoprotection throughout the continuum and that this may be related to their cardioprotective effects. More aggressive RAS targeting by combination blockade is under investigation. Telmisartan is an ARB that delays progression of incipient and overt diabetic nephropathy and brings about regression from microalbuminuria to normoalbuminuria in hypertensive and normotensive patients. The ultimate proof of benefit will come from the ONTARGET trial, which will evaluate the cardiovascular and renal protective effects of the combination of telmisartan and ramipril. PMID- 18449383 TI - A new dawn in cardio and vascular protection v. cardiovascular high-risk patients: treat to protect. PMID- 18449384 TI - Treating to protect: current cardiovascular treatment approaches and remaining needs. AB - Current best practice to reduce cardiovascular disease involves evaluating patients' global cardiovascular risk profiles and devising treatment strategies accordingly. Despite the proven efficacy of this approach, very few physicians are adequately assessing risk, and consequently patients are failing to achieve desired treatment targets. Modifying lifestyle factors, such as diet, exercise, and cessation of smoking, remains one of the simplest and most potent means of reducing risk. Newly emerging evidence suggests that moderate physical activity (such as brisk walking for 30 minutes a day), eg, by raising levels of circulating endothelial progenitor cells, improves endothelial function and enhances vascular repair. However, patients remain remarkably reluctant to lifestyle changes, even in the face of overt, life-threatening disease. Statin treatment reduces cardiovascular morbidity and death in both primary and secondary prevention studies. However, over 90% of adults at high risk for coronary heart disease fail to achieve target low-density lipoprotein cholesterol levels in spite of statin therapy. Similarly, only about 37% of patients with hypertension meet blood pressure targets. Antihypertensive drugs achieve different levels of cardioprotection. Mounting evidence links regimens containing beta-blockers or diuretics with higher incidence of type 2 diabetes. In contrast, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers appear to confer extra protection on target organs on top of blood pressure reduction. The ONTARGET Trial Program is designed to clarify the importance of this effect. Educating patients, raising physicians' awareness, and implementing effective and safe treatment regimens are all necessary steps to bring about the much-needed improvements in cardiac health outcomes. PMID- 18449385 TI - Dr. Janie Merkel is interviewed by Ryan Blum and Janice Friend. AB - Dr. Janie Merkel is the director of Yale's Chemical Genomics Screening Facility, a high-throughput screening laboratory that is part of the Yale University Center for Genomics and Proteomics. The Screening Facility connects Yale researchers with industry-quality robotic machinery and a diverse group of compound libraries, which have been used successfully to link therapeutic targets with potential therapies. PMID- 18449386 TI - Dr. David Rimm is interviewed by Feras Akbik. AB - Dr. David Rimm, MD PhD, is a professor of Pathology at the Yale University School of Medicine specializing in developing quantitative, diagnostic techniques. His lab recently engineered a fluorescence-based algorithm, Automated Quantitative Analysis (AQUA), to analyze tissue microarrays in the hope of moving toward personalized medicine and diagnoses. PMID- 18449387 TI - Why some people prefer pickle juice: the research of Dr. Richard P. Lifton. AB - In this essay, the author interviews Dr. Richard P. Lifton and examines the use of genomics throughout his studies on the molecular pathophysiology of hypertensive and hypotensive diseases. To date, Dr. Lifton has identified 10 different gene mutations that result in severe hypertension and another 10 that result in severe hypotension. PMID- 18449388 TI - Making a new technology work: the standardization and regulation of microarrays. AB - The translation of laboratory innovations into clinical tools is dependent upon the development of regulatory arrangements designed to ensure that the new technology will be used reliably and consistently. A case study of a key post genomic technology, gene chips or microarrays, exemplifies this claim. The number of microarray publications and patents has increased exponentially during the last decade and diagnostic microarray tests already are making their way into the clinic. Yet starting in the mid-1990s, scientific journals were overrun with criticism concerning the ambiguities involved in interpreting most of the assumptions of a microarray experiment. Questions concerning platform comparability and statistical calculations were and continue to be raised, in spite of the emergence by 2001 of an initial set of standards concerning several components of a microarray experiment. This article probes the history and ongoing efforts aimed at turning microarray experimentation into a viable, meaningful, and consensual technology by focusing on two related elements:1) The history of the development of the Microarray Gene Expression Data Society (MGED), a remarkable bottom-up initiative that brings together different kinds of specialists from academic, commercial, and hybrid settings to produce, maintain, and update microarray standards; and 2) The unusual mix of skills and expertise involved in the development and use of microarrays. The production, accumulation, storage, and mining of microarray data remain multi-skilled endeavors bridging together different types of scientists who embody a diversity of scientific traditions. Beyond standardization, the interfacing of these different skills has become a key issue for further development of the field. PMID- 18449389 TI - Personalized genomic medicine with a patchwork, partially owned genome. AB - "His book was known as the Book of Sand, because neither the book nor the sand have any beginning or end." - Jorge Luis BorgesThe human genome is a three billion-letter recipe for the genesis of a human being, directing development from a single-celled embryo to the trillions of adult cells. Since the sequencing of the human genome was announced in 2001, researchers have an increased ability to discern the genetic basis for diseases. This reference genome has opened the door to genomic medicine, aimed at detecting and understanding all genetic variations of the human genome that contribute to the manifestation and progression of disease. The overarching vision of genomic (or "personalized") medicine is to custom-tailor each treatment for maximum effectiveness in an individual patient. Detecting the variation in a patient's deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein structures is no longer an insurmountable hurdle. Today, the challenge for genomic medicine lies in contextualizing those myriad genetic variations in terms of their functional consequences for a person's health and development throughout life and in terms of that patient's susceptibility to disease and differential clinical responses to medication. Additionally, several recent developments have complicated our understanding of the nominal human genome and, thereby, altered the progression of genomic medicine. In this brief review, we shall focus on these developments and examine how they are changing our understanding of our genome. PMID- 18449390 TI - 454 life sciences: illuminating the future of genome sequencing and personalized medicine. PMID- 18449391 TI - KSR Int'l Co. v. Teleflex, Inc.: no obvious changes for the biotechnology market. AB - With the advent of molecular biology, genomics, and proteomics, the intersection between science and law has become increasingly significant. In addition to the ethical and legal concerns surrounding the collection, storage, and use of genomic data, patent disputes for new biotechnologies are quickly becoming part of mainstream business discussions. Under current patent law, new technologies cannot be patented if they are "obvious" changes to an existing patent. The definition of "obvious," therefore, has a huge impact on determining whether a patent is granted. For example, are modifications to microarray protocols, popular in diagnostic medicine, considered "obvious" improvements of previous products? Also, inventions that are readily apparent now may not have been obvious when discovered. Polymerase chain reaction, or PCR, is now a common component of every biologist's toolbox and seems like an obvious invention, though it clearly was not in 1983. Thus, there is also a temporal component that complicates the interpretation of an invention's obviousness. The following article discusses how a recent Supreme Court decision has altered the definition of "obviousness" in patent disputes. By examining how the obviousness standard has changed, the article illuminates how legal definitions that seem wholly unrelated to biology or medicine could still potentially have enormous effects on these fields. PMID- 18449393 TI - Genomas: battling side effects with physiotypes. PMID- 18449392 TI - Keck Foundation Biotechnology Resource Laboratory, Yale University. PMID- 18449395 TI - Foreword: 10th anniversary review: addressing land degradation and climate change in dryland agroecosystems through sustainable land management. PMID- 18449396 TI - 10th anniversary review: addressing land degradation and climate change in dryland agroecosystems through sustainable land management. AB - Sustainable land management (SLM) is proposed as a unifying theme for current global efforts on combating desertification, climate change and loss of biodiversity in drylands. A focus on SLM will achieve the multiple goals of the three UN Conventions (UNCCD, UNFCCC and UNCBD) and in particular will address the roots causes of poverty and vulnerability to climate change rather than a current focus on adapting to climate change. The interlinkages between land degradation, climate change and loss of biodiversity are outlined together with a proposed set of interventions to achieve multiple goals. It is argued that improved land productivity is a viable goal to reduce poverty in drylands provided it is linked to payments for environmental services and better crop and weather insurances and coupled with alternative livelihoods that are not primarily dependent on land productivity. Obstacles to the achievement of SLM are discussed and the steps necessary to overcome them are presented. It is suggested that promoting SLM would be a better focus for the UNCCD than combating desertification. PMID- 18449397 TI - The SSC cycle: a PDCA approach to address site-specific characteristics in a continuous shallow water quality monitoring project. AB - In any water quality-monitoring project there are several critical success factors that must be adequately addressed in order to ensure the implementation and realization of the monitoring objectives. Site selection is one of these critical success factors. The monitoring sites must be selected to comply with the monitoring and data quality objectives. In the real world, ideal monitoring setting conditions are difficult to achieve, and compromises must be made in order to locate the monitoring stations that best represent the environment to be monitored. Site-specific characteristics are all the environmental, logistical and management factors particular to the monitoring site, that could influence the fulfilment of the monitoring and data quality objectives. Therefore, during the site selection process, it is essential to properly consider and evaluate these site-specific characteristics. The SSC cycle was developed with this goal in mind, to assist the monitoring team to systematically address site-specific characteristics. The cycle is a methodology to organize the site-specific characteristics in different categories, and to ensure a comprehensive overview of these characteristics throughout the project life cycle. PMID- 18449398 TI - Toxic equivalent concentrations (TEQs) for baseline toxicity and specific modes of action as a tool to improve interpretation of ecotoxicity testing of environmental samples. AB - The toxic equivalency concept is a widely applied method to express the toxicity of complex mixtures of compounds that act via receptor-mediated mechanisms such as induction of the arylhydrocarbon or estrogen receptors. Here we propose to extend this concept to baseline toxicity, using the bioluminescence inhibition test with Vibrio fischeri, and an integrative ecotoxicity endpoint, algal growth rate inhibition. Both bioassays were validated by comparison with literature data and quantitative structure-activity relationships (QSARs) for baseline toxicity were developed for all endpoints. The novel combined algae test, with Pseudokirchneriella subcapitata, allows for the simultaneous evaluation of specific inhibition of photosynthesis and growth rate. The contributions of specific inhibition of photosynthesis and non-specific toxicity could be differentiated by comparing the time and endpoint pattern. Photosynthesis efficiency, measured with the saturation pulse method after 2 h of incubation, served as indicator of specific inhibition of photosynthesis by photosystem II inhibitors. Diuron equivalents were defined as toxicity equivalents for this effect. The endpoint of growth rate over 24 h served to derive baseline toxicity equivalent concentrations (baseline-TEQ). By performing binary mixture experiments with reference compounds and complex environmental samples from a sewage treatment plant and a river, the TEQ concept was validated. The proposed method allows for easier interpretation and communication of effect-based water quality monitoring data and provides a basis for comparative analysis with chemical analytical monitoring. PMID- 18449399 TI - Monitoring of the ecotoxicological hazard potential by polar organic micropollutants in sewage treatment plants and surface waters using a mode-of action based test battery. AB - We propose and evaluate a mode-of-action based test battery of low-complexity and in-vitro bioassays that can be used as a routine monitoring tool for sewage treatment efficiency and water quality assessment. The test battery comprises five bioassays covering five different modes of toxic action. The bioluminescence inhibition test with Vibrio fischeri and a growth rate inhibition test with the green algae Pseudokirchneriella subcapitata are measures of non-specific integrative effects. A second endpoint in the algae test, the specific inhibition of the efficiency of photosynthesis, gives an account of the presence of herbicides. An enzymatic assay covers an important aspect of insecticidal activity, the inhibition of the acetylcholine esterase activity. Estrogenic effects are assessed with the yeast estrogen screen (YES) and genotoxicity with the umuC test. Three field studies, each lasting six to seven consecutive days, were undertaken at a sewage treatment plant (STP) in Switzerland. Samples were collected in summer and late autumn, under dry and rainy conditions. None of the bioassays gave positive results with raw water in whole effluent toxicity testing. Therefore, water samples from various sites during wastewater treatment and from surface water were enriched with solid-phase extraction. The focus was on non-volatile compounds of average to moderate hydrophobicity, a range that includes most pesticides, biocides and pharmaceuticals. Various polar solid phases were evaluated for their extraction efficiency, disturbance by matrix components and overall performance. We finally selected a mixture of a polymeric sorbent and a C18-sorbent, Lichrolut EN and RP-18 or, alternatively, Empore SDB RPS disks. All bioassays gave clear and robust responses with the SPE extracts. With the bioassay data the treatment efficiency of the STP can be assessed with respect to different modes of toxic action and accordingly different groups of micropollutants. Furthermore, the data allowed for a comparison between the effluent and the receiving river. In all bioassays the primary effluent had a strong effect and this effect was reduced after passing the STP. Treatment efficiency was high (typically over 90%) but varied from bioassay to bioassay, which is expected because each bioassay detects different types of micropollutants and therefore we cannot expect a common answer. PMID- 18449400 TI - Preparation of a highly sensitive enzyme electrode using gold nanoparticles for measurement of pesticides at the ppt level. AB - A highly sensitive enzyme electrode was prepared based on gold nanoparticles for measurement of pesticides. Gold nanoparticles of 25-30 nm were synthesized on a glassy carbon electrode by double-pulse technique while the coverage was controlled by applied potential and time. The gold nanoparticles were modified to form a self-assembled monolayer, followed by covalent binding of tyrosinase. The TYR-AuNP-GC electrode was compared with bare GC, AuNP-GC, and modified AuNP-GC and TYR-Au (plate type) electrodes in terms of cyclic voltammetry. The voltammograms well represent the sensitivity of enzymatic oxidation of catechol, substrates for the enzyme activity. The prepared electrode integrated into a continuous flow system and was tested to detect pesticides, such as 2,4-D, atrazine, and ziram. Under the optimized conditions of the flow system, the electrode performed reasonably according to the inhibition mechanism in the concentration range of 0.001-0.5 ng mL(-1). The enhanced performance was attributed to the favored microenvironment for the enzyme activity provided by SAM on gold nanoparticles. PMID- 18449401 TI - Organotins in a medium-size Mediterranean basin (the Herault River). AB - This study reports the first assessment of organotin pollution in the Herault watershed, a medium size Mediterranean basin. Organotin compounds were analyzed in surface waters, wells supplying drinking water and sewage treatment plants (STPs). In surface and ground waters, a background contamination by total organotin compounds has been identified in the range of 0.51 +/- 0.02-71 +/- 2 ng(Sn) L(-1), which is of the same order of magnitude as those observed in other European areas. Organotins were systematically present in STP influents and sludge. Total or partial elimination of organotin compounds from treated wastewater was observed. STP effluents appeared nevertheless to be a non negligible source of contamination not only of rivers but also of aquifers tapped for drinking water supply. Tributyltin concentration was higher than the maximum allowable concentration proposed by the European Commission in some surface waters and wells supplying drinking water. This could compromise the water resource and have serious and irreversible consequences for the aquatic eco system. As it was the case for the ban of antifouling paints, a regulatory regime in decreasing point-source emissions of these harmful compounds used in household products might be applied. PMID- 18449402 TI - Dust exposure in indoor climbing halls. AB - The use of hydrated magnesium carbonate hydroxide (magnesia alba) for drying the hands is a strong source for particulate matter in indoor climbing halls. Particle mass concentrations (PM10, PM2.5 and PM1) were measured with an optical particle counter in 9 indoor climbing halls and in 5 sports halls. Mean values for PM10 in indoor climbing halls are generally on the order of 200-500 microg m( 3). For periods of high activity, which last for several hours, PM10 values between 1000 and 4000 microg m(-3) were observed. PM(2.5) is on the order of 30 100 microg m(-3) and reaches values up to 500 microg m(-3), if many users are present. In sports halls, the mass concentrations are usually much lower (PM10 < 100 microg m(-3), PM2.5 < or = 20 microg m(-3)). However, for apparatus gymnastics (a sport in which magnesia alba is also used) similar dust concentrations as for indoor climbing were observed. The size distribution and the total particle number concentration (3.7 nm-10 microm electrical mobility diameter) were determined in one climbing hall by an electrical aerosol spectrometer. The highest number concentrations were between 8000 and 12 000 cm( 3), indicating that the use of magnesia alba is no strong source for ultrafine particles. Scanning electron microscopy and energy-dispersive X-ray microanalysis revealed that virtually all particles are hydrated magnesium carbonate hydroxide. In-situ experiments in an environmental scanning electron microscope showed that the particles do not dissolve at relative humidities up to 100%. Thus, it is concluded that solid particles of magnesia alba are airborne and have the potential to deposit in the human respiratory tract. The particle mass concentrations in indoor climbing halls are much higher than those reported for schools and reach, in many cases, levels which are observed for industrial occupations. The observed dust concentrations are below the current occupational exposure limits in Germany of 3 and 10 mg m(-3) for respirable and inhalable dust. However, the dust concentrations exceed the German guide lines for work places without use of hazardous substances. In addition, minimizing dust concentrations to technologically feasible values is required by the current German legislation. Therefore, substantial reduction of the dust concentration is required. PMID- 18449403 TI - Quantitative PCR analysis of fungi and bacteria in building materials and comparison to culture-based analysis. AB - Prolonged moisture on building materials can lead to microbial growth on them. Microbes can emit spores, metabolites and structural parts into the indoor air and thus, cause adverse health effects of people living and working in these buildings. So far, culture methods have been used for assessment of microbial contamination of building materials. In this work, we used quantitative PCR (qPCR) for the detection of selected fungal and bacterial groups in 184 building materials of different types and compared the results with culture-based analysis. Nine either commonly found species, genera or groups of fungi, or those considered as moisture damage indicators, and one bacterial genus, Streptomyces, were determined using qPCR. Fungi and mesophilic actinomycetes were also cultivated using standard media and conditions of the routine analysis. The bacterial genus Streptomyces and the fungal group Penicillium/Aspergillus/Paecilomyces were the most prevalent microbial groups in all building material types, followed by Stachybotrys chartarum and Trichoderma viride/atroviride/koningii. The highest prevalences, concentrations and species diversity was observed on wooden materials. In general, the results of the two methods did not correlate well, since concentrations of fungi and streptomycetes were higher and their occurrence more prevalent when determined by qPCR compared to culture-based results. However, with increasing concentrations, the correlation generally increased. The qPCR assay did not detect Aspergillus versicolor and Acremonium strictum as often as culture. PMID- 18449404 TI - Pharmaceutical residues in the river Rhine--results of a one-decade monitoring programme. AB - In this paper, results of an extensive monitoring programme for pharmaceutical residues in the river Rhine are presented. For one decade (1997 until 2006), the occurrence of widely used human pharmaceuticals like analgesics, lipid regulators, antiepileptics and others has been studied at four locations along the river Rhine. The results of more than 500 analyses clearly prove that compounds such as carbamazepine or diclofenac are regularly found in the river Rhine in concentrations up to several hundred ng per litre. Combining concentration levels with data on water flow enables the calculation of transports, which e.g. for carbamazepine or diclofenac were in the range of several tons per year. The evaluation of the long-term monitoring data shows that only a slight decrease in concentration levels as well as in annual transports can be observed and thus the contamination of the river Rhine by pharmaceutical residues during the last decade has to be regarded as almost constant. Seasonal variations can be detected for bezafibrate, diclofenac and ibuprofen, for which the concentrations are much lower in the summer months. A more effective removal during wastewater treatment in the warmer periods of the year seems to be the major reason for those variations. For carbamazepine, no comparable seasonal effect can be found. PMID- 18449405 TI - Implementing infrared determination of quartz particulates on novel filters for a prototype dust monitor. AB - Research by the National Institute for Occupational Safety and Health (NIOSH) has pursued quartz analysis for the specialized filter assemblies of a new worker wearable personal dust monitor (PDM). The PDM is a real-time instrument utilizing a tapered element oscillating microbalance (TEOM). Standard fiberglass TEOM filters cannot accommodate the desired P-7 infrared analytical method used by the Mine Safety and Health Administration (MSHA). Novel filter materials were tested with the objective of demonstrating this type of analysis. Low temperature ashing and spectrometric examination were employed, revealing that nylon fiber candidate filters left minimal residual ash and produced no significant spectral interference. Avoiding titanium dioxide in all filter materials proved to be a key requirement. Fine quartz particulates were collected on prototype filters in a Marple chamber, either open-faced or through PDMs during test runs. The filters were then subjected to MSHA P-7 analysis and the spectrometrically based analytical results for quartz mass were compared to reference measurements. Also, PDM instrumental mass readings were compared to filter gravimetric measurements. Results suggest that the P-7 method is adaptable to variations in filter materials and that quartz dust analysis by the P-7 method when utilizing the new ashable PDM filters can have accuracy and precision within 10% and 4%, respectively. This is within the declared 13% accuracy and 7-10% precision of the P-7 method itself. Instrument mass readings had modest positive bias but met NIOSH accuracy criteria. Continued work with specialized PDM filters is merited, as they are a new type of TEOM sample amenable to ashing analysis of particulates. PMID- 18449406 TI - Propagating factor IX-producing hepatocytes for haemophilia B therapy. PMID- 18449407 TI - Thromboembolic complications of sepsis: what is the incidence and pathophysiological mechanisms involved? PMID- 18449408 TI - Therapeutic integrin inhibition: allosteric and activation-specific inhibition strategies may surpass the initial ligand-mimetic strategies. PMID- 18449409 TI - Current use of biologicals in thrombosis and haemostasis. PMID- 18449410 TI - Heparin and low-molecular-weight heparin. AB - Heparin is one of the oldest biological medicines, and has an established place in the prevention and treatment of venous thrombosis. Low-molecular-weight heparins (LMWH) have been developed by several manufacturers and have advantages in terms of pharmacokinetics and convenience of administration. They have been shown to be at least as effective and safe as unfractionated heparin and have replaced the latter in many indications. In this article the chemistry, mechanisms of action, measurement of anticoagulant activities, and clinical status of heparin and LMWH are reviewed. PMID- 18449411 TI - The direct thrombin inhibitor hirudin. AB - This review discusses the pharmacology and clinical applications of hirudin, a bivalent direct thrombin inhibitor (DTI). Besides the current major indication for hirudin--anticoagulation of patients with heparin-induced thrombocytopenia (HIT)--the experience with hirudin in other indications, especially acute coronary syndromes, are briefly presented. Hirudins have been formally studied prior to their regulatory approval; however, important information on their side effects and relevant preventative measures only became available later. Therefore, current recommendations and dosing schedules for hirudin differ considerably from the information given in the package inserts. Drawbacks of hirudin and important precautions for avoiding potential adverse effects are discussed in detail in the third part of this review. PMID- 18449412 TI - Bivalirudin. AB - Bivalirudin is a direct thrombin inhibitor (DTI) frequently used for anticoagulation in the setting of invasive cardiology, particularly percutaneous coronary intervention (PCI). Bivalirudin has a unique pharmacologic profile: unlike other marketed DTIs, it undergoes predominant non-organ elimination (proteolysis), and has the shortest half-life (approximately 25 min). Its affinity for thrombin is intermediate between that of lepirudin (highest) and argatroban (lowest)--this helps explain why it interferes with functional clotting assays to an extent intermediate between that achieved by these two other DTIs. This effect is best known for the PT (INR)--higher affinity for thrombin corresponds to lower molar DTI requirements to prolong the APTT; in turn, lower concentrations required for APTT prolongation (and, presumably, in vivo effect) result in reduced PT (INR) prolongation. Bivalirudin is primarily used for its first FDA-approved indication, namely anticoagulation during percutaneous transluminal coronary angioplasty ("balloon angioplasty"), the most frequent type of PCI. Bivalirudin is also indicated for PCI with provisional use of glycoprotein IIb/IIIa antagonist therapy, and for patients with, or at risk of, heparin-induced thrombocytopenia (HIT), or HIT with thrombosis syndrome (HITTS), undergoing PCI. The bivalirudin development program has used a "quadruple" endpoint comprising a "triple" efficacy endpoint plus major bleeding this approach anticipated the subsequent emphasis on strategies to improve clinical outcomes through bleeding reduction. Besides summarizing the key trials evaluating bivalirudin use for acute coronary syndrome (especially employing PCI), we review also the studies of bivalirudin as anticoagulant for "on-" and "off-pump" cardiac surgery, including both HIT and non-HIT situations. PMID- 18449413 TI - Recombinant clotting factors. AB - The recombinant era for haemophilia began in the early 1980s with the cloning and subsequent expression of functional proteins for both factors VIII and IX. Efficient production of recombinant clotting factors in mammalian cell culture systems required overcoming significant challenges due to the complex post translational modifications that were integral to their pro-coagulant function. The quick development and commercialization of recombinant clotting factors was, in part, facilitated by the catastrophic impact of viral contamination of plasma derived clotting factor concentrates at the time. Since their transition into the clinic, the recombinant versions of both factor VIII and IX have proven to be remarkable facsimiles of their plasma-derived counterparts. The broad adoption of recombinant therapy throughout the developed world has significantly increased the supply of clotting factor concentrates and helped advance aggressive therapeutic interventions such as prophylaxis. The development of recombinant VIIa was a further advance bringing a recombinant option to haemophilia patients with inhibitors. Recombinant DNA technology remains the platform to address ongoing challenges in haemophilia care such as reducing the costs of therapy, increasing the availability to the developing world, and improving the functional properties of these proteins. In turn, the ongoing development of new recombinant clotting factor concentrates is providing alternatives for patients with other inherited bleeding disorders. PMID- 18449414 TI - Plasma-derived biological medicines used to promote haemostasis. AB - Several biological medicines derived from human and animal plasmas can effectively improve haemostasis in individuals with inherited or acquired defects in haemostasis. Factor VIII and factor VIII/vWF and factor IX concentrates are used to treat haemophilia A, von Willebrand disease and hemophilia B respectively. Cryoprecipitates are used to treat hypofibrinogenemia and von Willebrand disease where desmopressin (DDAVP) is ineffective or when plasma derived factor VIII/vWF concentrates are unavailable. Thrombin-containing topical haemostatic agents and fibrin sealants are used to control perioperative bleeding. Intravenous immunoglobulin has several uses, including management of patients with autoimmune thrombocytopenias and patients with acquired factor VIII deficiency. Similar to most protein-based biological medicines, all the above products can elicit some level of antibody response, with clinical consequences that vary from mild anaphylaxis to loss of product efficacy. An ongoing potential safety concern with any biological medicine derived from blood/plasma is transmission of blood-borne pathogens. This safety concern has lessened significantly in the past decade as a result of the institution of more effective pre- and post-donation screening that tests for potential pathogens, and institution of pathogen reduction strategies to which many plasma-derived biological medicines are now routinely subjected. This article considers the manufacture, standardization, clinical efficacy and adverse event profiles of the plasma-derived biological medicines currently used to promote haemostasis in patients with inherited or acquired functional defects in haemostasis. It also considers approaches employed to minimize infectivity of biological medicines derived from human and animal plasmas and to manage patients who develop antibodies (inhibitors) to clotting factor concentrate infusions. PMID- 18449415 TI - Haematopoietic growth factors and their therapeutic use. AB - Haematopoietic growth factors constitute an important group of proteins that predominantly regulate the process of haematopoiesis. While some of these proteins have a very broad array of action on very early haematopoietic progenitors leading to multi-lineage increases in haematopoietic cell production and differentiation, others act in a restricted manner on specific committed terminally differentiated cell types. On the basis of their unique spectrum of activities, several factors are approved for clinical use in various indications while others are under investigation in the clinic either alone or as combination therapy. In this review, we have described factors which directly and in some cases indirectly influence haematopoiesis with particular focus on those factors which are either approved or show potential for clinical use. A brief description of the products that are currently available for clinical use is also provided. At present, several new products which include fusion proteins, peptide mimetics are either at the pre-clinical stage or in clinical development for various indications and these are also briefly described. PMID- 18449416 TI - Factors that contribute to the immmunogenicity of therapeutic recombinant human proteins. AB - Use of recombinant human proteins has revolutionized medicine by providing over 200 highly purified hormones and proteins that effectively treat many inherited and acquired peptide hormone and protein deficiencies. With the exception of therapeutic monoclonal antibodies, these biological medicines are synthesized by cultured cells using DNA sequences that would yield proteins with identical amino acid sequences as endogenous human proteins. Therefore, there was the broad expectation that recombinant human biological medicines would be non-immunogenic in patients capable of synthesizing even sub-optimal levels of these therapeutic proteins to which they are innately tolerant. However, the widespread clinical use of recombinant human proteins has demonstrated that nearly all of them are immunogenic. This observation suggests that factors additional to differences in amino acid sequences of endogenous and biotherapeutic proteins contribute to the immunogenicity of therapeutic proteins. The main aim of this review is to summarize some of the factors that are known to contribute to the immunogenicity of recombinant therapeutic proteins. PMID- 18449417 TI - Successful in vivo propagation of factor IX-producing hepatocytes in mice: potential for cell-based therapy in haemophilia B. AB - Cell-based therapies using isolated hepatocytes have been proposed to be an attractive application in the treatment of haemophilia B due to the normal production of coagulation factor IX (FIX) in these particular cells. Current cell culture technologies have largely failed to provide adequate isolated hepatocytes, so the present studies were designed to examine a new approach to efficiently proliferate hepatocytes that can retain normal biological function, including the ability to synthesize coagulation factors like FIX. Canine or human primary hepatocytes were transplanted into urokinase-type plasminogen activator severe combined immunodeficiency (uPA/SCID) transgenic mice. Both donor hepatocytes from canines and humans were found to progressively proliferate in the recipient mouse livers as evidenced by a sharp increase in the circulating blood levels of species-specific albumin, which was correlated with the production and release of canine and human FIX antigen levels into the plasma. Histological examination confirmed that the transplanted canine and human hepatocytes were able to proliferate and occupy >80% of the host livers. In addition, the transplanted hepatocytes demonstrated strong cytoplasmic staining for human FIX, and the secreted coagulation factor IX was found to be haemostatically competent using specific procoagulant assays. In all, the results from the present study indicated that developments based on this technology could provide sufficient FIX-producing hepatocytes for cell-based therapy for haemophilia B. PMID- 18449419 TI - P-selectin gene haplotypes modulate soluble P-selectin concentrations and contribute to the risk of venous thromboembolism. AB - The cell adhesion molecule P-selectin mediates the interaction of activated platelets or endothelial cells with leukocytes. In arterial and venous thromboembolism (VTE) increased soluble P-selectin (sP-selectin) concentrations have been found, and associations of P-selectin genotypes with thrombotic disease have been proposed. We assessed the effect of four single nucleotide polymorphisms (SNPs) [one in the promoter region (c.-2123C>G) and three (S290N, c.1087G>A; D562N, c.1902G>A; T715P, c.2363A>C) in the coding region] and the calculated haplotypes in the P-selectin gene (SELP) on sP-selectin concentrations and VTE risk. The analysis was carried out in 116 high-risk patients with a history of objectively confirmed recurrent VTE and 129 age- and sex-matched healthy individuals. Haplotypes were generated using computer-assisted haplotype reconstruction with Phase 2.1. sP-selectin (microg/l) was measured by ELISA. Frequencies of all four individual SNPs were not statistically significantly different between patients and controls. Ten haplotypes were obtained for the control population, and nine for the patient group. The most frequent haplotype among controls was CGGA (major allele at all positions) (27.8%; frequency in patients 19.0%), which was used as reference for statistical analyses. Among patients GGAA was most frequent (23.3%; frequency in controls 17.5%). Haplotypes were significantly associated with sP-selectin concentrations in patients and in controls (p<0.001 and p=0.011). Compared to CGGA some but not all haplotypes conferred an increased risk for VTE with odds ratios (ORs) between 5.4 (95% CI: 2.5-12.2) for CAGA, 3.3 (1.2-9.2) for CGAC, and 2.4 (1.3-4.7) for GGAA. All ORs remained statistically significant after adjustment for the factor V Leiden mutation, located in close proximity to SELP on chromosome 1, as well as all other established risk factors for VTE. In conclusion, SELP haplotypes modulate plasma concentrations of sP-selectin and affect the risk of recurrent VTE. PMID- 18449418 TI - Venous and arterial thromboembolism in severe sepsis. AB - The burden of thromboembolism (TE) in severe sepsis is largely unknown. We assessed the prevalence of venous and arterial TE in patients with severe sepsis over a four-week period. We performed a retrospective analysis of a pooled database of three randomized, placebo-controlled trials of two novel pharmacological agents for the treatment of severe sepsis, drotrecogin alfa (activated) (DrotAA) and secretory phospholipase A2 inhibitor (sPLA(2)I). The study was conducted at intensive care units of the participating institutions. A total of 2,649 patients with known or suspected infection and sepsis-associated acute organ dysfunction were enrolled in the three trials and were assigned to treatment groups (DrotAA=850; sPLA2I=578; placebo=1221). The database was queried for venous and arterial TE, using investigator reports of serious adverse events. Eighty-four of 2,649 patients (3.2%; 95% confidence interval, 2.5% to 3.9%) developed at least one thromboembolic event over 28 days. Nearly three-quarters of episodes were atheroembolic (n=62); 25% involved the deep venous system (n=25). Ischemic stroke (n=30) and venous thromboembolism (n=25) each occurred in about 1% of patients. Ischemic stroke and acute coronary syndrome had a higher peak incidence during the first five days compared to venous TE onset, which was more constant over the 28-day period. Subgroup analysis by pooled treatment groups yielded TE rates of 2.0% (DrotAA), 3.5% (placebo), and 4.0% (sPLA2I), respectively. Clinically manifest TE occurred in about 3% of severe sepsis patients treated in the intensive care unit over a 28-day period. Arterial TE may be more common than previously recognized. More accurate estimates of TE prevalence and relationship to sepsis await future studies. PMID- 18449420 TI - Association of ADAMDEC1 haplotype with high factor VIII levels in venous thromboembolism. AB - A suggestive locus on chromosome 8 could be shown to be associated with familial high factor VIII (FVIII) levels in venous thromboembolism. The ADAMDEC 1 gene is a candidate expressing an ectodomain sheddase. However, the ectodomain of the clearance receptor for FVIII, the low-density lipoprotein receptor-related protein (LRP), is subject to proteolysis by metalloproteases like ADAMDEC1. Other LRP-interacting proteins are lipoprotein lipase (LPL) and t-PA. For an association study, 165 thrombotic patients with high FVIII levels (from the MAISTHRO, i.e. Main-Isar-thrombosis register) were included. All patients with known causes for high FVIII levels had been previously excluded. The patients were compared with 214 healthy blood donors. Polymorphisms with usually a minor allele frequency >5%, i.e. 24 SNPs and two insertion/deletion polymorphisms of LPL gene, eight SNPs of the t-PA gene, and five SNPs of the ADAMDEC1 gene, were analyzed. Haplotype differences were calculated using PHASE. A new polymorphism in intron 7 of the t-PA gene with a minor allele frequency of 2.2% was identified. Analysis of each SNP by the Cochrane-Armitage trend test did not show any significant association between genotype and disease status. Interestingly, the ADAMDEC1 haplotype (rs12674766, rs10087305, rs2291577, rs2291578, rs3765124) differed between cases and controls (p = 0.04). In particular, the TGTGG haplotype showed a difference. In conclusion, the ADAMDEC 1 haplotype may indicate an underlying mechanism for high FVIII levels. The only moderate linkage disequilibrium may be due to a possible causal polymorphism in distant introns or the promoter region against a polygenic background. PMID- 18449421 TI - Microparticle-associated vascular adhesion molecule-1 and tissue factor follow a circadian rhythm in healthy human subjects. AB - An increased risk of death or severe injury due to late-morning thrombotic events is well established. Tissue factor (TF) is the initiator of the coagulation cascade, and endothelial stresses, coupled with production of pro-coagulant microparticles (MP) are also important factors in loss of haemostasis. TF and vascular cell adhesion molecule-1 (VCAM-1) -positive cell microparticles were assessed periodically over a 24-hour (h) period in healthy human subjects to ascertain if they followed a circadian rhythm. Eleven healthy male subjects were assessed in a temperature-controlled environment with dietary intake consistent between subjects. Blood samples were taken every 4 h by venipuncture, and TF and VCAM-1 positive microparticles were quantified by flow cytometry. A significant circadian rhythm was observed in VCAM-1 MP (p=or<0.0001), and a trend was shown, although not statistically significant (p=0.065) in TF microparticles. A peak was observed at 9 a.m. for VCAM-1 positive MP, followed by a decrease and subsequent peak at 9 p.m. and a minimum at 5 a.m. TF-positive MP followed a strikingly similar trend in both variation and absolute numbers with a delay. A circadian rhythm was observed in VCAM-1 and less so TF-positive MP. This has significant implications in terms of the well known increased risk of cardiovascular thrombotic events matching this data. To our knowledge this is the first such report of quantified measurements of these MP over a 24-h period and the only measurement of a 24-h variation of in-vivo blood-borne TF. PMID- 18449422 TI - Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: influence of glycosylation, proteolysis and gene mutations. AB - Reduced plasma survival of von Willebrand factor (VWF) may contribute towards the pathogenesis of type 1 von Willebrand disease (VWD). However, little is known about mechanism(s) of VWF clearance and factors that may affect it. The half-life of VWF-related parameters following the administration of DDAVP was measured in 26 patients with type 1 VWD and 10 haemophilia A controls. Binding of lectins Ricinus communis (RCA-I) and Erythina crystagalli (ECA) agglutinins to VWF and VWF susceptibility to ADAMTS-13-mediated proteolysis were investigated. Sequence analysis of targeted regions of the VWF gene was performed to inspect for mutations that have been associated with increased clearance. Post-DDAVP clearance of VWF was increased approximately three-fold in the type 1 VWD cohort overall. However this was not shown to consistently associate with steady-state VWF antigen (VWF:Ag) levels. Furthermore, increased VWF clearance was not consistently associated with increased ratios of VWF propeptide (VWFpp) to VWF:Ag indicating that a normal ratio does not necessarily reflect normal post-DDAVP survival in type 1 VWD patients. RCA-I and ECA binding to VWF were increased in type 1 VWD patients and, although inversely correlated with VWF levels, this was independent of VWF clearance. There was no association between VWF clearance and ADAMTS-13-mediated proteolysis. Three novel candidate mutations with an increased clearance phenotype were identified. The data are consistent with heterogeneity in pathogenic mechanisms in type 1 VWD and are consistent with type 1 VWD representing a complex genetic trait. PMID- 18449423 TI - The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors. Case-control study and meta-analysis. AB - Several small case-control studies have investigated whether factor V Leiden (FVL) is a risk factor for retinal vein occlusion (RVO) and generated conflicting data. To clarify this question we performed a large two-centre case-control study and a meta-analysis of published studies. Two hundred seven consecutive patients with RVO and a control group of 150 subjects were screened between 1996 and 2006. A systematic meta-analysis was done combining our study with further 17 published European case-control studies. APC resistance was detected in 16 out of 207 (7.7%) patients and eight out of 150 (5.3%) controls. The odds ratio (OR) estimated was 1.49 with a (non-significant) 95% confidence interval (CI) of 0.62 3.57. The meta-analysis including 18 studies with a total of 1,748 patients and 2,716 controls showed a significantly higher prevalence of FVL in patients with RVO compared to healthy controls (combined OR 1.66; 95% CI 1.19-2.32). All single studies combined in the meta-analysis were too small to reliably detect the effect individually. This explains the seemingly contradictory data in the literature. In conclusion, the prevalence of APC resistance (and FVL) is increased in patients with RVO compared to controls, but the effect is only moderate. Therefore, there is no indication for general screening of factor V mutation in all patients with RVO. We recommend this test to be performed in patients older than 50 years with an additional history of thromboembolic event and in younger patients without general risk factors like hypertension. PMID- 18449424 TI - Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. AB - A high platelet turnover rate produce a population of immature reticulated platelets (RP) that could confer, despite of antiplatelet drugs, a residual platelet reactivity (RPR) in coronary artery disease (CAD) patients. To assess the influence of RP on platelet reactivity in CAD patients on dual antiplatelet therapy we measured RP in 372 patients by using the Sysmex XE-2100 haematology analyzer and platelet function by optical platelet aggregometry (PA) on platelet rich-plasma induced by 1 mmol arachidonic acid (AA-PA) and 10 microM ADP (ADP PA). RPR was defined as either AA-PA>20% or ADP-PA>70%. RP were expressed as a percentage of RP of the total optical platelet count (immature platelet fraction; IPF) and as the percentage of RP highly fluorescent (highly fluorescent immature platelet fraction; H-IPF). Moderate but significant positive correlations between PA, IPF, H-IPF, and mean platelet volume (MPV) were found. According to tertiles of IPF, H-IPF and MPV, a significant trend for an increase of platelet aggregation by AA and ADP was evidenced. Furthermore, a significant difference for IPF, H-IPF and MPV between patients with and without RPR was observed. A linear regression analysis showed that IPF, H-IPF and MPV significantly affected PA measured by AA and ADP. At multivariate linear regression analysis these associations were confirmed. Moreover, a logistic regression analysis demonstrated that IPF, H-IPF and MPV significantly influenced the risk of RPR, and in the multivariate model these results remained significant. This study indicates that a high rate of platelet turnover is a new mechanism associated with platelet reactivity in high risk CAD patients on dual antiplatelet therapy. PMID- 18449425 TI - Crosstalk between coagulation and inflammation during Dengue virus infection. AB - Dengue fever is the most prevalent viral disease transmitted by vectors (Aedes aegypti, Aedes albopictus) in worldwide. More than 100 million cases occur annually with a mortality rate of 5% and no safe vaccine is available. The pathogenesis of Dengue, where host and viral factors participate in the establishment of Dengue haemorrhagic fever (DHF) and Dengue shock syndrome (DSS) remains unresolved. Clinical observations have revealed significant abnormalities in coagulation and inflammation systems, with increased levels of tissue factor (TF) and the chemokine IL-8, correlating with the severity of the disease and implicating damage to endothelial vascular cells (EVC). Here we present novel insights concerning the crosstalk between the regulatory signaling pathways of the coagulation-inflammation processes, during Dengue virus (DV) infection of EVC. We found that DV up-regulates Protease Activated receptor type-1 (inflammation) and TF (coagulation) receptors, via the phosphorylation of p38 and ERK1/2 MAPKs, which favor the activation of NF-kappaB transcription factor. This induces pro-inflammatory (IL-8) or pro-adhesive (VCAM-1) gene expression which may lead to EVC activation. The elucidation of the basic principles that signal these processes has important implications for the design of new therapeutic strategies for DHF/DSS. PMID- 18449426 TI - Polymorphisms in the IL6 gene in Asian Indian families with premature coronary artery disease--the Indian Atherosclerosis Research Study. AB - Inflammation plays a major role in coronary artery disease (CAD). We investigated the polymorphisms in the interleukin 6 (IL6) gene and their effect on the expression of acute-phase proteins in premature CAD in Asian Indian families. One hundred and ninety affected sibling pairs (ASPs) were genotyped for three tag single nucleotide polymorphisms (SNPs) in the IL6 gene for linkage analysis. We observed suggestive logarithm of odds (LOD) score for one SNP (rs2066992) in a subset of 62 ASPs with the age at onset less than 45 years (LOD score=1.114, p=0.011 in linkage analysis; pi=0.55, p=0.008 in identity by descent; LOD score=1.06, p=0.014 in quantitative trait locus for plasma levels of high sensitivity C-reactive protein, hsCRP). This was followed by sequencing of the promoter region and haplotype analysis in 46 probands and 40 controls. Five out of the eight previously reported promoter SNPs were found to be polymorphic (rs1800797, rs1800796, rs7802307, rs7802308, rs1800795). Two novel sequence variants were also found. One promoter haplotype (GGAAG) was detected with an odds ratio (OR) of 3.676 (p=0.0017, 95% confidence interval [CI]: 1.68-8.045) and population attributable risk of 21.1% (95%CI: 9.2%-31.5%). The plasma levels of both hsCRP and fibrinogen exhibited significant association with these promoter SNP genotypes (p<0.001). In conclusion, IL6 gene polymorphisms appear to be important genetic factors in premature CAD, and in the regulation of key atherogenic markers in Asian Indian families. PMID- 18449427 TI - Clinical and echocardiographic measures governing thromboembolism destination in atrial fibrillation. AB - Although infrequent, embolic occlusion to non-cerebral arteries may result in limb loss, organ failure, and death. The aim of this study was to define clinical and echocardiographic characteristics determining thromboembolism destination in non-valvular atrial fibrillation. An inception cohort of individuals (n=72) were identified with incident peripheral embolism in the setting of non-valvular atrial fibrillation (1995-2005). A randomly selected group of atrial fibrillation related stroke patients (n=100) were identified for comparison. Arteries of the extremities were the most common site of embolism (85%); lower extremity involvement was twice as common compared with the upper extremity. Clinical features distinguishing peripheral embolism from stroke included age>75, heart failure and hypertension. Severe left ventricular dysfunction, spontaneous echo contrast and left atrial thrombus were 2-3 fold more common in peripheral embolism patients. Mean CHADS-2 scores were low and comparable for both groups. By multivariate analysis, age>5 years (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.3-3.9; p=0.05) was predictive of peripheral embolism. After adjustment for age>75 years, severe left atrial enlargement (HR 1.8, 95% CI 0.99 3.1; p=0.055) and CHADS score (HR 1.2, 95% CI 0.99-1.6; p=0.06) were of borderline significance. In conclusion, several clinical and echocardiographic measures distinguish the clinical presentation of thromboembolism in non-valvular atrial fibrillation. Small emboli are destined to lodge in the cerebral circulation as a result of hydrodynamic, anatomic, and physical factors. Advanced age, atrial enlargement and other co-morbidities may increase the propensity for the formation of larger thrombi which may bypass the carotid orifice merely as a function of size. PMID- 18449428 TI - Automated registration of tail bleeding in rats. AB - An automated system for registration of tail bleeding in rats using a camera and a user-designed PC-based software program has been developed. The live and processed images are displayed on the screen and are exported together with a text file for later statistical processing of the data allowing calculation of e.g. number of bleeding episodes, bleeding times and bleeding areas. Proof-of principle was achieved when the camera captured the blood stream after infusion of rat whole blood into saline. Suitability was assessed by recording of bleeding profiles in heparin-treated rats, demonstrating that the system was able to capture on/off bleedings and that the data transfer and analysis were conducted successfully. Then, bleeding profiles were visually recorded by two independent observers simultaneously with the automated recordings after tail transection in untreated rats. Linear relationships were found in the number of bleedings, demonstrating, however, a statistically significant difference in the recording of bleeding episodes between observers. Also, the bleeding time was longer for visual compared to automated recording. No correlation was found between blood loss and bleeding time in untreated rats, but in heparinized rats a correlation was suggested. Finally, the blood loss correlated with the automated recording of bleeding area. In conclusion, the automated system has proven suitable for replacing visual recordings of tail bleedings in rats. Inter-observer differences can be eliminated, monotonous repetitive work avoided, and a higher through-put of animals in less time achieved. The automated system will lead to an increased understanding of the nature of bleeding following tail transection in different rodent models. PMID- 18449429 TI - Safety of bevacizumab in mild haemophilia B. PMID- 18449430 TI - Including the life-time cumulative number of joint bleeds in the definition of primary prophylaxis. PMID- 18449432 TI - Aspirin response variability assessed with the PFA-100 device. PMID- 18449434 TI - No clear link between VKORC1 genetic polymorphism and the risk of venous thrombosis or peripheral arterial disease. PMID- 18449435 TI - Utility of D-dimer testing in patients with clinically suspected pulmonary embolism and elevated C-reactive protein levels. PMID- 18449436 TI - Incidence and features of heparin-induced thrombocytopenia (HIT) in burn patients: a retrospective study. PMID- 18449437 TI - Acute coronary stent thrombosis: toward insights into possible mechanism using novel imaging methods. PMID- 18449438 TI - Prevention of venous thromboembolism after acute spinal cord injury with low-dose heparin or low-molecular-weight heparin. PMID- 18449439 TI - Protective role of metallothionein in coagulatory disturbance accompanied by acute liver injury induced by LPS/D-GalN. PMID- 18449440 TI - [V debate forum of the SENPE. Current issues on home-based and ambulatory artificial nutrition]. AB - A multidisciplinary and multiprofessional debate is established trying to detect and find plausible solutions regarding Home-based and Ambulatory Enteral Nutrition (HBAEN) in Spain, due to the little attention paid by the Administration to the global problem of hyponutrition, the little interest showed by the collectivity of health care professionals, and the lack of a regulation differentiating the patient at his/her home and the patient at a nursing home. It was concluded that the current legislation on Home Based Enteral Nutrition (HBEN) has been variedly applied and does not contemplate the real clinical health care, with some pathologies subsidiary of this kind of therapy being excluded. Proposals to improve both financing and pathologies irrespective of the kind of nutritional therapy are made. PMID- 18449441 TI - [Careful! Your bibliographic references may be examined]. AB - Reference to previous work represents a conceptual association of recognized scientific ideas that are beneficial for the citing author. I.e., a reference is an express recognition of an intellectual compromise towards a previous source of information. After all, advancement of science is supported by previous research. At present, the way to know and to measure the importance of a published item comes through its posterior citations, circumstance that obliges scientific journals to control the pertinence and relevance of the cited work. Therefore, when submitting a manuscript for consideration to a scientific journal, it must be beard in mind that the included references will be examined. PMID- 18449442 TI - [Intake of milk and dairy products in a college population]. AB - OBJECTIVE: To carry out a descriptive study on the consumption of milk and dairy products in a college population and analyzing their nutritional contribution to the diet of these university students. MATERIAL AND METHODS: Registry of food consumption during a school day (24-hour recall) in a random sample of 500 college students with ages ranging 19-24 years. Gender, age, level of university studies, class timetable, and type of residence were collected from each interviewee. RESULTS: 98.6% of the college students interviewed referred having consumed some dairy product during the last 24 hours: 92% milk, 60% yogurts, 32.6% cheese, and 13% other products. There were no differences in the frequency of consumption of different dairy products by age, type of residence, level of university studies, or class timetables; low-fat diary products consumption was higher (p < 0.05) in women. The mean number of dairy products servings was 2.07, being higher among males (p < 0.05) (2.32) as compared to women (1.99). 42.6% had consumed at least 2 servings, with percentage differences (p < 0.05) between both genders. Consumption of low-fat dairy products represented 24.3% of the whole daily consumption of these foods. In the dietary models of college students, dairy products constitute the main source of calcium and phosphorus, although they provide significant amounts of saturated fat and cholesterol. CONCLUSIONS: Although virtually all college students consumed milk and dairy products throughout the day, the mean value of servings consumed would be lower than the recommended one, particularly among girls. It would be convenient to recommend daily consumption of lowfat dairy products (milk and yogurts) and fresh cheese, which would increase minerals and vitamins intake without increase the caloric and saturated fat and cholesterol intake, as well as avoiding consumption of other dairy products (creme caramel, custard) rich in carbohydrates and cholesterol. PMID- 18449443 TI - [Registry of home-based enteral nutrition in Spain for the year 2006 (NADYA-SENPE Group)]. AB - OBJECTIVE: To communicate the results obtained from the registry of Home-Based Enteral Nutrition (HBEN) of the NADYA-SENPE group for the year 2006. MATERIAL AND METHODS: Recompilation of the data from the HBEN registry of the NADYA-SENPE group from January 1st to December 31st of 2006. RESULTS: During the year 2006, 3,921 patients (51% men) from 27 hospital centers were registered. Ninety-seven percent were older than 14 years. The mean age for those < 14 years was 4.9 +/- 3.9 (m +/- SD) and in those > or = 14 years, it was 68.5 +/- 18.2 years. The most common underlying disease was neurological pathology (42%), followed by cancer (28%). Enteral nutrition was administered p.o. in 44% of the patients, through nasogastric tube in 40%, gastrostomy in 14%, and jejunostomy in 1%. The average time of nutritional support was 8.8 months. The most common reasons for ending the therapy were patient's death (54%) and switching to oral feeding (32%). Thirty-one percent of the patients presented a limited activity and 40% were confined to bed/coach. Most of the patients required partial (25%) or total (43%) care assistance. The nutritional formula was provided by the hospital in 62% of the cases and from the reference pharmacy in 27%. The fungible material was provided by the hospital in 80% of the cases and by primary care in the remaining patients. CONCLUSIONS: Although the number of registered patients is slightly higher than that from the last years, there are no important changes in the patients characteristics, or way of administration and duration of enteral nutrition. PMID- 18449444 TI - [A protocol of assessment, follow-up and nutritional action at a nursing home]. AB - OBJECTIVE: 1) To assess the nutritional status of able elderly, institutionalized at a nursing home; 2) To propose the required nutritional interventions; 3) To establish a consensus protocol for nutritional assessment and follow-up at the Center. METHOD: Cross-sectional study on all able residents, carrying out: 1) Mini Nutritional Assessment Test; 2) Anthropometrical assessment; 3) Biochemical assessment; and 4) an additional questionnaire (gathering information on dental prostheses, swallowing difficulties, and special diets or oral supplements). Analysis of these data to implement appropriate recommendations and elaborating a nutritional protocol. RESULTS: The mean age of the 50 residents assessed was 84 years [66-97], mean weight 62 kg [35-87], mean height 154 cm [140-175], mean body mass index 26 [15.6-36], mean tricipital fold 18.1 mm [4-36], and mean muscle arm circumference 20.6 cm [14.7-27.1]. By using the Mini Nutritional Assessment Test we identified 3/50 (6% [95% CI: 1-16]) malnourished residents, and 6/50 (12% [95% CI: 4-24]) residents at risk for malnourishment. The body mass index allowed to identify 11/50 (22% [95% CI: 11-35]) overweighed residents-body mass index 27-29 , 10/50 (20% [95% CI: 10-33]) with grade I obesity -body mass index 30-35 and 1/50 (2% [95% CI: 0-10]) with grade II obesity-body mass index > 35-. None of them presented values below the 5th percentile for both the tricipital fold and the muscle arm circumference. Values above the 95th percentile were found in 10/50 (20% [95% CI: 10-33]) residents for the tricipital fold and in 7/50 (14% [95% CI: 5-26]) for the muscle arm circumference, both criteria being present in 3 residents. In all of them the body mass index mayor was > 27. When analyzing the biochemical parameters, the results were not concordant, since laboratory workups analyzed were not always done at the same time as the interview. After analyzing the data obtained, a nutritional assessment and follow-up protocol was elaborated in collaboration with the physicians in charge of the Center, in which five categories were defined according to the nutritional status. CONCLUSIONS: 1) 3/50 malnourished residents were identified, 6/50 at risk for malnourishment, and 22/50 with overweight. 2) We proposed the performance of a whole laboratory work up in these residents, reviewed their dietary habits in order to correct them or prescribe oral supplements, and recommended adapted physical exercise. 3) A nutritional assessment and follow-up protocol was elaborated. PMID- 18449445 TI - Immunoenhanced enteral nutrition formulas in head and neck cancer surgery: a prospective, randomized clinical trial. AB - INTRODUCTION: Significant malnutrition exists in a high percentage of patients with head and neck cancer. Malnutrition is associated with defects in immune function that may impair the host response to malignancy. Malnutrition and immunosupression make patients highly susceptible to postoperative infections and complications. OBJECTIVES: Compare two immunoenhanced enteral nutritions with a control diet, and evaluate the effect in postoperative infections, length of stay and inflammatory markers. PATIENTS: A population of 44 patients with oral and laryngeal cancer was enrolled in a randomized trial. At surgery, patients were randomly allocated to three groups: (group I); patients receiving an arginine enhanced formula (group II); patients receiving a standard polymeric formula, and (group III) patients receiving an arginine, RNA and omega-3 fatty acids enhanced formula, in an isonitrogenous way. RESULTS: The duration of enteral nutrition in the three groups was similar with an average duration of 14,5 +/- 8 days. The length of postoperative stay was similar, with an average of 19,8 +/- 8,5 days. Wound infections and general infections were more frequent in the control group. Fistula rates were not improved in the enhanced diet groups. No significant intergroup differences in the trend of the two plasma proteins (albumin, transferrin), lymphocytes, weight, IL-6, CPR and TNFalpha were detected. The control group showed the highest levels of TNFalpha at the fourteenth postoperative day. Gastrointestinal tolerance and diarrhoea rate were similar in all the patients. CONCLUSIONS: Immunoenhanced enteral nutrition formulas improved the infection rate in the postoperative of head and neck cancer patients. In the fistula rates, we observed that technical problems and nutritional status might have played an equally important role, and therefore the positive effect of immunonutrition in this parameter might have been overestimated. PMID- 18449446 TI - [Evaluation of two methods for correcting the impact factor using the investigation done at the "Del Rio Hortega" University Hospital (1999-2004) as the data source]. AB - BACKGROUND AND OBJECTIVE: To adjust the Impact Factor (IF) provided by the Institute for Scientific Information (ISI) is necessary for improving bibliometric analysis among the various areas of knowledge. Our objective was to evaluate two parameters (the maximum and the median value of each subject area) for IF adjustment using the original (not corrected) IF as the reference method in a tertiary hospital biomedical investigation model. MATERIAL AND METHOD: We retrieved articles from Hospital Universitario "Del Rio Hortega" from Valladolid (Spain) for the period 1999-2004 as data source. We have describe the characteristics of the followed IF distributions: IF Corrected by the Maximum value (IFCORMAX), IF Corrected by the Median value (IFCORMED) and IF without adjustments (IF). Besides, we have analyzed both the inter-annual and the inter subject differences obtained by the three methods. RESULTS: The three analyzed IF series shown not normal distributions that are positively skewed. The IF adjusted by the median showed the highest coefficient of variation (CV = 357.3%). The IF adjusted by the Maximum value increased the "weight" of journals with the highest not corrected IF for each subject category. Inter-annual differences were similarly estimated by the three methods. The IF adjusted by the median increased the inter-subject difference from 7.3% to 12.4%. CONCLUSIONS: Our results suggests that IF adjusted by the maximum value of each discipline is the best method to correct the ISI-IF values, because journals with the high IF are always rewarded, while IF adjusted by the median infra-estimated most of them. PMID- 18449447 TI - [Evolution of nutritional biochemical parameters in hemodialysis patients during a one-year follow-up period]. AB - Current high survival in hemodialysis patients (52% at 5 years) have made the chronic manifestations to emerge such as the high hyponutrition prevalence of these patients, as well as the importance of the nutritional status in their morbimortality. The reason for protein-caloric hyponutrition is multifactorial, although chronic inflammatory conditions associated to the dialysis technique are becoming more and more relevant. The variations in several nutritional biochemical parameters (total proteins, plasma albumin, transferrin, and total cholesterol) have been assessed in 73 hemodialysis patients for one year. The mean age of the patients was 53.3 +/- 18.69 years (43 males and 30 females). The average on hemodialysis program was 43 +/- 33 months, with a mean session duration of 246 +/- 24 minutes, and mean hemodialysis dose administered of 1.37 +/- 0.27 (KT/V) (second generation Daurgidas). A decrease in all the biochemical parameters assessed has been observed, with statistically significant differences: total proteins (p < 0.001), albumin (p < 0.00001), total cholesterol (p < 0.05), and transferrin (p < 0.01). The evolution of the nutritional biochemical parameters assessed showed an important nutritional deterioration of the patients remaining stable with the therapy. PMID- 18449448 TI - [Insulin therapy at the hospital setting]. AB - Hyperglycemia is defined in different studies as a poor prognostic factor relating with higher risk for post-surgical infections, neurological complications, increased hospital staying, and admission to intensive care units. Appropriate use of insulin therapy is one of the key factors assuring the best management of hospitalized patients. The aim of this review was to discuss the most important aspects of insulin use at the hospital setting. We analyzed the different types of insulin commercially available and the factors determining their efficacy, as well as the different regimens and administration routes available at the hospital according to the type of patient and the type of feeding or exogenous intake of carbohydrates. The fear of inducing hypoglycemic episodes at the hospital contributes to an inappropriate prescription of the programmed insulin doses, the use of flexible rapid insulin doses in monotherapy, and setting excessively high glycemia levels. Currently, individualized management of hospital hyperglycemias should replace obsolete insulin regimens in order to reach more stringent glycemia goals and decreasing the number of complications in the hospitalized patient. PMID- 18449449 TI - [Effect of an intensive nutritional treatment in nutritional status of head and neck cancer patients in stages III and IV]. AB - OBJECTIVE: Malnutrition and accelerated weight loss are frequent secondary diagnosis in patients with cancer. Head and neck cancer (H & N Cancer) affects nutritional status because of the tumor type and localization. The aim of the study was to assess the effect of an intensive nutritional treatment (INT) on nutritional status of H & N cancer patients, stages III and IV and to compare that with a historical control whose nutritional treatment was conventional (CT). METHODS: All patients were nutritionally assessed before oncological treatment started (anthropometrical, biochemical, and dietetically). A nutritional feeding plan according to their nutritional personal need was calculated. In case it was impossible to cover all the nutritional requirements orally, a feeding tube was placed. Nutritional follow up was performed each 21 days, during their oncological treatment in four occasions. The results obtained were compared with those obtained from the patients who received the CT that consisted only in nutritional counseling by the attending physician; the statistical test used was Mann Whitney U test. RESULTS: The INT was associated with maintenance of the nutritional status along their oncological treatment. The statistical significant parameters were: weight 55 to 47 kg in the CT group vs 59 a 58 kg in the INT group (p < 0.0001), and hemoglobin: from 13 to 11 g/dl in the CT group vs 14 to 13 g/dl in the INT group (p < 0.002) as the most important ones. In the rest of the data we can observe a clear tendency of increasing the nutrition parameters in patients the INT group, while in the CT group, they showed a persistent decrease. CONCLUSION: We concluded that patients who received the INT as part of their oncological treatment deteriorated less their nutritional status than those who received a CT. PMID- 18449450 TI - Effect of protein restriction diet on renal function and metabolic control in patients with type 2 diabetes: a randomized clinical trial. AB - OBJECTIVE: To assess the effect of a low protein diet (LPD) on renal function and metabolic control in three sub-groups of patients with type 2 diabetes those with or without nephropathy. RESEARCH DESIGN AND METHODS: A randomized clinical trial was conducted on 60 patients with type 2 diabetes in primary care -19 with normoalbuminuria, 22 with microalbuminuria, and 19 with macroalbuminuria-. All patients experienced a screening phase during the 3 months, and were designated according to percentages of daily caloric intake (e.g., carbohydrates 50%, fat 30%, and 20% of protein). After this period, they were randomly assigned to receive either LPD (0.6-0.8 g/kg per day) or normal protein diet (NPD) (1.0-1.2 g/kg per day) for a period of 4 months. Twenty nine patients received LPD and 31 received NPD. Primary endpoints included measures of renal function (UAER, serum creatinine and GFR) and glycemic control (fasting glucose and glycosylated hemoglobin A1c). RESULTS: Renal function improved among patients with macroalbuminuria who received LPD: UAER decreased (1,280.7 +/- 1,139.7 to 444.4 +/- 329.8 mg/24 h; p < 0.05) and GFR increased (56.3 +/- 29.0-74.2 +/- 40.4 ml/min; p < 0.05). In normoalbuminuric and microalbuminuric patients, there were no significant changes in UAER or GFR after either diet. HbA1c decreased significantly among microalbuminuric patients on both diets (LPD, 8.2 +/- 1.6-7.2 +/- 1.8%; p < 0.05; NPD, 8.8 +/- 1.9-7.1 +/- 0.8%; p < 0.05) and among macroalbuminuric patients who received NPD (8.1 +/- 1.8-6.9 +/- 1.6%; p < 0.05). CONCLUSIONS: A moderated protein restriction diet improved the renal function in patients with type diabetes 2 and macroalbuminuria. PMID- 18449451 TI - [Fat composition of several "fast food"]. AB - The percentage of fat of a variety of foods served in fast food establishments has been determined. This percentage is very variable, with mean contents of total fat of 35.83 +/- 10.68% in beef hamburgers, 35.84 +/- 8.66% in chips, 23.02 +/- 5.07% in chicken hamburgers and 34.02 +/- 13.49% in "hot dogs". The lipidic composition is mainly formed by saturated fatty acids (28-52% of total fat) and monounsaturated (46-48%), whereas the proportion of polyunsaturated fatty acids showed more variable values, ranging from 6.9% in beef hamburgers to 25.1% in chips. Statistical treatment of the results of relative percentage of fatty acids by multivariate methods revealed clusters of samples grouped as a function of the type of food and in some instances of its source, which can be interesting in case of healthy problems. Percentages of trans fatty acids slightly higher than the maximum recommended values have been detected in some cases. These results show the urgent need of modifying the laws to force fast food establishments to specify the type and amounts of fat used in the processing of these foods, as well as a greater control from the local administrations. PMID- 18449452 TI - [Publication of articles about paediatrics in Nutricion Hospitalaria]. PMID- 18449453 TI - [Massive intestinal resection: Nutricional adaptation process]. PMID- 18449456 TI - First description of the immature stages of Hemilucilia segmentaria (Diptera: Calliphoridae). AB - The immature stages oi Hemilucilia segmentaria (Fabricius, 1805) (Diptera: Calliphoridae) are described. Egg morphology and structures such as the cephalopharyngeal skeleton, anterior and posterior spiracles, and the dorsal spines between the prothorax and mesothorax from first, second and third instar larvae are characterized, using light and scanning electron microscopy. This species is abundant in Neotropical forests and, because of its necrophagous behavior, is of substantial medico-legal importance for estimating the postmortem interval in criminal investigations. Information presented herein may be useful to differentiate among eggs and larvae of closely related species and to supplement the database for blowfly identification. PMID- 18449455 TI - Co-operative effect of glutathione depletion and selenium induced oxidative stress on API and NFkB expression in testicular cells in vitro: insights to regulation of spermatogenesis. AB - Previous studies have shown that transcription factors, API and NFkB exert important roles in the process by which selenium regulates spermatogenesis. Glutathione, an intracellular thiol, acts as a source of reducing power and aids in maintenance of the cellular redox status. The activities of selenium are closely related to the availability of glutathione. Presently, mouse testicular cells were cultured in the presence of BSO, a known glutathione depletor, to generate oxidative stress. Selenium (Se) was added as sodium selenite to these cells at concentrations of 0.5 microM and 1.5 microM. It was observed that at 1.5 microM, Se acted as a pro-oxidant and significantly decreased the redox ratio. RT PCR analysis revealed that cjun, cfos expression increased in testicular cells cultured with Se compared to control. However, the major outcome was that the combined effect of Se supplementation and GSH depletion resulted in reduced expression of cjun and cfos while p65 expression increased. This suggests that selenium affects both these transcription factors differently. Our study indicates that though low levels of oxidative stress generated by moderate doses of selenium augments the expression of cjun and cfos, a robust increase in the ROS generation caused by the dual effect high levels of selenium and glutathione depletion leads to decrease in the expression of these genes. The present work substantiates our in vivo experiments and indicates the detrimental effect of excess selenium supplementation on male fertility. PMID- 18449457 TI - A micromethod for high throughput RNA extraction in forest trees. AB - A large quantity of high quality RNA is often required in the analysis of gene expression. However, RNA extraction from samples taken from woody plants is generally complex, and represents the main limitation to study gene expression, particularly in refractory species like conifers. Standard RNA extraction protocols are available but they are highly time consuming, and not adapted to large scale extraction. Here we present a high-throughput RNA extraction protocol. This protocol was adapted to a micro-scale by modifying the classical cetyltrimethylammonium (CTAB) protocol developed for pine: (i) quantity of material used (100-200 mg of sample), (ii) disruption of samples in microtube using a mechanical tissue disrupter, and (iii) the use of SSTE buffer. One hundred samples of woody plant tissues/organs can be easily treated in two working days. An average of 15 ?ig of high quality RNA per sample was obtained. The RNA extracted is suitable for applications such as real time reverse transcription polymerase chain reaction, cDNA library construction or synthesis of complex targets for microarray analysis. PMID- 18449458 TI - Effect of vitrification on viability and chromosome abnormalities in 8-cell mouse embryos at various storage durations. AB - This study was designed to investigate the effect of vitrification and post-thaw survival and chromosomal aberrations caused by vitrification of vitrified 8-cell mouse embryos in comparison with a control group. To this purpose the survival rate and the frequency of chromosomal aberrations were assessed in frozen-thawed 8-cell mouse embryos after various storage durations in the presence of ethylene glycol as cryoprotectant. eight-cell mouse embryos were obtained from NMRI mice 3 days after mating. Retrieved embryos were transferred to vitrification solution containing ethylene glycol as cryoprotectant, then transferred into a vitrification straw using standard technique, and vitrified in liquid nitrogen. Six groups of embryos according to storage duration (24 hours, 1 and 2 weeks, 1-6 months) were frozen. After appropriate storage periods embryos were thawed and studied for their viability 4-6 hours after thawing and intact embryos were transferred to fresh medium containing colcemid. After 48 hours, the embryos were fixed and studied for their chromosome abnormalities using Tarkowsky's drying technique. Results indicate that freezing affects the viability and chromosome structure of embryos when compared with the control group. Furthermore increasing the storage duration reduces the viability and increases the chromosome aberrations of embryos (such as aneuploidy and polyploidy). This result might indicate that the effects of vitrification on the cytoskeleton or other cellular organelle might produce chromosomal alterations leading to cell death. PMID- 18449459 TI - Apoptosis related genes expressed in cultured Fallopian tube epithelial cells infected in vitro with Neisseria gonorrhoeae. AB - BACKGROUND: Infection of the Fallopian tubes (FT) by Neisseria gonorrhoeae (Ngo) can lead to acute salpingitis, an inflammatory condition resulting in damage primarily to the ciliated cells, with loss of ciliary activity and sloughing of the cells from the epithelium. Recently, we have shown that Ngo infection induced apoptosis in FT epithelium cells by a TNF-alpha dependent mechanism that could contribute to the cell and tissue damage observed in gonococcal salpingitis. AIM: To investigate the apoptosis-related genes expressed during apoptosis induction in cultured FT epithelial cells infected in vitro by Ngo. MATERIALS AND METHODS: In the current study, we used cDNA macroarrays and real time PCR to identify and determine the expression levels of apoptosis related genes during the in vitro gonococci infection of FT epithelial cells. RESULTS: Significant apoptosis was induced following infection with Ngo. Macroarray analysis identified the expression of multiple genes of the TNF receptor family (TNFRSF1B, -4, -6, -10A, 10B and -10D) and the Bcl-2 family (BAK1, BAX, BLK, HRK and MCL-1) without differences between controls and infected cells. This lack of difference was confirmed by RT-PCR of BAX, Bcl-2, TNFRS1A (TNFR-I) and TNFRSF1B (TNFR-II). CONCLUSION: Several genes related to apoptosis are expressed in primary cultures of epithelial cells of the human Fallopian tube. Infection with Ngo induces apoptosis without changes in the pattern of gene expression of several apoptosis related genes. RESULTS strongly suggest that Ngo regulates apoptosis in the FT by post-transcriptional mechanisms that need to be further addressed. PMID- 18449460 TI - Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep. AB - Although evidence is accumulating that prenatal testosterone (T) compromises reproductive function in the female, the effects of excess T in utero on the postnatal development of male reproductive function has not been studied. The aim of this study was to assess the influence of prenatal T excess on age-related changes in pituitary and gonadal responsiveness to GnRH in the male sheep. We used the GnRH agonist, leuprolide (10 microg/kg), as a pharmacologic challenge at 5, 10, 20 and 30 weeks of age. These time points correspond to early and late juvenile periods and the prepubertal and postpubertal periods of sexual development, respectively. LH and T were measured in blood samples collected before and after GnRH agonist administration. The area under the response curve (AUC) of LH increased progressively in both controls and prenatal T-treated males from 5 to 20 weeks of age (P<0.01). The LH responses in prenatal T-treated males were lower at 20 and 30 weeks of age compared to controls (P<0.05). AUC-T increased progressively in control males from 5 through 30 weeks of age and prenatal T-treated males from 5 to 20 weeks of age. The T response in prenatal T treated males was higher at 20 weeks compared to controls of same age but similar to controls and prenatal T-treated males at 30 weeks of age (P <0.05). Our findings suggest that prenatal T treatment advances the developmental trajectory of gonadal responsiveness to GnRH in male offspring. PMID- 18449461 TI - Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit. AB - Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit. PMID- 18449462 TI - Volatile organic compounds produced by human skin cells. AB - Skin produces volatile organic compounds (VOCs) released to the environment with emission patterns characteristic of climatic conditions. It could be thought that these compounds are intermediaries in cell metabolism, since many intermediaries of metabolic pathways have a volatile potential. In this work, using gas chromatography, we answered the question of whether VOC profiles of primary cultures of human dermal fibroblasts were affected by the type of culture conditions. VOCs were determined for different types of culture, finding significant differences between skin cells grown in classical monolayer culture 2D- compared with 3D matrix immobilized cultures. This indicates that VOC profiles could provide information on the physiological state of skin cells or skin. PMID- 18449463 TI - A pilot study on genetic variation in purine-rich elements in the nephrin gene promoter in type 2 diabetic patients. AB - Diabetic nephropathy (DN) is one of the major complications of type 2 diabetes and is associated with coronary disease. Nephrin, a protein mainly expressed in glomeruli, is decreased in DN and other kidney diseases. Since insulin levels are misregulated in type 2 diabetes, a possible connection between DN and its decreased nephrin expression could be the presence of regulatory elements responsive to insulin in the nephrin gene (NPHS1) promoter region. In this work, using bioinformatic tools, we identified a purine-rich GAGA element in the nephrin gene promoter and conducted a genomic study in search of the presence of polymorphisms in this element and its possible association with DN in type 2 diabetic patients. We amplified and sequenced a 514 bp promoter region of 100 individuals and found no genetic variants in the purine-rich GAGA-box of the nephrin gene promoter between groups of patients with diabetes type 2 with and without renal and coronary complications, control patients without diabetes and healthy controls. PMID- 18449464 TI - High frequency of p16 promoter methylation in non-small cell lung carcinomas from Chile. AB - The inactivation of tumour suppressor genes by aberrant methylation of promoter regions has been described as a frequent event in neoplasia development, including lung cancer. The p16 gene is a tumour suppressor gene involved in the regulation of cell cycle progression that has been reported to be inactivated by promoter methylation in lung carcinomas at variable frequencies around the world in a smoking habit dependent manner. The purpose of this study was to investigate the methylation status of the promoter region of the p16 gene in 74 non-small cell lung carcinomas from Chile. The frequency of p16 gene inactivation by promoter methylation was determined as 79.7% (59/74). When we considered histological type, we observed that p16 promoter methylation was significantly higher in squamous cell carcinomas (30/33, 91%) compared with adenocarcinomas (21/30, 70%) (p=0.029). In addition, no association between p16 promoter methylation and gender, age or smoking habit was found (p=0.202, 0.202 and 0.147 respectively). Our results suggest that p16 promoter hypermethylation is a very frequent event in non-small cell lung carcinomas from Chile and could be smoking habit-independent. PMID- 18449465 TI - Pathways to care and treatment delays in first and multi episode psychosis. Findings from a developing country. AB - BACKGROUND: In contrast to findings from the developed world where general practitioners and mental health professionals are central in first episode psychosis pathways, studies from Africa have found GPs to play a less prominent role with other help providers such as traditional healers being more important. METHODS: We compared pathways to care, treatment delays and gender differences in patients with first versus multi episode psychosis. RESULTS: Private sector GPs were first contacts in first episode patients in as many as 38% of patients and were significantly more likely to be the first contact (odds ratio = 4.5, 95% CI = 1.38-14.67) and final referring agent (odds ratio = 6.8, 95% CI = 1.56-25.12) in first episode patients. Female multi episode patients were significantly more likely to make first contact with primary care practitioners whereas male multi episode patients were more likely to first come into contact with the police (P = 0.003) and be admitted compulsorily (P = 0.009). Only 5.6% (n = 4) of patients contacted traditional healers at some point in their pathway to care. Treatment delays and DUP in first episode patients were longer and reached a median of 4.5 versus 2.5 months in multi episode patients. Treatment discontinuation of antipsychotics occurred in 82% of multi episode patients. Despite significantly longer overall treatment delays in first episode patients the distribution of treatment delays in multi episode patients followed a similar pattern to DUP in first episode patients with a subgroup having very long delays. CONCLUSIONS: Pathways to care in this treatment setting correspond more to findings from first world and newly industrialized countries. A subgroup of multi episode patients had very long periods of untreated illness. Limitations include small sample size and the retrospective nature of data collection. PMID- 18449466 TI - Development of a toxicity identification evaluation protocol using chlorophyll-a fluorescence in a marine microalga. AB - Growth inhibition bioassays with the microalga Nitzschia closterium have recently been applied in marine Toxicity Identification Evaluation (TIE) testing. However, the 48-h test duration can result in substantial loss of toxicants over time, which might lead to an underestimation of the sample toxicity. Although shorter term microalgal bioassays can minimize such losses, there are few bioassays available and none are adapted for marine TIE testing. The acute (5-min) chlorophyll-a fluorescence bioassay is one alternative; however, this bioassay was developed for detecting herbicides in freshwater aquatic systems and its suitability for marine TIE testing was not known. In this study, a chlorophyll-a fluorescence bioassay using the marine microalga Isochrysis galbana was able to detect contaminants other than herbicides at environmentally relevant concentrations and tolerated the physical and chemical manipulations needed for a Phase I TIE. Phase I TIE procedures were successfully developed using this chlorophyll-a fluorescence bioassay and used to identify all classes of contaminants present in a synthetic mixture of known chemical composition. In addition, TIEs with both the acute fluorescence bioassay and the standard growth inhibition bioassay identified the same classes of toxicants in a sample of an unknown complex effluent. Even though the acute chlorophyll-a fluorescence end point was less sensitive than the chronic cell division end point, TIEs with the chlorophyll-a fluorescence bioassay provided a rapid and attractive alternative to longer-duration bioassays. PMID- 18449467 TI - Molecular community analysis of arbuscular mycorrhizal fungi in roots of geothermal soils in Yellowstone National Park (USA). AB - To better understand adaptation of plants and their mycorrhizae to extreme environmental conditions, we analyzed the composition of communities of arbuscular mycorrhizal fungi (AMF) in roots from geothermal sites in Yellowstone National Park (YNP), USA. Arbuscular mycorrhizal fungi were identified using molecular methods including seven specific primer pairs for regions of the ribosomal DNA that amplify different subgroups of AMF. Roots of Dichanthelium lanuginosum, a grass only occurring in geothermal areas, were sampled along with thermal and nonthermal Agrostis scabra and control plants growing outside the thermally influenced sites. In addition, root samples of Agrostis stolonifera from geothermal areas of Iceland were analyzed to identify possible common mycosymbionts between these geographically isolated locations. In YNP, 16 ribosomal DNA phylotypes belonging to the genera Archaeospora, Glomus, Paraglomus, Scutellospora, and Acaulospora were detected. Eight of these phylotypes could be assigned to known morphospecies, two others have been reported previously in molecular studies from different environments, and six were new to science. The most diverse and abundant lineage was Glomus group A, with the most frequent phylotype corresponding to Glomus intraradices. Five of the seven phylotypes detected in a preliminary sampling in a geothermal area in Iceland were also found in YNP. Nonthermal vegetation was dominated by a high diversity of Glomus group A phylotypes while nonthermal plants were not. Using multivariate analyses, a subset of three phylotypes were determined to be associated with geothermal conditions in the field sites analyzed. In conclusion, AMF communities in geothermal soils are distinct in their composition, including both unique phylotypes and generalist fungi that occur across a broad range of environmental conditions. PMID- 18449468 TI - Analysis of nucleotide sequence of Iranian maize mosaic virus confirms its identity as a distinct nucleorhabdovirus. AB - The nucleotide sequence of the Iranian maize mosaic rhabdovirus (IMMV) was obtained using a random-PCR method (rPCR) followed by PCR with specific primers. Analysis of the complete nucleotide sequence of the IMMV genes and intergenic regions comprising a total of 12,381 nucleotides (including the partial sequences of leader and trailer regions) revealed six open reading frames (ORF) on the viral complementary RNA (vcRNA). On the basis of its similarities to other rhabdovirus sequences, the IMMV genome consists of 3'-leader-N-P-3-M-G-L-5' trailer. The intergenic regions contained a characteristic consensus sequence, 3' AAUUCUUUUUGGGUUU/G-5'. The IMMV gene products showed a high similarity to those of maize mosaic virus and taro vein chlorosis virus and a more distant relationship to other rhabdoviruses. Together with the biological, serological and morphological features described earlier, our molecular data provide evidence that IMMV is a distinct member of the genus Nucleorhabdovirus in the family Rhabdoviridae. PMID- 18449469 TI - Ellipsoidal particles at fluid interfaces. AB - For partially wetting, ellipsoidal colloids trapped at a fluid interface, their effective, interface-mediated interactions of capillary and fluctuation-induced type are analyzed. For contact angles different from 90( degrees ) , static interface deformations arise which lead to anisotropic capillary forces that are substantial already for micrometer-sized particles. The capillary problem is solved using an efficient perturbative treatment which allows a fast determination of the capillary interaction for all distances between and orientations of two particles. Besides static capillary forces, fluctuation induced forces caused by thermally excited capillary waves arise at fluid interfaces. For the specific choice of a spatially fixed three-phase contact line, the asymptotic behavior of the fluctuation-induced force is determined analytically for both the close-distance and the long-distance regime and compared to numerical solutions. PMID- 18449470 TI - Microtubules in early development of the megagametophyte of Ginkgo biloba. AB - Food storage tissue in the seeds of gymnosperms is female gametophyte (megagametophyte) that develops before fertilization, whereas, in seeds of angiosperms, food is stored as endosperm initiated by double fertilization. The megagametophyte is haploid, and endosperm is usually triploid, at least initially. Despite differences in origin, ploidy level, and developmental trigger, the early events of female gametophyte development in ginkgo are very similar to nuclear endosperm development in the seeds of angiosperms. In both, development begins as a single cell that undergoes multiple mitoses without cytokinesis, to produce a large syncytium. This study provided evidence that microtubule involvement in organization of the syncytium into nuclear cytoplasmic domains (NCDs) via nuclear-based radial microtubule systems is a critical developmental feature in the ginkgo megagametophyte, as it is in endosperm. Once the initial anticlinal walls have been deposited at the boundaries of NCDs, cellularization proceeds by the process of alveolation. Continued unidirectional growth of the alveolar walls is an outstanding example of polar cytokinesis. Ginkgo megagametophyte development appears to occur uniformly throughout the entire chamber, whereas nuclear type endosperm usually exhibits distinct developmental domains. These observations suggest that there is a fundamental pathway for the development and cellularization of syncytia in seed development. PMID- 18449472 TI - Phase I dose-escalation study of the thioxanthone SR271425 administered intravenously once every 3 weeks in patients with advanced malignancies. AB - This study was performed to determine the dose limiting toxicity (DLT), the recommended phase II dose and the pharmacokinetic profile for SR271425, given over 1 h every 3 weeks. The initial starting dose of SR271425 was 17 mg/m(2). Patient selection was based on common phase I criteria as well as additional cardiac criteria. Thirty-eight patients were accrued to 16 dose levels from 17 to 1,320 mg/m(2). Patient characteristics included 24 males and 14 females ages 35 78 with an Eastern Cooperative Oncology Group performance status of 0 (ten patients), 1 (27) and 2 (1). Tumor types were typical for a phase I study. The maximum administered dose was 1,320 mg/m(2) with two DLTs, both QTc grade 3 prolongation. No drug related hematological toxicity was noted. Grade 1 toxicities included rash, flushing, pruritus, weight loss, diarrhea, hypertension and fatigue. Grade 2 toxicities included yellow discoloration of the skin, nausea and vomiting. QTc prolongation and hyperbilirubinemia were the only grade 3 toxicities noted. No confirmed tumor response was observed; however, two patients had prolonged stable disease. Both C(end) and area under the plasma concentration time curve increased in a dose related manner. Plasma drug concentrations declined in a biphasic manner with a mean terminal elimination half-life (t (1/2)) of 7.1 h (+/-1.3). There was no change in clearance or volume of distribution over the dose range studied. Due to cardiac toxicity occurring with both the parent compound, SR233377, as well as this analog, this series of agents was abandoned from further clinical development. PMID- 18449471 TI - The effect of P-gp (Mdr1a/1b), BCRP (Bcrp1) and P-gp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. AB - Imatinib is transported by P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), however, the exact impact of these transporters on absorption, distribution, metabolism and excretion (ADME) of imatinib is not fully understood due to incomplete data. We have performed a comprehensive ADME study of imatinib given as single agent or in combination with the well known BCRP/P-gp inhibitors, elacridar and pantoprazole, in wild-type and P-gp and/or BCRP knockout mice. The absence of P-gp and BCRP together resulted in a significantly higher area under the plasma concentration-time curve (AUC) after i.v. administration, whereas the AUC after oral dosing was unaltered. Both elacridar and pantoprazole significantly increased the AUC of orally administered imatinib in wild-type but also in P-gp/BCRP knockout mice. This lower clearance was not due to a (further) reduction in biliary excretion. Fecal excretion was significantly reduced in P-gp and P-gp/BCRP knockout but not in BCRP knockout mice, whereas the brain penetration was significantly higher in P-gp/BCRP knockout mice compared to single P-gp or BCRP knockout or wild-type mice. In conclusion, P-gp and BCRP have only a modest effect on the ADME of imatinib in comparison to metabolic elimination. P-gp is the most prevalent factor for systemic clearance and limiting the brain penetration. The considerable drug-drug interaction observed with elacridar or pantoprazole is only partly mediated by inhibition of P-gp and BCRP and far more by the inhibition of other elimination pathways. PMID- 18449473 TI - Aspirin is insufficient in inhibition of platelet aggregation and thromboxane formation early after coronary artery bypass surgery. AB - BACKGROUND: Aspirin administered early after coronary artery bypass grafting surgery (CABG) improves graft patency and patients survival. However, the antiplatelet effect of aspirin seems to be variable and aspirin resistance is currently still being discussed. The aim of the study was to assess aspirin efficacy in the early postoperative period. METHODS: Forty patients undergoing elective CABG surgery (20 in on-pump and 20 in off-pump) were enrolled in the study. Functional and biochemical responses to aspirin were evaluated by arachidonic acid (ARA)-induced platelet aggregation and urine 11-dehydro Thromboxane B2 metabolite excretion. Samples were collected before surgery (baseline; > or =7 days after aspirin withdrawal) and on days 1, 2 and 5 after surgery. RESULTS: Median baseline ARA aggregability was 55%. On day 1, platelet aggregability decreased (12%, P < 0.001). On day 2, despite the aspirin administration, platelet aggregability exceeded the values from day 1 (38%, P < 0.001). Only on day 5, sufficient inhibition of platelet aggregation was achieved (8%, P < 0.001). Median preoperative urine concentration of 11-dehydroTxB2 was 106 ng/mmol of creatinine. On day 1, the concentration decreased only slightly and insignificantly (97 ng/ml, P = NS), similarly as on day 2 (86 ng/ml, P = NS). Only on day 5, significant decrease in concentration of thromboxane metabolite was achieved compared to preoperative values (46 ng/ml, P = 0.001). CONCLUSION: Aspirin did not sufficiently inhibit platelet aggregation and thromboxane formation in the early postoperative period. Thus, antiplatelet treatment strategy should be intensified or modified in patients early after bypass surgery. PMID- 18449476 TI - The effect of estrus synchronization treatment on somatic cell count of transitional-anestrus local-Damascus cross breed goats' milk. AB - An experiment was conducted to examine the effect of estrus synchronization protocols and steroid hormones concentrations on somatic cell count (SCC) of transitional-anestrus local-Damascus cross goats' milk. Fifty-six goats (2-4-year old) were randomly assigned to three groups: fluorogestone acetate (FGA, n = 19), FGA-Prostaglandin (FGA-PGF, n = 19) and control (n = 18) groups. Intravaginal sponge containing 40 mg FGA was inserted for 13 days and an injection of 600 IU equine chorionic gonadotropin (eCG) was administered for goats of FGA and FGA-PGF groups at the time of sponge removal (day 0). In addition, goats of FGA-PGF group were injected with 10 mg dinoprost tromethamine (PGF2alpha) on day 0. Five fertile local-Damascus cross bucks were turned-in with all goats on day 0. Blood and milk samples were collected from all goats on days -13 (beginning of experiment), -6, 0, 1, 2, 7, 13 and 20 (end of the experiment). Four-year old and second-parity goats had significantly higher (p < 0.05) SCC of both udder halves than 2- and 3-year old and first-parity goats, respectively. There was a significant effect (p < 0.05) for treatment and number of kids born in the last kidding season on SCC of both udder halves. Neither estradiol nor progesterone concentrations were correlated with SCC in goats in this experiment. The SCC of both udder halves and left udder halves in goats of the control and FGA groups, respectively, increased significantly (p < 0.05) after sponge removal and buck introduction when compared with day 0, with no differences in the FGA-PGF group. This increase in SCC of the control and FGA groups coincided with peak estrus behavior. However, SCC was far below the upper limit of the current standard for normal milk. In conclusion, induction of estrus with progestagen based programs and buck introduction may cause temporary significant increase in SCC. However, the SCC values during this period of temporary increase were still in the range of acceptable values for normal milk. With the current standards for SCC of 1,000,000/ml as legal limit for abnormal milk control programs in goats, estrus synchronization programs and the estrus status should not be considered when bulk tank milk SCC is being investigated. PMID- 18449477 TI - Central retinal artery occlusion due to paroxysmal atrial fibrillation: the importance of Holter monitoring. PMID- 18449478 TI - Uptake of different species of iodine by water spinach and its effect to growth. AB - A hydroponic experiment has been carried out to study the influence of iodine species [iodide (I(-)), iodate (IO(-)(3)), and iodoacetic acid (CH(2)ICOO(-))] and concentrations on iodine uptake by water spinach. Results show that low levels of iodine in the nutrient solution can effectively stimulate the growth of biomass of water spinach. When iodine levels in the nutrient solution are from 0 to 1.0 mg/l, increases in iodine levels can linearly augment iodine uptake rate by the leafy vegetables from all three species of iodine, and the uptake effects are in the following order: CH(2)ICOO(-) >I(-)>IO(-)(3). In addition, linear correlation was observed between iodine content in the roots and shoots of water spinach, and their proportion is 1:1. By uptake of I(-), vitamin C (Vit C) content in water spinach increased, whereas uptake of IO(-)(3) and CH(2)ICOO(-) decreased water spinach Vit C content. Furthermore, through uptake of I(-) and IO(-)(3). The nitrate content in water spinach was increased by different degrees. PMID- 18449479 TI - Dual elicitation for improved production of withaferin A by cell suspension cultures of Withania somnifera. AB - High yielding transformed callus culture of W. somnifera was established by infecting hypocotyls with Agrobacterium tumefaciens MTCC-2250. Maximum withaferin A content of 0.0875 mg/g dry cell weight and transformation efficiency of 80% were obtained. Confirmation of transformation was done on the basis of the presence of the ags gene by using polymerase chain reaction. Various abiotic elicitors (arachidonic acid, methyl jasmonate, calcium chloride, and copper sulfate) and biotic elicitors (cell extracts and culture filtrates of Alternia alternata, Fusarium solani, and Verticilium dahaliae) were tested at different concentrations to enhance withaferin A production in suspension culture of transformed cells. Maximum enhancements of 5.4 times and 9.7 times, respectively, were obtained when copper sulfate (100 microM) and the cell extract of V. dahaliae (5% v/v) were added separately to suspension cultures. The dual elicitation strategy by the combined addition of these two elicitors resulted in 13.8-fold enhancement of withaferin A content in comparison to control cultures (2.65 mg/L). The present study indicates the potential of this biotechnology based methodology for the large-scale production of withaferin A. PMID- 18449480 TI - Toxicogenomics and classic toxicology: how to improve prediction and mechanistic understanding of human toxicity. AB - The field of toxicogenomics has been advancing during the past decade or so since its origin. Most pharmaceutical companies are using it in one or more ways to improve their productivity and supplement their classic toxicology studies. Acceptance of toxicogenomics will continue to grow as regulatory concerns are addressed, proof of concept studies are disseminated more fully, and internal case studies show value for the use of this new technology in concert with classic testing. PMID- 18449481 TI - Use of traditional end points and gene dysregulation to understand mechanisms of toxicity: toxicogenomics in mechanistic toxicology. AB - Microarray technologies can be used to generate massive amounts of gene expression information as an initial step to decipher the molecular mechanisms of toxicologic changes. Identifying genes whose expression is associated with specific toxic end points is an initial step in predicting, characterizing, and understanding toxicity. Analysis of gene function and the chronology of gene expression changes represent additional methods to generate hypotheses of the mechanisms of toxicity. Follow-up experiments are typically required to confirm or refute hypotheses derived from toxicogenomic data. Understanding the mechanism of toxicity for a compound is a critical step in forming a rational plan for developing counterscreens for toxicity and for increasing productivity of research and development while decreasing the risk of late-stage failure in pharmaceutical development. PMID- 18449482 TI - Quality control of microarray assays for toxicogenomic and in vitro diagnostic applications. AB - The generation of high-quality microarray data for toxicogenomics can be affected by the study design and methods used for sample acquisition, preparation, and processing. Bias can be introduced during animal treatment, tissue handling, and sample preparation. Metrics and controls used in assessing RNA integrity and the quality of microarray sample generation are reviewed in this chapter. Regulations and guidelines involved in the application of microarrays as a commercial in vitro diagnostic device are also described. PMID- 18449483 TI - Role of statistics in toxicogenomics. AB - In this chapter, we provide a structured approach to the statistical analysis of toxicogenomic data, from the assessment of data quality to data exploration, gene and pathway level analysis, and finally predictive model building. This type of analysis approach can yield toxicogenomic models that provide validated and reliable information about the toxicity of compounds. In addition, we provide study design recommendations for genomic studies in toxicology, covering areas of power, sample size, the need for replicates, and the issue of sample pooling. PMID- 18449484 TI - Predictive toxicogenomics in preclinical discovery. AB - The failure of drug candidates during clinical trials due to toxicity, especially hepatotoxicity, is an important and continuing problem in the pharmaceutical industry. This chapter explores new predictive toxicogenomics approaches to better understand the hepatotoxic potential of human drug candidates and to assess their toxicity earlier in the drug development process. The underlying data consisted of two commercial knowledgebases that employed a hybrid experimental design in which human drug-toxicity information was extracted from the literature, dichotomized, and merged with rat-based gene expression measures (primary isolated hepatocytes and whole liver). Toxicity classification rules were built using a stochastic gradient boosting machine learner, with classification error estimated using a modified bootstrap estimate of true error. Several types of clustering methods were also applied, based on sets of compounds and genes. Robust classification rules were constructed for both in vitro (hepatocytes) and in vivo (liver) data, based on a high-dose, 24-h design. There appeared to be little overlap between the two classifiers, at least in terms of their gene lists. Robust classifiers could not be fitted when earlier time points and/or low-dose data were included, indicating that experimental design is important for these systems. Our results suggest development of a compound screening assay based on these toxicity classifiers appears feasible, with classifier operating characteristics used to tune a screen for a specific implementation within preclinical testing paradigms. PMID- 18449485 TI - In vivo predictive toxicogenomics. AB - Reference databases consisting of large sample numbers and high-dimensional microarray data are now available for the investigation of adverse events in animal model systems such as the rat. This large volume of data, accompanied by appropriate study designs, compound and dose selection procedure, and minimization of technical and biological confounding effects, can yield successful predictive models for a variety of hypotheses. The process of training, validating, and implementing predictive models is cyclical and complex. This chapter highlights individual decisions that need to be made before, during, and after a model or set of models has been trained, with an emphasis on proper statistical methods and suitable interpretation of the results. PMID- 18449486 TI - Bioinformatics: databasing and gene annotation. AB - "Omics" experiments amass large amounts of data requiring integration of several data sources for data interpretation. For instance, microarray, metabolomic, and proteomic experiments may at most yield a list of active genes, metabolites, or proteins, respectively. More generally, the experiments yield active features that represent subsequences of the gene, a chemical shift within a complex mixture, or peptides, respectively. Thus, in the best-case scenario, the investigator is left to identify the functional significance, but more likely the investigator must first identify the larger context of the feature (e.g., which gene, metabolite, or protein is being represented by the feature). To completely annotate function, several different databases are required, including sequence, genome, gene function, protein, and protein interaction databases. Because of the limited coverage of some microarrays or experiments, biological data repositories may be consulted, in the case of microarrays, to complement results. Many of the data sources and databases available for gene function characterization, including tools from the National Center for Biotechnology Information, Gene Ontology, and UniProt, are discussed. PMID- 18449487 TI - Microarray probe mapping and annotation in cross-species comparative toxicogenomics. AB - Genomics-based tools, such as microarrays, do appear to offer promise in evaluating the relevance of one species to another in terms of molecular and cellular response to a given treatment. However, to fulfill this promise the individual end points (i.e., the genes, proteins, or mRNAs) measured in one species must be mapped to corresponding end points in another species. Several approaches, along with their strengths and weaknesses, are described in this chapter. A sequential approach is described that first makes use of a "Genome To Genome Through Orthology" method, where probe sequences for a given species are mapped into full-length sequences for that species, associated with the locus for those sequences and then into a second species by consulting orthology resources. The second step supplements these results by mapping the probe sequences for the given species into the best matching transcript from any organism, which then are mapped into the appropriate native locus and finally into the second species via an orthology resource. The results of this method are given for an experiment comparing the transcriptional response of canine liver to phenobarbital with that of rat liver. PMID- 18449488 TI - Toxicogenomics in biomarker discovery. AB - In the area of toxicology, the subdiscipline of toxicogenomics has emerged, which is the use of genome-scale mRNA expression profiling to monitor responses to adverse xenobiotic exposure. Toxicogenomics is being investigated for use in the triage of compounds through predicting potential toxicity, defining mechanisms of toxicity, and identifying potential biomarkers of toxicity. Whereas various approaches have been reported for the development of algorithms predictive of toxicity and for the interpretation of gene expression data for deriving mechanisms of toxicity, there are no clearly defined methods for the discovery of biomarkers using gene expression technologies. Ways in which toxicogenomics may be used for biomarker discovery include analysis of large databases of gene expression profiles followed by in silico mining of the database for differentially expressed genes; the analysis of gene expression data from preclinical studies to find differentially expressed genes that correlate with pathology (coincident biomarker) or precede pathology (leading biomarker) within a lead series; or gene expression profiling can be performed directly on the blood from preclinical studies or clinical trials to find biomarkers that can be obtained noninvasively. This chapter broadly discusses the issues and the utility of applying toxicogenomics to biomarker discovery. PMID- 18449489 TI - From pharmacogenomics to translational biomarkers. AB - There is a need for new biomarkers to enable faster detection of adverse events due to drugs and disease processes. One would prefer biomarkers that are useful in multiple species (i.e., translational or bridging biomarkers) so that it would be possible to directly link responses between species and follow such injury in both preclinical and clinical settings. This chapter will explore some of the issues surrounding the use of pharmacogenomics to identify and qualify such biomarkers, and examples will be provided. PMID- 18449490 TI - Public consortium efforts in toxicogenomics. AB - Public consortia provide a forum for addressing questions requiring more resources than one organization alone could bring to bear and engaging many sectors of the scientific community. They are particular well suited for tackling some of the questions encountered in the field of toxicogenomics, where the number of studies and microarray analyses would be prohibitively expensive for a single organization to carry out. Five consortia that stand out in the field of toxicogenomics are the Institutional Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Committee on the Application of Genomics to Mechanism Based Risk Assessment, the Toxicogenomics Research Consortium, the MicroArray Quality Control (MAQC) Consortium, the InnoMed PredTox effort, and the Predictive Safety Testing Consortium. Collectively, these consortia efforts have addressed issues such as reproducibility of microarray results, standard practice for assays and analysis, relevance of microarray results to conventional end points, and robustness of statistical models on diverse data sets. Their results demonstrate the impact that the pooling of resources, experience, expertise, and insight found in consortia can have. PMID- 18449491 TI - Applications of toxicogenomics to nonclinical drug development: regulatory science considerations. AB - Scientists in the pharmaceutical industry have ready access to samples from animal toxicology studies carefully designed to test the safety characteristics of a steady pipeline of agents advancing toward clinical testing. Applications of toxicogenomics to the evaluation of compounds could best be realized if this promising technology could be implemented in these studies fully anchored in the traditional study end points currently used to characterize phenotypic outcome and to support the safe conduct of clinical testing. Regulatory authorities worldwide have declared their support for toxicogenomics and related technological tools to positively impact drug development, and guidance has been published. However, applications of exploratory "omics" technologies to compounds undergoing safety testing remain inhibited due to two core data submission responsibility implications and ambiguities: (1) constraints arising from continual literature surveillance and data reanalysis burdens, under the shadow of looming subsequent reporting requirements to regulatory authorities as gene expression end points loosely linked to safety gain attention in the published literature, and (2) ambiguities in interpretation of validation stature remain between exploratory, probable valid, and known valid safety biomarkers. A proposal is offered to address these regulatory implementation barriers to open access for exploring this technology in prospective drug development animal toxicology studies. PMID- 18449492 TI - Role of combination therapy in the treatment of hypertension: focus on valsartan plus amlodipine. AB - Hypertension control is rare in clinical practice, particularly in high-risk patients. A large factor is therapeutic inertia deriving from poorly prescribed lifestyle changes, excess monotherapy use, and scarce on-treatment modifications. The use of drug combinations significantly improves blood pressure (BP) control; in particular, fixed combinations improve therapy without increasing daily pill intake, thereby favouring patient compliance and therapy continuation. The most widely used fixed combination is based on thiazide diuretics added to either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). Several large-scale clinical trials have been conducted showing that these combinations are effective in lowering BP. However, thiazide diuretics can reduce the metabolic benefits derived from renin-angiotensin-aldosterone system (RAAS) inhibitors in high metabolic risk patients. In contrast, ACE inhibitors or ARBs combined with dihydropyridine calcium channel antagonists (DHPCAs) exert a marked antihypertensive effect without decreasing metabolic protection by RAAS blockade. In the recent JIKEI heart study, approximately 60% of patients affected by hypertension, heart failure, coronary heart disease or their combination in the valsartan arm were simultaneously treated with DHPCAs. Of note, a 39% reduction in the primary endpoint of combined morbidity and mortality was reported in the valsartan compared with the non-valsartan arm. Furthermore, in a recent multinational study, 83% of 3161 hypertensive patients treated with valsartan and the DHCPA amlodipine reported a concontrolled BP after 8 weeks of treatment. As expected, amlodipine did not negatively influence the metabolic profile of patients, thereby supporting the role of ARB+DHPCA combinations as effective and promising tools in hypertension treatment. In summary, the combination of ARBs with DHPCAs is an effective strategy in hypertension treatment through synergy between their antihypertensive and vascular protective actions, persistent metabolic benefits deriving from RAAS inhibition, and reduced incidence of side effects. PMID- 18449496 TI - Cytotoxic components from the dried rhizomes of Zingiber officinale Roscoe. AB - Five compounds were isolated from the chloroform-soluble fraction of the methanolic extract of the dried rhizomes of Zingiber officinale (Zingiberaceae) through repeated column chromatography. Their chemical structures were elucidated as 4-, 6-, 8-, and 10-gingerols, and 6-shogaol using spectroscopic analysis. Among the five isolated compounds, 6-shogaol exhibited the most potent cytotoxicity against human A549, SK-OV-3, SK-MEL-2, and HCT15 tumor cells. 6 shogaol inhibited proliferation of the transgenic mouse ovarian cancer cell lines, C1 (genotype: p53(-/-), c-myc, K-ras) and C2 (genotype: p53(-/-), c-myc, Akt), with ED(50) values of 0.58 microM (C1) and 10.7 microM (C2). PMID- 18449497 TI - Synthesis of new imidazolyl acetic acid derivatives with anti-inflammatory and analgesic activities. AB - We synthesized 2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl) 5-oxo-4,5 dihydroimidazol-1-yl) acetic acid 3. Chlorination afforded the chloro derivative 4, which reacted with different amines and hydrazine to afford compounds 5-8. Pyrazole, pyrazolone, and thiazolidinone derivatives were also synthesized from Imidazol-1-ylacetic acid hydrazide 8 to give compounds 9-12. Compounds were then evaluated for their anti-inflammatory activity against carrageenan-induced rat paw edema and their analgesic activity using the writhing test in albino mice. Compounds 5, 9, 10, 12 exhibited maximum anti-inflammatory activity, and all the compounds inhibited writhing, with 10 and 12 being two times more effective than the reference standard. PMID- 18449498 TI - Anti-oxidative and inhibitory activities on nitric oxide (NO) and prostaglandin E2 (COX-2) production of flavonoids from seeds of Prunus tomentosa Thunberg. AB - Chemical investigation of the 80% Me(2)CO extract from the seeds of Prunus tomentosa led to the isolation and identification of six flavonoids: kaempferol (1), kaempferol 3-O-alpha-L-rhamnopyranoside (2; afzelin), kaempferol 3-O-beta-D (6-acetyl)-glucopyranosyl(1-->4)-alpha-L-rhamnopyranoside (3; multiflorin A), kaempferol 3-O-beta-D-glucopyranosyl(1-->4)-alpha-L-rhamnopyranoside (4; multiflorin B), quercetin 3-O-alpha-L-rhamnopyranoside (5; quercitrin), and quercetin 3-O-beta-D-glucopyranosyl (1-->4)-alpha-L-rhamnopyranoside (6; multinoside A). Anti-oxidative and inhibitory activities on nitric oxide (NO) and prostaglandin E(2) production in interferon-gamma (INF-gamma) and lipopolysaccharide (LPS)-activated RAW 264.7 cells in vitro (COX-2) of the isolated compounds were evaluated. Compounds 1, 5, and 6 exhibited potent anti oxidative activity in the DPPH radical scavenging assay with IC(50) values of 57.2, 59.4, and 54.3 microg/mL respectively. The positive control, ascorbic acid, had an IC(50) of 55.5 mug/mL. Compounds 1, 5, and 6 also reduced COX-2 levels in a dose dependent manner with IC(50) values of 10.2, 8.7, and 9.6 microg/mL respectively, with the positive control, indomethacin, having an IC(50) of 5.1 microg/mL. All six compounds inhibited NO production in a dose dependent manner with IC(50) values of 35.1, 42.8, 40.0, 44.8, 43.7, and 43.9 microg/mL respectively, while the positive control, L-NMMA, had an IC(50) of 42.1 microg/mL. PMID- 18449499 TI - In vitro antioxidant and anti-inflammatory activities of Jaceosidin from Artemisia princeps Pampanini cv. Sajabal. AB - Oxidized low-density lipoprotein (oxLDL) plays a key role in the inflammatory processes of atherosclerosis. Jaceosidin isolated from the methanolic extracts of the aerial parts of Artemisia princeps Pampanini cv. Sajabal was tested for antioxidant and anti-inflammatory activities. Jaceosidin inhibited the Cu(2+) mediated LDL oxidation with IC(50) values of 10.2 microM in the thiobarbituric acid-reactive substances (TBARS) assay as well as the macrophage-mediated LDL oxidation. The antioxidant activities of jaceosidin were exhibited in the conjugated diene production, relative electrophoretic mobility, and apoB-100 fragmentation on copper-mediated LDL oxidation. Jaceosidin also inhibited the generation of reactive oxygen species (ROS) concerning in regulation of NF-kappaB signaling. And jaceosidin inhibited nuclear factor-kappa B (NF-kappaB) activity, nitric oxide (NO) production, and suppressed expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. PMID- 18449500 TI - Induction of apoptosis by a stilbene analog involves Bax translocation regulated by p38 MAPK and Akt. AB - trans-Stilbenes have been reported to induce cytochrome P450 1B1 (CYP1B1) inhibition and cell death, however, the molecular mechanisms of the effects are not fully understood. We report here that (1-(2-{3-[2-(2,4-dimethoxy-phenyl) vinyl]-5-methoxy-phenoxy}ethyl)-1H-imidazole), a synthetic stilbene analog (SA) significantly suppressed TCDD-stimulated CYP1B1 mRNA expression. In HL-60 cells, SA induced apoptosis through activation of p38 MAPK and inactivation of Akt, which in turn activated Bad and mitochondrial death signaling pathway, as evidenced by Bax translocation and cytochrome c release. Expression of dominant negative p38 MAPK or constitutively active Akt significantly prevented cell death and mitochondrial Bax translocation, implicating that p38 MAPK and Akt signaling pathways play crucial roles in stilbene-induced apoptosis of HL-60 cells. These results suggest that SA induces apoptotic cell death as well as CYP1B1 inhibition and may thus be beneficial in cancer prevention. PMID- 18449501 TI - Antiallergic effect of the root of Paeonia lactiflora and its constituents paeoniflorin and paeonol. AB - The root of Paeonia lactiflora PALL (PL, Family Paeoniaceae) has been used frequently as an antipyretic and anti-inflammatory agent in traditional medicines of Korea, China and Japan. To evaluate antiallergic effect of PL, we isolated its main constituents, paeoniflorin and paeonol, and evaluated in vivo their inhibitory effects against passive cutaenous anaphylaxis (PCA) reaction induced by IgE-antigen complex and scratching behaviors induced by compound 48/80. PL, paeoniflorin and paeonol potently inhibited PCA reaction and scratching behaviors in mice. Paeoniflorin exhibited the most potent inhibition against scratching behaviors and the acetic acid-induced writhing syndrome in mice. Paeonol most potently inhibited PCA reaction and mast cells degranulation. These findings suggest that PL can improve IgE-induced anaphylaxis and scratching behaviors, and may be due to the effect of its constituents, paeoniflorin and paeonol. PMID- 18449502 TI - Propolis reverses acetaminophen induced acute hepatorenal alterations: a biochemical and histopathological approach. AB - The present study has been conducted to evaluate the curative effect of propolis extract, a honey bee-hive product, against acetaminophen (APAP) induced oxidative stress and dysfunction in liver and kidney. Animals were challenged with APAP (2 g/kg, p.o.) followed by treatment of propolis extract (100 and 200 mg/kg, p.o.) once only after 24 h. Release of transaminases, alkaline phosphatase, lactate dehydrogenase, and serum bilirubin were increased, whereas hemoglobin and blood sugar were decreased after APAP administration. Antioxidant status in both the liver and kidney tissues were estimated by determining the glutathione, malondialdehyde content and activities of the CYP enzymes, which showed significant alterations after APAP intoxication. In addition, activities of adenosine triphosphatase, acid phosphatase, alkaline phosphatase, and major cell contents (total protein, glycogen and cholesterol) were also altered due to APAP poisoning. Propolis extract successfully reversed the alterations of these biochemical variables at higher dose. Improvements in hepatorenal histoarchitecture were also consistent with biochemical observations. The results indicated that ethanolic extract of propolis has ability to reverse APAP-induced hepatorenal biochemical and histopathological alterations probably by increasing the antioxidative defense activities due to various phenolic compounds present in it. PMID- 18449503 TI - Dual regulation of dnaK and groE operons by HrcA and Ca++ in Streptococcus pneumoniae. AB - The dnaK and groE operons in Streptococcus pneumoniae are repressed by HrcA in the presence of Ca(++). However, it is unclear how HrcA and Ca(++) regulate the dnaK and groE operons. This study examined the dual regulation of the dnaK and groE operons in S. pneumoniae by HrcA and Ca(++). At 30 degrees C, the hrcA mutant showed a constitutively higher level of dnaK expression at both the protein and mRNA levels than that of the wild type whereas the level of groEL expression was relatively unchanged. On the other hand, the levels of both dnaK and groEL transcripts were increased after heat shock but the hrcA mutant was not sensitive to heat shock. Immunoblot analysis of the cells pretreated with the Ca(++) chelator, BAPTA-AM, revealed the induction of HrcA and GroEL at both 30 degrees C and 42 degrees C. However, at longer preincubation time with BAPTA-AM, GroEL was further induced but the level of HrcA decreased suggesting that Ca(++) regulates the dnaK and groE operons differently. Overall, Ca(++) and HrcA differentially regulate the transcription of the dnaK and groE operons in S. pneumoniae. These results are expected to contribute to resolving the relationship between DnaK/GroEL expression and the pathogenesis in S. pneumoniae. PMID- 18449504 TI - Inhibition of proliferation in colon cancer cell lines and harmful enzyme activity of colon bacteria by Bifidobacterium adolescentis SPM0212. AB - In this study, we assessed the anticancer activity and bacterial enzyme inhibition of Bifidobacterium adolescentis SPM0212. B. adolescentis SPM0212 inhibited the proliferation of three human colon cancer cell lines: HT-29, SW 480, and Caco-2. SPM0212 also dose-dependently inhibited TNF-a production and changes in cellular morphology. B. adolescentis SPM0212 inhibited harmful fecal enzymes, including a-glucuronidase, a-glucosidase, tryptophanase, and urease. Thus, B. adolescentis SPM0212 exerts an anticancer effect and inhibits harmful fecal enzymes. PMID- 18449505 TI - Characterization of functional roles of DRY motif in the 2nd intracellular loop of dopamine D2 and D3 receptors. AB - Dopamine D(2)R and D(3)R (D(2)R, D(3)R) show very high sequence homology and employ virtually identical signaling pathways even though D(2)R is 2 approximately 5 times more active. Among the structural motifs identified, a triplet sequence, Asp-Arg-Tyr (DRY motif), plays critical roles in the determination of receptor conformations for signaling and intracellular trafficking of G protein-coupled receptors by forming intramolecular interactions. Thus, it is possible that different signaling efficiencies of D(2)R and D(3)R might be caused by the receptor activation levels stabilized by their own DRY motifs. In this study, the Arg and Asp residues of D(2)R and D(3)R were mutated, and resulting changes in their signaling and intracellular trafficking properties were comparatively studied. Mutation of the Arg residues of D(2)R and D(3)R abolished their signaling but differently affected their intracellular localizations. The wildtype and R132H-D(2)R were expressed mainly on the plasma membrane. On the other hand, compared with the wildtype D(3)R, a substantial amount of R128H-D(3)R was localized intracellularly. The expression of receptor proteins on the plasma membrane and their signaling efficiencies were more drastically affected by the mutation of the Asp residue of D(3)R than D(2)R. Therefore, it was concluded that the different levels of conformational strain exerted by the DRY motif might partly determine the quantitative differences in the signaling efficiencies between D(2)R and D(3)R. PMID- 18449506 TI - KR-31762, a novel KATP channel opener, exerts cardioprotective effects by opening SarcKATP channels in rat models of ischemia/reperfusion-induced heart injury. AB - The cardioprotective effects of KR-31762, a newly synthesized K+(ATP) opener, were evaluated in rat models of ischemia/reperfusion (I/R) heart injury. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, KR-31762 (3 and 10 microM) significantly increased the left ventricular developed pressure (LVDP) and double product (heart rate x LVDP) after 30-min reperfusion in a concentration-dependent manner, while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31762 also significantly increased the time to contracture (TTC) during ischemic period (20.0, 22.4 and 26.4 min for control, 3 and 10 microM, respectively), while decreasing the release of lactate dehydrogenase (LDH) from the heart during 30 min reperfusion (30.4, 14.3 and 19.7 U/g heart weight, respectively). All these parameters except LDH release were reversed by glyburide (1 microM), a nonselective blocker of K+(ATP) channel, but not by 5-hydroxydecanoate, a selective blocker of mitoK+(ATP) channel. In anesthetized rats subjected to 45-min occlusion of left anterior descending coronary artery followed by 90-min reperfusion, KR-31762 significantly decreased the infarct size (60.8, 40.5 and 37.8% for control, 0.3 and 1.0 mg/kg, iv, respectively). KR-31762 slightly relaxed the isolated rat aorta precontracted with methoxamine (IC(50): 23.5 microM). These results suggest that KR-31762 exerts potent cardioprotective effects through the opening of sarcolemmal K(ATP) channel in rat hearts with the minimal vasorelaxant effects. PMID- 18449507 TI - Comparison of suppressive effects of demethoxycurcumin and bisdemethoxycurcumin on expressions of inflammatory mediators in vitro and in vivo. AB - Demethoxycurcumin and bisdemethoxycurcumin are the main active ingredients isolated from Curcumae Longae Radix. Recent studies demonstrated that both compounds exhibit antioxidative and anti-inflammatory effects as well as effects on cancer cell lines. In this study, we compared the activities of demethoxycurcumin and bisdemethoxycurcumin, and both compounds were evaluated on lipopolysaccharide (LPS)-induced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), cycloxygenase-2 (COX-2) and nuclear factor-kappaB (NF kappaB) activity in a RAW 264.7 macrophage cell line. The evaluation:results suggested that the anti-inflammatory properties of demethoxycurcumin and bisdemethoxycurcumin were attributed to the inhibition of iNOS and COX-2 expression, as initiated by the inhibition of NF-kappaB activity. Additionally, both of them significantly inhibited carrageenan-induced paw edema in mice. Taken together, all of the results showed that the suppressive effect of demethoxycurcumin was stronger than that of bisdemethoxycurcumin, indicating that the methoxy group had enhanced demethoxycurcumin's anti-inflammation effects. PMID- 18449508 TI - Combinatorial anti-Trichophyton effects of Ligusticum chuanxiong essential oil components with antibiotics. AB - The antifungal activities of ligustilide and butylidene phthalide, which are major oil components comprising the essential oil of Ligusticum chuanxiong, in combination with antifungal drugs were evaluated. Checkerboard microtiter and microdilution tests were used to measure combined effects against Trichophyton species, T. erinacei, T. mentagrophytes, T. rubrum, T. schoenleinii, T. tonsurans and T. soudanense. Susceptibility of these Trichophyton species to L. chuanxiong essential oil differed distinctly. The fractional inhibitory concentrations (FICIs) against Trichophyton species ranged between 0.27 and 0.56 for ketoconazole combined with ligustilde or butylidene phthalide, indicating synergism or additive effects between the antibiotic and essential oil compounds. Testing by itraconazole instead of ketoconazole, similar combination effects were observed with FICIs from 0.31 to 0.63 against the tested strains of T. mentagrophytes, T. rubrum, T. schoenleinii, and T. soudanense. Thus, data reported here showed that Trichophyton susceptibility to ketoconazole and itraconazole could be notably improved by ligustilde and butylidene phthalide. PMID- 18449509 TI - Prostaglandin E2-mediated dysregulation of proinflammatory cytokine production in pristane-induced lupus mice. AB - Systemic lupus erythematosus (SLE) is characterized by inflammatory and dysregulatory immune responses including overactive B cells, overproduction of proinflammatory cytokines, and T cell hyperactivity. PGE(2) modulates a variety of immune processes at sites of inflammation, including production of inflammatory cytokines. However, the role of PGE(2) in dysregulatory inflammatory and immune responses in lupus remains unclear. We investigated whether PGE(2) mediates production of inflammatory cytokines in pristane-induced lupus BALB/c mice. Our results showed that levels of serum and BAL PGE(2) and LPS-stimulated production of PGE(2) by peritoneal macrophages were remarkably increased in pristane-induced lupus mice compared to healthy controls. Exogenous PGE(2) enhanced production of IL-6, IL-10, and NO but decreased TNF-alpha by macrophages and augmented IFN-gamma, IL-6, and IL-10 by splenocytes from pristane-induced lupus mice compared to healthy controls. Exogenous PGE(2) also enhanced production of IFN-gamma, IL-6, and IL-10 by thymocytes from pristane-induced lupus mice. Indomethacin (Indo), a PGE(2) synthesis inhibitor, greatly inhibited LPS-induced production of IL-6 and IL-10 by macrophages from pristane-induced lupus mice, while enhanced TNF-alpha. Indo remarkably inhibited Con A-increased production of IFN-gamma, IL-6, and IL-10 by splenocytes and thymocytes from pristane-induced lupus mice. Therefore, our findings suggest that endogenous PGE(2) may mediate dysregulation of production of proinflammatory cytokines, such as IL-6, IL-10, and IFN-gamma, and NO in pristane-induced lupus mice. PMID- 18449510 TI - Anti-hyperalgesic and anti-inflammatory effects of ketorolac tromethamine gel using pulsed ultrasound in inflamed rats. AB - The aim of this study was to determine if a ketorolac tromethamine (KT) gel solution could be administered in vivo via phonophoretic transdermal delivery using pulsed ultrasound by examining its anti-hyperalgesic and anti-inflammatory effects in a rat carrageenan inflammation model. 1% carrageenan was injected into the plantar surface of the right hindpaw of a rat, and anti-hyperalgesic and anti inflammatory effects of KT via phonophoretic transdermal delivery were examined. The changes in the mechanical and thermal hyperalgesia, nociceptive flexor reflex (NFR), as well as the swelling changes were determined. According to the anti hyperagesia and anti-inflammation tests, which were used to determine the change in the pain threshold, NFR and swelling showed that the group given the phonophoretic transdermal delivery of KT exhibited significantly more noticeable anti-hyperalgesic and anti-inflammatory effects than those treated with the simple application of a KT gel. The transdermal application of KT gel using phonophoresis had significant anti-hyperalgesic and anti-inflammatory effects. These findings suggest that the transdermal administration of a KT gel using phonophoresis using pulsed ultrasound might be useful for treating acute inflammation and pain. PMID- 18449511 TI - Enhanced bioavailability of verapamil after oral administration with hesperidin in rats. AB - The aim of this study was to investigate the effects of hesperidin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of hesperidin (3 or 10 mg/kg). Compared to the control group, the presence of hesperidin significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 71.1-96.8% and the peak concentration (C(max)) of verapamil by 98.3-105.2%. Hesperidin significantly (p<0.01) decreased the total plasma clearance (CL/F) of verapamil by 41.6-49.2% in rats. However there was no significant change in the time to reach the peak plasma concentration (T(max)), the elimination rate constant (K(el)) and the terminal half-life (T(1/2)) of verapamil in the presence of hesperidin. The AUC and C(max) of norverapamil were significantly (p<0.05) higher in rats co administrated with hesperidin than those of the control. Consequently hesperidin significantly enhanced bioavailability of verapamil in rats. These results might be due to the decreased efflux and metabolism of verapamil in the intestine. Drug interactions should be concerned in the clinical setting when verapamil is used concomitantly with hesperidin or hesperidin-containing dietary. PMID- 18449512 TI - Enantioselective determination of chlorpheniramine in various formulations by HPLC using carboxymethyl-beta-cyclodextrin as a chiral additive. AB - A chiral mobile phase HPLC method is described for chiral separation and determination of chlorpheniramine (CP) enantiomers in various commercial preparations. Chromatographic separation was achieved on a conventional ODS column with a mixture of aqueous sodium phosphate (5 mM) containing 0.5 mM carboxymethyl-beta-cyclodextrin, methanol and triethylamine (73:25:2, v/v/v, pH 4.3) as the mobile phase. The flow rate of isocratic elution was 0.24 mL/min and peaks were detected at 224 nm. The method was applied to nine commercial CP preparations in six dosage forms and CP enantiomers were well separated without any disturbance of other ingredients or impurities present. The results showed that only one preparation was d-CP and the others were dl-CP preparations. The contents of all the preparations were found to be in the range of 97%-104% of labeled contents. This method was economical and convenient, affording sufficient accuracy, precision and reproducibility, as well as sensitivity and selectivity. PMID- 18449513 TI - Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105 polymeric micelles. AB - A novel polymeric micelle formulation of paclitaxel (PTX) has been prepared with the purpose of improving in vitro release as well as prolonging the blood circulation time of PTX in comparison to a current PTX formulation, Taxol injection. This work was designed to investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of PTX-loaded Pluronic P105 micellar system. The micelles were prepared by thin-film method using a nonionic surfactant Pluronic P105 and a hydrophobic anticancer drug, PTX. With a dynamic light scattering sizer and a transmission electron microscopy, it was shown that the PTX-loaded micelles had a mean size of approximately 24 nm with narrow size distribution and a spherical shape. The in vitro release profiles indicated that the release of PTX from the micelles exhibited a sustained release behavior. A similar phenomenon was also observed in a pharmacokinetic study in rats, in which t (1/2 beta) and AUC of the micelle formulation were 4.9 and 5.3 fold higher than that of Taxol injection. The biodistribution study in mice showed that the PTX-loaded micelles not only decreased drug uptake by liver, but also prolonged drug retention in blood and increased distribution of drug in lung, spleen and kidney. These results suggested that the P105 polymeric micelles may efficiently load, protect and retain PTX in both in vitro and in vivo environments, and could be a useful drug carrier for i.v. administration of PTX. PMID- 18449514 TI - Preparation of pH-sensitive, long-circulating and EGFR-targeted immunoliposomes. AB - A long-circulating formulation of pH-sensitive liposomes (PSLs) with antibodies against epidermal growth factor receptor (EGFR) attached was designed, expecting an increase in binding and delivery of liposomes to the target cells including non-small cell lung cancer (NSCLC) cells. Physicochemical properties of the PSLs were measured by SEM and DLS. Leakage of a self-quenching fluorescent probe, calcein, from the liposome was studied for the evaluation of pH-sensitivity. Encapsulation efficiency of gemcitabine (an anti-cancer drug) in PSLs was about 67%. Average size of liposomes was 88 nm in diameter. The PSL of DOPE/CHEMS (6:4 molar ratio) formulation showed a dramatic pH-sensitivity at/around pH 5.5, whereas non-PSL of DPPC/Chol or PC/CHEMS formulation did not. Anti-proliferation effect of gemcitabine-encapsulating PSLs & Ab-PSLs in A549 cells was 2-fold higher than the free drug, which was further elucidated by the apoptosis of the cells by gemcitabine (approximately 10% apoptosis for PSL or Ab-PSL formulation vs. approximately 1% for free drug or non-PSL formulation) using FACS analysis. These data demonstrate delivery of gemcitabine to tumor cells can be improved by long-circulating PSLs or Ab-PSLs formulations in vitro. PMID- 18449515 TI - Pharmacokinetics and biodistribution of surface modification polymeric nanoparticles. AB - The objective of this study is to investigate the pharmacokinetics and biodistribution of free breviscapine (BVP) and coated BVP-loaded poly (D, L lactic acid) nanoparticles (BVP-PLA-NPs) in rats after i.v. administration. Coated BVP-PLA-NPs were prepared by the spontaneous emulsification solvent diffusion method and characterized. The BVP content in the NPs, the biological samples and in vitro release was measured by the high-performance liquid chromatography (HPLC). The mean sizes of coated BVP-PLA-NPs were 177 and 319 nm with a narrow distribution and smooth sphere shapes, entrapment efficiency of 86.9% and 93.1%, respectively. Drug release profiles in phosphate buffer and plasma exhibited a biphasic release phenomenon. After i.v. administration of free BVP and NPs suspensions in rats, area under plasma concentration-time curve and elimination t(1/2) were increased 9.3-fold and 10.9-fold for 177 nm of NPs, and 4.4-fold and 17.1-fold for 319 nm of NPs compared with that of free BVP, respectively. NPs were mainly distributed in liver, spleen, heart and brain. In addition, NPs could penetrate blood brain barrier (BBB) and the particle size had some effect on pharmacokinetics and biodistribution. Coated BVP-PLA-NPs could effectively avoid the capture by the reticuloendothelial system and prolong the half-life of BVP. Moreover, these NPs could penetrate BBB and enhance the accumulation of BVP in brain. PMID- 18449516 TI - [Time in care of trauma patients in the air rescue service: implications for disposition?]. AB - BACKGROUND: Time plays a crucial role in treating multiple traumatized patients and delays in management worsen the prognosis. Furthermore, current studies show that trauma patients profit from primary delivery to a trauma center. Therefore, the goal of physician-staffed ground and air rescue services in Germany is to treat these patients as quickly as possible and deliver them to a suitable trauma center. The aim of the present study was to investigate prehospital treatment times for the air rescue team in terms of disposition and efficiency when a ground rescue team was already present at the scene. METHODS: In a nationwide, multicenter analysis emergency missions carried out for traumatological emergencies in 2006 by 28 air rescue centers (ARC) of the TeamDRF and 6 ARC of the federal police were evaluated using the medical database MEDAT of the German Air Rescue Service. A distinction was made between combined missions with (MEDAT 1 group) and without (MEDAT 2 group) physician-staffed ground emergency medical services already being present at the emergency site and in particular the rescue helicopter treatment times for both groups were investigated. Furthermore, combined missions (MAN 1 group) and solo missions (MAN 2 group) for traumatological emergencies in the period 01.05.2006 to 31.01.2007 were investigated in a complementary prospective regional study at the ARC Heidelberg/Mannheim "Christoph 53". In both groups the total treatment times for all physician-staffed emergency systems involved in treatment at the scene were investigated. RESULTS: Nationwide, 26,010 primary missions could be evaluated and of these, 11,464 missions were traumatological emergencies (44.1%) with 2,229 (19.4%) carried out by the MEDAT 1 group and 9,235 (80.6%) by the MEDAT 2 group. For both groups the helicopter treatment times depended on the severity of the injuries (NACA classification) and were between 17+/-12 min (NACA I) and 34+/-19 min (NACA VII) in MEDAT group 1 versus 21+/-10 and 36+/-19 min in MEDAT group 2 (p<0.05, p<0.001), respectively. In the MEDAT 1 group, the average treatment times were between 2.8 min (NACA VII) and 8.1 min (NACA VI) shorter compared with the MEDAT 2 group. Moreover, when taking the severity of the injury into consideration, a regular and significantly higher treatment effort (e.g. intubation, repositioning and chest tube insertion) and a greater proportion of patients who were transported to the clinic via rescue helicopter were observed for the MEDAT 1 group than for the MEDAT 2 group. In the regional study 670 primary missions were evaluated including 382 traumatological emergencies (57%). From these, 90 multiple trauma patients (NACA V) were not resuscitated or died at the scene, 58 from the MAN 1 group and 32 from the MAN 2 group, and were investigated more closely. The helicopter treatment times were comparable to those observed in the nationwide study and were found to be 26+/-12 min and 35+/ 20 min (p<0.05), respectively. In the MAN 1 group the treatment times for the ground rescue services up to the time when the helicopter arrived was 22+/-11 min on average; the total treatment time was 48+/-15 min and 12+/-8 min longer than the time for the MAN 2 group, which was statistically significant. In the MAN 1 group the helicopter was alerted on average 17+/-15 min after the physician staffed ground rescue services arrived at the emergency site. Treatment by the rescue helicopter teams was significantly more extensive in the MAN 1 group. CONCLUSIONS: The treatment times for the helicopter were several minutes shorter when a physician-staffed ground rescue team had already arrived at the emergency site. However, it must be assumed that the total prehospital time is significantly longer for such missions. These results directly affect the disposition at the emergency dispatch center and indicate that when air rescue is required to transport a patient to hospital, the helicopter should be alerted at an early stage. In such settings, it is likely that initiating the operation in this way would improve the prognosis of severely injured patients and save costs. PMID- 18449517 TI - ["Fast-track" rehabilitation in thoracic surgery. First experiences with a multimodal, interdisciplinary, and proven perioperative treatment course]. AB - OBJECTIVES: "Fast-track" rehabilitation is a multimodal perioperative treatment concept for accelerating postoperative recovery which has been already used successfully in visceral surgery. Of its use in thoracic surgery however, almost no data exist and the relevance of this concept for pulmonary operations is unknown. PATIENTS AND METHODS: In this prospective study we examined a new perioperative fast-track treatment concept for thoracic surgery and evaluated the results. This program employs detailed information of patients, intensive perioperative respiratory therapy, thoracic peridural analgesia, forced mobilization, and an early start of postoperative normal food intake. RESULTS: Fifty consecutive patients with benign or malignant diseases of the lung aged an average of 64 years (range 22-78) were operated on thoracoscopically (n=15) or with thoracotomy (n=35) and treated perioperatively using the fast-track program. All patients were mobilized beginning 4 h postoperatively and had normal food. The incidence of general postoperative complications was 0% in this study. Postoperative stay lasted 4.5 days (range 1.5-28.5). There was no increase in surgical complications, and 6% of the patients were readmitted. The patients' acceptance of this concept was high. CONCLUSION: Fast-track rehabilitation resulted in a decreased rate of general complications and accelerated rehabilitation in thoracic surgery. PMID- 18449518 TI - [Medical acting confronted with vague prognoses. Considerations about the structure of medical acting]. AB - The article examines the structures of the medical acting, especially in oncology. It discusses how to address the issue of an adequate response to the structures of medical acting. In addition to a commitment to certain goals (for the benefit of patients, to do no harm, respect of autonomy of the patient) a doctor has to act according to the rules of art. This requires specialist knowledge and skills. Additionally the always remaining uncertainty of medical acting requires an internal disposition, which is also understood as a virtue. PMID- 18449519 TI - [Experimental treatment of malignant melanoma and its rationale]. AB - To treat malignant melanoma successfully currently means to recognize the tumor at an early stage and to remove it immediately. Aside from individual cases, available treatment modalities are not able to increase survival, especially in the palliative situation. Thus innovative experimental approaches are urgently needed to strongly improve the palliative and adjuvant treatment of melanoma. Anti-tumor effects are expected from targeted therapies, which are directed against defined molecules decisive for tumor pathogenesis. Crucial points of attack are signaling pathways, angiogenesis and apoptosis resistance. New diagnostic and therapeutic developments have enhanced the efficacy of chemotherapies. Increasing insights into tumor immunology provide new treatment approaches of vaccination, cell transfer and especially of blocking immune tolerance mechanisms. It will be challenging for the future to identify and characterize more precisely those patients who might most benefit from a certain treatment approach. PMID- 18449520 TI - Are we poised to target ACE2 for the next generation of antihypertensives? AB - Antihypertensive drugs based on the blockade of the renin-angiotensin system (RAS) target classical components of this system, i.e., angiotensin-converting enzyme (ACE) and angiotensin (Ang) II type 1 receptor. These antihypertensives are well-recognized and successful, if prescribed properly, in reducing high blood pressure, but much less effective in preventing and reverting end-organ damage induced by cardiovascular disease (CVD) and hypertension. Thus, new strategies and new drug targets that are more effective must be discovered. Recent identification of a counterregulatory axis of the RAS [ACE2, Ang-(1-7), and Mas receptor] that is potentially important in promoting vasoprotective effects offers a novel target for CVD therapeutics. In this brief review, we will highlight the functional characteristics of this axis with special emphasis on ACE2 and its possible involvement in the pathophysiology of the CVD. In addition, we will present our views on the potential of ACE2 as a new target for the development of innovative antihypertensives by highlighting the development and functional findings obtained with small molecules ACE2 activators. PMID- 18449522 TI - [Treatment of hip joint related fractures]. PMID- 18449521 TI - Targeting brain angiotensin and corticotrophin-releasing hormone systems interaction for the treatment of mood and alcohol use disorders. AB - The brain renin-angiotensin system (RAS) participates importantly in the regulation of endocrine, autonomic, and behavioral response to stress. Recent data indicate that central action of AT(1) receptor antagonists can reduce anxiety symptoms in experimental animals. Furthermore, central inhibition of RAS activity decreases ethanol intake in an animal model of alcoholism. Pathological anxiety responses and the development of substance dependence are both critically mediated through corticotrophin-releasing hormone (CRH) systems, and the RAS is positioned to interact both with hypothalamic as well as extrahypothalamic CRH systems. The thesis of this paper is that the RAS is part of the neurochemical dysregulation underlying negative affective states, anxiety disorders, and ethanol dependence and that medications targeting the RAS should be considered to augment the treatment of these disorders. PMID- 18449523 TI - [An interdisciplinary unit for major psychiatric/somatic comorbidity: concept and 22 years of experience]. AB - In this article we describe in detail a specialised facility geared toward caring for patients presenting with major psychiatric and somatic comorbidity. Located in a psychiatric hospital, an important feature of the treatment offered in this unit is that psychiatric/psychotherapeutic and somatic care are provided by the same team members. Working in this unit places high demands on the medical team, which must be competent in both fields, especially during emergency situations. Due to the severity of the patients' symptomatology, the unit requires more staff than regular psychiatric wards. Frequent psychiatric diagnoses necessitating the transfer of patients to this ward include delirium associated with internal/neurologic disorders or occurring postoperatively, and affective syndromes and dementia due to general medical conditions. Somatic disorders frequently requiring treatment in this ward include acute cardiovascular syndromes, liver or renal failure, infections, and conditions arising postoperatively or following trauma. PMID- 18449524 TI - [Proof of botulinum toxin antibodies with the Extensor Digitorum Brevis Test]. AB - INTRODUCTION: Some patients treated with botulinum toxin (btx) develop neutralizing btx antibodies (btx-ab). The expensive Mouse Diaphragm Bioassay (MDB) is considered as the gold standard by many authors. We wanted to examine whether the Extensor Digitorum Brevis Test (EDB test) is a reliable method to test for btx-ab. METHOD: We performed an electroneurography of the m. extensor digitorum brevis on both feet of 23 patients with known MDB. Afterwards the right feet were injected with 25 U of btx, and 21-28 days later the electroneurography was performed on both sides again. Finally we correlated the measured values (muscular wave latency, amplitude, area, and duration) intraindividually and with the MDB results. RESULTS: The parameters area and amplitude correlated highly significantly with the MDB (P<0.001 for both tests). Decreasing the amplitude to at least 65% of its initial value indicated the presence of btx-ab. In that way 22 of 23 EDB classifications were identical to those of the MDB, yielding a sensitivity of 92.86% and a specificity of 100%. CONCLUSION: The EDB test is a reliable technique for detecting btx-ab with high sensitivity and specificity. The EDB test can replace the MDB. PMID- 18449525 TI - The proposed terminology 'A(1c)-derived average glucose' is inherently imprecise and should not be adopted. AB - The proposed use of a more precise standard for glycated (A(1c)) and non-glycated haemoglobin would lead to an A(1c) value, when expressed as a percentage, that is lower than that currently in use. One approach advocated to address the potential confusion that would ensue is to replace 'HbA(1c)' with a new term, 'A(1c) derived average glucose.' We review evidence from several sources suggesting that A(1c) is, in fact, inherently imprecise as a measure of average glucose, so that the proposed terminology should not be adopted. PMID- 18449526 TI - Integrity of cerebral white matter in type 1 diabetes. PMID- 18449527 TI - Src activation generates reactive oxygen species and impairs metabolism-secretion coupling in diabetic Goto-Kakizaki and ouabain-treated rat pancreatic islets. AB - AIMS/HYPOTHESIS: Na(+)/K(+)-ATPase inhibition by ouabain suppresses ATP production by generating reactive oxygen species (ROS) and impairs glucose induced insulin secretion from pancreatic islets. To clarify the signal transducing function of Na(+)/K(+)-ATPase in decreasing ATP production by the generation of ROS in pancreatic islets, the involvement of Src was examined. In addition, the significance of Src activation in diabetic islets was examined. METHODS: Isolated islets from Wistar rats and diabetic Goto-Kakizaki (GK) rats (a model for diabetes) were used. ROS was measured by 5-(and 6)-chloromethyl-2',7' dichlorofluorescein fluorescence using dispersed islet cells. After lysates were immunoprecipitated by anti-Src antibody, immunoblotting was performed. RESULTS: Ouabain caused a rapid Tyr(418) phosphorylation, indicating activation of Src in the presence of high glucose. The specific Src inhibitor 4-amino-5-(4 chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) restored the ouabain induced decrease in ATP content and the increase in ROS production. Both PP2 and ROS scavenger restored the impaired insulin release and impaired ATP elevation in GK islets, but had no such effect in control islets. PP2 reduced the high glucose induced increase in ROS generation in GK islet cells but had no effect on that in control islet cells. Moreover, ouabain had no effect on ATP content and ROS production in the presence of high glucose in GK islets. CONCLUSIONS/INTERPRETATION: These results indicate that Src plays a role in the signal-transducing function of Na(+)/K(+)-ATPase, in which ROS generation decreases ATP production in control islets. Moreover, ROS generated by Src activation plays an important role in impaired glucose-induced insulin secretion in GK islets, in which Src is endogenously activated independently of ouabain. PMID- 18449528 TI - The use of hyperventilation therapy after traumatic brain injury in Europe: an analysis of the BrainIT database. AB - OBJECTIVE: To assess the use of hyperventilation and the adherence to Brain Trauma Foundation-Guidelines (BTF-G) after traumatic brain injury (TBI). SETTING: Twenty-two European centers are participating in the BrainIT initiative. DESIGN: Retrospective analysis of monitoring data. PATIENTS AND PARTICIPANTS: One hundred and fifty-one patients with a known time of trauma and at least one recorded arterial blood-gas (ABG) analysis. MEASUREMENTS AND RESULTS: A total number of 7,703 ABGs, representing 2,269 ventilation episodes (VE) were included in the analysis. Related minute-by-minute ICP data were taken from a 30 min time window around each ABG collection. Data are given as mean with standard deviation. (1) Patients without elevated intracranial pressure (ICP) (< 20 mmHg) manifested a statistically significant higher P(a)CO(2) (36 +/- 5.7 mmHg) in comparison to patients with elevated ICP (> or = 20 mmHg; P(a)CO(2): 34 +/- 5.4 mmHg, P < 0.001). (2) Intensified forced hyperventilation (P(a)CO(2) < or = 25 mmHg) in the absence of elevated ICP was found in only 49 VE (2%). (3) Early prophylactic hyperventilation (< 24 h after TBI; P(a)CO(2) < or = 35 mmHg, ICP < 20 mmHg) was used in 1,224 VE (54%). (4) During forced hyperventilation (P(a)CO(2) < or = 30 mmHg), simultaneous monitoring of brain tissue pO(2) or S(jv)O(2) was used in only 204 VE (9%). CONCLUSION: While overall adherence to current BTF-G seems to be the rule, its recommendations on early prophylactic hyperventilation as well as the use of additional cerebral oxygenation monitoring during forced hyperventilation are not followed in this sample of European TBI centers. DESCRIPTOR: Neurotrauma. PMID- 18449529 TI - Possible reflex pathway between medial meniscus and semimembranosus muscle: an experimental study in rabbits. AB - Meniscus is a well innervated tissue with four types of receptors. These receptors are mainly concentrated at the anterior and posterior horns. Although they are intended to be a part in reflex arc, this function has not been thoroughly evaluated. We hypothesized that electrical stimulation of the normal meniscus would elicit electromyographic activity of the hamstring muscle via the reflex arc. Five adult domestic male rabbits were used in this study. Under general anesthesia, knee arthrotomy and thigh dissection were done to expose medial meniscus and semimembranosus muscle. Menisci were stimulated by Teflon coated bipolar needle electrodes. Needles were placed in the posterior horn of the medial menisci. Two Teflon-coated monopolar needle electrodes were placed in semimembranosus muscle. A four-channel electromyograph was used for recording. Two different potentials were recorded from the target muscle. The first response had a very short distal latency and its amplitude was changing in accordance with the strength of the stimulus, suggesting that this response was being elicited by direct muscle stimulation. The second delayed response with less amplitude also appeared in some traces. The latency and the amplitude of this second response were fairly stable stating that this delayed response was being generated by a reflex pathway and seen in all subjects. PMID- 18449530 TI - Detrimental effects of prenatal exposure to filtered diesel exhaust on mouse spermatogenesis. AB - We recently showed that prenatal exposure to diesel exhaust (DE) disrupts spermatogenesis in mouse offspring. This study was undertaken to determine whether filtered DE in which 99.97% of diesel exhaust particles >0.3 microm in diameter were removed affects spermatogenesis in growing mice. After prenatal exposure to filtered DE for 2-16 days postcoitum, we examined daily sperm production (DSP), testicular histology, serum testosterone levels and mRNA expression of hormone synthesis process-related factors. In the filtered DE exposed group, DSP was markedly reduced at 12 weeks compared with the control group; clean air exposed group. Histological examination showed multinucleated giant cells and partial vacuolation in the seminiferous tubules of the exposed group. Testosterone was elevated significantly at 5 weeks. Moreover, luteinizing hormone receptor mRNA at 5 and 12 weeks, 17alpha-hydroxylase/C17-20-lyase and 17beta-hydroxysteroid dehydrogenase mRNAs at 12 weeks were significantly elevated. These results suggest that filtered DE retains its toxic effects on the male reproductive system following prenatal exposure. PMID- 18449531 TI - Pharmacokinetic and pharmacodynamic studies of drug interaction following oral administration of imipramine and sodium alginate in rats. AB - Recently, the use of health foods has increased due to growing interest in health maintenance. Previous in vitro studies have shown some drugs to be adsorbed by sodium alginate, a dietary fiber, and that such adsorption was marked with tricyclic antidepressants, such as imipramine. This study investigated the pharmacokinetic and pharmacological interactions between imipramine and sodium alginate in rats. The simultaneous administration of imipramine (30 mg/kg, oral (p.o.)) and sodium alginate (3.0%, p.o.) decreased the antidepressant-like activity of imipramine in a forced swimming test. In the rats administrated imipramine and 0.3%, 1.0%, or 3.0% sodium alginate, the geometric mean ratio of the Cmax values of imipramine was 72% [90% confidence intervals (CI) = 53-91%], 64% (90% CI = 47-80%), and 58% (90% CI = 50-67%), respectively. The geometric mean ratio of the AUC(0-6) values of imipramine were 68% (90% CI = 56-80%), 74% (90% CI = 60-89%), and 87% (90% CI = 73-102%), respectively. The decrease in Cmax and AUC(0-6) was judged to be significant with a 90% CI outside the 80-125% boundaries. In addition, the Tmax value of imipramine significantly increased (P < 0.05) by coadministration with 3.0% sodium alginate. These results suggested that simultaneous administration of sodium alginate decreased the serum concentration and pharmacological action of imipramine, through a delay in its absorption. Although the clinical relevance of these findings is unclear, it is important to pay considerable attention to the interactions between imipramine and sodium alginate. PMID- 18449532 TI - A solid-state NMR study of the interaction of fish antifreeze proteins with phospholipid membranes. AB - Fish antifreeze proteins and glycoproteins (AF(G)Ps) prevent ice crystal growth and are able to protect mammalian cells and tissues from hypothermic damage in the sub-zero Polar oceans. This protective mechanism is not fully understood, and further data is required to explain how AF(G)Ps are able to stabilize lipid membranes as they pass through their phase transition temperatures. Solid-state NMR spectroscopy was used as a direct method to study the interaction of the 37 residue alpha-helical type I AFP, TTTT, and the low molecular weight fraction glycoprotein, AFGP8, with dimyristoylphosphatidylcholine membranes above and below the gel-fluid phase transition temperature. In contrast to previous studies in fluid phase bilayers these experiments have provided direct information regarding both the mobility of the phosphate headgroups and perturbation of the acyl chains at a range of temperatures under identical conditions on the same sample. At 5 degrees C changes in the 2H and 31P spectra and a dramatic increase in the 31P T1 relaxation times were consistent with a significant disruption of the membrane by TTTT. Heating to 30 degrees C appeared to expel the peptide from the lipid and re-cooling showed that the interaction of TTTT was not reversible. By contrast, 31P spectra of the membranes with AFGP8 were consistent with interaction with the phosphate headgroups at both 5 and 30 degrees C. Although both peptides interact with the phospholipid bilayer surface, which may stabilize the membrane at lower temperatures, the longer 31P T1 values and the 2H NMR data obtained for TTTT compared with AFGP8 suggest that TTTT causes a greater reduction of phosphate headgroup mobility and has a greater effect on the lipid acyl chains at 5 degrees C. PMID- 18449533 TI - Discrimination between red blood cell and platelet components of blood clots by MR microscopy. AB - Magnetic resonance imaging (MRI) of pulmonary emboli obtained ex vivo, verified by immunohistochemistry, showed that platelet layers display brighter signal intensity than areas containing predominantly red blood cells (RBC) in T1 weighted MRI. These results were surprising since platelets do not contain paramagnetic haemoglobin that would enhance magnetic relaxation. Our assumption was that the fibrin meshwork areas with entrapped RBC retain abundant extracellular space filled with serum, whereas platelets regroup into tight aggregates lacking serum, essentially mimicking solid tissue structure, rich with cellular proteins that enhance T1-relaxation. Our hypothesis was examined by MRI and NMR relaxometry of in vitro RBC suspensions and sedimented platelets, as well as by MRI of model clots and pulmonary emboli obtained ex vivo. Pure sedimented platelets exhibited shorter proton spin lattice relaxation times (T1 = 874 +/- 310 ms) than those of venous blood of a healthy male with 40% haematocrit (T1 = 1277 +/- 66 ms). T1-values of RBC samples containing high haematocrit (> or = 80%) resembled T1 of platelet samples. In T1-weighted spin-echo MRI echo time and repetition time (TE/TR = 10/120 ms) the ratio of signal intensities between a non retracted whole blood clot (with a haematocrit of 35%) and a pure platelet clot was 3.0, and the ratio between a retracted whole blood clot with an estimated haematocrit of about 58% and a pure platelet clot was 2.6. We conclude that T1 weighted MRI can discriminate between platelet layers of thrombi and RBC-rich areas of thrombi that are not compacted to a haematocrit level of > or = 80%. PMID- 18449534 TI - Solution NMR and CD spectroscopy of an intrinsically disordered, peripheral membrane protein: evaluation of aqueous and membrane-mimetic solvent conditions for studying the conformational adaptability of the 18.5 kDa isoform of myelin basic protein (MBP). AB - The stability and secondary structure propensity of recombinant murine 18.5 kDa myelin basic protein (rmMBP, 176 residues) was assessed using circular dichroic and nuclear magnetic resonance spectroscopy (1H-15N HSQC experiments) to determine the optimal sample conditions for further NMR studies (i.e., resonance assignments and protein-protein interactions). Six solvent conditions were selected based on their ability to stabilise the protein, and their tractability to currently standard solution NMR methodology. Selected solvent conditions were further characterised as functions of concentration, temperature, and pH. The results of these trials indicated that 30% TFE-d2 in H2O (v/v), pH 6.5 at 300 K, and 100 mM KCl, pH 6.5 at 277 K were the best conditions to use for future solution NMR studies of MBP. Micelles of DPC were found to be inappropriate for backbone resonance assignments of rmMBP in this instance. PMID- 18449535 TI - Adjustment of conformational flexibility of glyceraldehyde-3-phosphate dehydrogenase as a means of thermal adaptation and allosteric regulation. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Thermotoga maritima (TmGAPDH) is a thermostable enzyme (Tm = 102 degrees C), which is fully active at temperatures near 80 degrees C but has very low activity at room temperature. In search for an explanation of this behavior, we measured the conformational flexibility of the protein by hydrogen-deuterium exchange and compared the results with those obtained with GAPDH from rabbit muscle (RmGAPDH). At room temperature, the conformational flexibility of TmGAPDH is much less than that of RmGAPDH, but increases with increasing temperature and becomes comparable to that of RmGAPDH near the physiological temperature of Thermotoga maritima. Using the available three-dimensional structures of the two enzymes, we compared the B factors that reflect the local mobility of protein atoms. The largest differences in B factors are seen in the coenzyme and NAD binding regions. The likely reason for the low activity of TmGAPDH at room temperature is that the motions required for enzyme functions are restricted. The findings support the idea of "corresponding states" which claims that over the time span of evolution, the overall conformational flexibility of proteins has been preserved at their corresponding physiological temperatures. PMID- 18449537 TI - Composition of nifH in a wastewater treatment system reliant on N(2) fixation. AB - High levels of nitrogen fixation have been observed in the wastewaters of pulp and paper mills. In this study, we show that nitrogen fixation in a model pulp and paper wastewater treatment system is supported by a high density of nifH sequences that are of low diversity. Quantitative PCR revealed a ratio of nifH to 16S rDNA of 1.14 +/- 0.76 which shows that very high levels of the nifH gene were enriched to support the high rates of nitrogen fixation that occur in this wastewater. Changes in wastewater composition and dissolved oxygen levels did not affect the nifH levels and allowed stable wastewater treatment. The nifH sequences identified display a similar profile to those seen in forest soil environments where nifH sequences derived from alpha-proteobacteria and beta proteobacteria are also prevalent. PMID- 18449538 TI - A comparative study on the formation and characterization of aerobic 4 chloroaniline-degrading granules in SBR and SABR. AB - The formation and characterization of the aerobic 4-chloroaniline-degrading granules in the three column-type sequencing batch reactors were investigated in this paper. The granular sludge was observed since 15 days after start-up in R2 and R3 which had the high ratio of height to diameter (H/D). Since then and within the subsequent 75 days, the granulation of aerobic sludge was apparently developed by the decreased settling time and gradually increased 4-chloroaniline (4-ClA) concentration to above 400 mg.L(-1) in R1 to R3. The aerobic granules tended to be mature in all reactors continuously operated with 4-ClA loading rates of around 800 g.m(-3).d(-1), and the removal efficiencies of chemical oxygen demand, total nitrogen, and 4-ClA were maintained above 93%, 70%, and 99.9%, respectively. Mature aerobic granules in R1 to R3 featured with the average diameter of 0.78, 1.68, and 1.25 mm, minimal settling velocity of 20.5, 70.1 and 66.6 m.h(-1), specific 4-ClA degradation rates of 0.14, 0.21, and 0.27 g.gVSS(-1).d(-1), and the ratio of proteins to polysaccharides of 8.2, 10.8, and 13.7 mg.mg(-1), respectively. This study demonstrates that the reactor with a high H/D ratio and internal circulation favors the granulation and stabilization of aerobic sludge. PMID- 18449536 TI - Two-pore potassium channels in the cardiovascular system. AB - Two-pore domain (K(2P)) channels emerged about a decade ago and since then have been an expanding area of interest. This is because their biophysical and pharmacological properties make them good candidates to support background potassium currents and membrane potential in many cell types. There is clear evidence for TREK-1 and TASK-1 in the heart and these channels are likely to regulate cardiac action potential duration through their regulation by stretch, polyunsaturated fatty acids, pH, and neurotransmitters. TREK-1 may also have a critical role in mediating the vasodilator response of resistance arteries to polyunsaturated fatty acids, thus contributing to their protective effect on the cardiovascular system. TASK-1, on the other hand, is a strong candidate for a role in hypoxic vasoconstriction of pulmonary arteries. Many other members of the K(2P) channel family have been identified in the cardiovascular system, although their functional roles are still to be demonstrated. This review provides an up to date summary of what is known about the involvement of members of the K(2P) channel family in cells of the heart and arterial circulation. Our knowledge of their roles will improve with the rapidly increasing interest in them and as new selective pharmacological tools emerge. As their physiological roles emerge, the K(2P) family of potassium channels may offer promising therapeutic solutions to target cardiovascular diseases. PMID- 18449539 TI - Role of interleukin-6 levels in cardiovascular autonomic dysfunction in type 2 diabetic patients. AB - PURPOSE: Increased serum interleukin-6 (IL-6) levels are associated with an increased risk of cardiovascular disease, and cardiovascular autonomic dysfunction is associated with high mortality in type 2 diabetic patients. However, the relationship between IL-6 levels and cardiovascular autonomic dysfunction has not been fully elucidated. The aim of this study was to determine whether serum IL-6 levels are associated with cardiovascular autonomic dysfunction in type 2 diabetic patients. METHODS: Eighty type 2 diabetic patients who did not have organic heart disease were categorized into a high IL-6 group (>2.5 pg/ml, n = 40, age 59 +/- 12 years) or a non-high IL-6 group (<2.5 pg/ml, n = 40, 61 +/- 12 years). Cardiac autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations and (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: The body mass index values (BMI), fasting insulin levels and homeostasis model assessment index values were higher in the high IL-6 group than in the non-high IL-6 group (p < 0.01). Early and delayed (123)I-MIBG myocardial uptake values were lower (p < 0.01), and the percent washout rate of (123)I-MIBG was higher (p < 0.05) in the high IL-6 group than in the non-high IL-6 group. Furthermore, multiple regression analysis revealed that the IL-6 level was independently predicted by the BMI and the myocardial uptake of (123)I-MIBG during the delayed phase. CONCLUSIONS: The results indicate that elevated IL-6 levels are associated with depressed cardiovascular autonomic function and obesity in type 2 diabetic patients. PMID- 18449541 TI - A delay stochastic process with applications in molecular biology. AB - Molecular processes of cell differentiation often involve reactions with delays. We develop a mathematical model that provides a basis for a rigorous theoretical analysis of these processes as well as for direct simulation. A discrete, stochastic approach is adopted because several molecules appear in small numbers only. Our model is a non-Markovian stochastic process. The main theoretical results include a constructive proof of the existence of the process and a derivation of the rates for initiation and completion of reactions with delays. These results guarantee that the stochastic process is a consistent and realistic description of the molecular system. They also serve as a theoretical justification of recent work on delay stochastic simulation. We apply our model to an important process in developmental biology, the formation of somites in the vertebrate embryo. Simulation of the molecular oscillator controlling this process reveals major differences between stochastic and deterministic models. PMID- 18449542 TI - Efficient transformation of wheat by using a mutated rice acetolactate synthase gene as a selectable marker. AB - Acetolactate synthase (ALS) is a target enzyme for many herbicides, including sulfonylurea and imidazolinone. We investigated the usefulness of a mutated ALS gene of rice, which had double point mutations and encoded an herbicide-resistant form of the enzyme, as a selectable marker for wheat transformation. After the genomic DNA fragment from rice containing the mutated ALS gene was introduced into immature embryos by means of particle bombardment, transgenic plants were efficiently selected with the herbicide bispyribac sodium (BS). Southern blot analysis confirmed that transgenic plants had one to more than ten copies of the transgene in their chromosomes. Adjustment of the BS concentration combined with repeated selection effectively prevented nontransgenic plants from escaping herbicide selection. Measurement of ALS activity indicated that transgenic plants produced an herbicide-resistant form of ALS and therefore had acquired the resistance to BS. This report is the first to describe a selection system for wheat transformation that uses a selectable marker gene of plant origin. PMID- 18449543 TI - Cadmium induced oxidative stress and changes in soluble and ionically bound cell wall peroxidase activities in roots of seedling and 3-4 leaf stage plants of Brassica juncea (L.) czern. AB - Metabolic adaptations to heavy metal toxicity in plants are thought to be related with developmental growth stage and the type of metal by which plant is affected. In the present study, changes in ionically bound CWP, soluble peroxidase activity, H(2)O(2) level and Malonaldehyde content in roots of cadmium and copper stressed seedlings and cadmium stressed 3-4 leaf stage plants of Brassica juncea were investigated. Cadmium inhibits root growth and reduces fresh biomass. The reduction in root growth and fresh biomass is correlated with increased lipid peroxidation and reduced tolerance. Treatment with cadmium resulted in an increase in ionically bound CWP activity in roots of seedlings but no significant change in its activity was found in roots of 3-4 leaf stage plants. Increased level of H(2)O(2) in roots of cadmium and copper treated seedlings, show a direct correlation with increased activity of ionically bound CWP. H(2)O(2) level in 3-4 leaf stage plant roots was found to be very low. Soluble peroxidase activity decreased in cadmium (50 and 100 mu-icroM) treated seedlings but it was ineffective to cause any change in its activity in 3-4 leaf stage plants. Copper treated seedlings showed an increase in ionically bound CWP activity, H(2)O(2) level and MDA content. Ascorbic acid (50 mM) pretreated seedlings shows significant decrease in ionically bound CWP activity when exposed to 50 muM cadmium. Hence, it is concluded that inhibition of root growth in Brassica juncea seedlings by cadmium, is associated with CWP catalyzed H(2)O(2) dependent reactions which are involved in metabolic adaptations to heavy-metal stress. PMID- 18449544 TI - Agrobacterium-mediated transformation of apricot (Prunus armeniaca L.) leaf explants. AB - A protocol for Agrobacterium-mediated stable transformation for scored, whole leaf explants of the apricot (Prunus armeniaca) cultivar Helena was developed. Regenerated shoots were selected using a two-step increased concentrations of paromomycin sulphate. Different factors affecting survival of transformed buds, including possible toxicity of green fluorescent protein (GFP) and time of exposure to high cytokine concentration in the regeneration medium, were examined. Transformation efficiency, based on PCR analysis of individual putative transformed shoots from independent lines was 5.6%, when optimal conditions for bud survival were provided. Southern blot analysis on four randomly chosen PCR positive shoots confirmed the presence of the nptII transgene. This is the first time that stable transformation of an apricot cultivar is reported and constitutes also one of the few reports on the transformation of Prunus cultivars. PMID- 18449540 TI - Nox enzymes in immune cells. AB - The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of phagocytes is a multi-component electron transferase that uses cytoplasmic NADPH to convert molecular oxygen to superoxide anion, consequently delivering reactive oxygen species to the site of invading microorganisms. Together with soluble factors and other phagocyte-derived agents, the resultant toxic species kill and degrade the ingested microbe. Flavocytochrome b (558), a heterodimeric protein composed of gp91 phox and p22 phox, is the membrane component of the NADPH oxidase and was previously thought to be uniquely expressed in phagocytes. Based on structural homology with gp91 phox, recent studies have defined a family of NADPH oxidase proteins (Nox) that is widely distributed throughout the plant and animal kingdoms and in many tissues in multicellular organisms. The goals of this review are to review features of the phagocyte NADPH oxidase that serve as a paradigm for exploiting oxidants for host defense, and to discuss contributions of other Nox proteins to innate immunity. PMID- 18449545 TI - Phenolic compound localisation in Polypodium vulgare L. rhizomes after mannitol induced dehydration and controlled desiccation. AB - Polypodium vulgare L. is a desiccation-tolerant fern that can withstand successive dry periods in its life cycle. To better understand this mechanism, the current study was undertaken to assess the role of phenolic compounds in rhizome dehydration and determine their localisation in the rhizome cells after enforced dehydration in mannitol solution or controlled desiccation with or without abscisic acid (ABA) pretreatment. Phenolic distribution at the subcellular level was studied using gold particle-complexed laccase. Cells from different tissues: cortical parenchyma, endodermis and stelar elements- pericycle, sieve cells and vascular parenchyma were observed under a transmission electron microscope (TEM). The content of phenolic compounds was greater in ABA untreated rhizomes after enforced dehydration in mannitol solution and subsequent rehydration. After controlled desiccation the phenolic content significantly increased in ABA-untreated rhizomes. A large number of phenolic compound deposits were present in all types of rhizomatous cells. Phenolics were widely distributed in the vacuoles of all cells, and in the secondary cell walls of sieve cells, although scattered labelling was hardly ever observed in the primary cell walls. In dehydrated and plasmolysed cells from the cortex and endodermis, phenolic compounds were present in the apoplastic compartments between the plasma membranes and the cell walls. There is evidence that abscisic acid plays a role as a crucial antioxidant resulting in no damage and a lower level of phenolic increase as compared to ABA-untreated rhizomes. Moreover, the location of phenolics suggests a protective chemical barrier against environmental stresses. PMID- 18449546 TI - Characterization of differential ripening pattern in association with ethylene biosynthesis in the fruits of five naturally occurring banana cultivars and detection of a GCC-box-specific DNA-binding protein. AB - MA-ACS1 and MA-ACO1 are the two major ripening genes in banana and play crucial role in the regulation of ethylene production during ripening. Here, we report a comparative ripening pattern in five different naturally occurring banana cultivars namely Cavendish (AAA), Rasthali (AAB), Kanthali (AB), Poovan (AAB) and Monthan (ABB), which have distinct genome composition. We found a distinct variation in the climacteric ethylene production and in-vivo ACC oxidase activity level during the ripening stages in the five cultivars. We identified the cDNAs for MA-ACS1 and MA-ACO1 from the five cultivars and studied the transcript accumulation patterns of the two genes, which correlated well with the differential timing in the expression of these two genes during ripening. The GCC box is one of the ethylene-responsive elements (EREs) found in the promoters of many ethylene-inducible genes. We have identified a GCC-box motif (putative ERE) in the promoters of MA-ACS1 and MA-ACO1 in banana cultivars. DNA-protein interaction studies revealed the presence of a GCC-box-specific DNA-binding activity in the fruit nuclear extract and such DNA-binding activity was enhanced following ethylene treatment. South-Western blotting revealed a 25-kDa nuclear protein that binds specifically to GCC-box DNA in the climacteric banana fruit. Together, these results indicate the probable involvement of the GCC-box motif as the cis-acting ERE in the regulation of MA-ACS1 and MA-ACO1 during ripening in banana fruits via binding of specific ERE-binding protein. PMID- 18449548 TI - Insufficiency fractures of both femoral necks in a young adult caused by osteoporosis: a case report. AB - Insufficiency fractures of femoral necks due to osteoporosis of unknown aetiology occurring coincidentally on both sides in young adults, have not been described in English literature so far. A 18-year-old young girl presented with a 3-month history of gradual onset of bilateral thigh pain and progressive inability to walk. At the first look, plain radiographs of both hips showed no gross abnormal findings other than some tips on reduced bone mineral density of the femoral necks. MRI was ordered upon a high suspicion of fracture and T1-weighed MRI showed a linear low signal on both femoral necks. Dual-energy X-ray absorptiometry of the lumbar spine and femoral neck showed low mineral density. She was treated surgically with in-situ internal fixation using cannulated screws. The bilateral thigh pain was resolved and walking started immediately after the treatment. Insufficiency fracture of the femoral neck due to osteoporosis should be kept in mind even in young adults complaining of atypical pain without evidence of unusual activities. We used both the terms of stress fracture and insufficiency (osteoporotic) fracture interchangeably as the mechanism of fractures resemble each other. PMID- 18449547 TI - Global left-ventricular function assessment using dual-source multidetector CT: effect of improved temporal resolution on ventricular volume measurement. AB - The purpose was to compare global left-ventricular (LV) function parameters measured with cine MRI with results from multiphase dual-source CT (DSCT) using 10 and 20 reconstruction phases. Twenty-eight patients with suspected or known CAD underwent DSCT coronary angiography. LV end-diastolic (EDV), end-systolic (ESV) and stroke volumes (SV), and ejection fraction (EF) were determined using LV segmentation and selection of specific phases from DSCT image sets reconstructed either at 5% or 10% steps through the R-R interval. Cine MRI served as the reference investigation. Threshold-based 3D-segmentation was feasible in all DSCT data sets. EDV and ESV were underestimated by DSCT, but showed excellent correlation (Pearson's correlation coefficient 0.95/0.97) to values obtained with MRI. Using data from 5% DSCT image reconstructions instead of 10% phase reconstructions, the position of the ED and ES phase was changed in 16 of 28 patients; ESVs were to found to be slightly smaller, whereas EDV were slightly larger, resulting in a systematic overestimation of LV EF by 1.9% (p=0.56). Threshold-based 3D segmentation enables accurate and reliable DSCT determination of global LV function with excellent correlation to cine MRI. Minor differences in LV EF indicate that both modalities are virtually interchangeable, even if the number of reconstructed phases is limited to 10% phase reconstructions. PMID- 18449549 TI - Vaginal misoprostol for cervical priming prior to diagnostic hysteroscopy- efficacy, safety and patient satisfaction: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness and safety of vaginal misoprostol for cervical priming prior to diagnostic hysteroscopy and to assess impact on pain scores and patient satisfaction. METHODS: One hundred women undergoing hysteroscopy were randomly allocated into two groups. The study group (n = 50) received 400 microg of misoprostol vaginally (self administered) 4-6 h prior to hysteroscopy while the control group (n = 50) did not receive any cervical priming. Primary outcome measured was need for cervical dilatation, analgesia or sedation. Secondary outcomes were pain scores, patient satisfaction and side effects. RESULTS: There was no significant difference in the need for cervical dilatation, analgesia or sedation in the two groups (P = 0.25, 0.64 and 0.5, respectively). In addition, there was no difference in subjective patient satisfaction (P = 0.70). However, those in the control group recorded a higher pain score (median +/- SD = 5 +/- 1.8) when compared to those who received misoprostol (median +/- SD = 4.5 +/- 2, P = 0.03). Only two women (4%) had bleeding per vaginum and one (2%) had a slight fever attributable to misoprostol. CONCLUSION: Vaginal misoprostol prior to diagnostic hysteroscopy did not facilitate cervical dilatation. It did effect a reduction in pain scores, but there was no difference in patient satisfaction, need for analgesia or sedation. No significant side effects were reported. PMID- 18449550 TI - Large angioleiomyoma, rich of mast cell and sex hormone receptor expression. AB - BACKGROUND: Angioleiomyoma is a rare benign solitary tumor, arising from the vascular smooth muscle. This tumor usually occurs in the subcutis of extremities, uncommonly in abdomen, often presents as a small (<2 cm) and is treated with excision. CASE: We report an extremely rare case of unusually large angioleiomyoma, first diagnosed as an ovarian tumor with some malignant possibilities by diagnostic imaging. We resected 1.7 kg of tumor from the extra peritoneal cavity in the lower abdomen. Histological study revealed that this case's angioleiomyoma had abundant mast cells and sex hormone receptor expression. CONCLUSION: This angioleiomyoma is not an obvious malignant tumor because of low mitosis, coagulative necrosis and cellular atypia. However, it seems to have low potential malignancy, because it has massive size, marked degeneration and abundant mast cells. There are some possibilities that sex hormones are related with the growth and degeneration of this case's tumor, because those receptors are strongly expressed in the nucleus of tumor cells. PMID- 18449551 TI - Survival analysis between patients with invasive ductal and invasive lobular breast cancer. AB - OBJECTIVE: Differences in overall survival (OS) and disease-free survival (DFS) between patients with invasive ductal (IDC) and invasive lobular breast cancer (ILC) are controversial. STUDY DESIGN: The study population was selected from a database of 5,689 female patients with invasive breast cancer. In order to focus on the impact of tumour histology, all primary metastatic patients and patients with adjuvant chemotherapy or anti-hormonal treatment were excluded. Only patients with pure invasive lobular and invasive ductal histology were included. RESULTS: Multivariate survival analyses of 2,058 eligible patients confirmed tumour histology as an independent prognostic factor for OS in invasive breast cancer (p = 0.046) but not for DFS (p = 0.599). Kaplan-Meier survival analysis of OS between IDC and ILC patients showed a statistically significantly better OS for patients with ILC (p = 0.0302). DFS was not statistically different (p = 0.6659) between IDC and ILC. Univariate survival analyses of tumour size, tumour grading and nodal status in our study population were highly statistically significant for OS and DFS (p < 0.0000). CONCLUSION: Patients in our study population with ILC have significantly better OS than patients with IDC. Differences in DFS are not statistically significant. PMID- 18449552 TI - Benign ovarian dermoid cyst complicated with rectal fistula formation: an unusual case. AB - BACKGROUND: Fistulation in benign cystic teratomas has not been commonly reported in the literature. We present a case of a benign ovarian dermoid cyst complicated with a recto-ovarian fistula. CASE REPORT: A 30-year-old nonpregnant woman admitted to the gynecological outpatient clinic because of lower abdominal pain and purulent diarrhea. Gynecological examination and ultrasonography revealed a 10-cm heterogeneous cystic mass in the left ovary. Abdominopelvic CT scan revealed a left ovarian mass (10 x 9 cm) thought to be a dermoid cyst, which was seen to penetrate the proximal part of the rectum. Left adnexectomy and low anterior rectum resection were performed. The pathological evaluation suggested benign ovarian dermoid tumor penetrating the rectum wall. CONCLUSION: Fistula formation by a dermoid ovarian cyst is not always related to malignant transformation of the cyst. In addition to factors such as torsion, infection, trauma, and chronic pressure during labor, spontaneous rupture of the dermoid cyst resulting in leakage of fluid could be the cause of fistula formation. PMID- 18449553 TI - Lumbar tattoos and lumbar epidural analgesia: still a matter of concern? PMID- 18449554 TI - Early detection of a twin tubal pregnancy by Doppler sonography allows fertility conserving laparoscopic surgery. AB - BACKGROUND: Vital twin tubal gestation is a rare complication in pregnancy. CASE: An asymptomatic gravida 1 female presented with increasing beta-HCG levels without an intrauterine gestation. Doppler sonography revealed cardiac motion of unilateral tubal twins. The patient was treated laparoscopically by partial tubectomy allowing a subsequent tubal re-anastomosis. CONCLUSION: Doppler sonography may detect vital ectopic pregnancies early enabling fertility conserving surgery. PMID- 18449555 TI - Circular isthmic-cervical sutures can be an alternative method to control peripartum haemorrhage during caesarean section for placenta praevia accreta. AB - OBJECTIVE: To study the control of peripartum bleeding in cases of caesarean section for placenta praevia accreta with the Circular isthmic-cervical sutures. METHOD: Circular isthmic-cervical sutures were applied in six cases. To avoid ureter and bladder injury, the bladder was reflected downward. A silastic drain was inserted into internal and through the external os, so as to drain the uterine cavity and to keep the cervical canal open. Firstly, at the left side of the uterus, a Vicryl number two (No..2) stitch was inserted very close to the cervix from the anterior to the posterior side of the broad ligament. The stitch was then passed posteriorly to the right side of the uterus. The needle then was inserted again very close to the cervix from the posterior to the anterior wall of the broad ligament and was tightened on the anterior uterine surface, above the reflexion of the bladder as tightly as possible. RESULT: Circular isthmic cervical sutures were effective in all cases. CONCLUSION: Circular isthmic cervical suture is a quick, safe, simple and effective technique for controlling peripartum haemorrhage during caesarean section for placenta praevia accreta. PMID- 18449556 TI - Familial aggregation of endometriosis in the Yale Series. AB - OBJECTIVE: To investigate the familial aggregation and the risk of endometriosis among the female relatives of women with endometriosis. We also compared the epidemiologic characteristics of women with and without family history of endometriosis. PATIENT(S): A total of 485 women with endometriosis and 197 infertile women without endometriosis underwent surgical investigation between August 1996 and February 2002. MAIN OUTCOME MEASURE(S): The relative risk of endometriosis in a first-degree relative and the association between potential risk factors was estimated by chi2 and by crude adjusted odds ratios (95% CI). RESULTS: Endometriosis was identified in 9.5% of first-degree relatives of women with endometriosis versus only 1% of controls. The odds ratio for endometriosis in a first-degree relative was 10.21 (95% CI 2.45-42.5; P<0.001). In 3.9% of cases women with endometriosis reported that their mother had been diagnosed with endometriosis and 5.6% of cases that at least one sister had been diagnosed. Compared to the control group the odds ratio for the mother having endometriosis (7.99, 95% CI 1.06-60.1) or at least one sister having (11.55, 95% CI 1.56-85.59) were significantly elevated. Among women with endometriosis who reported a family history of endometriosis, and women with endometriosis who did not report a family history of endometriosis, there were no differences in demographic characteristics, body habitus, or menstrual parameters. CONCLUSION(S): Women with endometriosis have a tenfold increased risk of endometriosis in their first degree relatives. PMID- 18449557 TI - Term extrauterine pregnancy in a Nigerian mother: a complication of uterine dehiscence. AB - Abdominal pregnancy is an uncommon but life-threatening form of ectopic pregnancy. It is associated with high maternal/fetal morbidity and mortality. We present a rare case of term abdominal pregnancy resulting from anterior uterine wall dehiscence, in a 36-year-old woman with three previous caesarean sections. The diagnosis was made at laparotomy for the fourth "caesarean section". PMID- 18449559 TI - Legal regulations of pathology in Russia. PMID- 18449558 TI - Sites of strong Rec12/Spo11 binding in the fission yeast genome are associated with meiotic recombination and with centromeres. AB - Meiotic recombination arises from Rec12/Spo11-dependent formation of DNA double strand breaks (DSBs) and their subsequent repair. We identified Rec12-binding peaks across the Schizosaccharomyces pombe genome using chromatin immunoprecipitation after reversible formaldehyde cross-linking combined with whole-genome DNA microarrays. Strong Rec12 binding coincided with previously identified DSBs at the recombination hotspots ura4A, mbs1, and mbs2 and correlated with DSB formation at a new site. In addition, Rec12 binding corresponded to eight novel conversion hotspots and correlated with crossover density in segments of chromosome I. Notably, Rec12 binding inversely correlated with guanine-cytosine (GC) content, contrary to findings in Saccharomyces cerevisiae. Although both replication origins and Rec12-binding sites preferred AT-rich gene-free regions, they seemed to exclude each other. We also uncovered a connection between binding sites of Rec12 and meiotic cohesin Rec8. Rec12-binding peaks lay often within 2.5 kb of a Rec8-binding peak. Rec12 binding showed preference for large intergenic regions and was found to bind preferentially near to genes expressed strongly in meiosis. Surprisingly, Rec12 binding was also detected in centromeric core regions, which raises the intriguing possibility that Rec12 plays additional roles in meiotic chromosome dynamics. PMID- 18449560 TI - Origin of renal myofibroblasts in the model of unilateral ureter obstruction in the rat. AB - Tubulo-interstitial fibrosis is a constant feature of chronic renal failure and it is suspected to contribute importantly to the deterioration of renal function. In the fibrotic kidney there exists, besides normal fibroblasts, a large population of myofibroblasts, which are supposedly responsible for the increased production of intercellular matrix. It has been proposed that myofibroblasts in chronic renal failure originate from the transformation of tubular cells via epithelial-mesenchymal transition (EMT) or from infiltration by bone marrow derived precursors. Little attention has been paid to the possibility of a transformation of resident fibroblasts into myofibroblasts in renal fibrosis. Therefore we examined the fate of resident fibroblasts in the initial phase of renal fibrosis in the classical model of unilateral ureter obstruction (UUO) in the rat. Rats were perfusion-fixed on days 1, 2, 3 and 4 after ligature of the right ureter. Starting from 1 day of UUO an increasing expression of alpha-smooth muscle actin (alphaSMA) in resident fibroblasts was revealed by immunofluorescence and confirmed by the observation of bundles of microfilaments and webs of intermediate filaments in the electron microscope. Inversely, there was a decreased expression of 5'-nucleotidase (5'NT), a marker of renal cortical fibroblasts. The RER became more voluminous, suggesting an increased synthesis of matrix. Intercellular junctions, a characteristic feature of myofibroblasts, became more frequent. The mitotic activity in fibroblasts was strongly increased. Renal tubules underwent severe regressive changes but the cells retained their epithelial characteristics and there was no sign of EMT. In conclusion, after ureter ligature, resident peritubular fibroblasts proliferated and they showed progressive alterations, suggesting a transformation in myofibroblasts. Thus the resident fibroblasts likely play a central role in fibrosis in that model. PMID- 18449561 TI - Identification of positive charges situated at the outer mouth of the CFTR chloride channel pore. AB - We have used site-directed mutagenesis and functional analysis to identify positively charged amino acid residues in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel that interact with extracellular anions. Mutation of two positively charged arginine residues in the first extracellular loop (ECL) of CFTR, R104, and R117, as well as lysine residue K335 in the sixth transmembrane region, leads to inward rectification of the current voltage relationship and decreased single channel conductance. These effects are dependent on the charge of the substituted side chain and on the Cl(-) concentration, suggesting that these positive charges normally act to concentrate extracellular Cl(-) ions near the outer mouth of the pore. Side chain charge dependent effects are mimicked by manipulating charge in situ by mutating these amino acids to cysteine followed by covalent modification with charged cysteine reactive reagents, confirming the location of these side chains within the pore outer vestibule. State-independent modification of R104C and R117C suggests that these residues are located at the outermost part of the pore. We suggest that ECL1 contributes to the CFTR pore external vestibule and that positively charged amino acid side chains in this region act to attract Cl(-) ions into the pore. In contrast, we find no evidence that fixed positive charges in other ECLs contribute to the permeation properties of the pore. PMID- 18449562 TI - Differential contribution of cardiac sarcomeric proteins in the myofibrillar force response to stretch. AB - The present study examined the contribution of myofilament contractile proteins to regional function in guinea pig myocardium. We investigated the effect of stretch on myofilament contractile proteins, Ca(2+) sensitivity, and cross-bridge cycling kinetics (K (tr)) of force in single skinned cardiomyocytes isolated from the sub-endocardial (ENDO) or sub-epicardial (EPI) layer. As observed in other species, ENDO cells were stiffer, and Ca(2+) sensitivity of force at long sarcomere length was higher compared with EPI cells. Maximal K (tr) was unchanged by stretch, but was higher in EPI cells possibly due to a higher alpha-MHC content. Submaximal Ca(2+)-activated K (tr) increased only in ENDO cells with stretch. Stretch of skinned ENDO muscle strips induced increased phosphorylation in both myosin-binding protein C and myosin light chain 2. We concluded that transmural MHC isoform expression and differential regulatory protein phosphorylation by stretch contributes to regional differences in stretch modulation of activation in guinea pig left ventricle. PMID- 18449564 TI - OsCO3, a CONSTANS-LIKE gene, controls flowering by negatively regulating the expression of FT-like genes under SD conditions in rice. AB - The photoperiod is an important environmental stress that determines flowering time. The CONSTANS (CO) and Heading date 1 (Hd1) genes are known to be central integrators of the photoperiod pathway in Arabidopsis and rice, respectively. Although they are both members of the CONSTANS-LIKE (COL) family and have two B boxes and a CCT domain, rice also possesses novel COL genes that are not found in Arabidopsis. Here, we demonstrate that a novel COL gene, OsCO3, containing a single B-box and a CCT domain, modulates photoperiodic flowering in rice. The circadian expression pattern of OsCO3 mRNA oscillated in a different phase from Hd1 and was similar to that of OsCO3 pre-mRNA, suggesting that the diurnal expression pattern of OsCO3 transcripts may be regulated at the transcriptional level. Overexpression of OsCO3 specifically caused late flowering under short day (SD) conditions relative to wild-type rice plants. The expression of Hd3a and FTL decreased in these transgenic plants, whereas the expression of Hd1, Early heading date 1 (Ehd1), OsMADS51, and OsMADS50 did not significantly change. Our results suggest that OsCO3 primarily controls flowering time under SD conditions by negatively regulating Hd3a and FTL expression, independent of the SD-promotion pathway. PMID- 18449563 TI - PKC stimulated by glucagon decreases UT-A1 urea transporter expression in rat IMCD. AB - It is well-known that glucagon increases fractional excretion of urea in rats after a protein intravenous infusion. This effect was investigated by using: (a) in vitro microperfusion technique to measure [(14)C]-urea permeability (Pu x 10( 5)cm/s) in inner medullary collecting ducts (IMCD) from normal rats in the presence of 10(-7)M of glucagon and in the absence of vasopressin and (b) immunoblot techniques to determine urea transporter expression in tubule suspension incubated with the same glucagon concentration. Seven groups of IMCDs (n = 47) were studied. Our results revealed that: (a) glucagon decreased urea reabsorption dose-dependently; (b) the glucagon antagonist des-His(1)-[Glu(9)], blocked the glucagon action but not vasopressin action; (c) the phorbol myristate acetate, decreased urea reabsorption but (d) staurosporin, restored its effect; e) staurosporin decreased glucagon action, and finally, (f) glucagon decreased UT A1 expression. We can conclude that glucagon reduces UT-A1 expression via a glucagon receptor by stimulating PKC. PMID- 18449566 TI - Novel processes invaginate the pre-synaptic terminal of retinal bipolar cells. AB - Mixed-rod cone bipolar (Mb) cells of goldfish retina have large synaptic terminals (10 microm in diameter) that make 60-90 ribbon synapses mostly onto amacrine cells and rarely onto ganglion cells and, in return, receive 300-400 synapses from gamma-aminobutyric acid (GABA)-ergic amacrine cells. Tissue viewed by electron microscopy revealed the presence of double-membrane-bound processes deep within Mb terminals. No membrane specializations were apparent on these invaginating processes, although rare vesicular fusion was observed. These invaginating dendrites were termed "InDents". Mb bipolar cells were identified by their immunoreactivity for protein kinase C. Double-label immunofluorescence with other cell-type-specific labels eliminated Muller cells, efferent fibers, other Mb bipolar cells, dopaminergic interplexiform cells, and somatostatin amacrine cells as a source of the InDents. Confocal analysis of double-labeled tissue clearly showed dendrites of GABA amacrine cells, backfilled ganglion cells, and dendrites containing PanNa immunoreactivity extending into and passing through Mb terminals. Nearly all Mb terminals showed evidence for the presence of InDents, indicating their common presence in goldfish retina. No PanNa immunoreactivity was found on GABA or ganglion cell InDents, suggesting that a subtype of glycine amacrine cell contained voltage-gated Na channels. Thus, potassium and calcium voltage-gated channels might be present on the InDents and on the Mb terminal membrane opposed to the InDents. In addition to synaptic signaling at ribbon and conventional synapses, Mb bipolar cells may exchange information with InDents by an alternative signaling mechanism. PMID- 18449565 TI - Characterization and intracellular localization of putative Chlamydia pneumoniae effector proteins. AB - We here describe four proteins of Chlamydia pneumoniae, which might play a role in host-pathogen interaction. The hypothetical bacterial proteins CPn0708 and CPn0712 were detected in Chlamydia pneumoniae-infected host cells by indirect immunofluorescence tests with polyclonal antisera raised against the respective proteins. While CPn0708 was localized within the inclusion body, CPn0712 was identified in the inclusion membrane and in the surrounding host cell cytosol. CPn0712 colocalizes with actin, indicating its possible interaction with components of the cytoskeleton. Investigations on CPn0809 and CPn1020, two Chlamydia pneumoniae proteins previously described to be secreted into the host cell cytosol, revealed colocalization with calnexin, a marker for the ER. Neither CPn0712, CPn0809 nor CPn1020 were able to inhibit host cell apoptosis. Furthermore, transient expression of CPn0712, CPn0809 and CPn1020 by the host cell itself had no effect on subsequent infection with Chlamydia pneumoniae. However, microarray analysis of CPn0712-expressing host cells revealed six host cell genes which were regulated as in host cells infected with Chlamydia pneumoniae, indicating the principal usefulness of heterologous expression to study the effect of Chlamydia pneumoniae proteins on host cell modulation. PMID- 18449567 TI - Inulinase production in a batch bioreactor using agroindustrial residues as the substrate: experimental data and modeling. AB - The production of inulinase employing agroindustrial residues as the substrate is a good alternative to reduce production costs and to minimize the environmental impact of disposing these residues in the environment. This study focused on the use of a phenomenological model and an artificial neural network (ANN) to simulate the inulinase production during the batch cultivation of the yeast Kluyveromyces marxianus NRRL Y-7571, employing a medium containing agroindustrial residues such as molasses, corn steep liquor and yeast extract. It was concluded that due to the complexity of the medium composition it was rather difficult to use a phenomenological model with sufficient accuracy. For this reason, an alternative and more cost-effective methodology based on ANN was adopted. The predictive capacity of the ANN was superior to that of the phenomenological model, indicating that the neural network approach could be used as an alternative in the predictive modeling of complex batch cultivations. PMID- 18449568 TI - CTLA-4 +49 A/G genotype and HLA-DRB1 polymorphisms in Turkish patients with Henoch-Schonlein purpura. AB - The pathogenesis of Henoch-Schonlein purpura (HSP) remains unknown; however, it is generally considered to be an immune complex-mediated disease. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is expressed on activated T cells, and, thus, it is critically involved in the immune response. We aimed to investigate the possible influence of CTLA-4 polymorphisms for susceptibility to HSP and determine if there were associations with human leukocyte antigen (HLA)-DRB1 genotypes. Using polymerase chain reaction-based DNA genotyping, we investigated the polymorphisms located in the genes encoding CTLA-4 in 100 patients with HSP and 156 ethnically matched healthy controls. When CTLA-4 +49 A/G polymorphism of HSP patients and control group was compared, no associations with joint, gastrointestinal or renal manifestations, or susceptibility to HSP, were observed. However, patients with nephrotic proteinuria had higher HLA-DRB1*13 positivity [odds ratio (OR) = 3.76, 95% confidence interval (95%CI) = 1.25-11.23, P = 0.025]. When the patients were stratified according to CTLA-4 polymorphism, a significant association between nephrotic proteinuria patients and carriage of the AG genotype was also found (OR = 15.42, 95%CI = 1.59-148.82, P = 0.008). These results suggested that CTLA-4 +49 A/G polymorphism does not contribute to susceptibility to HSP; however, the presence of CTLA-4 AG genotype and HLA DRB1*13 could be a risk factor for developing nephrotic-range proteinuria in these patients. PMID- 18449569 TI - [Physiotherapy, exercise and strength training and physical therapies in the treatment of fibromyalgia syndrome]. AB - BACKGROUND: A guideline for the treatment and diagnostic procedures for fibromyalgia syndrome (FMS) was developed in cooperation with 10 German medical and psychological associations and 2 patient self-help groups. METHODS: A systematic literature search including all controlled studies evaluating physiotherapy, exercise and strength training as well as physical therapies was performed in the Cochrane Collaboration Reviews (1993-12/2006), Medline (1980 12/2006), PsychInfo (1966-12/2006) and Scopus (1980-12/ 2006). Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine. Grading of the strengths of recommendations was done according to the German program for disease management guidelines. Standardized procedures to reach a consensus on recommendations were used. RESULTS: Aerobic exercise training is strongly recommended (grade A) and the temporary use of whole body hyperthermia, balneotherapy and spa therapy is recommended (grade B). CONCLUSION: The significance which can be assigned to most of the studies on the various procedures for therapy is restricted due to short study duration (mean 6 12 weeks) and small sample sizes. PMID- 18449570 TI - Antimicrobial chlorhexidine/silver sulfadiazine-coated central venous catheters versus those uncoated in patients undergoing allogeneic stem cell transplantation. AB - INTRODUCTION: Only a minimum is known about clinical effect of antimicrobial coated central venous catheters (CVC) in stem cell transplantation settings, where CVC-related infections impose major threat to severely immunocompromised patients. MATERIALS AND METHODS: In this prospective, non-sponsored and nonrandomized study, there were 49 uncoated multi-lumen and non-tunneled CVCs and 58 antimicrobial chlorhexidine/silver sulfadiazine-coated CVCs inserted in allogeneic stem cell transplanted patients to facilitate treatment during conditioning and pre-engraftment phase (<30days after transplantation). RESULTS AND DISCUSSION: No significant differences were found between the two groups with respect to gender, age, intensity of pretransplant chemotherapy conditioning, duration of leucopenia, number of days with inserted CVC, number of CVC occlusive dressing changes performed per patient, and number of non-CVC-related infections. In the antimicrobial coated CVC group, there were observed less median days with fever [2 (0-18) vs. 4 (0-16), p = 0,17], fever incidence (67% vs. 77.5%, p = 0.28), and less days with fever per 1,000 catheter-days (108 vs. 147, p = 0.001), less patients with positive CVC blood cultures (36% vs. 45%, p = 0.05), repeatedly positive CVC blood cultures (8.6% vs. 26%, p = 0,018), less positive CVC blood cultures per 1,000 catheter-days (14 vs. 29, p = 0.005), and less positive CVC tip cultures (17.3% vs. 34.6%, p = 0.065) observed. CONCLUSION: Lower number of patients with fever, days with fever, and lower number of patients with positive and repeatedly positive CVC blood cultures indicates less intensive antibiotic and antipyretic treatment probably needed in neutropenic allo-transplanted patients with indwelling antimicrobial-coated CVCs. Real impact on antibiotic consumption should be verified in large randomized study. PMID- 18449571 TI - Peritoneal catheter for continuous drainage of ascites in advanced cancer patients. AB - INTRODUCTION: Advanced cancer patients with refractory ascites do not often respond to dietary sodium restriction and diuretics. While paracentesis is effective, the condition invariably recurs, necessitating repeated procedures. A continuous peritoneal drainage by an indwelling catheter has been reported to be hugely beneficial symptomatically, avoiding the hazards and disadvantages of multiple repeated procedures and direct and indirect costs. MATERIALS AND METHODS: Forty patients with advanced cancer patients admitted to an acute pain relief and palliative care unit, who presented symptomatic ascites, were recruited for continuous drainage of peritoneal fluid. A central venous catheter set for Seldinger technique was used. Technical failure was defined as an unsuccessful drainage of fluid through the catheter. Immediate and late complications, including hypotension, haemorrhage, tube blockage, dislodgment and sepsis were recorded. Record of daily drainage during admission were noted. At time of discharge, patients were asked to rate their global symptom burden as improved, unchanged or worsened. The follow-up was performed with frequent phone contacts or day-hospital admission in case of problems. RESULTS: The mean patients' age was 68 years, and 21 were men. Patients were receiving unsuccessfully a mean dose of furosemide of 32 mg/day. The technique was not painful and was easily accepted by patients. Insertion was technically successful in almost all patients. Mean admission time was 5.5 days (range 2-14), and the mean drained volume during admission was 8,499 ml (range 800-20,700), 2,850 ml (300-4,200) being drained on the first 24 h. No immediate complications were recorded. Six patients died during admission. The mean survival was 38.9 days (range 1-120). Of the 34 patients who were discharged home, 22 patients stated that symptom burden had improved, while in 10 patients symptom burden did not change or worsened, probably due to the advanced status of diseases and multiple contributing factors. Five, two, and one patients required skin sutures at 1, 2 and 3 months, respectively. About one third of patients had mechanical problems, some of them requiring a catheter replacement. No infection was recorded. CONCLUSION: In conclusion, a permanent peritoneal catheter was a valuable method to remove abdominal fluids and reduce symptom burden attributable to ascites and was also easy to use at home. Complication rate was acceptable and balanced by the benefits of the technique which avoided frequent paracentesis and associated complications. PMID- 18449572 TI - Life goals and purpose in life in cancer patients. AB - GOAL OF WORK: The purpose of the study was to analyze associations between life goals and purpose in life in cancer patients. PATIENTS AND METHODS: A sample of 153 cancer patients was assessed before the start of chemotherapy and about 9 months later. Purpose in life was measured with a German version of Crumbaugh and Maholick's purpose in life test, and the perceived importance of social, psychological, materialistic, and health-related goals was assessed with Likert scales. MAIN RESULTS: High importance of social, psychological, and health related goals was related to higher purpose in life. In addition, having high levels of social goals at the first time of measurement predicted an increase in purpose of life over time. However, higher importance of material goals was associated with lower purpose in life at the second time of measurement and with a decline of purpose in life over time. CONCLUSIONS: There is continuity and change in the sources of purpose in life during cancer therapy, and a lack of fit between goals and changed living conditions is a risk factor for a decline in purpose in life. PMID- 18449573 TI - Patients' perceptions of having a central venous catheter or a totally implantable subcutaneous port system-results from a randomised study in acute leukaemia. AB - GOALS OF WORK: The selection process of type of central venous access device (CVAD) in patients with acute leukaemia (AL) is generally based on appropriate catheter capacity/function and risk of complications in relation to the planned length of therapy. Advantages and disadvantages of the CVAD from the patient's perspective should also be important parts in the selection of type of device. Perceptions on having a CVAD were thus analysed in a series of adult patients with AL included in a prospective randomised study evaluating the use of a double lumen totally implantable subcutaneous port system (PORT) or a double lumen central venous catheter (CVC) regarding survival time and complication rate. MATERIALS AND METHODS: Perceptions were registered in 32 patients (median age 68 years, range 24-83 years) on three occasions (T1; the day after placement, T2; 3 weeks after placement and T3 after 12 weeks and/or when the CVAD was removed) with the use of two study specific questionnaires. MAIN RESULTS: Overall, many patients reported minor catheter related discomfort, feelings of anxiety and restrictions. Half of the patients (6/11) who experienced a local bleeding after CVAD insertion described the placement procedure as unpleasant. More patients in the CVC group compared with the PORT group stated that they thought of having a CVAD (T3; p = 0.02) and that the CVAD interfered when dressing themselves (T2; p = 0.02 and T3; 0.04) or taking a shower (T3; p = 0.009). CONCLUSION: Our findings support the view that the PORT is less restrictive in daily life than the CVC. PMID- 18449574 TI - A survey of the views of palliative care healthcare professionals towards referring cancer patients to participate in randomized controlled trials in palliative care. AB - GOALS OF WORK: Clinical trials in palliative care (PC), especially randomised controlled trials (RCTs), are notoriously difficult to complete. One perceived challenge is gatekeeping, the reluctance of some healthcare professionals (HCPs) to refer patients for research studies. This study aimed to identify the extent of gatekeeping from palliative RCTs. MATERIALS AND METHODS: An anonymous questionnaire was sent to 597 HCPs with an interest in PC in Australia and New Zealand to assess their willingness to refer patients for RCTs. Respondents considered key issues that might affect their decision, documented willingness to refer to RCTs of increasing complexity in a hypothetical pain situation and documented the degree of patient inconvenience considered acceptable. Demographic data were collected. MAIN RESULTS: One hundred ninety-eight questionnaires were returned (33%), 122 from doctors and 76 from other HCPs. Very few were willing to refer to complicated studies involving many extra tests and/or hospital visits. Non-medical HCPs were less interested than doctors in studies that involved randomisation, placebo controls or double-blind methodology. The majority would refer patients for non-pharmacological studies, but were less willing to refer for pharmacological studies with possible side effects. Non-medical HCPs were less willing than doctors to refer to trials that involved patient inconvenience. Two factors predicted for greater willingness to refer: previous research experience and male gender. CONCLUSION: The survey revealed an unwillingness on the part of many HCPs to refer patients for RCTs in PC. It identifies trial related factors that may encourage or discourage referral. Gatekeeping has the potential block recruitment and introduce a selection bias. PMID- 18449575 TI - A study of NO trafficking from dinitrosyl-iron complexes to the recombinant E. coli transcriptional factor SoxR. AB - SoxR is a transcriptional factor in Escherichia coli that induces the expression of SoxS to initiate the production of enzymes in response to oxidative stress. In addition to superoxide, SoxR is also sensitive to cellular NO to produce a protein-bound dinitrosyl-iron complex (DNIC) with a characteristic electron paramagnetic resonance (EPR) signal at g(av)=2.03. Toward developing a strategy for NO sensing based on this property of SoxR, we have overexpressed and purified the recombinant His-tagged SoxR protein. Upon treatment of the purified protein under anaerobic conditions with (1) NO solution, (2) S-nitrosothiol (RSNO), and (3) chemically synthesized low molecular weight DNICs (LMW-DNICs), we have observed enhancement of the EPR signal at g(av)=2.03 from the protein-bound DNICs over time, reflecting the redistribution of NO from the NO solution, RSNO and LMW DNICs to the SoxR. We have exploited this NO exchange to investigate the kinetics and mechanisms of release and delivery of NO from various LMW-DNICs to an isopropyl-beta-D-thiogalactopyranoside-dependent SoxR expressed in E. coli cells. These experiments revealed that the NO from RSNO and LMW-DNICs could cross the biological membrane and enter the cytoplasm of the cell to form the SoxR protein bound DNIC complex. For comparison, we have also studied the direct NO transfer from the LMW-DNICs to the SoxR protein in buffer. The NO transfer was found to be rapid. From the kinetic data derived, we showed that LMW-DNICs with bidentate thiolate ligands displayed greater stability in aqueous solution but exhibited more facile NO delivery to cytoplasmic SoxR in whole cells. PMID- 18449576 TI - Loss of enzyme activity during turnover of the Bacillus cereus beta-lactamase catalysed hydrolysis of beta-lactams due to loss of zinc ion. AB - Metallo-beta-lactamases are zinc-ion-dependent and are known to exist either as mononuclear or as dinuclear enzymes. The kinetics and mechanism of hydrolysis of the native zinc Bacillus cereus metallo-beta-lactamase (BcII) have been investigated under pre-steady-state conditions at different pHs and zinc-ion concentrations. Biphasic kinetics are observed for the hydrolysis of cefuroxime and benzylpenicillin with submicromolar concentrations of enzyme and zinc. The initial burst of product formation far exceeds the concentration of enzyme and the subsequent slower rate of hydrolysis is attributed to a branched kinetic pathway. The pH and metal-ion dependence of the microscopic rate constants of this branching were determined, from which it is concluded that two enzyme species with different metal-to-enzyme stoichiometries are formed during catalytic turnover. The dizinc enzyme is responsible for the fast route but during the catalytic cycle it slowly loses the less tightly bound zinc ion via the branching route to give an inactive monozinc enzyme; the latter is only catalytic following the uptake of a second zinc ion. The rate constant for product formation from the dinuclear enzyme and the branching rate constant show a sigmoidal dependence on pH indicative of important ionizing groups with pK(a)s of 9.0+/-0.1 and 8.2+/-0.1, respectively. The rate constant for the regeneration of enzyme activity depends on zinc-ion concentration. This unusual behaviour is attributed to an intrinsic property of metallo hydrolytic enzymes that depend on a metal bound water both as a ligand for the second metal ion and as the nucleophile which is consumed during hydrolysis of the substrate and so has to be replaced to maintain the catalytic cycle. PMID- 18449577 TI - The 3D structure of the defense-related rice protein Pir7b predicted by homology modeling and ligand binding studies. AB - To better understand the ligand-binding mechanism of protein Pir7b, important part in detoxification of a pathogen-derived compound against Pyricularia oryzae, a 3D structure model of protein Pir7b was constructed based on the structure of the template SABP2. Three substrates were docking to this protein, two of them were proved to be active, and some critical residues are identified, which had not been confirmed by the experiments. His87 and Leu17 considered as 'oxyanion hole' contribute to initiating the Ser86 nucleophilic attack. Gln187 and Asp139 can form hydrogen bonds with the anilid group to maintain the active binding orientation with the substrates. The docking model can well interpret the specificity of protein Pir7b towards the anilid moiety of the substrates and provide valuable structure information about the ligand binding to protein Pir7b. PMID- 18449578 TI - ParaFrag--an approach for surface-based similarity comparison of molecular fragments. AB - A frequent task in computer-aided drug design is to identify novel chemotypes similar in activity but structurally different to a given reference structure. Here we report the development of a novel method for atom-independent similarity comparison of molecular fragments (substructures of drug-like molecules). The fragments are characterized by their local surface properties coded in the form of 3D pharmacophores. As surface properties, we used the electrostatic potential (MEP), the local ionization energy (IE(L)), local electron affinity (EA(L)) and local polarizability (POL) calculated on isodensity surfaces. A molecular fragment can then be represented by a minimal set of extremes for each surface property. We defined a tolerance sphere for each of these extremes, thus allowing us to assess the similarity of fragments in an analogous manner to classical pharmacophore comparison. As a first application of this method we focused on comparing rigid fragments suitable for scaffold hopping. A retrospective analysis of successful scaffold hopping reported for Factor Xa inhibitors [Wood MR et al (2006) J Med Chem 49:1231] showed that our method performs well where atom-based similarity metrics fail. PMID- 18449579 TI - Application of the PM6 method to modeling the solid state. AB - The applicability of the recently developed PM6 method for modeling various properties of a wide range of organic and inorganic crystalline solids has been investigated. Although the geometries of most systems examined were reproduced with good accuracy, severe errors were found in the predicted structures of a small number of solids. The origin of these errors was investigated, and a strategy for improving the method proposed. PMID- 18449580 TI - The prevalence of plasmid-mediated AmpC beta-lactamases among clinical isolates of Escherichia coli and Klebsiella pneumoniae from five children's hospitals in China. AB - The purpose of this study was to investigate the prevalence of plasmid-mediated AmpC beta-lactamases in Escherichia coli and Klebsiella pneumoniae from five children's hospitals in China. A total of 494 E. coli and 637 K. pneumoniae isolates were collected from five children's hospitals in China from 2005 to 2006. The isolates with decreased susceptibility to cefoxitin were subjected to confirmation test with 3-aminophenyl boronic acid. Polymerase chain reaction (PCR) amplification of the blaAmpC, blaTEM, blaCTXM, and blaSHV genes and their gene sequencing were performed. Transconjugants were achieved by conjugation experiments. Plasmid-mediated AmpC beta-lactamases were found in 10.1% of K. pneumoniae (64/637) and in 2.0% of E. coli (10/494) strains. The proportion of plasmid-mediated AmpC-producing strains significantly increased from 2005 (2.6%) to 2006 (9.3%) (p<0.001). The DHA-1-producing isolates were the most prevalent type (93.2%, 69/74). The sequences of blaDHA-1 genes were all identical to those from the GenBank. Strains of blaCMY-2 were isolated from five isolates (6.8%), which were all from E. coli. One sequence of blaCMY-2 differs from blaCMY-2 in the GenBank. Eighteen of the 74 (24.3%) AmpC-producing K. pneumoniae and E. coli isolates coproduced an extended-spectrum beta-lactamase (ESBL). Cefoxitin resistance was transferred to 15 of the 74 positive strains (20.3%). Our study has demonstrated the occurrence of plasmid-mediated AmpC beta-lactamases in E. coli and K. pneumoniae in Chinese pediatric patients and DHA-1 type AmpC enzymes had the highest prevalent rate. The CMY-2 AmpC beta-lactamases from the children's hospitals in China in this study are the first reported. Hence, continuous surveillance of the prevalence and evolution of AmpC beta-lactamase is important. PMID- 18449581 TI - Bloodstream infections among human immunodeficiency virus-infected adult patients: epidemiology and risk factors for mortality. AB - This study was undertaken to describe the epidemiology and sensitivity pattern of pathogens causing community-acquired (CA) and nosocomial (N) bloodstream infection (BSI) in adult HIV-infected patients and to establish risk factors for mortality. The type of study was a retrospective analysis of BSI episodes prospectively collected through a blood culture surveillance program from January 1991 to December 2006. We used non-conditional logistic regression methods with death as a dependent variable. One thousand and seventy-seven episodes of BSI (6%) occurred in HIV-infected patients out of 16,946 episodes during the period of study. CA and N BSI were 634 (59%) and 443 (41%) respectively. S. pneumoniae and S. aureus were the most frequent pathogens (n = 279, 44%) in CA BSI. Coagulase-negative staphylococci and S. aureus were the most frequent micro organisms isolated in N cases (n = 169, 38%). Cotrimoxazole resistance was common in CA and N BSI and was caused by gram-negative bacilli (50% and 61% respectively). However, resistance rates to ceftriaxone were low (3%). Crude mortality accounted for 140 cases (13%). The independent risk factors associated with mortality were: liver cirrhosis (OR: 2.90, p = 0.001), corticosteroids treatment (OR: 3.51, p < 0.001), neutropenia (OR: 2.21, p = 0.02), inappropriate empirical therapy (OR: 2.44, p = 0.006), and isolate of C. albicans (OR: 7.58, p = 0.010). BSI in adult HIV-infected patients was often caused by gram-positive pathogens in both CA and N settings. Inappropriate empirical therapy and the presence of other immunosuppressive factors were independent risk factors for mortality. Ceftriaxone could be used as the initial empiric therapy for HIV infected patients with suspected CA BSI. PMID- 18449582 TI - Pulmonary cryptococcosis in patients without HIV infection: factors associated with disseminated disease. AB - Cryptococcus neoformans is an uncommonly recognized cause of pneumonia in HIV negative patients. Because of its propensity to disseminate to the meninges and other sites, a lumbar puncture is recommended for patients with pulmonary cryptococcosis, regardless of other risk factors. This study explored clinical and laboratory features to help predict which patients had pulmonary disease alone versus those who had pulmonary plus extrapulmonary disease. A retrospective chart review at 15 medical centers was performed from 1990 to 2000 of all HIV negative patients who had pulmonary cryptococcosis. Demographic, clinical, radiographic, and laboratory features were evaluated to determine factors that differentiated those patients who had extrapulmonary disease. Among 166 patients who had pulmonary cryptococcosis, 122 had pulmonary infection only and 44 had pulmonary plus extrapulmonary (disseminated) disease. A negative serum cryptococcal antigen titer was more common in patients with pulmonary disease alone (p < 0.01). Multivariate analysis demonstrated that patients who had disseminated disease were more likely than those who only had pulmonary disease to have cirrhosis (p = 0.049), headache (p < 0.001), weight loss (p = 0.003), fever (p = 0.035), altered mental status (p < 0.001), and to be receiving high dose corticosteroids (p = 0.008). In this large cohort of HIV-negative patients with pulmonary cryptococcosis, there were easily distinguished clinical and laboratory features among patients with pulmonary disease alone versus those with pulmonary plus extrapulmonary disease. These findings may be helpful in the evaluation of HIV-negative patients with pulmonary cryptococcosis with regard to the need for lumbar puncture or to search for disseminated disease. PMID- 18449583 TI - Oral therapy for urinary tract infections in infants aged 3 to 12 months. PMID- 18449585 TI - siRNA silencing of angiotensin-converting enzyme 2 reduced severe acute respiratory syndrome-associated coronavirus replications in Vero E6 cells. AB - The outbreak of severe acute respiratory syndrome (SARS) in 2002-2003 has had a significant impact worldwide. No effective prophylaxis or treatment for SARS is available up to now. Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for SARS-associated coronavirus (SARS-CoV). By expressing a U6 promoter driven small interfering RNA containing sequences homologous to part of ACE2 mRNA, we successfully silenced ACE2 expression in Vero E6 cells. By detecting negative strand SARS-CoV RNA and measuring RNA copy numbers of SARS-CoV by real time reverse transcription polymerase chain reaction (RT-PCR), we demonstrated that SARS-CoV infection was reduced in the ACE2-silenced cell lines. These findings support the involvement of ACE2 in SARS-CoV infections and provide a basis for further studies on potential use of siRNA targeting ACE2 as a preventive or therapeutic strategy for SARS. PMID- 18449584 TI - Outcome for invasive Staphylococcus aureus infections. AB - We report a survey of invasive Staphylococcus aureus (ISA) infections concerning outcome variables such as mortality, recurrence and residual symptoms. A prospective, population-based study of all cases of ISA was conducted in the catchment area of Skaraborg Hospital (population 255,109) in western Sweden during the period from 1st March 2003 to 28th February 2005. One hundred and fifty-seven patients were included. Recurrences were seen in 13 cases (9.3%). Thirty patients (19.1%) died during the first 28 days. Mortality rates for complicated bacteraemia and severe sepsis were 32% and 54%, respectively. Older patients (>65 years of age), patients with concomitant heart disease and patients with endovascular infections all suffered higher mortality. Line-associated infections had a higher recurrence rate. Residual symptoms were common, with 34% of the living patients reporting incomplete recovery. Accessory gene regulator (agr) type within the bacteria did not affect disease presentation. We conclude that ISA infections are of major medical importance, with high rates of mortality (19.1%), recurrence (9.3%) and residual functional impairment (34%). PMID- 18449586 TI - Enterobacter cloacae SLD1a-1 gains a selective advantage from selenate reduction when growing in nitrate-depleted anaerobic environments. AB - Enterobacter cloacae SLD1a-1 is capable of the complete reduction of selenate to selenium and the initial reaction is catalysed by a membrane-bound selenate reductase. In the present study, continuous culture experiments were employed to investigate the possibility that selenate reduction, via the selenate reductase, might provide sufficient energy to maintain cell viability when deprived of the preferred anaerobic terminal electron acceptor nitrate. The evidence presented indicates that the selenate reductase supports slow growth that retards the wash out of the culture when switching to nitrate-depleted selenate-rich medium, and provides a proton motive force for sustained cell maintenance. In contrast, a strain of E. cloacae (sub sp. cloacae) that does not readily reduce selenate, cannot sustain cell maintenance when switching to a selenate-rich medium. This work demonstrates for the first time that respiratory linked selenate reduction gives E. cloacae SLD1a-1 a selective advantage when inhabiting selenate contaminated environments and highlights the suitability of utilising E. cloacae SLD1a-1 when developing selenium remediation strategies. PMID- 18449587 TI - Screening of tropical fungi producing polyethylene terephthalate-hydrolyzing enzyme for fabric modification. AB - Microfungi were selectively isolated for production of polyethylene terephthalate (PET) fiber-degrading enzymes potentially to be used to modify the surface of polyester fabric. A range of fungi were isolated from plant surfaces and soil samples using a polycaprolactone (PCL) plate-clearing assay technique, and screened for cutinolytic esterase (cutinase) activity. Twenty-two of 115 isolates showed clearing indicating the production of cutinase. The ability of the fungi to produce cutinase in mineral medium (MM) using either potato suberin or PET (1 cm of untreated pre-washed PET fiber) fiber as substrates was assessed based on the hydrolysis of p-nitrophenyl butyrate (p-NPB). All isolates exhibited activity towards p-NPB, isolate PBURU-B5 giving the highest activity with PET fiber as an inducer. PBURU-B5 was identified as Fusarium solani based on its conidial morphology and also nucleotide sequencing from internal transcribed spacer region of the ribosomal RNA gene (rDNA-ITS). Enzymatic modification of PET cloth material properties using crude enzyme from strain PBURU-B5 showed hydrolysis of ester bonds of the PET fiber. The modification of the PET fabric resulted in increase of water and moisture absorption, and general enhancement of hydrophilicity of the fabric, properties that could facilitate processing of fabric ranging from easier dyeing while also yielding a softer feeling fabric for the user. PMID- 18449588 TI - Characterization of kinetic parameters and the formation of volatile compounds during the tequila fermentation by wild yeasts isolated from agave juice. AB - The production of aroma compounds during tequila fermentation using four native yeast strains isolated from agave juice was quantified at controlled (35 degrees C) and uncontrolled temperatures (room temperature) by gas chromatography (FID). Three of the four strains were identified as Saccharomyces cerevisiae (MTLI 1, MALI 1 and MGLI 1) and one as Kloeckera apiculata (MALI 2). Among the aroma compounds produced, acetaldehyde has the highest accumulation at the controlled temperature and before 50% of sugar was consumed. The S. cerevisiae strains produced ethyl acetate in almost the same quantity at a concentration of 5 mg/L and the K. apiculata produced six-times more (30 mg/L) than the S. cerevisiae strains, independent of the fermentation temperature. The rate and amount of 1 propanol, amyl alcohols and isobutanol production were affected by the type of yeast used. The K. apiculate strain produced 50% less of the higher alcohols than the Saccharomyces strains. The results obtained showed that indigenous isolated yeasts play an important role in the tequila flavor and suggest that mixtures of these yeasts may be used to produce tequila with a unique and desirable aroma. PMID- 18449589 TI - Relationships between physiological responses and presyncope symptoms during tilting up in patients with spinal cord injury. AB - This study attempted to use the eyesight range to quantify presyncope symptoms (PS), assess the relation between angle of head-up tilt, severity of injury on the American Spinal Injury Association (ASIA) scale, and PS on physiological signals, and determine the notable signals that represent PS in spinal cord injury (SCI) patients. Thirty-eight quadriplegic SCI subjects were recruited, in which the mean blood pressure (MBP), oxygen saturation (SpO(2)), heart rate (HR), and the low-frequency/high-frequency (LF/HF) ratio of the HR variability were measured during tilting up of the head. The SpO(2) and LF/HF differed significantly with the level of PS. These findings of the studied variables suggest that SpO(2) and LF/HF are the physiological signals that are most sensitive to detect in PS, and could be used for the optimal biofeedback design of tilt-table training systems aimed at overcoming posture hypotension in SCI patients. PMID- 18449590 TI - Random perturbations of spiking activity in a pair of coupled neurons. AB - We examine the effects of stochastic input currents on the firing behaviour of two coupled Type 1 or Type 2 neurons. In Hodgkin-Huxley model neurons with standard parameters, which are Type 2, in the bistable regime, synaptic transmission can initiate oscillatory joint spiking, but white noise can terminate it. In Type 1 cells (models), typified by a quadratic integrate and fire model, synaptic coupling can cause oscillatory behaviour in excitatory cells, but Gaussian white noise can again terminate it. We locally determine an approximate basin of attraction, [see text] of the periodic orbit and explain the firing behaviour in terms of the effects of noise on the probability of escape of trajectories from [see text]. PMID- 18449591 TI - Pathology week. Abstracts of the 92nd Annual Meeting of the German Society for Pathology and the 8th National Congress of the Professional Union of German Pathologists together with the International Academy for Pathology, German Section. May 15-18, 2008. Berlin, Germany. PMID- 18449592 TI - The sympathetic skin response habituation in sedentary subjects and sportsmen. AB - The aim of the present study was to investigate the habituation rates of the sympathetic skin response (SSR) in sedentary subjects and trained sportsmen. A total of 52 voluntary male students (30 sedentary subjects and 22 trained sportsmen) participated in the experiment. SSR was recorded with the contralateral electrical stimulation of the ulnar nerve (of the upper extremities). In order to initiate the SSRs, 16 square-wave consecutive electrical shock stimuli were presented to each subject over the left ulnar nerve. In 52 subjects, 16 stimuli were applied at random time intervals (20-50 s). In sedentary subjects, the mean amplitude of the SSRs decreased from 4.83 +/- 0.36 mV at the first stimulus, to 0.80 +/- 0.12 mV at the 16th stimulus. In trained sportsmen, the mean amplitude of the SSRs decreased from 3.95 +/- 0.51 mV at the first stimulus, to 0.80 +/- 0.17 mV at the 16th stimulus. In the sedentary subjects, at the S1-S9 stimuli, the mean amplitudes of SSRs were higher than those of trained sportsmen. Depending upon these findings we can say that the trained sportsmen showed a more rapid habituation than sedentary subjects. In these processes, changes of amplitude and latency values reflect changes in amount of neuronal activation. Amplitude reflects the amount of neuronal activation, which is concerned with number of neuronal populations. Neuroplasticity, known as the habituation of the brain, is the adaptation of autonomic nervous system, which can be reflected by SSRs. PMID- 18449593 TI - Activation of peripheral opioid receptors has no effect on heart rate variability. AB - Opioid receptors involved in regulating the motility of the gastrointestinal tract have been localized in both contractile and neuronal tissues. Trimebutine, a peripheral opioid receptor agonist, modulates gastrointestinal motor activity in both directions and also may act on cardiac tissue. This study investigated the effects of trimebutine in clinical doses on cardiac autonomic functions with heart rate variability. The effect of trimebutine on cardiac autonomic outflows was evaluated in 11 healthy subjects. Trimebutine (200 mg) or placebo was administered orally at random in a double-blind, cross-over manner. Continuous electrocardiography recordings were obtained before and after drug administration during three states: rest, controlled breathing, and a hand grip exercise. Heart rate variability analysis showed that there was no significant difference between subjects administered with placebo or trimebutine throughout rest, controlled breathing, or the hand grip exercise. We concluded that trimebutine, in clinical doses, has no significant effect on cardiac autonomic functions. PMID- 18449594 TI - Influence of age and gender on the occurrence and presentation of reflex syncope. AB - BACKGROUND: The clinical history is the cornerstone of diagnosing patients with transient loss of consciousness (TLOC). Reflex syncope is the most common cause of TLOC in patients across all ages. Knowledge of the variation in incidence and clinical features of reflex syncope by age and gender provides important background information to acquire an accurate diagnosis. METHODS: In a cohort of 503 patients presenting with TLOC we established a final diagnosis after systematic evaluation and two years of follow-up. The occurrence of prodromal signs, symptoms, and triggers in patients with reflex syncope was analyzed by both age (< 40 yrs, 40-59 yrs and > or = 60 years) and gender. RESULTS: Reflex syncope was the most frequently obtained diagnosis (60.2%) in patients of all ages presenting with TLOC. Its occurrence was higher in patients under 40 years (73.4%), than above 60 years of age (45.3%). Pallor (79.9%), dizziness (73.4%), and diaphoresis (63.0%) were the most frequently reported prodromal signs and symptoms. Most triggers and prodromal signs and symptoms were more common in patients under 40 years of age and in women. CONCLUSIONS: Reflex syncope is nearly twice as common in patients under 40 years of age than in patients aged 60 years or above. Typical signs and symptoms of reflex syncope are more common in younger patients and in women. Therefore, age and gender provide important diagnostic information and can help to decide whether additional testing is necessary. PMID- 18449595 TI - Is total thyroidectomy the surgical procedure of choice for benign multinodular goiter? An evidence-based review. AB - BACKGROUND: Benign multinodular goiter is one of the most common endocrine surgical problems. The appropriate surgical procedure for its effective and safe management is a matter of debate. Though seen by some as an overly hazardous procedure because of the risk of recurrent laryngeal nerve injury and damage to parathyroid function, total thyroidectomy has replaced subtotal thyroidectomy as the procedure of choice, as the latter is associated with significant recurrences. METHODS: A systemic literature review was undertaken of all available medical literature to evaluate whether total thyroidectomy is the appropriate, safe and effective surgical procedure for benign multinodular goiter. RESULTS: There is consistent level II-IV evidence that subtotal thyroidectomy results in recurrence in up to 50% patients. Incidental thyroid cancers are detected in 3%-16.6% of apparently benign goiters in numerous studies, mostly providing level IV evidence, one third of which would need further surgical treatment after subtotal thyroidectomy. Studies comparing subtotal thyroidectomy and total thyroidectomy, including two each of prospective randomized and prospective nonrandomized ones, provide level II-IV evidence that permanent complication rates associated with subtotal thyroidectomy and total thyroidectomy are not different, although the rate of transient hypocalcemia is higher with total thyroidectomy. On basis of these findings, a grade B recommendation can be made that subtotal thyroidectomy is associated with significant recurrence of goiter, leaves a small number of incidentally detected thyroid cancers inadequately treated, and provides little significant safety advantage over total thyroidectomy. Grade C recommendations can also be made about total thyroidectomy being a safe and effective procedure for benign multinodular goiters in the hands of expert surgeons, based on the extensive level IV evidence, and limited level II and level III evidence, which show that the risk of permanent vocal cord palsy and hypoparathyroidism associated with total thyroidectomy is below the acceptable 2% rate, but not without exceptions. CONCLUSION: Total thyroidectomy is the procedure of choice for the surgical management of benign multinodular goiter. PMID- 18449596 TI - A novel approach to treatment of unexpected vertebroplasty complication. AB - We report a novel approach to treatment of an unexpected complication of vertebroplasty. During initial positioning of transpedicular vertebroplasty needles in a 73-year-old woman, we encountered unexpected ease of needle advancement resulting in progression of the needle through the anterior cortex of the thoracic vertebral body. The transpedicular needle advanced into the mediastinum and, presumably, the adventitia of the descending thoracic aorta. Administration of polymethylmethacrylate cement was performed to tamponade bleeding at the time of the procedure and to reduce the risk of potential delayed bleeding complications within the mediastinum. The treatment was successful and the patient had no immediate or delayed complications as a result of the unintended needle advancement. PMID- 18449597 TI - Imaging of the coronary venous system: validation of three-dimensional rotational venous angiography against dual-source computed tomography. AB - Information on the anatomy of the cardiac venous system (CVS) is increasingly important for cardiac resynchronization therapy or percutaneous transvenous mitral valve annuloplasty. Three-dimensional (3D) imaging can further improve the understanding of the relationship of cardiac structures. This study was performed to validate the accuracy of rotational coronary sinus angiography (CSA) displaying the 3D anatomy of the CVS compared to ECG-gated, contrast-enhanced, cardiac dual-source computed tomography (DSCT). Five domestic pigs (60 kg) underwent DSCT using a standardized examination protocol. Using a standard C-arm for fluoroscopy, a rotational CSA was obtained and 3D-image reconstructions performed. Side branches were identified using both methods and enumerated. Vessel visibility was estimated for each side branch and great cardiac vein/anterior interventricular vein. Also, vessel diameters were measured at distinct landmarks, i.e., side branching. The amount of contrast medium was determined and the effective radiation exposure of both methods was calculated. There was no significant difference regarding the vessel diameter of the great cardiac vein/anterior interventricular vein or its side branches. Also, estimation of vessel visibility was not different between the two imaging modalities. Estimated radiation exposure and amount of contrast medium were lower for rotational CSA. In conclusion, a 3D reconstruction of rotational CSA images is possible. All parts of the CVS are well depicted, allowing a 3D overview of the CVS anatomy. On-site 3D visualization might improve decision making during cardiac interventions. In contrast to DSCT, rotational CSA does not demonstrate the anatomy of the mitral annulus or the course of the left circumflex artery. PMID- 18449599 TI - Fundoplication for gastroesophageal reflux and factors associated with the outcome 6 to 10 years after the operation: multivariate analysis of prognostic factors using the propensity score. AB - BACKGROUND: The impact from the mode of operation (partial vs total fundoplication) on long-term outcome after fundoplication still is unknown, although short-term randomized studies have not shown significant differences in the efficacy of reflux control. To obtain some insight concerning the long-term results, the data of a nonrandomized cohort were analyzed using propensity score statistics. METHODS: For 134 patients who underwent laparoscopic fundoplication for gastroesophageal reflux disease (GERD), the time until recurrence of reflux symptoms was assessed. The impact of putative prognostic factors and the mode of operation (partial vs total fundoplication) on outcome were tested for significance using univariate and multivariate statistics, including the propensity score, correcting for nonrandomized treatment groups. The follow-up period was 60 to 123 months (median, 93 months). In this study, 45 patients had a partial (Toupet) fundoplication, and 89 patients underwent a total (Nissen) fundoplication. RESULTS: The rate of recurrence after 93 months (the median follow-up interval) was 14% after Nissen and 9% after Toupet fundoplication (nonsignificant difference) as estimated according to Kaplan and Meier. Massive acid exposure to the esophagus was associated with an increased risk of recurrence for 23% of the patients with a DeMeester score of 50 or higher, but only for 9% of the patients with less severe reflux (DeMeester score <50; p < 0.05). Multiple proportional hazard regression using the propensity score did not show additional significance for the variables of age, gender, presence of a Barrett esophagus, and mode of operation. CONCLUSION: The operation method did not have a significant impact on the efficacy of laparoscopic fundoplication in a cohort during a follow-up period of 60 to 123 months (median, 93 months). PMID- 18449600 TI - Nutrient limitation is the main regulatory factor for carotenoid accumulation and for Psy and Pds steady state transcript levels in Dunaliella salina (Chlorophyta) exposed to high light and salt stress. AB - Dunaliella salina (Dunal) Teodoresco (1905) is a green unicellular alga able to withstand severe salt, light, and nutrient stress, adaptations necessary to grow in harsh environments such as salt ponds. In response to such growth conditions, this microalga accumulates high amounts of beta-carotene in its single chloroplast. In this study, we show that carotenoid accumulation is consistently inhibited in cells grown in nutrient-supplemented media and exposed either to high-light or medium-low-light conditions. Likewise, carotenogenesis in cells shifted to higher salinity (up to 27% NaCl) under medium-low-light conditions is inhibited by the presence of nutrients. The steady-state levels of transcripts encoding phytoene synthase and phytoene desaturase increased substantially in D. salina cells shifted to high light or high salt under nutrient-limiting conditions, whereas the presence of nutrients inhibited this response. The regulatory effect of nutrient availability on the accumulation of carotenoids and messenger RNA levels of the first two enzymes committed to carotenoid biosynthesis is discussed. PMID- 18449601 TI - Morphological and biochemical alterations of abalone testicular germ cells and spawned sperm and their fertilizing ability. AB - In this study, we aimed to detect morphological and biochemical changes in developing germ cells (Gc), testicular sperm (Tsp), and spawned sperm (Ssp) using capacitation-associated characteristics. Gradual changes in the profiles of two membrane proteins, namely NaCl- and detergent-extractable proteins, were observed as compared Gc with Tsp and Tsp with Ssp. These membrane modifications were accomplished mostly through the introduction of new protein sets, both peripheral and integral, into Tsp and Ssp membranes. Activation of serine proteases, particularly in Ssp detergent-extracted proteins with the molecular masses of 38 130 kDa was evident and marked a major difference between Ssp and Tsp. An increase in the level of tyrosine phosphorylation of the proteins ranging from 15 to 20 kDa was noted in Tsp and remained constant in Ssp. Specifically, these three capacitation-associated characteristics could be detected in Ssp, possessing full fertilizing capacity. The lack of an activated proteolytic activity in Tsp resulted in a delayed fertilization, but not affected fertilizing ability. We believe that these characteristics should be advantageous in predicting abalone sperm fertilizing capability, particularly in cases when isolated germ cells or purified Tsp are used in place of spawned sperm in abalone aquaculture. PMID- 18449602 TI - Ornamental expression of red fluorescent protein in transgenic founders of white skirt tetra (Gymnocorymbus ternetzi). AB - Although the transgenic technology has been successfully used to generate fluorescent zebrafish and medaka for ornamental purposes, the practicability of the technology has not been demonstrated in other ornamental fish species. In the present study, we have tested the transgenic technology in a bona fide ornamental fish species, the white skirt tetra (Gymnocorymbus ternetzi). First, its embryonic development was briefly described. Second, we successfully introduced an rfp (red fluorescent protein) gene construct driven by a strong muscle specific mylz2 promoter from the zebrafish into the white skirt tetra and demonstrated muscle-specific expression of the RFP reporter protein. Importantly, the vivid red fluorescent color was prominently visible in adult transgenic founders under the normal daylight, like the currently marketed red fluorescent transgenic zebrafish. Thus, our current study demonstrated the feasibility of using the well-characterized zebrafish mylz2 promoters to produce useful fluorescent ornamental fish in other fish species by the transgenic technology. PMID- 18449603 TI - Characterization of cupric glutamate extinguishing mechanism of Alexandrium sp. LC3 with two-dimensional electrophoresis and MALDI-TOF MS. AB - Mechanisms by which cupric glutamate, a novel algicide, extinguishes Alexandrium sp. LC3 are shown in this study. We show that cupric glutamate not only stimulated the production of malonaldehyde (MDA) and dramatically promoted cell plasma membrane permeability (p < 0.01) but also remarkably reduced sulfhydryl (SH) group content (p < 0.01). Analysis of protein expression profiles by two dimensional electrophoresis (2-DE) indicated that only 47 protein spots were detected in both control and cupric glutamate treated cells. Three reliable spots were identified by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) as ribulose-bisphosphate carboxylase large subunit precursor, RNA polymerase beta chain, and hypothetical protein, which can be well correlated with cupric glutamate stress. Based on above results, we hypothesize that the extinguishing mechanisms include (1) the cell membrane being damaged by cupric glutamate; (2) cupric glutamate probably induced denaturation and disintegration of intracellular protein, which led to inhibition of cell growth. PMID- 18449605 TI - Issues surrounding PACS archiving to external, third-party DICOM archives. AB - In larger health care imaging institutions, it is becoming increasingly obvious that separate image archives for every department are not cost effective or scalable. The solution is to have each department's picture archiving communication system (PACS) have only a local cache, and archive to an enterprise archive that drives a universal clinical viewer. It sounds simple, but how many PACS can truly work with a third-party Integration of the Health Care Enterprise Compliant Image Archive? The answer is somewhat disappointing. PMID- 18449604 TI - Transplantation of mouse embryonic stem cells into the cochlea of an auditory neuropathy animal model: effects of timing after injury. AB - Application of ouabain to the round window membrane of the gerbil selectively induces the death of most spiral ganglion neurons and thus provides an excellent model for investigating the survival and differentiation of embryonic stem cells (ESCs) introduced into the inner ear. In this study, mouse ESCs were pretreated with a neural-induction protocol and transplanted into Rosenthal's canal (RC), perilymph, or endolymph of Mongolian gerbils either 1-3 days (early post-injury transplant group) or 7 days or longer (late post-injury transplant group) after ouabain injury. Overall, ESC survival in RC and perilymphatic spaces was significantly greater in the early post-injury microenvironment as compared to the later post-injury condition. Viable clusters of ESCs within RC and perilymphatic spaces appeared to be associated with neovascularization in the early post-injury group. A small number of ESCs transplanted within RC stained for mature neuronal or glial cell markers. ESCs introduced into perilymph survived in several locations, but most differentiated into glia-like cells. ESCs transplanted into endolymph survived poorly if at all. These experiments demonstrate that there is an optimal time window for engraftment and survival of ESCs that occurs in the early post-injury period. PMID- 18449607 TI - Meta-analysis results need to be evaluated with caution. PMID- 18449608 TI - Preoperative radiation response evaluated by 18-fluorodeoxyglucose positron emission tomography predicts survival in locally advanced rectal cancer. AB - PURPOSE: This study focuses on the prognostic survival value of postirradiation metabolic activity in primary rectal cancer as measured with 18 fluorodeoxyglucose positron emission tomography. METHODS: From July 1995 to March 2002, all 59 patients underwent two series of fluorodeoxyglucose positron emission tomography: one before preoperative radiation (standardized uptake values-1), and the other two to three weeks after radiation (standardized uptake values-2). Standardized uptake values-1 and standardized uptake values-2 correspond to before and after radiation, respectively. RESULTS: In univariate analysis, the following emerged as significant prognostic variables: with or without residual tumor, pathologic differentiation, with or without recurrence, standardized uptake values-2, and with or without lymph node metastases. In multivariate analysis, residual tumor and standardized uptake values-2 were significant prognostic factors for survival. The median survival and the five year overall survival rate comparing standardized uptake values-2 values <5 vs. >5 were 95 vs. 42 months and 70 vs. 44 percent, respectively (P = 0.042). CONCLUSION: A significant survival benefit was observed in patients with low fluorodeoxyglucose uptake after preoperative radiotherapy in primary tumors of rectal cancer. PMID- 18449609 TI - Persistent symptoms after elective sigmoid resection for diverticulitis. AB - PURPOSE: Despite technically successful surgery for diverticular disease, a significant group of patients who experience persistent or recurrent symptoms remains. This study was designed to determine the incidence and pattern of persistent symptoms and their association with peroperative parameters. METHODS: Follow-up (33 (range, 4-72) months) through structured interviews with patients who had surgery for diverticulitis in our department from December 1999 to November 2004 was conducted. Of 162 patients, 124 (76.5 percent) were available for follow-up. Nonparametric tests were used for comparison of patients who had undergone elective (n = 68) or emergency (n = 56) procedures. RESULTS: Of patients who had elective surgery, 25 percent suffered persistent symptoms, including painful constipation, painful abdominal distension, abdominal cramps, and frequent painful diarrhea. Neither the stage of disease (complicated or uncomplicated) nor the surgical technique (laparotomy or laparoscopy) were significantly related to the occurrence of symptoms. Recurrent diverticulitis was not observed. Similar results were obtained from comparisons with emergency patients. CONCLUSIONS: The prevalence of persistent symptoms after successful surgery for diverticular disease may be an additional reason to carefully discuss the indication for prophylactic surgery. In any case, preoperative counseling and informed consent regarding the possibility of persistent symptoms after prophylactic elective surgery is essential. PMID- 18449610 TI - Portal vein segmentation of a 3D-planning system for liver surgery--in vivo evaluation in a porcine model. AB - BACKGROUND: Computer systems allow the planning of complex liver operations. The segmentation of intrahepatic vessels builds the basis for the calculation of liver segments and resection proposals. For surgical use, it is essential to know the capabilities and limitations of the segmentation. The aim of this study was to determine the sensitivity and precision of the portal vein segmentation of a computer planning system for liver surgery in vivo. METHODS: Segmentations were performed with the software system HepaVision on computed tomography (CT) scan data of domestic pigs. An in situ corrosion cast of the portal vein served as the gold standard. The segmentation results of the portal vein and the corrosion cast were compared with regard to sensitivity, precision, and amount of short-circuit segmentations. RESULTS: The methodology demonstrated high resolution ex situ. The in vivo sensitivity of the portal vein segmentation was 100% for vessels of more than 5 mm in diameter and 82% for vessels of 3-4 mm. All segment branches were detected as well as 84% of the first subsegment branches with a diameter of more than 3 mm. The precision of the system was 100% for segment branches and 89% for the first subsegment vessels. The amount of internal short-circuit segmentations was less than 3.0%. No external short-circuits were found. CONCLUSION: The system has a high precision and sensitivity under clinical conditions. The segmentation is suitable for portal vein branches of the first and second order and for vessels of >/=3 mm in diameter. PMID- 18449611 TI - Prevalence of musculoskeletal pain and statin use. AB - BACKGROUND: Muscle effects are the most common reported adverse effects of 3 hydroxy-3-methylglutaryl coenzyme A inhibitors (statins). However, in placebo controlled trials the incidence of muscle pain is most often similar for placebo and active control groups. OBJECTIVE: We sought to evaluate whether statin use was associated with a higher prevalence of musculoskeletal pain in a nationally representative sample. METHODS: Cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Participants were 3,580 adults > or =40 years without arthritis who were interviewed at home and examined in a mobile examination center. Participants were asked about sociodemographic characteristics, health conditions, medication use, and musculoskeletal pain. Height, weight, blood pressure, ankle brachial index, and cholesterol were measured. MEASUREMENTS AND MAIN RESULTS: Prevalence and adjusted odds ratios (OR) of any musculoskeletal pain and musculoskeletal pain in 4 different anatomical regions (neck/upper back, upper extremities, lower back, and lower extremities) by statin use during the last 30 days. Among statin users (n = 402), 22.0% (95%CI 18.0-26.7%) reported musculoskeletal pain in at least 1 anatomical region during the last 30 days, compared with 16.7% (95%CI 15.1-18.4%) of those who did not use a statin. Compared to persons who did not use statins, those who used statins had multivariable-adjusted odds ratios (95%CI; p value) of 1.50 (1.07-2.11; p = .01) for any musculoskeletal pain, 1.59 (1.04-2.44, p = .03) for lower back pain, and 1.50 (1.02-2.22, p = .03) for lower extremity pain. CONCLUSION: Musculoskeletal pain is common in adults > or =40 years without arthritis. In this nationally representative sample, statin users were significantly more likely to report musculoskeletal pain. PMID- 18449612 TI - Teaching internal medicine residents quality improvement techniques using the ABIM's practice improvement modules. AB - INTRODUCTION/AIM: Standard curricula to teach Internal Medicine residents about quality assessment and improvement, important components of the Accreditation Council for Graduate Medical Education core competencies practiced-based learning and improvement (PBLI) and systems-based practice (SBP), have not been easily accessible. PROGRAM DESCRIPTION: Using the American Board of Internal Medicine's (ABIM) Clinical Preventative Services Practice Improvement Module (CPS PIM), we have incorporated a longitudinal quality assessment and improvement curriculum (QAIC) into the 2 required 1-month ambulatory rotations during the postgraduate year 2. During the first block, residents complete the PIM chart reviews, patient, and system surveys. The second block includes resident reflection using PIM data and the group performing a small test of change using the Plan-Do-Study Act (PDSA) cycle in the resident continuity clinic. PROGRAM EVALUATION: To date, 3 resident quality improvement (QI) projects have been undertaken as a result of QAIC, each making significant improvements in the residents' continuity clinic. Resident confidence levels in QI skills (e.g., writing an aim statement [71% to 96%, P < .01] and using a PDSA cycle [9% to 89%, P < .001]) improved significantly. DISCUSSION: The ABIM CPS PIM can be used by Internal Medicine residency programs to introduce QI concepts into their residents' outpatient practice through encouraging practice-based learning and improvement and systems based practice. PMID- 18449613 TI - Proctocolectomy-ileal pouch-anal anastomosis for ulcerative colitis after liver transplantation for primary sclerosing cholangitis: a multi-institutional analysis. AB - BACKGROUND: The association between primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) often mandates their contemporaneous management. Orthotopic liver transplantation (OLTX) has emerged as the only curative therapy for PSC, and total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the definitive treatment for refractory UC. The published experience to date describing IPAA after OLTX has been limited; we sought to examine outcomes associated with proctocolectomy-IPAA after OLTX. MATERIALS AND METHODS: We reviewed our multi-institutional experience performing proctocolectomy-IPAA for UC after OLTX for PSC. RESULTS: Twenty-two patients underwent proctocolectomy IPAA for UC after OLTX for PSC at four academic medical centers between 1989 and 2006. No perioperative complications or allograft dysfunction were observed. During a median follow-up of 52 months, complications have included transient dehydration (n = 6), chronic pouchitis (n = 2), recurrent PSC (n = 2), small bowel obstruction (n = 2), and pouch-anal anastomotic stricture (n = 1). Median 24-h stool frequency was 5, and fecal continence was reported as satisfactory by all patients. CONCLUSIONS: This multi-institutional experience suggests that proctocolectomy-IPAA can be performed safely after OLTX. Management strategies should include optimization of small bowel length during pouch and ileostomy construction, vigorous postoperative hydration, early ileostomy closure, and careful monitoring for pouchitis. PMID- 18449614 TI - Bariatric surgery in adolescents: preliminary 1-year results with a novel technique (Santoro III). AB - BACKGROUND: Bariatric surgery (BS) was recognized as the only treatment for morbid obesity in adolescents. Classic surgical procedures are based on mechanical restriction and/or malabsorption, resulting in a large number of possible complications and demanding lifelong medical attention. A novel BS design, the Santoro III procedure, relies on modifying secretion of the satiogenic hormones GLP-1 and PYY. This approach avoids common BS complications such as prostheses, narrow anastomoses, excluded segments, and malabsorption. This study describes the 1-year follow-up of the first ten adolescents operated on using the Santoro III technique in a pediatric surgical service. METHODS: Ten adolescents, mean age 16.1 +/- 1.7 years with body mass index (BMI) greater than 40 kg/m(2) (range 44 to 72 kg/m(2)), refractory to at least 2 years of medical weight loss treatment were selected by a multidisciplinary team to undergo BS. This operation consists of a sleeve gastrectomy with enteroomentectomy and partial gastro-ileal derivation. RESULTS: After 1 year, mean body weight decreased from 140.3 to 88.6 kg, and BMI decreased from 52.8 +/- 9.5 kg/m(2) to 33.4 +/- 7.7 kg/m(2), with percent of excess BMI lost as 83.9 +/- 17.1%. Glucose, insulin, total cholesterol, LDL-cholesterol, and triglyceride levels decreased significantly, while HDL-cholesterol, hemoglobin, and albumin levels remained unchanged. There were no mortalities or reoperations. The two complications that presented during the trial (intraperitoneal abscess and polyneuritis) resolved with medical treatment without sequelae. All the patients returned to their normal activities and their BMI began to stabilize approximately 2 years following surgery. CONCLUSIONS: The Santoro III procedure is an attractive option for adolescent BS, with promising 1-year follow-up results. These initial studies should be monitored for long-term outcomes and confirmed on a larger group of patients. PMID- 18449615 TI - BioEnterics intragastric balloon for treatment of morbid obesity in Prader-Willi syndrome: specific risks and benefits. AB - BACKGROUND: Obesity in Prader-Willi Syndrome (PWS) is progressive, severe, and resistant to dietary, pharmacological, and behavioral treatment. A body weight reduction is mandatory to reduce the risk of cardio-respiratory and metabolic complications. The aim of the study was to assess risks and benefits of BioEnterics Intragastric Balloon (BIB) for treatment of morbid obesity in PWS patients. METHODS: Twenty-one BIB were positioned in 12 PWS patients (4 M, 8 F), aged from 8.1 to 30.1 years, and removed after 8 +/- 1.4 months (range: 5-10 months). Auxological, clinical, and nutritional evaluations were performed every 2 months. Variations in body composition were analysed by dual energy X-ray absorbiometry (DXA). RESULTS: One patient (28.5 years, BMI: 59.3 kg/m(2)) died 22 days after BIB positioning because of gastric perforation. In another case (26.2 years, BMI: 57.6 kg/m(2)), BIB was surgically removed after 25 days because of symptoms suggesting gastric perforation (not confirmed). The remaining ten patients showed a significant decrease of BMI (p = 0.005) and of fat tissue as measured by DXA (p = 0.012). No significant modifications in bone mineral density (BMD) occurred, but a slight loss in lean body mass (p = 0.036) was documented. In five patients, BIB treatment was repeated more than once. CONCLUSION: This study shows that when noninvasive pharmacological therapies fail, BIB may be effective to control body weight in PWS patients with morbid obesity, particularly when treatment is started in early childhood. However, careful clinical follow-up and close collaboration with parents are crucial to avoid severe complications, which can be caused by persisting unrestrained food intake. PMID- 18449616 TI - Successful management of tendinopathy with injections of the MMP-inhibitor aprotinin. AB - Aprotinin is a broad spectrum proteinase inhibitor (including matrix metalloproteinase [MMP] inhibitor) used for treating patellar and Achilles tendinopathies. One previous randomized control trial demonstrated aprotinin injections superior to both corticosteroid and saline injections in patellar tendinopathy (Level II), whereas results reported for aprotinin treatment in Achilles tendinopathy have been mixed. We performed a case review and followup questionnaire for 430 consecutive patients with tendinopathy treated by 997 aprotinin injections (30,000 KIU). A response rate of 72% was achieved with a minimum followup of 3 months (average, 12.2 months; range, 3-54 months). Seventy six percent of patients had improved, 22% of patients reported no change, and 2% were worse. Sixty-four percent of patients thought aprotinin injections were helpful, while 36% believed they had neither a positive nor negative effect. Mid Achilles tendinopathy patients (84% improvement) were more successfully treated than patellar tendinopathy patients (69% improvement). Despite stronger published evidence of benefit in patellar tendinopathy, clinical outcomes appeared better with aprotinin use in Achilles tendinopathies. LEVEL OF EVIDENCE: Level IV, case series. PMID- 18449617 TI - Mean 20-year followup of Bernese periacetabular osteotomy. AB - The goal of the Bernese periacetabular osteotomy is to correct the deficient acetabular coverage in hips with developmental dysplasia to prevent secondary osteoarthrosis. We determined the 20-year survivorship of symptomatic patients treated with this procedure, determined the clinical and radiographic outcomes of the surviving hips, and identified factors predicting poor outcome. We retrospectively evaluated the first 63 patients (75 hips) who underwent periacetabular osteotomy at the institution where this technique was developed. The mean age of the patients at surgery was 29 years (range, 13-56 years), and preoperatively 24% presented with advanced grades of osteoarthritis. Four patients (five hips) were lost to followup and one patient (two hips) died. The remaining 58 patients (68 hips) were followed for a minimum of 19 years (mean, 20.4 years; range, 19-23 years) and 41 hips (60%) were preserved at last followup. The overall mean Merle d'Aubigne and Postel score decreased in comparison to the 10-year value and was similar to the preoperative score. We observed no major changes in any of the radiographic parameters during the 20 year postoperative period except the osteoarthritis score. We identified six factors predicting poor outcome: age at surgery, preoperative Merle d'Aubigne and Postel score, positive anterior impingement test, limp, osteoarthrosis grade, and the postoperative extrusion index. Periacetabular osteotomy is an effective technique for treating symptomatic developmental dysplasia of the hip and can maintain the natural hip at least 19 years in selected patients. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 18449625 TI - Liv.52 regulates ethanol induced PPARgamma and TNF alpha expression in HepG2 cells. AB - Liver is a prime target of alcohol-induced damage by inducing inflammatory cytokines especially tumor necrosis factor alpha (TNFalpha). Activator of peroxisome proliferator activator receptor gamma (PPARgamma) is protective against alcohol-induced liver injury in animals. Liv.52, one of the major herbal hepatoprotective drugs, is shown to protect the liver from toxicity and is considered to be an effective hepatoprotective agent. However, the signal pathway involved in the Liv.52-induced hepatoprotection is not understood well especially in the case of cultured liver cells treated with ethanol. Hence, the study was aimed at determining whether ethanol and Liv.52 could modulate PPARgamma and TNFalpha induction in human hepatoma cells, HepG2. The present study with RT-PCR and confocal microscopy experiments showed that ethanol (100 mM) induced suppression of PPARgamma expression in HepG2 cells. The ethanol-induced PPARgamma suppression was abrogated by Liv.52. Moreover, Liv.52 also induced upregulation of PPARgamma mRNA in liver cells as compared to the untreated cells. Further, 100 mM ethanol has also induced TNFalpha gene expression in HepG2 cells and interestingly Liv.52 abolished ethanol-induced TNFalpha. The study also shows that Liv.52 alone downregulated TNFalpha expression in HepG2 cells. Taken together, these findings suggest that Liv.52 is capable of attenuating ethanol induced expression of TNFalpha and abrogating ethanol-induced suppression of PPARgamma in liver cells. These results indicate that Liv.52-induced PPARgamma expression and concomitant suppression of ethanol-induced elevation of TNFalpha in HepG2 cells suggest the immunomodulatory and hepatoprotective nature of Liv.52. PMID- 18449626 TI - Doxorubicin loaded pH-sensitive micelle: antitumoral efficacy against ovarian A2780/DOXR tumor. AB - PURPOSE: To evaluate pH-sensitive mixed micelles for multidrug resistant (MDR) ovarian tumor targeting and optical imaging of solid tumors. METHOD: Doxorubicin (DOX) encapsulated pH-sensitive mixed micelles composed of poly(L-histidine)(MW 5K)-b-PEG(MW 2K) and poly(L-lactic acid)(3K)-b-PEG (2K)-folate (PHSM-f) were prepared. Folate receptor-mediated endocytosis, drug uptake, endosomal disruption and cell viability were investigated at the cellular level. For in vivo tumor growth inhibition tests, multidrug resistant ovarian A2780/DOX(R) xenografted nude mice were used. Optical imaging was performed by using a Cy5.5 fluorescence dye-labeled mixed micelle system. Cy5.5 fluorescence intensity at the tumor site was measured in KB epidermoid xenografted nude mice. RESULTS: In vitro cell viability and drug distribution in the cytoplasm demonstrated the significantly superior efficacy of PHSM-f to free DOX and a control sample of DOX loaded pH insensitive micelle composed of poly(L-lactic acid)(3K)-b-PEG(2K)/poly(L-lactic acid)(3K)-b-PEG(2K)-folate (80/20 wt/wt%) (PHIM-f). The mechanisms of these results were proved by folate receptor mediated endocytosis of micelle and endosomal disruption function by it. In addition, the optical imaging demonstrated the future application of the diagnositic area. PHSM-f inhibited the growth of multidrug resistant ovarian tumors efficiently in mice, with minimum weight loss. CONCLUSIONS: The pH-sensitive mixed micelle system demonstrates effective antitumor efficacy against the multidrug resistant ovarian tumor A2780/DOX(R). PMID- 18449627 TI - Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER). AB - PURPOSE: Carbonyl reductase 1 (CBR1) reduces the anticancer anthracyclines doxorubicin and daunorubicin into the cardiotoxic metabolites doxorubicinol and daunorubicinol. We evaluated whether the cardioprotectant monoHER inhibits the activity of polymorphic CBR1. METHODS: We performed enzyme kinetic studies with monoHER, CBR1 (CBR1 V88 and CBR1 I88) and anthracycline substrates. We also characterized CBR1 inhibition by the related flavonoids triHER and quercetin. RESULTS: MonoHER inhibited the activity of CBR1 V88 and CBR1 I88 in a concentration-dependent manner. The IC(50) values of monoHER were lower for CBR1 I88 compared to CBR1 V88 for the substrates daunorubicin and doxorubicin (daunorubicin, IC(50)-CBR1 I88 = 164 microM vs. IC(50)-CBR1 V88 = 219 microM; doxorubicin, IC(50)-CBR1 I88 = 37 microM vs. IC(50)-CBR1 V88 = 59 microM; p < 0.001). Similarly, the flavonoids triHER and quercetin exhibited lower IC(50) values for CBR1 I88 compared to CBR1 V88 (p < 0.001). MonoHER acted as a competitive CBR1 inhibitor when using daunorubicin as a substrate Ki = 45 +/- 18 microM. MonoHER acted as an uncompetitive CBR1 inhibitor for the small quinone substrate menadione Ki = 33 +/- 17 microM. CONCLUSIONS: The cardioprotectant monoHER inhibits CBR1 activity. CBR1 V88I genotype status and the type of anthracycline substrate dictate the inhibition of CBR1 activity. PMID- 18449629 TI - Optimizing metrics for the assessment of bioequivalence between topical drug products. AB - PURPOSE: Stratum corneum tape stripping post-application of a drug product followed by analysis of the active agent in this tissue layer is an approach being seriously considered for the comparative assessment of topical bioavailability. Key issues revolve around how best to perform this experiment and interpret the data. METHODS: Using previously published results from a comparative study of three 0.025% tretinoin gel products, alternative data analysis approaches are presented that may render the technique more accessible to the evaluation of new and generic topical dosage forms. RESULTS: For the tretinoin gel study, the conclusions for bioequivalence from measurements of drug levels at only one uptake and one clearance time were the same as those from the original study, which required measurements at eight different treatment times. Furthermore, comparisons of drug levels at one uptake and one clearance time discriminated differences in bioequivalence for clearance and uptake, which had previously been missed. Half-life estimates, derived from time course data of drug clearance, can be related to lag time for drug penetration through the SC. CONCLUSIONS: This new data analysis demonstrates that comparative bioequivalence might be assessed more easily. PMID- 18449628 TI - Flux across [corrected] microneedle-treated skin is increased by increasing charge of naltrexone and naltrexol in vitro. AB - PURPOSE: The purpose of this investigation was to evaluate the in vitro microneedle (MN) enhanced percutaneous absorption of naltrexone hydrochloride salt (NTX x HCl) compared to naltrexone base (NTX) in hairless guinea pig skin (GP) and human abdominal skin. In a second set of experiments, permeability of the major active metabolite 6-beta-naltrexol base (NTXOL) in the primarily unionized (unprotonated) form at pH 8.5 was compared to the ionized form (pH 4.5). METHODS: In vitro fluxes of NTX, NTX.HCl and ionized and unionized NTXOL were measured through microneedle treated or intact full thickness human and GP skin using a flow through diffusion apparatus. Solubility and diffusion samples were analyzed by HPLC. RESULTS: Both GP and human skin show significant increases in flux when treated with 100 MN insertions as compared to intact full thickness skin when treated with NTX.HCl or ionized NTXOL (pH 4.5; p < 0.05). MN increased GP skin permeability for the hydrophilic HCL salt of NTX by tenfold and decreased lag time by tenfold too. Similar results were found using human skin, such that skin permeability to NTX.HCl was elevated to 7.0 x 10(-5) cm/h. Permeability of the primarily unionized (unprotonated) form of NTXOL at pH 8.5 was increased by MN only threefold and lag time was only modestly reduced. However, MN treatment with the primarily ionized (protonated) form of NTXOL at pH 4.5 increased skin permeability fivefold and decreased lag time fourfold. CONCLUSION: Enhancement was observed in vitro in both GP and human skin treated with MN compared to intact skin with the salt form of NTX and the ionized form of NTXOL. We conclude that transdermal flux can be optimized by using MN in combination with charged (protonated) drugs that have increased solubility in an aqueous patch reservoir and increased permeability through aqueous pathways created by MN in the skin. PMID- 18449630 TI - Trying to lose or maintain weight during pregnancy-United States, 2003. AB - OBJECTIVES: Current pregnancy weight gain recommendations are for women to gain between 15 and 40 pounds; weight loss or weight maintenance is not recommended. However, for many women, overweight and obesity are chronic conditions, and commitment to weight loss or maintenance could override advice to gain weight during pregnancy. Our objective was to determine the prevalence of trying to lose or maintain weight among U.S. women during pregnancy. METHODS: The Behavioral Risk Factor Surveillance System is a state-based, random-digit-dialed telephone survey of noninstitutionalized, U.S. civilians aged > or =18 years. We identified women aged 18-44 years who reported being pregnant during 2003 (n = 2,464), assessed the prevalence of trying to lose or maintain weight and assessed independent associations with selected demographic, clinical, and behavioral factors using multinomial logistic regression. RESULTS: Among women who reported being pregnant, 7.5% (confidence interval [CI] = 5.7-9.8%) and 34.3% (CI = 31.0 37.7%) were trying to lose or maintain weight, respectively. Among women who reported trying to lose or maintain weight, exercise was a more prevalent weight control strategy than dietary change. After adjustment, women who drank alcohol during the past 30 days (Odds ratio [OR] = 8.86, CI: 4.51-17.42) or women who received advice in the past year to lose weight (OR = 9.10, CI: 3.20-25.87) were more likely to report trying to lose weight; women advised to maintain (OR = 0.20, CI: 0.07-0.60) or gain (OR = 0.04, CI: 0.01-0.23) weight were less likely to report trying to lose weight. CONCLUSIONS: Despite guidelines to gain weight during pregnancy, about 8% and 34% of U.S. pregnant women reported trying to lose or maintain weight, respectively. Providers may encounter an increasing number of pregnant women whose weight control intentions conflict with current guidelines for pregnancy weight gain. Further research in this area is warranted. PMID- 18449631 TI - Issues and biases in matching medicaid pregnancy episodes to vital records data: the Arkansas experience. AB - OBJECTIVES: This study examines the extent of selection biases identified in the process of linking Medicaid claims with evidence of pregnancy to vital records. METHODS: Two years of Medicaid claims were scanned to identify pregnancy-related diagnoses and procedures. Information on 55,764 Medicaid recipients was provided to the Division of Health Statistics, which linked the information to vital records data on a range of identifying characteristics. Claims were then clustered by date and then into episodes of care surrounding the birth date of the infant. We identified 38,222 pregnancy episodes matched to vital records; 8,474 episodes unmatched to vital records that appeared to terminate before a delivery; and 5,278 episodes that appeared to include a delivery but did not match to vital records. The characteristics of matched episodes and unmatched episodes and the characteristics of matched episodes with and without delivery claims are compared. RESULTS: Unmatched episodes spanned fewer weeks than matched episodes, included more diagnostic indicators of elevated risk, and occurred more frequently in more impoverished populations. Among the matched records, 13% did not include claims for delivery services. These episodes occurred more frequently among Hispanic women, women delivering out of hospitals and women with preterm births and infant deaths. CONCLUSIONS: The results provide evidence, as other studies have demonstrated, that matching Medicaid claims and vital records data is feasible. However, the matched analytic data set does tend to under-represent the outcomes of high-risk pregnancies. An additional source of selection bias can be avoided by using evidence of pregnancy as the Medicaid index for matching against vital records, rather than using only index cases with evidence of delivery. PMID- 18449632 TI - Neonates with culture proven sepsis have lower amounts and percentage of CD45RA+ T cells. AB - To evaluate the expression of lymphocyte subsets in newborns diagnosed as culture proven or culture negative sepsis and to investigate the differentiation. The aim of this study is to explore neonatal immunology in newborns diagnosed as culture proven or culture negative neonatal sepsis and to identify their place in the diagnosis. This prospective study was performed in newborns who were diagnosed as neonatal sepsis and hospitalized in a tertiary care hospital and who were classified as culture proven sepsis (n=12), as culture negative sepsis (n=21) and healthy (n=17). Lymphocyte subsets were obtained at time of diagnosis. Culture proven sepsis had statistically significant increase of WBC compared to culture negative sepsis and control groups (p<0.05). Significant decreases were observed of percentage of lymphocyte, when compared to culture negative sepsis and control group (p<0.05). Percentage of CD4(+) was lower in culture proven sepsis and absolute count of CD4(+) was lower in culture negative sepsis (p<0.05). Percentage and absolute count of CD45RA(+) were lower in culture negative sepsis than control and percentage of CD45RA(+) was lower in culture proven sepsis than control (p<0.05). Percentage of CD45RO(+) was higher in culture proven sepsis than control group (p<0.05). It is clear that during neonatal sepsis lymphocyte subsets are different from healthy controls. Whether the described abnormalities represent the absence of a normal maturation process, rather, pathological events is still not clear. PMID- 18449633 TI - Violent crime in Asperger syndrome: the role of psychiatric comorbidity. AB - Although several studies have suggested an association between violent crime and Asperger syndrome (AS), few have examined the underlying reasons. The aim of this review is to determine to what extent psychiatric factors contribute to offending behavior in this population. Online databases were used to identify relevant articles which were then cross-referenced with keyword searches for "violence," "crime," "murder," "assault," "rape," and "sex offenses." Most of the 17 publications which met the inclusion criteria were single case reports. Of the 37 cases described in these publications, 11 cases (29.7%) cases had a definite psychiatric disorder and 20 cases (54%) had a probable psychiatric disorder at the time of committing the crime. These findings underscore the role of psychiatric disorders in the occurrence of violent crime in persons with Asperger syndrome and highlight the need for their early diagnosis and treatment. PMID- 18449634 TI - Color perception in children with autism. AB - This study examined whether color perception is atypical in children with autism. In experiment 1, accuracy of color memory and search was compared for children with autism and typically developing children matched on age and non-verbal cognitive ability. Children with autism were significantly less accurate at color memory and search than controls. In experiment 2, chromatic discrimination and categorical perception of color were assessed using a target detection task. Children with autism were less accurate than controls at detecting chromatic targets when presented on chromatic backgrounds, although were equally as fast when target detection was accurate. The strength of categorical perception of color did not differ for the two groups. Implications for theories on perceptual development in autism are discussed. PMID- 18449635 TI - Regression, developmental trajectory and associated problems in disorders in the autism spectrum: the SNAP study. AB - We report rates of regression and associated findings in a population derived group of 255 children aged 9-14 years, participating in a prevalence study of autism spectrum disorders (ASD); 53 with narrowly defined autism, 105 with broader ASD and 97 with non-ASD neurodevelopmental problems, drawn from those with special educational needs within a population of 56,946 children. Language regression was reported in 30% with narrowly defined autism, 8% with broader ASD and less than 3% with developmental problems without ASD. A smaller group of children were identified who underwent a less clear setback. Regression was associated with higher rates of autistic symptoms and a deviation in developmental trajectory. Regression was not associated with epilepsy or gastrointestinal problems. PMID- 18449636 TI - Follicular fluid VEGF levels directly correlate with perifollicular blood flow in normoresponder patients undergoing IVF. AB - BACKGROUND: It has become increasingly clear that the follicular microenvironment of the maturing human oocyte is a determining factor for the implantation potential of an embryo deriving from that oocyte. Indeed the quality and maturity of an oocyte are influenced by the level of intrafollicular oxygen content which, in turn, is proportional to the degree of follicular vascularity. The aim of the study was to establish whether there is a relationship between follicular fluid VEGF concentrations, perifollicular vascularity and reproductive outcome in normal responders under the age of 35 undergoing IVF. MATERIALS AND METHODS: Sixty-one consecutive patients, all at their first IVF cycle, were included in the study. All patients had primary infertility due to male factor or tubal factor. At oocyte retrieval, the perifollicular vascularity of two follicles per ovary was estimated qualitatively through power Doppler blood flow, for a total of two hundred forty-four follicles. The follicular fluid from the identified follicles was centrifuged and stored until VEGF assay. The maturity and fertilization rate of the corresponding oocytes as well as embryo quality and pregnancy rate were recorded. RESULTS: In our study, we found VEGF levels to be significantly correlated with grade of perifollicular vascularity. Oocytes obtained from follicles with the higher grade of vascularization also showed a higher rate of fertilization, embryos, a better quality and higher pregnancy rates were obtained in women with highly vascularized follicles. Perifollicular blood flow doppler indices seem to predict oocyte viability and quality. Moreover, VEGF may play a potential role in the development of the perifollicular capillary network. DISCUSSION: The ability of a given follicle to express VEGF and develop an adequate vascular network may be inter-related in patients under the age of 35. An adequate blood supply may be fundamental important in the regulation of intrafollicular oxygen levels and the determination of oocyte quality. PMID- 18449637 TI - A structural equation modeling approach to the study of stress and psychological adjustment in emerging adults. AB - Today's society puts constant demands on the time and resources of all individuals, with the resulting stress promoting a decline in psychological adjustment. Emerging adults are not exempt from this experience, with an alarming number reporting excessive levels of stress and stress-related problems. As a result, the present study addresses the need for a comprehensive model of emerging adult adjustment in the context of stress and coping variables and highlights the importance of accounting for differences between males and females in research concerning stress, social support, coping, and adjustment. Participants for this study are 239 college students (122 males and 117 females), the majority of whom are Caucasian. Results of structural equation modeling suggest that stress, social support, coping, and adjustment show unique patterns of relationships for males versus females. For both males and females, stress and social support show similar relationships to adjustment. In contrast, social support is related only to coping behaviors in females. Finally, social support appears to be a more important variable for female adjustment, whereas other coping behaviors appear to be more pertinent to male adjustment. Limitations and suggestions for future research will be discussed. PMID- 18449639 TI - Relationship between functional capacity and community responsibility in patients with schizophrenia: differences between independent and assisted living settings. AB - We examined factors potentially associated with level of community responsibility among middle-aged and older patients with schizophrenia. Participants in residential care facilities engaged in significantly fewer community responsibilities than those residing in the community. However, demographic and clinical characteristics did not explain these differences. Further, greater functional capacity was associated with greater community responsibility among participants residing in the community, but not those in residential care facilities. These results suggest that, despite capacity, patients residing in residential care facilities are not engaging in community responsibilities. Further, among participants residing in the community, functional capacity may predict level of responsibility. PMID- 18449638 TI - Hazard assessment of commonly used agricultural antibiotics on aquatic ecosystems. AB - In this study, eleven commonly used antibiotics including sulfonamides, tetracyclines, aminoglycosides, fluoroquinolones, and beta-lactams were evaluated for their acute and chronic aquatic toxicities using standard test organisms e.g., Vibrio fischeri, Daphnia magna, Moina macrocopa, and Oryzias latipes. Among the antibiotics tested for acute toxicity, neomycin was most toxic followed by trimethoprim, sulfamethoxazole and enrofloxacin. Sulfamethazine, oxytetracycline, chlortetracycline, sulfadimethoxine and sulfathiazole were of intermediate toxicity, while ampicillin and amoxicillin were least toxic to the test organisms. There were no trends in sensitivity among test organisms or among different classes of the antibiotics. Only the beta-lactam class was the least toxic. In chronic toxicity test, neomycin affected reproduction and adult survival of D. magna and M. macrocopa with low mg/l levels exposure. Predicted no effect concentrations (PNECs) were derived from the acute and chronic toxicity information gleaned from this study and from literature. When the PNECs were compared with measured environmental concentrations (MECs) reported elsewhere for the test compounds, hazard quotients for sulfamethoxazole, sulfathiazole, chlortetracycline, oxytetracycline, and amoxicillin exceeded unity, which suggests potential ecological implication. Therefore, further studies including monitoring and detailed toxicological studies are required to assess potential ecological risk of these frequently used veterinary antibiotics. PMID- 18449640 TI - Client-level measures of services integration among chronically homeless adults. AB - INTRODUCTION: While several major studies have examined services integration at the system or interagency level, there has been far less effort to measure the integration of services at the client-level and its correlates. METHODS: This study presents three client-level measures of services integration, two objective measures, representing the proportion of needed services received and the number of outpatient services received by each client, and one subjective measure, a five-item scale measuring perceived coordination of care among clients' service providers. Data from the evaluation of the collaborative initiative to help end chronic homelessness (CICH) are used to examine bivariate and multivariate relationships of these three client-level measures to two system-level measures of services integration, one addressing interagency services coordination/planning and the other interagency trust/respect as well as to baseline client characteristics among 734 chronically homeless adults in 11 cities. RESULTS: Client-level measures of service integration were not strongly associated to each other or to the system-level measures, except for weak associations (r = 0.10) between one objective client measure and the system-level measure of service coordination and planning, and another between client-level use of outpatient mental health services and system-level trust and respect. Multivariate analysis showed that clients who received a greater array of needed services received more service overall and were more likely to have a diagnosis of PTSD and more medical problems, but less serious alcohol problems. Clients who reported more outpatient mental health and substance abuse visits were significantly more likely to be married, to be veterans, to have more serious drug problems, and to be dually diagnosed. Clients with more serious drug problems reported poorer coordination among their service providers on the subjective measure of client-level service integration. CONCLUSION: Three client level measures of services integration were, at best, weakly associated with measures of system-level integration. Positive associations between client-level measures of integration and health status, outpatient service use and negative relationships with indicators of substance abuse suggest they may usefully represent the experiences of chronically homeless clients, even though they are not strongly related to system-level measures. PMID- 18449641 TI - Validation of hemoglobin glycation models using glycemia monitoring in vivo and culturing of erythrocytes in vitro. AB - Glycated hemoglobin A1c (HbA1c) concentration in blood is an index of the glycemic control widely used in diabetology. The aim of the work was to validate two mathematical models of HbA1c formation (assuming irreversible or reversible glycation, respectively) and select a model, which was able to predict changes of HbA1c concentration in response to varying glycemia courses with higher accuracy. The experimental procedure applied consisted of an original combination of: in vivo continuous glucose concentration monitoring, long-term in vitro culturing of the human erythrocytes and mathematical modeling of HbA1c formation in vivo and in vitro with HbA1c values scaled according to the most specific analytical methods. Sixteen experiments were conducted in vitro using blood samples collected from healthy volunteer and stable type 1 diabetic patients whose glycemia was estimated beforehand based on long-term monitoring. The mean absolute difference of the measured and predicted HbA1c concentrations for the in vitro experiments were equal to 0.64 +/- 0.29% and 1.42 +/- 0.16% (p = 0.0007) for irreversible and for reversible model, respectively, meaning that the irreversible model was able to predict the glycation kinetics with a higher accuracy. This model was also more sensitive to a deviation of the erythrocytes life span. PMID- 18449642 TI - Handheld subcellular-resolution single-fiber confocal microscope using high reflectivity two-axis vertical combdrive silicon microscanner. AB - We introduce a handheld single-fiber laser-scanning confocal microscope, incorporating a high-reflectivity two-axis silicon vertical combdrive microscanner, aimed at in vivo early detection of epithelial precancers. The approach adopted is motivated by need for a portable, economical, biopsy-free, early precancer screening technology in low-infrastructure environments. Our microelectromechanical system (MEMS) based handheld probe integrates the microscanners with miniature objective lens system and flexible electrical routing in a forward-imaging configuration, with 4.8 mm distal probe tip outer diameter for unrestricted imaging access in biological sites such as the oral cavity and cervix. Reflectance confocal videos of a USAF 1951 resolution target and biological samples were obtained over 200 microm x 110 microm field of view, with 0.80 and 9.55 microm lateral and axial resolution, at 3.5-5.0 frames per second. With improvements to objective numerical aperture, our probe can enable precise evaluation of nuclear size, density, nucleus-to-cytoplasm ratio and cell density, which are important visual identifiers of epithelial precancers. PMID- 18449710 TI - Abstracts of the Second Annual International Conference on Urban Health. October 15-18, 2003. New York, New York, USA. PMID- 18449643 TI - Preparedness for the spread of influenza: prohibition of traffic, school closure, and vaccination of children in the commuter towns of Tokyo. AB - In Greater Tokyo, many people commute by train between the suburbs and downtown Tokyo for 1 to 2 h per day. The spread of influenza in the suburbs of Tokyo should be studied, including the role of commuters and the effect of government policies on the spread of disease. We analyzed the simulated spread of influenza in commuter towns along a suburban railroad, using the individual-based Monte Carlo method, and validated this analysis using surveillance data of the infection in the Tokyo suburbs. This simulation reflects the mechanism of the real spread of influenza in commuter towns. Three measures against the spread of influenza were analyzed: prohibition of traffic, school closure, and vaccination of school children. Prohibition of traffic was not effective after the introduction of influenza into the commuter towns, but, if implemented early, it was somewhat effective in delaying the epidemic. School closure delayed the epidemic and reduced the peak of the disease, but it was not as effective in decreasing the number of infected people. Vaccination of school children decreased the numbers not only of infected children but also of infected adults in the regional communities. PMID- 18449804 TI - Bone tumors in adolescents and young adults. AB - OPINION STATEMENT: Bone tumors, particularly osteosarcomas and members of the Ewing Sarcoma Family of Tumors (ESFT), are typical malignancies of adolescents and young adults. Current diagnostic and therapeutic guidelines for patients of all ages were developed in this specific age group. The aim of bone sarcoma therapy should be to cure the patient from both the primary tumor and all (micro )metastatic deposits while maintaining as much (extremity) function and causing as few treatment-specific late effects as possible. Bone sarcoma therapy requires close multidisciplinary cooperation. Usually, it consists of induction chemotherapy, followed by local therapy of the primary tumor (and, if present, primary metastases) and further, adjuvant chemotherapy. Local treatment for osteosarcoma should be surgery whenever feasible. Surgery is also gaining importance in ESFT, which was long considered a domain of radiotherapy. Modern reconstructive techniques continue to expand the indications for limb salvage, particularly for patients who have not yet reached skeletal maturity. Treatment within the framework of prospective, multi-institutional trials should be considered standard of care not only for children, but also for affected adolescents and (young) adults. Such trials are essential in guaranteeing that all patients have access to appropriate care and that progress from biological studies can be translated into prognostic improvements without undue delay. The rarity of bone sarcomas increasingly requires trials to be multinational. PMID- 18449805 TI - Who should be involved in health care decision making? A qualitative study. AB - Most countries appear to believe that their health system is in a state of semi crisis with expenditures rising rapidly, with the benefits of many services unknown and with pressure from the public to ensure access to a comprehensive range of services. But whose values should inform decision-making in the health area, and should the influence of different groups vary with the level of decision-making? These questions were put to 54 members of the public and health professionals in eight focus groups. Adopting a different perspective from other studies, participants were not asked if particular groups should be involved in decisions but rather through deliberation and discussion nominated their own potential decision makers. This delivered a clear message that participants saw a legitimate role for a broad range of stakeholders in priority-setting decisions so as to incorporate a diversity of expertise and opinion. Companion themes were the acknowledgment that decisions involve ethical judgments and are not purely technical, that the power of special interest groups (such as clinicians) should be kept in check, and that the process by which decisions are reached is important. The results suggest that qualitative methods of investigation have the potential to improve the legitimacy of policy decisions by contributing to a better understanding of the values of the public and health professionals, and by expanding the range of options available for further research. PMID- 18449806 TI - An ethical analysis of international health priority-setting. AB - Health care systems throughout the developed world face 'crises' of quality, financing and sustainability. These pressures have led governments to look for more efficient and equitable ways to allocate public resources. Prioritisation of health care services for public funding has been one of the strategies used by decision makers to reconcile growing health care demands with limited resources. Priority setting at the macro level has yet to demonstrate real successes. This paper describes international approaches to explicit prioritisation at the macro governmental level in the six experiences most published in the English literature; analyzes the ways in which values, principles and other normative concepts were presented in these international priority setting experiences; and identifies key elements of a more robust framework for ethical analysis which could promote meaningful and effective health priority setting. PMID- 18449807 TI - Leaping "out of the doubt"--nutrition advice: values at stake in communicating scientific uncertainty to the public. AB - This article deals with scientific advice to the public where the relevant science is subject to public attention and uncertainty of knowledge. It focuses on a tension in the management and presentation of scientific uncertainty between the uncertain nature of science and the expectation that scientific advisers will provide clear public guidance. In the first part of the paper the tension is illustrated by the presentation of results from a recent interview study with nutrition scientists in Denmark. According to the study, nutrition scientists feel their roles as ''public advisers'' and ''scientists'' differ in that the former involves an expectation that they will provide unambiguous advice of the kind that might relegate scientific uncertainty to the background. In the second, more general, part of the paper we provide a normative analysis of different strategies of dealing with the tension. The analysis is structured around the extremes of either total concealment or full openness regarding scientific uncertainty. The result of analysis is that scientific advisers should not simply ''feed'' scientific conclusions to the public. They should rather attempt to promote the ability and willingness of the public to assess and scrutinize scientific knowledge by displaying uncertainties in the scientific basis of advice. On the other hand, scientific advisers must accommodate the public's need for guidance. Such guidance should be restricted by careful consideration of what it is relevant for the public to know in order to evaluate scientific advice in practical terms. PMID- 18449808 TI - Placement of external ventricular drains and intracranial pressure monitors by neurointensivists. AB - INTRODUCTION: External ventricular drains (EVDs) and intracranial pressure (ICP) monitors are widely used in the Neurological Critical Care Unit (NCCU) to measure ICP and divert cerebrospinal fluid (CSF). EVDs and ICP monitors have historically been placed by neurosurgeons; however, with recent staffing of NCCUs by neurointensivists, a growing number of EVDs and ICP monitors are being placed by these specialists. RESULTS: Limited data are available concerning the safety or feasibility of such placements by neurointensivists. We present our experience with EVD and ICP monitor placement by a neurointensivist in the NCCU. A retrospective chart review of 29 patients with EVD placement and 7 patients with ICP monitors--all placed by a single neurointensivist--was conducted for patients admitted to the NCCU from August 2005 to January 2008. DISCUSSION: These findings were compared to published outcomes from neurosurgeon placements. All 29 patients with EVDs remained infection-free, with CSF pleocytosis occurring in one patient (3.4%). All 7 patients receiving ICP monitors remained free from infection. Complications after drain placement occurred in 20.7% (n = 6) of patients, with all six complications being EVD tract hematoma measuring less than 5 cm(3). CONCLUSION: Patients receiving ICP monitors had no complications. These complication rates are comparable to published rates, which suggest that placement of EVDs and ICP monitors by neurointensivists may be safe and effective. However, small sample size (n = 36) prohibits definitive safety and efficacy conclusions. For this reason, further research analyzing a larger patient sample is warranted. PMID- 18449809 TI - Cell death in brain development and degeneration: control of caspase expression may be key! PMID- 18449812 TI - Acute coronary syndrome revisited - markers, interventions and complications. PMID- 18449810 TI - Effect of a high-fat diet on 24-h pattern of circulating levels of prolactin, luteinizing hormone, testosterone, corticosterone, thyroid-stimulating hormone and glucose, and pineal melatonin content, in rats. AB - Circadian rhythmicity is affected in obese subjects. This article analyzes the effect of a high-fat diet (35% fat) on 24-h changes circulating prolactin, luteinizing hormone (LH), testosterone, corticosterone, thyroid-stimulating hormone (TSH) and glucose, and pineal melatonin content, in rats. When body weight of rats reached the values of morbid obesity, the animals were sacrificed at six different time intervals throughout a 24-h cycle, together with age matched controls fed a normal diet (4% fat). Plasma hormone levels were measured by specific radioimmunoassays and glucose concentration by an automated glucose oxidase method. In rats under a high-fat diet, a significant disruption of the 24 h pattern of plasma TSH, LH, and testosterone and a slight disruption of prolactin rhythm were found. Additionally, high-fat fed rats showed significantly lower total values of plasma TSH and testosterone and absence of correlation between testosterone and circulating LH levels. Plasma corticosterone levels increased significantly in high-fat fed rats and their 24-h variation became blunted. In obese animals, a significant hyperglycemia developed, individual plasma glucose values correlating with circulating corticosterone in high-fat fed rats only. The amplitude of the nocturnal pineal melatonin peak decreased significantly in high-fat fed rats. The results underlie the significant effects that obesity has on circadian organization of hormone secretion. PMID- 18449811 TI - Expression of VEGF and microvessel density in patients with multiple myeloma: clinical and prognostic significance. AB - The conflicting data are reported on the clinical significance of VEGF deregulation and intensity of angiogenesis in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of VEGF expression and microvessel density (MVD) in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of VEGF and MVD was analyzed using standard immunohistochemical method (antibodies against VEGF and CD34, respectively) on B5-fixed and routinely processed paraffin-embedded bone marrow specimens. MVD was estimated by counting the number of microvessels in three "hot spots" at 400x magnification. VEGF immunoreactivity was estimated on the basis of intensity and percentage of positive plasma cells. VEGF was expressed in 47/59 (79.7%) specimens. There was no significant correlation between VEGF overexpression and age, clinical stage, the extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, and albumins, the extent of bone marrow infiltration, histological grade, and proliferative activity index (measured with Ki-67 immunoreactivity). No significant difference was observed regarding the overall survival between VEGF positive and VEGF-negative patients (29 vs. 34 months, P = 0.8). Median MVD was 15, ranging from 1 to 89 microvessels per three "hot spots". There was significant correlation between MVD and histological grade, the extent of bone marrow infiltration, and proliferative activity. Significant difference was observed regarding the overall survival between patients with low MVD (<15) and patients with high MVD (> or = 15) (46 vs. 22 months, P = 0.009; univariate analysis). The results of this study did not reveal clinical significance of VEGF overexpression in multiple myeloma. On the contrary, the extent of bone marrow angiogenesis is an indicator of biological potency of malignant clone and a predictor of poor survival in newly diagnosed myeloma. PMID- 18449813 TI - Management of 'no-reflow' complicating reperfusion therapy. AB - No-reflow phenomenon, defined as inadequate myocardial perfusion of the adequately dilated target vessel without evidence of angiographic mechanical obstruction. It is a multifactorial, well-recognised, secondary phenomenon following reperfusion therapy such as thrombolysis or percutaneous coronary interventions (PCI). The pathophysiological mechanisms leading to the no-reflow state are incompletely understood. Embolization of the atheromatous material to the distal vasculature and intense arteriole vasospasm caused by microembolization of platelet-rich thrombi that release vasoactive agents resulting in microvascular obstructions are likely mechanisms. Current prophylaxis and management strategies are derived from limited clinical data. Intracoronary verapamil, adenosine and nitroprusside have been most frequently studied and administered for angiographic no-reflow during PCI for acute myocardial infarction or saphenous vein graft (SVG) lesions and have been shown to improve epicardial flow and microvascular perfusion. The use of distal embolic protection devices in SVG interventions also provide microvascular protection and improve clinical outcomes. However, by far the most important measures are prevention and anticipation during PCI as once no-reflow established, complete reversal of the situation may not be possible. PMID- 18449814 TI - Catheter induced aortocoronary dissection. AB - Catheter induced coronary dissection is an uncommon and possibly an underreported complication. We report patient with dissection of left main coronary artery, extending into the ascending aorta following diagnostic angiography and discuss the possible mechanisms. PMID- 18449815 TI - Antiplatelet effects of licking an aspirin tablet can be detected by thrombelastography. AB - Aspirin is a cornerstone of treatment in cardiovascular disease. However, individual responses vary and hyporesponsiveness has been associated with poor outcomes following percutaneous intervention. Point of care assays for detecting the effects of aspirin in individual patients would therefore be useful. Thrombelastography has been shown to correlate with optical aggregation in the assessment of antiplatelet therapies and is suitable for use as a point of care assay. We demonstrate the ability of thrombelastography to detect the profound effects of even the tiny doses of aspirin obtained by licking an aspirin tablet. PMID- 18449816 TI - HIV/AIDS: a long-term research agenda for social sciences. PMID- 18449817 TI - Sexual prevention of HIV within the couple after prenatal HIV-testing in West Africa. AB - The resumption of sexual activity after delivery is a key moment in the management of the risk of sexual HIV transmission within the couple for women who have been prenatally tested for HIV. In this study, we have investigated consistent condom use during the resumption of sexual activity and its evolution over time among women tested for HIV infection during pregnancy. We tested for HIV during pregnancy 546 HIV-infected and 393 HIV-negative women within the Ditrame Plus ANRS project in Abidjan; these women were followed-up for two years after delivery. Most HIV-negative women (96.7%) disclosed their HIV-test result to their partners, whereas only 45.6% of HIV-infected women did so (p<0.001). Partners of HIV-infected women were more likely to be tested for HIV before resuming sexual activity than partners of HIV-negative women (11.7% vs. 7.4%, p=0.054). Less than one third of both HIV-infected and HIV-negative women reported having systematically used condoms during the resumption of sexual activity. The proportions of HIV-infected and HIV-negative women having consistently used condoms were respectively 26.2% and 19.8% (p=0.193) at 3 months post-partum, 12.1% and 15.9% (p=0.139) at 12 months post-partum, and 8.4% and 10.6% (p=0.302) at 18 months post-partum. In our study, although women had been prenatally tested for HIV and properly counselled on the sexual risk of HIV transmission, male partners were not tested for HIV before the resumption of sexual activity after delivery, very few couples were using condoms systematically and condom use was decreasing over time. PMID- 18449818 TI - Ageing with HIV: newly diagnosed older adults in Italy. AB - The prevalence of HIV/AIDS among people in midlife and late adulthood has been increasing in Western countries over the last decade. We analyzed data from a prospective, observational multi-centre study on individuals newly diagnosed with HIV between January 2004 and March 2007 in 10 public counselling and testing sites in Latium, Italy. At diagnosis, routine demographic, epidemiological, clinical and laboratory data are recorded, and patients are asked to complete a questionnaire investigating socio-demographic and psycho-behavioural aspects. To analyze the association of individual characteristics with age, we compared older adults (> or = 50 years) with their younger counterpart (18-49 years). To adjust for potential confounding effect of the epidemiological, clinical and behavioural characteristics, to identify factors associated with older age at HIV diagnosis, multivariate logistic regression analysis was performed. Overall, 1073 individuals were identified, 125 of whom (11.6%) were aged 50 years or above. The questionnaire was completed by 41% (440/1073). Compared with their younger counterparts, a higher proportion of older patients were males, born in Italy, reported heterosexual or unknown HIV risk exposure, were never tested for HIV before and were in a more advanced stage of HIV infection at diagnosis. In addition, older adults had a lower educational level and were more frequently living with their partners or children. With respect to psycho-behavioural characteristics, older patients were more likely to have paid money for sex and have never used recreational drugs. Interestingly, no differences were found regarding condom use, which was poor in both age groups. These findings may have important implications for the management of older adults with HIV, who should be targeted by appropriate public health actions, such as opportunistic screening and easier access to healthcare. Moreover, strategies including information on HIV and prevention of risk behaviours are needed. PMID- 18449819 TI - Sexual risk reduction needs of adolescents living with HIV in a clinical care setting. AB - As anti-retroviral therapy becomes increasingly available, young people living with HIV need tailored support to adopt healthy sexual behaviors. There has been a gap in the availability of culturally appropriate techniques for secondary prevention and sexual risk reduction in this target group. This formative study assessed sexual and reproductive health needs and problems, as well as determinants of sexual risk-taking among young people living with HIV aged 11-21 years attending the Paediatric Infectious Disease Clinic in Kampala, Uganda. Theoretical guidance was provided by the Information-Motivation-Behavioral Skills Model. Socio-demographic and selected psychosexual data were assessed using a brief anonymous questionnaire. A total of 75 young people living with HIV participated in eight focus group discussions. In addition, one focus group was conducted with adult key informants (service providers). About a quarter of the young participants reported prior or current sexual experience. The study revealed knowledge gaps relating to reproductive health, HIV transmission, and contraceptive methods. Motivations for protection included hope for the future, good counseling, and fear of the consequences of sexual activity such as unwanted pregnancies. Barriers to adopting preventive behaviors included peer pressure, poverty, HIV-related stigma, ignorance of their partners, alcohol use, and a desire to have children for the older ones. Young sero-positive people in this setting lacked specific behavioral skills, such as disclosure of HIV status to their sexual partners, this being closely linked to fear of rejection and stigma. HIV-positive youths need support in developing the appropriate behavioral skills to adopt healthy sexual behaviors. Interventions in this field need to be developmentally appropriate and tailored to young people's specific needs. Structural interventions should at the same time address and reduce HIV-related stigma and socio-economic needs of young people living with HIV. PMID- 18449820 TI - Gender attitudes, sexual power, HIV risk: a model for understanding HIV risk behavior of South African men. AB - The Gender Attitudes-Power-Risk (GAPR) model of HIV risk behavior was tested using survey data collected from among 309 men who were attending STI services in a primary health care clinic in Cape Town, South Africa. Results showed that negative attitudes towards women were significantly positively associated with a high level of HIV risk behavior, and that endorsement of traditional male roles was negatively associated with HIV risk behavior. Endorsement of traditional male gender roles was also inversely related to relationship control but positively to a high degree of decision-making dominance in one's relationship. Sexual relationship power did not significantly mediate the relationships between gender attitudes and HIV risk behavior. A better understanding of gender roles and ideologies in combination with one's power in sexual relationships as they relate to HIV risk behavior among men could better inform future HIV prevention interventions. PMID- 18449822 TI - The societal burden of HIV/AIDS in Northern Italy: an analysis of costs and quality of life. AB - This study aims to measure the direct and indirect costs of HIV/AIDS care and quality of life (QoL) of HIV-infected patients in Northern Italy. We conducted a prospective cohort study over 12 months, enrolling a sample of 121 patients with HIV infection from two cities in Northern Italy. Patients were surveyed at baseline and were followed-up at 6 and 12 months. To assess the relationship between costs and stage of disease, patients were categorized into three groups at baseline: "No HAART" (asymptomatic and never before on highly active antiretroviral therapy (HAART)), "Stable HAART" (HAART with mild HIV infection and no prior opportunistic infections) and "HAART failure" (primary HAART regimen was altered because of severe side effects or immunological failure). Direct medical costs were based on utilization of (day) hospital admissions, diagnostic procedures, laboratory tests, clinic visits, consultations and antiretroviral drug use. Indirect costs included production losses due to absence from work, reduced productivity at work and reduced unpaid labour participation. QoL was assessed by visual analogue scale. Parametric regression was used to estimate the expected value and the standard deviation of annual costs per patient. The expected value of total annual costs was 1818 euros and 9820 euros and 12,332 euros, for groups "No HAART", "Stable HAART" and "HAART failure" respectively. We estimated annual expected earnings as 14,994 euros and 10,811 euros and 9820 euros for the same respective groups. The expected value of QoL on a scale of 0-1 in these same patient groups was 0.80, 0.78 and 0.64. We conclude that indirect costs contribute substantially to total costs and are comparable in magnitude to the direct costs excluding antiretroviral drugs. The costs of inpatient care in our cohort were almost negligible compared to total costs. Despite being in treatment, many patients were still gainfully employed and generated substantial expected annual earnings. PMID- 18449821 TI - Adherence to antiretroviral treatment in patients with HIV in the UK: a study of complexity. AB - Adherence to HIV treatment regimes is a core element to viral suppression. Yet measurement of adherence is complex. Although adherence levels are good predictors of outcome, they do not always provide full explanations of observed variations in responses. This study was set up to examine the complexity of adherence measurement and to examine rates of adherence in the presence of complex measurement. A total of 502 consecutive attenders at HIV clinics in the UK (80.5% response rate) provided detailed measurement on adherence in the preceding 7 days, setting out dose adherence, as well as measures of timing and dietary conditions. In addition, a range of psychological, demographic and relationship data were gathered to understand predictors of full and partial adherence. Although 79.1% reported dose adherence in the previous 7 days, 42.8% had not taken the dose at the correct time, and 27.2% had not taken the dose under the correct circumstances. Using a more complex composite measure of full adherence, rates reduced from 79.1% to 41.5%. Comparisons of those deemed fully adherent, partially adherent and non-adherent were carried out. Those that were fully adherent were significantly more likely to be older (F=7.8, p<0.001), UK born (F=6.8, p=0.03), code ethnicity as white (F=5.3, p=0.07), record higher quality of life (chi(2)=8.7, p=0.01), lower psychological symptoms (chi(2)=15.2, p=0.001) and lower global distress symptoms (chi(2)=6.9, p=0.03). There were no differences according to education, behavioural and attitudinal variables (disclosure, stable relationship, STI diagnosed, number of sexual partners, unprotected sex, optimism or treatment switching). Fully adherent groups were significantly more likely to be in agreement with their doctor on treatment initiation (chi(2)=6.2, p=0.045), satisfied with the amount of involvement in the decision-making process (chi(2)=7.3, p=.026), their wishes were considered (chi(2)=12.5, p=0.002) and had monitoring of their condition (chi(2)=7.1, p=0.028). Multivariate analysis showed that variables which contributed significantly at a 5% criterion level to complex adherence were physical symptoms (OR=0.56, p=0.05), psychological symptoms (OR=2.37, p<0.001), age (OR=0.96, p=0.02), education (OR=0.54, p=0.03), having more than one sexual partner (OR=0.46, p=0.03), having risky sex (OR=4.30, p=0.002) and being optimistic about treatments (OR=0.42, p=0.01). The softer markers of adherence are not usually measured in follow up and may account for variations in treatment responses. The complexity of adherence needs to be understood and addressed to maximise treatment efficacy. PMID- 18449823 TI - HIV interventions affect behavior indirectly: results from the AIDS Community Demonstration Projects. AB - Behavioral theory informs HIV prevention programs by identifying important predictors of the relevant behavior. Changes in those predictors brought about by program messages should theoretically translate into behavior change. Program evaluation, however, may examine only whether message exposure is associated with behavior change, assuming that if people changed their behavior, the intervention must have effectively changed the determinants. This practice obscures how intervention programs work in the field. We use data from the AIDS Community Demonstration Projects (ACDP) to illustrate this important idea. Earlier research found that the ACDP moved at-risk communities to more consistent condom use with both main and non-main partners. This study demonstrates that these behavioral effects are explained by the ACDP's ability to improve intention and self efficacy for condom use with both main and non-main partners. We conclude that to understand how HIV prevention programs work, program evaluations need to assess how the intervention affected what it was designed to change: one or more critical behavioral determinants. PMID- 18449824 TI - Attitudes toward needle-sharing and HIV transmission risk behavior among HIV+ injection drug users in clinical care. AB - Risky behavior related to injection drug use accounts for a considerable proportion of incident HIV infection in the United States. Large numbers of injection drug users (IDUs) currently receive antiretroviral therapy in clinical settings and are accessible for risk-reduction interventions to reduce transmission of drug-resistant HIV and spread of HIV to uninfected others. The current study examined attitudes toward needle- or equipment-sharing among 123 HIV-positive IDUs in clinical care in an effort to understand the dynamics of such behavior and to create a basis for clinic-based risk-reduction interventions. Results indicate that at baseline, participants who reported extremely negative attitudes toward needle-sharing were less likely to have shared during the past month than those with less-extreme negative attitudes. Demographic, behavioral, and attitudinal variables were entered into a logistic regression model to examine needle-sharing group membership among HIV-positive IDUs. Being female and having less-extreme negative attitudes toward sharing were independent and significant correlates of sharing behavior. Interventions targeting needle-sharing attitudes deployed within the clinical care setting may be well-positioned to reduce HIV transmission among HIV-positive IDUs. PMID- 18449826 TI - Frequent and systematic unprotected anal intercourse among men using the Internet to meet other men for sexual purposes in France: results from the "Gay Net Barometer 2006" survey. AB - For men who have sex with men (MSM), the Internet has imposed itself in the past decade as the place to be to meet other men with similar interests for sex or just to surf in search of excitement. This is a biennial study on the MSM in France. Between December 2005 and February 2006, 15,085 MSM completed an online questionnaire on their social and sexual uses of the Internet. Participants in the "The Gay Net Barometer 2006" study responded to questions related to their sexual and sexual risk behaviours. One third of respondents reported at least one event of unprotected anal intercourse while 11.1% reported frequent or systematic unprotected anal intercourse. These sexual risk behaviours were associated with various sociodemographic and sexual variables in addition to the recruitment website. The study suggests Internet users are not a homogeneous group and intervention targeting of them should be based on an in-depth understanding of the sexual cultures operating within websites. PMID- 18449825 TI - Potential markers of female condom use among inner city African-American women. AB - Despite the availability of the female condoms and theoretically based interventions to promote its use, studies have indicated a low level of acceptability of their use among women in most populations. We aimed to determine female condom use prevalence and the potential markers among African-American women. In an intervention trial to test the efficacy of the Information Motivation-Behavioral Skills model in increasing condom use, we utilized the baseline data of 280 subjects and examined the potential predictors of female condom use. Chi square statistic and unconditional logistic regression were used to test for group independence among users and non-users of the female condom and to assess the potential markers of female condom use respectively. After adjustment for relevant covariates associated independently with female condom use, the significant potential markers for female condom use were age, multiple sexual relationships, knowledge of female condom, and educational status. Women having multiple sexual relationships compared with a monogamous relationship were five times more likely to use the female condom, while women with high school education were three times more likely to use the female condom; prevalence odds ratio, POR=5.32, 95% CI=1.79-15.83 and POR=3.01, 95% CI=1.01-8.93. Women who were not knowledgeable of the female condom, compared to those who were, were 81% less likely to use the female condom, POR=0.19, 95% CI=0.08-0.45. Among African American women in this sample, knowledge of female condom use, age, educational status, and multiple sexual relationships were significant markers of female condom use. This study is therefore suggestive of the need to educate African American women on female condom use, given the obstacles in male condom negotiation, especially among the socio-economically challenged. PMID- 18449827 TI - The face of HIV and AIDS: can we erase the stigma? AB - Facial lipoatrophy can be obvious and stigmatising. Poly-L-lactic acid (PLLA) has been used widely for the correction of HIV-associated facial lipoatrophy. Analysis of the PLLA treatment protocols of 441 consecutive patients was undertaken. Product dilution, product volume per session, number of sessions, time between sessions, facial areas treated, plane of injection and incidence of injection-site nodules were recorded. Assessments included the Hospital Anxiety and Depression Scale and the Appearance Satisfaction Questionnaire. During the learning curve 30 patients were treated every 2 weeks for a minimum of three sessions. A 3-ml dilution was used and a total of 5 ml was injected in the deep dermis of the buccal areas. The incidence of nodule formation was 31% and 52% of patients did not achieve resolution of their facial disfigurement. A total of 411 patients were treated every 4 weeks for a minimum of four sessions. A minimum 5 ml dilution was used and a minimum total of 10-ml was injected subcutaneously in the temporal, infraorbital and buccal areas. The incidence of nodule formation was 2.9% and 10% of patients did not achieve resolution of their facial disfigurement. Patient anxiety and depression scores and appearance satisfaction scores improved significantly with treatment. PMID- 18449828 TI - Cofactor infections and HIV epidemics in developing countries: implications for treatment. AB - This article shows that the burden of certain tropical disease infections, after controlling for other factors, is positively correlated with HIV prevalence. Using cross-national data and multivariate linear regression analysis, we investigate the determinants of HIV prevalence in low- and middle-income countries. We begin with social and economic variables used in other cross national studies and then incorporate data on parasitic and infectious diseases endemic in poor populations, which are found to be strongly and significantly correlated with--and are potent predictors of--HIV prevalence. The paper concludes by arguing that treating tropical diseases may be a cost-effective add on to HIV-prevention and -treatment programs, thus slowing the spread of HIV in disease-burdened populations. PMID- 18449829 TI - The usefulness of the Multidimensional Health Locus of Control Form C (MHLC-C) for HIV+ subjects: an Italian study. AB - In the last few years, highly active antiretroviral therapy (HAART) has resulted in a remarkable decrease in HIV-related morbidity and mortality. This "new deal" encouraged clinical research in investigating patients' manifest behaviours and their beliefs regarding their health status, which likely influence not only their treatment-linked behaviours but also their quality of life. Locus of control has been shown to be a construct that can predict and explain health related behaviours. The Multidimensional Health Locus of Control Form C (MHLC-C) is a condition-specific locus of control scale that can be easily adapted for use with any medical or health-related condition. With the aim to enhance the knowledge about the HIV+ patients' point of view of their complex health condition, this study preliminarily investigated the psychometrics properties of the MHLC-C Italian version and its generalizability across samples defined both by being adherent or not and by gender. Two more samples of chronic patients (Cardiac Surgery and Cancer) were enrolled to better characterize the HIV+ patient's MHLC-C profile. The results showed the validity, reliability and generalizability of the 4-factor structure of MHLC-C. More interestingly, HIV+ subjects revealed a peculiar pattern of beliefs regarding their health condition that clinicians should take into account when managing patients' complex bio psychosocial condition. PMID- 18449830 TI - Sero-silence and sero-sharing: managing HIV in serodiscordant heterosexual relationships. AB - Research shows that couples with differing HIV status can face a number of social, sexual and relationship challenges. Communication is often emphasised as the key to couples' ability to cope with these challenges. Silence by implication becomes positioned as inherently negative, even dysfunctional. The privileging of communication as proper therapeutic adjustment to illness forecloses consideration of the complexities of managing HIV as a serodiscordant couple, let alone any enabling aspects of silence. Drawing on qualitative research interviews with HIV-serodiscordant couples in Australia, this article examines the usefulness of this polarisation between communication and silence and explores alternative ways of understanding silence that might offer useful tools for HIV health workers and researchers. PMID- 18449832 TI - Informal social support networks and the maintenance of voluntary driving cessation by older rural women. AB - Seventy-five rural women over the age of 77 participated in this study to describe the impact of informal social support on the maintenance of voluntary driving cessation. After being screened for mental status, they completed a demographic questionnaire and the Lubben Social Network Scale (2006). They also participated in a semistructured interview designed to probe factors leading to driving cessation and the ability to maintain it. Findings suggest that most participants stopped driving due to a decline in physical function and/or involvement in a nonfatal accident. Adequate support from family and friends was critical to the maintenance of driving cessation. Those with a limited informal social network resumed driving due to the lack of transportation, feelings of insecurity and fear for their survival, and the desire to assist friends who were less fortunate. Implications for community health nurses working in rural areas are discussed. PMID- 18449833 TI - Printed health information materials: evaluation of readability and suitability. AB - This study examined readability and suitability of printed health information materials colleted from multiple sources. In phase I, nursing students used Simple Measure of Gobbledygook (SMOG; McLaughlin, 1969) to assess the readability of 21 materials collected from the community. In phases II and III, nursing students and registered nurses used SMOG and the Suitability Assessment of Materials (SAM; Doak, Doak, & Root, 1996) to evaluate 15 prenatal materials from a Healthy Start program. SMOG assigns a reading grade level based on the number of words with 3 or more syllables. SAM has 22 items in 6 evaluation areas: content, literacy demand, graphics, layout and typography, learning stimulation and motivation, and cultural appropriateness. Major findings included that 53% to 86% of the printed materials had a reading level at or higher than 9th grade; materials lacked summary, interaction, and modeled behaviors, and registered nurses rated more materials as not suitable and fewer as superior for suitability qualities than students. Improving printed materials to have lower reading levels and better suitability qualities are indicated. PMID- 18449834 TI - From homeless to housed: caring for people in transition. AB - This ethnographic study was conducted to determine what homeless people experience during the transition from street life into community housing. Data were gathered through participant observation at a program designed to secure housing and support services for homeless people upon discharge from a psychiatric hospital. Sixty homeless, mentally ill adults were followed from hospital discharge through their first 2 years in community housing. Homeless people interact with health care providers across a cultural divide produced by vast differences in their lived experiences. This cultural distance limits access to the services that these individuals require to achieve residential stability. PMID- 18449835 TI - Factors related to smoking in college women. AB - Cigarette smoking among American women attending college has increased dramatically since the 1980's. To develop effective smoking prevention and cessation programs, a better understanding of factors associated with smoking in college women is needed. Therefore, the purpose of this study was to examine if selected factors (stress, stress management, nutrition, physical activity, alcohol consumption, and race) were related to smoking in college women. A sample of 354 college women in a southeastern state, 18-22 years of age, participated in the study. Logistic regression analysis indicated that White race (p = < .001), alcohol consumption (p = .0013), and limited physical activity (p = .0078) were significantly associated with smoking. Physically active college women were 2 times less likely to be smokers. However, physical activity mediated the effect of stress and stress management on smoking. Additionally, stress management confounded the effect of stress on smoking. Therefore, in addition to alcohol avoidance, exercise (as a stress management strategy) may be an important component of primary prevention and smoking cessation programs for college women. PMID- 18449838 TI - Dual-task performance in late proficient bilinguals. AB - A dual task, consisting of speeded tapping during concurrent silent and aloud reading, was employed to investigate hemispheric specialisation for both first (L1) and second (L2) language in late proficient bilinguals living in the L2 environment. Overall, bilinguals and matched monolinguals showed more right- than left-hand interference during concurrent tasks, indicating left lateralised speech, and more interference while reading aloud than while reading silently. Importantly, however, bilinguals showed more left-hand interference compared to monolinguals during both L1 and L2, suggesting that the right hemisphere may participate to a greater extent during language tasks in bilinguals relative to monolinguals. The data indicate more bilateral hemispheric involvement for both L2 and L1 in late proficient bilinguals living in the L2 environment. PMID- 18449839 TI - Sex and hemisphere differences when mentally rotating meaningful and meaningless stimuli. AB - The purpose of the current study was to investigate the influence of stimulus type and sex on strategy use and hemispheric processing during the mental rotation task. Participants included 67 right-handed men and women who completed three mental rotation tasks, all presented bilaterally. Participants rotated human stick figures, alphanumeric stimuli, and a two-dimensional (2D) meaningless object. No hemispheric differences were observed when rotating human stick figures, suggesting that men and women may rely on the same strategy. A left hemisphere advantage was observed in women when rotating alphanumeric stimuli, suggesting they may be relying on a verbal strategy, whereas no hemispheric differences were observed for men. Finally, inconsistent with predictions, no hemisphere differences were observed when rotating two-dimensional objects. The findings from the current study suggest that both the meaningfulness and the type of stimulus presented may influence strategy use differently for men and women. PMID- 18449840 TI - Is left-handedness associated with a more pronounced age-related cognitive decline? AB - The effect of handedness on cognitive functioning has been the subject of much controversy. The influential "pathological left-handedness theory" posited by Coren and Halpern (1991) claims that left-handedness is probabilistically related to deviations from the neurological and cognitive norm. Many studies have failed to find negative effects of left-handedness on cognitive functioning, but most of these studies related handedness to cognition at one moment in time. Such studies do not exclude the possibility that sinistrality may be related to a more pronounced age-related longitudinal decline in cognitive functions. This hypothesis was tested in the present study. In a longitudinal study involving a large population sample of cognitively intact people aged at least 50 years at baseline, we evaluated the effect of handedness on age-related decline in four major cognitive domains: speed of information processing, verbal learning, long term verbal memory, and executive functioning. The results failed to provide support for the hypothesis that sinistrality is associated with a more pronounced age-related cognitive decline. Recommendations for future studies are provided. PMID- 18449841 TI - Linear versus non-linear measures of temporal variability in finger tapping and their relation to performance on open- versus closed-loop motor tasks: comparing standard deviations to Lyapunov exponents. AB - The nature of temporal variability during speeded finger tapping was examined using linear (standard deviation) and non-linear (Lyapunov exponent) measures. Experiment 1 found that right hand tapping was characterised by lower amounts of both linear and non-linear measures of variability than left hand tapping, and that linear and non-linear measures of variability were often negatively correlated with one another. Experiment 2 found that increased non-linear variability was associated with relatively enhanced performance on a closed-loop motor task (mirror tracing) and relatively impaired performance on an open-loop motor task (pointing in a dark room), especially for left hand performance. The potential uses and significance of measures of non-linear variability are discussed. PMID- 18449847 TI - Genome-based approaches to the authentication of medicinal plants. AB - Medicinal plants are the source of a large number of essential drugs in Western medicine and are the basis of herbal medicine, which is not only the primary source of health care for most of the world's population living in developing countries but also enjoys growing popularity in developed countries. The increased demand for botanical products is met by an expanding industry and accompanied by calls for assurance of quality, efficacy and safety. Plants used as drugs, dietary supplements and herbal medicines are identified at the species level. Unequivocal identification is a critical step at the beginning of an extensive process of quality assurance and is of importance for the characterization of the genetic diversity, phylogeny and phylogeography as well as the protection of endangered species. DNA-based methods have been developed for the identification of medicinal plants. Nuclear and chloroplast DNA is amplified by the polymerase chain reaction and the reaction products are analyzed by gel electrophoresis, sequencing, or hybridization with species-specific probes. Genomic fingerprinting can differentiate between individuals, species and populations and is useful for the detection of the homogeneity of the samples and presence of adulterants. Although sequences from single chloroplast or nuclear genes have been useful for differentiation of species, phylogenetic studies often require consideration of DNA sequence data from more than one gene or genomic region. Phytochemical and genetic data are correlated but only the latter normally allow for differentiation at the species level. The generation of molecular "barcodes" of medicinal plants will be worth the concerted effort of the medicinal plant research community and contribute to the ongoing effort of defining barcodes for every species on earth. PMID- 18449842 TI - Effects of early adverse experiences on behavioural lateralisation in rhesus monkeys (Macaca mulatta). AB - In the past 15 to 20 years, evidence of population-level handedness in non-human primates has emerged from a plethora of studies, although considerable inconsistency is also apparent. The study reported here examined two factors that may contribute to the expression of hand preference: early rearing history and sex differences. Handedness was assessed in rhesus monkeys (Macaca mulatta) using a task that measures coordinated bimanual actions and is referred to as the TUBE task. Nursery-reared monkeys demonstrated greater left-hand bias in the TUBE task when compared to their mother-reared counterparts. Females showed greater right hand preference and stronger bias on the TUBE task compared to males. These results provide evidence that early rearing experiences significantly influence the development of lateralisation in nonhuman primates. PMID- 18449848 TI - A detailed view on the constituents of EPs 7630. AB - Extracts of PELARGONIUM SIDOIDES, commonly known as EPs 7630, are produced by extraction of milled roots with 11 % (w/w) ethanol in water. This solvent leads to a spectrum of constituents which differs significantly from extracts obtained by extraction with non-polar solvents. EPs 7630 is composed of six main groups of constituents, namely unsubstituted and substituted oligomeric prodelphinidins, monomeric and oligomeric carbohydrates, minerals, peptides, purine derivatives and highly substituted benzopyranones. The oligoprodelphinidins, frequently supposed to be compounds with unspecific tanning interactions, show, in contrast to other polyphenols, an amazing variety of substructures and connectivities which results in an uncommon diversity even at a low degree of polymerization. Three distinct purine derivatives, second messengers and probably intermediates of DNA synthesis, were identified and characterized by phytochemical means. The main benzopyranones of EPs 7630 are highly oxygenated at the phenyl moiety (three to four oxygens) and in addition sulfated at distinct positions. A disulfate of 6,7,8-trihydoxybenzopyranone has been identified for the first time in plants. Taken together, these constituents amount to about 70 to 80 % of the total weight of EPs 7630, the active ingredient of the phytopharmaceutical Umckaloabo (Iso Arzneimittel Ettlingen). PMID- 18449849 TI - EPs 7630 improves acute bronchitic symptoms and shortens time to remission. Results of a randomised, double-blind, placebo-controlled, multicentre trial. AB - Acute bronchitis commonly associated with cough is predominantly caused by viral infections. The burden on health-care systems and society is enormous. A randomised, placebo-controlled, multicentre clinical trial to investigate the efficacy and safety of a liquid herbal drug preparation from the roots of Pelargonium sidoides (EPs 7630) was conducted in 217 adult outpatients with acute bronchitis. The primary efficacy variable was the bronchitis symptom score (BSS) ranging from 0 to 20. Primary data of this study were already published in 2007. Now, we present further analyses of these already published data combined with new results in order to focus on both the most important features of acute bronchitis and pharmaco-economic aspects of the disease. The BSS decreased by 7.6 +/- 2.2 (mean +/- SD) points for the active treatment group and 5.3 +/- 3.2 points for placebo (p < 0.0001). As compared with placebo, a marked improvement has been shown for EPs 7630 for all disease symptoms (cough, sputum, rales, dyspnoe, pain on coughing, hoarseness, headache, fatigue, fever, limb pain) categorised in severity classes by the patient. Especially strong antitussive and "anti-fatigue" effects with an early onset during treatment were observed. Patients in the EPs 7630 group were sooner able to work and to a lesser extent confined to bed. In both treatment groups, 3 x 30 drops of the trial medication administered for 7 days were well tolerated. No serious adverse events have been observed. In conclusion, EPs 7630 is superior to placebo in the treatment of acute bronchitis and leads to faster remission of bronchitis related symptoms. PMID- 18449850 TI - Polydrug use, cannabis, and psychosis-like symptoms. AB - OBJECTIVE: To examine psychosis-like symptoms in users of legal and illicit drugs. METHODS: Schizotypal Personality Questionnaire (SPQ) scores were compared in groups of people with different exposure to cannabis, with the use of other drugs serving as a covariate. Supplemental analyses compared users of legal and illicit drugs with cannabis use as a covariate. RESULTS: Weekly (n = 111) and monthly (n = 136) cannabis users had higher scores on the SPQ than former (n = 143) and non-users (n = 81). The use of other drugs accounted for the links between cannabis and schizotypy. Lifetime use of psychomotor stimulant drugs plus ecstasy accounted for associations between cannabis and scores on the SPQ and its different subscales. Dividing groups by type of drug use revealed that those who used only cannabis and legal drugs (CLDs) (n = 126) were no different from those who used only legal drugs (LDs) (n = 74) but both groups scored significantly lower on the SPQ than polydrug users (n = 247). When controlling for marijuana use in the last month, the significant difference across drug use groups remained. CONCLUSIONS: The results suggest that research on marijuana and schizotypy requires careful assessment of the use of other drugs, especially psychomotor stimulants and ecstasy. PMID- 18449851 TI - Formation of [b3 - 1 + cat]+ ions from metal-cationized tetrapeptides containing beta-alanine, gamma-aminobutyric acid or epsilon-aminocaproic acid residues. AB - The presence and position of a single beta-alanine (betaA), gamma-aminobutyric acid (gammaABu) or epsilon-aminocaproic acid (Cap) residue has been shown to have a significant influence on the formation of b(n)+ and y(n)+ product ions from a series of model, protonated peptides. In this study, we examined the effect of the same residues on the formation of analogous [b3 - 1 + cat]+ products from metal (Li+, Na+ and Ag+)-cationized peptides. The larger amino acids suppress formation of b3+ from protonated peptides with general sequence AAXG (where X = beta-alanine, gamma-aminobutyric acid or epsilon-aminocaproic acid), presumably because of the prohibitive effect of larger cyclic intermediates in the 'oxazolone' pathway. However, abundant [b3 - 1 + cat]+ products are generated from metal-cationized versions of AAXG. Using a group of deuterium-labeled and exchanged peptides, we found that formation of [b3 - 1 + cat]+ involves transfer of either amide or alpha-carbon position H atoms, and the tendency to transfer the atom from the alpha-carbon position increases with the size of the amino acid in position X. To account for the transfer of the H atom, a mechanism involving formation of a ketene product as [b3 - 1 + cat]+ is proposed. PMID- 18449852 TI - Effects of metabolic inhibitors on activity of Cry1Ab toxin to inhibit growth of Ephestia kuehniella larvae. AB - BACKGROUND: Although the toxins of Bacillus thuringiensis Berliner (Bt) are frequently used to control lepidopteran pests, the tolerance or resistance of some lepidopteran moth strains may limit Bt applications. In this study, insecticidal cocktails consisting of sublethal doses of Cry1Ab toxin and additive compounds were tested for their suppressive effect on larval relative growth rate (RGR) in Ephestia kuehniella Zeller under laboratory conditions. RESULTS: In the first step, the suppressive effect of diflubenzuron, soybean trypsin inhibitor (STI) and chitinase on RGR was confirmed. In the second step, these compounds were incorporated into a mixture of crushed kernels of Bt maize hybrid MON 810 YieldGard and its isoline with concentrations of Cry1Ab toxin ranging from 0.011 to 0.091 microg g(-1) diet. An additive effect on the suppression of larval RGR in E. kuehniella was found in a combination of diflubenzuron, STI and STI + chitinase as secondary compounds in insecticidal cocktails. Chitinase showed no additive effect on RGR. CONCLUSION: The highest suppression level was found in cocktails with STI + chitinase as a secondary compound. It is hypothesized that the protease inhibitor (STI) protects both chitinase and Cry1Ab proteins from endogenous proteases in the larval midgut and prolongs their insecticidal activities. The possible application of insecticidal cocktails in the control of E. kuehniella is discussed. PMID- 18449853 TI - High-resolution NMR spectra of n-alkanes penetrating into carbon fibers and of protons in carbon fibers. AB - We present a simple NMR method for microscopically exploring the local environment in carbon fibers. The method utilizes n-alkanes as probe molecules, where the n-alkanes penetrate carbon fibers of interest. The high-resolution (1)H NMR spectra for a mixture of a carbon fiber and n-alkanes acquired by this method show a shift of the resonance line, which is due to the local structure of the fiber. The utility of this method is discussed on the basis of the (1)H NMR spectra obtained. In addition, the (1)H distribution and the local motion in the structure of the carbon fiber are revealed in view of the (1)H NMR spectra. PMID- 18449854 TI - 1H and 13C NMR assignments of two new diaryl ethers phomopsides A and B from the mangrove endophytic fungus (ZZF08). AB - Two new diaryl ethers, named phomopside A (1) and B (2), together with known excelsione (3) were isolated from the mangrove endophytic fungus Phomopsis sp. (ZZF08) obtained from the South China Sea coast. The structure of 1 was elucidated by NMR spectroscopy and confirmed by X-ray crystallography. Compounds 2 and 3 were identified by NMR spectroscopy and comparing the spectroscopic data with literature values. In addition, the plausible biogenetic path of 1, 2 and 3 is discussed. PMID- 18449855 TI - Gene expression signatures that classify the mode of invasion of primary oral squamous cell carcinomas. AB - To identify molecular signatures and establish a new diagnostic model for progressive oral squamous cell carcinoma (OSCC). Total RNAs were isolated from primary OSCCs from both node-positive and -negative patients and used in cDNA microarray analysis. To identify marker genes representing a malignant phenotype, their expression was further examined by quantitative reverse transcription-PCR (QRT-PCR) in 64 OSCC tissues. Using Fisher's linear discriminant analysis (LDA) fitted with a stepwise increment method, we created discriminatory predictor models. The stability of these models was examined using leave-one-out cross validation. Immunohistochemical analysis was performed. Among the 16,600 possible target cDNAs in the array analysis, 83 genes demonstrated significantly differential signals (>2-fold). We further identified 53 marker genes that can be implicated in the Yamamoto-Kohama's (YKs) mode of invasion for OSCCs (P < 0.06). Using LDA fitted with a stepwise increment method, we created four discriminatory predictor models based on 16- to 25-gene signatures which could best distinguish the five established grades of YKs mode of invasion. Leave-one out validation demonstrated that the stability of these models was 92-95%. For validation, we also examined an independent set of 13 primary OSCCs; the predictor models determined the invasion status from 77% to 100% (on average, 85%) fidelity with the pathological observations. TGM3 protein expression was markedly suppressed in highly invasive OSCCs. We reveal novel gene expression alterations during the progression of OSCC, and have constructed prediction models for the evaluation of the invasion status of these cancers. PMID- 18449856 TI - UVB irradiation regulates Cox-2 mRNA stability through AMPK and HuR in human keratinocytes. AB - Considerable evidence has demonstrated that UVB irradiation is a strong carcinogen for nonmelanoma skin cancer. Up-regulation of cyclooxygenase-2 (Cox-2) has been shown to be a crucial event in human keratinocytes in their responses to UVB irradiation. To further understand the molecular mechanisms governing Cox-2 regulation, we found that UVB irradiation significantly increased Cox-2 mRNA stability by inducing cytoplasmic localization and protein abundance of human antigen R (HuR). We also found that AMP-activated kinase (AMPK) mediates these events and that UVB reduces AMPK activity by down-regulating LKB1 kinase. Finally, we propose a novel model in which UVB regulates Cox-2 mRNA stability through the LKB1/AMPK pathway. PMID- 18449858 TI - Human Y-chromosome haplotyping by allele-specific polymerase chain reaction. AB - We describe the application of allele-specific PCR (AS-PCR) for screening biallelic markers, including SNPs, within the nonrecombining region of the human Y-chromosome (NRY). The AS-PCR method is based on the concept that the perfectly annealed primer-template complex is more stable, and therefore, more efficiently amplified under the appropriate annealing temperature than the complex with a mismatched 3'-residue. Furthermore, a mismatched nucleotide at the primer's 3'-OH end provides for a poor extension substrate for Taq DNA polymerase, allowing for discrimination between the two alleles. This method has the dual advantage of amplification and detection of alleles in a single expeditious and inexpensive procedure. The amplification conditions of over 50 binary markers, mostly SNPs, that define the major Y-haplogroups as well as their derived lineages were optimized and are provided for the first time. In addition, artificial restriction sites were designed for those markers that are not selectively amplified by AS-PCR. Our results are consistent with allele designations derived from other techniques such as RFLP and direct sequencing of PCR products. PMID- 18449857 TI - Polyacrylamide gel plugs enabling 2-D microfluidic protein separations via isoelectric focusing and multiplexed sodium dodecyl sulfate gel electrophoresis. AB - In situ photopolymerized polyacrylamide (PAAm) gel plugs are used as hydrodynamic flow control elements in a multidimensional microfluidic system combining IEF and parallel SDS gel electrophoresis for protein separations. The PAAm gel plugs offer a simple method to reduce undesirable bulk flow and limit reagent/sample crosstalk without placing unwanted constraints on the selection of separation media, and without hindering electrokinetic ion migration in the complex microchannel network. In addition to improving separation reproducibility, the discrete gel plugs integrated into critical regions of the chip enable the use of a simple pressure-driven sample injection method which avoids electrokinetic injection bias. The gel plugs also serve to greatly simplify operation of the spatially multiplexed system by eliminating the need for complex external fluidic interfaces. Using an FITC-labeled Escherichia coli cell lysate as a model system, the use of gel plugs is shown to significantly enhance separation reproducibility in a chip containing five parallel CGE channels, with an average variance in peak elution time of only 4.1%. PMID- 18449859 TI - Nuclear proteome analysis of undifferentiated mouse embryonic stem and germ cells. AB - Embryonic stem cells (ESCs) and embryonic germ cells (EGCs) provide exciting models for understanding the underlying mechanisms that make a cell pluripotent. Indeed, such understanding would enable dedifferentiation and reprogrammation of any cell type from a patient needing a cell therapy treatment. Proteome analysis has emerged as an important technology for deciphering these biological processes and thereby ESC and EGC proteomes are increasingly studied. Nevertheless, their nuclear proteomes have only been poorly investigated up to now. In order to investigate signaling pathways potentially involved in pluripotency, proteomic analyses have been performed on mouse ESC and EGC nuclear proteins. Nuclei from ESCs and EGCs at undifferentiated stage were purified by subcellular fractionation. After 2-D separation, a subtractive strategy (subtracting culture environment contaminating spots) was applied and a comparison of ESC, (8.5 day post coitum (dpc))-EGC and (11.5 dpc)-EGC specific nuclear proteomes was performed. A total of 33 ESC, 53 (8.5 dpc)-EGC, and 36 (11.5 dpc)-EGC spots were identified by MALDI-TOF-MS and/or nano-LC-MS/MS. This approach led to the identification of two isoforms (with and without N-terminal acetylation) of a known pluripotency marker, namely developmental pluripotency associated 5 (DPPA5), which has never been identified before in 2-D gel-MS studies of ESCs and EGCs. Furthermore, we demonstrated the efficiency of our subtracting strategy, in association with a nuclear subfractionation by the identification of a new protein (protein arginine N-methyltransferase 7; PRMT7) behaving as proteins involved in pluripotency. PMID- 18449860 TI - Simultaneous separation of basic and acidic proteins using 1-butyl-3 methylimidazolium-based ion liquid as dynamic coating and background electrolyte in capillary electrophoresis. AB - 1-Butyl-3-methylimidazolium tetrafluoroborate ionic liquids (1B-3MI-TFB ILs) were employed as a coating material and BGE in CE for simultaneous separation of basic and acidic proteins such as lysozyme, cytochrome C, ribonuclease A, albumin, and alpha-lactalbumin. 1B-3MI-TFB ILs effectively reversed the surface charges on the capillary inner surface, preventing the adsorption of positively charged proteins onto the silica surface, as well as associated with proteins, thus benefiting the separation efficiencies and reproducibility. Consequently, simultaneous baseline separation of five proteins was achieved within 14 min by using 10 mM of 1B-3MI TFB ILs as dynamic coating and the only running electrolyte at the voltage of +20 kV. The proposed coating technique is simple, less time-consuming, reproducible, and also stable enough for proteins separation without the need of additives. Symmetrical peaks with efficiencies up to 670,000 plates/m were obtained. Recoveries of proteins with RSD (for migration times) of 0.23-0.42% (run-to-run) and 2.5-3.8% (day-to-day) were achieved, respectively. The applicability of the proposed method in proteins separation was evaluated by the separation of egg white samples. PMID- 18449861 TI - Detection of PEGylated proteins in polyacrylamide gels by reverse staining with zinc and imidazole salts. AB - The reverse staining, with imidazole-SDS-zinc, of PEG-linked proteins separated by SDS-PAGE was studied. Using model conjugates (interferon-alpha 2b (IFN alpha2b) reacted with either a branched-chain (40,000) PEG (PEG2,40) or a linear monomethoxy PEG polymer (Mr of 12,000) and chromatographically purified monoPEG2,40-IFN-alpha2b), conventional small-format analytical gels (<1 mm thick) showed typical detection patterns (i.e., transparent, colorless bands clearly discernible against a zinc imidazolate-generated white gel background), in less than 20 min. Nonreacted (free) PEG was almost undetected, as expected. The reverse-stained PEGylated IFN-alpha2b patterns were qualitatively indistinguishable from those of parallel gels stained with iodine (I2). The LOD was estimated in the low nanogram range (e.g., at about 7 ng for mono- or bi PEG2,40 IFN-alpha2b per lane on gradient (4-17%) gels). Also, this stain allowed the visualization of Coomassie blue-undetected PEG-IFN bands, and could be restained with I2. PEGylated species of lysozyme, a low-molecular-weight peptide, ovalbumin, and chymotrypsin were used to demonstrate the generality of this stain. We also show (i) how to counteract the adverse effect of some parameters (e.g., gel thickness above 1 mm, long gel length, low (e.g., 4-6%) acrylamide concentration) on the reverse staining process and (ii) that the properties of the reverse-stained PEGylated proteins remain unchanged, as judged by analyzing both the ion exchange chromatography-based positional isomer separation profile and enzyme-linked immunosorbent response of PEG-IFN recovered from gels. Consequently, this technique may be useful for the rapid analysis or the small scale preparation of PEGylated proteins. PMID- 18449862 TI - Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population. AB - Several lines of evidence suggest that oxidative stress plays a role in the pathogenesis of schizophrenia, and that glutathione (GSH) plays a crucial role in antioxidant defense mechanisms. In this study, we performed association studies between GSH-related genes (GSTM1, GSTP1, GSTO1, GSTT1, GSTT2, GPX1, and GCLM) and schizophrenia in a Japanese population. The overall distributions of the genotypes and alleles of each gene were not different between schizophrenic patients and controls. Subjects with residual-type schizophrenia showed different distributions in the analysis of GSTM1 genotype and in the combination analysis of GSTs, GPX1, and GCLM genotypes although the small sample size should be considered as a limitation of this study. In addition, our findings revealed that there were large ethnic differences in the genotype distributions of those GSH related genes. The present study suggests that GSH-related genes may not play a major role in the pathogenesis of schizophrenia in a Japanese population. However, a dysregulation of GSH metabolism may be one of the vulnerability factors contributing to the development of a certain type of schizophrenia, and it is likely that the ethnic background should be considered in further study for those GSH-related genes. PMID- 18449863 TI - Comparing the transcriptional profile of mesenchymal cells to cardiac and skeletal muscle cells. AB - Marrow-derived stroma cells (MSCs) can differentiate into multiple lineages including myogenic cells. However, the molecular mechanisms that direct MSCs to each differentiation pathway are poorly understood. Our study was designed to gain insights into the potential regulatory pathways that may assist in defining MSC commitment and differentiation properties. This will delineate the similarities or differences in the expression of genes between several cell types of mesenchymal origin. In this study, we established in vitro models, which allow following the discrete stages of differentiation of cardio- and myogenic-cells compared with MSC. Gene expression of each cell type at several stages of their differentiation path was evaluated by means of Affymetrix Gene Chips. Bioinformatic clustering of genes confirmed that with time in culture the myogenic cells ceased proliferating and commenced with differentiation. The expression profile analysis revealed the similarity and differences between myogenic cells and MSCs. This research compared at the molecular levels snapshots of gene expression patterns and elaborated on the overlap or differences between the analyzed cellular systems. Our results shed light on gene profiles of cells throughout their differentiation pathways. Establishing the gene signature of the differentiation process of cells that belong to several mesenchymal lineages may contribute to the understanding of molecular pathways that underlay mesenchymal tissue remodeling. PMID- 18449864 TI - Association study of the estrogen receptor alpha gene (ESR1) and childhood-onset mood disorders. AB - Depressive disorders are heterogeneous psychiatric disorders involving deficits in cognitive, psychomotor, and emotional processing. Depressive disorders have a significant genetic component, with severe, recurrent and early-onset forms demonstrating elevated heritability. In this study we genotyped eleven single nucleotide polymorphisms (SNPs) spanning the estrogen receptor alpha gene (ESR1) in a large family-based childhood-onset mood disorder (COMD) sample. None of the individual SNP or global haplotype analyses was significant in the entire COMD sample, but haplotype analysis of three SNPs in strong linkage disequilibrium (rs746432, rs2077647, and rs532010) uncovered an association with COMD, specifically in females. Our data are consistent with previous studies demonstrating a female-specific association between ESR1 and neurobehavioral phenotypes. These results suggest the existence of sex-specific etiological factors in depressive disorders, related to estrogen, with onset in childhood. PMID- 18449866 TI - Transgenic sheep designed for transplantation studies. AB - Lentiviral vectors have recently emerged as an efficient method of transgene delivery to the germline of animals. We now demonstrate that combining this efficiency with embryo splitting procedures enables the production of monozygotic twins, one of which is transgenic. We propose that this approach can be used to generate animals in which cell or tissue transplantation can be achieved without the use of immunosuppressive regimes. PMID- 18449865 TI - The validity of the family history screen for assessing family history of mental disorders. AB - There is a need to collect psychiatric family history information quickly and economically (e.g., for genome-wide studies and primary care practice). We sought to evaluate the validity of family history reports using a brief screening instrument, the Family History Screen (FHS). We assessed the validity of parents' reports of seven psychiatric disorders in their adult children probands from the Dunedin Study (n = 959, 52% male), using the proband's diagnosis as the criterion outcome. We also investigated whether there were informant characteristics that enhanced accuracy of reporting or were associated with reporting biases. Using reports from multiple informants, we obtained sensitivities ranging from 31.7% (alcohol dependence) to 60.0% (conduct disorder) and specificities ranging from 76.0% (major depressive episode) to 97.1% (suicide attempt). There was little evidence that any informant characteristics enhanced accuracy of reporting. However, three reporting biases were found: the probability of reporting disorder in the proband was greater for informants with versus without a disorder, for female versus male informants, and for younger versus older informants. We conclude that the FHS is as valid as other family history instruments (e.g., the FH-RDC, FISC), and its brief administration time makes it a cost-effective method for collecting family history data. To avoid biasing results, researchers who aim to compare groups in terms of their family history should ensure that the informants reporting on these groups do not differ in terms of age, sex or personal history of disorder. PMID- 18449867 TI - Sculpting an RNA conformational energy landscape by a methyl group modification- a single-molecule FRET study. PMID- 18449868 TI - The bound conformation of microtubule-stabilizing agents: NMR insights into the bioactive 3D structure of discodermolide and dictyostatin. AB - A protocol based on a combination of NMR experimental data with molecular mechanics calculations and docking procedures has been employed to determine the microtubule-bound conformation of two microtubule-stabilizing agents, discodermolide (DDM) and dictyostatin (DCT). The data indicate that tubulin in assembled microtubules recognizes DDM through a conformational selection process, with minor changes in the molecular skeleton between the major conformer in water solution and that bound to assembled microtubules. For DCT, the deduced bound geometry presents some key conformation differences around certain torsion angles, with respect to the major conformer in solution, and still displays mobility even when bound. The bound conformer of DCT resembles that of DDM and provides very similar contacts with the receptor. Competition experiments indicate that both molecules compete with the taxane-binding site. A model of the binding mode of DDM and DCT to tubulin is proposed. PMID- 18449869 TI - Phase transfer of enantiopure Werner cations into organic solvents: an overlooked family of chiral hydrogen bond donors for enantioselective catalysis. PMID- 18449870 TI - Supramolecular bidentate ligands by metal-directed in situ formation of antiparallel beta-sheet structures and application in asymmetric catalysis. AB - The principles of protein structure design, molecular recognition, and supramolecular and combinatorial chemistry have been applied to develop a convergent metal-ion-assisted self-assembly approach that is a very simple and effective method for the de novo design and the construction of topologically predetermined antiparallel beta-sheet structures and self-assembled catalysts. A new concept of in situ generation of bidentate P-ligands for transition-metal catalysis, in which two complementary, monodentate, peptide-based ligands are brought together by employing peptide secondary structure motif as constructing tool to direct the self-assembly process, is achieved through formation of stable beta-sheet motifs and subsequent control of selectivity. The supramolecular structures were studied by (1)H, (31)P, and (13)C NMR spectroscopy, ESI mass spectrometry, X-ray structure analysis, and theoretical calculations. Our initial catalysis results confirm the close relationship between the self-assembled sheet conformations and the catalytic activity of these metallopeptides in the asymmetric rhodium-catalyzed hydroformylation. Good catalyst activity and moderate enantioselectivity were observed for the selected combination of catalyst and substrate, but most importantly the concept of this new methodology was successfully proven. This work presents a perspective interface between protein design and supramolecular catalysis for the design of beta-sheet mimetics and screening of libraries of self-organizing supramolecular catalysts. PMID- 18449871 TI - Mechanistic investigations of the acid-catalyzed cyclization of a vinyl ortho quinone methide. PMID- 18449872 TI - Mechanical-force-induced nucleation and growth of peptide nanofibers at liquid/solid interfaces. PMID- 18449874 TI - Bovine endometrial legumain and TIMP-2 regulation in response to presence of a conceptus. AB - The precise mechanism of placentation in the bovine species where a restricted trophoblast invasion occurs to form the synepitheliochorial placenta is not fully understood. This study initially investigated the conceptus-maternal interactions in the peri-attachment period by comparing the proteins present at Days 16 and 18 in uterine luminal fluid (ULF) of pregnant with nonpregnant cows using 2-D gel electrophoresis. Nine protein spots were identified that were present in greater amounts in pregnant compared to nonpregnant ULF: carbonic anhydrase, ezrin, heat shock protein 70, isocitrate dehydrogenase, nucleoside diphosphate kinase, peroxiredoxin 1, purine nucleoside phosphorylase, thioredoxin and triosephosphate isomerase and four proteins that were less abundant in ULF from the gravid compared to the nongravid horns or nonpregnant uteri: cystatin E/M, legumain, retinol-binding protein (RBP) and tissue inhibitor of matrix metalloproteinase 2 (TIMP-2). Successful placentation requires the remodelling of the endometrial surface therefore uterine mRNA and protein expression of legumain, a protease activator, and TIMP-2, a protease inhibitor, was examined in detail during the oestrous cycle and from Days 13 to 31 of pregnancy. Both mRNAs were up-regulated in the endometrium during the luteal phase of the oestrous cycle and during early pregnancy. Although legumain and TIMP-2 mRNA expression levels were similar between uterine horns at the same day of pregnancy, the amount of protein differed between gravid and nongravid horns possibly modulated by interferon-tau or by other factors produced by the conceptus. These events at the conceptus maternal interface may provide localised control of protease activity necessary for controlling trophoblast invasion of the endometrium. PMID- 18449873 TI - Oxidative double dehalogenation of tetrachlorocatechol by a bio-inspired CuII complex: formation of chloranilic acid. AB - Copper(II) complexes of the potentially tripodal N,N,O ligand 3,3-bis(1 methylimidazol-2-yl)propionate (L1) and its conjugate acid HL1 have been synthesised and structurally and spectroscopically characterised. The reaction of equimolar amounts of ligand and CuII resulted in the complexes [Cu(L1)]n(X)n (X=OTf-, PF6(-); n=1,2), for which a new bridging coordination mode of L1 is inferred. Although these complexes showed moderate catecholase activity in the oxidation of 3,5-di-tert-butylcatechol, surprising reactivity with the pseudo substrate tetrachlorocatechol was observed. A chloranilato-bridged dinuclear CuII complex was isolated from the reaction of [Cu(L1)]n(PF6)n with tetrachlorocatechol. This stoichiometric oxidative double dehalogenation of tetrachlorocatechol to chloranilic acid by a biomimetic copper(II) complex is unprecedented. The crystal structure of the product, [Cu2(ca)Cl2(HL1)2], shows a bridging bis-bidentate chloranilato (ca) ligand and ligand L1 coordinated as its conjugate acid (HL1) in a tridentate fashion. Magnetic susceptibility studies revealed weak antiferromagnetic coupling (J= -35 cm(-1)) between the two copper centres in the dinuclear complex. Dissolution of the green complex [Cu2(ca)Cl2(HL1)2] resulted in the formation of new pink-purple mononuclear compound [Cu(ca)(HL1)(H2O)], the crystal structure of which was determined. It showed a terminal bidentate chloranilato ligand and N,N-bidentate coordination of ligand HL1, which illustrates the flexible coordination chemistry of ligand L1. PMID- 18449876 TI - Rational design of platinum-based bimetallic catalysts with enhanced hydrogenation activity. PMID- 18449875 TI - Different intervals of ovum pick-up affect the competence of oocytes to support the preimplantation development of cloned bovine embryos. AB - The objective of this study was to determine the effect of different frequencies of transvaginal ovum pick-up (OPU) on the quantity of recovered cumulus oocyte complexes (COCs) and subsequently the competence of matured oocytes to support the preimplantation development of cloned bovine embryos. The COCs were aspirated from the ovaries of 6 Chinese Holstein cows by transvaginal follicle aspiration twice a week (every 3 or 4 days) (Group I), every 5 days (Group II), once a week (every 7 days) (Group III), every 10 days (Group IV), and once every 2 weeks (every 14 days) (Group V). The developmental stages of the follicles were confirmed by the diameter of the dominant follicle (DF) and harvested COCs, and the dynamics of the follicular wave were clarified. In addition, extrusions of the first polar body (PB I) from the oocytes were observed at different time intervals after the initiation of in vitro maturation (IVM) to identify the appropriate culture time window for somatic cell nuclear transfer. Matured oocytes were used to produce cloned bovine embryos that were subsequently cultured in the goat oviduct. After 7 days, the embryos were flushed out, and the developmental rates of the blastocysts were compared among the five groups. The results showed that the aspirations of all follicles >or=3 mm in diameter (D1) induced and synchronized the dynamics of the follicular wave, and the subordinate follicles became atretic after 4 days (D5). Another follicular wave started between D7 and D10, and atresia in the subordinate follicles in the second follicular wave began on D14. The timing of meiotic progression (from the initiation of IVM to the extrusion of PB I) in the oocytes obtained by OPU was later than that of the oocytes obtained from the abattoir. Between 20 and 24 hr after the initiation of IVM, 20% of the oocytes extruded their PB I. Further, 80% (520/650) of the harvested COCs were arrested at metaphase II (MII) by 22 hr of the initiation of IVM and were used as cytoplast donors. The rates of development of the reconstituted embryos to the blastocyst stage were 23.1% (Group I), 15.0% (Group II), 10.9% (Group III), 4.9% (Group IV), and 29.0% (Group V). The results indicate that the developmental potential of follicles from the same living donors were different when different intervals of OPU were adopted and early atretic follicles from the second follicular wave had higher competence to support the early development of cloned bovine embryos. PMID- 18449877 TI - A prospective study of surgical margin status in oral squamous cell carcinoma: a preliminary report. AB - A protocol was created for prospective margin status evaluation of patients with Oral SCC. Margins are evaluated intra- and post-operatively during three stages. Patients were divided into three groups: group 1 in which one margins were sampled randomly, group 2 with frozen sections taken from the surgical bed and 3 in which they were taken from the tumor specimen itself. Patients in group 3 showed the best correlation with final margin status and survival. PMID- 18449878 TI - Symposium on the evolution and development of the vertebrate head. AB - Among the symposia held at the seminal meeting of the European Society for Evolutionary Developmental Biology was one centered on the development and evolution of the vertebrate head, an exquisitely complex anatomical system. The articles presented at this meeting have been gathered in a special issue of the Journal of Experimental Zoology, and are here reviewed by the organizers of the symposia. These articles cover a breadth of subjects, including interactions between cells derived from the different germ layers, such as those underlying neural crest cell migration and fate and cranial muscle specification, as well as placode development and the origin, development, and evolution of important evolutionary innovations such as jaws and the trabecula cranii. In this introduction, we provide a short historical overview of themes of research into the fundamental organization, structure, and development of the vertebrate head, including the search for head segmentation and the relevance of the New Head Hypothesis, and subsequently present the topics discussed in each of the articles. This overview of the past and the present of head evo-devo is then followed by a glimpse at its possible future and a brief examination of the utility of the notions of heterochrony, heterotopy, and heterofacience in describing evolutionarily important changes in developmental events. PMID- 18449879 TI - Prognostic values of pathologic findings and hypoxia markers in 21 patients with salivary duct carcinoma. AB - BACKGROUND: Salivary duct carcinoma (SDC) is associated with aggressive clinical behavior. METHODS: We examined the prognostic values of clinicopathologic variables and hypoxia biomarker expression in 21 patients with SDC treated by resection with/without neck dissection and radiotherapy. Tissue microarrays constructed from tumor blocks were stained with monoclonal antibodies to hypoxia inducible factor (HIF)-1alpha, HIF-2alpha, carbonic anhydrase-9, glucose transporter-1, and erythropoietin receptor. Locoregional control and survival rates were calculated by the Kaplan-Meier method and prognostic factors were calculated from uni- and multivariate analyses. RESULTS: The cervical nodal metastasis rate was 67% at initial diagnosis and the distant metastasis rate was 71% during follow-up. The only significant predictor of distant metastasis was nodal metastasis (P = 0.006). Actuarial 5-year locoregional control, distant metastasis-free survival, and overall survival rates were 57%, 40%, and 44%. Multivariate analysis showed that lymphovascular and perineural invasion and radiotherapy were independent predictors of overall survival (P < 0.025). None of the hypoxia biomarkers, however, was a significant predictor of locoregional control, distant metastasis, or survival. CONCLUSIONS: Lymphovascular and perineural invasion, but not hypoxia biomarkers, were significant prognostic factors for patients with SDC. PMID- 18449881 TI - Novel human polyomaviruses--re-emergence of a well known virus family as possible human carcinogens. AB - Polyomaviruses belong to a family of DNA tumor viruses that frequently cause cancer upon inoculation into heterologous hosts. The rhesus monkey virus SV40 and mouse polyomavirus have been studied in particular detail. Two members of the polyomavirus family, BK and JC viruses, were identified as human pathogens more than 30 years ago. Both are oncogenic when inoculated into newborn rodents. Their possible role in human cancers has been intensively investigated; conclusive results are, however, still missing. During the past year 3 new members of the polyomavirus family have been identified in humans, KI, WU, and MC-Polyomavirus. Whereas the first 2 were only found in respiratory fluids of children with respiratory infections and in healthy individuals, the third virus was found to be specifically linked to Merkel tumors, a rare human cancer of neuroendocrine origin. The positive Merkel cells contain viral DNA in an integrated and clonal form, suggesting an involvement of this virus in the etiology of those tumors. This article will summarize the results of recent polyomavirus isolations from humans and animals and also address the potential role of members of this virus family in other human malignancies. It also makes reference to observations of polyomavirus-like particles in other conditions, particularly in hair-follicle cell-related proliferations. PMID- 18449880 TI - Tumoricidal activity of high-dose tumor necrosis factor-alpha is mediated by macrophage-derived nitric oxide burst and permanent blood flow shutdown. AB - This study investigates the role of tumor nitric oxide (NO) and vascular regulation in tumor ulceration following high-dose tumor necrosis factor-alpha (TNF) treatment. Using TNF-responsive (MethA) and nonresponsive (LL2) mouse tumors, tumor NO concentration was measured with an electrochemical sensor and tumor blood flow by Doppler ultrasound. Mice were also pretreated with a selective inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. Tumors harvested from TNF-treated mice were cryosectioned and immunostained for murine macrophages, or/and iNOS. MethA tumor-bearing mice were depleted of macrophages. Pre- and post-TNF tumor NO levels were measured continuously, and mice were followed for gross tumor response. In MethA tumors, TNF caused a 96% response rate, and tumor NO concentration doubled. Tumor blood flow decreased to 3% of baseline by 4 hr and was sustained at 24 hr and 10 days post-TNF. Selective NO inhibition with 1400 W blocked NO rise and decreased response rate to 38%. MethA tumors showed tumor infiltration by macrophages post-TNF and the pattern of macrophage immunostaining overlapped with iNOS immunostaining. Depletion of macrophages inhibited tumor NO increase and response to TNF. LL2 tumors had a 0% response rate to TNF and exhibited no change in NO concentration. Blood flow decreased to 2% of baseline by 4 hr, recovered to 56% by 24 hr and increased to 232% by 10 days. LL2 tumors showed no infiltration by macrophages post-TNF. We conclude that TNF causes tumor infiltrating, macrophage-derived iNOS-mediated tumor NO rise and sustained tumor blood flow shutdown, resulting in tumor ulceration in the responsive tumor. PMID- 18449882 TI - Alterations in the protein kinase C signaling activated by a parthenogenetic agent in oocytes from reproductively old mice. AB - To investigate the effect of female age on oocyte developmental competence, we focused on protein kinase C (PKC), a major component of the signalling pathway involved in oocyte activation, and put forward the hypothesis that, as it occurs in many organs and tissues, aging affects PKC function in mouse oocytes. Biochemical activity of PKC along with the expression and subcellular distribution of some PKC isoforms were monitored in young and old mouse oocytes parthenogenetically activated by SrCl(2). We found that PKC activity increased reaching a level that was lower in old compared to young oocytes in association with an incomplete translocation of PKCbetaI to the plasma membrane. Moreover, old oocytes exhibited a reduced expression of PKCbeta1 and PKCalpha at the protein level, without significant effects on the expression of the Ca(2+) independent PKCdelta. Detectable amounts of PKCbeta1 mRNA were observed in young and old oocytes at GV stage with no difference between the two groups of age. When meiotic progression to anaphase II up to first cleavage were analyzed, a delay in meiosis resumption and significantly lower rates of pronuclei formation and first cleavage were observed in old compared to young oocytes. Moreover, we found that, in contrast to SrCl(2), PMA (12-O-tetradecanoyl phorbol-13-acetate), a PKC agonist, was ineffective in activating old oocytes. Present findings provide evidence that aging affects the correct storage and activation of some PKCs, functional components of the machinery involved in oocyte activation, and suggest that these changes may negatively influence the activation competence of old oocytes. PMID- 18449883 TI - The influence of age on fecal steroid hormone levels in male Budongo Forest chimpanzees (Pan troglodytes schweinfurthii). AB - Potential interactions between age and endocrinological functioning have been understudied in wild ape populations. Therefore, we examined the relationship between age and the secretion of androgens and glucocorticoids in 15 juvenile, subadult, and adult male chimpanzees (Pan troglodytes schweinfurthii) free ranging in the Budongo Forest of Uganda. One hundred and nine fecal samples were opportunistically collected, between 07:30 and 13:30 hr, during the wet season. Fecal samples were preserved, by oven drying, and steroid content extracted before radioimmunoassay for dehydroepiandrosterone-sulfate (DHEA-S), testosterone (TEST), cortisol (CORT), and corticosterone (CCT). Employing indexes of age as predictive factors, linear mixed-effects modeling and non-parametric statistical comparisons of fecal steroid levels were conducted. Age was observed to significantly influence the production of both glucocorticoids and androgens in male Budongo Forest chimpanzees. Basically, whereas TEST and CORT increased, DHEA S and CCT levels slightly declined as animals matured. PMID- 18449884 TI - Variation in the prevalence of gastric cancer in Peru. AB - Most cases of gastric cancers occur in non-industrialized countries but there is scarce information about the epidemiology of this illness in these countries. Our study examined whether there was a variation in the prevalence of gastric cancer in Lima, Peru over the last 2 decades. Subjects older than 29 years of age were included. They underwent an esophagogastroduedonoscopy at 3 socioeconomically different health facilities in Lima: a county hospital (7,168 subjects), a Peruvian-Japanese Clinic (14,794 individuals) and a private hospital (4,893 individuals). Birth cohort prevalence of gastric cancer was used. Regression models were calculated to predict the future prevalence of gastric cancer. It was found that the birth cohort prevalence of gastric cancer decreased in Peru from 22.7 to 2% (p < 0.001), from 12 to 0.5% (p < 0.001), and from 6.5 to 0.1% (p < 0.001) in the low, middle and high socioeconomic group, respectively. The prevalence of intestinal metaplasia decreased from 44.3 to 12.5% (p < 0.001), from 28.4 to 5% (p < 0.001), and from 19.4 to 2.2% (p < 0.001) in the low, middle and high socioeconomic status, respectively. These trends will likely persist over the future decades. Nevertheless, the prevalence of gastric cancer remains high in subjects older than 59 years of age in the low socioeconomic status. It is concluded that the prevalence of gastric cancer is decreasing in Peru, similar to the current trend undergoing in industrialized nations. However, there are still specific groups with high prevalence that might benefit from screening for early detection and treatment. PMID- 18449886 TI - Obesity and the risk for non-Hodgkin lymphoma. PMID- 18449887 TI - Body size and risk of epithelial ovarian and related cancers: a population-based case-control study. AB - Different subtypes of ovarian cancer appear to have different causes; however, the association between body mass index (BMI) and the different subtypes is unclear. We examined the associations between body-mass index (BMI) and weight gain and risk of the different histological subtypes of epithelial ovarian cancer in a case-control study in Australia. Cases aged 18-79 with a new diagnosis of invasive epithelial ovarian cancer (n = 1,269) or borderline tumor (n = 311) were identified through a network of clinics and cancer registries throughout Australia. Controls (n = 1,509) were selected from the Electoral Roll. Height and weight (1 year previously, at age 20 and maximum weight) and other risk factor information were ascertained via a self-administered questionnaire. Obesity was positively associated with clear cell tumors (Odds Ratio 2.3; 95% confidence interval 1.2-4.2) but not invasive endometrioid or mucinous tumors. Although there was no association with invasive serous tumors overall (0.9; 0.7-1.2), we did see an increased risk of serous peritoneal tumors (2.9; 1.7-4.9), but not of serous tumors of the ovary and fallopian tube. Of the borderline subtypes, obesity was positively associated with serous (1.8; 1.1-2.8) but not mucinous tumors (1.1; 0.7-1.7). Overweight was not associated with any subtype overall. There was no association with BMI at age 20, or weight gain for any of the histological subtypes. These results add to the current evidence that obesity increases a woman's risk of developing distinct histological subtypes of ovarian cancer. PMID- 18449888 TI - Variants in DNA double-strand break repair and DNA damage-response genes and susceptibility to lung and head and neck cancers. AB - Cigarette smoking is the major risk factor for lung cancer, and together with alcohol for head and neck (H--N) cancer. These genotoxics produced DNA damage and particularly double-strand breaks (DSB) that are removed by various repair pathways. To understand the initiation of these cancers, we performed a genotype analysis to correlate some variants in specific genes in a case-control study of lung and H-N cancers. In a discovery phase, we sequenced DNA samples of 32 healthy Caucasians to describe genetic variants in 30 genes involved in the repair of DSB and in DNA damage response. 625 variants were detected on 29 out of the 30 genes successfully screened by sequencing exons, parts of introns and flanking regions. These included 470 non-exonic variants, from which 33 insertions/deletions, and 155 exonic alterations, corresponding to 59 non synonymous polymorphisms. 223 of these variants were not previously described. In total, 379 variants were successfully genotyped in a case-control study restricted to smokers including 151 lung cases, 251 H-N cases, and 172 controls. To account for multiple testing, we associated to each p-value a proportion of false positives (q-value). Haplotype-analysis suggested potential associations (p < 0.05) between lung cancer and 2 genes (RECQL4 and RAD52), which came with q value of 8%, and between H-N cancer and 1 gene (DNA-PK) but with q-value of 56%. The 3 genes are key players for regulating the efficiency of DSB repair. Large scale studies are needed to show if any of these 3 variants are truly associated with an increased risk of cancer. PMID- 18449889 TI - Telomeric 3' overhangs in chronic HBV-related hepatitis and hepatocellular carcinoma. AB - Telomeric 3' overhang is a key component of telomere structure, but little is known about its role in hepatocarcinogenesis. We examined the 3' overhang and telomere length, mRNA levels of hTERT, POT1, TRF1 and cytokeratin 19 (CK19) in 41 hepatitis B virus (HBV)-related hepatocellular carcinomas (HCCs) and adjacent non HCCs of B viral chronic hepatitis/cirrhosis. 3' overhang length was positively correlated with telomere length (p < 0.001). In non-HCCs, the 3' overhang shortened with increasing age (p = 0.043). Twenty-six HCCs had shorter and 15 HCCs had longer 3' overhangs than the adjacent non-HCCs. The mRNA levels of hTERT, POT1 and TRF1 were upregulated in HCCs than in non-HCCs. HCCs with lengthened 3' overhangs expressed higher hTERT mRNA levels than those with shortened 3' overhangs, when compared to 3' overhangs in non-HCCs (p = 0.044). POT1 and TRF1 showed no significant difference according to the 3' overhangs. HCCs with long 3' overhangs had higher mitosis (p = 0.046) and more frequent multipolar mitosis compared to those with short 3' overhangs (p = 0.034). HCCs with high cytokeratin 19 mRNA levels, a marker for hepatic progenitor cells, had longer 3' overhangs than HCCs with low cytokeratin 19 mRNA levels (p= 0.019). In conclusion, the 3' overhang erosion might be closely related to the number of cell divisions in telomerase-negative hepatocytes of chronic hepatitis/cirrhosis. In telomerase-positive HCCs, an altered 3' overhang are involved in HBV-related hepatocarcinogenesis and hTERT might be involved in regulation of 3' overhang. PMID- 18449890 TI - Characterization of a novel epigenetically-silenced, growth-suppressive gene, ADAMTS9, and its association with lymph node metastases in nasopharyngeal carcinoma. AB - By using a functional complementation approach, suppression of tumorigenicity was observed after transfer of intact or truncated copies of chromosome 3 into a nasopharyngeal carcinoma (NPC) HONE1 cell line. The extra exogenous chromosome 3 in the microcell hybrids (MCHs) significantly extended the lag period of tumor formation, which may be associated with loss or inactivation of wild type alleles from the normal donor chromosome 3. Representative tumors, which grew in nude mice were reconstituted into culture and expanded as tumor segregants (TSs). In our study, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9 (ADAMTS9), a gene mapping to 3p14.2, was identified to be critically associated with tumor suppression in NPC. Gene expression analysis showed that ADAMTS9 was either not expressed or was downregulated in HONE1 cells, TSs and NPC cell lines. The mechanism of ADAMTS9 gene inactivation in the NPC cell lines and tissues was attributed to promoter hypermethylation. Using a tissue microarray and immunohistochemical staining, 31 of 66 (47%) of the NPC cases showed downregulated or absence of ADAMTS9 expression. ADAMTS9 expression was downregulated or lost in 17 of 23 (73.9%) lymph node metastatic NPC specimens, which was significantly higher than in 14 of 43 (32.6%) primary tumors. After transfection of the ADAMTS9 gene into 7 NPC cell lines, a dramatic reduction of colony forming ability was observed. These findings support ADAMTS9 as a putative tumor suppressor gene in vivo in NPC that is significantly associated with lymph node metastases. PMID- 18449891 TI - miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. AB - microRNAs are endogenous small noncoding RNAs that regulate gene expression negatively at posttranscriptional level. This latest addition to the complex gene regulatory circuitry revolutionizes our way to understanding physiological and pathological processes in the human body. Here we investigated the possible role of microRNAs in the development of multidrug resistance (MDR) in gastric cancer cells. microRNA expression profiling revealed a limited set of microRNAs with altered expression in multidrug- resistant gastric cancer cell line SGC7901/VCR compared to its parental SGC7901 cell line. Among the downregulated microRNAs are miR-15b and miR-16, members of miR-15/16 family, whose expression was further validated by qRT-PCR. In vitro drug sensitivity assay demonstrated that overexpression of miR-15b or miR-16 sensitized SGC7901/VCR cells to anticancer drugs whereas inhibition of them using antisense oligonucleotides conferred SGC7901 cells MDR. The downregulation of miR-15b and miR-16 in SGC7901/VCR cells was concurrent with the upregulation of Bcl-2 protein. Enforced mir-15b or miR-16 expression reduced Bcl-2 protein level and the luciferase activity of a BCL2 3' untranslated region-based reporter construct in SGC7901/VCR cells, suggesting that BCL2 is a direct target of miR-15b and miR-16. Moreover, overexpression of miR-15b or miR-16 could sensitize SGC7901/VCR cells to VCR-induced apoptosis. Taken together, our findings suggest that miR-15b and miR-16 could play a role in the development of MDR in gastric cancer cells at least in part by modulation of apoptosis via targeting BCL2. PMID- 18449892 TI - Morphology and innervation of the human cremaster muscle in relation to its function. AB - The electromyographic properties of the cremaster muscle (CM) are quite different from other skeletal muscles. It shows excessive spontaneous discharges, and the motor unit shape and firing frequency of the CM muscle differ from that of limb muscles. In this study, CM of six adult cadavers and six orchiectomy specimens were used to reveal the detailed histology of the muscle and provide an anatomophysiological explanation for these unusual electromyographic properties. Routine histochemical stains revealed the CM was composed of several distinct bundles of smooth and striated muscle fibers within connective tissue. The smooth muscle fibers that were more profuse than previously known and were not arranged in layers, but widely dispersed between striated muscle fibers. Bielschowsky silver staining technique, anti-neurofilament and anti-synaptophysin immunostaining showed the presence of multiple motor end-plates observed as a series of small dots or lines running along the striated muscle fibers and several nerve endings on a single muscle fiber. Myosin immunostaining confirmed the CM is a slow-twitch muscle, and alpha-actin smooth muscle immunostaining confirmed the presence of a large number of smooth muscle fibers. There were also small multipolar neurons forming nerve plexuses between smooth muscle fibers. Anti-GFAP immunostaining confirmed the presence of glial cells similar to astrocytes. In conclusion, the findings of this detailed anatomical study showed the CM, widely known as a striated muscle, contains a large number of smooth muscle fibers, and the spontaneous electromyographic discharges are due to the presence of multiple motor end-plates and dense innervation. PMID- 18449893 TI - Heteropterys aphrodisiaca infusion reduces the collateral effects of cyclosporine A on the testis. AB - Cyclosporine A (CsA) is known to have testicular toxicity, leading to male infertility. Stimulant and aphrodisiac properties have been attributed to the plant, Heteropterys aphrodisiaca. Thus, the present work was undertaken to evaluate the association of the drug and the medicinal herb in Wistar rats, applying testicular morphometry and ultrastructure. Twenty-four rats were used, divided into four groups: I, control; II, CsA; III, simultaneous use of CsA and H. aphrodisiaca; IV, H. aphrodisiaca. Daily administration by gavage was carried out, during 56 days, of water (sham), CsA in a dose of 15 mg/kg per day and/or H. aphrodisiaca in a dose of 0.5 ml of the infusion prepared with 25 g of roots/100 ml of boiling water. Increased body weight was observed for all groups, but the animals that received only CsA showed the smallest body weight gain. Morphometry showed increased connective tissue volumetric proportion and decreased Leydig cell volumetric proportion in CsA-treated rats. Using transmission electron microscopy, it was possible to ascertain that CsA caused seminiferous epithelium degeneration, resulting in Sertoli cell vacuolization, abnormal round and elongated spermatids and large accumulation of residual cytoplasm at the epithelium border next to the lumen. Expanded intercellular spaces between germ cells were still observed in H. aphrodisiaca-treated rat testes. The administration of H. aphrodisiaca infusion to CsA-treated rats diminished nearly all the CsA-induced damage to the testis ultrastructure, suggesting that H. aphrodisiaca infusion may be used combined with CsA to reduce CsA-induced injuries in the testis. PMID- 18449895 TI - Adjudin-mediated germ cell depletion alters the anti-oxidant status of adult rat testis. AB - Successful spermatogenesis is dependent on the proper attachment of developing germ cells to Sertoli cells. Manipulation of these interactions by drugs like Adjudin can hamper the development of germ cells and lead to conditions of temporary infertility. Although studies have shown the contraceptive potential of Adjudin, much is not known about its action in the testis. In this study, we sought to investigate the effect of Adjudin on the oxidative status of mammalian testis. Adult male rats were administered with a single dose of Adjudin (50 mg/kg body weight) by oral gavage and were killed at 1, 2, 4, 7, 15, or 30 days of treatment. Adjudin caused a significant increase in the production of hydrogen peroxide and lipid peroxidation from 4 to 7 days after treatment. There was a significant decrease in the activities of anti-oxidant enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase from 4 to 7 days after treatment with Adjudin. However, the state of oxidative stress was less pronounced from 15 to 30 days after Adjudin treatment. The level of androgen binding protein (ABP) remained unchanged following Adjudin treatment. These results show that there is an induction of oxidative stress accompanying adherens junction restructuring which suggests a role for reactive oxygen species in the regulation of these testicular junctions. However, transient elevation in reactive oxygen species levels did not affect androgen transport. PMID- 18449896 TI - Gene expression profiling of single bovine embryos uncovers significant effects of in vitro maturation, fertilization and culture. AB - In vitro production (IVP) has been shown to affect embryonic gene expression and often result in large offspring syndrome (LOS) in cattle and sheep. To dissect the effects of in vitro maturation, fertilization and culture on bovine embryos, we compared the expression profiles of single blastocysts generated by: (1) in vitro maturation, fertilization and culture (IVF); (2) in vivo maturation, fertilization and in vitro culture (IVD); and (3) in vivo maturation, fertilization and development (AI). To conduct expression profiling, total RNA was isolated from individual embryos, linearly amplified and hybridized to a custom bovine cDNA microarray containing approximately 6,300 unique genes. There were 306, 367, and 200 genes differentially expressed between the AI and IVD, IVF and IVD, and AI and IVF comparisons, respectively. Interestingly, 44 differentially expressed genes were identified between the AI embryos and both the IVF and IVD embryos, making these potential candidates for LOS. There were 60 genes differentially expressed between the IVF embryos and the AI and IVD embryos. The Gene Ontology category "RNA processing" was over-represented among the genes that were down-regulated in the IVF embryos, indicating an effect of in vitro oocyte maturation/fertilization on the ability to transcribe maternal RNA stores. A culture effect on the expression of genes involved in translation was also observed by the comparison of AI with IVD embryos. PMID- 18449897 TI - Lack of association between DRD3 gene polymorphism and response to clozapine in Turkish schizoprenia patients. AB - It is hypothesized that molecular components of dopaminergic system, especially the dopamine D3 receptor gene (DRD3), may play a crucial role in the pathophysiology of schizophrenia, because it is abundant in the limbic system of the brain and it binds antipsychotic drugs. Several groups attempted to find an association between a serine-to-glycine polymorphism of the DRD3 gene (Ser9Gly) and schizophrenia; however, the results were inconsistent. In this study, we aimed to investigate the relationship of the Serine/Glycine polymorphism of the DRD3 gene with therapeutic response to clozapine treatment between Turkish schizophrenia patients (N = 92) and healthy controls (N = 100). Genotype groups were comparable in BPRS, SAPS, SANS analysis of response to clozapine. Our results suggest that an association between the Ser/Gly polymorphism of DRD3 gene and response to clozapine in Turkish schizophrenia patients is unlikely to exist. PMID- 18449898 TI - Spectrum of HLXB9 gene mutations in Currarino syndrome and genotype-phenotype correlation. AB - Currarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development. Thus far, 43 different heterozygous mutations have been reported in patients fulfilling CS criteria. Mutation detection rate is about 50%, and reaches 90% in familial cases. Here, we report 23 novel mutations in 26 patients among a series of 50 index cases with CS, and review mutational reports published since the identification of the causative gene. Three cytogenetic anomalies encompassing the HLXB9 gene are described for the first time. Truncating mutations (frameshifts or nonsense mutations) represent 57% of those identified, suggesting that haploinsufficiency is the basis of CS. No obvious genotype-phenotype correlation can be drawn thus far. Genetic heterogeneity is suspected, since at least 19 of the 24 patients without HLXB9 gene mutation harbor subtle phenotypic variations. PMID- 18449900 TI - Effects of temperature regime through premetamorphic ontogeny on shape of the chondrocranium in the American toad, Anaxyrus americanus. AB - If one considers the substantial amount of information that exists about phenotypic plasticity in amphibians, it is surprising that few studies have examined abiotic factors that influence phenotype through ontogeny. Phenotypic change and stability of morphology are artifacts of organisms that bear significant relevance to evolution within and among taxonomic groups. Here, we examine development as a phenotypically plastic aspect of larval anurans. Fertilized eggs of the American Toad, Anaxyrus (= Bufo) americanus (Holbrook, 1836), were obtained from two pairs of adults, and larvae were reared in four temperature treatments (constant Mean, constant High, constant Low, and Fluctuating regime [Low night-High day]); developmental series were collected from each treatment, representing larvae of this species from Gosner Stages 28 40. Cleared and stained larvae were analyzed with landmark-based geometric morphometric methods to facilitate examination of differences in overall shape change of the larval chondrocranium through ontogeny, as a result of developmental temperature or temperature regime. Changes in shape of the chondrocranium and in amount and direction of phenotypic change through ontogeny were found in response to temperature treatment and temperature regime. Mean chondrocranial shape of the Fluctuating regime was more similar to the consensus shape of the overall data set than were those of all other treatments. Given that differences in amount and direction of shape change were observed among these treatments and throughout ontogeny, one should consider the affects of abiotic factors (such as temperature) when rearing larval anurans for studies of developmental morphology. PMID- 18449901 TI - Systematic morphology and evolutionary anatomy of the autonomic cardiac nervous system in the lesser apes, gibbons (hylobatidae). AB - We examined the morphology of the autonomic cardiac nervous system (ACNS) on 20 sides of 10 gibbons (Hylobatidae) of three genera, and we have inferred the evolution of the anatomy of the primate ACNS. We report the following. (1) Several trivial intraspecific and interspecific variations are present in gibbons, but the general arrangement of the ACNS in gibbons is consistent. (2) Although the parasympathetic vagal cardiac nervous system is extremely consistent, the sympathetic cardiac nervous system, such as the composition of the sympathetic ganglia and the range of origin of the sympathetic cardiac nerves, exhibit topographical differences among primates. (3) The vertebral ganglion, seldom observed in the Old World monkeys (Cercopithecidae), was consistently present in gibbons as well as in humans. (4) There are fewer thoracic ganglia contributing to the cervicothoracic ganglion in humans than in gibbons and in gibbons than in Old World monkeys. (5) The superior cardiac nerve originating from the superior cervical ganglion, rarely observed in Old World monkeys but commonly observed in humans, was present in 13 of 20 sides (65%), mostly on the left. Accordingly, the ACNS morphology exhibits evolutionary changes within the primate lineage. These evolutionary differences between Old World monkeys, gibbons, and humans are most parsimoniously interpreted as resulting from regular changes in the lineages leading from their common ancestor to the extant species that we dissected. They include the reduction in the number of thoracic ganglia contributing to the cervicothoracic ganglion and the expansion of the range of the cardiac nervous origin. PMID- 18449899 TI - Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. AB - Glucose-6-phosphatase-alpha (G6PC) is a key enzyme in glucose homeostasis that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis. Mutations in the G6PC gene, located on chromosome 17q21, result in glycogen storage disease type Ia (GSD-Ia), an autosomal recessive metabolic disorder. GSD-Ia patients manifest a disturbed glucose homeostasis, characterized by fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation. G6PC is a highly hydrophobic glycoprotein, anchored in the membrane of the endoplasmic reticulum with the active center facing into the lumen. To date, 54 missense, 10 nonsense, 17 insertion/deletion, and three splicing mutations in the G6PC gene have been identified in more than 550 patients. Of these, 50 missense, two nonsense, and two insertion/deletion mutations have been functionally characterized for their effects on enzymatic activity and stability. While GSD-Ia is not more prevalent in any ethnic group, mutations unique to Caucasian, Oriental, and Jewish populations have been described. Despite this, GSD-Ia patients exhibit phenotypic heterogeneity and a stringent genotype phenotype relationship does not exist. PMID- 18449902 TI - Microanatomy of the palatal mucosa of the semiaquatic malayan box turtle, Cuora amboinensis, and functional implications. AB - Scanning Electron Microscopy (SEM) revealed that the palate of Cuora amboinensis has a flat surface with keratinized and non-keratinized regions. Keratinization is reflected in disc-shaped keratinized dead cells with rough microplicae on the surface, and is concentrated close to the rhamphotheca. The surface of the non keratinized hexagonal epithelial cells is dotted with microvilli and sometimes with cilia. Taste buds are present both in lightly keratinized and non keratinized regions and exhibit a crater-like shape. Light microscopy shows the different tissue layers of the oral mucosa and the different epithelial structures. In keratinized regions, keratinocytes mature from basal to superficial, where they build up keratin layers of varying thickness. In non keratinized regions, the epithelial cells are arranged in a stratified fashion, and cuboidal to cylindric cells form a superficial layer. Goblet cells appear to be diffusely distributed, but are often organized in goblet cell fields which can be folded into crypts. Taste buds consist of slender epithelial cells, exhibit the typical barrel-like shape and are specially concentrated in the anterior, praechoanal palate. This anterior concentration of taste buds is shown by kinematographic analysis to correlate with the food prehension mode in Cuora amboinensis. The lamina propria of the palatal mucosa consists of loose connective tissue with inflammatory cells between capillaries. All these structures of the oral mucosa act as a functional entity and help determine how successfully an organism adapts ecologically to the environment. PMID- 18449894 TI - Identification and quantification of differentially represented transcripts in in vitro and in vivo derived preimplantation bovine embryos. AB - Identification of transcripts at key development stages of preimplantation embryos is critical for a better understanding of early embryogenesis. The current study had two aims. The first was to characterize the relative abundance of multiple transcripts during several developmental stages, namely, metaphase II stage oocytes (MPII), as well as 2-cell, precompact morula (PCM) and in vitro produced blastocyst (IVTBL) stage embryos. The second was to characterize differences in the relative abundance of transcripts present in in vivo- (IVVBL), in vitro- (IVTBL), and nuclear transfer-derived (NTBL) blastocysts. It was hypothesized that the identification of differentially represented transcripts from these embryos would reveal not only developmentally important genes, but also genes that might be aberrantly expressed due to embryo production techniques. Individual clusters from a large bovine expressed sequence tag (EST) library (http://genome.rnet.missouri.edu/bovine/) of female reproductive tissues and embryos were compared using Fisher's Exact Test weighted by number of transcripts per tissue by gene. Of the 3,144 transcripts that were present during embryogenesis, 125 were found to be differentially represented (P < or = 0.01) in at least one pairwise comparison. Fifteen of these transcripts were selected for further examination using quantitative real-time PCR (qRTPCR) to determine differences in transcript abundance. Twelve of the 15 transcripts were differentially represented (n = 9, P < or = 0.01; n = 3, P < or = 0.05) in at least one pairwise comparison. In summary, identification of differentially represented transcripts in early embryo development, which are modulated by in vitro techniques, should provide markers to ensure the production of embryos closer to those developed in vivo. PMID- 18449903 TI - Unique microanatomy of ileal peyer's patches of the one humped camel (Camelus dromedarius) is not age-dependent. AB - The Peyer's patches (PP) have been intensely investigated in several species because this is an important entry site for antigens and infectious agents. There are many PP in the jejunum, and in some species such as ruminants, carnivores, and omnivores, a different continuous PP is found in the terminal ileum. This PP disappears with age in these species studied. So far the ileal PP (IPP) has only been examined in the camel by light microscopy. Therefore, the localization of ileal Peyer's patches in the dromedary camel at different ages, as well as the histology and ultrastructures were now investigated. The IPP were characteristically seen as dark rose-colored isolated structures in the shape of a cup, arranged in three irregular rows. The central row was antimesenteric. Each patch was formed by several mainly elongated dome regions flanked by intestinal villi. In cross-sections these domes appeared as short, wide villi. The domes were formed from lymphoid follicles covered with a typical dome-associated epithelium of enterocytes and M cells without any goblet cells. The M cells showed variable appearance depending on the functional status. The lymphoid follicles expressed clear germinal centers. High endothelial venules were localized in the interfollicular region. In contrast to other species the IPP were still present with a comparable macroscopic and histological structure in camels of 25 years of age. PMID- 18449904 TI - Functional connectivity of the secondary somatosensory cortex of the rat. AB - The hierarchical relationship of the rat primary somatosensory cortex (S1) and secondary somatosensory cortex (S2) is controversial. The existence of a direct thalamocortical projection from ventral posterolateral thalamic nucleus (VPL) to S2 is a key factor in determining the relative position of S2 in the processing flow. In this study, the inter-connections of forepaw and hindpaw representations in VPL, S1, and S2 were examined by neuroanatomical tracing and electrophysiological approaches. In the tracing experiments, VPL, S1, and S2 were electrophysiologically identified, and then iontophoretically injected with biotinylated dextran amine (BDA, a bi-directional tracer). In the double-labeling experiments, two of the following retrograde tracers-BDA, Rhodamine dextran (RD), and/or Fluoro-Gold (FG)-were injected into homotypical S1 and S2 forepaw representations simultaneously. In the electrophysiological studies, paired somatic evoked multiunit responses in S1 and S2 were compared. Our results revealed that: (1) VPL forepaw and hindpaw neurons projected to corresponding S1 and S2 areas in a parallel and somatotopic manner; (2) very low percentage of double projecting VPL neurons were found, indicating parallel and independent pathways from forepaw VPL to S1 and S2; (3) forepaw S1 and S2 were symmetrically and reciprocally connected; (4) response latencies of the S1 and S2 multiunits to forepaw stimulation were in accordance with a direct and parallel pathway. This study provides further evidence to support the equivalent hierarchy of S1 and S2 in processing sensory information of the rat. PMID- 18449905 TI - Heparin inhibits BMP-2 osteogenic bioactivity by binding to both BMP-2 and BMP receptor. AB - Heparin demonstrates several kinds of biological activities by binding to various extracellular molecules and plays pivotal roles in bone metabolism. However, the role of heparin in the biological activity of bone morphogenetic protein (BMP) remains unclear. In the present study, we examined whether heparin has the effects on osteoblast differentiation induced by BMP-2 in vitro and also elucidated the precise mechanism by which heparin regulates bone metabolism induced by this molecule. Our results showed that heparin inhibited alkaline phosphatase (ALP) activity and mineralization in osteoblastic cells cultured with BMP-2. Heparin was found to suppress the mRNA expressions of osterix, Runx2, ALP and osteocalcin, as well as phosphorylation of Smad1/5/8 and p38 MAPK. Further, heparin bound to both BMP-2 and BMP receptor (BMPR). These results suggest that heparin suppresses BMP-2-BMPR binding, and inhibits BMP-2 osteogenic activity in vitro. PMID- 18449906 TI - Heparin activates Wnt signaling for neuronal morphogenesis. AB - Wnt factors are secreted ligands that affect different aspects of the nervous system behavior like neurodevelopment, synaptogenesis and neurodegeneration. In different model systems, Wnt signaling has been demonstrated to be regulated by heparan sulfate proteoglycans (HSPGs). Whether HSPGs modulate Wnt signaling in the context of neuronal behavior is currently unknown. Here we demonstrate that activation of Wnt signaling with the endogenous ligand Wnt-7a results in an increased of neurite outgrowth in the neuroblastoma N2a cell line. Interestingly, heparin induces glycogen synthase kinase-3beta (GSK-3beta) inhibition, beta catenin stabilization and morphological differentiation in both N2a cells and in rat primary hippocampal neuronal cultures. We also show that heparin modulates Wnt-3a-induced stabilization of beta-catenin. Several extracellular matrix and membrane-attached HSPGs were found to be expressed in both in vitro neuronal models. Changes in the expression of specific HSPGs were observed upon differentiation of N2a cells. Taken together, our findings suggest that HSPGs may modulate canonical Wnt signaling for neuronal morphogenesis. PMID- 18449907 TI - Genetic upregulation of matriptase-2 reduces the aggressiveness of prostate cancer cells in vitro and in vivo and affects FAK and paxillin localisation. AB - The cellular function and the role of matriptase-2 in cancer progression are poorly understood. This study assesses the importance of this protease in prostate cancer cell lines. Two prostate cancer cell lines, PC-3 and DU-145, previously displaying minimal expression of matriptase-2, were forced to over express matriptase-2 using a human mammalian expression construct. Over expression of matriptase-2 significantly reduced the invasive capacity and significantly slowed the migration rates of PC-3 and DU-145 cells in vitro. Similarly, PC-3 cells containing the matriptase-2 expression plasmid were dramatically less able to survive, grow and develop into noticeable tumours, compared to control PC-3 cells containing an empty plasmid alone, following subcutaneous inoculation into CD1 nude mice. This trend was observed throughout the experiment, becoming apparent after the initial reading on day 7 (P = 0.0002) and continuing to the experimental end point at day 27 (P = 0.0002). Enhanced matriptase-2 levels were also seen to correlate with increased fluorescent staining of the paxillin and FAK adhesion molecules, where a greater extent of these molecules were localised to the focal adhesion complexes. This data suggests a suppressive role for matriptase-2 in the invasion and migration of prostate cancer cells in vitro and also in their development and growth in vivo, highlighting the potential of this molecule to interfere with key stages of metastasis. Furthermore, the data presented implies a possible connection between matriptase-2 and the paxillin and FAK adhesion molecules which may ultimately contribute to the reduced migration rates seen in this study. PMID- 18449908 TI - Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis. AB - Alzheimer's disease is a complex progressive neurodegenerative disorder with profound cognitive decline. Multiple susceptibility genetic variants have been identified with equivocal replication. While rare, collections of extended pedigrees with multiple affected family members are invaluable for genome-wide screens. We have used two extended pedigrees, having 14-15 siblings with four to five affected late-onset Alzheimer's disease patients in each, to identify the gene, transient receptor potential cation channel, subfamily C, member 4 associated protein (TRPC4AP), on chromosome 20q11.22, as relevant for the disease. Multiple significant SNPs in this gene were found with the initial genome scan (after Bonferroni correction). Additional SNPs were assessed in the families and in the controls which were also significant by haplotype analysis. Moreover, 36% of the patients' haplotypes in our collection of late-onset patients had the same haplotype. These results suggest that TRPC4AP is involved with the disease in these late-onset Alzheimer's families. The results also confirm the use of the genome-wide association study for identifying new genetic variants of complex diseases. PMID- 18449909 TI - Support for schizophrenia susceptibility locus on chromosome 2q detected in a Swedish isolate using a dense map of microsatellites and SNPs. AB - Extended pedigrees are not only very useful to identify disease genes for rare Mendelian conditions, but they may also help unravel the genetics of complex diseases such as schizophrenia. In this study we performed genome-wide multipoint non-parametric linkage (NPL) score calculations using 825 microsatellites and 5,366 single nucleotide polymorphisms (SNPs), respectively, and searched for haplotypes shared by affected individuals, in three multiplex families including 29 genotyped affected individuals which in total contains 49 relative pairs useful for linkage studies. The most consistent results for microsatellites and SNPs were observed on 2q12.3-q14.1 (NPL scores 2.0, empirical P-value 0.009). However, the overall highest NPL score was observed on chromosome 2q33.3 using SNPs (NPL score 2.2, empirical P-value 0.007). Other chromosomal regions were detected on 5q15-q22.1, with microsatellites (NPL scores 1.7, empirical P-value 0.021) and with SNPs (NPL scores 2.0, empirical P-value 0.010) and on 5q23.1 (NPL score 1.9, empirical P-value 0.012) and 8q24.1-q24.2 (NPL score 2.1, empirical P value 0.009) when using SNPs. The analysis of extended pedigrees allowed the search for haplotypes inherited identical by decent (IBD) by affected individuals. In all regions with NPL score >1.9 we found haplotypes inherited IBD by multiple cases. However, no common haplotypes were found for affected individuals in all families. In conclusion our NPL results support earlier findings suggesting that 2q and possibly 5q and 8q contain susceptibility loci for schizophrenia. Haplotype sharing in families helped to delimit the detected regions that potentially are susceptibility loci for schizophrenia. PMID- 18449910 TI - Genome-wide scan in 124 Indonesian sib-pair families with schizophrenia reveals genome-wide significant linkage to a locus on chromosome 3p26-21. AB - Variation in incidence of schizophrenia between populations with different ethnical background may reflect population specific differences in nature and composition of genetic and environmental factors. In order to investigate whether there are population specific susceptibility genes for schizophrenia, we collected in Indonesia families with two or more affected siblings and, as far as available, parents and unaffected siblings, suitable for genetic linkage- and association studies. After checking extensively for incompatibilities with Mendelian inheritance as well as for errors in sampling, we used 124 families from the sample of 152 originally ascertained families for linkage analysis. Genotyping was performed at the NHLBI Mammalian Genotyping Service at Marshfield Research Organisation using the Screening Set 16, which comprises 402 Short Tandem Repeat Polymorphisms (STRPs). The genotypes of 540 individuals including 267 affected with schizophrenia were used for analysis. Multipoint sib-pair linkage analysis was carried out by estimation of--allele sharing derived- maximum likelihood LOD scores (MLS) in 154 sib-pair combinations. We obtained a genome-wide significant MLS of 3.76 on chromosome 3p26.2-25.3. Genome-wide significance was estimated by performing 10,000 simulated genomescans. Additional loci were detected on 1p12, which produced suggestive evidence for linkage (MLS = 2.35), as well as on 5q14.1 (MLS = 1.56), 5q33.3 (MLS = 1.11), and 10q (MLS = 1.17), where linkage had been reported previously. In conclusion, our study detected a region with genome-wide significant linkage, which will serve as starting point for identification of schizophrenia susceptibility genes in the Indonesian population. PMID- 18449911 TI - Evaluation of in silico splice tools for decision-making in molecular diagnosis. AB - It appears that all types of genomic nucleotide variations can be deleterious by affecting normal pre-mRNA splicing via disruption/creation of splice site consensus sequences. As it is neither pertinent nor realistic to perform functional testing for all of these variants, it is important to identify those that could lead to a splice defect in order to restrict transcript analyses to the most appropriate cases. Web-based tools designed to provide such predictions are available. We evaluated the performance of six of these tools (Splice Site Prediction by Neural Network [NNSplice], Splice-Site Finder [SSF], MaxEntScan [MES], Automated Splice-Site Analyses [ASSA], Exonic Splicing Enhancer [ESE] Finder, and Relative Enhancer and Silencer Classification by Unanimous Enrichment [RESCUE]-ESE) using 39 unrelated retinoblastoma patients carrying different RB1 variants (31 intronic and eight exonic). These 39 patients were screened for abnormal splicing using puromycin-treated cell lines and the results were compared to the predictions. As expected, 17 variants impacting canonical AG/GT splice sites were correctly predicted as deleterious. A total of 22 variations occurring at loosely defined positions (+/-60 nucleotides from an AG/GT site) led to a splice defect in 19 cases and 16 of them were classified as deleterious by at least one tool (84% sensitivity). In other words, three variants escaped in silico detection and the remaining three were correctly predicted as neutral. Overall our results suggest that a combination of complementary in silico tools is necessary to guide molecular geneticists (balance between the time and cost required by RNA analysis and the risk of missing a deleterious mutation) because the weaknesses of one in silico tool may be overcome by the results of another tool. PMID- 18449912 TI - Improved local control by surgery and paclitaxel-based chemoradiation for esophageal squamous cell carcinoma: results of a retrospective non-randomized study. AB - BACKGROUND AND OBJECTIVES: To investigate the impact of using paclitaxel in chemoradiation on locally advanced esophageal squamous cell carcinoma (SCC) treated with or without surgery. METHODS: Of 127 patients with AJCC stages II-III esophageal SCC undergoing definitive chemoradiation (DefCRT, n = 44) or neoadjuvant chemoradiation plus surgery (NeoCRT + S, n = 83), 57 received chemotherapy with paclitaxel and cisplatin (TP), and 70 received 5-fluorouracil and cisplatin (PF). Three-year local progression-free survival (LPFS), distant metastasis-free survival, overall survival, and prognostic factors were retrospectively analyzed. RESULTS: The median survival was 30 months. Pathological complete response rate was 41% and 27% with TP and PF, respectively (P = 0.19). NeoCRT + S achieved significantly higher LPFS than DefCRT (71% vs. 39%, P < 0.001). Patients receiving TP had significantly higher LPFS than PF (74% vs. 48%, P = 0.04). Local control was similar between DefCRT with TP and NeoCRT + S. Distant metastasis-free survival and overall survival were not different between treatment modalities or chemotherapy regimens. In multivariate analysis, surgery (HR 0.30, P < 0.001), TP regimen (HR 0.38, P = 0.007), and mediastinal lymphadenopathy (HR 2.37, P = 0.008) were independent factors for LPFS. CONCLUSIONS: Both surgery and the use of paclitaxel-based chemoradiation may improve local disease control. Future randomized trials should integrate paclitaxel into definitive chemoradiation. PMID- 18449913 TI - Multiple primary malignancies in patients with sporadic pancreatic endocrine tumors. AB - BACKGROUND: To investigate the appearance of multiple primary malignancies in patients with sporadic neuroendocrine pancreatic tumors (NEPTs). METHODS: One hundred forty-five patients with NEPTs were treated at the Department of Surgery, Philipps-University Marburg. Multiple primary malignancies included tumors that were not considered to be a metastasis, invasion, or recurrence of NEPTs. Data on sex, age at diagnosis of cancer, follow-up time after diagnosis, and death rate were collected. RESULTS: Of 115 patients with sporadic NEPTs, 15 (13.0%) patients were identified with at least one malignant tumor, other than a NEPT. The median age at diagnosis of the associated tumor(s) was 57 years (range, 10-72 years). Two of the 15 patients had insulinomas, 5 had gastrinomas and 8 had non functioning NEPTs, respectively. The risk of developing multiple cancers was the highest for patients with gastrinoma (21.7%), followed by patients with non functioning NFPTs (20.5%). CONCLUSIONS: In patients with NEPTs multiple primary malignancies are found more frequently than in the general population. The etiology of the increased risk of other primaries is not clearly defined, but it may be the result of accumulated growth stimulation by the secreted hormones or a genetic alteration that leads to tumorogenesis in these patients. PMID- 18449914 TI - The significance of ANXA7 expression and its correlation with poor cellular differentiation and enhanced metastatic potential of gastric cancer. AB - BACKGROUND: Annexin-A7 (ANXA7) exhibits biological and genetic properties expected of a tumor suppressor gene and may play a role in cancer progression. However, the ANXA7 expression in different histological subtypes of gastric adenocarcinomas and its correlation with invasive potentials has not been elucidated. METHODS: Immunohistochemical staining of ANXA7 for 84 primary gastric adenocarcinomas was performed, and data was correlated with clinicopathological parameters of patients. RESULTS: The ANXA7 expression was well correlated with the grade of differentiation of primary tumors. Its expression was detected in 100% (8/8), 64.9% (24/37), 66.7% (2/3), 31.9% (13/31), 0% (0/3), and 0% (0/2) of well-differentiated tubular, moderately-differentiated tubular, papillary, poorly differentiated, signet-ring cell, and mucinous adenocarcinoma, respectively. According to the Lauren's classification, the ANXA7 expression was higher in intestinal type than in diffuse type tumor (71.9% vs. 6.1%, P = 0.003). The loss of expression of ANXA7 expression was significantly related to distant metastasis (P = 0.04). However, there were no significant associations between the ANXA7 expression and survival of cancer patients (P = 0.159). CONCLUSIONS: A striking correlation between ANXA7 expression and cell differentiation of gastric cancer was observed. The loss of expression of ANXA7 is associated with distant metastasis. PMID- 18449915 TI - Assessing the optimal duration of chemotherapy in patients with colorectal liver metastases. AB - BACKGROUND AND OBJECTIVES: Few studies have addressed the optimal duration of chemotherapy, particularly prior to liver resection for colorectal liver metastases (CLM). The purpose of this retrospective analysis was to evaluate time to maximal response in patients receiving systemic +/- hepatic arterial infusion (HAI) chemotherapy alone for the treatment of CLM. METHODS: We reviewed 35 patients with CLM on clinical trials of HAI floxuridine/dexamethasone plus systemic oxaliplatin with 5-fluorouracil/leucovorin or irinotecan (PUMP + SYSTEMIC). We retrospectively identified 35 patients with CLM who received first line systemic 5FU/leucovorin/oxaliplatin (FOLFOX) +/- bevacizumab (SYSTEMIC) during the same time period. Measurable disease was evaluated on CT scans performed at 2-month intervals. The sum of the products of bi-dimensional tumor measurements for representative lesions was compared both to baseline imaging and between consecutive time points. RESULTS: In responders to therapy, mean cumulative tumor reduction increased from 61% at 2 months to 73% at 4 months in the PUMP + SYSTEMIC group (P < 0.01) and from 39% to 56% in the SYSTEMIC group (P < 0.01). No significant incremental tumor reduction occurred between 4 and 6 months in either group. CONCLUSIONS: In responders to preoperative therapy, surgical resection should be considered after 2-4 months, when most patients have achieved maximal response. PMID- 18449917 TI - Influence of polymeric excipients on crystal hydrate formation kinetics in aqueous slurries. AB - Crystalline anhydrous active pharmaceutical ingredients (APIs) can potentially transform to the hydrate form during manufacturing processes involving water. The ability to understand and manipulate these transformations is important to maintain control of the solid state form of the API. The influence of various polymeric excipients on the anhydrate to hydrate transformation of caffeine, carbamazepine, and sulfaguanidine was investigated in this study. The transformation of the APIs in aqueous slurries was monitored using in-line Raman measurements and the resultant kinetic profiles provided insight into the inhibitory ability of the polymers investigated. The results showed that cross linked poly(acrylic acid) inhibited the caffeine transformation and hydroxypropyl methylcellulose inhibited the carbamazepine transformation. None of the polymers tested were able to inhibit the sulfaguanidine transformation although some polymers were able to reduce the rate of the transformation with poly(vinylpyrrolidone) showing the greatest effect. It was found that the inhibitory polymers were able to either reduce crystal growth rates and/or increase the induction time preceding the nucleation event. PMID- 18449918 TI - Solid state yellow and orange lasers for flow cytometry. AB - Diode and DPSS lasers emitting a variety of wavelengths are now commonly incorporated into flow cytometers, greatly increasing our capacity to excite a wide variety of fluorochromes. Until recently, however, virtually no practical technology existed for generating yellow or orange laser light for flow cytometry that was compatible with smaller instrumentation. In this study, we evaluate several new solid state laser systems that emit from the 570 to 600 nm as excitation sources for flow cytometry. DPSS 580, 589, and 592 nm sources were integrated into a cuvette-based flow cytometer (BD LSR II) and a stream-in-air cell sorter (FACSVantage DiVa), and used to excite a variety of yellow, orange, and red excited fluorochromes, including Texas Red, APC, and its tandem conjugates, and the genetically encoded red fluorescent protein HcRed and the more recently developed Katushka. All laser sources were successfully incorporated into the indicated flow cytometry platforms. The yellow and orange sources (particularly 592 nm) were ideal for exciting Texas Red, and provided excitation of APC and its tandems that was comparable to a traditional red laser source, albeit at higher power levels than red sources. Yellow and orange laser light was optimal for exciting HcRed and Katushka. Practical yellow and orange laser sources are now available for flow cytometry. This technology fills an important gap in the laser wavelengths available for flow, now almost any fluorochrome requiring visible light excitation can be accommodated. PMID- 18449919 TI - Assessing departure from Hardy-Weinberg equilibrium in the presence of disease association. AB - Assessing Hardy-Weinberg equilibrium (HWE) is often employed as an important initial step for genotype data quality checking in genetics studies. Tests for HWE often assume that the genotypes are randomly sampled from the general population. However, in many human genetics studies, subjects are ascertained through their disease status, and affected individuals (and their relatives in family-based studies) are overly represented in the ascertained sample than in the general population. As a result, when a marker is associated with the disease, the type I error rate in the HWE tests can be inflated, leading to false exclusion of associated markers from future analysis. Here we develop a general likelihood framework that allows assessment of departure from HWE while taking into account potential association with the disease. Our method can differentiate HWE departure caused by disease association from departure caused by other reasons, such as genotyping errors. The framework can be used for various data structures, including unrelated cases and controls, nuclear families with one or more offspring, or a mixture of them. The type I error rate of our test is under control for a broad range of scenarios. For case-control data, compared to the traditional HWE test that uses only controls, our test is more powerful to detect HWE departure for common diseases and has comparable power for rare diseases. For case-parents trios, our test is more powerful than the traditional HWE test that uses parents only. PMID- 18449920 TI - Recurrent mutation in SNPs within Y chromosome E3b (E-M215) haplogroup: a rebuttal. AB - In a previous issue of AJHB, Fernandes et al. (2008. Am J Hum Biol 20:185-190.) describe instances of identity by state at multiple short tandem repeat loci between human Y chromosomes belonging to different E-M35 sub-haplogroups. They interpret these findings as evidence for multiple mutational events in at least two loci (M78 and M81). Here, we introduce a novel polymorphic marker (V68), potentially useful to investigate the issue. This marker and sequence data, reported here for the first time, reinforce our previous interpretations on the phylogenetic structure of the E3b haplogroup. We discuss these results in the frame of general approaches to attain robust phylogenetic inferences based on biallelic polymorphism data. PMID- 18449921 TI - A genome wide linkage scan of metacarpal size and geometry in the Framingham Study. AB - Bone geometry is a significant component of bone strength, and has a clinical utility in predicting fractures and quantifying bone loss. Bone geometry is known to have a substantial genetic component. We performed linkage analysis to identify chromosomal regions governing metacarpal bone geometry. A genome-wide scan (with a set of 615 markers with spacing of approximately 5.7 cM) was performed on 1,702 individuals from 330 extended families of the Framingham Study. Midshaft width was measured and several indices calculated, namely Metacarpal Cortical Thickness (MCT), Cortical Index (MCI), and Section Modulus (MZ), using digitized X-rays of 1,380 participants (men, n = 666, mean age 55.2 yr, women, n = 714, 55.5 yr). Metacarpals 2, 3, and 4 were averaged. Heritability was significant for all indices, ranging from 0.51 to 0.72. Linkage analysis of indices adjusted for age, age(2), and estrogen status in women, identified chromosomal regions 6p21, 9p21, 11q21-q22, and Xq26-Xq27, with LOD scores >2.0. Additional adjustment for smoking, height, and BMI, generally reduced the LOD scores. Finally, bivariate linkage analysis confirmed that a QTL on chr. 6 (51 cM) was shared by midshaft width and MZ (LOD = 2.40, adjusted for all covariates). Neither MCT nor MCI shared linkage loci with width or MZ. In conclusion, we have identified chromosomal regions potentially linked to bone geometry. Genes in these regions may regulate bone geometry via effects on body size. Identification and subsequent characterization of loci for bone geometry can further elucidate the genetic contributions to bone's resistance to stress. PMID- 18449922 TI - The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells. AB - Chronic hepatitis B virus (HBV) infection is a major cause of liver fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma. Although the involvement of the X protein of HBV (HBx) in viral replication and tumor development has been extensively studied, little is known about its possible role in the development of fibrosis. In this work we show that expression of HBx in hepatocytes results in paracrine activation and proliferation of hepatic stellate cells (HSCs), the main producers of extracellular matrix proteins in the fibrotic liver. Both human primary HSCs and rat HSCs exposed to conditioned medium from HBx-expressing hepatocytes showed increased expression of collagen I, connective tissue growth factor, alpha smooth muscle actin, matrix metalloproteinase-2, and transforming growth factor-beta (TGF-beta), together with an enhanced proliferation rate. We found that HBx induced TGF-beta secretion in hepatocytes and that the activation of HSCs by conditioned medium from HBx-expressing hepatocytes was prevented by a neutralizing anti-TGF-beta antibody, indicating the involvement of this profibrotic factor in the process. CONCLUSION: Our results propose a direct role for HBx in the development of liver fibrosis by the paracrine activation of stellate cells and reinforce the indication of antiviral treatment in patients with advanced HBV-related chronic liver disease and persistent liver replication. PMID- 18449923 TI - Evidence that parent-of-origin affects birth-weight reductions at high altitude. AB - Hypoxia exerts a profound depressant effect on fetal growth, lowering birth weight, and raising mortality risk. Multigenerational high-altitude populations are relatively protected from this birth-weight decline, leading us to hypothesize that genetic factors were involved. We asked if the amount of high- versus low-altitude ancestry influenced birth weight at high altitude and, specifically, whether such influences were affected by parent-of-origin effects (i.e., genomic imprinting). Medical records were reviewed from 1,343 consecutive, singleton deliveries in La Paz, Bolivia (3,600 m) of high- (Andean) or low- (European) altitude ancestry. Parental surnames were used to classify ancestry as Andean, European, Mestizo ("mixed") or some combination thereof. The effects of population ancestry on birth weight were determined by categorical, conditional linear regression. Babies born at altitude with two Andean parents weighed 252 g more than their European counterparts, with the protective effect being proportional to the amount of Andean parentage and independent of maternal parity, body size, smoking, or socioeconomic status. Paternal compared with maternal transmission raised birth weight 81 g for a given ancestry group. We concluded that indigenous high-altitude ancestry protected against hypoxia associated fetal growth reduction in a dose-dependent fashion consistent with the involvement of genetic factors. Further, some of the genes involved appeared to be influenced by parent-of-origin effects, given that maternal transmission restricted and paternal transmission enhanced fetal growth. PMID- 18449924 TI - Heritability of fluctuating asymmetry in a human twin sample: the effect of trait aggregation. AB - Fluctuating asymmetry is thought to reflect developmental instability, which may in turn indicate genetically influenced fitness. Controversy surrounding these claims has centered on the extent to which fluctuating asymmetry is heritable. Most studies have estimated its heritability to be very low using single-trait measures. This study uses data from a human twin sample to demonstrate that the heritability estimate resulting from the aggregation of fluctuating asymmetry across multiple traits is non-zero. This is the case even when the estimates of fluctuating asymmetries of the individual traits do not differ significantly from 0. PMID- 18449925 TI - Clinical delineation of Giuffre-Tsukahara syndrome: another case with microcephaly and radio-ulnar synostosis with apparent X-linked semi-dominant inheritance. AB - Two families and three sporadic cases have been described so far with the combination of radio-ulnar synostosis and microcephaly as main features. Some authors have discussed whether the first family reported by Giuffre et al. [1994] and the second family described by Tsukahara et al. [1995] had the same syndrome. Although there is phenotypic variability among the described cases (especially with respect to facial dysmorphisms and mental retardation), the clinical patterns do not seem to be clearly distinguishable from each other. We describe another family with apparent X-linked semi-dominant inheritance with milder features in the female patient due to skewed X-inactivation. From a clinical synopsis, we consider the Giuffre-Tsukahara syndrome as one genetic entity, which is characterized by the association of microcephaly and radio-ulnar synostosis, mental retardation in male patients and variable minor features. Patients with the Giuffre-Tsukahara syndrome do not present with a characteristic pattern of facial features. PMID- 18449926 TI - Cryptic 17q22 deletion in a boy with a t(10;17)(p15.3;q22) translocation, multiple synostosis syndrome 1, and hypogonadotropic hypogonadism. AB - We report on a boy who had multiple synostosis syndrome 1, an autosomal dominant disorder characterized by progressive symphalangism, multiple joint fusions, conductive deafness, and mild facial dysmorphism. In addition the boy developed delay of puberty, bone age, and closure of the epiphyseal lines of long bones with tall stature. These findings and decreased plasma LH and FSH levels at age 19 years were compatible with hypogonadotropic hypogonadism. G-banded chromosomes showed a balanced translocation t(10;17)(p15.3;q22). Chromosomal FISH analysis, using a series of BAC clones surrounding the translocation breakpoints, detected a 2.2-3.9 Mb deletion at 17q22. The deletion encompassed NOG, a gene responsible for multiple synostosis syndrome 1. It was assumed that a gene for pituitary secretion of gonoadotropic hormones was deleted at the 17q22 segment. PMID- 18449927 TI - Evidence suggesting the inheritance mode of the human P gene in skin complexion is not strictly recessive. PMID- 18449928 TI - A selective clinical cytogenetic study in prenatal and pediatric pathology: a comparison with unselected studies. PMID- 18449929 TI - Is trisomy 14 mosaic a clinically recognizable syndrome?--case report and review. PMID- 18449930 TI - Genotoxicity testing of the herbicide trifluralin and its commercial formulation Treflan using the piscine micronucleus test. AB - In this study, the genotoxic effects of a widely used herbicide, trifluralin, and its commercial formulation, Treflan, were evaluated using the micronucleus test in a commercially important fish species, Oreochromis niloticus (Nile Tilapia). Fish were exposed to 1, 5, and 10 microg/L doses of trifluralin and Treflan for 3, 6, and 9 days under laboratory conditions. Ethylmethanesulfonate, at a single dose of 10 mg/L, was used as positive control. Micronuclei were evaluated on the peripheral erythrocytes. Both Treflan and trifluralin treatments significantly increased the micronucleus frequencies in peripheral erythrocytes of O. niloticus. Furthermore, the genotoxicity of the active ingredient, trifluralin, was observed to be higher than that of the commercial formulation Treflan. Our results indicate that herbicide trifluralin has genotoxic potential in fish. PMID- 18449931 TI - A multi center study of granulocyte and monocyte adsorption apheresis therapy for ulcerative colitis-clinical efficacy and production of interleukin-1 receptor antagonist. AB - Granulocyte and monocyte adsorption apheresis (GCAP) is a useful strategy for intractable ulcerative colitis, but its mechanisms of therapy is not fully explained. Previously, depleting activated granulocytes and monocytes (GMs) and modifying product of proinflammatory cytokines had been proposed. In addition, activated GMs are releasing anti-inflammatory cytokines, interleukin-1 receptor antagonist (IL-1ra) that may contribute to the clinical efficacy of GCAP therapy. Hence, to investigate contribution of IL-1ra as well as to confirm clinical efficacy of this therapy based on clinical activity index (CAI), we performed a multicenter study. Twenty-five of 38 (65.8%) patients achieved remission state (CAI < or = 4) and two of 38 (5.3%) revealed clinical improvement. Almost effective cases significantly decreased CAI even at 3rd session of GCAP. Plasma level of IL-1ra from outflow of the GCAP column at 30 min was significantly increased rather than inflow. Median exact elevated level of IL-1ra was 221 pg/ml and median of increasing ratio was 1.6 times. Furthermore, the responsive patients, who well released the IL-1ra at outflow more than 100 pg/ml compared with inflow, tended to show clinical effectiveness. While, the increased ratio of IL-1ra in effective cases did not differ from ineffective cases, and there were no significant relationship with improvement of CAI score. These conflict results suggest that the increase of IL-1ra at outflow is not a direct factor to the clinical improvement, but the induction of clinical improvement is accompanied by the release of IL-1ra. The IL-1ra may be involved in the multiple steps for the improvement induced by GCAP. PMID- 18449932 TI - Characterization of the genotoxicity of nitrilotriacetic acid. AB - The chelating agent nitrilotriacetic acid (NTA), classified as an epigenetic rodent carcinogen, was assessed in the in vivo rodent Comet assay on isolated kidney cells. Unexpected potent increases in DNA damage were obtained in both the short (3-6 hr) and long-term (22-26 hr) expression times after a single oral treatment at 1,000-2,000 mg/kg bw. NTA was assayed in the Ames test using TA1537, TA98, TA100, and TA102 tester strains, and in the in vitro micronucleus assay on L5178Y mouse lymphoma cells and on CTLL2 and CTLL2/Bcl2 cells coupled to the apoptosis measurement, both with and without metabolic activation by aroclor 1254 induced liver or kidney rat S9-mix. Whatever the S9 origin, neither genotoxicity nor apoptosis was detected, while a strong increase in the micronuclei formation was observed without S9 without any apoptosis induction. The direct genotoxicity of NTA was confirmed in the mouse lymphoma tk+/- gene mutation assay and in the chromosomal aberrations test on human lymphocytes. When tested in combination with an excess of Ca2+, NTA gave negative results on L5178Y mouse lymphoma cells in the in vitro Comet and micronucleus assays but still induced DNA damage on rat primary kidney cells. The higher sensitivity of renal cells to Ca2+ variations could explained the positive response observed in vivo. The carcinogenicity of NTA could be a consequence of the survival of kidney cells to intracellular variations of Ca2+, leading to a local and indirect genotoxicity. This suggests that threshold dose exists beyond which tumor-generating events will be displayed. PMID- 18449933 TI - Discrepant DNA analysis in three patients with inherited arrhythmia: molecular genetic test results deserve a second glance. AB - Molecular results provide a basis for diagnosis, risk assessment, medical management and genetic counseling. Unlike other areas of laboratory medicine, molecular genetic tests are rarely repeated. We describe three patients with suspected inherited arrhythmia in whom genetic testing was arranged via clinical and/or research laboratories. In all three instances, initial test results appeared falsely negative, with no deleterious mutations detected by various methodologies in selected long-QT or catecholaminergic polymorphic ventricular tachycardia-related genes. Discordant results emerged upon repeat analysis in separate laboratories. The cases highlight the importance of clinical judgment and assessment of genetic test results and methodology, in addition to the role of re-testing in molecular genetic medicine, particularly in the case of uninformative negative results. PMID- 18449934 TI - Craniosynostosis in a patient with a de novo 15q15-q22 deletion. AB - Interstitial deletions involving the chromosomal band 15q15 are very rare. A total of five cases were previously reported. Here another case of a 15q15.2 q22.2 deletion is reported, presenting with severe craniosynostosis of coronary, metopic, and sagittal sutures. The chromosome 15 with the 17.7-Mb deletion was of the paternal origin. A critical region for craniosynostosis may be located at the 734-kb segment at 15q15.2. Interestingly, the entire FBN1 gene was deleted in this patient. PMID- 18449935 TI - Corrosion resistance and cytocompatibility of biodegradable surgical magnesium alloy coated with hydrogenated amorphous silicon. AB - The fast degradation rates in the physiological environment constitute the main limitation for the applications of surgical magnesium alloys as biodegradable hard-tissue implants. In this work, a stable and dense hydrogenated amorphous silicon coating (a-Si:H) with desirable bioactivity is deposited on AZ91 magnesium alloy using magnetron sputtering deposition. Raman spectroscopy and Fourier transform infrared spectroscopy reveal that the coating is mainly composed of hydrogenated amorphous silicon. The hardness of the coated alloy is enhanced significantly and the coating is quite hydrophilic as well. Potentiodynamic polarization results show that the corrosion resistance of the coated alloy is enhanced dramatically. In addition, the deterioration process of the coating in simulated body fluids is systematically investigated by open circuit potential evolution and electrochemical impedance spectroscopy. The cytocompatibility of the coated Mg is evaluated for the first time using hFOB1.19 cells and favorable biocompatibility is observed. PMID- 18449936 TI - Aqueous versus non-aqueous salt delivery strategies to enhance oral bioavailability of a mitogen-activated protein kinase-activated protein kinase (MK-2) inhibitor in rats. AB - A potent pyridine-containing MK2 inhibitor has recently been internally discovered. In pre-clinical dosing, the low solubility of the neutral form limited oral bioavailability and dose escalation in toxicity studies. A mesylate salt was developed as part of a formulation strategy to enhance both oral bioavailability and dose escalation orally in pre-clinical rat studies. Several non-aqueous systems were used to deliver the mesylate salt, which resulted in varied oral bioavailability. It was found that administration of an aqueous chaser immediately after dosing drastically increased the oral bioavailability of the salt. This finding implies that the quantity of water present in vivo is an important consideration when evaluating salts of free bases with low aqueous solubility in pre-clinical in vivo rat models where limited aqueous vehicle may be presented. PMID- 18449937 TI - Formulation development and process scale up of a high shear wet granulation formulation containing a poorly wettable drug. AB - Aplaviroc 200 mg tablets were made by a high shear wet granulation process. A formulation and process DOE were carried out to define formulation and process parameters at pilot scale in GSKs R&D facility. During the scale up, several batches made at the production facility dissolved slower than the R&D batches. Extensive studies were conducted to examine a variety of factors to identify the root cause of this small but consistent drop in dissolution. Tablet hardness and lubrication time had a rather surprising impact on drug dissolution. Softer tablets dissolved slower despite disintegrating faster. Lubricating the granules with magnesium stearate for 3 h produced faster dissolving tablets than lubricating the granules for 3 min. Visual observations made during the dissolution trials shed some light on these surprising phenomena. As tablets disintegrated, some fragments floated to the top of the dissolution vessels and remained floating throughout the test. Due to poor wetting and lack of shear force, the drug was entrapped in these floating particles. Softer tablets and "lightly-lubricated" tablets disintegrated faster and had the floating fragments appear earlier in the dissolution trial. Sourcing of magnesium stearate may also play a role on the floating behavior. PMID- 18449938 TI - Human beta defensin 2 promotes intestinal wound healing in vitro. AB - Limiting microbial threats, maintenance and re-establishment of the mucosal barrier are vital for intestinal homeostasis. Antimicrobial peptides have been recognized as essential defence molecules and decreased expression of these peptides has been attributed to chronic inflammation of the human intestinal mucosa. Recently, pluripotent properties, including stimulation of proliferation and migration have been suggested for a number of antimicrobial peptides. However, it is currently unknown, whether the human beta-defensin 2 (hBD-2) in addition to its known antimicrobial properties has further effects on healing and protection of the intestinal epithelial barrier. Caco-2 and HT-29 cells were stimulated with 0.1-10 microg/ml hBD-2 for 6-72 h. Effects on cell viability and apoptosis were monitored and proliferation was quantified by bromo-deoxyuridine incorporation. Migration was quantified in wounding assays and characterized by immunohistochemistry. Expression of mucins was determined by quantitative PCR and slot-blot analysis. Furthermore, anti-apoptotic capacities of hBD-2 were studied. Over a broad range of concentrations and stimulation periods, hBD-2 was well tolerated by IECs and did not induce apoptosis. hBD-2 significantly increased migration but not proliferation of intestinal epithelial cells. Furthermore, hBD 2 induced cell line specific the expression of mucins 2 and 3 and ameliorated TNF related apoptosis-inducing ligand (TRAIL) induced apoptosis. In addition to its known antimicrobial properties, hBD-2 might have further protective effects on the intestinal epithelium. Results of this in vitro study suggest, that hBD-2 expression may play a dual role in vivo, i.e. in impaired intestinal barrier function observed in patients with inflammatory bowel disease. PMID- 18449939 TI - Sympathectomy alters bone architecture in adult growing rats. AB - Sympathetic nervous system (SNS) fibres and alpha- and beta-receptors are present in bone, indicating that the SNS may participate in bone metabolism. The importance of these observations is controversial because stimulation or inhibition of the SNS has had various effects upon both anabolic and catabolic activity in this tissue. In this study we evaluated the effects of pharmacological sympathectomy, using chronic treatment of maturing male rats with 40 mg of guanethidine/kg i.p., upon various parameters in bone. Double labelling with tetracycline injection was also performed 20 and 2 days before sacrifice. Bone mass, mineral content, density and histomorphometric characteristics in different skeletal regions were determined. Bone metabolic markers included urinary deoxypyridinoline and serum osteocalcin measurements. Guanethidine significantly reduced the accretion of lumbar vertebral bone and of mineral content and density, compared to controls. Femoral bone mineral content and density were also significantly reduced, compared to controls. Histomorphometric analyses indicated these effects were related to a reduction of cortical bone and mineral apposition rate at femoral diaphysials level. Both markers of bone metabolism were reduced in controls as they approached maturity. Guanethidine significantly decreased serum osteocalcin compared to controls, while urinary deoxypyridinoline was unchanged. These data indicate that guanethidine-induced sympathectomy caused a negative balance of bone metabolism, leading to decreased mass by regulating deposition rather than resorption during modeling and remodeling of bone. PMID- 18449940 TI - Receiving inconclusive genetic test results: an interpretive description of the BRCA1/2 experience. AB - We examined the experience of 21 women diagnosed with breast or ovarian cancer who received inconclusive BRCA1/2 genetic test results. Although these women received similar information on the technical meaning of an inconclusive result, their interpretations of personal risk for a probable, inherited cancer mutation differed. Their interpretations ranged from confidence that they probably carried an undetected gene mutation to believing that their cancer had no genetic basis. Women drew from their personal experience with genetic testing and from distinctive perceptions and beliefs in attempting to understand their test results; they variously drew upon such evidence as observations of similarities and differences within familial breast/ovarian cancer patterns to explain their ultimate conclusions as to their own genetic status. PMID- 18449941 TI - The neuroglial population in the primary visual cortex of the aging rhesus monkey. AB - The effects of age on neuroglial cells have been examined in the primary visual cortices of rhesus monkeys that had been behaviorally tested. The assessment of changes in the neuroglial populations was made on the basis of the frequency of occurrence of profiles of neuroglial cells in semithick sections of osmicated tissue stained with toluidine blue. No changes were found in the numbers of astrocytes and microglial cells with age, but the numbers of oligodendrocytes increased by about 50%. The myelinated nerve bundles at the level of layer 4 were also examined by electron microscopy to assess the effects of age on the nerve fibers. The numbers of nerve fiber profiles showing age-related alterations in their myelin sheaths increase with age. There was also an age-related increase in the frequency of profiles of nerve fibers sectioned through paranodes, indicating that shorter lengths of myelin are being produced by remyelination. These changes in sheaths both correlate significantly with the frequency of oligodendrocyte profiles, suggesting that with age additional oligodendrocytes are required to remyelinate nerve fibers whose sheaths have broken down, probably by death of the original parent oligodendroglial cell. Also the most cognitively impaired monkeys had the greatest numbers of oligodendrocytes, but this is probably a secondary correlation, reflecting the fact that altered myelin slows down the rate of conduction along nerve fibers, which leads to cognitive decline. PMID- 18449942 TI - Perceived stress in survivors of suicide: psychometric properties of the Perceived Stress Scale. AB - The purpose of this study was to evaluate the psychometric properties of three versions of the Perceived Stress Scale (PSS; American Sociological Association) in adults who had survived the death of a family member or significant other by suicide. Reliability and validity were examined. Exploratory factor analysis was conducted to assess dimensionality of the underlying constructs. All three versions of the PSS demonstrated acceptable reliability. Two shorter versions retained good psychometric properties and demonstrated convergent and concurrent validity with measures of posttraumatic stress symptoms and mental health quality of life. Factor analysis provided further evidence of their usefulness as brief and valid measures of perceived stress in acutely bereaved adult survivors of suicide. In a sub-sample of closely related survivors, the psychometric properties of the 4-item version of the PSS were retained. PMID- 18449944 TI - Alumina ceramic particles, in comparison with titanium particles, hardly affect the expression of RANK-, TNF-alpha-, and OPG-mRNA in the THP-1 human monocytic cell line. AB - Particle-induced osteolysis is the most frequent cause of aseptic loosening after total joint replacement. We performed a study to illuminate the effect of ceramic particles with different diameters and concentrations on the mRNA expression of certain key regulators in particle-induced aseptic osteolysis (RANK, RANKL, OPG, and TNF-alpha) in THP-1 macrophage-like cells. Titanium particles were used as a positive control. RNA was analyzed by quantitative RTPCR. Our results demonstrate that alumina ceramic particles, regardless of particle size, caused only slight upregulations of RANK, TNF-alpha, and OPG mRNA, whose levels were significantly lower in comparison with those of titanium particles (p < 0.05). The continuous increasing tendency to time and particle-dependent mRNA expression of all the parameters stimulated by titanium particles was not found after stimulation with ceramic materials. Even after the concentration of ceramic particles was increased, only a mild upregulation of mRNA expression was found. Furthermore, we observed that the bioinert properties of ceramic particles did not change much in diameters ranging from 0.5 to 1.5 microm. At most of the measuring time points, there was no significant difference between the reactions of the large and small particles in this range. Our results support the theory about the relative bioinert properties of alumina ceramic particles. PMID- 18449945 TI - Microglial phagocytosis is enhanced by monomeric alpha-synuclein, not aggregated alpha-synuclein: implications for Parkinson's disease. AB - Gathering evidence has associated activation of microglia with the pathogenesis of numerous neurodegenerative diseases of the central nervous system (CNS) such as Alzheimer's disease and Parkinson's disease. Microglia are the resident macrophages of the CNS whose functions include chemotaxis, phagocytosis, and secretion of a variety of cytokines and proteases. In this study, we examined the possibility that alpha-synuclein (alpha-syn), which is associated with the pathogenesis of Parkinson's disease, may affect the phagocytic function of microglia. We found that extracellular monomeric alpha-syn enhanced microglial phagocytosis in both a dose- and time-dependent manner, but beta- and gamma- syn did not. We also found that the N-terminal and NAC region of alpha-syn, especially the NAC region, might be responsible for the effect of alpha-syn on microglial phagocytosis. In contrast to monomeric alpha-syn, aggregated alpha-syn actually inhibited microglial phagocytosis. The different effects of monomeric and aggregated alpha-syn on phagocytosis might be related to their localization in cells. This study indicates that alpha-syn can modulate the function of microglia and influence inflammatory changes such as those seen in neurodegenerative disorders. PMID- 18449943 TI - A novel method to establish microglia-free astrocyte cultures: comparison of matrix metalloproteinase expression profiles in pure cultures of astrocytes and microglia. AB - Increased matrix metalloproteinase (MMP) proteolytic activity contributes to the pathogenesis of many neuroinflammatory and neurodegenerative conditions in the CNS. To fully understand this process, it is important to define the MMP expression profile of specific cell types, including the CNS-resident cells astrocytes and microglia. While previous studies have characterized astrocyte MMP expression by using mixed glial cultures, these results are likely complicated by the presence of contaminating microglia within these cultures. In the current study, we sought to clarify this complexity, by taking a novel approach to prepare pure astrocyte cultures entirely devoid of microglia, by promoting neural stem cell (NSC) differentiation into astrocytes. The MMP expression profile of mixed glial cultures, neurosphere-derived astrocytes, and pure microglia was characterized by RNase protection assay. This revealed that MMP gene expression is largely cell-type specific. Astrocytes constitutively expressed MMP-11, MMP 14, and MMP-2 and showed induction of MMP-3 in response to IL-1beta but did not respond to lipopolysaccharide (LPS). In contrast, microglia constitutively expressed high levels of MMP-12 and showed strong induction of MMP-9 and MMP-14 in response to LPS. Gelatin zymography confirmed that LPS and TNF-alpha induced strong expression of MMP-9 in microglia but not astrocytes. In summary, these studies demonstrate that neurosphere-derived astrocytes represent an attractive alternative system in which to study astrocyte behavior in vitro. Using this system, we have shown that astrocytes and microglia express distinct sets of MMP genes and that microglia, not astrocytes, are the major source of MMP-9 in response to LPS or TNF-alpha. PMID- 18449946 TI - Expression of Notch-1 receptor and its ligands Jagged-1 and Delta-1 in amoeboid microglia in postnatal rat brain and murine BV-2 cells. AB - Notch-1 receptor signaling pathway is involved in neuronal and glial differentiation. Its involvement in microglial functions, however, has remained elusive. This study reports the localization of Notch-1 receptor immunoreactivity in the amoeboid microglial cells (AMC) in the postnatal rat brain. By immunofluorescence, Notch-1 receptor was colocalized with its ligands, Jagged-1 and Delta-1, in the AMC in the corpus callosum and subventricular zone. Notch-1 immunopositive cells were confirmed to be microglia labeled by OX42 and lectin. Immunoexpression of Notch-1 receptor was progressively reduced with age. Western blot analysis showed that Notch-1 protein level in the corpus callosum in which the AMC were heavily populated was concomitantly decreased. In postnatal rats challenged with lipopolysaccharide (LPS), Notch-1 receptor immunofluorescence in AMC was noticeably enhanced. Furthermore, Notch-1 protein level in the corpus callosum was increased as revealed by Western blotting analysis. In primary microglial culture treated with LPS, mRNA expression of Notch-1 and its ligand Jagged-1 was upregulated but that of Delta-1 was reduced. The expression pattern of Notch-1 and its ligands was confirmed in murine BV-2 cells. Furthermore, Notch 1 neutralization with its antibody reduced its protein expression. More importantly, neutralization of Notch-1 concomitantly suppressed the mRNA expression of IL-6, IL-1, M-CSF, and iNOS; TNF-alpha, mRNA expression, however, was enhanced. Western blot confirmed the changes of protein level of the above except for IL-6, which remained relatively unaltered. It is concluded that Notch 1 signaling in the AMC and LPS-activated microglia/BV-2 cells modulates the expression of proinflammatory cytokines and nitric oxide. PMID- 18449947 TI - Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. AB - Early studies demonstrated that whole-body androgen receptor (AR)-knockout mice with hypogonadism exhibit insulin resistance. However, details about the mechanisms underlying how androgen/AR signaling regulates insulin sensitivity in individual organs remain unclear. We therefore generated hepatic AR-knockout (H AR(-/y)) mice and found that male H-AR(-/y) mice, but not female H-AR(-/-) mice, fed a high-fat diet developed hepatic steatosis and insulin resistance, and aging male H-AR(-/y) mice fed chow exhibited moderate hepatic steatosis. We hypothesized that increased hepatic steatosis in obese male H-AR(-/y) mice resulted from decreased fatty acid beta-oxidation, increased de novo lipid synthesis arising from decreased PPARalpha, increased sterol regulatory element binding protein 1c, and associated changes in target gene expression. Reduced insulin sensitivity in fat-fed H-AR(-/y) mice was associated with decreased phosphoinositide-3 kinase activity and increased phosphenolpyruvate carboxykinase expression and correlated with increased protein-tyrosine phosphatase 1B expression. CONCLUSION: Together, our results suggest that hepatic AR may play a vital role in preventing the development of insulin resistance and hepatic steatosis. AR agonists that specifically target hepatic AR might be developed to provide a better strategy for treatment of metabolic syndrome in men. PMID- 18449948 TI - Transcription factor Sp1 dysregulation in Alzheimer's disease. AB - Altered gene expression occurs in central nervous system disorders, including Alzheimer's disease (AD). Transcription factor Sp1 may be involved insofar as it can regulate the expression of several AD-related proteins, including amyloid precursor protein (APP) and tau. Sp1 could itself be regulated by inflammatory and other factors associated with AD, such as interleukin-1beta. We measured an almost threefold elevation in the number of mRNA molecules of this cytokine in the AD frontal cortex. Sp1 mRNA was found to be up-regulated in these AD brains (along with Sp1-regulated COX-2), and the Sp1 increase was also seen at the protein level by Western immunoblotting. To determine whether this would also occur in transgenic mice developing AD pathology, we examined the expression of Sp1 in the cortex and hippocampus and observed higher levels of Sp1 mRNA and protein. These results indicate that elements of regulatory pathways involving transcription factor Sp1 may be useful targets for therapeutic intervention to prevent or reverse AD. PMID- 18449949 TI - Influence of antidepressants on glycaemic control in patients with diabetes mellitus. AB - PURPOSE: Anecdotal evidence suggests that antidepressants (ADs) may complicate glycaemic control. The objective of this longitudinal study was to investigate the influence of ADs on glycaemic control within diabetes patients. METHODS: From the pharmacy registry database PHARMO, we selected insulin users who did not use oral antidiabetics. The study population comprised: 133 patients with at least 12 months insulin use before and 6 months during an AD episode, including 56 patients with an additional 6 months of insulin use after the AD episode; 180 patients with 24 months insulin use without an AD episode. Glycaemic control was measured as the amount of insulin used, which was calculated intra-individually in 3-month periods. We stratified for selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). RESULTS: Mean age (s.d.) of the subjects was 53.9 (19) years; 46.9% were men. Overall, the amount of insulin used did not change during or after AD use. No-AD users showed an increase of 16% in amount of insulin used over a period of 2 years (p < 0.001). SSRI users showed a decrease of 13% in amount of insulin used during the AD episode (p = 0.029), while no change was seen in TCA users. Notable was the large intra- and interindividual variation in amount of insulin used across all groups. CONCLUSIONS: Overall, AD use did not influence glycaemic control in diabetes patients. The tendency for a difference between SSRIs and TCAs is suggestive for a pharmacologic effect of ADs rather than a general effect of depression on glycaemic control. PMID- 18449950 TI - Therapy adapted to molecular response in patients with chronic myelogenous leukaemia in first chronic phase: results of the Duesseldorf study. AB - This study evaluates response-adapted treatment of chronic myelogenous leukaemia (CML) in chronic phase using molecular response criteria. bcr-abl/G6PDH ratios were assessed by Light-Cycler quantitative real-time polymerase chain reaction (PCR( in 277 peripheral blood samples from 33 patients, before and every 3 months during therapy. Sixty-six per cent (22/33) of the patients fulfiled our molecular response criterion of > or = 1 log decrease in bcr-abl transcript after 6 or > or = 2 log decrease after 9 and every following 3 months. Dose escalation was necessary for 33% (11/33) of the patients. Of these, 54% (6/11) achieved a reduction of bcr-abl mRNA by > or = 2 log (n = 3) or > or = 3 log (n = 3) with 800 mg Imatinib. Forty-five per cent (5/11) showed insufficient molecular response with 800 mg Imatinib and received Nilotinib. In conclusion, the assessment of molecular response permits an individual patient-tailored treatment of CML in first chronic phase, resulting in the majority of patients achieving a major molecular response after 2 years of therapy. PMID- 18449951 TI - Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. AB - AIM: To describe spontaneously reported cases of torsades de pointes (TdP) in Sweden and to investigate if this adverse drug reaction (ADR) was labelled in the summary of product characteristics (SPC) for the drugs implicated. METHODS: Reported cases of TdP 1991-2006 were identified and evaluated with regard to drug use and other possible risk factor. RESULTS: Among a total of 61 788 ADRs, 88 cases of TdP were identified. In these cases, 27 different suspected drugs were implicated. Cardiac drugs were involved in most reports (74%; 65/88), with sotalol being the most frequently suspected drug (57%, 58/88). In addition to drug treatment two or more established risk factors were present in 85% of the cases (75/88). Heart disease (90%; 79/88) was the most common risk factor followed by age over 65 years (72%; 63/88) and female gender (70%; 62/88). TdP or QT prolongation were labelled in the SPC for 33% (9/27) of the drugs implicated in the 88 cases. However, supporting evidence for an association was found elsewhere in 56% (15/27) for the different drugs implicated in the reports. Although citalopram was the third most common suspected drug in the reports (10%; 9/88), TdP was not listed in the SPC. CONCLUSION: TdP is a rarely reported ADR. Several risk factors are often present. In two thirds of the drugs implicated in the reports neither TdP nor QT prolongation was labelled in the SPC. Further investigations are needed regarding the association between citalopram and TdP. PMID- 18449952 TI - Influence of social network characteristics on cognition and functional status with aging. AB - OBJECTIVE: To determine whether more frequent engagement in larger social networks, and more emotional support protect against cognitive and functional decline with aging. METHODS: We examined the influence of social networks on cognition and instrumental activities of daily living (IADLs) over a median interval of 10.9 years. Data were from the Baltimore follow-up of the Epidemiologic Catchment Area (ECA) study, a community-based sample of adults in eastern Baltimore. Eight hundred and seventy-four participants completed cognitive testing at both the third and fourth study waves (1993-1996 and 2003 2004) on the Mini-Mental State Examination (MMSE) and a delayed word recall task. Functional status at both waves was self-reported on the Lawton-Brody IADL scale. Social network characteristics, assessed at the third study wave, included network size, frequency of contact, and emotional support. RESULTS: In cross sectional analyses at wave 3, larger networks were associated with higher MMSE and better delayed recall scores. This association persisted after adjustment for covariates. More emotional support was associated with better functional status, before and after adjustment. By contrast, social networks were not longitudinally associated with cognitive change, with two counter-intuitive exceptions: more frequent contact and more emotional support were associated with worse delayed recall and IADL scores after adjustment. CONCLUSIONS: There was no evidence of a longitudinal association between social networks and cognition or IADLs, although a clear cross-sectional association exists. Together, these findings suggest the emergence of social isolation in individuals declining in cognition and functioning, rather than a protective effect of social networks. PMID- 18449953 TI - Vascular factors and depression. AB - OBJECTIVE: This paper examines possible mechanisms that may explain the bi directional relationship between vascular disease and depression. DESIGN: A literature review was carried out using Medline from 1996 to 2007, using relevant key words including vascular depression, and supplemented by key references to earlier work. RESULTS: Several mechanisms were considered including: autonomic dysfunction, platelet activation, hypothalamic pituitary axis activation, endothelial dysfunction, cytokines, omega 3 fatty acids, genetics, homocysteine and effects of treatment. CONCLUSIONS: The relationship between vascular disease and depression cannot solely be explained by current established risk factors or the effects of treatment for depression. Other mechanisms must apply, and there is some evidence for common genetic factors. Promising future lines of investigation include homocysteine, cytokines and endothelial dysfunction. More longitudinal studies combined with measurements of these biomarkers are needed. PMID- 18449954 TI - Neural correlates of verbal episodic memory in patients with MCI and Alzheimer's disease--a VBM study. AB - OBJECTIVE: The hippocampus is a key area for episodic memory processes. Hippocampal atrophy is a hallmark feature of Alzheimer's disease (AD). We used a new and automatized morphometric technique to better characterize brain atrophy in subjects with different levels of cognitive deficit. METHODS: In this study 21 participants with Mild Cognitive Impairment (MCI), 12 patients with early AD and 29 elderly control subjects were subjected to high resolution MRI and a neuropsychological test battery. Brain volume across participants, measured by voxel-based morphometry (VBM), was correlated with verbal memory capacity, measured with a verbal memory test (VLMT). RESULTS: Atrophy in the anterior hippocampus, the ento- and perirhinal cortex as well as the parahippocampal gyrus, middle temporal gyrus and anterior cingulate cortex correlated closely with episodic memory performance. CONCLUSIONS: These brain areas are known to subserve episodic encoding of verbal material. The data contribute to a better understanding of atrophic brain processes in subjects at risk for AD. A combination of neuropsychological testing and voxel-based morphometry may serve as a diagnostic tool in the future. PMID- 18449955 TI - Studies on inclusion complexes of calix[4]arenes capped by diamide bridges with small organic molecules. AB - The inclusion of small neutral organic guests (acetonitrile, toluene, pyrazine, butylamine, nitromethane) by cyclic calix[4]arene diamide receptors was studied by (1)H NMR spectroscopy. The binding constants determined by (1)H NMR titration, and the results obtained by T(1) relaxation measurements and DOSY confirm the importance of the acidity of the C-H bond of the guests and highlight the role of steric interactions including conformational properties of the receptors in the recognition process. PMID- 18449957 TI - What has happened to measles mortality in Zimbabwe? In this issue. PMID- 18449958 TI - Bibliography. Current world literature. Androgens. PMID- 18449959 TI - The tragedy of the commons in microbial populations: insights from theoretical, comparative and experimental studies. AB - First principles of thermodynamics imply that metabolic pathways are faced with a trade-off between the rate and yield of ATP production. Simple evolutionary models argue that this trade-off generates a fundamental social conflict in microbial populations: average fitness in a population is highest if all individuals exploit common resources efficiently, but individual reproductive rate is maximized by consuming common resources at the highest possible rate, a scenario known as the tragedy of the commons. In this paper, I review studies that have addressed two key questions: What is the evidence that the rate-yield trade-off is an evolutionary constraint on metabolic pathways? And, if so, what determines evolutionary outcome of the conflicts generated by this trade-off? Comparative studies and microbial experiments provide evidence that the rate yield trade-off is an evolutionary constraint that is driven by thermodynamic constraints that are common to all metabolic pathways and pathway-specific constraints that reflect the evolutionary history of populations. Microbial selection experiments show that the evolutionary consequences of this trade-off depend on both kin selection and biochemical constraints. In well-mixed populations with low relatedness, genotypes with rapid and efficient metabolism can coexist as a result of negative frequency-dependent selection generated by density-dependent biochemical costs of rapid metabolism. Kin selection can promote the maintenance of efficient metabolism in structured populations with high relatedness by ensuring that genotypes with efficient metabolic pathways gain an indirect fitness benefit from their competitive restraint. I conclude by suggesting avenues for future research and by discussing the broader implications of this work for microbial social evolution. PMID- 18449961 TI - Toothache prevalence and associated factors: a population based study in southern Brazil. AB - OBJECTIVES: The aim of this study was to estimate toothache prevalence and associated factors among adult residents in Pelotas, a southern Brazilian city. METHODS: A cross-sectional population-based study was carried out in individuals aged > or = 20 years (n = 3353). A multi-stage sampling scheme was adopted, and data collection was performed at participants' homes through standardized pre tested questionnaires. Toothache in the past 6 months was regarded as the outcome. Socioeconomic and demographic data as well as health-related behavioural data were collected. All analyses were undertaken with a Poisson regression model, following a hierarchical conceptual model. RESULTS: The response rate was 93.5% and toothache prevalence was 17.7% (95% CI 16.0-19.3). Multivariable analyses revealed that toothache was more likely to be reported by those with low educational attainment and low family income. Younger subjects, women and black people were also more likely to report toothache. Current smokers and problem drinkers were at increased risk of experiencing toothache in the past 6 months. CONCLUSIONS: The toothache prevalence reported in the present study is not negligible and should initiate the formulation of preventive policies and support the planning of local oral health services. PMID- 18449960 TI - Cigarette smoking, alcohol drinking, and oral and pharyngeal cancer mortality in Japan. AB - OBJECTIVES: To prospectively examine the association of cigarette smoking and alcohol drinking with oral and pharyngeal carcinogenesis, we analyzed data from a nation-wide large-scale cohort study in Japan. METHODS: A total of 34 136 men and 43 711 women aged 40-79 years were included in the study. The Cox proportional hazard model was used to estimate the relative risk (RR) and 95% confidence interval (95% CI) of oral and pharyngeal cancer for smoking and drinking by sex, while adjusting for age, consumption of green tea, preference for salty foods, and consumption of green yellow vegetables. RESULTS: Current smokers were found to have a higher risk of death caused by oral and pharyngeal cancer compared with non-smokers in both sexes: the RR was 2.6 (95% CI: 1.0-6.7) in men and 8.2 (95% CI: 2.1-32.1) in women. Men who drank more than 46 g ethanol per day had an approximately threefold increased risk of oral and pharyngeal cancer. Simultaneous exposure to both factors was significantly associated with an elevated risk of oral and pharyngeal cancer (RR: 3.3, 95% CI: 1.1-9.6). CONCLUSIONS: The result supports the carcinogenic effect of cigarette smoking and alcohol drinking on the oral cavity and pharynx. PMID- 18449962 TI - Ability of oral bacteria to induce tissue-destructive molecules from human neutrophils. AB - AIM: The induction of tissue-destructive molecules from neutrophils by periodontopathic bacteria has been suggested as one of the mechanisms of periodontal destruction. The aim of this study was to determine whether the ability to stimulate neutrophils is an authentic characteristic of periodontopathic bacteria. METHODS: We evaluated, along with phagocytosis, the production of reactive oxygen species (ROS), matrix metalloproteinase-8 (MMP-8), and interleukin-1beta by neutrophils in response to non-periodontopathic Streptococcus sanguinis and periodontopathic bacteria Fusobacterium nucleatum and Treponema denticola, in the absence or presence of antibodies. Phagocytosis, the death of neutrophils, and intracellular ROS production were measured by flow cytometry and the concentrations of MMP-8 and interleukin-1beta secreted into medium were determined by enzyme-linked immunosorbent assay. RESULTS: S. sanguinis and F. nucleatum induced greater production of ROS, MMP-8, and interleukin-1beta than did T. denticola. The levels of tissue-destructive molecules produced by neutrophils had a positive correlation with phagocytosis. Opsonization of bacteria with antibodies significantly increased phagocytosis and ROS production and release, thus increasing both bacterial clearance and potential tissue damage. CONCLUSION: The ability of oral bacteria to induce tissue-destructive molecules from neutrophils is not an inherent characteristic of periodontopathic bacteria, which would provide a new insight into the role of neutrophils in periodontal destruction. PMID- 18449965 TI - Use of complementary and alternative medicine among minority women. PMID- 18449963 TI - The BMP signaling and its Smads in mandibular distraction osteogenesis. AB - AIM: The aim of the present study was to clarify the mechanism of signal transduction of bone morphogenetic proteins (BMPs) through their specific down signaling molecules Smads inducing bone formation in response to mechanical stimulus during distraction osteogenesis (DO) in the rat mandible. MATERIALS AND METHODS: Osteotomy of the left mandible was performed in 45 rats. Thirty rats underwent mandibular distraction (protocol; 5 days latency, 8 days distraction, and 2 weeks consolidation) while 15 rats served as non-distracted (fracture healing) group. The expression of BMPs-2,-4 and Smads 1, 5, and 8 were evaluated in the new regenerate area using immunohistochemistry. RESULTS: Expressions of BMPs-2,-4 and Smads 1, 5, and 8 were moderate during latency, significantly increased during distraction and decreased towards consolidation period. CONCLUSIONS: The enhanced expression of BMPs and its Smads during distraction compared to the non-distracted group suggests the possible role of BMP signaling pathway in translation of mechanical forces into biological results during DO. PMID- 18449964 TI - Reelin is overexpressed in the liver and plasma of bile duct ligated rats and its levels and glycosylation are altered in plasma of humans with cirrhosis. AB - Reelin is an extracellular matrix protein secreted by a variety of cell types in both embryonic and adult tissues, including the liver. However, the physiological significance of Reelin in normal and cirrhotic liver has thus far not been elucidated. We have investigated Reelin levels in the liver and plasma of bile duct ligated (BDL) rats. We observe a 115% increase in full-length Reelin and its 310- and 180-kDa fragments in liver extracts from BDL rats, compared to sham operated controls (p = 0.005). The overall increase in protein levels was associated with a 30% increase of Reelin transcripts (p = 0.03). Immunohistochemical analysis demonstrated that hepatic stellate cells are the major source of Reelin in the injured liver. Increased liver Reelin in BDL rats leads to a pronounced 165% increase in the plasma levels (p < 0.001), particularly in the less abundant 180-kDa fragment (300% increase; p < 0.001). The data provides evidence that a fraction of plasma Reelin is synthesized in the liver. In human subjects suffering liver cirrhosis the level of the 180-kDa fragment was also increased by 140% in the plasma (p < 0.001). Analysis of Reelin glycosylation by lectin binding demonstrated that the 180- and predominant 310 kDa Reelin fragments in the plasma of cirrhotic patients are differentially glycosylated compared to non-diseased control subjects. The data show that Reelin is up-regulated in experimental liver cirrhosis and that its levels and glycosylation are altered in plasma from patients with cirrhosis, thereby supporting that Reelin is involved in the pathogenesis of liver disease. PMID- 18449966 TI - A better understanding of arteries and valves would help prevent heart disease. PMID- 18449967 TI - Language may prevent some Hispanics from receiving good health care. PMID- 18449968 TI - Patient safety alert. Initiative gives families access to rapid response team. PMID- 18449969 TI - CMV infection and CMV disease in kidney transplant recipients--our experience. PMID- 18449970 TI - A loop formation of Meckel's diverticulum causes intestine ischemia. PMID- 18449971 TI - Thin-layer chromatography. PMID- 18449972 TI - The graphic strategy: the uses and functions of illustrations in Wundt's Grundzuge. PMID- 18449973 TI - [Abstracts of the 81st General Meeting of the Japanese Leprosy Association and the 20th Co-Medical Meeting]. PMID- 18449974 TI - [Step by step: differential indication and specialized in-door psychotherapy as implemented in a psychiatric-psychotherapeutic state hospital]. AB - Different patients need different treatment, when in-door psychotherapy is the indication. Also, in the course of psychotherapeutic treatment a change of setting might be useful or necessary. It is shown how this knowledge can be put into work in a psychiatric-psychotherapeutic state hospital with obligatory service, using an integrated group of several specialized wards. PMID- 18449975 TI - [Celebral vasculitis and autoimmune thyreoiditis]. AB - Hashimoto's encephalopathy- or steroid responsive encephalopathy with autoimmune thyreoiditis (SREAT) - is a disease that can show multiple neurologic manifestations. So far, the pathogenesis of Hashimoto's encephalopathy is not clear. We report on a 47-year-old male patient suffering from a cerebral infarction of the right posterior cerebral artery within the framework of an angiographic confirmed cerebral vasculitis and an autoimmune thyreoiditis. The clinical presentation of the disease could hardly be distinguished from the symptoms of Hashimoto's encephalopathy. The concurrence of the present results supports the view of a possible vasculitic origin of Hashimoto encephalopathy. PMID- 18449976 TI - [Symposium of pneumology, Moneasa, July 12-14, 2007]. PMID- 18449977 TI - [The 4th National Conference of Bronchology]. PMID- 18449978 TI - [Observation law in homicide criminal cases with schizophrenia undergoing psychiatric evaluation]. PMID- 18449979 TI - [Social demands and operational problems in the observation law for criminals with mental disorder]. PMID- 18449980 TI - [Determining S-1 dosage at hospitals prioritizing cancer chemotherapy]. AB - Although it is recommended that the standard S-1 dosage should be based on how large the body surface area is, an on-site setting of the appropriate dosage is often lower than the standard one, depending on the individual's condition and considering possible side effects and so, on. Here, we investigated usage conditions for S-1 as a part of field training for expert pharmacists at our hospital that performs total clinical treatments. Decreases in dosage per day for elderly patients were although the standard dosage is generally determined according to the amount of a patient's body surface. We conducted a retrospective survey with a total 90 patients by creating a tree-diagram to identify a reduction standard. It was found that the S-1 dosage was decreased when there were side effects, aggravation in performance status, decrease in kidney function, old age, combined injection chemotherapy, and a decrease in radiation therapy performance. The dosage decreases without such medical reasons were seen in only 4 of the 90 patients. The individual target dosage on the basis of daily medical examination. PMID- 18449981 TI - [Beginning forensic psychiatry]. PMID- 18449982 TI - Osler in Japan. PMID- 18449983 TI - The close links between the Oslers and the Howards. PMID- 18449984 TI - Comparison of a novel Fiberwire-button construct versus metallic screw fixation in a syndesmotic injury model. PMID- 18449985 TI - [Basis of clinical economics (8)]. PMID- 18449986 TI - [Health and welfare of the aged. (6) "Nutritional care and management in nursing prevention"]. PMID- 18449988 TI - Immunoinformatics. Predicting immunogenicity in silico. Preface. PMID- 18449987 TI - [Consensus document of the Spanish Society of Liver Transplantation]. PMID- 18449989 TI - Immunoinformatics and the in silico prediction of immunogenicity. An introduction. AB - Immunoinformatics is the application of informatics techniques to molecules of the immune system. One of its principal goals is the effective prediction of immunogenicity, be that at the level of epitope, subunit vaccine, or attenuated pathogen. Immunogenicity is the ability of a pathogen or component thereof to induce a specific immune response when first exposed to surveillance by the immune system, whereas antigenicity is the capacity for recognition by the extant machinery of the adaptive immune response in a recall response. In thisbook, we introduce these subjects and explore the current state of play in immunoinformatics and the in silico prediction of immunogenicity. PMID- 18449990 TI - IMGT, the international ImMunoGeneTics information system for Immunoinformatics. Methods for querying IMGT databases, tools, and Web resources in the context of immunoinformatics. AB - IMGT, the international ImMunoGeneTics information system (http://imgt.cines.fr), was created in 1989 by the Laboratoire d'lmmunoGenetique Moleculaire (LIGM) (Universite Montpellier II and CNRS) at Montpellier, France, in order to standardize and manage the complexity of immunogenetics data. IMGT is recognized as the international reference in immunogenetics and immunoinformatics. IMGT is a high quality integrated knowledge resource, specialized in (i) the immunoglobulin (IG), T cell receptors (TR), major histocompatibility complex (MHC) of human and other vertebrates; (ii) proteins that belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF); and (iii) related proteins of the immune systems (RPI) of any species. IMGT provides a common access to standardized data from genome, proteome, genetics, and three-dimensional (3D) structures for the IG, TR, MHC, IgSF, MhcSF, and RPI. IMGT interactive on-line tools are provided for genome, sequence, and 3D structure analysis. IMGT Web resources comprise 8,000 HTML pages of synthesis and knowledge (IMGT Scientific chart, IMGT Repertoire, IMGT Education, etc.) and external links (IMGT Bloc-notes and IMGT other accesses). PMID- 18449991 TI - The IMGT/HLA database. AB - The human leukocyte antigen (HLA) complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and include many highly polymorphic HLA genes. The naming of new HLA genes and allele sequences and their quality control is the responsibility of the WHO Nomenclature Committee for Factors of the HLA System. The IMGT/HLA Database acts as the repository for these sequences and is recognized as the primary source of up-to-date and accurate HLA sequences. The IMGT/HLA website provides a number of tools for accessing the database: these include allele reports, sequence alignments, and sequence similarity searches. The website is updated every 3 months with all the new and confirmatory sequences submitted to the WHO Nomenclature Committee. Submission of HLA sequences to the committee is possible through the tools provided by the IMGT/HLA Database. PMID- 18449992 TI - IPD: the Immuno Polymorphism Database. AB - The Immuno Polymorphism Database (IPD) (http://www.ebi.ac.uk/ipd/) is a set of specialist databases related to the study of polymorphic genes in the immune system. IPD currently consists of four databases: IPD-KIR, contains the allelic sequences of killer cell immunoglobulin-like receptors (KIRs); IPD-MHC, a database of sequences of the major histocompatibility complex (MHC) of different species; IPD-HPA, alloantigens expressed only on platelets; and IPD-ESTAB, which provides access to the European Searchable Tumour Cell Line Database, a cell bank of immunologically characterized melanoma cell lines. The IPD project works with specialist groups or nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The IPD project stores all the data in a set of related databases. Those sections with similar data, such as IPD-KIR and IPD-MHC, share the same database structure. PMID- 18449993 TI - SYFPEITHI: database for searching and T-cell epitope prediction. AB - Reverse immunology has been used for about 12 years in order to identify T-cell epitopes from pathogens or tumor-associated antigens. In this chapter, we discuss the advantages and pitfalls of T-cell epitope prediction compared to classical experimental procedures such as epitope mapping and cloning experiments. We introduce our three established programs, SYFPEITHI, PAProc, and SNEP, which are freely accessible at no cost in the World Wide Web for the prediction of either HLA-peptide binding or proteasomal processing of antigens. We demonstrate the performance of our epitope prediction programs with several examples and in comparison to other epitope prediction programs available. We also reflect the actual possibilities and limitations of such computer-aided work. PMID- 18449994 TI - Searching and mapping of T-cell epitopes, MHC binders, and TAP binders. AB - This chapter describes searching and mapping tools of MHCBN database, which is a curated database. It comprises over 23,000 peptide sequences, whose binding affinity with major histocompatibility complex (MHC) or transporter associated with antigen processing (TAP) molecules has been assayed experimentally. Each entry of the database provides full information (such as sequence, its MHC- or TAP-binding specificity, and source protein) about peptide whose binding affinity (IC50) and T-cell activity is experimentally determined. MHCBN has number of web based tools for analyzing and retrieving information. In this chapter, we describe how to use web tools integrated in MHCBN that include (i) mapping of experimentally determined antigenic regions on the query sequence, (ii) creation of allele-specific peptide data set, and (iii) BLAST search against MHC or antigen databases. PMID- 18449995 TI - Searching and mapping of B-cell epitopes in Bcipep database. AB - One of the major challenges in the field of subunit vaccine design is to identify the antigenic regions in an antigen, which can activate B cell. These antigenic regions are called B-cell epitopes. In this chapter, we describe how to use Bcipep, which is a database of experimentally determined linear B-cell epitopes of varying immunogenicity collected from literature and other publicly available databases. The current version of Bcipep database contains 3,031 entries that include 763 immunodominant, 1,797 immunogenic, and 471 null-immunogenic epitopes. The database provides a set of tools for analysis and extraction of data that includes keyword search, peptide mapping, and BLAST search. The database is available at http://www.imtech.res.in/raghava/bcipep/. PMID- 18449996 TI - Searching haptens, carrier proteins, and anti-hapten antibodies. AB - Haptens are small molecules that are usually nonimmunogenic unless coupled to some carrier proteins. The generation of anti-hapten antibodies is important for the development of immunodiagnostics and therapeutics. Recently, our group has developed a database called HaptenDB, which provides comprehensive information about 1,087 haptens. In this chapter, we describe following web tools integrated in HaptenDB: (i) keyword search facility allows search on major fields, (ii) browsing service, to display all haptens, carrier proteins and antibodies, and (iii) structure similarity search, which allows the users to search their structure against hapten structures. PMID- 18449997 TI - The classification of HLA supertypes by GRID/CPCA and hierarchical clustering methods. AB - Biological experiments often produce enormous amount of data, which are usually analyzed by data clustering. Cluster analysis refers to statistical methods that are used to assign data with similar properties into several smaller, more meaningful groups. Two commonly used clustering techniques are introduced in the following section: principal component analysis (PCA) and hierarchical clustering. PCA calculates the variance between variables and groups them into a few uncorrelated groups or principal components (PCs) that are orthogonal to each other. Hierarchical clustering is carried out by separating data into many clusters and merging similar clusters together. Here, we use an example of human leukocyte antigen (HLA) supertype classification to demonstrate the usage of the two methods. Two programs, Generating Optimal Linear Partial Least Square Estimations (GOLPE) and Sybyl, are used for PCA and hierarchical clustering, respectively. However, the reader should bear in mind that the methods have been incorporated into other software as well, such as SIMCA, statistiXL, and R. PMID- 18449998 TI - Structural basis for HLA-A2 supertypes. AB - The human leukocyte antigen (HLA) alleles are extremely polymorphic among ethnic population, and the peptide-binding specificity varies for different alleles in a combinatorial manner. However, it has been suggested that majority of alleles can be covered within few HLA supertypes, where different members of a supertype bind similar peptides, yet exhibiting distinct repertoires. Nonetheless, the structural basis for HLA supertype-like function is not clearly known. Here, we use structural data to explain the molecular basis for HLA-A2 supertypes. PMID- 18449999 TI - Definition of MHC supertypes through clustering of MHC peptide-binding repertoires. AB - Identification of peptides that can bind to major histocompatibility complex (MHC) molecules is important for anticipation of T-cell epitopes and for the design of epitope-based vaccines. Population coverage of epitope vaccines is, however, compromised by the extreme polymorphism of MHC molecules, which is in fact the basis for their differential peptide binding. Therefore, grouping of MHC molecules into supertypes according to peptide-binding specificity is relevant for optimizing the composition of epitope-based vaccines. Despite the fact that the peptide-binding specificity of MHC molecules is linked to their specific amino acid sequences, it is unclear how amino sequence differences correlate with peptide-binding specificities. In this chapter, we detail a method for defining MHC supertypes based on the analysis and subsequent clustering of their peptide binding repertoires. PMID- 18450000 TI - Grouping of class I HLA alleles using electrostatic distribution maps of the peptide binding grooves. AB - Human leukocyte antigen (HLA) molecules involved in immune function by binding to short peptides (8-20 residues) have different sequences in different individuals belonging to distinct ethnic population. Hence, the peptide-binding function of HLA alleles is specific. Class I HLA alleles (alternative forms of a gene) are associated with CD8+ T cells, and their allele-specific sequence information is available at the IMGT/HLA database. The available sequences are one-dimensional (ID), and the peptide-binding functional inference often requires 3-dimensional (3D) structural models of respective alleles. Hence, 3D structures were constructed for 1,000 class I HLA alleles (310 A, 570 B, and 120 C) using MODELLER (a comparative protein modeling program for modeling protein structures). The electrostatic distribution maps were generated for each modeled structure using Deep View (Swiss PDB Viewer Version 3.7). The 1,000 models were then grouped into different categories by visual inspection of their electrostatic distribution maps in the peptide binding grooves. The distribution of the models based on electrostatic distribution was 30% negative (300), 1% positive (12), 8% neutral (84), and 60% (604) mixed (random mixture of negative, positive, and neutral). This grouping provides insight toward the inference for functional overlap among HLA alleles. PMID- 18450001 TI - Prediction of peptide-MHC binding using profiles. AB - Prediction of peptide binding to major histocompatibility complex (MHC) molecules is a basis for anticipating T-cell epitopes. Peptides that bind to a given MHC molecule are related by sequence similarity. Therefore, a position-specific scoring matrix (PSSM)---also known as profile--derived from a set of aligned peptides known to bind to a given MHC molecule can be used as a predictor of both peptide-MHC binding and T-cell epitopes. In this approach, the binding potential of any peptide sequence (query) to the MHC molecule is determined by its similarity to a set of known peptide-MHC binders and can be obtained by comparing the query to the PSSM. Following structural considerations of the peptide-MHC interaction, we will describe here how to derive alignments and PSSMs that are suitable for the prediction of peptide-MHC binding. PMID- 18450002 TI - Application of machine learning techniques in predicting MHC binders. AB - The machine learning techniques are playing a vital role in the field of immunoinformatics. In the past, a number of methods have been developed for predicting major histocompatibility complex (MHC)-binding peptides using machine learning techniques. These methods allow predicting MHC-binding peptides with high accuracy. In this chapter, we describe two machine learning technique-based methods, nHLAPred and MHC2Pred, developed for predicting MHC binders for class I and class II alleles, respectively. nHLAPred is a web server developed for predicting binders for 67 MHC class I alleles. This sever has two methods: ANNPred and ComPred. ComPred allows predicting binders for 67 MHC class I alleles, using the combined method [artificial neural network (ANN) and quantitative matrix] for 30 alleles and quantitative matrix-based method for 37 alleles. ANNPred allows prediction of binders for only 30 alleles purely based on the ANN. MHC2Pred is a support vector machine (SVM)-based method for prediction of promiscuous binders for 42 MHC class II alleles. PMID- 18450003 TI - Artificial intelligence methods for predicting T-cell epitopes. AB - Identifying epitopes that elicit a major histocompatibility complex (MHC) restricted T-cell response is critical for designing vaccines for infectious diseases and cancers. We have applied two artificial intelligence approaches to build models for predicting T-cell epitopes. We developed a support vector machine to predict T-cell epitopes for an MHC class I-restricted T-cell clone (TCC) using synthesized peptide data. For predicting T-cell epitopes for an MHC class II-restricted TCC, we built a shift model that integrated MHC-binding data and data from T-cell proliferation assay against a combinatorial library of peptide mixtures. PMID- 18450004 TI - Toward the prediction of class I and II mouse major histocompatibility complex peptide-binding affinity: in silico bioinformatic step-by-step guide using quantitative structure-activity relationships. AB - Quantitative structure-activity relationship (QSAR) analysis is a cornerstone of modern informatics. Predictive computational models of peptide-major histocompatibility complex (MHC)-binding affinity based on QSAR technology have now become important components of modern computational immunovaccinology. Historically, such approaches have been built around semiqualitative, classification methods, but these are now giving way to quantitative regression methods. We review three methods--a 2D-QSAR additive-partial least squares (PLS) and a 3D-QSAR comparative molecular similarity index analysis (CoMSIA) method- which can identify the sequence dependence of peptide-binding specificity for various class I MHC alleles from the reported binding affinities (IC50) of peptide sets. The third method is an iterative self-consistent (ISC) PLS-based additive method, which is a recently developed extension to the additive method for the affinity prediction of class II peptides. The QSAR methods presented here have established themselves as immunoinformatic techniques complementary to existing methodology, useful in the quantitative prediction of binding affinity: current methods for the in silico identification of T-cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate computational prediction of peptide-MHC affinity. We have reviewed various human and mouse class I and class II allele models. Studied alleles comprise HLA A*0101, HLA-A*0201, HLA-A*0202, HLA-A*0203, HLA-A*0206, HLA-A*0301, HLA-A*1101, HLA-A*3101, HLA-A*6801, HLA-A*6802, HLA-B*3501, H2-K(k), H2-K(b), H2-D(b) HLA DRB1*0101, HLA-DRB1*0401, HLA-DRB1*0701, I-A(b), I-A(d), I-A(k), I-A(S), I-E(d), and I-E(k). In this chapter we show a step-by-step guide into predicting the reliability and the resulting models to represent an advance on existing methods. The peptides used in this study are available from the AntiJen database (http://www.jenner.ac.uk/AntiJen). The PLS method is available commercially in the SYBYL molecular modeling software package. The resulting models, which can be used for accurate T-cell epitope prediction, will be made are freely available online at the URL http://www.jenner.ac.uk/MHCPred. PMID- 18450005 TI - Predicting the MHC-peptide affinity using some interactive-type molecular descriptors and QSAR models. AB - The ligand-receptor interaction between some peptidomimetic inhibitors and a class II major histocompatibility complex (MHC)-peptide presenting molecule, the HLA-DR4 receptor, can be modeled using some 3D quantitative structure-activity relationship (QSAR) methods such as the comparative molecular field analysis (CoMFA) and some molecular descriptors using the Cerius2 program. The structures of these peptidomimetic inhibitors can be generated theoretically, and the conformations used in the 3D QSAR studies can be defined by aligning them against the known structure of HLA-DR4 receptor through a least-square fitting procedure. The best CoMFA models can be constructed using the aligned structures of the best fitting result. The principal components analysis (PCA) module of the Cerius2 program can be used to trim outliers of the CoMFA columns generated. Procedures for a direct QSAR analysis using the Cerius2 descriptors and regression analysis by the genetic function module are also presented PMID- 18450006 TI - Implementing the modular MHC model for predicting peptide binding. AB - The challenge of predicting which peptide sequences bind to which major histocompatibility complex (MHC) molecules has been met with various computational techniques. Scoring matrices, hidden Markov models, and artificial neural networks are examples of algorithms that have been successful in MHC peptide-binding prediction. Because these algorithms are based on a limited amount of experimental peptide-binding data, prediction is only possible for a small fraction of the thousands of known MHC proteins. In the primary field of application for such algorithms--vaccine design--the ability to make predictions for the most frequent MHC alleles may be sufficient. However, emerging applications of leukemia-specific T cells require a patient-specific MHC-peptide binding prediction. The modular model of MHC presented here is an attempt to maximize the number of predictable MHC alleles, based on a limited pool of experimentally determined peptide-binding data. PMID- 18450007 TI - Support vector machine-based prediction of MHC-binding peptides. AB - The use of major histocompatibility complex (MHC) class I binding peptides for immunotherapeutic purposes has shown promising results in recent years. The identification of such peptides mostly starts with predicting MHC-binding peptides, given a protein of interest. An accurate prediction method can reduce the number of peptides that needs to be tested experimentally. This protocol describes in this describes how support vector machines (SVMs) can be used for predicting MHC class I binding peptides. Focus is given on data representation, the concept of cross-validation, and how optimal SVM-specific parameters are obtained. PMID- 18450008 TI - In silico prediction of peptide-MHC binding affinity using SVRMHC. AB - The binding between peptide epitopes and major histocompatibility complex (MHC) proteins is a major event in the cellular immune response. Accurate prediction of the binding between short peptides and class I or class II MHC molecules is an important task in immunoinformatics. SVRMHC which is a novel method to model peptide-MHC binding affinities based on support rector machine regression (SVR) is described in this chapter. SVRMHC is among a small handful of quantitative modeling methods that make predictions about precise binding affinities between a peptide and an MHC molecule. As a kernel-based learning method, SVRMHC has rendered models with demonstrated appealing performance in the practice of modeling peptide-MHC binding. PMID- 18450009 TI - HLA-peptide binding prediction using structural and modeling principles. AB - Short peptides binding to specific human leukocyte antigen (HLA) alleles elicit immune response. These candidate peptides have potential utility in peptide vaccine design and development. The binding of peptides to allele-specific HLA molecule is estimated using competitive binding assay and biochemical binding constants. Application of this method for proteome-wide screening in parasites, viruses, and virulent bacterial strains is laborious and expensive. However, short listing of candidate peptides using prediction approaches have been realized lately. Prediction of peptide binding to HLA alleles using structural and modeling principles has gained momentum in recent years. Here, we discuss the current status of such prediction. PMID- 18450010 TI - A practical guide to structure-based prediction of MHC-binding peptides. AB - The binding of bound peptide ligands to major histocompatibility complex (MHC) molecules plays a key role in the activation of normal immune responses and is an intricate theoretical problem that remains unsolved. Geometric and energetic complementarities between an MHC molecule and its corresponding bound peptide ligand are critical in determining the stability of the complex. In this context, the introduction of structural information can greatly facilitate our understanding of how well a peptide ligand can associate with a particular MHC molecule. This chapter introduces the use of structural models as a predictive method to determine whether a peptide sequence can bind to a specific MHC allele. PMID- 18450011 TI - Static energy analysis of MHC class I and class II peptide-binding affinity. AB - Antigenic peptide is presented to a T-cell receptor (TCR) through the formation of a stable complex with a major histocompatibility complex (MHC) molecule. Various predictive algorithms have been developed to estimate a peptide's capacity to form a stable complex with a given MHC class II allele, a technique integral to the strategy of vaccine design. These have previously incorporated such computational techniques as quantitative matrices and neural networks. A novel predictive technique is described, which uses molecular modeling of predetermined crystal structures to estimate the stability of an MHC class II peptide complex. The structures are remodeled, energy minimized, and annealed before the energetic interaction is calculated. PMID- 18450012 TI - Molecular dynamics simulations: bring biomolecular structures alive on a computer. AB - The molecular dynamics (MD) simulations play a very important role in science today. They have been used successfully in binding free-energy calculations and rational design of drugs and vaccines. MD simulations can help visualize and understand structures and dynamics at an atomistic level when combined with molecular graphics programs. The molecular and atomistic properties can be displayed on a computer in a time-dependent way, which opens a road toward a better understanding of the relationship of structure, dynamics, and function. In this chapter, the basics of MD are explained, together with a step-by-step description of setup and running an MD simulation. PMID- 18450013 TI - An iterative approach to class II predictions. AB - An iterative approach to resolving protein-peptide binding motifs is appropriate when the length of the binding protein is variable and a variety of amino acid residues may successfully occupy multiple positions. This chapter describes an iterative algorithm that first aligns binding peptides of variable lengths and then extracts a quantitative motif from the resulting alignment. Numerous examples are presented to illustrate the utility of the iterative process. PMID- 18450014 TI - Building a meta-predictor for MHC class II-binding peptides. AB - Prediction of class II major histocompatibility complex (MHC)-peptide binding is a challenging task due to variable length of binding peptides. Different computational methods have been developed; however, each has its own strength and weakness. In order to provide reliable prediction, it is important to design a system that enables the integration of outcomes from various predictors. In this chapter, the procedure of building such a meta-predictor based on Naive Bayesian approach is introduced. The system is designed in such a way that results obtained from any number of individual predictors can be easily incorporated. This meta-predictor is expected to give users more confidence in the prediction. PMID- 18450015 TI - Nonlinear predictive modeling of MHC class II-peptide binding using Bayesian neural networks. AB - Methods for predicting the binding affinity of peptides to the MHC have become more sophisticated in the past 5-10 years. It is possible to use computational quantitative structure-activity methods to build models of peptide affinity that are truly predictive. Two of the most useful methods for building models are Bayesian regularized neural networks for continuous or discrete (categorical) data and support vector machines (SVMs) for discrete data. We illustrate the application of Bayesian regularized neural networks to modeling MHC class II binding affinity of peptides. Training data comprised sequences and binding data for nonamer (nine amino acid) peptides. Peptides were characterized by mathematical representations of several types. Independent test data comprised sequences and binding data for peptides of length < or = 25. We also internally validated the models by using 30% of the data in an internal test set. We obtained robust models, with near-identical statistics for multiple training runs. We determined how predictive our models were using statistical tests and area under the receiver operating characteristic (ROC) graphs (A(ROC)). Some mathematical representations of the peptides were more efficient than others and were able to generalize to unknown peptides outside of the training space. Bayesian neural networks are robust, efficient "universal approximators" that are well able to tackle the difficult problem of correctly predicting the MHC class II-binding activities of a majority of the test set peptides. PMID- 18450016 TI - TAPPred prediction of TAP-binding peptides in antigens. AB - The transporter associated with antigen processing (TAP) plays a crucial role in the transport of the peptide fragments of the proteolysed antigenic or self altered proteins to the endoplasmic reticulum where the association between these peptides and the major histocompatibility complex (MHC) class I molecules takes place. Therefore, prediction of TAP-binding peptides is highly helpful in identifying the MHC class I-restricted T-cell epitopes and hence in the subunit vaccine designing. In this chapter, we describe a support vector machine (SVM) based method TAPPred that allows users to predict TAP-binding affinity of peptides over web. The server allows user to predict TAP binders using a simple SVM model or cascade SVM model. The server also allows user to customize the display/output. It is freely available for academicians and noncommercial organization at the address http://www.imtech.res.in/raghava/tappred. PMID- 18450017 TI - Prediction methods for B-cell epitopes. AB - In this chapter, two prediction servers of linear B-cell epiotpes have been described; (i) BcePred, based on physico-chemical properties that include hydrophilicity, flexibility/mobility, accessibility, polarity, exposed surface, turns, and antigenicity and ii) ABCpred, based on recurrent neural network. Both of the servers assist in locating linear epitope regions in a protein. PMID- 18450018 TI - HistoCheck. Evaluating structural and functional MHC similarities. AB - The HistoCheck webtool provides clinicians and researchers with a way of visualizing and understanding the structural differences among related major histocompatibility complex (MHC) molecules. In the clinical setting, human leukocyte antigen (HLA) matching of hematopoietic stem cell donors and recipients is essential to minimize "graft versus host disease" (GvHD). Because exact HLA matching is often not possible, it is important to understand which alleles present the same structures (HLA-peptide complexes) to the T-cell receptor (TCR) despite having different amino acid sequences. HistoCheck provides a summary of amino acid mismatches, positions, and functions as well as 3-dimensional (3D) visualizations. In this chapter, we describe how HistoCheck is used and offer advice in interpreting the query results. PMID- 18450019 TI - Predicting virulence factors of immunological interest. AB - In this chapter, three prediction servers used for predicting virulence factors, bacterial toxins, and neurotoxins have been described. VICMpred server predicts the functional proteins of gram-negative bacteria that include virulence factors, information molecule, cellular process, and metabolism molecule. BTXpred server allows users to predict bacterial toxins, its release, and further classification of exotoxins. NTXpred server allows prediction of neurotoxins and further classifying them based on their function and source. PMID- 18450020 TI - Lorenzo Tenchini (1852-1906): neuroanatomy and criminal anthropology. AB - Lorenzo Tenchini was born in Brescia and studied Medicine in Pavia where he became lecturer of Anatomy in 1880. In 1881, at the age of 29 years, he was appointed Professor of Anatomy at the University of Parma. In this city Tenchini began to study the morphology of the brains of criminals, later founding the "Museum of Criminal Anthropology". He collected brains of delinquents and their wax masks and studied the relationship between neuroanatomy and criminality. He promoted the building of a lunatic asylum in the province of Parma and was interested in social medicine, including the pellagra scourge in Northern Italy. Tenchini conducted important research work in the field of neuropsychiatry and anthropology. He was one of the founders of criminal anthropology in Italy and sought to explain criminal behavior through the study of neuroanatomy. PMID- 18450021 TI - [A topical subject in the Lombardy of 1906: the regeneration of nerves]. AB - The author informs about a manuscript containing a communication of Agostino Gemelli's to the Brescia University (1906). He analyzes end compares it with a similar communication given by Gemelli to the Lombard Institute in Milan, concerning the regeneration of peripheral nerves. PMID- 18450022 TI - [Printed works and unpublished manuscripts. G.F. d'Acquapendente on the nervous system]. AB - Fabrici gives limited description of neurological interest only in the treatises (De visione voce auditu, Pentateuchum Chirurgicum and Operationes chirurgicae). Therefore, apart the collection of 21 coloured paintings preserved in the Marciana Library, neither a systematic description nor an iconographic record regarding the nervous system have been published by Fabrici. However, two lists of manuscripts, respectively contained in the testament of 1615 and in a letter of 1622 written by the Rettori to the Riformatori dello Studio di Padova, demonstrate that Fabrici had composed neurological works. We found three manuscripts bearing the name of Fabrici d'Acquapendente. The first is titled Consilia medica; the second De ulceribus; the third De methodo anatomico Excellentissimi Aquapendentis and De anathomia quaedam excerpta sub Excellentissimo Aquapendente. The authors began studying the latter of them. It probably deals with a collection of notes taken at a lecture by an unknown student, but its interest remains noticeable, because it constitutes the only written description, although indirect, of neuroanatomical structures by Fabrici. PMID- 18450023 TI - [Literature, care of the body and love sickness in modern age]. AB - A short Italian text dating the end of XVIII century examines the problem of convulsions of women relating them to the ancient topic of love sickness. Ancient Greek and Roman medical and non medical literature, together with literary texts are used by the author Giovanni Pirani to draw the picture of a moral illness strictly related to a physical dimension. PMID- 18450024 TI - [Francois Franck against the James-Lange theory]. AB - The controversy which followed the theory of emotions outlined by William James and Carl Lange saw also the active involvement of Charles Francois-Franck, Professor of Physiology at the "College de France". Nevertheless his refusal of the aforementioned theory is as yet unknown to the audience. In the light of his previous work on the vascular innervation of the organs, the French physiologist rejected firmly Lange's hemodynamics version, hence anticipating on many points the work of W.B. Cannon. PMID- 18450025 TI - [A wide-ranging project to the best use of S. Niccolo Psychiatric Hospital]. AB - The S. Niccolo Psychiatric Hospital was one of the most important health institutions not only for Siena but for the entire Tuscan district and beyond. It was known to serve all the catchment area for mentally ill patients coming from other cities. At a national level, it is also one of the most beautiful models of hospital architecture of the "village" type, the expression of a late nineteenth century tendency to perceive mental disorders as illnesses that could be improved and cured through "moral treatment", with work and distraction as the principal therapeutic instruments. The closure of the psychiatric hospital in Siena provided for by the Italian psychiatric reform of 1978 actually took place over an extremely long period of time. It was definitively closed only on 30 September 1999 and was the last psychiatric hospital in Tuscany to cease its activity. Its history, the importance it had for the considerable number of committed patients, the extension of the area of the hospital over 183,574 m2 and its organization in 16 edifices, mean that S. Niccolo is now an architectonic complex of great value and interest but also subject to progressive deterioration. This reality, together with the urgency of salvaging the collections of books from its very rich library and its archives of administrative documents and medical records, has led the author to prepare a wide-ranging and extremely complex project that aims at the best use of S. Niccolo. Thanks to the collaboration of a group of experts from various Faculties of the University of Siena, and beginning with a multidisciplinary study of S. Niccolo's history, the project proceeds to the identification of concrete actions of cultural policy as well. PMID- 18450026 TI - [The heart goes to the war: a review of the so-called "soldier's heart" or "irritable heart of soldiers" syndrome]. AB - The paper deals with a form of functional heart disorder that caused substantial disability among men in military service. By viewing the condition through the dual lenses of history and modern medical knowledge we can analyse the syndrome and trace the changing medical and social attitudes to it. The disorder is still now present after harrowing events, including natural disasters, assault of individuals, episods of mass violence and combat. A historical review of the syndrome is also useful in extending our understanding of the natural history of stress reactions, their prognostic indicators and the way in which we can intervene to reduce the effects of trauma. PMID- 18450027 TI - [A.M. Fiamberti and 'psycosurgery']. AB - A.M. Fiamberti has been the Director of Psychiatric Hospital in Varese from its opening to 1964, allowing the structure to gain an important role in the history of Psychiatric Hospitals in Northen Italy in 20th century. Fiamberti has been the 'inventor' of a discussed therapeutical technique of 'psycosurgery' he began to use in 1937. The article analyzes the history and characters of this surgical technique at the light of testimonies in contemporary journals and reviews. PMID- 18450028 TI - [Pathobiographyand Torquato Tasso's case]. AB - The Authors report the hypotheses about Torquato Tasso psychiatric illness, formulated along two centuries. Correspondence, more than his poetic works, and his good interpersonal relations also with people who shut him in Sant'Anna, suggest the diagnosis of an Affective Disorder: "Bipolar Disorder with mood incongruent delusions" or "Schizoaffective Disorder". PMID- 18450029 TI - [Tommaso Campailla: dream stuff and the hypochondria of an eclectic]. AB - Born on 7th April 1668 in Modica, Ciceronian 'Agrum Motucanum', the Modican county of Chiaramontes and Chiabreras, Tommaso Campailla, a poet and a physician, is mostly known as the author of a philosophical poem in octaves--Adam or the Created World. In his 1727 Problemi naturali [Natural Problems], his essay Del disordinato discorso dell'uomo [On Man's Disorderly Discourse] distinguishes itself by its intellectual wit on both the speculative and the experimental research aspects. He formulates concepts on the darkness which often reason has to fare through; he substantializes the body/soul syncretic dimension, and underlines how this disrupts the perfect bodily mechanism. His observations are born in a scientific and historical period which was absorbed within an iatromechanical scenario of which they are reliable proofs and physiological foundations. If on the one hand he reduces the spiritual (psychical) stance to a physical one, on the other hand he gives substance to his questioning his own inner torments, his own hypochondriac being. He died of apoplexy aged 72, on 7th February 1740. PMID- 18450030 TI - [Oscar Giacchi and 'spermatic malincholy']. AB - Oscar Giacchi was the Director of the Psychiatric Hospital in Racconigi. In one of this works, he presented the clinical case of a malinconic patient affected by a jealousy delirium. The article analyzes the text in the light of Giacchi's scientific production and according to the principal psychiatric theories at the and of XIX century. PMID- 18450031 TI - [Arrigo Tamassia and the judicial trial of Ch. J. Guiteau]. AB - The international reputation of the judicial trial of Ch. J. Guiteau, the killer of the U.S.A. President J. A. Garfield led Arrigo Tamassia, professor of Legal Medicine of the University of Pavia, to harshly criticized the work of the judicial court. PMID- 18450032 TI - [The mechanism of operation of the malaria therapy]. AB - This article intends to synthetically introduce a meaningful Italian monographic contribution to the debate of the years '30 relatively to the mechanism of operation of the malariatherapy on the "paralytic" subjects to the light of the laboratory investigation own of neuropsychiatric medicine in that age. PMID- 18450033 TI - The Medici Project first anthropological and paleopathological results of the exploration of the Medici tombs in Florence. AB - Within the framework of the Medici Project, a paleopathological team of experts from the University of Pisa, the University of Florence and the Superintendence for Florentine Museums, is carrying out a study on 49 tombs of some of the Medici family members (16th-18th centuries) housed in the so-called Basilica of San Lorenzo in Florence. The project involves disciplines such as paleopathology, funerary archeology, physical anthropology, paleonutrition, parasitology, histology, histochemistry, immuno-histochemistry, electron microscopy, molecular biology, and identification of ancient pathogens. The most recent biomedical imaging technologies have been employed to obtain as much information as possible about the genetic make-up, eating habits, life styles and diseases of these important rulers of Renaissance Florence. The first anthropological and paleopathological results are presented here. PMID- 18450034 TI - [The pacifism of Henry Dunant]. AB - From various writings of the founder of the International Red Cross and above all from his late work L'avenir sanglant it is deduced as the Dunant anticipating and prophetically interpreting the curse of the war is an internationalist (for some aspects a romantic anarchist) and a convinced pacifist. We show therefore how much has been false and backbiters the defamations that followed to the attribution of the first Nobel prize for the peace. PMID- 18450035 TI - [Between Pavia and Brescia: Luigi Porta (1800-1875)]. AB - The authors present two records from the Ateneo di Brescia, about Luigi Porta (1800-1875), surgeon at Pavia University (1832-1875). They were written by Bartolomeo Gualla (1810-1870), Porta's student and surgeon in Brescia. A manuscript concerning Porta's lessons on surgery, written by Martino Tommasi, student at Pavia in 1844, and other records concerning another student and surgeon, Antonio Rota (1838-1897), are presented too. All these records allow us to define precisely some aspect of Porta's bioergography, and advance some problem concerning history of Pavia's surgical milieu in 19th century. PMID- 18450036 TI - [The guiacum barrels between science and esoterism: Tommaso Campailla genius loci]. AB - Tommaso Campailla, as a typical man of his time, had a good humanistic and scientific education. He was born in Modica in 1668 [corrected] from an aristocratic family. When he was sixteen years old he moved to Catania to study law, but in a short time he came back to his native town where he preferred to study as an autodidact. He got married and had children and was elected senator seven times. In spite of his particular look, he was appreciated for his vast culture and his great sensibility. Giovanna Finocchiaro Chimirri noticed his very kind soul and called him: "the christian and Italian Lucretio". In addition, he was a friend of the Arcadian poet Girolama Lorefice Grimaldi. Campailla was a very good medical doctor, although he was an autodidact, and he was very able to inculcate love for medical studies in many students. He fought syphilis rheumatism in a "modern" way, using the "guaiacum barrels" or "vapour stovens" that he had invented. He died in 1740 in Modica. PMID- 18450037 TI - [Steri's graffiti of Palermo and medical knowledges]. AB - The graffiti left by prisoners in the Inquisition gaols of Palermo's represent a testimony of the historical period between 1600 to 1793. In that period, by order of the viceroy Caracciolo, all the testimonies were removed at the same time in which the Inquisition court was suppressed. In this work the historical subdivision between sacred and profane themes is analyzed with the purpose to study human body in an anthropological key as a language in condition of limited freedom and under torture. Many of the profane graffiti are devoted to medical knowledge suggesting that doctors were involved in the activities of this religious court likewise happened in civil courts. Giovanni Filippo Ingrassia, the well-known proto-medical physician of the kingdom, in his treatise, wrote in 1578 and entitled Methodus dandi relationes ... reports many examples of the role of medical doctors in attesting fitness to torture of inquired people or the necessity of graduating torture when they were hill or in a morbid conditions. PMID- 18450039 TI - [Preformation and epigenesis in the works of M. Malpighi]. AB - The article analyzes the scientific debate arosen between Marcello Malpighi and Giovan Battista Trionfetti about the possibility of 'preformation' in plants and living organisms, the existence of spontaneous generation and the meaning and usefullness of particular structures in plants, as 'folia seminalia'. PMID- 18450038 TI - [Medical, social and economics aspects in the sulphur mines in Sicily(1791 - 1964)]. AB - In Sicily the sulphur extraction represented an occasion of economic growth and a development for the dignity of the workers. The "carusi", young boys from 6 to 14 years old, were given up by their parents in return of a hardly payed of loan; it was the so called "soccorso morto" (dead aid). They were submitted to an enormous very hard physical work that caused severe damage to the skeleton and this was the reason of their inability to military service. The anthropometric surveys of "carusi" and pupils highlight for the first ones a reduced increase of the height and for the second ones the presence of "gibbo". For this reasons the inhabitans of Racalmuto were called racalmutesi immiruti" which means that people who lives in Racalmuto were hunchbacked. Nowadays it's possible to say that dietary and nutritional causes determined metabolic damages to the skeleton. A comparison between people who have been declared unable for military service belonged to the two lower clones of farmers and miners showed a lower incidence of the first ones. The law of 1866 on child labour assigned to medical doctors the task of certifying their suitability to work: the first step of normalisation on a medical care basis. PMID- 18450040 TI - [Helicobacter pylori, the story so far]. AB - Helicobacter pylori is a bacterial pathogen infecting the gastric antrum of half the population worldwide. H. pylori has been discovered in 1982 by J. Robin Warren and Barry J. Marshall as the major cause of gastroduodenal pathologies, including gastric and duodenal ulcer, gastric cancer and gastric B-cell lymphoma of mucosa-associated lymphoid tissue. For this great discovery Warren and Marshall deserved the Nobel Prize for Medicine and Physiology in 2005. PMID- 18450041 TI - [Angelo de Vincenti and the history of neurology]. AB - Angelo De Vincenti was been considered are of the pioneers of neurology in Italy. He left few printed works and of testimonies of his clinical and managerial activity; this article deals in particular with De Vincenti's fundamental promoting the therapeutical role in value of Terme di Salice in the first years of xx XIX century. PMID- 18450042 TI - Study design: the basics. AB - In biomedical research, meaningful conclusions can only be drawn based on data collected from a valid scientific design using appropriate statistical methods. Therefore, the selection of an appropriate study design is important in order to provide an unbiased and scientific evaluation of the research questions. In this chapter, the different kinds of experimental studies commonly used in biology and medicine are introduced. A brief survey of basic experimental study designs, randomization, blinding, possible biases, issues in data analysis, and interpretation of the study results are mainly provided. PMID- 18450043 TI - Observational study design. AB - Much can be learned about a process by observing changes over time or by comparing two different processes under different conditions. This chapter introduces the major types of observational study designs: the longitudinal or cohort study, the comparative or case-control study, and some of their variants. It also includes examples of the key measures of relationship between factor and outcome in observational studies, the relative risk and the odds ratio. The similarity of the two measures for low incidence outcomes is illustrated, as is the use of attributable risk to assess how much of a binary outcome is due to a single factor. PMID- 18450044 TI - Descriptive statistics. AB - Statistics is defined by the Medical Subject Headings (MeSH) thesaurus as the science and art of collecting, summarizing, and analyzing data that are subject to random variation. The two broad categories of summarizing and analyzing data are referred to as descriptive and inferential statistics. This chapter considers the science and art of summarizing data where descriptive statistics and graphics are used to display data. In this chapter, we discuss the fundamentals of descriptive statistics, including describing qualitative and quantitative variables. For describing quantitative variables, measures of location and spread, for example the standard deviation, are presented along with graphical presentations. We also discuss distributions of statistics, for example the variance, as well as the use of transformations. The concepts in this chapter are useful for uncovering patterns within the data and for effectively presenting the results of a project. PMID- 18450045 TI - Basic principles of statistical inference. AB - In this chapter, we discuss the fundamental principles behind two of the most frequently used statistical inference procedures: confidence interval estimation and hypothesis testing, both procedures are constructed on the sampling distributions that we have learned in previous chapters. To better understand these inference procedures, we focus on the logic of statistical decision making and the role that experimental data play in the decision process. Numerical examples are used to illustrate the implementation of the discussed procedures. This chapter also introduces some of the most important concepts associated with confidence interval estimation and hypothesis testing, including P values, significance level, power, sample size, and two types of errors. We conclude the chapter with a brief discussion on statistical and practical significance of test results. PMID- 18450046 TI - Statistical inference on categorical variables. AB - Categorical data are data that capture a characteristic of an experimental unit (such as a tissue specimen) rather than a numerical value. In this chapter, we first describe types of categorical data (nominal and ordinal) and how these types of data are distributed (binomial, multinomial, and independent multinomial). Next, methods for estimation and making statistical inferences for categorical data in commonly seen situations are presented. This includes approximation of the binomial distribution with a normal distribution, estimation and inference for one and two binomial samples, inference for 2 x 2 and R x C contingency tables, and estimation of sample size. Relevant data examples, along with discussions of which study designs generated the data, are presented throughout the chapter. PMID- 18450047 TI - Development and evaluation of classifiers. AB - Diagnostic tests, medical tests, screening tests, biomarkers, and prediction rules are all types of classifiers. This chapter introduces methods for classifier development and evaluation. We first introduce measures of classification performance including sensitivity, specificity, and receiver operating characteristic (ROC) curves. We then review some issues in the design of studies to assess and compare the performance of classifiers. Approaches for using the data to estimate and compare classifier accuracy are then introduced. Next, methods for combining multiple classifiers into a single classifier are presented. Lastly, we discuss other important aspects of classifier development and evaluation. The methods presented are illustrated with real data. PMID- 18450048 TI - Comparison of means. AB - This chapter describes statistical methods to test for differences between means or other measures of central tendency of 2 or more populations. Parametric tests and nonparametric tests are included. Methods for pairwise comparisons when more than 2 groups are being compared are included. PMID- 18450049 TI - Correlation and simple linear regression. AB - This chapter highlights important steps in using correlation and simple linear regression to address scientific questions about the association of two continuous variables with each other. These steps include estimation and inference, assessing model fit, the connection between regression and ANOVA, and study design. Examples in microbiology are used throughout. This chapter provides a framework that is helpful in understanding more complex statistical techniques, such as multiple linear regression, linear mixed effects models, logistic regression, and proportional hazards regression. PMID- 18450050 TI - Multiple linear regression. AB - This chapter describes multiple linear regression, a statistical approach used to describe the simultaneous associations of several variables with one continuous outcome. Important steps in using this approach include estimation and inference, variable selection in model building, and assessing model fit. The special cases of regression with interactions among the variables, polynomial regression, regressions with categorical (grouping) variables, and separate slopes models are also covered. Examples in microbiology are used throughout. PMID- 18450051 TI - General linear models. AB - This chapter presents the general linear model as an extension to the two-sample t-test, analysis of variance (ANOVA), and linear regression. We illustrate the general linear model using two-way ANOVA as a prime example. The underlying principle of ANOVA, which is based on the decomposition of the value of an observed variable into grand mean, group effect and random noise, is emphasized. Further into this chapter, the F test is introduced as a means to test for the strength of group effect. The procedure of F test for identifying a parsimonious set of factors in explaining an outcome of interest is also described. PMID- 18450052 TI - Linear mixed effects models. AB - Statistical models provide a framework in which to describe the biological process giving rise to the data of interest. The construction of this model requires balancing adequate representation of the process with simplicity. Experiments involving multiple (correlated) observations per subject do not satisfy the assumption of independence required for most methods described in previous chapters. In some experiments, the amount of random variation differs between experimental groups. In other experiments, there are multiple sources of variability, such as both between-subject variation and technical variation. As demonstrated in this chapter, linear mixed effects models provide a versatile and powerful framework in which to address research objectives efficiently and appropriately. PMID- 18450053 TI - Design and analysis of experiments. AB - This chapter is primarily devoted to experiments that compare 2 treatments with respect to an outcome measure. Six design scenarios are discussed: (a) completely randomized designs (treatments are assigned completely at random); (b) randomized block designs (experimental units are subdivided into blocks of like subjects, with one subject in each block randomly assigned to each treatment); (c) stratified designs (subjects are categorized into subpopulations called strata, and within each stratum, a completely randomized design is conducted); (d) crossover designs (each subject gets both treatments, but order is completely at random); (e) 2 x 2 factorial designs [design can be in any of the formats (a)-(d) but there are 4 not 2 treatments representing 2 types of treatment interventions, each with 2 levels]; and (f) randomized designs with "random" effects. This is much like the stratified design, except there is only 1 sample, at least conceptually, from the strata. Examples might be litters of laboratory animals, surgical practices, or batches of a therapeutic agent. The desire is to make inferences about treatments in the population as a whole, not just in the strata that were actually sampled. PMID- 18450055 TI - Logistic regression. AB - The Medical Subject Headings (MeSH) thesaurus used by the National Library of Medicine defines logistic regression models as "statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable." Logistic regression models are used to study effects of predictor variables on categorical outcomes and normally the outcome is binary, such as presence or absence of disease (e.g., non-Hodgkin's lymphoma), in which case the model is called a binary logistic model. When there are multiple predictors (e.g., risk factors and treatments) the model is referred to as a multiple or multivariable logistic regression model and is one of the most frequently used statistical model in medical journals. In this chapter, we examine both simple and multiple binary logistic regression models and present related issues, including interaction, categorical predictor variables, continuous predictor variables, and goodness of fit. PMID- 18450054 TI - Analysis of change. AB - When the same subjects or laboratory animals are observed across a set of different conditions or over time, we are usually interested in studying change. In these study designs, each subject serves as its own control. In this chapter, we consider different ways to assess change over time, for example, analyses for evaluating changes from a baseline condition. Study designs and analyses for single group studies and studies with two groups are discussed in detail. Examples come from published data. Statistical methods used in the examples include paired t-tests and analysis of covariance. The use of difference scores is discussed relative to analysis of covariance. PMID- 18450056 TI - Survival analysis. AB - This chapter introduces some fundamental results in survival analysis. We first describe what is censored failure time data and how to interpret the failure time distribution. Two nonparametric methods for estimating the survival curve, the life table estimator and the Kaplan-Meier estimator, are demonstrated. We then discuss the two-sample problem and the usage of the log-rank test for comparing survival distributions between groups. Lastly, we discuss in some detail the proportional hazards model, which is a semiparametric regression model specifically developed for censored data. All methods are illustrated with artificial or real data sets. PMID- 18450057 TI - Basic Bayesian methods. AB - In this chapter, we introduce the basics of Bayesian data analysis. The key ingredients to a Bayesian analysis are the likelihood function, which reflects information about the parameters contained in the data, and the prior distribution, which quantifies what is known about the parameters before observing data. The prior distribution and likelihood can be easily combined to from the posterior distribution, which represents total knowledge about the parameters after the data have been observed. Simple summaries of this distribution can be used to isolate quantities of interest and ultimately to draw substantive conclusions. We illustrate each of these steps of a typical Bayesian analysis using three biomedical examples and briefly discuss more advanced topics, including prediction, Monte Carlo computational methods, and multilevel models. PMID- 18450058 TI - Overview of missing data techniques. AB - Missing data frequently arise in the course of research studies. Understanding the mechanism that led to the missing data is important in order for investigators to be able to perform analyses that will lead to proper inference. This chapter will review different missing data mechanisms, including random and non-random mechanisms. Basic methods will be presented using examples to illustrate approaches to analyzing data in the presence of missing data. PMID- 18450059 TI - Statistical topics in the laboratory sciences. AB - This chapter concerns statistical concepts and procedures that are applicable to diagnostic testing performed in the clinical laboratory. Three important laboratory issues are addressed: the estimation of analytical imprecision, the design of an effective laboratory quality control strategy, and the establishment of population reference ranges. These three topics were selected because each demonstrates a valuable statistical principle. Estimation of analytical imprecision highlights the important role of study design. Evaluating laboratory quality control strategies emphasizes the importance of choosing appropriate statistical models. The estimation of population reference ranges demonstrates that there can be many different approaches to developing good statistical estimators. PMID- 18450060 TI - Power and sample size. AB - In this chapter, we discuss the concept of statistical power and show how the sample size can be chosen to ensure a desired power. Power is the probability of rejecting the null hypothesis when the null hypothesis is false, that is the probability of saying there is a difference when a difference actually exists. An underpowered study does not have a sufficiently large sample size to answer the research question of interest. An overpowered study has too large a sample size and wastes resources. We will show how the power and required sample size can be calculated for several common types of studies, mention software that can be used for the necessary calculations, and discuss additional considerations. PMID- 18450061 TI - Microarray analysis. AB - Microarrays and related technologies have allowed investigators to ask biological questions in far greater detail than has previously been possible. Microarrays had a troubled beginning, but most of these problems resulted from the growing pains of this technology, which, like many new things, was initially more promise than delivery. Nevertheless, over the past few years, investigators have learned how to achieve optimal performance of technology, and now exciting discoveries are made using microarray-based research. Many of the advances have come from the realization that microarrays are not a magic tool but rather are like any other measurement device. Unless microarray experimentation is coupled with good experimental practices, it will not yield valid results or, worse yet, may lead to misleading results. In this chapter, we highlight some of the important steps that should be taken to successfully conduct a microarray study. These steps include a clearly stated biological question, experimental design, careful experimental conduct, complete statistical analysis, validation/verification of results, and dissemination of the data. PMID- 18450062 TI - Association methods in human genetics. AB - Genetic association studies are increasingly used in the search for susceptibility variants for human traits. While many of the statistical tools available for such studies are well established, the field is advancing rapidly, as biological and technological developments allow investigators to generate vast amounts of detailed genetic data. This chapter gives an overview of the statistical evaluation of genetic data in both unrelated individuals and families. A brief introduction to fundamental population genetics concepts is followed by detailed examinations of measures of linkage disequilibrium and single-marker and haplotype association tests. Emphasis is given to the historical development of family-based tests to provide the context for more recent advancements. The chapter concludes with a discussion of design strategies for genetic association studies with dense genotyping of hundreds or thousands of markers, such as those planned for follow up of a linkage-candidate region or genome-wide association studies. PMID- 18450063 TI - Genome mapping statistics and bioinformatics. AB - The unprecedented availability of genome sequences, coupled with user-friendly, web-enabled search and analysis tools allows practitioners to locate interesting genome features or sequence tracts with relative ease. Although many public model organism- and genome-mapping resources offer pre-mapped genome browsing, biologists also still need to perform de novo mapping analyses. Correct interpretation of the results in genome annotation databases or the results of one's individual analyses requires at least a conceptual understanding of the statistics and mechanics of genome searches, the expected results from statistical considerations, as well as the algorithms used by different search tools. This chapter introduces the basic statistical results that underlie mapping of nucleotide sequences to genomes and briefly surveys the common programs and algorithms that are used to perform genome mapping, all available via public hosted web sites. Selection of the appropriate sequence search and mapping tool will often demand tradeoffs in sensitivity and specificity relating to the statistics of the search. PMID- 18450064 TI - Working with a statistician. AB - This chapter presents some guidelines for working with a statistician, beginning with when and why you should consult one. We emphasize the importance of good communication between the statistician and the client and the need for clearly defined tasks and a timetable. Other considerations, such as security, confidentiality, and business arrangements are discussed. PMID- 18450065 TI - Animal Learning & Behavior has consistently published high-quality and important articles. PMID- 18450066 TI - Tracking of the expected time to reinforcement in temporal conditioning procedures. AB - In one experiment, the rate and pattern of responding (head entry into the food cup) under different distributions of intervals between food deliveries were examined. Separate groups of rats received fixed-time (45, 90, 180, or 360 sec), random-time (45, 90, 180, or 360 sec), or tandem fixed-time (45 or 90 sec) random time (45 or 90 sec) schedules of reinforcement. Schedule type affected the pattern of responding as a function of time, whereas mean interval duration affected the mean rate of responding. Responses occurred in bouts with characteristics that were invariant across conditions. Packet theory, which assumes that the momentary probability of bout occurrence is negatively related to the conditional expected time remaining until the next reinforcer, accurately predicted global and local measures of responding. The success of the model advances the prediction of multiple measures of responding across different types of time-based schedules. PMID- 18450067 TI - Stimulus control in fixed interfood intervals. AB - The control exerted by various portions of fixed-time and fixed-interval schedules was assessed with a trace-conditioning procedure. The intervals were segmented into 10 bins. In all but 1 of those bins, the stimuli were presented in different random orders on each trial. In 1 bin, the stimulus was the same on each trial. The position of this trace stimulus was varied across phases. The results indicated that a trace stimulus can come to control behavior and that differential control can extend to even the second tenth of an interfood interval. The results were interpreted as indicating that traditional explanations of the rate loss in earlier portions of an interfood interval are inadequate and that models such as Palya's (1993) bipolar model or Miller and Schachtman's (1985) comparator model may provide a principled framework with which to understand within-trial effects. PMID- 18450068 TI - The role of temporal variables in inhibition produced through extinction. AB - In two experiments with rats as subjects, the temporal characteristics of inhibition produced through extinction were investigated. Each experiment established two independent signals for unconditioned stimulus presentation, one trace and one delay. Following initial training, either the trace or the delay conditioned stimulus (CS) was massively extinguished. In Experiment 1, a summation test established that an extinguished delay CS (but not a neutral CS) passed a summation test with a delay, but not with a trace, transfer excitor, and an extinguished trace CS (but not a neutral CS) passed a summation test with a trace, but not with a delay, transfer excitor. In Experiment 2, a retardation test showed retarded behavioral control by an extinguished delay CS when the CS was retrained as a delay CS, but not as a trace CS, and by an extinguished trace CS when the CS was retrained as a trace CS, but not as a delay CS. The results are discussed in terms of contemporary theories of extinction. PMID- 18450069 TI - Savings in classical conditioning in the rabbit as a function of extended extinction. AB - In the present experiments, savings phenomena following a limited amount of initial acquisition and extended extinction were examined. Experiments 1 and 2 compared rates of reacquisition following brief acquisition and various amounts of extinction in conditioning of the rabbit's nictitating membrane and heart rate response, respectively. Experiment 3 compared rates of acquisition to a novel stimulus (e.g., light) following brief acquisition and various amounts of extinction to another stimulus (e.g., tone). In addition, in Experiment 3 recovery of responding to the extinguished stimulus during acquisition to the novel, cross-modal stimulus was examined. Experiments 1, 2, and 3 demonstrated that with a limited number of acquisition trials (1) there was a graded reduction in the rate of reacquisition as a function of the number of extinction trials in both conditioning preparations, (2) there was a graded reduction in the rate of cross-modal acquisition as a function of the number of extinction trials, but (3), in Experiment 3, recovery of responding to the extinguished stimulus during cross-modal training of the novel stimulus appeared uniformly robust even in the face of extended extinction. PMID- 18450070 TI - Impact of brief or extended extinction of a taste aversion on inhibitory associations: evidence from summation, retardation, and preference tests. AB - In five conditioned taste aversion experiments with rats, summation, retardation, and preference tests were used to assess the effects of extinguishing a conditioned saccharin aversion for three or nine trials. In Experiment 1, a summation test showed that saccharin aversion extinguished over nine trials reduced the aversion to a merely conditioned flavor (vinegar), whereas three saccharin extinction trials did not subsequently influence the vinegar aversion. Experiment 2 clarified that result, with unpaired controls equated on flavor exposure prior to testing; the results with those controls suggested that the flavor extinguished for nine trials produced generalization decrement during testing. In Experiment 3, the saccharin aversion reconditioned slowly after nine extinction trials, but not after three. Those results suggested the development of latent inhibition after more than three extinction trials. Preference tests comparing saccharin consumption with a concurrently available fluid (water in Experiment 4, saline in Experiment 5) showed that the preference for saccharin was greater after nine extinction trials than after three. However, saccharin preference after nine extinction trials was not greater, as compared with that for either latent inhibition controls (Experiments 4 and 5) or a control given equated exposures to saccharin and trained to drink saline at a high rate prior to testing (Experiment 5). Concerns about whether conditioned inhibition has been demonstrated in any flavor aversion procedure are discussed. Our findings help explain both successes and failures in demonstrating post-extinction conditioned response recovery effects reported in the conditioned taste aversion literature, and they can be explained using a memory interference account. PMID- 18450071 TI - Overshadowing as a function of trial number: dynamics of first- and second-order comparator effects. AB - In two conditioned lick suppression experiments with rats, we examined the permanence of the overshadowing effect as a function of the number of compound reinforced training trials. In Experiment 1, robust overshadowing was observed following 4 compound-US pairings but dissipated with 36 pairings. Overshadowing decreased because responding to the overshadowed stimulus increased, not because responding by the control group decreased. This dissipation was stimulus specific and not attributable to a response ceiling. Experiment 2 extended the generality of the effect to a sensory preconditioning design and further demonstrated that overshadowing lost through many compound-US pairings was restored by posttraining extinction of the training context. The results are explicable in terms of the extended comparator hypothesis (Denniston, Savastano, & Miller, 2001) under the assumption that the impacts of first- and second-order comparator processes grow differentially as a function of number of trials. PMID- 18450072 TI - "Artificial grammar learning" in pigeons: a preliminary analysis. AB - An avian analogue to human artificial or synthetic grammar learning (Reber, 1967) was developed. Pigeons viewed horizontal strings of three to eight colored letters. These strings either conformed to Reber's artificial grammar or violated it in one or two locations. Pigeons categorized the letter strings as grammatical (left keypeck) or nongrammatical (right keypeck). Overall accuracy of categorization was above chance to both familiar training strings and to novel transfer strings, thereby satisfying a conventional criterion for learning an abstract concept. The results support a multiple mechanisms point of view according to which pigeons, like humans, learn both abstract concepts and specific strings, or specific parts of strings, in artificial grammar learning tasks. PMID- 18450073 TI - [Experience in preventing early treatment discontinuance in patients with tuberculosis in the Kemerovo Region]. AB - By taking into account the revealed reasons for early chemotherapy discontinuance, a package of measures to prevent this phenomenon has been worked out. The package includes improvement of hospital conditions; meticulous monitoring of the consumption of antituberculous drugs; social support of the destitute; creation of motivation for rather prolonged, and continuous chemotherapy via preparation at a tuberculosis patient school; provision of continuity in the treatment between the in- and outpatient stages, a penitentiary medical and civil health care tuberculosis facilities; the use of hospital replacement technologies, judicial practice of attraction of the bacteria discharging persons who deliberately avoid treating; and interdepartmental interaction. Introduction of a package of measures to prevent early treatment discontinuance could reduce the proportion of such patients among the first detected ones from 30 to 7% and from 51.9 to 32.8% among the ineffectively treated patients. PMID- 18450074 TI - [Incidence of tuberculosis in officials from penitentiaries of the Republic of Udmurtia]. AB - The staff of penitentiaries is at high risk for tuberculosis due to its professional occupation. Tuberculosis morbidity was studied in the officials of the reformatory system in the Republic of Udmurtia over the period of 1997 to 2006. Throughout the follow-up, there were high tuberculosis morbidity rates in the officials of reformatories, in 2000-2002 in particular. In the structure of patients with new-onset tuberculosis, there was a preponderance of young males (75.6%), mainly qualified staff (89.3%). Pulmonary tuberculosis was prevalent (92.9%), extrapulmonary tuberculosis accounted for 7.1%. Infiltrative pulmonary tuberculosis was the major clinical type (76%) in the patients with new-onset tuberculosis. The study indicated the low proportion of patients showing bacteria discharge and lung tissue destruction, suggesting the timeliness of tuberculosis detection in the officials of penitentiaries. The results of treatment for tuberculosis in the officials of the penitentiary system were high, which was associated with their discipline and responsibility for their health. PMID- 18450075 TI - [Pulmonary function in patients with focal pulmonary tuberculosis]. AB - Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/VC%, PEF, MEF25, MEF50, MEF75, TLC, TGV, pulmonary residual volume (PRV), Raw, Rin, Rcx, DLCO-SB, DLCO-SS/VA, PaO2, and PaCO2 were determined in 40 patients with focal pulmonary tuberculosis. Changes were found in lung volumes and capacities in 75%, impaired bronchial patency and pulmonary gas exchange dysfunction were in 57.5 and 25%, respectively. The lung volume and capacity changes appeared mainly as increased TGV and PRV; impaired bronchial patency presented as decreased MEF50, MEF75, and FEV1/VC%; pulmonary gas exchange dysfunction manifested itself as reduced DLCO-SB, PaO2, and PaCO2. The magnitude of the observed functional changes was generally slight. TGV and PRL increased up to 148-187 and 142-223% of the normal values, respectively; MEF50, MEF75, FEV1/VC%, and DLCO decreased to 59-24, 58-26, 78-57, and 78-67% of the normal values and PaO2 and PaCO2 did to 79-69 and 34-30 cm Hg. PMID- 18450076 TI - [Evaluation of the effects of antituberculous drugs on the cytochemical status of lymphocytes in vitro]. AB - The effects of basic drugs of chemotherapy for tuberclosis, such as isoniazid and rifampicin, on the activity of the most important mitochondrial enzymes of lymphocytic energy metabolism were studied in patients with infiltrative tuberculosis and healthy donors. The authors detected the significantly inhibited activity of succinate dehydrogenase and the redistribution of lymphocytic populations with the increased proportion of cells with the low and high activities of the enzyme. The more significant negative effect on the lymphocytes of patients with tuberculosis was observed when rifampicin was administered. In patients with pulmonary tuberculosis, the suppressed enzymatic activity of peripheral blood lymphocytes was shown to be more pronounced when the cells were incubated with rifampicin and isoniazid for 2 hours than for 1 hour. PMID- 18450077 TI - [Role of cytokines in the modulation of lymphocytic subpopulational composition in patients with pulmonary tuberculosis]. AB - The parameters of the lymphocytic CD-population composition and the production of cytokines in the cell cultures of peripheral blood mononuclear cells were studied in patients with infiltrative pulmonary tuberculosis. A marked reduction in the relative and absolute count of CD3+ and CD4+ lymphocytes and an increase in the level of CD8- and CD16-positive cells were established in both drug-sensitive and drug-resistant types of the disease. A significant increase in the production of IL-12 and a reduction in the spontaneous elaboration of interferon-gamma were observed in all the examinees. Addition of lipid and protein myobacterial antigens (Beijing strains) caused a notable decrease in the generation of the study cytokines as compared with the respective parameters in healthy donors and their basal secretion irrespective of the type of a tuberculous process. PMID- 18450078 TI - [Comparative analysis of molecular genetic studies using DNA samples isolated from blood treated with EDTA or heparin]. AB - A molecular genetic investigation of five genes: CFTR, GSTM1, GCTT1, MTHFR, and TP53 using DNA samples isolated from blood treated with either EDTA or stabilized heparin was conducted. Twenty DNA samples obtained from 10 persons. The results prove that heparin used as an anticoagulant instead of EDTA had no inhibitory effect on PCR and PCR/RFLP results, at least when DNA was isolated with a DNA sorb-B kit. The results suggest that heparin-treated blood samples can be also used to study other genes. PMID- 18450080 TI - [The quality indices of enzyme immunoassay for markers of viral infections (HIV, hepatitis B and C) according to the data of the Federal External Quality Assessment System]. PMID- 18450079 TI - [Comparison of two methods for rapid determination of C-reactive protein with the Tina-quant]. AB - C-reactive protein (CRP) as an acute phase protein is an important diagnostic marker for the presence and course of human processes. Out of the acute phase proteins it is one of those the concentrations increase most rapidly with its sensitivity being superior to other markers of inflammation, such as leukocytosis, erythrocytic sedimentation rate, and fever. This study compared two point-of-care assays with the standard laboratory method Tina-quant CRP processed on a Hitachi 917: the immunofiltration assay NycoCard CRP Whole Blood and the turbidimetric immunoassay Micros CRP. Both methods are carried in the presence of a patient, by using capillary or venous blood. Seventy-eight blood samples were analyzed first in the standard laboratory routine and then by both rapid test assays. The precision of both assays was determined from the confidence interval. The results were statistically analyzed by arithmetic standard deviation mean method, variation coefficient, Spearman correlation index, Wilcoxon and Bland Altman tests, and Passing-Bablock regression. NycoCard CRP Whole Blood showed a correlation coefficient of R = 0.9838; the precision had a coefficient of variation of CV = 1.8759% while As compared with Tina-quant CRP had R = 0.9934 and CV = 0.9160%. Both assays indicated the same results as Tina-quant CRP. Both Tina-quant CRP and NycoCard CRP Whole Blood give the best fit for the rapid determination of CRP. PMID- 18450081 TI - [Harmonization in laboratory medicine: a current approach to improving the quality of clinical and laboratory studies]. PMID- 18450082 TI - [Procedures for optimizing the intralaboratory quality control in mass screening for hepatitis C virus antibodies]. AB - The paper presents data on the optimization of intralaboratory quality control of tests for hepatitis C virus antibodies by enzyme immunoassay in the mass screening scope of studies. It is concluded that the control material prepared without assistance is suitable only to assess the convergence of the results of a study. The problems in the monitoring of the reproducibility of study results and in the standardization of on-line quality control involving the construction and keeping of control charts are solved by using standardized commercial materials and a computer-based data processing system. PMID- 18450083 TI - [Comparative assessment of criteria for postoperative renal dysfunction in cardiosurgical patients]. AB - The paper presents data on comparison of the detection rate of renal dysfunction after cardiac surgery, by using the criteria developed by Cockroft-Gault, C. M. Mangano, L.-G. Andersson, and G. Zanardo. It is shown that it is expedient to calculate creatinine phosphokinase by the Cochroft-Gault formula that using a patient's individual parameters provides a more objective approach to making the diagnosis of renal dysfunction. The rate of development of renal dysfunctions in patients who have undergone cardiac surgery under extracorporeal circulation (EC) depends on the type of an operation and the duration and temperature of perfusion. By postoperative day 14, renal function became normal in the vast majority of patients. Renal function became chronic in 1% of the patients operated on the heart under EC. PMID- 18450084 TI - [Detection of clostridia toxin markers in different types of the course of acute intestinal infections]. AB - The purpose of the investigation was to study the detection rates of markers and the level of C. diffcile A and B toxins and C. perfringens type A enterotoxin in patients with acute intestinal infections (AII). Two hundred and seventy-three patients with AII of varying etiology were followed up. According to the clinical syndrome, the patients were divided into 3 groups: (1) patients with the gastroenteritic (GE) type; (2) those with the gastroenterocolitic (GEC) type; (3) those with enterocolitic (EC) type. The circulation of markers of C. difficile A and B toxins and C. perfringens type A enterotoxin was studied, by employing the immunological test systems in the coagglutination test using the plates. The higher levels of antigens of all toxins were identified in the acute period of the disease in the GE and EC types than in the GEC type. There was a short increase in the levels of antigens of the test toxins in the GEC type and a gradual decrease in the GE and EC types. By discharge from hospital, the markers of toxins (more commonly of C. diffcile A) were preserved in 16.4% of the patients mainly in the GEC type. PMID- 18450085 TI - [Serum detection of human urogenital mycoplasma]. AB - The authors compared the detection rate of DNA of urogenital Mycoplasmas (Ureaplasma spp. and M. hominis) in the urogenital tract (UGT) and serum samples by polymerase chain reaction. Testing the smears and serum samples from the same patients (n = 112) showed that Ureaplasma was more frequently detected in the UGT smears than in the serum samples. There was the same trend towards M. hominis although the difference was not so significant. Therefore, the detection of these microorganisms in UGT is of more informative value for diagnostic purposes. Examination of the serum samples for these purposes provides useful information in understanding the mechanisms of generalization of Mycoplasma infections and studying the routes and modes of spreading these bacteria in the organism. PMID- 18450086 TI - [All-Russian Scientific-and-Practical Forum of Laboratory Specialists]. PMID- 18450087 TI - [Resolution of the results of the All-Russian Scientific-and-Practical Symposium on the Key Problems in the Improvement of Laboratory Provision of Health Care with the international participation]. PMID- 18450088 TI - [The role of stretching in the process of fracture formation]. AB - The author analyses various kinds of bone deformations. The stretching development and its influence on fracture formation are described in the article. Morphological signs confirming presence of stretching as a destroy moment are represented. PMID- 18450089 TI - [Posttraumatic periosteal reaction in the skull arch bones]. AB - The mechanisms of genesis, morphological features of posttraumatic periosteal reaction in skull cap bones were considered. The forensic-medical assessment of this reaction was given. PMID- 18450090 TI - [Forensic-medical significance of determination of concentration of water, potassium and sodium ions in diagnostics of infliction of sequences of stab-and cut wounds]. AB - The results of analyses of content of water, potassium and sodium ions by Yu. A. Medvedev's method (1988) in muscular tissue from damage region in experiment, are represented. These analyses make possible to determine sequences of stab-and-cut wounds inflicted at short time before death. PMID- 18450091 TI - [Typing of ABO locus with biological microchip as a new level in solution of problems in forensic-medical biological expertise of material evidences]. AB - There are cases in practice when during expertise of material evidences, discrepancies between results of typing of ABO antigens and molecular-genetic typing of DNA occur. In this work, as a radical approach to objective solution of similar conflict situations, for some contradictory case of expertise, all examinations were performed on the unified methodological base--DNA level. Instead of biological (isoserological) typing of ABO antigen, molecular-genetic typing of ABO locus with biological microchip was performed. In all cases the results, received with the use of biological microchip, do not contradict but completely conform to the results of others molecular-genetic examinations performed in the case. Given results indicate irrationality of further use of traditional methods of isoserological typing of ABO antigen for primary differentiation of biological material. These analyses, if necessary, have to be performed on DNA level with molecular-genetic expertise. PMID- 18450092 TI - [Using subjective method for personal identification (authentication) during mass arrival of unidentified casualties]. PMID- 18450093 TI - [Osteometric method of determination of ordinal localization of the ribs using discriminant analysis]. AB - III-XI right ribs from 86 skeletons of the Caucasoid, stored in the Chair of Anthropology of Moscow State University, were examined. The ribs were measured by A. I. Turovtsev's program (1972) including 13 signs. The results have been analyzed with statistic program SPSS. Diagnostic models, based on incremental discriminant analysis, were calculated for expert practice. It is recommended to perform the expertise in 2 stages. On 1st stage group belonging of the rib has to be established. 1st group include III-V ribs, 2nd group--VI-VIII and 3rd--IX-XI ones. To determine ordinal localization of I, II and XII ribs is not difficult in view of uniqueness of its anatomic structure. Precision of classification of group localization of a rib is 99.6%. On 2nd stage individual number of the rib has to be determined. Precision of classification in case of belongings of the rib to 1st or 3rd groups is 80.2% and 85.7% respectively, to 2nd group it is lower (41.7-69%). PMID- 18450094 TI - [Concerning the criteria of expert assessment of unfavorable outcomes in implantological stomatology]. AB - The state of complex forensic-medical expertise in implantological stomatology was analyzed in the article. The questions of assessment of medical aid quality with the use of score system of risk degree and factors determination are considered. The authors suggest to use the score system of unfavorable outcomes with the purpose of objectification of expert conclusions. PMID- 18450095 TI - [Chemical-toxicological analysis of butorphanol]. AB - The conditions of butorphanol isolation from biological fluids were studied. The method of its extraction with the mix of organic solvents by pH 12 was proposed. How to identify butorphanol with the methods of thin-layer chromatography, ultraviolet spectrometry, high-performance liquid chromatography, gas chromatography with a detector of electron capture, chromato-mass spectrometry was developed. Possibility of use ultraviolet spectrometry for quantitative assessment of butorphanol was shown. PMID- 18450096 TI - [Distribution of dipyridamole in the organism of warm-blooded animals]. AB - Characteristics of distribution of dipyridamolum in the organism of warm-blooded animals (rats) after its intragastric introduction were studied. It was established that intact dipyridamolum in great quantity was present in visceras, blood and excrements of poisoned animals. In the greatest quantity dipyridamolum was present in excrements, tissues of stomach, small intestine, lung, spleen and kidney. PMID- 18450097 TI - [Experience of state forensic-expert organizations of Russian Federation Ministry of Defense in conditions of local armed conflicts and during extreme situations]. PMID- 18450098 TI - [Forensic-medical expertise in civil court]. PMID- 18450099 TI - [Infliction of face indelible injury as a result of shooting from gas gun]. PMID- 18450100 TI - [The Bologna Process and high medical education in Russia]. PMID- 18450101 TI - [To 180th anniversary of the textbook "Guide to forensic medical science" by Vasilii Tile, inspector of Kazan Medical Council]. PMID- 18450103 TI - [Nipah encephalitis]. AB - Nipah encephalitis is a particular dangerous disease that affects animals and man. Fatal cases of the disease have been identified in the persons looking after pigs in the villages of Malaysia. The causative agent is presumably referred to as morbilliviruses of the Paramixoviridae family. Two hundred persons died among the ill patients with the signs of encephalitis. The principal hosts of the virus were fox-bats (Megaschiroptera) inhabiting in the surrounding forests. The present paper descries the epidemiological features of the disease, its clinical manifestations, abnormal anatomic changes, diagnosis, and implemented controlling measures. PMID- 18450102 TI - [Role of host in spontaneous recovery from viral hepatitis C: the body's condition at the moment of infection]. AB - The condition of the host at the moment of infection is that its immune competence largely determines the efficiency, kinetics, and profile (Thl/Th2) of a further specific immunity response and, accordingly, the outcome of penetration of hepatitis C virus (HCV) into the body and subsequent acute infection (if it occurs). The parameters determining immune competence may include age, traumatizing exposures (operations, burns, wounds, and fractures), immunosuppressive therapy, stresses, con-infections, and alcohol use. The highest rates of spontaneous convalescence from HCV infection are observed in children and adolescents. Other human conditions are much shorter, transient; their impact is difficult to determine in the retrospective review and therefore it has not been adequately studied. Previous operations, posttransplantation immune suppression, immune modulation after blood transfusion, alcohol-induced immune imbalance, drug and narcotic intoxication are poor predictors. Immunosuppression and immune imbalance caused by viral and parasitic infections are observed among the host's temporary conditions affecting the outcome of HCV infection. The authors have analyzed the sequels of superinfections in patients with chronic hepatitis C, other hepatotropic viruses and the common liver fluke Schistosoma mansoni. The interesting therapeutic activities against HCV and parasitic infection (contamination with Echinococcus granulosus in particular), which are shown in the treatment of co-infection patients with alpha-interferon preparations that ensure normalization of immune deficiency caused by each of the infections and their increased combination. A deeper insight into the correlation between the condition of the host and its ability to eliminate the virus may be one more step on the road to the prevention of the infection and to the designing an effective vaccine against HCV. PMID- 18450104 TI - [Epizooty caused by high-virulent influenza virus A/H5N1 of genotype 2.2 (Qinghai Siberian) among wild and domestic birds on the paths of fall migrations to the north-western part of the Azov Sea basin (Krasnodar Territory)]. AB - Isolation, followed by the sequencing the full-size genome of strains of A/chicken/Krasnodarl300/07 and A/Cygnus cygnus/Krasnodar/329/07, has shown that they belong to genotype 2.2 (Qinghai-Siberian). The strains were deposited at the State Virus Collection of the Russian Federation and nucleotide consequences were at the International databank GenBank. The strains contained 10 unique amino acid replacements in reference to the consensus of the Qinghai-Siberian genotype in the PB2, PA, HA, NA, and NS1, which suggests that regional variants may form in different parts of an area. PMID- 18450105 TI - [Analysis of the efficiency of tick-borne encephalitis vaccination in the population in the natural foci of Austria]. AB - Tick-borne encephalitis (TBE), the preventive measure against which is vaccination, is a disease caused by flavivirus (TBE virus). The infection is common in many European countries and in much of Central and Eastern Asia. Formaline-killed whole-virion high-purified vaccine inactivated is widely used for immunization of the population in Europe; however, the coverage of the population with vaccination greatly differs in the country where the natural foci of TBE are recorded. The exception is Austria where 88% of the population has been at least vaccinated against TBE and 58% has been regularly inoculated as evidenced by the officially recommended scheme. The present study has analyzed the efficacy of the above vaccine made in Austria in 2000 to 2006 in different age groups on the basis of documentary data on the cases of admissions for TBE among the unvaccinated and vaccinated and estimated the incidence of this disease in these groups, by taking into account the results of representative surveys. Our investigation has demonstrated that the efficiency of vaccination by the officially recommended scheme among the regularly inoculated persons is about 99% without statistically significant differences between the age groups. This result was observed after the first two vaccinations before completion of the basic course of vaccination, i.e. before the third vaccination; however, the efficiency of vaccination was substantially lower (about 95%) in the persons who had been irregularly inoculated, as shown by the records, i.e. they received the vaccine by the unofficial scheme. The findings confirm the high efficiency of vaccination of the population of Austria against TBE by the officially recommended scheme, which is shown in the prevention of about 2800 cases of TE. PMID- 18450106 TI - [Molecular and epidemiological characteristics of tick-borne encephalitis virus in the Sverdlovsk Region on the basis of genotype-specific RT-PCR]. AB - Studies and complete awareness of the regional and epidemiological properties of tick-borne encephalitis virus (TBEV) allow one to improve methods for preventing, diagnosing, and treating its severe neurological infection. The authors have developed reverse-transcriptase polymerase chain reaction (RT-PCR) systems for the detection of RNA of TBEV and for the determination of its genotype in the ticks and clinical materials. RT-PTC was shown to have a higher sensitivity and specificity than the practically used enzyme immunoassay system. Despite significant variations in the spread of infected ticks in some districts of the Sverdlovsk Region (5-12%), the average regional value was 8% over the study period. The authors have studied more than a thousand of ticks collected from the nature and humans in the epidemic season of 2005-2006. There was a virtually complete predominance (more than 95%) of the Ural-Siberian genotype, with rare cases of the European genotype (slightly more than 4%) being detected. The Far Eastern genotype was not detected. PMID- 18450107 TI - [Infection of macrophages with tick-borne encephalitis virus]. AB - Virological and morphological studies have established that tick-borne encephalitis (TBE) from virus-containing liquid is able to adhere to the surface of macrophages, to penetrate, and to multiple in them. Viral particles come into and out through local macrophageal plasmolemma lysis. The type of macrophageal infection is considered to be autonomic as genomic activation and TBE reproduction occurred in the cell cytoplasm. Productive acute lytic infection in the macrophages was due to the appearance of reproduction-induced adequate TBE with a pronounced cytopathic effect on cultured porcine embryo kidney cells and to the synthesis of virus-specific and virus-induced cytoplasmic organelles that caused cell deaths upon toxic and mechanical exposure. PMID- 18450108 TI - [Detection of a new natural virus focus Dobrava in the Astrakhan Region]. AB - A natural focus of Dobrava hantavirus was first revealed in an arid zone of the Astrakhan Region, by using molecular genetic methods. A polymerase chain reaction was employed to examine 389 lung tissue suspension samples taken from 9 species. Hantavirus RNA was found in 35 samples from 22 field mice (Apodemus agrarius), 8 tamarisk gerbils (Meriones temariscinus), 4 common voles (Microtus arvalis), and 1 house mouse (Mus musculus). Sequencing determined the taxonomic affiliation of 18 new isolates to the Dobrava species and 1 isolate to the Puumala species although the new Dobrava isolated greatly differed from all known strains of this virus in the nucleotide sequence of the genomic M and S segments. Hantavirus infected rodents were found in 3 of 4 districts of the Astrakhan Region, located in the steppe and semidesert zones and at the intrazonal stations of the Volga Akhtuba flood-lands. The high (up to 12%) hantavirus infection rates were ascertained in a tamarisk gerbil, the typical inhabitant of desert and semidesert ecosystems. PMID- 18450109 TI - [Interaction of influenza A and B viruses with a carbon-containing sorbent]. AB - The investigation demonstrated that influenza A and B viruses actively interacted with a sorbent obtained from modified oxygen-containing graphite via hydrothermal treatment irrespective of the antigenic structure of surface proteins. Virionic sorption occurred in a wide range of temperatures from 8 to 34 degrees C for 15 min or more. After interaction with the sorbent, the titer of a virus decreased 4 to 256-fold. The immobilized viruses were able to interact with homologous antibodies and immune sera. Desorption of viruses with the sorbent was extremely slight. In addition to viruses, the proteins of nonviral nature--those of allantoic hen embryo liquid, immune serum, and 1% bovine serum albumin--could be immobilized to the sorbent. PMID- 18450110 TI - [Diagnostic value of enzyme immunoassay test for the detection of specific IgM antibodies to measles virus]. AB - The diagnostic value of enzyme immunoassay systems manufactured by different companies was comparatively studied to detect specific IgM antibodies to measles virus. The assay systems were shown to have a high sensitivity. The specificity was higher in the assay systems designed on the capture principle, a type of solid-phase enzyme immunoassay. PMID- 18450111 TI - The bald-faced hornet, Dolichovespula maculata. PMID- 18450112 TI - Pathophysiology of chronic urticaria. AB - OBJECTIVE: To review the literature on the pathogenesis of chronic urticaria (excluding physical urticaria). DATA SOURCES: PubMed was searched using the keywords urticaria and either chronic or autoimmune or pathogenesis for articles published from January 1972 to June 2007. All searches were limited to the English language. References from review articles on chronic urticaria were also considered for inclusion in this review. STUDY SELECTION: The authors selected relevant and current sources for inclusion in this review. RESULTS: No concise pathogenic mechanism has been identified for all cases of chronic urticaria, although evidence for a serologic mediator that may be autoimmune in nature has been identified in many cases. The activation of basophils and/or mast cells is a central feature in any theory proposed to explain this troubling disease. CONCLUSION: Further research is needed to better define the mechanism or mechanism(s) responsible for the development of chronic urticaria. Such research will lead to more effective and possibly even curative treatments. PMID- 18450114 TI - A flow- and pressure-controlled offline method of exhaled nitric oxide measurement in children. AB - BACKGROUND: Exhaled nitric oxide (eNO) is a noninvasive marker of airway inflammation. However, previous studies show that the offline value is lower than the online value. OBJECTIVE: To compare a standard offline eNO measurement apparatus with a modified apparatus that can monitor flow volume and respiratory pressure. METHODS: We studied 73 cooperative individuals aged 5 to 28 years (32 children: mean age, 8.3 years; 41 adults: mean age, 21.5 years). We modified the standard device by including a flow meter with a manometer and attaching a plastic tube connected to a 3-way valve to control the resistance. The online and offline (measured using the modified device and the standard device) eNO determinations were compared in a single session and were analyzed using a nitric oxide analyzer. RESULTS: There was a good relationship between the online and modified offline eNO measurements in children. The modified offline method showed a stronger correlation with the online method (r = .97 vs. r = .92), and the modified offline eNO value was more similar to the online eNO value than to the standard offline value. The mean difference between the online and standard offline eNO values was 52%, whereas the mean difference between the online and modified offline eNO values was only 10%. CONCLUSIONS: Using the offline method, we can easily control the resistance and flow volume to reach the same value measured by the online method in childhood respiratory diseases. PMID- 18450113 TI - Insurance status and asthma-related health care utilization in patients with severe asthma. AB - BACKGROUND: Medicaid insurance has been associated with worse asthma outcomes, but the degree to which demographic factors contribute to this relationship has not been well explored. OBJECTIVE: To evaluate whether insurance status is independently associated with health care utilization (HCU) and asthma control when demographic differences are taken into account. METHODS: We used baseline data from adults with severe asthma in the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. HCU was defined as hospitalization or emergency department visit for asthma in the past 3 months. Asthma control was evaluated using the Asthma Therapy Assessment Questionnaire. Multiple logistic regression was used to compare HCU and asthma control in patients with Medicaid vs those with private health insurance. RESULTS: Of 1315 patients analyzed, 130 (9.9%) had Medicaid insurance and 1,185 (90.1%) had private insurance. Medicaid insurance was associated with younger age, female sex, race other than white, obesity, active smoking, lower education level, and unemployment. In unadjusted analyses, Medicaid patients had significantly higher HCU (odds ratio [OR], 3.08; 95% confidence interval [CI], 2.11-4.50) and poorer asthma control (OR, 2.56; 95% CI, 1.84-3.57) compared with patients with private insurance. After adjusting for demographic differences, insurance status was no longer associated with HCU (OR, 1.43; 95% CI, 0.92-2.23), and the strength of its association with asthma control was reduced (OR, 1.67; 95% CI, 1.17-2.40). CONCLUSIONS: Medicaid insurance is not associated with increased HCU in patients with severe asthma once demographic factors have been taken into account but remains modestly associated with poorer asthma control. PMID- 18450115 TI - Effect of house dust mite immunotherapy on transforming growth factor beta1 producing T cells in asthmatic children. AB - BACKGROUND: Recent evidence suggests that regulatory T cells (Treg cells) and immunosuppressive cytokines, such as transforming growth factor BETA1 (TGF-BETA1) and interleukin 10 (IL-10), may have a role in clinically effective allergen specific immunotherapy (SIT). OBJECTIVE: To evaluate the effect of SIT on the induction of Treg cells in house dust mite-allergic children and on the expression of specific Treg cell markers (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], IL-10, and TGF-BETA1). METHODS: In this uncontrolled open label study, the percentage of peripheral blood CD4+ Treg cells (CD69 CD45RO+CTLA 4+ and CD3+CD4+CD25+FOXP3+) and the expression of molecules associated with their functions (CTLA-4, TGF-BETA1, and IL-10) were analyzed using flow cytometry in 16 children allergic to house dust mites before and at 3 and 12 months of subcutaneous SIT. Clinical variables, such as symptom score, medication requirements, forced expiratory volume in 1 second, peak expiratory flow rate, and serum IgE levels, were also determined. Ten healthy children were included as controls. RESULTS: All the clinical variables improved during immunotherapy. The percentage of CD4+CD25+CD69-CD45RO+ Treg cells remained unchanged. The percentage of CTLA-4+ -expressing Treg cells transiently increased after 3 months of immunotherapy, whereas the percentage of FOXP3+ Treg cells did not change after 1 year of immunotherapy. Levels of IL-10+ cells transiently decreased after 3 months of immunotherapy. Four children who required inhaled fluticasone propionate administration for significant symptom worsening had no statistically significant increase in TGF-BETA1-secreting T cells at 12 months of SIT, in contrast to 12 children without inhaled corticosteroid treatment. CONCLUSIONS: The increase in TGF-BETA1-positive T cells only in children without significant symptom worsening requiring inhaled corticosteroid treatment limits the usefulness of TGF-BETA1 in monitoring response to allergen immunotherapy. PMID- 18450116 TI - The perceived obstacles in performing patch test to detect allergic contact dermatitis: a comparison between community allergists and directors of allergy training programs. AB - BACKGROUND: Patch testing (PT) is the gold standard test to detect allergic contact dermatitis. Despite its usefulness, it is not universally performed in allergy practices. OBJECTIVES: To determine obstacles in performing PT and to evaluate the differences in perception of these obstacles between community allergists and directors of training programs. METHODS: Two anonymous Web-based questionnaires were distributed to 65 program directors (PDs) across the United States and to 200 community allergists in the mid-Atlantic region. Program directors and community allergists were categorized based on PT performance. Community allergists were categorized based on type of practice. Comparisons between categories were made using the chi2 test. RESULTS: Perceived obstacles among community allergists and PDs were similar; this remained unchanged regardless of performing PT. When community allergists in solo practice were compared with those in group private practice, the difference in perception was significant (P < .01). Previous training in PT among PDs and community allergists was associated with a higher likelihood of performing PT. CONCLUSIONS: Previous training in PT among PDs and community allergists was associated with a higher likelihood of performing PT. We recommend that training in the application and interpretation of PT for diagnosis of allergic contact dermatitis should be an integral part of the curriculum of allergy fellowship training programs and should also be incorporated into the continuing medical education program of practicing allergists. Furthermore, although allergists may continue to rely on dermatologists for more comprehensive PT, use of the thin-layer rapid use epicutaneous test is a simple screening tool that should be available to all allergy practices. PMID- 18450117 TI - Multicenter study of patients with angiotensin-converting enzyme inhibitor induced angioedema who present to the emergency department. AB - BACKGROUND: Recent data are lacking about the number of patients with angiotensin converting enzyme inhibitor (ACEI)-induced angioedema who present to the emergency department (ED). Current management of the condition and clinical outcomes also are not known. OBJECTIVE: To describe the clinical epidemiology of ACEI-induced angioedema in patients who present to the ED. METHODS: We performed a medical record review of ACEI-induced angioedema in patients who presented to 5 EDs in the Emergency Medicine Network. A structured data abstraction form was used to collect each patient's demographic factors, medical history, and details about the angioedema that prompted the ED visit. The medical record review also focused on treatment provided in the ED and subsequent need for hospitalization. RESULTS: We identified a total of 220 patients with ACEI-induced angioedema. The frequency of ACEI-induced angioedema among all patients with angioedema who presented to the ED was 30% (95% confidence interval, 26%-34%). The annual rate of visits for ACEI-induced angioedema was 0.7 per 10,000 ED visits. The most frequent presenting signs were shortness of breath, lip and tongue swelling, and laryngeal edema. Most patients (58%) were sent home directly from the ED, whereas 12% were regular inpatient admissions, 11% were admitted to the intensive care unit, and 18% were admitted under observation status (<24 hours). Pharyngeal swelling and respiratory distress were independent predictors of hospital admission and longer length of stay. CONCLUSION: ACEI-induced angioedema accounted for almost one-third of angioedema treated in the ED, although it remains a rare ED presentation. A subgroup of these patients still needs inpatient hospitalization for management of upper airway angioedema. PMID- 18450118 TI - The logarithmic transformation and the geometric mean in reporting experimental IgE results: what are they and when and why to use them? AB - BACKGROUND: Immunologic data, such as IgE and interleukin 4, tend to have positively skewed distributions with a long tail of larger values. This renders analyses based on normal distribution theory questionable (eg, t tests and analysis of variance) and distorts the sample mean as a measure of central tendency. These problems can be addressed through analysis of log-transformed data. Data analyzed in this fashion are summarized with the geometric mean. OBJECTIVE: To elucidate the use of the logarithmic transform and the geometric mean in the analysis of immunologic data. METHODS: The analysis may be conducted by transforming the data to a logarithmic scale to achieve a bell-shaped (approximately normal) distribution. The bell-shaped distribution needed to validate statistical inferences is only achieved in the transformed scale. In summarizing the research findings, the statistical analyst usually will transform means and confidence intervals from the logarithmic scale back to the original scale of measurement. Statistical inferences in the log scale remain valid for the data. The result of back transforming the mean of logarithmic values to the original scale is the geometric mean. This statistic is less subject to distortion by the unusually large values in the tail of the positively skewed distribution of the data. RESULTS: A brief example is used to illustrate this type of analysis. CONCLUSIONS: Logarithmic transformation permits valid statistical inference for positively skewed immunologic data. A result of this analysis is the geometric mean, which is a better measure of central tendency of this data type than the usual sample mean. PMID- 18450119 TI - Effect of Lactobacillus rhamnosus GG on rBet v1 and rMal d1 specific IgA in the saliva of patients with birch pollen allergy. AB - BACKGROUND: Lactobacillus rhamnosus GG (LGG) has demonstrated promising results in the treatment and prevention of atopic eczema. OBJECTIVE: To study the effects of LGG on the oral immune response in adolescents and adults with birch pollen allergy combined with oral allergy syndrome. METHODS: Patients received either LGG (n = 19) or a placebo (n = 19) for 5.5 months (from February 8 to August 6, 1999), starting 2.5 months before the birch pollen season. An oral apple challenge test was performed before, during, and after the pollen season. Saliva samples were collected before and after the challenges, and serum samples were collected before the challenges. Total IgA, IgG, and IgM and rBet v1 and rMal dl specific IgA, IgG, IgG1, and IgG4 levels were measured from saliva with an enzyme linked immunosorbent assay (ELISA). Serum rBet v1 specific IgE ELISA and birch radioallergosorbent testing were performed. RESULTS: After 5.5 months, rBet v1 and rMal dl specific IgA levels had increased from baseline in the LGG compared with the placebo group (delta rBet v1 IgA, 0.319 vs. -0.136 relative units; P = .02; delta rMal d1 IgA, 0.097 vs -0.117, P = .02). rBet v1 specific IgE serum levels did not differ between the groups. In the LGG group, rBet v1 specific IgE levels correlated positively with stimulated total IgA (P = .04) and IgG (P = .003) in saliva. In the placebo group, rBet vl specific IgE levels correlated negatively with stimulated rBet v1 and rMal d1 IgA levels (P = .009 for both) and IgG (P = .02 and P = .03, respectively). CONCLUSION: LGG showed immunostimulating effects on oral mucosa seen as increased allergen specific IgA levels in saliva. PMID- 18450120 TI - Effect of sublingual immunotherapy with grass monomeric allergoid on allergen specific T-cell proliferation and interleukin 10 production. AB - BACKGROUND: Sublingual immunotherapy (SLIT) is safe and efficacious in the treatment of patients with allergic rhinitis. Although favorable clinical effects have been observed with controlled trials as early as a few months since the beginning of treatment, few biological changes induced by SLIT have been demonstrated. OBJECTIVE: To investigate in grass-allergic patients the effect of a 2-month SLIT regimen, administered with a simplified protocol without up dosing, on proliferation and production of cytokines characteristic of the regulatory T-cell phenotype (interleukin 10 [IL-10] and transforming growth factor beta [TGF-beta]) by allergen-specific T cells. METHODS: Patients were recruited to the study in January 2006. SLIT was performed by self-administration and was continued for 60 days from February to April 2006. Eleven grass pollen allergic patients with seasonal rhinitis were treated daily before the pollen season for 2 months with a modified allergen (monomeric allergoid) derived from a 3-grass pollen extract. Allergen-specific proliferation and production of IL-10 and TGF-beta were measured on peripheral blood mononuclear cells at baseline and treatment end. Tetanus toxoid served as the control antigen. RESULTS: After SLIT, allergen-specific (P = .002) but not tetanus toxoid-specific proliferation decreased, whereas IL-10 transcription increased (P < .001). TGB-beta transcription was also increased after treatment, although not statistically significantly (P = .06). Changes in proliferation to allergen and in IL-10 transcription were correlated (r = -0.82, P = .003). CONCLUSIONS: A short-term course of SLIT with modified allergen in grass-allergic patients is associated with the reduction of allergen-specific proliferation and with the up-regulation of the IL-10 regulatory cytokine. PMID- 18450121 TI - Smoking exposure and allergic sensitization in children according to maternal allergies. AB - BACKGROUND: Although the negative impact of environmental tobacco smoke (ETS) on airway diseases in children is well known, the effect of ETS on allergic sensitization is still debated. OBJECTIVE: To evaluate how maternal allergies modulate the effect of tobacco exposure on allergic sensitization in childhood. METHODS: Of 9000 children in grades 4 and 5 selected in 6 cities in France, 7798 participated in a survey that consisted of an epidemiologic questionnaire, skin prick testing to common allergens, and skin examination for eczema. Tobacco exposure was obtained from parent questionnaires. RESULTS: Twenty-five percent of the children had allergic sensitization, 25.2% had eczema, 11.6% had allergic rhinitis, 9.9% had asthma, and 8.3% had exercise-induced asthma. Twenty percent of the children were exposed to tobacco in utero. Maternal exposure had a greater impact than paternal exposure on children's allergic sensitization. Prenatal exposure was more associated with sensitization than postnatal exposure. Children with maternal allergies and exposure to maternal ETS during pregnancy were at higher risk for sensitization to house dust mite (25.7% vs. 14.0%; odds ratio, 1.95; 95% confidence interval, 1.19-3.18; P = .006). In contrast, sensitization to food allergens was not associated with tobacco exposure. CONCLUSIONS: Children exposed to maternal smoking had a higher risk of sensitization to house dust mite, especially when the mothers were allergic. PMID- 18450122 TI - Classroom aeroallergen exposure in Arkansas head start centers. AB - BACKGROUND: The impact of preschool environmental conditions on classroom aeroallergen concentrations is not fully understood. OBJECTIVE: To examine the relationship between school environmental conditions and classroom aeroallergen concentrations in the Pulaski County Head Start (HS) Program. METHODS: Thirty three HS centers in Pulaski County, Arkansas, underwent a detailed environmental evaluation. Classroom settled dust samples were analyzed for the presence of common indoor allergens. RESULTS: Classroom eating (70%), wall-to-wall carpeting (58%), and water damage (33%) were common. Median classroom allergen levels were as follows: dust mite (Der p 1 and Der f 1), 0.6 microg/g; Fel d 1, 0.4 microg/g; Can f 1, 1.7 microg/g; cockroach, below detection; Mus m 1, 0.18 microg/g; and mold spores, 17,800 CFU/g. Can f 1 and Mus m 1 allergens were detected in 100% of HS centers. Facilities with carpeting, increased humidity, and single-use facilities showed trends toward increased dust mite concentrations. Detectable cockroach allergen was more common in classrooms cleaned by teachers than by professional housekeepers. CONCLUSIONS: Aeroallergens were commonly detected in Pulaski County HS center classrooms, with dog and mouse allergens detected in 100% of centers. Median classroom allergen concentrations were low, and classroom characteristics were not strongly predictive of increased allergen exposure. PMID- 18450123 TI - Alternaria measures in inner-city, low-income housing by immunoassay and culture based analysis. AB - BACKGROUND: Sensitivity to Alternaria allergens has been associated with severe asthma and life-threatening exacerbations, and a high prevalence of Alternaria sensitivity has been reported among inner-city populations. Traditionally, epidemiologic studies have measured indoor Alternaria concentrations by cultural analyses; however, the number of viable spores may not be a good proxy for allergen levels. Furthermore, other genera share epitopes with Alternaria that may contribute to the allergenic effect. OBJECTIVE: To compare measures of Alternaria antigen by enzyme-linked immunosorbent assay with measures of Alternaria and cross-reactive genera (Ulocladium, Curvularia, Epicoccum, and Stemphylium) by cultural analysis. METHOD: Antigen assays and cultural analyses were performed on vacuum-collected bed dust samples collected between June 18, 2002, and February 9, 2004, from 3 inner-city, low-income public housing developments. RESULTS: Alternaria antigen was found in all bed dust samples regardless of season. However, culturable Alternaria, Ulocladium, Curvularia, Epicoccum, and Stemphylium were only found in 50%, 35%, 6%, 11%, and 0% of bed samples, respectively. No correlations were found between Alternaria antigen and culturable concentrations of Alternaria or of its cross-reactive genera except for marginal correlation with Ulocladium culturable concentrations. CONCLUSIONS: The results confirm that exposure to Alternaria antigens and allergens can occur even in the absence of culturable Alternaria or its cross-reactive genera, so further refinement and use of assays are essential for characterizing the distribution and determinants of indoor fungal allergen levels forsensitive populations. PMID- 18450124 TI - Comparison of single 2000-microg dose treatment vs. sequential repeated-dose 500 microg treatments with nebulized budesonide in acute asthma exacerbations. AB - BACKGROUND: High repeated doses of inhaled corticosteroids (ICSs) are recognized as having a more rapid improvement of outcomes than a single dose of ICS in severe acute asthma. However, to our knowledge, there has been no direct comparison of the early effects of single or repeated administration of the same total dosage of ICS in children with moderate to severe exacerbations of asthma. OBJECTIVE: To compare the efficacy of a single dose of 2000 microg of nebulized budesonide with 4 repeated doses of 500 microg of nebulized budesonide in 40 children with an acute asthma exacerbation. METHODS: Randomized, double-blind, parallel study that compared the efficacy of 2000 microg of nebulized budesonide, administered in a single dose, with repeated doses (4 doses of 500 microg each) during the first 90 minutes in 40 children (mean [SD] age, 10.7 [2.4] years) with an acute asthma exacerbation that required treatment with an oral corticosteroid. Forced expiratory volume in 1 second, asthma attack score, and oxygen saturation were evaluated at 20, 40, 60, 90, 120, 180, and 240 minutes after initial treatment. Oral corticosteroids were given to all patients at 90 minutes. RESULTS: There were no significant differences in forced expiratory volume in 1 second (P = .54) at any times between the groups. Also, asthma scores and oxygen saturation were not different in either group within 90 minutes (P = .51 and P = .64, respectively) and thereafter (P = .35 and P = .87, respectively). CONCLUSION: The use of a single dose of nebulized budesonide is as effective as repeated administration of the same total dosage during the first 90 minutes before giving oral corticosteroids in children with moderate to severe exacerbations of asthma. PMID- 18450125 TI - Antibiotics for simple upper respiratory tract infections: a survey of academic, pediatric, and adult clinical allergists. AB - BACKGROUND: The Centers for Disease Control and Prevention (CDC), the American Academy of Family Practice, and the American Academy of Pediatrics published guidelines for judicious antibiotic use: antibiotics are injudicious for the treatment of short-term purulent rhinorrhea, otitis media with effusion, and acute wheezy bronchitis. OBJECTIVE: To determine how academic, pediatric, and adult clinical allergists differed in use of antibiotics for upper respiratory tract infections (URIs). METHODS: Surveys were sent to 424 allergists in private clinical practice and 156 allergists in academic settings. Three clinical pediatric vignettes were described. Questions about possible antibiotic use followed. Vignettes were as follows: simple URI in a toddler, the same child with short-duration green rhinorrhea, and the same child with otitis media with effusion. RESULTS: Of 580 mailed surveys, 358 were returned, for an overall response rate of 61.7%. Thirty-nine of these surveys did not meet inclusion criteria, reducing the response rate to 55.0%. Of these, 47.0% (n=150) were familiar with the guidelines: 85.3% answered that they usually adhered to them in practice. The academic allergist respondents demonstrated the best adherence to the guidelines for the 3 vignettes, followed closely by the clinical pediatric allergist respondents. For the population surveyed, adult clinical allergists were more likely than the other 2 groups to prescribe antibiotics for a simple URI (P < .001) and for a URI with short-duration green rhinorrhea (P = .004). CONCLUSIONS: Academic allergists adhered to the CDC guidelines more closely than did adult allergists. Pediatric allergists in clinical practice were in agreement with the academic allergists. Despite self-reported knowledge of the CDC guidelines, many adult allergists in clinical practice did not adhere to them in their answers to the questions after several vignettes. PMID- 18450126 TI - Effects of echinacea on the frequency of upper respiratory tract symptoms: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Upper respiratory tract infection symptoms are a common cause of morbidity. Herbal preparations of the plant Echinacea purpurea have immune enhancing properties. OBJECTIVE: To compare the frequency of upper respiratory tract symptoms in individuals receiving E. purpurea capsules and those receiving placebo to evaluate the preventive efficacy of echinacea. METHODS: In a randomized, double-blind clinical trial, 90 volunteers recruited from hospital personnel were randomly assigned to receive 3 capsules twice daily of either placebo (parsley) or E. purpurea for 8 weeks during the winter months. Upper respiratory tract symptoms were reported weekly during this period. RESULTS: Fifty-eight individuals were included in the final data analysis: 28 in the echinacea group and 30 in the placebo group. Individuals in the echinacea group reported 9 sick days per person during the 8-week period, whereas the placebo group reported 14 sick days (z = -0.42; P = .67). Mild adverse effects were noted by 8% of the echinacea group and 7% of the placebo group (P = .24). CONCLUSION: Prophylactic treatment with commercially available E. purpurea capsules did not significantly alter the frequency of upper respiratory tract symptoms compared with placebo use. PMID- 18450127 TI - Potential bias in studies of accidental needle sticks. PMID- 18450128 TI - Evaluation and clinical interpretation of hypergammaglobulinemia E: differentiating atopy from immunodeficiency. AB - Increases in total serum IgE levels can be observed in many diverse conditions, from infection to atopy to primary immunodeficiency. The differentiation of atopy from immunodeficiency most often is made on a clinical basis, after taking findings from history, physical examination, and laboratory studies into consideration. However, total IgE level is neither a sensitive nor a specific diagnostic marker for any particular disease and, therefore, should not be relied on to establish a diagnosis of either atopy or primary immunodeficiency. PMID- 18450130 TI - The pancake syndrome (oral mite anaphylaxis) by ingestion and inhalation in a 52 year-old woman in the northeastern United States. PMID- 18450129 TI - Asymptomatic long-standing panhypogammaglobulinemia with impaired antibody responses. PMID- 18450131 TI - Adolescent presentation of x-linked lymphoproliferative disease. PMID- 18450132 TI - Safety needles. PMID- 18450133 TI - In obstetrics and gynecology, ultrasound has become indispensable. PMID- 18450134 TI - Ultrasound of adnexal masses. AB - Current advancements in imaging technology, especially three-dimensional/four dimensional ultrasound and contrast-enhanced imaging, have increased the diagnostic yield of adnexal masses. The benefit of ultrasound is the characterization of an adnexal mass, suggesting the probable etiology of the mass. Masses may be divided as solid, cystic, or complex. It is predominantly the solid and complex masses that need a thorough evaluation. The role of color-flow imaging is now gaining importance and criteria for distinguishing between benign and malignant masses are often possible. Availability of a scoring system enables the differentiation of small adnexal masses. Several benign lesions may present as complex masses but can be distinguished and diagnosed on sonography. The availability of 3D ultrasound has been of great use to understand spatial relations and vascular morphology. Sonography allows a more detailed assessment of morphologic features of an adnexal mass. With a benign-appearing adnexal mass on sonography, the need for any further diagnostic tests is often obviated. PMID- 18450135 TI - Ultrasound of the pediatric female pelvis. AB - Pelvic pain is a common indication for ultrasound examinations in female pediatric patients. Many pathological processes affect the female pelvis in childhood. Knowledge of the normal ultrasound appearance of the pelvic organs is the basis for the recognition of pathologic findings. Pelvic pain in children is a nonspecific clinical finding often prompting use of ultrasound. Other indications for pelvic ultrasound in female children include workup of cysts seen on fetal ultrasound, urogenital malformations in newborns, precocious puberty, vaginal discharge or abnormal bleeding, and amenorrhea. Knowledge of differential diagnosis for disease processes of the female pelvic organs is essential. Ultrasound is the imaging modality of choice for evaluating the pediatric female pelvis. PMID- 18450136 TI - Is ultrasound the new gold standard for the diagnosis of ectopic pregnancy? AB - Ultrasound technology and in particular the use of transvaginal imaging has taken the guesswork out of ectopic pregnancy diagnosis. The vast majority of ectopic pregnancies can and should be diagnosed with a high degree of certainty before management is commenced. More and more women with ectopic pregnancy are eligible for nonsurgical intervention because ultrasound has enabled clinicians to make the diagnosis much earlier in its natural history. We believe that laparoscopy, traditionally the gold standard in diagnosis of ectopic pregnancy, should not be used in modern management. There is more and more evidence to support the use of transvaginal ultrasound as the primary diagnostic tool for ectopic pregnancy. In this review we hoped to demonstrate that transvaginal ultrasound is the new gold standard for the diagnosis of ectopic pregnancy. PMID- 18450137 TI - First-trimester ultrasound: current uses and applications. AB - This article is aimed to aid the sonographer and medical care provider in better interpretation and clinical application of first-trimester ultrasound findings in early pregnancy. We review current uses, applications, and interpretations of first-trimester ultrasound. A discussion of basic embryology and normal as well as abnormal first-trimester sonographic findings are discussed. We also cover the utility of the first-trimester ultrasound in screening for fetal aneuploidy. Attention is also given to the role of the first-trimester ultrasound in the prediction of adverse perinatal and maternal outcomes. PMID- 18450138 TI - Ethics is an essential dimension of first-trimester risk assessment for trisomy 21. AB - We identify the clinical implications of the ethics of informed consent for risk assessment for trisomy 21. Based on the ethics of informed consent, we argue that routinely offering first-trimester risk assessment in centers qualified to provide it is ethically obligatory. We describe how pregnant women can be expected to respond to this offer. We then argue that routinely withholding the results of first-trimester risk assessment is ethically unjustified. The ethics of informed consent is an essential dimension of first-trimester risk assessment for trisomy 21. PMID- 18450139 TI - Evaluation of fetal growth and fetal well-being. AB - This article reviews the actual knowledge and future developments of ultrasound techniques for the evaluation of fetal growth and well-being. Sonography allows the visualization of the fetus in utero and is utilized worldwide for the evaluation of fetal growth and well-being. Fetal biometry assessment is performed in the second half of pregnancy when deviations of fetal growth can be best recognized through alterations of fetal abdominal circumference growth. Doppler velocimetry of utero-placental vessels identifies alterations of placental perfusion and is valuable in the assessment of fetal brain, heart, and liver perfusion, thus being utilized in the timing of delivery. Recently, three dimensional ultrasound evaluation of fetal organs and placenta is being developed. PMID- 18450140 TI - Three-dimensional obstetric ultrasound. AB - Three-dimensional ultrasound has gained a significant popularity in obstetrical practice in recent years. The advantage of this modality in some cases is in question, however. This article provides a basic review of volume acquisition, mechanical positioning, and display modalities. Multiple uses of this technique in obstetrical care including first trimester applications and its utility in clarification of fetal anatomy such as brain, face, heart, and skeleton is discussed. PMID- 18450141 TI - Safety assurance in obstetrical ultrasound. AB - Safety assurance for diagnostic ultrasound in obstetrics began with a tacit assumption of safety allowed by a federal law enacted in 1976 for then-existing medical ultrasound equipment. The implementation of the 510(k) pre-market approval process for diagnostic ultrasound resulted in the establishment of guideline upper limits for several examination categories in 1985. The obstetrical category has undergone substantial evolution from initial limits (ie, 46 mW/cm2 spatial peak temporal average [SPTA] intensity) set in 1985. Thermal and mechanical exposure indices, which are displayed onscreen according to an Output Display Standard, were developed for safety assurance with relaxed upper limits. In 1992, with the adoption of the Output Display Standard, the allowable output for obstetrical ultrasound was increased in terms of both the average exposure (eg, to a possible 720 mW/cm2 SPTA intensity) and the peak exposure (via the Mechanical Index). There has been little or no subsequent research with the modern obstetrical ultrasound machines to systematically assess potential risks to the fetus using either relevant animal models of obstetrical exposure or human epidemiology studies. The assurance of safety for obstetrical ultrasound therefore is supported by three ongoing means: (1) review of a substantial but uncoordinated bioeffect research literature; (2) the theoretical evaluation of diagnostic ultrasound exposure in terms of thermal and nonthermal mechanisms for bioeffects; and (3) the skill and knowledge of professional sonographers. At this time, there is no specific reason to suspect that there is any significant health risk to the fetus or mother from exposure to diagnostic ultrasound in obstetrics. This assurance of safety supports the prudent use of diagnostic ultrasound in obstetrics by trained professionals for any medically indicated examination. PMID- 18450142 TI - [Sleep quality in aged patients with peripheral vascular diseases]. AB - Peripheral vascular diseases (PVD) are prevalent among the elderly, and, due to their chronic character, result in poor quality of life and poor sleep quality. This study aimed at evaluating sleep quality of elderly people diagnosed with PVD who undergo clinical ambulatory treatment in a university hospital in Campinas, in the State of Sao Paulo. Subjects (n=50, aged 74 +/- 8 years old) answered the Pittsburgh Sleep Quality Index (PSQI) and provided basic demographic data and PVD history (35 subjects had arterial blockage in lower limbs). Results showed that 34 subjects presented bad sleep quality; sleep length was 5.8 (+/- 2.3) hours, and, according to 23 subjects, night sleep was frequently disturbed by pain (thrice a week or more). Eighteen subjects took analgesics; four took sleep medicines. Findings may have important implications for nurses working with PVD patients, stressing the need to take into account consequences of PVD on sleep disturbances when planning their interventions. PMID- 18450143 TI - [Coping strategies developed by caregivers of elderly with chronic diseases]. AB - Care for a dependent elderly individual with a chronic disease can be a threat and cause stress. Success in dealing with this situation will depend on coping strategies, defined as processes used in order to control the demands of the individual-environment relationship. In this study the goal was to detect coping strategies used by caregivers for the elderly. A qualitative study was carried out through the analysis of coping discourse and theoretical reference. The sample was comprised of 16 individuals. It was observed that the coping strategies most used by caregivers were centered on emotion, and that caregiving tasks imply many changes in the life of caregivers, who perform them with no aid, with work overload, loss of liberty, and frustration. The greatest stress is related to the lack of help from family members and of shared responsibilities. Stimulating the involvement of the family, educating and giving basic orientation, which may reduce the difficulties of caregiving, could improve these individuals' well-being. PMID- 18450144 TI - [Changes in the care of the elderly after the enactment of the elderly statute according to professionals of a geriatric hospital]. AB - This study was aimed at finding out how an interdisciplinary team deals with the Elderly Statute and how it interfered in the care of institutionalized elderly. The setting was a geriatric hospital in Sio Paulo where 297 elderly people reside. Thirty-five professionals from the facility's interdisciplinary team took part in the study and answered a questionnaire with open and close questions. Results were divided into categories and submitted to a descriptive analysis. It was observed that 68.6% of the professionals thought that after the enactment of the Statute there have been changes in the care provided, even if slowly, and that they occurred in the interdisciplinary staff, which went after specialization in order to improve care; in the facilities, which adapted so as to attend to the needs of the elders; and in the elderly people themselves and in their families, whom, feeling protected by the law, increased the demands for their rights. PMID- 18450145 TI - [Ethical occurrences involving nursing staff and professionals: a quantitative approach]. AB - This study aimed at identifying characteristics of ethical occurrences related to nursing care in a large private hospital in the city of Sao Paulo. There were 190 occurrences reported to the hospital's Nursing Ethical Committee (NEC) between 1995 and 2004. Most occurrences caused no damages to the patient, the health institution, the nursing staff or the professional involved. From the total of 398 procedures taken, 94.5% of the cases were advices given to nursing staff members by the NEC, including advice from the immediate superiors to the staff members involved. In 93.7% of the occurrences only one staff member was involved. Clinical units accounted for 76.3% of the services involved with ethical occurrences. As a result, it may be said that the study showed the importance of giving advices to the staff in order to prevent customers from damaging occurrences. PMID- 18450146 TI - [Technological organization of labor in an emergency service and nursing worker's autonomy]. AB - This research was aimed at examining the organization of labor processes in an emergency service as well as the autonomy nursing workers have when providing care. It is a qualitatively-oriented case study. Data were collected by free observation, with focus on the service provided to users. It was observed that the labor process is organized around the treatment of the main complaint, having the doctor's visit as its core action. Technological organization places doctors as the main power holders, followed by nurses in their spaces of powerandautonomy an autonomy that is seldom exercised by the remaining agents. Nurses' work is crucial, traversing all spaces of service and interlinking actions; however, it is seen as supplementary to primary care activities. PMID- 18450147 TI - [Comprehensive health care: indications from the training of nurses]. AB - This study has the objective of understanding the training of nurses for comprehensive health care. It used data from interviews with teachers, students and service nurses submitted to discourse analysis. There is an understanding of comprehensive care in the training of nurses from the perspective of establishing a healthcare model in which care is directed to the patient. There are reflections regarding the technologies and the form of organization of the work, expressed in a permanent tension: Clinical versus Collective Health as a challenge for comprehensive care. It was identified that building completeness in the formation implies assuming acting in health as an educative principle in a new form of learning-teaching in health, which breaks up with pre-formed, out-of context knowledge. The conclusion is that comprehensive health care is taken as an object of reflection in the movement for change in the pedagogical practices, and that it is reflected in health attention. PMID- 18450148 TI - [Nursing students' life quality: building a process and interventions]. AB - This is a research-action studies whose objectives were to know Nursing undergraduate students' perceptions concerning their quality of life; to understand and analyze the demands they highlight when rescuing situations they have experienced; and to make operational, by means of the operative group, directions and strategies that can improve their quality of life. The study was carried out at Sao Paulo's Catholic University. The data were obtained, in a first stage, through individual interviews. The analysis of the topics from this first stage guided the themes of the five meetings of the focus group in the second stage. The data from the work group were analyzed according to the thematic analysis mode and adapted from the Ecological Model of Quality of Life of Students. The results showed that the University is a place that provides experiences that may promote or not students' quality of life. They also showed the need for systematic meetings in which both students and teachers can discuss the individual and collective development of strategies for facing the problems related to life quality. PMID- 18450149 TI - [Dialectics for humanized care in ICU's: contradictions between professional nursing discourse and practice]. AB - This study attempts to unveil contradictions in humanized nursing care in ICUs. It is a qualitative, dialectic-based study involving 7 nurses, 4 family members and one patient of the Adult ICU of the Hospital of the Federal Universityof Santa Catarina. Participatory observation and semi-structured interviews were applied to collect the data. Marxist and Gramscian ideas of contradiction were used as the theoretical-philosophical reference. This study demonstrates that humanized care is part of a complex network, in which care knowledge seems to give way to closer network ties, while care practicefollows an impersonalized strategy within the logic of partitioned and routine health care production. The dissociation between knowledge and practice also contemplates the difficulties in dealing with the burdens of suffering and institutional-professional limitations. The conclusion is that knowledge of this reality should be a renewed, yet age-old challenge for the nurse in the search for the constant construction/ reconstruction of Nursing in terms of practice, knowledge and work relations. PMID- 18450150 TI - [Music for institutionalized elderly: perceptions of the intervening musicians]. AB - This qualitative study analyzed musicians' perception of their musical activities with institutionalized elderly in Portugal and France using a questionnaire and the Collective Subject Discourse to organize the data. The musicians see their performance as a human experience; they intentionally look for proximity and communication; they recognize the old persons' reality and wish to transform it; they present difficulties in interpersonal communication and in professional development, and adopt musical, personal and intuitive criteria when choosing their repertoire. The results indicate social, human and professional commitment from the musicians analyzed, and may be used as a source for reflection for the health team. PMID- 18450151 TI - [Menopause knowledge and experience for a group of women]. AB - This ethnographic study is aimed at understanding a group of women's knowledge about menopause and how they experience it. The methods used for data collection were participant observation, recorded interviews and previously produced drawings. Data were analyzed based on a theoretical framework using both the ethnographic method and biographic interpretativism. From the narratives the authors obtained the cultural categories and themes. Thus it was possible to conclude that menopause is understood as a result of a unique construction integrated to a network of meanings built by the group that condition knowledge and experience within certain cultural patterns, among them the fact that menopause means leaving womanhood behind. PMID- 18450152 TI - [How infected women in Fortaleza-CE cope with AIDS]. AB - The objective of this study was to learn how women with Aids cope with daily living after receiving their diagnosis. It is an exploratory, descriptive study with a qualitative approach based on thematic oral history for data collection and analysis. Ten women with Aids were interviewed at a reference hospital in Fortaleza, State of Ceara, from December 2004 to March 2005. A semi-structured questionnaire was used for data collection. The results revealed different ways of coping, related to the fragility of the discovery of the diagnosis, to the need to hide the infection due to the discrimination and prejudice faced by the victims, and to the constant perception of death. In addition, the women expressed feelings such as shame, concern about family, abandonment, solitude, sadness, fear and anxiety. The authors conclude that, two decades after the epidemic broke out, women still face evident difficulties when they experience their infection. PMID- 18450153 TI - [Coverage of directly observed treatment (DOTS) of tuberculosis in the state of Sao Paulo (1998-2004)]. AB - The Supervised Treatment (ST) in the 36 priority municipalities for TB control of the State of Sao Paulo between 1998 and 2004 was analyzed with the aim of describing the coverage of the DOTS. This exploratory study used information from the State of Sao Paulo's Health Secretary's EPI-TB database. An instrument of data collection was elaborated and the coverage of the ST was calculated. The data was put in the Excel program. In the municipalities that implemented the ST in 1998, coverage was under 20%. In 1999 half of the municipalities had coverage between 11% and 49%. In 2000, the implementation was 100%, but the maximum coverage was 61%. Between 2001 and 2002 the coverage increased in 69.44% of the municipalities. In 2003, coverage was below of 50% in 22 municipalities. In 2004 there was a trend to increasing coverage in 63.89% of the municipalities. PMID- 18450154 TI - [Prenatal care in Quixada-CE according to SISPRENATAL's process indicators]. AB - This is a descriptive, documental survey aimed at analyzing the process indicators of the Prenatal Information System (Sisprenatal) in the municipality of Quixada, State of Ceara. The records of 1544 pregnant women from 2001 through 2004 were studied. Data were collected from February through April, 2005 in Sisprenatal, located in the Epidemiology sector of the local Health Secretary. The results were presented in a single chart containing absolute and relative frequency. They were analyzed in the light of current literature and the authors' experience. In the period was verified a growing percentage of pregnant women with indicators of at least six appointments, all the basic exams, anti-HIV test, antitetanic immunization and puerperal consultation, from zero percent (2001), to 2.6% (2002), to 5.68% (2003) to 21.11% (2004). Thus it is necessary to improve the use of the system, as well as the systematic reading of the process indicators, in order to obtain subsidies for the enhancement of the quality of prenatal assistance. PMID- 18450155 TI - [Profile of newborns who underwent cardiac surgery in a private hospital in the city of Sao Paulo]. AB - The aim of this cross-sectional study was to characterize newborns that underwent cardiac surgery in a private hospital, a reference center in neonatal cardiac surgery, in the city of So Paulo. Data were collected from medical reports from July, 2001 to December, 2005. Newborns with gestational age of more than 35 weeks were included in the study. Newborns that died on the first 48 postoperative hours and with other malformations were excluded. Most of the neonates were term, weighted 2500 grams or more, and underwent surgery in the first week of life. There were 24 different diagnoses identified and 14 different types of surgery performed. In the first post-operative day, all newborns had invasive devices for vital signs monitoring or for treatment and life support, which shows not only the complexity of the treatment but the need for planning and organizing health services in order to provide adequate care for these patients. PMID- 18450157 TI - [Centers of psycho-social attention and the strategies for family insertion]. AB - This research has the objective of identifying the mental health activities developed at Centers of Psycho-Social Attention (CAPSs) directed to the family in the care of individuals in psychological suffering. It is a descriptive, analytic survey of the case study type with a qualitative approach. Data collection was carried out through observation and semi-structured interviews with professionals of a CAPS. The results showed that the work at a CAPS becomes successful only when there is family partnership and participation. Individual sessions, family groups, active searches, home visits and workshops are strategies used at CAPSs for the effective insertion of the family. In this partnership, bonding appears as essential in the construction of less suffering and less stigmatized ways of psychical suffering. PMID- 18450156 TI - [Analysis of risk indicators for the arterial hypertension in children and teenagers]. AB - The aim of this study was to evaluate the risk indicators for high blood pressure in children and teenagers. A cross-sectional study developed with 342 individuals of 6-18 years of age in a school of Fortaleza city. The most individuals were male (51.5%). The age mean was 11.7 years (+/-3.19). It was frequent the scholars with overweight/obesity (16.8%) and blood pressure above of the 90th percentile (44.7%). Sedentarism, smoking and drinking were present in 51.5%, 38% and 15.5% of the sample. The systolic blood pressure was correlated with the variable age, weight, height, waist and hip circumferences, subscapular skinfold thickness and body mass index. There was correlation of the diastolic blood pressure with age, weight, height, and waist and hip circumferences. It was confirm the influence of risk factors on the blood pressure values of children and teenagers. The systolic blood pressure was especially influenced by anthropometric indicators. PMID- 18450158 TI - [Social representations of families and users about their participation in the treatment of persons with mental diseases]. AB - This study was aimed at investigating the social representations of families and users of mental health services regarding their participation in the treatment of persons with severe mental disease. The study was based on the Theory of Social Representations. Data collection was carried out through the application of a free association of words test and an interview with a script with relatives and users of two day-hospitals in Fortaleza, State of Ceara. The results showed that the subjects of the research consider the care in this kind of service beneficial and think that family support is essential for progress in the treatment of persons with mental disease. PMID- 18450159 TI - [Alteration in attention and cancer pain treatment]. AB - Cognitive impairment can negatively impact daily routine. This fact encouraged the elaboration of this study, which analyzed the impact of pain treatment with opioids on attention. Patients were divided into groups that were given (n=14) and were not given opioids (n=12). Three interviews were conducted to assess attention using the Trail Making Test and the Digit Span Test. The groups were homogeneous regarding socio-demographic variables, pain and depression; they were not homogeneous regarding the Karnofsky scale and the use of adjuvant analgesics. The patients in treatment without opioids had better performance in the Digit Span Test-reverse order, in the second assessment (p = 0.29); no differences were observed on the Trail Making Test. The observed impairments were limited, but while new studies do not confirm the findings, patients, professionals and caregivers must be alert about the possible deleterious effects of opioids on the cognitive function. PMID- 18450160 TI - [Time spent on the nursing assistance system after the implementation of a standard language system]. AB - This prospective, exploratory-descriptive study was aimed at analyzing the results of the change of model of the Nursing Assistance System (SAE), with the introduction of a nursing diagnosis classification, on the time spent by the nurse in the realization of this system, identifying the estimated time and the measured time. The study was based on a sample of 42 nurses from different units of the University of Sao Paulo's Hospital Universitario, with in average 11 years of professional experience, who were observed in average 5 times while carrying out the phases of the SAE. The data were collected from August, 2005 to February, 2006, after the introduction and consolidation of the nursing diagnosis classification. The results showed that the time estimated by the nurses was significantly longer than the time actually measured; and that the time spent for patient evaluation was, on average, longer during his/her admission compared to the follow-up. PMID- 18450161 TI - [Efficacy of the pasteur oven as sterilization equipment in dental offices]. AB - This study was aimed at assessing the efficacy of the use of the Pasteur oven as sterilization equipment in dental offices through biological monitoring. For this assessment were taken into account how adequately the material is loaded into the equipment; time/temperature used; and preventive maintenance of the oven. The data were collected in 101 dental offices in the Central District of GoiPnia, in the State of Goias, through observation, interviews and performance of tests with biological indicator. The results showed a lack of standardization of some of the procedures recommended by the Ministry of Health for sterilization of items in the oven, and positive results of the biological test in 46 (45.5%) of the tested cycles. The intervening factors with most significance regarding sterilization problems were: absence of an accessory thermometer to control the cycles' temperature and non-observance of the time/temperature relations recommended for the sterilization cycle through dry heat. PMID- 18450162 TI - Daughter of time: the postmodern midwife (part 2). AB - Any effort to make sense of the complexities of contemporary midwifery must deal not only with biomedical and governmental power structures but also with the definitions such structures impose upon midwives and the ramifications of these definitions within and across national and cultural borders. The international definition of a midwife requires graduations from a government-recognized educational program. Those who have not are not considered midwives but are labeled traditional birth attendants. Since there are myriad local names for midwives in myriad languages, the impact of this naming at local levels can be hard to assess. But on the global scale, the ramifications of the distinction between midwives who meet the international definition and those who do not have been profound. Those who do are incorporated into the health care system. Those who do not remain outside of it, and suffer multiple forms of discrimination as a result. PMID- 18450163 TI - [Dialogue as a pressuposition in the humanistic nursing theory: relationship mother-nurse-newborn]. AB - This is a critical-reflective study carried out in 2005 aiming at analyzing dialogue as a presupposition in Peterson and Zderad's Humanistic Theory. Using as a starting point two Master's degree theses, the authors adopted the Meleis Model of Analysis, in the scope of theory description, focusing on the unit of analysis named theory presuppositions. The authors clearly perceive the quest for and the construction of the dialogue in the stages of the theory's methodological process: Preparation in order to get to know, Knowing the other intuitively, Knowing the other scientifically, Complementary synthesis of the others' knowledge, Succession within the nurse from the many to the paradoxical one. The presupposition of dialogue was brought up in an explicit manner in the theory, grounded on the philosophical bases of existentialism, humanism, and phenomenology. There was a distinct behavior in each experience, in spite of the common aspects, such as having been experienced with neonates and in the same institution. PMID- 18450164 TI - [International classification of Nursing Practices in Collective Health-CIPESC]. AB - The project International Classification of the Nursing Practices in Collective Health-CIPESC was the Brazilian contribution for the incorporation of the notion of collectiveness in the International Classification of Nursing Practice-ICNP. This article aims at analyzing the bibliographical production concerning nursing classifications available in the virtual library in health database since 1990. This is a bibliographical survey of nursing practice classification systems and is part of a larger research that intends to identify the collective face of the CIPESC instrument in the municipal health network of the city of Curitiba, in the State of Parana. The result shows that the majority of the texts are based on the clinical-individual model, and those that emphasize the social-epidemiologic model are still a minority. In addition, most studies focused on the collective were disseminated through the publications of the Brazilian Nursing Association, which has the hegemony in the diffusion of the knowledge about the collective face of classification systems. PMID- 18450165 TI - [Risk factors for urinary incontinence in women]. AB - The goal of this study was to conduct a review of the main papers published between 1983 and 2003 on the main risk factors for urinary incontinence (UI) in women. Thirty-eight publications in English and Portuguese were analyzed using the MEDLINE and LILACS databases as well as through research in libraries. There is evidence that the main risk factors are age, pelvic floor trauma, hereditary factors, race, menopausal status, obesity, chronic diseases, use of some sympathomimetics and parasympatholitics, constipation, smoking, coffee consumption and intense abdominal exercises. Nurses are able to identify these factors through anamnesis and determine interventions for the prevention and treatment of UI, thus contributing to improve incontinent women's quality of life. PMID- 18450166 TI - [Use of topic iodine in acute wounds]. AB - The purpose of this study was to carry out a systematic review of the literature regarding the use of topic iodine and/or compounds in the treatment of acute wounds. The clinical trials were searched at the Cochrane's database using the following descriptors: iodine, acute wound, treatment, healing, infection, surgery, surgical. Twenty studies (52.6%) out of 38 met the criteria for inclusion. The articles were analyzed regarding journal and study characteristics and classified into five groups: iodine versus other topic agents (4/20%); iodine versus types of dressings (1/5%); iodine versus saline solution (5/25%); iodine versus no iodine (8/40%); and iodine at different concentrations (2/10%). Favorable results for the use of iodine and/or compounds occurred in 45% of the studies. Three out of 5 studies showed favorable results for healing and prevention of infection and 9 out of 15 studies were not favorable when only infection prevention was investigated. PMID- 18450167 TI - Understanding schizophrenia in the 21st century. PMID- 18450168 TI - Combining ERP and structural MRI information in first episode schizophrenia and bipolar disorder. AB - The electrical activity in the electroencephalogram (EEG) and the event-related potentials extracted from the EEG provide the greatest temporal resolution for examining brain function. When coupled with the high spatial resolution of structural magnetic resonance imaging (sMRI), the combined techniques provide a powerful tool for neuroscience in the examination of brain abnormalities in major psychiatric illnesses. Over the last 20 years, our work has examined brain structure and function in schizophrenia. Both EEG and MRI measures have indicated profound abnormalities in schizophrenia within the temporal lobe, particularly marked over the left hemisphere. Our studies of patients first hospitalized due to psychosis revealed the early course of the disease to be characterized by progressive impairment and cortical gray matter reduction, most intense near the time of first hospitalization. Knowledge of those locations and brain signals affected early should help understand the basic physiological defect underlying this progression, with potential implications for new therapeutic interventions. PMID- 18450169 TI - Simultaneous EEG-fMRI: perspectives in psychiatry. AB - Neurophysiological findings such as reduced amplitudes of the P300 potential in patients with schizophrenia are among the most robust findings in biological psychiatry. An enormous literature with findings of abnormal central processing in psychiatric diseases has been acquired during the last decades. However, the benefit of this research has been limited in part due to the unresolved problem of precise and correct localization of the underlying neural generators. The difficulty of correct localization is due to the fact that different constellations of cortical neuroelectric generators can produce identical EEG activity. Therefore, even concerning several major event related potentials no generally accepted knowledge about their cerebral generation exists. While correct localization can easily be obtained by imaging methods based on hemodynamic changes such as functional magnetic resonance imaging (fMRI), these techniques can not distinguish between different aspects of neural activity such as oscillation modes or stages of information processing that are only some milliseconds apart. Accordingly, the integration of simultaneous measurements of EEG and fMRI has become a methodological key issue today. EEG-fMRI may prove to be crucial in providing much deeper understanding of brain activity over the next decades. This review summarizes the basic physiology, methodological issues and interesting applications in psychiatry. PMID- 18450170 TI - Visual gamma oscillations in schizophrenia: implications for understanding neural circuitry abnormalities. AB - Gamma oscillations may play an important role in the representation of information in the brain by synchronizing the firing of neurons in local and distributed neural circuits. The Bleulerian conceptualization of schizophrenia as "disintegration of thought and personality" suggests that neural mechanisms responsible for the integration of neural activity, such as gamma oscillations, might be particularly disrupted in this disorder. Here we review studies of gamma oscillations in healthy and schizophrenic individuals performing visual perception tasks. The findings suggest that schizophrenia is associated with a variety of abnormalities of visual gamma oscillations, which appear to be linked to core symptoms and cognitive deficits of schizophrenia. The relationships between these abnormalities and neural circuitry abnormalities in schizophrenia are discussed. PMID- 18450171 TI - Sensory gating: a translational effort from basic to clinical science. AB - Sensory gating (SG) is a prevalent physiological process important for information filtering in complex systems. SG is evaluated by presenting repetitious stimuli and measuring the degree of neural inhibition that occurs. SG has been found to be impaired in several psychiatric disorders. Recent animal and human research has made great progress in the study of SG, and in this review we provide an overview of recent research on SG using different methods. Animal research has uncovered findings that suggest (1) SG is displayed by single neurons and can be similar to SG observed from scalp recordings in humans, (2) SG is found in numerous brain structures located in sensory, motor and limbic subregions, (3) SG can be significantly influenced by state changes of the organism, and (4) SG has a diverse pharmacological profile accented by a strong influence from nicotine receptor activation. Human research has addressed similar issues using deep electrode recordings of brain structures. These experiments have revealed that (1) SG can be found in cortical regions surrounding hippocampus, (2) the order of neural processing places hippocampal involvement during a later stage of sensory processing than originally thought, and (3) multiple subtypes of gating exist that could be dependent on different brain circuits and more or less influenced by alterations in organismal state. Animal and human research both have limitations. We emphasize the need for integrative approaches to understand the process and combine information between basic and clinical fields so that a more complete picture of SG will emerge. PMID- 18450173 TI - Validating endophenotypes for schizophrenia using statistical modeling of twin data. AB - The use of endophenotypes (intermediate quantitative traits) is one strategy that may provide valuable information about the neural mechanisms underlying disease etiology and facilitate discovery of susceptibility genes. For a trait to be an appropriate endophenotype, several key features should exist. In this article we discuss validating potential electrophysiological endophenotypes for schizophrenia based on conventionally accepted criteria. We focus on applying a twin study design and model fitting techniques to evaluate whether three event related potential paradigms (P300, P50, and MMN) meet criteria as valid endophenotypes of schizophrenia. PMID- 18450172 TI - Endophenotypes, dimensions, risks: is psychosis analogous to common inherited medical illnesses? AB - Psychiatric illnesses are perceived as fundamentally different from common medical disorders, a view arising from the mind-body problem and difficulties relating the brain's emergent properties to its physiological substrates. However, schizophrenia and many common medical illnesses are heritable and result from the influence of both genetic and environmental sources. Unlike illnesses such as Huntington's disease, which are caused by a fully penetrant dominant mutation, no single "schizophrenia gene" has been identified. Instead, schizophrenia is likely caused by common variants of many genes, each contributing a subtle effect. Schizophrenia genetically resembles common medical illnesses such as type 2 diabetes, ischemic heart disease, and familial hypercholesterolemia, that have an associated genetic variant, but that are also influenced by other factors such as diet, culture and habits. Just as these illnesses operate through complex gene/environment interaction, schizophrenia is likely caused by several gene variants, neurodevelopmental processes, and learned behavioral response biases. These clinical diseases, however, represent severe forms of the phenotype for both psychiatric and medical illnesses. From a dimensional perspective, individuals possessing the same genotype could express milder forms of the clinical disorder along a spectrum of related traits. We discuss this perspective in the context of an endophenotypic and biological marker approach to understanding schizophrenia and present a research strategy to compare schizophrenia endophenotypes to risk for common medical illnesses. PMID- 18450174 TI - Corollary discharge dysfunction in schizophrenia: evidence for an elemental deficit. AB - Evidence is accumulating that schizophrenia is characterized by dysfunction of efference copy/corollary discharge mechanisms that normally allow us to unconsciously recognize and disregard sensations resulting from our own actions. This dysfunction may give rise to subtle but pervasive sensory/perceptual aberrations in schizophrenic patients, altering their experience of their own overt and covert actions, as well as their interactions with the environment. It may also contribute to symptoms such as hallucinations and delusions, and may disrupt the motivation to engage with people and in activities. We developed neurophysiological paradigms to study motor-sensory feed-forward processes, or efference copy/corollary discharge mechanisms, in the speech-auditory system, and showed these processes to be deficient in chronic schizophrenia. Specifically, we observed neural responses during talking that made evident the suppressive consequences of a successful corollary discharge mechanism. We also observed synchronous neural activity preceding talking that we believe reflects the efference copy in action. Recently, we extended this neurophysiological research to the somatosensory system, again finding evidence of deficient motor-sensory feed-forward processes in schizophrenia. If dysfunction of this elemental mechanism is reliable, valid, and not the result of antipsychotic medications, it might represent a major new class of electrophysiological measures sensitive to a fundamental and ubiquitous pathophysiological process in schizophrenia. PMID- 18450175 TI - Auditory/Verbal hallucinations, speech perception neurocircuitry, and the social deafferentation hypothesis. AB - Auditory/verbal hallucinations (AVHs) are comprised of spoken conversational speech seeming to arise from specific, nonself speakers. One hertz repetitive transcranial magnetic stimulation (rTMS) reduces excitability in the brain region stimulated. Studies utilizing 1-Hz rTMS delivered to the left temporoparietal cortex, a brain area critical to speech perception, have demonstrated statistically significant improvements in AVHs relative to sham simulation. A novel mechanism of AVHs is proposed whereby dramatic pre-psychotic social withdrawal prompts neuroplastic reorganization by the "social brain" to produce spurious social meaning via hallucinations of conversational speech. Preliminary evidence supporting this hypothesis includes a very high rate of social withdrawal emerging prior to the onset of frank psychosis in patients who develop schizophrenia and AVHs. Moreover, reduced AVHs elicited by temporoparietal 1-Hz rTMS are likely to reflect enhanced long-term depression. Some evidence suggests a loss of long-term depression following experimentally-induced deafferentation. Finally, abnormal cortico-cortical coupling is associated with AVHs and also is a common outcome of deafferentation. Auditory/verbal hallucinations (AVHs) of spoken speech or "voices" are reported by 60-80% of persons with schizophrenia at various times during the course of illness. AVHs are associated with high levels of distress, functional disability, and can lead to violent acts. Among patients with AVHs, these symptoms remain poorly or incompletely responsive to currently available treatments in approximately 25% of cases. For patients with AVHs who do respond to antipsychotic drugs, there is a very high likelihood that these experiences will recur in subsequent episodes. A more precise characterization of underlying pathophysiology may lead to more efficacious treatments. PMID- 18450176 TI - Hallucinations, thought disorders, and the language domain in schizophrenia. AB - Auditory hallucinations and formal thought disorders are major diagnostic features of schizophrenia. From a neurobiological point of view, they are of particular interest since both can be attributed to the language domain of human communication. In the last decade, brain imaging studies have contributed to the understanding of the functional dynamics underlying these phenomena. In particular, auditory hallucinations were found to involve the regions generating inner speech as well as the primary acoustical cortex and the intrahemispheric fiber bundles connecting the left frontal with the temporal lobe. In patients with formal thought disorders, on the other hand, the left temporal language area showed structural deficits and functional abnormalities, i.e., reduced reactivity to stimulation and increased activity at rest; left frontal language regions were also hyperactive at rest but showed no structural deficits. The available evidence indicates a dynamic imbalance of the language system, triggered by subtle structural changes, as the possible common neurobiological basis of hallucinations and formal thought disorders. PMID- 18450177 TI - Future directions for examining semantic memory in schizophrenia spectrum disorders. AB - Language abnormalities in schizophrenia are regarded as a hallmark of the disease. Clinical investigations provided accurate descriptions of the different manifestations of abnormal language use, and behavioral studies suggested several mechanisms that might contribute to these abnormalities. This review focuses on semantic memory dysfunction and, primarily, on functional methodologies such as ERP and fMRI that provide more direct measures of abnormal neural mechanisms related to language use in schizophrenia. In addition, the review points to future directions of study of the areas that received little attention thus far and whose investigation might contribute to a more detailed understanding of semantic memory dysfunction in schizophrenia. PMID- 18450178 TI - Building meaning in schizophrenia. AB - The schizophrenia syndrome is clinically characterized by abnormal constructions of meaning during comprehension (delusions), perception (hallucinations), action (disorganized and non-goal-directed behavior) and language production (thought disorder). This article provides an overview of recent studies from our laboratory that have used event-related potentials and functional magnetic resonance imaging to elucidate abnormalities in temporal and spatial patterns of neural activity as meaning is built from language and real-world visual events in schizophrenia. Our findings support the hypothesis that automatic activity across semantic memory spreads further within a shorter period of time in thought disordered patients, relative to non-thought-disordered patients and healthy controls. Neuroanatomically, increased activity to semantic associates is reflected by inappropriate recruitment of temporal cortices. In building meaning within sentences, the fine balance between semantic memory-based mechanisms and semantic-syntactic integration (dictating "who does what to whom") is disrupted, such that comprehension is driven primarily by semantic memory-based processes. Neuroanatomically, this imbalance is reflected by preserved (and sometimes increased) activity within temporal and inferior prefrontal cortices, but abnormal modulation of dorsolateral prefrontal and parietal cortices. In building meaning across sentences (discourse), patients fail to immediately construct coherence links, but may show inappropriate recruitment of temporal and inferior prefrontal cortices to incoherent discourse, again reflecting inappropriate semantic memory-based processing (abnormal inferencing). Finally, these abnormalities may generalize to real-world visual event comprehension, where patients show reduced neural activity in determining relationships around goal directed actions, and comprehension is again dominated by semantic memory-based mechanisms. PMID- 18450179 TI - Semantic activation and verbal working memory maintenance in schizophrenic thought disorder: insights from electrophysiology and lexical ambiguity. AB - We have examined language processing using ambiguous words (homographs like panel or toast) and rapid or slow presentation rates while recording event-related brain potentials (ERPs). Homographs allow for tracking the train of thought at points of lexical ambiguity and detecting modulation of associative threads by previous context. Rapid presentation rates stress automatic semantic activation, and slow rates stress controlled verbal working memory contextual modulation. In conjunction with reaction times and performance, ERPs allow for objective measurement of activity related to language processing from word presentation through overt behavioral response. Smaller N400 to related and unrelated items at short stimulus onset asynchronies (SOAs), the presence of a semantic bias, and large N400 to related and unrelated items at long SOAs are present in schizophrenia. We describe a model of initial semantic memory hyper-priming and subsequent decay of information in verbal working memory stores, the activation maintenance model of schizophrenic thought disorder hypothesized to underlie the thought disorder in schizophrenia. PMID- 18450181 TI - Progress in dentistry. PMID- 18450180 TI - Attenuated modulation of the N170 ERP by facial expressions in schizophrenia. AB - In psychiatrically-well subjects the modulation of event related potentials (ERPs) by emotional facial expressions is found in several ERPs from -100 ms and later. A face-related EPR, the N170, is abnormally reduced in schizophrenia to faces relative to other complex objects and research suggests emotional modulation of N170 may be reduced as well. To further examine facial emotion modulation of N170, subjects detected neutral facial expressions from among five emotional expressions (happy, sad, fearful, angry, and disgusted). Over occipitotemporal sites, psychiatrically-well subjects showed bilateral differences in N170 amplitude among expressions (P = 0.014). Schizophrenia subjects failed to show this modulation (P = 0.551). Accuracy on the task did not differ between groups, nor did the pattern of errors. However, in patients, greater positive and negative symptom ratings were associated with increased failure to button press to neutral faces, suggesting misattribution of emotion to neutral expressions in the more ill patients. Because the N170 is largely specific to faces, these results suggest that an impairment specific to the visual processing of facial expressions contributes to the well-known behavioral abnormalities in facial emotion tasks in schizophrenia. PMID- 18450182 TI - Changes in New York law broaden rights of disabled patients. PMID- 18450183 TI - Dentistry and dental technology. PMID- 18450184 TI - Stem cells and the future of dental care. AB - What are stem cells? As dentists, why should we be concerned with stem cells? How would stem cells change dental practice? Is it possible to grow a tooth or TMJ with stem cells? This article summarizes the latest stem cell research and development for dental, oral and craniofacial applications. Stem cell research and development will, over time, transform dental practice in a magnitude far greater than did amalgam or dental implants. Metallic alloys, composites and even titanium implants are not permanent solutions. In contrast, stem cell technology will generate native tissue analogs that are compatible with the patient's own. PMID- 18450185 TI - Use of metal conditioner on reinforcement wires to improve denture repair strengths. AB - The purpose of this study was to evaluate the transverse strength of denture base resin repaired with autopolymerizing resin and metal wire using a metal conditioner, along with the synergistic effect of a surface preparation for denture base resin. It was found that the use of Co-Cr-Ni wires air abraded with 50 microm alumina, followed by treatment with a metal conditioner and dichloromethane for denture base resin, was the most effective method for repairing fractured denture base resin. PMID- 18450186 TI - Treatment of a mandibular cleft using distraction. AB - Distraction osteogenesis is an alternative treatment method for correction of mandibular hypoplasia. This paper outlines the use of mandibular distraction in a patient with mandibular hypoplasia and a history of a mandibular cleft. PMID- 18450187 TI - The Bennett angle. Clinical comparison of different recording methods. AB - The use of interocclusal records with semi-adjustable articulators has been proposed as an easier alternative to axiograph. The operator measured the Bennett angle of 30 participants using an axiograph Quick-Axis, an arcon Whip-Mix and non arcon Dentatus articulators. Wax and polyether interocclusal recording materials were used with both types of articulators. Compared to the reference axiograph, the Whip-Mix plus wax combination was the nearest one and the Dentatus plus polyether was the most significantly different combination. PMID- 18450188 TI - Epilepsy and dental procedures. A review. AB - This paper is a review of the dental management of patients with epilepsy. It includes discussion of the effects anti-epileptic drugs have on dental procedures and addresses complications and side effects of these drugs. A clinical case photo is presented to show gingival hyperplasia, along with four tables on which common antiepileptic medications are enumerated. PMID- 18450189 TI - Gingival hemangioma with port wine nevi of the face. A case report. AB - Hemangioma is a proliferating mass of blood vessels. Its occurrence in gingiva is rare. The diagnosis and treatment of hemangioma is complex, and any attempt to carry out biopsy/surgical excision may lead to fatal consequences due to severe hemorrhage. A rare case of gingival hemangioma with port wine nevi of face is reported. The case is of periodontal interest because the lesion occurred on the gingiva, a reliable diagnostic approach (Ultrasound Spectra Doppler Flow) was used and a conservative treatment using a sclerosing agent was employed. PMID- 18450190 TI - Preferred treatment methods for primary tooth vital pulpotomies. A survey. AB - This investigation evaluated preferred treatment methods for primary tooth vital pulpotomies. One hundred and thirty surveys were sent to a randomly selected sample of board-certified pediatric dentists practicing in the United States. Ninety-two questionnaires were returned, for a 71% response rate. This yielded a sample group of 92 board-certified pediatric dentists. The most commonly used medicament was formocresol. Seventy-three percent using formocresol said they were not concerned about adverse side effects of formocresol and formaldehyde. Sixty-one percent of respondents used formocresol for primary tooth vital pulpotomies. Twenty-eight percent of respondents used undiluted, and 33% used diluted. The results of this survey suggest that the majority of dentists who used formocresol were not concerned with any adverse effects. PMID- 18450191 TI - Peripheral ossifying fibroma and pyogenic granuloma. Are they interrelated? AB - Peripheral ossifying fibroma (POF) and pyogenic granuloma (PG) belong to the group of "focal reactive overgrowths," having different histomorphologic representations. The pathogenesis of POF remains controversial. It has been observed that POF in some cases may initially develop as a PG that undergoes subsequent fibrous maturation and calcification. A case of focal reactive gingival overgrowth with a recurrence is presented. Clinical, radiological and histological examinations were performed and included a detailed history of the lesions to come up with the proper diagnosis. The primary lesion was diagnosed as POF and the recurrent lesion as PG. The POF might have developed initially as PG and subsequent maturation led to the ossification of the lesion. These two lesions represent the progressive stages of the same spectrum of pathosis. PMID- 18450192 TI - Cardiovascular nurses speak out on wait times. PMID- 18450193 TI - Pulmonary hypertension: a review for nurses. AB - Pulmonary hypertension (PH) is a progressive disease resulting from increased pulmonary vasoconstriction, vascular remodelling and thrombosis, leading to right heart failure. Symptoms at clinical presentation are often vague and difficult to differentiate from other diseases. A good history and identification of key physical findings will facilitate earlier diagnosis resulting in tailored treatment to alleviate symptoms and improve outcomes. This article will provide an overview of PH including pathophysiology, clinical presentation, diagnostic testing, and treatment modalities with a Canadian perspective. The main focus is directed towards the care of patients with pulmonary arterial hypertension (PAH). Implications for nursing will also be discussed, focusing on education and support of patients and families. PMID- 18450194 TI - Interview with Gillian Yates, RN, NP (cardiology), nurse practitioner, QE II Health Sciences Centre, Halifax. PMID- 18450195 TI - Interview with Karen Schnell-Hoehn, RN, BN, MN, CCN(C), clinical nurse specialist, St. Boniface General Hospital, Winnipeg. PMID- 18450196 TI - [Interview with Bilkis Vissandjee, University of Montreal]. PMID- 18450197 TI - Interview with Andrea M, patient, and Annemarie Kaan, RN, MCN, clinical nurse specialist, St. Paul's Hospital, Vancouver. PMID- 18450198 TI - Interview with Amy Graham, RN, BNSc, former nurse educator CCU, St. Paul's Hospital, Vancouver, Jean Carme, RN, BScN, CCN(C), operations leader CCU, St. Paul's Hospital, Vancouver. PMID- 18450199 TI - Interview with Jim Rankin, Karen Then and Nancy Gwadry. PMID- 18450200 TI - Commentary: arguments about which sex is the bigger "victim" of heart disease do little to inform nursing practice. PMID- 18450201 TI - From eminence-based to error-based to evidence-based surgery. PMID- 18450202 TI - Should the 'C' in 'ABCDE' be altered to reflect the trend towards hypotensive resuscitation? AB - BACKGROUND: Fluid resuscitation of trauma victims currently differs, depending on whether the Advanced Trauma Life Support (ATLS), Prehospital Trauma Life Support (PHTLS) or Battlefield Advanced Trauma Life Support (BATLS) algorithm is utilised. Resuscitation protocol depends on the situation of the patient before definitive surgical control of the haemorrhage can be achieved, that is, in the prehospital phase (the urban, rural or battlefield setting) or in the emergency room. The principle difference is between hypotensive (PHTLS and BATLS, in the prehospital phase) and normotensive (ATLS, in the emergency room) resuscitation. The aim of this review was to determine if there is sufficient evidence to consider altering the ATLS resuscitation algorithm to a hypotensive model prior to definitive surgical control of haemorrhage. METHOD: A literature review was conducted of the experimental and clinical evidence for hypotensive resuscitation. RESULTS: Uncontrolled haemorrhage models are too severe. They do not realistically mimic--and their results cannot easily be extrapolated into- clinical scenarios. One important clinical trial, inspired by these experimental models, has rightly influenced resuscitation of shocked prehospital patients towards a 'scoop and run' approach and permissive hypotension but it is specific to patients with penetrating trauma alone. CONCLUSION: There is insufficient evidence to alter the current ATLS algorithm in the emergency room in favour of hypotensive resuscitation. The future of resuscitation is considered. PMID- 18450203 TI - Scandinavian Guidelines--"The massively bleeding patient". PMID- 18450204 TI - Prospective evaluation of symptom responses to successful operation for mild moderate primary hyperparathyroidism. AB - BACKGROUND: Parathyroidectomy is claimed to strongly improve the hypercalcemic symptoms in patients with primary hyperparathyroidism (HPT). The object of this study was to register the patients own experience of symptom changes in response to successful parathyroid surgery. METHODS: Material one. 44 HPT patients filled in a questionnaire consisting of 8 visual analogue scales referring to "typical" hypercalcemic symptoms before as well as 2 and 12 months after neck surgery. Their results were compared with those obtained from an age- and sex-matched group of patients undergoing surgery for non-toxic thyroid disease. Material two. 25 elderly women with mild-moderate HPT were followed more closely up to 3 years after neck surgery with the same type of questionnaire. RESULTS: HPT patients expressed significantly more of fatigue, muscular weakness, impaired memory, thirst and polyuria than patients with non-toxic thyroid disorders. These differences were eliminated 2 months after surgery. The pattern of response to parathyroidectomy was similar for most symptoms: an impressive improvement after 2 months and then a gradual return towards the preoperative value. However, the response was still significant for fatigue, weakness, thirst, polyuria and inactivity after 1 year. The effect of normalization of serum calcium on symptom scoring varied considerably between different individuals and also between different symptoms in the same individual. The elderly women responded in a similar biphasic way but their improvements were less pronounced. CONCLUSIONS: HPT patients experience significant improvements of most "hypercalcemic" symtoms after successful parathyroidectomy, but the effects are transient and vary considerably between different individuals. PMID- 18450205 TI - Clinicopathological characteristics and non-adhesive organ culture of insulinomas. AB - BACKGROUND AND AIMS: Insulinoma is a very rare type of islet cell tumour, but nevertheless the most common endocrine tumour of the pancreas. We aimed at reviewing our clinical experience with this tumour type and to assess whether organ culture could be obtained from surgically resected insulinoma material. MATERIAL AND METHODS: All patients with insulinomas (6 men and 10 women) referred to Haukeland University Hospital between 1986 and 2006 were included in the study. Median age of onset was 53 years (range 21-74). Biochemical diagnosis was established during a 72 h fast test. Imaging and localization of the tumours were performed with intra-operative ultrasonography, endoscopic ultrasonography, CT scan and/or transcutaneous ultrasonography. For six patients, organ cultures were set up from tumour tissue fragments. RESULTS: The annual incidence of insulinoma was 0.8 per million. The patients generally presented with non-specific, episodic symptoms, which often were mistaken for cardiovascular, neurological or diabetic disease and in some cases delayed the diagnosis with several years. Two patients had diabetes prior to the diagnosis of insulinoma. Patient weight gain was probably due to increased food intake, compensating for the hypoglycemia. Intra operative ultrasonography detected all tumours correctly, whereas 73% were detected by endoscopic ultrasonography and 38% by CT scan. Five insulinomas were located in the head, eight in the body and three in the tail of the pancreas. All were removed by open-access surgery, eleven cases by resection and five by enucleation. One tumour was malignant with liver metastases and two patients had tumours defined as borderline. Insulinoma tissue fragments developed into spheroids during the first week of culturing and insulin secretion into the media was demonstrated. CONCLUSIONS: Insulinomas are rare and diagnostically challenging tumours. Intra-operative ultrasonography was superior to other imaging modalities to locate the lesion. In organ culture, insulinomas readily form spheroids which may be used to yield insight into beta-cell biology. PMID- 18450206 TI - Impact of endovascular treatment on clinical status and health-related quality of life. AB - BACKGROUND AND AIMS: Investigating the impact of percutaneous transluminal angioplasty (PTA) on clinical status and health related quality of life in patients with claudication and critical limb ischaemia (CLI). MATERIAL AND METHODS: 61 patients and 64 limbs underwent a primary PTA (30 claudication and 34 CLI cases). Clinical status was graded according to Ahn and Rutherford and ankle/brachial index (ABI). Quality of life was assessed using the Nottingham Health Profile (NHP) preoperatively, one month and one year after the procedure. Triplex scan evaluation of the treated arterial segment was carried out postoperatively and one year after the procedure. RESULTS: Claudication: 24/27 patients underwent one-year follow up, after which 20/24 had no claudication. In triplex evaluation 17 (63.0%) treated segments were open with 0-50% restenosis, 9 (33.3%) with 51-99% restenosis and one (3.7%) was occluded. CLI: 13/34 (38.2%) patients underwent one-year follow-up after which eight patients (61.5%) were asymptomatic and five (38.1%) had claudication. In triplex evaluation there was 0 50% restenosis in 6 (46.2%) segments treated with PTA and 51-99% restenosis in 7 (53.8%) segments. 21 (61.8%) patients did not conclude the one year follow up: 7 had died, 5 had undergone bypass surgery and 6 an amputation and 3 did not attend the follow-up up for unknown reasons. Quality of life: For CLI patients, improvement was observed in the domain of pain, which continued throughout the follow-up period. Among the claudicants, the domain of physical mobility was improved at one month's follow-up, but this effect disappeared during the following year and could not be seen at one the one- year follow-up. CONCLUSIONS: Technical success and one-year results in claudication are good, and the rate of complications is low. However, although PTA resulted in an immediate improvement in the quality of life, this effect was not seen in the long term. In critical limb ischemia there was a group of patients in whom PTA led to a significant benefit in terms of limb salvage and quality of life. PMID- 18450207 TI - Treatment with autologous bone marrow mononuclear cells in patients with critical lower limb ischaemia. A pilot study. AB - BACKGROUND AND AIMS: Treatment with autologous, bone marrow mononuclear stem cells has shown effects in patients with chronic limb ischaemia in one randomized clinical study. The aim of the study was to test the potential effect of stem cell treatment in a strict defined group of patients with stable critical limb ischaemia (CLI). DESIGN: A prospective, combined-centre pilot study. MATERIAL: Eight patients with CLI of the lower extremities, and without any other treatment options. METHODS: Bone marrow cells were harvested from the patient's iliac crest and, after separation, injected into the calf muscles of the affected leg. Outcome was evaluated by digital subtraction angiography (DSA), visual analogue scale (VAS) and several non-invasive circulatory physiological tests. RESULTS: There were no complications from the procedures. Two patients were amputated two months after cell injection. Five patients reported pain relief after four months. Five patients could be evaluated at eight months. According to VAS and physiological tests, they were all either stable or showed improvement. CONCLUSION: This method seems to be a safe option for treating patients with CLI. Inclusion of patients took a long time, mainly because many patients with CLI are offered endovascular treatment in our institution. While symptomatic improvement was found in individual patients, larger trials are required to investigate efficacy. This will probably require multi-centre participation. PMID- 18450208 TI - Minimally invasive repair for treating pectus excavatum--early results. AB - Minimally invasive repair of pectus excavatum (MIRPE) is the preferred technique for repair of funnel chest deformity. The aim of this study is to evaluate our initial postoperative results, to identify factors related to postoperative complications and to examine the acceptability of MIRPE by the patients. PATIENTS, MATERIALS AND METHODS: 25 MIRPE patients (20 male and 5 female) were operated on between November 2002 and February 2007 at the Department of Pediatric Surgery, Turku University Central Hospital. The median age of the patients was 14 years (range from 5 to 23 years). One patient had undergone previously open Sulamaa reconstruction and one had a history of intrathoracic lymphoma. The remaining 23 patients had primary pectus excavatum. A right thoracoscopy was performed to every patient. RESULTS: Operative mortality was zero and there were no clinically significant bleeding complications. Epidural analgesia was necessary for adequate pain control. Small symptomless residual pneumothoraxes and pleural effusions were common after the operation but neither required intervention. One patient had a hemothorax 7 months postoperatively, which was cured with a single puncture. Bar displacement took place in 2 patients but required correction in only one of these patients. There were 2 wound infections, one superficial and one which led to removal of the bar was 6 months after the operation. This may have been unnecessary. Two patients had pneumonia, one probably unrelated to the operation. One patient required psychiatric ward treatment, and 3 patients had mild psychological symptoms not requiring specific therapy. The preliminary cosmetic results were good or excellent in 90% of the cases, but a longer follow-up is needed for information on the final outcome. CONCLUSIONS: MIRPE is a safe operation and gives a cosmetically good result. Thoracoscopy is needed during the operation. The early postoperative period in hospital is painful and there the patients need intensive care. We found the high epidural analgesia beneficial and safe during early period of pain treatment. The bar is removed not earlier than 3 years after the operation as a day care surgical procedure. PMID- 18450209 TI - Congenital diaphragmatic hernia: improved surgical results should influence abortion decision making. AB - AIMS: To compare surgical results for congenital diaphragmatic hernia (CDH) in two Scandinavian university hospitals and to evaluate the effects of abortions on the clinical profile of CDH in Iceland. METHODS: A retrospective study including all CDH-cases in Iceland 1983-2002 and children referred to Lund University Hospital 1993-2002. Aborted fetuses with CDH from a nation-wide Icelandic abort registry were also included. RESULTS: In Iceland, 19 out of 23 children with CDH were diagnosed < 24 hours from delivery, one with associated anomalies. Eight fetuses were diagnosed prenatally and seven of them aborted, three having isolated CDH at autopsy. In Iceland, 15 of 18 children operated on survived surgery (83% operative survival). In Lund 28 children were treated with surgery, 23 of them diagnosed early after birth or prenatally. Four children did not survive surgery (86% operative survival) and 9 (31%) had associated anomalies. All the discharged children treated in Iceland and Lund are alive, 3-22 years postoperatively. CONCLUSION: CDH is a serious anomaly where morbidity and mortality is directly related to other associated anomalies and pulmonary hypoplasia. However, majority of CDH patients do not have other associated anomalies. In spite of improved surgical results (operative mortality < 20%), a large proportion of pregnancies complicated with CDH are terminated. We conclude that the improved survival rate after corrective surgery must be emphasized when giving information to parents regarding abortion of fetuses with a prenatally diagnosed CDH. PMID- 18450210 TI - Introducing an asymmetric cleft lift technique as a uniform procedure for pilonidal sinus surgery. AB - BACKGROUND AND AIMS: Asymmetric techniques for surgery in pilonidal sinus disease (PSD) have been reported to provide better results than simple excision and closure in the midline. The aim of this retrospective study was to evaluate the results after introducing the Bascom asymmetric cleft lift procedure in our hospital on a day care basis. MATERIAL AND METHODS: From a total of 33 patients operated from April 2002 to September 2004 with the Bascom asymmetric cleft lift technique, we were able to contact 29 who were invited to a follow up study. Eighteen (62%) of these patients accepted a consultation in the outpatient clinic while 11 (38%) were interviewed by phone. RESULTS: At follow up mean 17 (range 10 27) months after the operation 24 (83%) of the wounds were healed while recurrences were present in 5 (17%) of the patients. In two of the patients with recurrences errors in the procedures were identified. Further results related to pre-, per- and postoperative conditions are discussed in this paper. CONCLUSION: Early results after surgery for PSD with the Bascom asymmetric cleft-lift technique are promising. The technique has now become our standard procedure for treating chronic, symptomatic PSD. PMID- 18450211 TI - Employing components-of-variance to evaluate forensic breath test instruments. AB - The evaluation of breath alcohol instruments for forensic suitability generally includes the assessment of accuracy, precision, linearity, blood/breath comparisons, etc. Although relevant and important, these methods fail to evaluate other important analytical and biological components related to measurement variability. An experimental design comparing different instruments measuring replicate breath samples from several subjects is presented here. Three volunteers provided n = 10 breath samples into each of six different instruments within an 18 minute time period. Two-way analysis of variance was employed which quantified the between-instrument effect and the subject/instrument interaction. Variance contributions were also determined for the analytical and biological components. Significant between-instrument and subject/instrument interaction were observed. The biological component of total variance ranged from 56% to 98% among all subject instrument combinations. Such a design can help quantify the influence of and optimize breath sampling parameters that will reduce total measurement variability and enhance overall forensic confidence. PMID- 18450212 TI - Hair characteristics of four Indian bear species. AB - Dorsal guard hairs of four species of bear (family: Ursidae) found in India were characterized using light microscopy by studying features including colour, hair thickness, cuticle pattern, medulla pattern, medullary index, cross-section and scale count index. The gross cuticular pattern was quite similar for the four species but a distinct difference was observed in the scale count index. Medulla type was narrow and amorphous with a very low medullary index (< 0.15) except for brown bear which showed a comparatively higher medullary index (0.38) and a vacuolated medulla. By combining together the parameters mentioned above it was possible to characterize bear species on the basis of their hair characteristics. PMID- 18450213 TI - Determination of mouth alcohol using the Drager Evidential Portable Alcohol System. AB - Drivers suspected of alcohol intoxication are observed for a period of 15 min prior to quantitative breath alcohol testing. This is to preclude the interference of alcohol-based substances such as cough medicine, mouthwash, and breath spray just prior to actual evidential testing. To determine whether a 15 min observation period was necessary when performing evidential breath tests in the field, a mouth alcohol experiment was performed using the Drager Evidential Portable Alcohol System (EPAS). Five types of alcohol beverages and the effects of expectorating versus swallowing were tested on twenty-five volunteer subjects. Serial measurements of breath and blood alcohol levels were performed at fixed time intervals. All alcohol beverage types gave two sequential measurements within 0.02 g/210 L of each other before 15 min had passed. Fifteen minutes was necessary to ensure there was no residual mouth alcohol. If the 15 min waiting period was not observed, the safety feature of the EPAS requiring two sequential measurements 2 min apart within 0.02 g/210 L would not ensure against mouth alcohol interference. PMID- 18450214 TI - Nature and place of crime scene management within forensic sciences. AB - This short paper presents the preliminary results of a recent study aimed at appreciating the relevant parameters required to qualify forensic science as a science through an epistemological analysis. The reader is invited to reflect upon references within a historical and logical framework which assert that forensic science is based upon two fundamental principles (those of Locard and Kirk). The basis of the assertion that forensic science is indeed a science should be appreciated not only on one epistemological criteria (as Popper's falsification raised by the Daubert hearing was), but also on the logical frameworks used by the individuals involved (investigator, expert witness and trier of fact) from the crime scene examination to the final interpretation of the evidence. Hence, it can be argued that the management of the crime scene should be integrated into the scientific way of thinking rather than remain as a technical discipline as recently suggested by Harrison. PMID- 18450215 TI - The Forensic Science Society Summer Conference "Benefits of Hindsight" Crowne Plaza Hotel, Glasgow, Drug Profiling, 6th-8th July 2007. PMID- 18450216 TI - The Forensic Science Society AGM & Autumn Conference, Fact or Fiction--the Sequel, 3rd-5th November 2006, Wyboston, Convenors: Colin Ratcliff & Shirley Marshall. PMID- 18450218 TI - In vitro antifungal activity of 2-(4-substituted phenyl)-3(2H)-isothiazolones. AB - The in vitro antifungal activity of several N2-phenyl-3(2H)-isothiazolones substituted at C4 of the phenyl moiety with heterocyclic nucleus or groups of different physico-chemical properties against four human pathogenic fungi was determined by broth macrodilution method; results were compared with those obtained with itraconazole and ketoconazole. These isothiazolones showed moderate to high activity against some or all tested strains and in comparison with the reference drugs, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g), 5-chloro-2 phenylisothiazol-3-one (1c), 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]-1,4 dihydrotriazol-5-one (1s) and 2-(4-nitrophenyl)isothiazol-3-one (2g) against Aspergillus niger, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g) and 4-[4-(5 chloro-3-oxo-3H-isothiazol-2-yl)phenyl]piperazine-1-carboxamide (1q) against Trichophyton mentagrophytes had comparable activity, compounds 1g and 2g showing higher activity against Microsporum canis. Antifungal activity was favored by the presence of chlorine at C5 of the isothiazolone and/or the presence of nitro group or heterocyclic nucleus at C4 of the phenyl ring and proper hydrophilicity of the molecule. PMID- 18450217 TI - Chromosome segregation in Bacillus subtilis. AB - Bacillus subtilis, a Gram-positive bacterium commonly found in soil, is an excellent model organism for the study of basic cell processes, such as cell division and cell differentiation, called sporulation. In B. subtilis the essential genetic information is carried on a single circular chromosome, the correct segregation of which is crucial for both vegetative growth and sporulation. The proper completion of life cycle requires each daughter cell to obtain identical genetic information. The consequences of inaccurate chromosome segregation can lead to formation of anucleate cells, cells with two chromosomes, or cells with incomplete chromosomes. Although bacteria miss the classical eukaryotic mitotic apparatus, the chromosome segregation is undeniably an active process tightly connected to other cell processes as DNA replication and compaction. To fully understand the chromosome segregation, it is necessary to study this process in a wider context and to examine the role of different proteins at various cell life cycle stages. The life cycle of B. subtilis is characteristic by its specific cell differentiation process where, two slightly different segregation mechanisms exist, specialized in vegetative growth and in sporulation. PMID- 18450219 TI - Casitone-dependent transcriptional regulation of the prtP and prtM genes in the natural isolate Lactobacillus paracasei subsp. paracasei. AB - The prtP-prtM intergenic region of Lactobacillus paracasei subsp. paracasei BGHN 14 was cloned and sequenced. The nucleotide sequence of the prtP-prtM intergenic region in BGHN 14, containing divergently orientated P(prtP) and P(prtP) promoters, was shorter by 35 bp in comparison with that in lactococci. The nucleotide sequence involved in casitone-dependent transcriptional regulation of the lactococcal prt genes was not found in the BGHN14. The activity of P(prtM) in L. lactis NZ9000 was very low and insignificantly changed in the presence of casitone, whereas P(prtP) was completely inactive. When L. casei ATCC393(T) was used as host, both P(prtP) and P(prtM) were active and strongly regulated by casitone. The results strongly indicate that the mechanisms of the casitone dependent regulation of the prt genes in BGHN14 and lactococci are different. PMID- 18450220 TI - Cell-protective and antioxidant activity of two groups of synthetic amphiphilic compounds--phenolics and amine N-oxides. AB - Two classes of newly synthesized amphiphilic compounds, phenolic antioxidants ("phenolics") and N-oxides exert in vivo antioxidant effects on live S. cerevisiae cells. Both groups have low toxicity, phenolics being more toxic than N-oxides and compounds with a longer alkyl chain having higher toxicity than those with a shorter alkyl chain. Phenolic antioxidants protect yeast cells exposed to the superoxide producer paraquat and peroxyl generator tert butylhydroperoxide better than N-oxides at 3-fold higher concentration. Both types of antioxidants enhance the survival of pro-oxidant-exposed cells of S. cerevisiae mutants deficient in cytosolic and/or mitochondrial superoxide dismutase and could be good compounds which mimic the role of superoxide dismutases. The results of measurement of antioxidant activity in an in vitro chemiluminescence test differ from the results obtained in vivo with S. cerevisiae superoxide dismutase mutants. In contrast to their action on live cells, phenolics are less effective than N-oxides in preventing lipid peroxidation of an emulsion of lipids isolated from S. cerevisiae membranes. PMID- 18450222 TI - Production of Yarrowia lipolytica Nha2 Na+/H+ antiporter improves the salt tolerance of Saccharomyces cerevisiae. AB - Yarrowia lipolytica plasma-membrane Na+/H+ antiporter, encoded by the YlNHA2 gene, is a very efficient exporter of surplus sodium from the cytosol. Its heterologous expression in Saccharomyces cerevisiae wild-type laboratory strains increased their sodium tolerance more efficiently than the expression of ZrSod2 22 antiporter from the osmotolerant yeast Zygosaccharomvces rouxii. PMID- 18450221 TI - In vitro activity of telithromycin and quinupristin/dalfopristin against methicillin-resistant coagulase-negative staphylococci with defined resistance genotypes. AB - We determined the activities of new antibiotics telithromycin (ketolide) and quinupristin/dalfopristin (streptogramins) against 88 macrolide and/or lincosamide resistant coagulase-negative staphylococci (CoNS) isolates with defined resistance gene status. Telithromycin susceptibility was determined only in erythromycin-sensitive isolates (15) indicating the same mechanisms of resistance. In contrast, all erythromycin-resistant isolates (73) were either constitutively resistant to telithromycin (13 isolates with constitutive erm genes) or demonstrated telithromycin D-shaped zone (60 isolates with inducible msr(A) and/or erm). However, the level of inducible resistance conferred by msr(A) (35 isolates) was borderline even after induction by erythromycin. No quinupristin/dalfopristin resistant isolate was observed if tested by disk diffusion method (DDM) but 18 isolates were intermediate (MIC = 1-3 mg/L) and two isolates resistant (MIC = 8 mg/L) if tested by E-test. All these isolates were resistant to streptogramin A and harbored vga(A) gene (1 isolate) or vga(A)LC gene (19 isolates). MICs for quinupristin/dalfopristin were higher for isolates with combination of streptogramin A resistance and constitutive MLSB resistance (MIC = 3-8 mg/L in 4 isolates) than for streptogramin A-resistant isolates susceptible to streptogramin B (MIC = 0.5-2 mg/L in 16 isolates). In addition to S. haemolyticus, vga(A)LC was newly identified in S. epidermidis and S. warnerii indicating its widespread occurrence in CoNS. Misidentification of low-level resistant isolates by DDM may contribute to dissemination of streptogramin A resistance. PMID- 18450223 TI - Survival and reproduction in some algae under stress conditions. AB - Pithophora oedogonia and Cladophora glomerata survived lowest 60 and 58%, respectively, in June when the pond diurnal water temperature (PDWT) increased to a maximum of 28 degrees C. The lowering of PDWT only by 1 degrees C in July improved survivability of both algae to their almost maximum level of 100 and 96%, respectively. Further lowering of PDWT to 17-22 degrees C in November initiated akinete formation in P. oedogonia. The process of akinete initiation, maturation and germination continued till April when PDWT increased to 20-24 degrees C, but not beyond that in May when PDWT was 21-26 degrees C. By this time, probably all akinetes have germinated in situ, and the alga was entirely vegetative. P. oedogonia population is not synchronous in nature, since during the 5-6-month reproductive season, some filaments were in active vegetative stage, some had akinete initiation, some had completed akinete formation, and some had akinetes germinating. C. glomerata grew dense vegetative in November and initiated (zoo)sporangial primordia formation (to some extent) in February (when PDWT was lowest, viz. 10-14 degrees C) till April. Meanwhile, no (zoo)-sporangial primordia either produced any zoospore or germinated into a germ tube; and all released their cytoplasmic content and died (along with some vegetative cells) with an increase in PDWT to 21-26 degrees C in May. Vaucheria geminata vegetative patches appeared on the soil surface, 2nd week of January by lowering of atmospheric diurnal temperature (ADT) to 9-16 degrees C in the 1st week. The alga started sexual reproduction by the 2nd week of March (when ADT increased to 20-23 degrees C) and completed the process of reproduction by the 1st week of April (when ADT increased to 24-26 degrees C) and died thereafter. P. oedogonia, C. glomerata and V. geminata survived better and longer in submerged conditions than air-exposed (which was true for P. oedogonia and C. glomerata aquatic habitat and also indicated that the soil alga V. geminata could survive to some extent if submerged in rain water). P. oedogonia formed akinetes and C. glomerata (zoo)sporangial primordia only in submerged condition and not when air-exposed on moist soil surface. V. geminata did not complete the life cycle both under submerged and air-exposed conditions. Vegetative survival in P. oedogonia, C. glomerata, V. geminata, Aphanothece pallida, Gloeocapsa atrata, Scytonema millei, Myxosarcina burmensis, Phormidium bohneri, Oscillatoria animalis, O. subbrevis, Lyngbya birgei, L. major, Microcoleus chthonoplastes and Rhizoclonium crassipellitum, reproduction in P. oedogonia, C. glomerata and V. geminata, cell division in A. pallida and G. atrata, heterocyst and false branch formation in S. millei, all, were adversely affected at approximately 28.5 degrees C for t12 h at light intensity of approximately 160 micromol m(-2) s(-1); high intensity does not ameliorate high temperature damage to any algae. The presence of liquid water, than its absence, outside the different algae moderated the severity of heat to some extent but not when the heat was severe. PMID- 18450224 TI - Effects of monocolonization with Escherichia coli strains O6K13 and Nissle 1917 on the development of experimentally induced acute and chronic intestinal inflammation in germ-free immunocompetent and immunodeficient mice. AB - Germ-free immunocompetent (BALB/c) and immunodeficient (SCID) mice were colonized either by E. coli O6K13 or by E. coli strain Nissle 1917 and intestinal inflammation was induced by administering 2.5% dextran sulfate sodium (DSS) in drinking water. Controls were germ-free mice which demonstrated only mild inflammatory changes after induction of an acute intestinal inflammation with DSS as compared with conventional mice in which acute colitis of the colon mucosa similar to human ulcerative colitis is elicited. In mice monocolonized with the nonpathogenic E. coli Nissle 1917 the inflammatory disease did not develop (damage grade 0) while animals monocolonized with uropathogenic E. coli O6K13 exhibited inflammatory changes similar to those elicited in conventionally reared mice (damage grade 3). In the chronic inflammation model, immunocompetent BALB/c mice monocolonized with E. coli Nissle 1917 showed no conspicuous inflammatory changes of the colon mucosa whereas those monocolonized with E. coli O6K13 developed colon inflammation associated with marked infiltration of inflammatory cells. In contrast to germ-free immunodeficient SCID mice that died after application of DSS, the colon mucosa of SCID mice monoassociated with E. coli Nissle 1917 exhibited only moderate inflammatory changes which were less pronounced than changes of colon mucosa of SCID mice monoassociated with E. coli O6K13. PMID- 18450225 TI - Humic acid-like material from sewage sludge stimulates culture growth of ectomycorrhizal fungi in vitro. AB - Significant effects of humic acid-like material (HALM) extracted from sewage sludge on dry matter production of cultures of ectomycorrhizal basidiomycetes were found in vitro. Mycelial growth of the majority of isolates tended to increase in the presence of the HALM and this effect was significant for 6 isolates. Strongest stimulation was observed in the case of Amanita muscaria, Leccinum aurantiacum and Lactarius deterrimus. The results suggest that the HALM can be used as an additive to media for cultivation of ectomycorrhizal basidiomycetes. PMID- 18450226 TI - Francisella tularensis strain LVS resides in MHC II-positive autophagic vacuoles in macrophages. AB - The Francisella tularensis strain LVS phagosome disintegrates during the first few hours after bacterial entry and microbes are released to the cytosol. Within 12 h both rapid multiplication of microbes and a steep increase of apoptosis of infected macrophages occur. We searched for signals involved in the death of macrophages and detected molecules associated with the autophagy machinery cathepsin D, PTEN, p53 and LC3, whose levels or modification were influenced by ongoing in vitro tularemic infection. The sequestration of cytoplasmic F. tularensis LVS into autophagosomes was confirmed by co-localization of the LVS strain containing vacuoles with LC3 (an autophagosomal marker). We also demonstrated the presence of MHC II antigens in these autophagosomes, indicating that they might act as a source of endogenous tularemic antigens for presentation to CD4+ T lymphocytes. PMID- 18450227 TI - Highly efficient galvanotaxis apparatus for cleaning and concentrating rumen ciliates. AB - Galvanotaxis was shown to be an efficient method for cleaning and concentrating rumen ciliate protozoa whose harvesting (centrifugation of large volumes of in vitro cultures followed by repeated washing of the sediment to remove plant debris) is time consuming. We suggested the use of a new galvanotaxis apparatus (a small-capacity two-way glass stopcock) to improve cell yield in concentrating the rumen ciliate protozoa and cleaning them from impurities. Migration of the ciliates (Entodinium caudatum, Entodinium furca monolobum and Diploplastron affine) into the cathode compartment under different electric currents (0, 5, 10, and 15 mA) and intervals (5, 10, 20, and 30 min) was evaluated. The lethal current level was 20 mA. Cell yield was 9-81%, depending on ciliate species, migration time and current. The migration time significantly affected both E. caudatum and D. affine. The electric current-migration time interplay was shown to be significant in both E. caudatum and D. affine. The advantages and disadvantages of the tested apparatus were determined; the two-way glass stopcock was very convenient for both cleaning and concentrating rumen ciliate in vitro cultures by galvanotaxis. PMID- 18450228 TI - Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate. AB - There is a strong advocacy movement for large doses of vitamin C. Some authors argue that the biological half-life for vitamin C at high plasma levels is about 30 minutes, but these reports are the subject of some controversy. NIH researchers established the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. The dynamic flow model refutes the current low dose recommendations for dietary intakes and links Pauling's mega-dose suggestions with other reported effects of massive doses of ascorbate for the treatment of disease. Although, a couple of controlled clinical studies conducted at The Mayo Clinic did not support a significant benefit for terminal cancer patients after 10 grams of once-a-day oral vitamin C, other clinical trials have demonstrated that ascorbate may indeed be effective against tumors when administered intravenously. Recent studies confirmed that plasma vitamin C concentrations vary substantially with the route of administration. Only by intravenous administration, the necessary ascorbate levels to kill cancer cells are reached in both plasma and urine. Because the efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated. One limitation of current studies is that pharmacokinetic data at high intravenous doses of vitamin C are sparse, particularly in cancer patients. This fact needs prompt attention to understand the significance of intravenous vitamin C administration. This review describes the current state-of-the-art in oral and intravenous vitamin C pharmacokinetics. In addition, the governmental recommendations of dose and frequency of vitamin C intake will also be addressed. PMID- 18450229 TI - Microbiological assessment of house and imported bottled water by comparison of bacterial endotoxin concentration, heterotrophic plate count, and fecal coliform count. AB - Consumers increasingly use bottled water and home water treatment systems to avoid direct tap water. According to the International Bottled Water Association (IBWA), an industry trade group, 5 billion gallons of bottled water were consumed by North Americans in 2001. The principal aim of this study was to assess the microbial quality of in-house and imported bottled water for human consumption, by measurement and comparison of the concentration of bacterial endotoxin and standard cultivable methods of indicator microorganisms, specifically, heterotrophic and fecal coliform plate counts. A total of 21 brands of commercial bottled water, consisting of 10 imported and 11 in-house brands, selected at random from 96 brands that are consumed in Puerto Rico, were tested at three different time intervals. The Standard Limulus Amebocyte Lysate test, gel clot method, was used to measure the endotoxin concentrations. The minimum endotoxin concentration in 63 water samples was less than 0.0625 EU/mL, while the maximum was 32 EU/mL. The minimum bacterial count showed no growth, while the maximum was 7,500 CFU/mL. Bacterial isolates like P. fluorescens, Corynebacterium sp. J-K, S. paucimobilis, P. versicularis, A. baumannii, P. chlororaphis, F. indologenes, A. faecalis and P. cepacia were identified. Repeated measures analysis of variance demonstrated that endotoxin concentration did not change over time, while there was a statistically significant (p < 0.05) decrease in bacterial count over time. In addition, multiple linear regression analysis demonstrated that a unit change in the concentration of endotoxin across time was associated with a significant (p < 0.05) reduction in the bacteriological cell count. This analysis evidenced a significant time effect in the average log bacteriological cell count. Although bacterial growth was not detected in some water samples, endotoxin was present. Measurement of Gram-negative bacterial endotoxins is one of the methods that have been suggested as a rapid way of determining bacteriological water quality. PMID- 18450230 TI - Evaluation of pediatric patients with vascular malformations managed with endovascular and radiosurgical techniques using a modified Rankin Disability Scale. AB - BACKGROUND: Pre- and postoperative evaluation of the pediatric patient with a cerebrovascular malformation can be cumbersome. This may be due to several factors, including age and ability to verbalize. Functional evaluation scales have been devised, yet application to a retrospective study, where information can be limited, may not be possible. Simpler scales, serving the purpose of functional description and categorization would be beneficial in these cases. METHODS: Between December 1997 and December 2003, 24 patients between the ages of 4 months to 17 years old underwent endovascular treatment for cerebrovascular lesions at our institution. The majority of the arteriovenous malformation cases underwent further radiosurgical treatment. Mean follow-up period from the time of the last endovascular or radiosurgical intervention was 22 months. A pediatric modification of the Rankin Disability Scale was used for evaluation of pre procedural and post-procedural functional status. RESULTS: Combined embolization/radiosurgical approach had 4% mortality and 4% morbidity rates. This combined technique achieved a 46% cure in a variety of pediatric vascular anomalies. Overall improvement in disability using the pediatric modification of the Rankin Scale was noted for all of the cases, and a tendency for improvement was noted in the arteriovenous malformation subgroup though not statistically significant, p = 0.0547. CONCLUSIONS: These results indicate that a pediatric modification of the Rankin Disability Scale can be used for functional evaluation in this population. Although other functional evaluation scales are available and validated, using a Rankin Disability Scale modification is straightforward, and it can provide functional categorization in retrospective studies. PMID- 18450231 TI - Kinetics of monoclonal anti-epidermal growth factor receptor antibody (IOR EGF/r3)-induced apoptosis in human carcinoma bearing nude mice. AB - Apoptosis seems to play an important role in cancer immunotherapy outcome. We have studied the kinetic pattern of apoptosis induction in H125 human lung carcinoma xenografts after treatment with the monoclonal antibody (MAb) anti epidermal growth factor receptor (EGFr) IOR EGF/r3. Tumor-bearing nude mice were injected intravenously with a single 8 mg/kg dose of IOR EGF/r3 and tumor specimens were taken up to 30 days post treatment. Apoptosis was measured by morphometric analysis of the histological sections at each tumor specimen over time points. The results showed a significant apoptotic response in tumors within six days after injection of this MAb reaching a peak at 20 days post treatment. The kinetics were very broad, with apoptotic cells present over the entire time frame. However, the time course of the apoptotic index showed a significant difference to the mitotic index. Finally, the MAb-induced apoptosis was related to tumor growth delay indicating a probable arrest of cell cycle and a corresponding inhibition of tumor progression, which was corroborated by the Ki67 and proliferating cell nuclear antigen (PCNA) biomarkers. PMID- 18450232 TI - Timing of ondansetron administration to prevent postoperative nausea and vomiting. AB - BACKGROUND: The original guidelines for using ondansetron recommending its administration prior to induction of anesthesia have been questioned. METHOD: In an effort to determine the most effective timing of ondansetron administration to prevent postoperative nausea and vomiting (PONV), a prospective, randomized, double-blind study was performed. Patients undergoing ambulatory plastic surgery procedures estimated to last two hours or more and who had at least two risk factors for PONV (female gender, non-smoker, previous history of PONV and postoperative opioids) participated in the study. General anesthesia for all patients followed the same standard institutional protocol and all patients received dexamethasone 4 mg intravenously at the start of surgery. The control group (n = 188) received 4 mg of ondansetron intravenously prior to the induction of anesthesia. The study group (n = 184) received 4 mg of ondansetron intravenously 30 minutes prior to completion of the surgery. The incidence of PONV during the early (0-2 hours) and delayed (2-24 hours) postoperative periods was recorded. RESULTS: No significant difference was found between the groups regarding early postoperative nausea or vomiting (p > 0.05). However, a significant difference (p < 0.05) was noted in both late postoperative nausea (control: 30% vs. study group: 20%) and late postoperative vomiting (control: 17% vs. study group: 8%). CONCLUSION: This clinical study indicates that when performing prolonged surgical procedures, late administration of ondansetron (within 30 minutes prior to completing the surgery) is significantly more effective in the prevention of late PONV than when administered prior to the induction of anesthesia. PMID- 18450233 TI - Formula labeling violations to the WHO Code: a quantitative and qualitative analysis. AB - BACKGROUND: The WHO Code on Marketing of Breastmilk Substitutes is intended to be adopted as a minimum requirement by all governments and aims to protect infant health by preventing inappropriate marketing of breastmilk substitutes. Labels need to have correct and clear dispositions since they frequently are the only source of vital information for consumers regarding the content of the product and its uses. OBJECTIVE: The purpose of this study was to determine violations to the provisions of the International Code Article 9 regarding infant formula labeling existing in Puerto Rico. METHODS: A quantitative and qualitative evaluation of 34 labels of infant formula was done. Instrument 4-A of the IBFAN Monitoring Project (IMPIII) and the Standard IBFAN Monitoring (SIM) was utilized. This instrument included 14 criteria that identified violations to the International Code of Breastmilk Substitutes on labeling. Descriptive analysis was used for all variables. The 34 labels evaluated represent 77.3% of infant formula labels of the four companies which market them in the island. RESULTS: All the labels (100%) that were evaluated were found to violate the Code in one or more of its dispositions. Most striking violations include: a statement that breastfeeding is best is lacking in 73.5%, as well as a statement that the product should be used only on the advice of a health worker. None of the labels are written in Spanish, the local language. Text which may idealize the use of infant formula or discourage breastfeeding is present in 97.1% of the samples, and the same percentage has a photo or picture idealizing the use of infant formula. CONCLUSIONS: It is vital to produce legislation that implants the WHO Code in Puerto Rico in order to regulate indiscriminate marketing practices and their subsequent ill effects on children's health and breastfeeding practices. PMID- 18450234 TI - Visualization of six unique morphological subpopulations of adult frog dorsal root ganglion neurons at the light microscopic level. AB - Subpopulations of adult frog dorsal root ganglion (DRG) neurons respond to different physiological stimuli, and have unique biophysical and pharmacological properties. Two broad-based subpopulations of DRG neurons appear under phase optics, "large clear" and "small dark" neurons, while immunochemical and electrophysiological techniques allow identification of additional subpopulations. Nevertheless, most studies of DRG neurons involve randomly selected neurons. Under bright field illumination, we found dark and clear DRG neurons are distinctly different, with dark neurons composed of four subpopulations, each with unique numbers and distribution of bright rusty-colored cytoplasmic granules, and statistically significant difference in the soma diameter distribution. The clear neurons are granule-free, but the two subpopulations have statistically significant differences in soma size distributions. Thus, morphological criteria alone allow identification of six distinct subpopulations of DRG neurons in the light microscope, although further studies are required to determine whether they correspond to physiologically different subpopulations of sensory neurons. PMID- 18450235 TI - Formulation and characterization of nystatin gel. AB - The main objective of this research is to develop and characterize a series of carbopol 934 (CP) hydroxypropyl methylcellulose (HPMC) and a combination of carbopol-HPMC as a gel base for topical delivery of nystatin. The drug level was held constant at 1.72% w/w and the level of propylene glycol which is used as a co-solvent and penetration enhancer was also kept constant at 2% w/w. The total level of the polymer was held constant at 1.5% w/w as a single polymer or combination of two polymers. The polymers combination selected were: carbopol 934 to HPMC at a ratio of 0:1, 1:0, 1:2, 2:1 and 1:1. The batch size was 500 g and triethanolamine was used to adjust the pH of the gel. The rheological study showed that formulation containing combination of 2 carbopol and 1 HPMC ratio gave the highest viscosity, and exhibited an apparent pseudoplastic thixotropic behavior. The diffusion study indicated that gel formulation containing carbopol HPMC at a ratio of 2:1 gave the highest percent drug diffusion compared to formulation containing low carbopol to HPMC ratio, carbopol alone or HPMC alone. Both in-vitro release and rheological study indicated that carbopol-HPMC had the best gel strength, physical properties and ability to diffuse the drug than carbopol or HPMC alone. The results obtained in this study demonstrated that the combination of carbopol and hydroxypropyl methylcellulose can be used as a gel vehicle for nystatin topical application. PMID- 18450236 TI - Reliability of a sugar consumption questionnaire for rural Haiti. AB - OBJECTIVE: Studies of dental caries should account for sugar consumption as a potential confounder or effect modifier of other exposure-caries associations. The purpose of this study was to assess the reliability of a sugar consumption score for rural Haiti through correlation of test-retest scores derived from a structured, interviewer-administered questionnaire. METHODS: A structured, interviewer-administered questionnaire of sugar consumption was developed for rural Haiti to achieve contextual validity. The resulting questionnaire had two parts; one part captures the child's consumption of sugar products frequency; the second part captures sugar additions to the child's food preparation. A test retest, one week apart, was conducted on a sample of 30 mother-child pairs (children ages 9-17). Test-retest correlations and paired t-testing was conducted to assess the questionnaire's reliability. RESULTS: All test-retest (Part 1, children's questions; Part 2, mother's questions; the combined scores) had Pearson product correlation coefficients of 0.7 or greater, respectively. All test-retest scores had paired t-test p-values3 0.95. CONCLUSIONS: A reliable, contextually valid relative sugar consumption questionnaire specific for rural Haiti is presented. The questionnaire and methodology employed in its development and testing may have utility for dental caries researchers in investigations in less developed countries. PMID- 18450237 TI - Use of the Internet by physicians in Puerto Rico. AB - OBJECTIVE: To determine the extent of the use of the Internet by physicians in Puerto Rico to support their clinical practice. METHODS: Personal interviews were conducted among a representative sample of 385 physicians from different specialties and geographical regions in Puerto Rico. RESULTS: Eighty-one percent physicians who participated in the survey reported the use the Internet in their practices. Rheumatologists, endocrinologists and cardiologists were the specialties with the highest usage rate. Internet use decreased as age of the physicians increased. The great majority of those who use the Internet do it from home (81%) followed by the office (68%). Almost two-thirds used dial-up to connect to the Internet at home or at office. The Internet was used mainly for professional purposes to look for references (92%), communicate with colleagues (33%) and obtain continuing education (31%). CONCLUSION: There was a high Internet utilization rate among physicians in Puerto Rico, regardless of the specialty. The utilization rate was similar to that reported among physicians from other countries. PMID- 18450238 TI - Fetal ultrasound biometry: normative charts for a Puerto Rican population. AB - PURPOSE: To evaluate fetal growth parameters throughout gestation in Puerto Rican women and compare them to other mixed U.S. populations. METHODS: Cross-sectional study of 548 patients who met inclusion criteria of Puerto Rican ancestry, no history of drug, alcohol or tobacco use, no identifiable fetal anomalies, normal amniotic fluid and certainty of last menstrual period. Standard sonographic biometric data (biparietal diameter, occipito-frontal diameter, head circumference, abdominal circumference, femur length and estimated fetal weight) was obtained for each gestational age between 13 and 38 weeks and the 10th, 50th, and 90th percentile determined for each one. Results were compared to those of other mixed U.S. populations. RESULTS: Biometric data on fetal growth throughout gestation among Puerto Ricans is presented. Comparison with other mixed populations did not show any significant differences in fetal biometric measurements throughout pregnancy. CONCLUSIONS: Different to other ethnic groups, Puerto Ricans show similar fetal growth patterns as those reported from mixed U.S. populations. This information validates the use of these reference values in the evaluation of fetuses in Puerto Rico. PMID- 18450239 TI - Relationship between loss of libido and signs and symptoms of depression in a sample of Puerto Rican middle-aged women. AB - Female sexual dysfunction is a multi-causal and multidimensional problem combining sexual, physiological, physical, psychological, and interpersonal determinants. Loss of libido or loss of sexual desire, as a symptom of one of the primary sexual dysfunctions described in females, is highly prevalent in the general female population. Research on the psychological aspect associated with loss of libido among Hispanic female populations is limited. The objective of this study was to determine how the loss of libido is affected by signs and symptoms of depression, once potential confounders are controlled. Nine-hundred and nineteen Puerto Rican women ages 40 to 59 years living in Puerto Rico participated in health-fairs conducted in twenty-two municipalities between May 2000 and November 2001. Contingency tables and chi-square statistics were used to evaluate the bivariate associations of loss of libido with demographic and lifestyle characteristics, symptom experience and obstetric and gynecologic histories. A logistic regression model was used to estimate the magnitude of the association between loss of libido and signs and symptoms of depression, after controlling for confounders. The overall prevalence of loss of libido in this population was 40.8%. Loss of libido was significantly associated with depressive symptoms (p < 0.05) after adjusting for age, educational attainment, employment status, physical activity, menopausal status/ hormone therapy use and genitourinary symptoms. Women reporting 1-2 depressive symptoms were 67% (95% CI = 1.08-2.60) more likely than women reporting no symptomatology to report loss of libido. The odds of loss of libido increased as the number of depressive symptoms increased [(3-4 symptoms: POR = 3.67, 95% CI = 2.16-5.56); (5-6 symptoms: POR = 5.52, 95% CI = 3.16-9.66)]. Consistent with previous studies, signs and symptoms of depression were significantly associated with loss of libido. Future longitudinal studies should further elucidate the temporal sequence between depression and sexual dysfunctions in this population. PMID- 18450241 TI - The role of the American College of Obstetricians and Gynecologists in graduate medical education. PMID- 18450240 TI - Abortion within and around the law in the Caribbean. AB - Small island exigencies and a legacy of colonial jurisprudence set the stage for this three-year study in 2001-2003 of abortion practice on several islands of the northeast Caribbean: St. Martin, St. Maarten, Anguilla, Antigua and St Kitts. Based on in-depth interviews with 26 physicians, 16 of whom were performing abortions, it found that licensed physicians are routinely providing abortions in contravention of the law, and that those services, tolerated by governments and legitimised by European norms, are clearly the mainstay of abortion care on these islands. Medical abortion was being used both under medical supervision and through self-medication. Women travelled to find anonymous services, and also to access a particular method, provider or facility. Sometimes they settled for a less acceptable method if they could not afford a more comfortable one. Significantly, legality was not the main determinant of choice. Most abortion providers accepted the current situation as satisfactory. However, our findings suggest that restrictive laws were hindering access to services and compromising quality of care. Whereas doctors may have the liberty and knowledge to practise illegal abortions, women have no legal right to these services. Interviews suggest that an increasing number of women are self-inducing misoprostol abortions to avoid doctors, high fees and public stigma. The Caribbean Initiative on Abortion and Contraception is organising meetings, training providers and creating a public forum to advocate decriminalisation of abortion and enhance abortion care. PMID- 18450242 TI - Babinski's signe de l'eventail: a turning point in the history of neurology. AB - PURPOSE: The Babinski sign is a finding known since the start of the teachings of physical diagnosis by almost all medical students. This reflex is an incredibly helpful phenomenon that enables physicians to distinguish between central and the peripheral nervous system diseases right at the bedside. Yet, most students as well as physicians remain oblivious to the remarkable history behind the Babinski sign and what it means to evolutional history of the modern neurological exam. We intend to study the birth of the "signe de l'eventail" (the fanning sign) and how it transformed medical diagnosis as we practice it today. METHODS: An extensive search was conducted through the Internet to identify historical documents referring to Babinski and other physicians who also observed the phenomenon as early as the 17th and 18th century. We also conducted a search through medical journals that examined the Babinski sign and its history. RESULTS: The Babinski reflex had been observed much earlier than 1896, when Babinski referred to his finding for the first time. The reflex had been reported in the literature as far back as 1784 and afterwards reobserved several times before Babinski. However, it was Babinski who first offered an interpretation of the reflex and suggested that it was related to an organic disruption in the central nervous system. By identifying the sign, Babinski separated himself from Charcot in the sense of creating a new tradition in neurology where the findings in a neurological exam were of far more importance than just a plain history as his mentor had relied upon. CONCLUSIONS: Babinski was not only responsible for suggesting the significance of such sign, but also transformed the role that physical diagnosis plays in modern medicine, where physical examination is key in revealing underlying pathology. PMID- 18450243 TI - Bladder pheochromocytoma: case presentation and the use of OctreoScan for localization of extra-adrenal tumor sites in a pediatric patient. AB - An eleven year old boy presented with headaches and dizziness associated to micturition. On radiologic imaging, he was found with a bladder mass. The biochemical work up was suggestive of pheochromocytoma. An OctreoScan (111In pentreotide) was used to rule out metastatic extension or other extra-adrenal locations of the pheochromocytoma. OctreoScan data correlated well with other radiologic studies, operative findings and with the final diagnosis, validating its use on pediatric patients. PMID- 18450245 TI - Lung transplantation in children with cystic fibrosis--new concerns. PMID- 18450244 TI - Root cause analysis of medical errors. PMID- 18450246 TI - The utilisation and expenditure of medicines for the prophylaxis and treatment of osteoporosis. AB - The elderly population represent the fastest growing age-group and the incidence of osteoporotic related fractures is likely to increase with continued ageing of the population. This study determined the prescribing patterns on the Health Services Executive's (HSE) Primary Care Reimbursement Services Scheme (HSE-PCRS) of medicines dispensed for the prophylaxis and treatment of osteoporosis in Ireland. The HSE - PCRS prescription databases were analysed for the years 2004/2005. Approximately 65% of patients (total 60,000) were dispensed either Alendronate (Fosamax once weekly) or Risedronate (Actonel once weekly). The majority of the patients (69.3%) were over 70 years. The study identified that the longer a patient was prescribed prednisolone the greater the likelihood of subsequently being prescribed a bisphosphonate. Approximately 50% of patients on long-term steroids did not receive prophylaxis for osteoporosis. There were low levels of co-prescribing (2.5%) with potentially interacting drugs. Levels of co prescribing with proton pump inhibitors was 22%. PMID- 18450247 TI - The impact of acute urological admissions on the surgical workload in a general hospital. AB - Urological services remain underdeveloped in the existing Irish Hospital network. Outside of the main teaching centres patients frequently present to their local hospital with acute urological problems and are referred to specialist units following preliminary investigations. Over six months we examined the impact of emergency urological presentations on the general surgical workload in an acute general hospital. A total of 54 of patients were admitted with urological presentations representing 6.7% of total surgical admissions. The average length of stay was 4.9 days and a total of 24.5% were transferred to urological units for inpatient treatment. Urology outpatient referrals were required for 40%. This paper illustrates the impact of urological admissions on peripheral hospitals and the need to expand urological services in regional hospitals to reduce the amount of patients transferred to tertiary centres for routine urological procedures. PMID- 18450248 TI - The impact of a pre-hospital medical response unit on patient care and emergency department attendances. AB - A rapid response team was instigated in Cork to improve prehospital care and reduce unnecessary Emergency Department (ED) visits. This consisted of a Specialist Registrar (SpR) in Emergency Medicine and a Paramedic who attended all "999" calls in a designated rapid response vehicle on the allotted study days. Two hundred and sixty-three patients were seen on designated days between Jan 2004 and March 2006. Presentations seen included; road traffic accident (23%) collapse (12%), fall (10%) and seizure (8%). The majority of calls were to houses (36%). The most common medical intervention was intravenous cannulation (25%). Intravenous medications were administered in 21% of these patients--morphine sulphate was the most common drug given. It was possible to safely discharge 31% of patients on scene. In our experience skilled Emergency Medicine doctors attending at scene could provide advanced care and reduce ambulance transportation and patient attendance. PMID- 18450249 TI - Efficacy of intravenous immunoglobulin in the management of haemolytic disease of the newborn. AB - Intravenous immunoglobulin (IVIG) is indicated for use in Rhesus and ABO hemolytic disease of the newborn (HDN) to reduce the need for exchange transfusion, to decrease hospital stay and the duration of phototherapy. 11 infants received IVIG and the effect of IVIG on the total serum bilirubin (TSB) level, and its effect on the rate of rise of TSB was quantified. There was a statistically significant decrease in bilirubin levels before and after treatment with IVIG from 234 to 219 micromol/L (p = 0.001). In addition, the rate of change in bilirubin level significantly altered from an upward to a downward trend. (p = 0.001). The Number Needed to Treat (NNT) to prevent an exchange transfusion was 2.75--comparable with the recent systematic review of IVIG with a NNT of 2.7. PMID- 18450250 TI - The use of metformin as first line treatment in polycystic ovary syndrome. AB - This study evaluated the use of metformin as first line treatment for patients with polycystic ovary syndrome. A retrospective review of patients' files diagnosed with PCOS over 16 months in Department of obstetrics and gynaecology of a Regional hospital. The outcome was the response to metformin treatment regardless of the main complaint. Treatment response was measured by change in LH/FSH ratio, fasting insulin, testosterone, day 21 progesterone and/or pregnancy. A day 21 progesterone greater than 25.5 nmol/l and/or pregnancy were the parameter of ovulation. Thirty-four patients were diagnosed with PCOS. Twenty five complained of infertility (14 primary and 11 secondary), six patients had oligomenorrhoea or amenorrhoea and three presented with hirsutism. Seventeen patients received metformin as first line treatment. Eight received it with other treatment (5 clomiphene citrate and 3 ant androgens). Nine patients did not receive metformin. This study justifies the use of metformin as an appropriate first line treatment for PCOS. PMID- 18450251 TI - The decline of laparoscopic sterilisation. AB - Female sterilisation is an extensively used method of contraception all over the world but there appears to be a decline in the performance of this procedure in Ireland. There also appears to be an increased uptake of safe, long-acting contraceptive alternatives. We set out to establish the extent of the decline of laparoscopic sterilisation and to explore possible explanations. Data for female sterilisation from Ireland was obtained from the Hospital In-Patient Enquiry Scheme (HIPE) section of the Economic and Social Research Institute for the years 1999 to 2004. Recent sales figures for long acting reversible contraceptives, specifically the levo-norgestrel-loaded intrauterine system (LNG-IUS) (Mirena) and the etonogestrel implant (Implanon) were also obtained. Laparoscopic tubal ligations reduced from 2,566(1999) to 910 (2004). In the corresponding period the use of Mirena coils increased from 4,840 (1999) to 17,077 (2004). PMID- 18450252 TI - Paediatric trauma associated with all-terrain vehicles. AB - All-terrain vehicles (ATVs) are used extensively in the agricultural and forestry industries where they are marketed as an inexpensive alternative to tractors. Recent years have seen an increase in recreational use of ATVs, particularly quad bikes. More worrying is the increased use of privately owned ATVs among the paediatric population. In Ireland it is a legal requirement to provide adequate professional training for ATV use in the agriculture and forestry industries, however, at present there is no legislation that regulates the recreational use of ATVs by children. The United States Consumer Product Safety Commission CPSC collects data on ATV related death and trauma. Between 1982 and 2005 there have been 7188 reports of ATV related deaths, 917 (13%) of victims were under 12 years of age. It is estimated that there is one death for every 10,000 four-wheeled ATV in use. We report four cases of paediatric trauma associated with ATV use. The children had been taking part in an organised racing event. The discussion includes a literature review and a call for new legislation that bans recreational ATV use in children below sixteen years of age. PMID- 18450253 TI - Percutaneous management of a traumatic arteriovenous fistula. AB - The diagnosis of arteriovenous fistulae can be inhibited by inadequate clinical information and the presence of non specific signs. We describe how a patient was diagnosed with an arteriovenous fistula 19 years following penetrating trauma. We describe our successful treatment of this fistula using radiological endovascular techniques. PMID- 18450254 TI - Re: New lessons: classic treatments in convulsive status epilepticus. PMID- 18450255 TI - [The "right" way for nursing]. PMID- 18450256 TI - [Specialized care of patients with dementia undergoing surgery: "more than just holding hands" (interview by Ivonne Rammoser)]. PMID- 18450257 TI - ["Nursing patients with chronic wounds" expert standard: qualification of needs]. PMID- 18450258 TI - [Treatment of therapy refractory wounds with amelogenin: "hard to heal"--what to do?]. PMID- 18450259 TI - [Patients with MRSA colonization or infection in ambulatory nursing care: gaps in hygiene endanger patients and co-workers]. PMID- 18450260 TI - [Violence against nurses--1: Breaking through accustomed patterns]. PMID- 18450261 TI - [Medication error in the hospital--prevalence and approach to prevention: need for improvement in the system]. PMID- 18450262 TI - [One euro jobs in nursing: routine services are not allowed]. PMID- 18450263 TI - [Step by step to nursing care confidence--11: Massage to stimulate breathing]. PMID- 18450264 TI - [Pressure ulcer prevention and therapy: results of a descriptive study]. AB - Pressure ulcers are a common nursing care issue in hospitals. Sick children, premature infants and toddlers, but also disabled and impaired children are at a high risk of developing pressure ulcers. The aim of this descriptive cross sectional study was to describe the patients at risk as well as to identify the preventive and therapeutic interventions in a pediatric care setting. Of 213 hospitalised children, 155 (82 percent) from the age of 0 to 18 years could be included in the study. Altogether, preventive actions of any kind were performed with 92 percent of the patients. These were repositioning (84 percent), mobilisation of the patients (75 percent), followed by skin inspection (61 percent) and the application of lotions (56 percent). The high risk rate of pediatric patients considered at risk according to the Braden Scale is disconcerting and requires further exploration in terms of effective preventive and therapeutic interventions to improve the outcome for this patient group. PMID- 18450265 TI - [Introduction of the National Expert Standard in nursing: possibilities, opportunities and limits in adoption]. PMID- 18450266 TI - [Continuing nursing education behavior of coworkers in inpatient nursing: a great thirst for knowledge exists]. PMID- 18450267 TI - [Flexible 5-day week for inpatient nursing: resources according to need and coworker oriented organization]. PMID- 18450268 TI - [From case to case: quick management required]. PMID- 18450269 TI - [Recognizing and understand diseases: pruritus as chief symptom]. PMID- 18450270 TI - Comparative analysis of seronegative and seropositive rheumatoid arthritis regarding some epidemiological and anamnestic characteristics. AB - Classifying patients into two subsets of the disease--seronegative RA and seropositive RA--has been the subject of many studies which aim to clarify this phenomenon--without any conclusive or acceptable answer so far. The aim of this prospective study was to establish a scientific comparative analysis between seronegative and seropositive rheumatoid arthritis (RA) regarding some epidemiological and anamnestic characteristics. The studied group consisted of seronegative patients with titers lower than 1:64 as defined by Rose-Waaler test, while the control group consisted of seropositive patients with titers of 1:64 or higher. All patients belonged to 2nd and 3rd functional class according to the ARA criteria, were between 25-60 years of age (Xb=49.96), with disease duration between 1-27 years (Xb=6.41). Education, residence, economic and living conditions did not show any significant statistical difference regarding serostatus. Familial clustering of RA confirmed higher susceptibility in the seropositive group (chi2=7.02; p<0.01). In both subsets banal diseases, psychic and physical trauma, weakness, and numbness of hands and legs dominated, without any statistical differenceregarding serostatus. Some differences between groups regarding sex were noticed, but were not statistically significant, except regarding physical trauma, which was more present in seronegative females (chi2=8.05; p<0.01). PMID- 18450271 TI - [The cervical spine involvement in patients with psoriatic arthritis]. AB - Psoriatic arthritis (PsA) is a systemic disease and cervical spine can be affected. The data regarding cervical spondylitis are very rare and diverse in literarture. The aim of study was to assess the prevalence of cervical spine involvement in patients with PsA. Between totally 41 patients with PsA we confirmed the incidence of 68% (29 patients) with symptomatic cervical spine disease and 29% (12 patients) with radiological evidence of inflammatory involvement. The most frequent radiological findings were apophyseal joint changes, rarely ligamentous calcification and syndesmophytes. Only one patient had subaxial subluxation. The most common type of PsA was axial disease with or without peripheral arthritis (46%) and the least common was oligoarthritis (22%). There was no statistically significant difference between any type of PsA and cervical involvement. CONCLUSION: inflammatory cervical spine changes are not common radiographic finding in patients with PsA and apophyseal joint affection is the most common radiologic sign. PMID- 18450272 TI - [Proposal for anti-TNFalpha therapy in adult patients with rheumatoid arthritis]. AB - Rheumatoid arthritis is a chronic, inflammatory disease with the prevalence about 1%. Rheumatoid arthritis is characterized with synovitis, erosive changes of the joints, pain and functional deficit. Etiology of the disease is unknown. In the pathogenesis of rheumatoid arthritis the key role have proinflammatory citokines, particularly, tumour necrosis factor (TNFalpha). TNFalpha blockers have documented, fast and continuous efficacy with generaly well accepted safety profile. Nowadays, TNFalpha antagonists are established drugs in early and late phase of rheumatoid arthritis. Prescription of TNFalpha antagonists is controlled, according local restrictions, regarding high costs of the therapy. On behalf of the Croatian Society for Rheumatology we propose recommendations for the TNFalpha antagonist therapy in rheumatoid arthritis. PMID- 18450273 TI - [Proposal of Croatian Society for Rheumatology for anti-TNF-alpha therapy in adult patients with spondyloarthritides]. AB - Spondyloarthritides (SpA) as a group are one of the most common rheumatic disorders with a predominant affection of the spine. Conventinal disease modifying antirheumatic drugs which are effective in rheumatoid arthritis have poor effect on spinal inflammation. Today there is confirmed efficacy ofbiologics in spondylitis. This therapy is expensive and potentially hazaradous. Croatian Society for Rheumatology set up recommendations for the use of TNF-alpha blockers in SpA. There are several important points to be considered before their use: diagnosis of Spa, duration and disease activity, previous therapy and it's efficacy, application and efficacy ofbiologics, contraindications and safety preacutions and finally a decision for continuous tretament with biologics. PMID- 18450274 TI - Disaster management among pediatric surgeons: preparedness, training and involvement. AB - INTRODUCTION: Contemporary events in the United States (eg, September 2001, school shootings), Europe (eg, Madrid train bombings), and the Middle East have raised awareness of mass casualty events and the need for a capable disaster response. Recent natural disasters have highlighted the poor preparation and infrastructure in place to respond to mass casualty events. In response, public health policy makers and emergency planners developed plans and prepared emergency response systems. Emergency response providers include first responders, a subset of emergency professionals, including firemen, law enforcement, paramedics, who respond to the incident scene and first receivers, a set of healthcare workers who receive the disaster victims at hospital facilities. The role of pediatric surgeons in mass casualty emergency response plans remains undefined. The authors hypothesize that pediatric surgeons' training and experience will predict their willingness and ability to be activated first receivers. The objective of our study was to determine the baseline experience, preparedness, willingness, and availability of pediatric surgeons to participate as activated first receivers. METHODS: After institutional review board approval, the authors conducted an anonymous online survey of members of the American Pediatric Surgical Association in 2007. The authors explored four domains in this survey: (1) demographics, (2) disaster experience and perceived preparedness, (3) attitudes regarding responsibility and willingness to participate in a disaster response, and (4) availability to participate in a disaster response. The authors performed univariate and bivariate analyses to determine significance. Finally, the authors conducted a logistic regression to determine whether experience or preparedness factors affected the respondent's availability or willingness to respond to a disaster as a first receiver RESULTS: The authors sent 725 invitations and received 265 (36.6 percent) completed surveys. Overall, the authors found that 77 percent of the respondents felt "definitely" responsible for helping out during a disaster but only 24 percent of respondents felt "definitely"prepared to respond to a disaster. Most felt they needed additional training, with 74 percent stating that they definitely or probably needed to do more training. Among experiential factors, the authors found that attendance at a national conference was associated with the highest sense of preparedness. The authors determined that subjects with actual disaster experience were about four times more likely to feel prepared than those with no disaster experience (p < 0.001). The authors also demonstrated that individuals with a defined leadership position in a disaster response plan are twice as likely to feel prepared (p = 0.002) and nearly five times more willing to respond to a disaster than those without a leadership role. The authors found other factors that predicted willingness including the following: a contractual agreement to respond (OR 2.3); combat experience (OR 2.1); and prior disaster experience (OR 2.0). Finally, the authors found that no experiential variables or training types were associated with an increased availability to respond to a disaster. CONCLUSIONS: A minority of pediatric surgeons feel prepared, and most feel they require more training. Current training methods may be ineffectual in building a prepared and willing pool of first receivers. Disaster planners must plan for healthcare worker related issues, such as transportation and communication. Further work and emphasis is needed to bolster participation in disaster preparedness training. PMID- 18450275 TI - Deploying and using volunteer health practitioners in response to emergencies: proposed uniform state legislation provides liability protections and workers' compensation coverage. AB - To respond effectively to natural disasters and other public health emergencies, government resources must be augmented with the resources of volunteer organizations. Governmental actors are prepared to utilize volunteer health practitioners (VHPs) to meet patient surge capacity and provide essential public health services. However, difficult legal challenges arise regarding licensure, the scope of practice of volunteers, the relationship of volunteers to local healthcare delivery systems, disciplinary enforcement, the extent of exposure to civil liability, and how to provide compensation for volunteers injured or killed during disaster response activities. The Uniform Emergency Volunteer Health Practitioner Act (UEVHPA) seeks to address these problems and provide a better legal environment that facilitates VHPs efforts. This article discusses two important provisions of the UEVHPA, Section 11 which provides immunity against claims for negligence, under certain circumstances, for volunteers and organizations engaged in the deployment and use of volunteers, and Section 12 which provides workers' compensation benefits to VHPs when other sources of coverage are not available. Disaster relief organizations and healthcare provider organizations have consistently identified uncertainty and a lack of uniformity with respect to these issues as a major source of concern to volunteer practitioners and as a potential deterrent to their effective recruitment and utilization. Uniform state enactment of the UEVHPA would resolve many inconsistencies and gaps in the regulation and protection of VHPs across states. PMID- 18450276 TI - Visual disability in selected acts of terror, warfare, and natural disasters of the last 25 years: a concise narrative review. AB - OBJECTIVE: A review of ocular injury related to mass disaster over the past 25 years, including injury type, treatment, and final visual outcome. DESIGN: Retrospective review. MAIN OUTCOME MEASURES: Injury types, treatment, and final visual acuity. RESULTS: Acts of terror and war result in significant and increasingly more common ocular injury. Natural disasters were much less likely to cause lasting or permanent injury. CONCLUSIONS: Final visual acuity was rarely reported. Primary prevention is superior to treatment in acts of war and terror. Ocular injury is rarely reported by first response to natural disaster. PMID- 18450277 TI - Gendered dimensions of disaster care: critical distinctions in female psychosocial needs, triage, pain assessment, and care. AB - OBJECTIVE: This research highlights and identifies some critical distinctions in female disaster care including the following: socially constructed gender risk factors; gender and posttraumatic stress; women and pain (presentation and sensitivity); and postdisaster support and services, especially in the arenas of obstetrics and gynecology (breastfeeding, menstruation, contraception, rape, and sexually transmitted disease [STDs]). The research also includes a brief, anonymous survey of 50 adult female Hurricane Katrina evacuees which queried women on their usage of postdisaster health and counseling services. CONCLUSIONS: Our literature review shows a pattern of gender differentiation in all areas of the disaster process-in preparedness, response, physical and psychological impact, risk perception and exposure, recovery, and reconstruction. Some research highlights include: six disaster gender risk factors affecting vulnerability, impact and exposure; heightened risks and differing clinical manifestations of posttraumatic stress disorder and pain presentation; "pregnancy status" triage screening; as well gender-sensitive supplies and services (private breastfeeding and obstetrics and gynecology (OB/GYN) exam areas, birth control, feminine hygiene, and prenatal nutrition advocacy). The results of the small voluntary survey are presented that supports the contention that many gender-sensitive services were needed in posthurricane Katrina clinical settings, but were inadequate or nonexistent. This research not only identified issues, but emphasized feasible interventions, which could significantly reduce pain, suffering, and long-term postdisaster care costs. The research's most important conclusions are the current dearth of gender-disaggregated disaster data, as well as the tremendous need for disaster healthcare planners and providers to take a more cognizant and proactive approach to gender-specific care in triage, psychosocial needs assessment, medical care, and advocacy. PMID- 18450278 TI - Violence-related mortality and morbidity of humanitarian workers. AB - OBJECTIVES: (1) To determine the rate of violence-related deaths, medical evacuations, and hospitalizations occurring to national and expatriate staff of participating humanitarian organizations; (2) to describe the distribution of all cause and cause-specific mortality and morbidity of humanitarian workers with regard to possible risk factors. DESIGN: Surveillance study of field-based humanitarian workers; data were regularly collected from headquarters of participating organizations via e-mail and telephone between September 2002 and December 2005. PARTICIPANTS: Eighteen humanitarian organizations reported on any death, medical evacuation, or hospitalization of any national or expatriate staff for any cause, in any field location during the study period. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Risk of violence-related events was calculated as the number of deaths, medical evacuations, and hospitalizations during the study period divided by the total number of field staff for organizations that had staff in those countries where events occurred to the staff of any participating organization. Distribution descriptions are presented as simple proportions. RESULTS: Risk of violence-related deaths, medical evacuations, and hospitalizations was six per 10,000 aid worker person-years. Fifty percent of intentional violence cases were lethal. Intentional violence accounted for 55 percent of all deaths reported, followed by coincidental illness (27 percent) and accidents (15 percent). CONCLUSIONS: Aid worker deaths in this group were more frequently caused by intentional violence than either accidents or coincidental illness. The rate of six intentional violence events per 10,000 person-years can be used as a baseline by which to track changes in risk over time. PMID- 18450279 TI - Suicidal bomb explosions in Sri Lanka. AB - Injuries due to explosive devices are often seen in Sri Lanka. The involvement of suicide bombers is the peculiar feature of these bomb explosions. Analysis of injuries observed in the suicide bombers showed distinctive injury patterns consisting of detachment of the head and limbs, severe disruption of the trunk, burns at the transected tissue margins, presence of cyanide capsule in the neck, and absence of the shrapnel injuries. These findings are helpful in recognition of the perpetrator for the subsequent legal proceedings and also important in organization of preventive measures. In this context, suicide bomber could be defined as an individual carrying high explosive device, attached to his/her body and must be recognized as a separate medicolegal entity. PMID- 18450281 TI - What do you think needs to be done to improve UK nursing practice? PMID- 18450280 TI - Epidemiology of suicide after natural disasters: a review on the literature and a methodological framework for future studies. AB - On one hand, there is an association between exposure to natural disasters and becoming mentally distressed, and on the other hand, there is also a relation between being mentally distressed and committing suicide; therefore, it is possible that one finds a relation between exposure to natural disasters and committing suicide. This review, therefore, will not only seek such relations in the literature but also try to highlight the most important methodological issues of finding such connection. PMID- 18450282 TI - Nurse role in Malta. AB - The tiny island of Malta has health challenges to tackle. But next week (April 4 8) it plays host to the Commonwealth Nurses Federation. PMID- 18450283 TI - Patients thank their champions. AB - When patients were asked to nominate nurses who had gone the extra mile in providing care, there was a huge response. PMID- 18450284 TI - The chants of a lifetime. PMID- 18450285 TI - A practical guide to venepuncture and blood sampling. AB - This article provides an overview of the knowledge and skills required for peripheral venepuncture, including anatomy and physiology, psychological issues, consent, vein selection, infection control, venepuncture technique, sharps disposal and the prevention and management of complications. A period of supervision and assessment of competency is required to consolidate this theoretical knowledge, and practitioners should comply with the policies and procedures of their organisation. PMID- 18450286 TI - Promoting good nutrition in patients with dementia. AB - This article aims to raise awareness of good nutrition, the specific nutritional needs of individuals with dementia and the importance and implementation of protected mealtimes to prevent malnutrition in the hospital setting. PMID- 18450287 TI - Obstructive sleep apnoea. PMID- 18450288 TI - Crunch the numbers. PMID- 18450289 TI - Winning is a big boost. PMID- 18450290 TI - Developing intelligent feelings. PMID- 18450291 TI - [The civil ambulances during the Franc-Prussion war (July 19, 1870 to January 28, 1871)]. AB - The civil ambulances joined together under the emblem of the Red Cross: the Company of Help to the Wounded Soldiers, directed from the Palate of Industry by Chenu and Le Fort; the Ambulance of the Press, directed by Ricord and Mgr Bailer; and multiple ambulances disseminated in Paris. They brought a decisive help to the French medical military Corps. On the ground, eigtheen civil Ambulances from Countryside formed in Paris looked after the casualties of the two camps: around Sedan, then in the battles of the Loire and the East, where 13 ambulances formed secondarily in province joined them. During the siege of Paris, flying Ambulances went out the ramparts and brought back the wounded to the Palate of Industry or to Longchamp 'street Press ambulancy. They were integrated in November in a great Coordination of 10 hospitals distributors, directed by Hippolyte Larrey. The surgical care, limited to the members, to the head and the neck, were simple, rapids and conservatives, and the number of amputations was limited. But secondary infectious complications were frequent, had a raised mortality, worsened by the associated diseases, infectious (smallpox, typhoid, pneumonia, and by the cold, hunger, denutrition. The war of 1870-1871 brought: a large humane progress due to the neutralization of the casualties, places and actors of care; a better approach of the infection and shown the need for an autonomy of the French Military Corps. PMID- 18450292 TI - [The disfigured men represented by the great painters (O. Dix - G. Grosz - R. Freida.) Disfiguration in the history of art]. AB - Sophie Delaporte's book, Philippe Paillard's, Chantal Roussels's novels and Dupeyron's movie underline the difficulties of repairing physical and moral sufferings of the "disfigured men" wounded during the Great War. Beside medical and technical didactic aimed drawings the exhibition of wasted, mutilated or out of repair faces remains little known. In France, Germany or Great Britain there are many artists who took part in war. Among the artists the French painter Raphael Freida and some German expressionists like Otto Dix, Max Beckmann or George Grosz are the most famous. Their works are often confidential, set apart in the museums and showed in rare exhibitions in Great Britain and the United States of America. The sight of ruined faces inspired such horror that the artists depicted it only exceptionally and with discretion, before 1914. Without doubt it is the fear of touching the privacy of the face which is a part of the human identity. There are no "disfigured men" in the countless religious paintings of torture, neither in the Disasters of Warfrom painters or engravers like Goya or Jacques Callot. PMID- 18450293 TI - [A special collection, testimony of the national assistance for the fight against tuberculosis in the trenches (1914 - 1917)]. AB - The authors try to explain the human and patriotic reasons of the sale of vignettes and little medals in 1917. It was the year when tuberculosis raged in trenches. On Leon Bourgeois's instigation the country was urged for the difficult struggle and people were thanked for their gift by vignettes and medals some of which were signed by the famous artist Rene Lalique (1860-1945). The authors show a rare and complete collection human and patriotic reasons. PMID- 18450294 TI - [Birth of medical electricity]. AB - In the mid-eighteenth century Jallabert treated an hemiplegia using electrostatic electricity and published the patient's recovery. Immediately, physicians and clergymen started to use the Nollet's machine to treat many neurological diseases and published their results. The Galvani's constant was also a medical seism when he though the had discovered animal electricity. Galvanism entered immediately medical practice for a long time. PMID- 18450295 TI - [Alzheimer: did he discover or create Alzeheimer's disease?]. AB - This paper reviews and discusses the two opposing interpretations which have been given of the emergence of Alzheimer's disease (AD) in the medical literature (1906-1911). The commonest interpretation is that Kraepelin coined the eponym in order to describe a disease that had been discovered by Alzheimer. In the last years, however, a growing number of authors argued that Alzheimer and Kraepelin did not discover but create AD, that they did not proceed like botanists cataloguing species in an exotic garden but rather like sculptors carving shapes out of formless matter. The paper emphasizes the interests and the limits of both approaches and proposes an alternative approach which insists on Alzheimer's reasoning and argues that he neither 'discovered' nor 'created', but invented AD. PMID- 18450296 TI - [The museum of the history of medicine in Varna]. AB - The subject concerns the unrecognised European Bulgaria whose the alone museum of History of Medicine is worth of seeing. The 1869 building is of an ancient hospital which reminds of the hundred-year-old history of the modern Bulgaria. The miscellance of the objects, the strictness and the clearness of the show afford to follow through five rooms the development of Medicine as practice, art and science from Antiquity till the Second World War. The interest stemming from the general character of the museum is underlined by the constant references to the evolution of the Bulgarian Medicine. Then the local specific characteristics could totally integrate into the evolution of European Medicine. The role of France in the education of the first Bulgarian practitioners is worth reminding. The visitors get out of the museum through a delightful garden rich in Medicinal plants. PMID- 18450297 TI - [Francois Joseph Double and auscultation]. AB - Francois-Joseph Double, co-founder of the Academie de Medecine, was one of those doctors who, right at the beginning of the nineteenth century, developped the accurate observation of the clinical signs of illness, which called earlier practice into question. This led him to study the unaided auscultation of respiratory and cardiac ailments. Shortly before Laennec's fundamental discovery of aided auscultation, Double was describing different sorts of sounds such as those which would later be called tubal breathing, and pulmonary rales or crackles; listening to the heart, he concentrated on problems of the beat, on unusual sounds but did not know how to link them to any specific ailment. The fact that his findings precede those of Laennec have not allowed him the recognition that his pioneering work deserves. PMID- 18450298 TI - [Francois Melier (1798-1866). Limousin pioneer of public health and epidemiology in 19th century Paris]. PMID- 18450299 TI - [The influence of three American dentists during the Civil War (1861-1865)]. AB - In 1861, the bloodiest conflict in American history broke out. It only ended up in 1865, the Union being victorious. Surprisingly, dentists, thanks to their military cleverness, their diplomatic know-how or their medical devotion, had a major influence on this fratricidal war. PMID- 18450300 TI - [Claude Perrault, famous architect, unknown physician, untiring researcher]. AB - As a famous architect Charles Perrault persuaded Colbert to appoint a committee of the "Batiments du Roi" made up of three persons: Le Vau, Le Brun and one of his brothers Claude whose Louis XIV chose the plan. While Le Vau was busy in Versailles Perrault's influence became dominating. Although he was an unknown medical practitioner he managed to be allowed to practise and to teach medicine and to be a member of theses' jury for twenty five years. He was highly regarded by his colleagues who did not hesitate to hold a consultation. His trip in Bordeaux was consecrated to look after his brother but because of his numerous occupations he gave up practising medicine and he only treated the members of his family, his friends and some poor. He was a tireless researcher and at the "Academie des Sciences" he looked after the "Histoire naturelle des animaux" (Natural History of the Animals). In "Les Essais de Physique" he tackled numerous problems of physiology such as elasticity and contractility of arteries, studied the sense organs and did some experiments about blood transfusion. As an exceptional man he could practise the three of the occupations. PMID- 18450301 TI - Strugging to a monumental re-assessing the final phases of the smallpox eradication program in India, 1960-1980. AB - The global smallpox program is generally presented as the brainchild of a handful of actors from the WHO headquarters in Geneva and at the agency's regional offices. This article attempts to present a more complex description of the drive to eradicate smallpox. Based on the example of India, a major focus of the campaign, it is argued that historians and public health officials should recognize the varying roles played by a much wider range of participants. Highlighting the significance of both Indian and international field officials, the author shows how bureaucrats and politicians at different levels of administration and society managed to strengthen--yet sometimes weaken--important program components. Centrally dictated strategies developed at WHO offices in Geneva and New Delhi, often in association with Indian federal authorities, were reinterpreted by many actors and sometimes changed beyond recognition. PMID- 18450302 TI - [The city of Santos and the expansion of Brazilian public health services in homeopathy]. AB - In consonance with the principles of comprehensiveness, equity, and universality that underlie Brazil's sanitary reform and creation of its Unified Health System, some municipalities have begun offering homeopathy as a treatment option. The article explores the context in which homeopathic treatment was introduced and gained ground in the city of Santos, Sao Paulo, down through its incorporation as an alternative in the public healthcare network. Homeopathy was introduced in Santos not only by doctors and pharmacists but also by prescribing mediums from spiritist centers. The request that the municipality's primary-care services offer this alternative was possible thanks to the presence of all these players. The present analysis was based on interviews with the professionals who took part in the process, on technical reports, newspaper articles, and scientific journals, and on a book about the city's first spiritist society. PMID- 18450303 TI - [Ilha Grande Lazaretto: isolation, imprisonment, and surveillance in the fields of health care and politics (1884-1942)]. AB - The Ilha Grande pest house, located on the coast of Rio de Janeiro state, was built in 1884 to control the spread of epidemics via Brazilian ports. Separated from the continent, the buildings that housed patients could be kept under constant surveillance. Isolation regimens differed in accordance with the class on which passengers had traveled. The complex was used at different times as a military prison and eventually deactivated. In 1942, it was restored and became the Candido Mendes Penal Colony. PMID- 18450304 TI - [Sociocultural transformations in hospital food]. AB - The article seeks to identify the historical roots of food culture in hospital settings. It assumes that diet is not merely the result of technical and scientific concerns but is also historically constructed, created, and recreated in response to economic and sociocultural elements. The study conducted a preliminary survey of university, municipal, and hospital archives in Campinas, Sao Paulo, and included interviews with food service workers at three hospital institutions. Our conclusion is that more value has been placed on initiatives and actions related to technology than on initiatives identified with the domestic world; this may have contributed to a certain tendency for hospitals to neglect the issue of food, deemed of minor importance. PMID- 18450305 TI - [Casa Siloe: the history of an NGO for children with HIV/AIDS]. AB - Casa Siloe (Siloam House) is a Catholic support house that shelters children with human immunodeficiency virus or acquired immunodeficiency syndrome. The article presents a history of the institution and discusses its work. A qualitative approach was used, relying on oral history techniques and documental analysis. Eight key informants were interviewed: the president of the institution, two coordinators who worked at the home, a member of the supporting foundation, a volunteer social worker, a member of the state NGO/AIDS forum, a physician, and a psychologist from the state public service. Topics addressed include the Catholic Church and AIDS, community mobilization, the Casa Siloe, the State and civil society, and project evaluation and outlook. PMID- 18450306 TI - [Curriculum reform and research in dentistry at the undergraduate level: history under construction]. AB - Approaching from the perspective of curriculum organization, the article examines the development of undergraduate research in dentistry. Based on Brazilian and international printed or electronic publications, the authors examine the institutionalization of higher education in dentistry, university reform, and the enactment of Curriculum Guidelines. From the earliest days of higher education in dentistry, there has been a concern with research. But Brazil's university reform assigned research to graduate studies and scientific instruction to undergraduate studies. In recent years, Curriculum Guidelines have reconsidered the position of research and have recommended changes that allow research to be viewed as an educational principle. PMID- 18450307 TI - [A tribute to Manoel da Gama Lobo (1835-1883), pioneer in the epidemiology of vitamin A deficiency in Brazil]. AB - This analysis of the contributions of Manoel da Gama Lobo (physician born in Para), to the epidemiology of vitamin A deficiency in Brazil focuses primarily on "Da oftalmia brasiliana" [On Brazilian ophthalmia], originally published in 1865. An analysis of Gama Lobo's academic trajectory, and especially of this work, points up the tight ties between the scientist and doctors within the Escola de Medicina Tropicalista Baiana. Although one cannot claim that Gama Lobo was a proponent of the ideas of the abolitionist movement, some passages of "Da oftalmia brasiliana" lead us to recognize this scientist at the very least as an advocate of Brazilian slaves' human right to food. PMID- 18450308 TI - [A challenge to Peronism's social justice: hydatidosis in the province of Buenos Aires, 1946-1952]. AB - This analysis of the sanitary policies enforced in the province of Buenos Aires by Domingo Alfredo Mercante--Juan Domingo Peron's right-hand man--focuses on one of his most fascinating efforts: the eradication of hydatidosis. In exploring an issue largely forgotten by historiography, the article describes how the Mercante administration (1946-52) used statistical, socioeconomic, and symbolic legitimization to place hydatidosis on the State agenda. The administration's strategies are also pinpointed: the passing of regulatory laws against this endemic disease; the creation of specific state anti-hydatidosis institutions; the creation of space for information and for interdisciplinary, interministerial, and even supranational education aimed at achieving greater knowledge of the disease and at the exchange of experiences; and, lastly, the definition of initiatives focused on relief, treatment, and prevention in animals and people. PMID- 18450309 TI - [The physical and health status of runaway slaves announced in Jornal do Commercio (RJ) in 1850]. AB - The article examines the state of health of a population of runaway slaves, based on announcements published in Rio de Janeiro's Jornal do Commercio in 1850. Two strategies were used. The first entailed analysis of the slaves' physical characteristics, as described by their masters. Taking into account the slave's health, the second step was to describe his or her physical problems as viewed by the era's medical or folk knowledge. This evidence can be traced to procedures found in the slave system, which sought to maximize use of captives. PMID- 18450310 TI - [War and oranges: a radiophonic lecture on the nutritional value of Brazilian fruits (1940)]. AB - Since the early twentieth-century, sanitarians have relied on the radio for educational purposes. Men like Geraldo Horacio de Paula Souza and Borges Vieira used radio waves to popularize hygienic habits and disseminate information on sanitary topics. On April 16, 1940, Paula Souza stood before the microphones at Radio Educadora Paulista and gave a lecture on the nutritional value of oranges and the need to eat them as a patriotic act. Touting the fruit's nutritional qualities, Paula Souza launched the 'orange campaign'. Its success reached beyond the borders of Sao Paulo state, as the campaign found space in the press and took form as an advertising brochure published by the Agricultural Information Service, with the unconditional support of the Minister of Agriculture, Fernando Costa. PMID- 18450311 TI - Prevalence on beef carcasses of Mycobacterium avium subsp. paratuberculosis DNA. AB - Fifty samples were collected from each of skinned and dressed carcasses, from each of culled beef breeding cows and fed beef cattle <18 months old at two beef packing plants A and B, and from culled dairy cows at a packing plant C. The 450 samples were collected by swabbing an area of about 1000 cm2 in the anal region of each carcass. DNA extracted from each swab was tested for the IS900 and F57 sequences of the Mycobacterium avium subsp. paratuberculosis (MAP) genome by two stage, nested polymerase chain reaction (PCR) procedures. An internal amplification control (IAC) was detected in 45 or more of each group of 50 DNA preparations. IS900 and F57 were detected in some IAC-positive preparations from all and all but one of the groups of carcasses, respectively. Of the IAC-positive preparations in each group, between 6 and 54% were positive for IS900, and between 4 and 20% were positive for F57. When preparations were tested by single stage, quantitative PCR procedures, IS900 was detected in two samples but F57 was detected in none. The MAP DNA on carcasses was probably derived from small numbers of MAP from the environment that contaminated the animals' hides. PMID- 18450312 TI - Analysis of bacterial community during the fermentation of pulque, a traditional Mexican alcoholic beverage, using a polyphasic approach. AB - In this study, the characterization of the bacterial community present during the fermentation of pulque, a traditional Mexican alcoholic beverage from maguey (Agave), was determined for the first time by a polyphasic approach in which both culture and non-culture dependent methods were utilized. The work included the isolation of lactic acid bacteria (LAB), aerobic mesophiles, and 16S rDNA clone libraries from total DNA extracted from the maguey sap (aguamiel) used as substrate, after inoculation with a sample of previously produced pulque and followed by 6-h fermentation. Microbiological diversity results were correlated with fermentation process parameters such as sucrose, glucose, fructose and fermentation product concentrations. In addition, medium rheological behavior analysis and scanning electron microscopy in aguamiel and during pulque fermentation were also performed. Our results showed that both culture and non culture dependent approaches allowed the detection of several new and previously reported species within the alpha-, gamma-Proteobacteria and Firmicutes. Bacteria diversity in aguamiel was composed by the heterofermentative Leuconostoc citreum, L. mesenteroides, L. kimchi, the gamma-Proteobacteria Erwinia rhapontici, Enterobacter spp. and Acinetobacter radioresistens. Inoculation with previously fermented pulque incorporated to the system microbiota, homofermentative lactobacilli related to Lactobacillus acidophilus, several alpha-Proteobacteria such as Zymomonas mobilis and Acetobacter malorum, other gamma-Proteobacteria and an important amount of yeasts, creating a starting metabolic diversity composed by homofermentative and heterofermentative LAB, acetic and ethanol producing microorganisms. At the end of the fermentation process, the bacterial diversity was mainly composed by the homofermentative Lactobacillus acidophilus, the heterofermentative L. mesenteroides, Lactococcus lactis subsp. lactis and the alpha-Proteobacteria A. malorum. After a 6-h fermentation, 83.27% of total sugars detected after inoculation were consumed (228.4 mM hexose equivalents) and a carbon (C) recovery of 66.18% in fermentation products was estimated. They were produced 284.4 mM C as ethanol, 71.5 mM C as acetic acid and 19 mM C as lactic acid, demonstrating the presence of homo- and heterofermentative, acetic and alcoholic metabolisms in the final product. It was also found, after hydrolysis, that the exopolysaccharide produced during the fermentation was mainly composed by fructose residues, probably inulin or levan. PMID- 18450313 TI - Preparation and characterization of PE38KDEL-loaded anti-HER2 nanoparticles for targeted cancer therapy. AB - The clinical use of immunotoxins is severely limited by nonspecific toxicity. To overcome this limitation, PE38KDEL was used as a model protein toxin to prepare PE38KDEL-loaded poly(lactic-co-glycolic acid) (PLGA) antibody modified nanoparticles (NPs), which were covalently conjugated with Fab' fragments of a humanized anti-HER2 monoclonal antibody (rhuMAbHER2) by a two-step carbodiimide method. The characterization of the PE38KDEL-loaded nanoparticles-anti-Fab' bioconjugates (PE-NPs-HER), such as particle size, zeta potential and morphology, were evaluated by dynamic light-scattering detector and transmission electron microscope (TEM). Micro BCA assay was used to determine the drug encapsulation efficiency and the quantity of Fab' conjugated with NPs. The binding affinity and internalization efficiency of PE-NPs-HER were demonstrated by flow cytometry and laser-scanning confocal microscopy. In comparison with PE38KDEL-loaded nanoparticles (PE-NPs) that lack anti-HER2 Fab', PE-NPs-HER had superior in vitro cytotoxicity against HER2-overexpressing breast cancer cell lines. Progressively, PE-NPs-HER has superior protective antitumor activity in HER2-overexpressing tumor-bearing mice than the control immunotoxin PE-HER constructed by chemically coupling PE38KDEL to rhuMAbHER2. Most strikingly, in developed HER2 overexpressing tumor xenograft model, administration of PE-NPs-HER (0.9 mg/kg) showed a much better therapeutic efficacy in inhibiting tumor growth compared with PE-HER and other controls: final mean tumor load was 13+/-6 mm(3) (mean+/ SD; n=8, significantly smaller than all other groups by ANOVA at 95% confidence interval). In addition, PE-NPs-HER were well tolerated in mice with a much higher MTD (maximally tolerated dose) than PE-HER (2.92 mg/kg vs. 0.92 mg/kg), indicating the systemic toxicity of PE38KDEL was dramatically reduced by PLGA encapsulation. Thus, the bioconjugates PE-NPs-HER may represent a potentially useful strategy for cancer therapy. PMID- 18450314 TI - Lack of knowledge of glycosylated hemoglobin in patients with diabetic retinopathy. AB - We surveyed 220 patients with diabetic retinopathy attending a tertiary eye hospital in Australia, and found that knowledge of HbA(1c), and the proportion achieving target level of <7%, remained low in patients with diabetic retinopathy. These data re-emphasize the gap between clinical guidelines and actual management of patients with diabetes. PMID- 18450315 TI - Random monoallelic expression: making a choice. AB - Monoallelic gene expression exposes an organism to the risks associated with the unmasking of recessive mutations. A recent study by Gimelbrant and colleagues, supported by results from two methodologically different studies, demonstrated that random monoallelic expression is surprisingly widespread among autosomal genes. This raises important questions about why, when and how cells choose and tolerate monoallelism and whether functional hemizygosity might provide an unappreciated advantage. PMID- 18450316 TI - Environmental RNA interference. AB - The discovery of RNA interference (RNAi), the process of sequence-specific gene silencing initiated by double-stranded RNA (dsRNA), has broadened our understanding of gene regulation and has revolutionized methods for genetic analysis. A remarkable property of RNAi in the nematode Caenorhabditis elegans and in some other multicellular organisms is its systemic nature: silencing signals can cross cellular boundaries and spread between cells and tissues. Furthermore, C. elegans and some other organisms can also perform environmental RNAi: sequence-specific gene silencing in response to environmentally encountered dsRNA. This phenomenon has facilitated significant technological advances in diverse fields including functional genomics and agricultural pest control. Here, we describe the characterization and current understanding of environmental RNAi and discuss its potential applications. PMID- 18450317 TI - Less is more: decreasing the number of scientific conferences to promote economic degrowth. PMID- 18450318 TI - Low-frequency sonophoresis: current status and future prospects. AB - Application of ultrasound enhances skin permeability to drugs, a phenomenon referred to as sonophoresis. Significant strides have been made in sonophoresis research in recent years, especially under low-frequency conditions (20 kHzA; -202 A>C) were identified with PCR-based restriction fragment length polymorphism (PCR-RFLP) and SNaPshot primer extension assay in 415 Korean lung cancer patients and 415 matched normal controls. Although the genotype and allele frequency distribution of each SNP did not differ significantly between cases and controls in the single-locus analysis, we found that the polymorphisms of -1590A and -202C were associated with increased risk for lung cancer in females (-1590 C>A; adjusted OR=2.11, 95% CI=1.08-4.12, -202 A>C; adjusted OR=1.96, 95% CI=1.02 3.75, respectively) and never-smokers (-1590 C>A; adjusted OR=2.06, 95% CI=1.12 3.78, -202 A>C; adjusted OR=1.99, 95% CI=1.10-3.62, respectively) in a dominant model after stratification for gender and smoking history. Haplotype analysis showed that carriers of A-C had significantly higher risk for lung cancer in females (dominant aOR=2.05, 95% CI=1.14-3.68) and in never-smokers (codominant aOR=1.71, 95% CI=1.11-2.64 and dominant aOR=1.99, 95% CI=1.17-3.40). Functional analysis in H1703 cell line using DNA fragments containing A-C haplotype of the promoter region showed significantly decreased transcriptional activity. Furthermore, there was a negative correlation between the number of polymorphic alleles in -1590/-202 loci and serum levels of IGFBP-3 in lung cancer patients, but it was not statistically significant in the test for linear trend. These results suggest that IGFBP-3 promoter polymorphisms of -1590 C>A and -202 A>C might be a genetic risk factor for lung cancer by means of decreased IGFBP-3 expression among females or never-smoking Koreans. PMID- 18450320 TI - Pathologic and molecular features of screening low-dose computed tomography (LDCT)-detected lung cancer: a baseline and 2-year repeat study. AB - Detailed studies on the pathologic and molecular features of low-dose computed tomography (LDCT)-detected carcinomas and comparison with unscreened tumors are still lacking. We evaluated the histopathologic features of 89 LDCT-detected lung cancers resected between 2004 and 2006. These tumors occurred within a cohort of 5202 volunteers undergoing annual LDCT, aged > or =50 years, and with a minimum 20 pack-year index. In adenocarcinomas, central scar diameter, invasion foci size and K-ras mutations were also assessed. The results were compared with those of 89 consecutive lung carcinomas matched for confounding factors (sex, smoking habit), selected from group of 363 consecutive clinically worked-up lung cancer, surgically resected in the same period and at the same Institution. The tumors were diagnosed in 63 males and 26 females (range 50-79 years), 55 of which diagnosed at the baseline (1.05%) and 34 (including 10 repeat cancers) operated after work-up during the second year (0.72%). LDCT-detected tumors showed high resectability rate (89%), earlier stage (63%) and prevalence of adenocarcinoma nodules (72%), most often of the mixed subtype, in comparison with unscreened tumors. A similar prevalence of K-ras mutations was found in both screened and unscreened adenocarcinomas. Repeat cancers were found in 10 screened patients, and were predominantly stage I adenocarcinomas of mixed subtype exhibiting smaller dimension but greater central scar diameter and stromal invasion size in comparison with the other second-year, slower-growing adenocarcinomas. Multiple tumor nodules were identified in 10 patients exclusively at the baseline, were mostly mixed adenocarcinomas and differed in their K-ras mutation profile. Screening-detected lung cancers shared most of the histologic features of fully malignant tumors, in addition to a similar prevalence of K-ras mutations, despite their earlier detection and less advanced clinical stage. Repeat cancers are potentially aggressive tumors. K-ras mutation analysis supports the impression that multifocal tumors at baseline are separate synchronous primaries. PMID- 18450321 TI - Correlation of EGFR mutations with chromosomal alterations and expression of EGFR, ErbB3 and VEGF in tumor samples of lung adenocarcinoma patients. AB - INTRODUCTION: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are frequently detected in lung adenocarcinomas with bronchioloalveolar (BAC) differentiation and have been associated with increased response to small molecule EGFR inhibitors in some clinical studies. However, further molecular characterization of tumor cells carrying EGFR mutations (EGFR mut) is warranted. METHODS: By DNA sequencing, 120 patients with lung adenocarcinomas (70 tumors with BAC components) were screened for EGFR mutations within exons 18-21. Performing comparative genomic hybridization (CGH) and immunohistochemistry, chromosomal imbalances and protein expression levels of EGFR, ErbB3 and VEGF (vascular endothelial growth factor) were analyzed, respectively. RESULTS: EGFR mutations were detected in 20/120 tumors. Tumors with BAC components carried more frequently EGFR mutations compared to adenocarcinomas without BAC histology (17/70=24% vs 3/50=6.0%; p=0.012). In a subsequent matched pair analysis, CGH-analysis demonstrated similar mean numbers of chromosomal imbalances for EGFR mutated and wild-type tumors (8.6 vs 7.8 gains; 2.4 vs 2.7 losses), respectively. Furthermore, tumors with mutated EGFR demonstrated gains in chromosomes 7p, 16p and 20q and losses in chromosome 8p. Interestingly, EGFR mutated tumors showed higher VEGF expression (p=0.03) while differences in EGFR expression were not statistically significant. CONCLUSION: EGFR gene mutations are frequently seen in lung adenocarcinomas with BAC differentiation and can be linked to chromosomal imbalances and increased VEGF expression. PMID- 18450323 TI - Does double-blind review benefit female authors? PMID- 18450322 TI - Gemcitabine plus conventional-dose epirubicin versus gemcitabine plus cisplatin as first-line chemotherapy for stage IIIB/IV non-small cell lung carcinoma--a randomized phase II trial. AB - BACKGROUND: Epirubicin was effective for the treatment of non-small cell lung carcinoma (NSCLC). This study compared the efficacy and safety of gemcitabine plus conventional-dose epirubicin (GE) with gemcitabine-cisplatin (GC) as first line chemotherapy for stage IIIB/IV NSCLC and evaluated the predictive value of nuclear expression of excision repair cross-complementing group 1 (ERCC1) and topoisomerase IIalpha (TopoIIalpha) on treatment outcome. PATIENTS AND METHODS: Patients were randomized to GE (gemcitabine, 1000mg/m(2) on days 1, 8, and 15 and epirubicin, 70mg/m(2) on day 15) or GC (gemcitabine, 1000mg/m(2) on days 1, 8, and 15 and cisplatin, 80mg/m(2) on day 15). Treatment cycles were repeated every 4 weeks. Immunohistochemical study of ERCC1 and TopoIIalpha was done for patients with available tumor specimens. RESULTS: The response rate was 31.0% (95% CI 16.4 45.5%) for GC (n=41) and 37.2.0% (95% CI 22.2-52.3%) for GE (n=39). No significant differences in median time-to-treatment-failure (TTF) (GC, 6.1 months; GE, 6.2 months) or overall survival (GC, 13.2 months; GE, 21.5 months) were found between the two arms. Grade 3/4 neutropenia and febrile neutropenia were more common in GE. However, delay of protocol treatment due to leukopenia was similar between the two arms. Patients with expression of both ERCC1 and TopoIIalpha had a significantly shorter TTF (median 2.4 months, 95% CI 0.7-4.1 months) than other patients (median 8.8 months, 95% CI 5.8-11.8 months) (p=0.04). CONCLUSION: GE regimen is effective and well-tolerated for NSCLC patients. Expression of both ERCC1 and TopoIIalpha may be associated with poor response to chemotherapy. PMID- 18450325 TI - Ozonation of pentachlorophenol in unsaturated soils. AB - A heterogeneous model was developed to describe interactions between ozone and hydrophobic organic compounds, exemplified by pentachlorophenol, in highly gas saturated vadose zones where water moisture was limited to a thin film on soil particle surfaces. The soil was assumed to be free of soil organic matter. The model included a set of transient equations considering diffusion with simultaneous chemical reaction and hydrophobic partitioning. From dimensionless analysis, it was found that the film concentrations of ozone and the hydrophobic organic component were dependent on the Damkohler numbers. Effects of Damkohler numbers on the film profiles of components were examined. With the interfacial flux of ozone calculated from film profiles, dimensionless governing equations of ozone transport and contaminant removal across an experimental column were established. These equations were dependent on the Stanton number. One dimensional column experiments were conducted to test the model. The optimal time for flow rate adjustment during the process was approximated. Finally, effects of ozone velocity and ozone gas concentration on the Stanton number were evaluated. PMID- 18450326 TI - How trust in institutions and organizations builds general consumer confidence in the safety of food: a decomposition of effects. AB - This paper investigates the relationship between general consumer confidence in the safety of food and consumer trust in institutions and organizations. More specifically, using a decompositional regression analysis approach, the extent to which the strength of the relationship between trust and general confidence is dependent upon a particular food chain actor (for example, food manufacturers) is assessed. In addition, the impact of specific subdimensions of trust, such as openness, on consumer confidence are analyzed, as well as interaction effects of actors and subdimensions of trust. The results confirm previous findings, which indicate that a higher level of trust is associated with a higher level of confidence. However, the results from the current study extend on previous findings by disentangling the effects that determine the strength of this relationship into specific components associated with the different actors, the different trust dimensions, and specific combinations of actors and trust dimensions. The results show that trust in food manufacturers influences general confidence more than trust in other food chain actors, and that care is the most important trust dimension. However, the contribution of a particular trust dimension in enhancing general confidence is actor-specific, suggesting that different actors should focus on different trust dimensions when the purpose is to enhance consumer confidence in food safety. Implications for the development of communication strategies that are designed to regain or maintain consumer confidence in the safety of food are discussed. PMID- 18450327 TI - The chart is dead--long live the chart. PMID- 18450328 TI - "Left without being seen": a national profile of children who leave the emergency department before evaluation. AB - STUDY OBJECTIVE: The epidemiology of children who present to the emergency department (ED) and leave without being seen has not been well characterized. We evaluate rates and secular trends of children who leave without being seen, identify factors associated with pediatric leave without being seen cases, and determine whether there are differences in leaving patterns between children and adults seeking emergency care. METHODS: Data were obtained from the National Hospital Ambulatory Medical Care Survey, which collects information on patient visits to EDs throughout the United States. We examined data for children (less than or equal to 18 years of age) and adults who presented to EDs during the 6 year period ending in 2005. RESULTS: During the study period, there were an estimated 11,848,351 leave without being seen visits nationally, accounting for 1.79% of all ED visits. The prevalence of leaving without being seen was 2.46% (95% confidence interval [CI] 1.71% to 3.55%) for pediatric patients presenting to pediatric EDs, 1.86% (95% CI 1.65% to 2.10%) for pediatric patients presenting to general EDs, and 1.73% (95% CI 1.57% to 1.91%) for adults presenting to general EDs. The leave without being seen rates did not increase significantly during the study period. Factors associated with leave without being seen visits included hospital urban location, self-pay insurance status, and less acute triage level for children and adults, as well as race/ethnicity and arrival time for adult patients. CONCLUSION: In this national sample of patients, leave without being seen rates were similar for pediatric and adult patients and did not increase during the 6-year study period, although some variation in rates was observed for specific patient and ED characteristics. These national estimates provide an important reference for institutions to assess their ED performance. PMID- 18450329 TI - Comparison of the Cerebral Performance Category score and the Health Utilities Index for survivors of cardiac arrest. AB - STUDY OBJECTIVE: The Cerebral Performance Category score is an easy to use but unvalidated measure of functional outcome after cardiac arrest. We evaluate the comparability of results from the Cerebral Performance Category scale versus those of the validated but more complex Health Utilities Index scale for health related quality of life. METHODS: This prospective substudy of the Ontario Prehospital Advanced Life Support (OPALS) Study included adult out-of-hospital cardiac arrest patients treated in 20 cities. This prospective cohort study included all survivors of out-of-hospital adult cardiac arrest enrolled in phase II (rapid basic life support with defibrillation) and phase III (advanced life support) of the OPALS Study, as well as the intervening run-in phase. Survivors were interviewed at 12 months for Cerebral Performance Category Score and the Health Utilities Index Mark 3 (Health Utilities Index). RESULTS: Of 8,196 eligible out-of-hospital cardiac arrest patients between 1995 and 2002, 418 (5.1%) survived to discharge, and 305 (3.7%) completed the Health Utilities Index interview and had Cerebral Performance Category scored at 12 months. The 305 patients had the following data: mean age 63.9 years; male 78.0%; paramedic witnessed arrest 25.6%; bystander cardiopulmonary resuscitation 32.1%; initial rhythm ventricular fibrillation/ventricular tachycardia 86.9%, Cerebral Performance Category 1 267, Cerebral Performance Category 2 26, Cerebral Performance Category 3 12. Overall, the median scores (interquartile range) were Cerebral Performance Category 1 (1 to 1) and Health Utilities Index 0.84 (0.61 to 0.97). The Cerebral Performance Category score ruled out good quality of life (Health Utilities Index >0.80), with a sensitivity of 100% (95% confidence interval [CI] 98% to 100%) and specificity 27.1% (95% CI 20% to 35%); thus, when the Cerebral Performance Category score was 2 or 3, it was unlikely that the Health Utilities Index score would be good. The Cerebral Performance Category score had sensitivity 55.6% (95% CI 42% to 67%) and specificity 96.8% (95% CI 94% to 98%) for predicting poor quality of life (Health Utilities Index >0.40); ie, when Cerebral Performance Category was 1, it was highly unlikely that the Health Utilities Index score would be poor. The weighted kappa was 0.39 and the interclass correlation was 0.51. CONCLUSION: This represents the largest study yet conducted of the performance of the Cerebral Performance Category score in 1 year survivors of out-of-hospital cardiac arrest. Overall, the Cerebral Performance Category score classified patients well for their quality of life, ruling out a good Health Utilities Index score with high sensitivity and ruling in poor Health Utilities Index score with high specificity. The Cerebral Performance Category is an important tool in that it indicates broad functional outcome categories that are useful for a number of key clinical and research applications but should not be considered a substitute for the Health Utilities Index. PMID- 18450330 TI - Synthesis and in vitro antibacterial activity of new steroidal thiosemicarbazone derivatives. AB - We investigated the antibacterial activity of some new steroidal thiosemicarbazone derivatives, prepared from the reaction of cholest-5-en-7-one with thiosemicarbazides, in ethanol in the presence of a few drops of HCl at 80 degrees C in high yield. All the compounds have been characterized by means of elemental analyses, IR, 1H NMR and mass spectroscopic data, to find an effective antibacterial agent. The antibacterial activity was first tested in vitro by the disk diffusion assay against two Gram-positive and two Gram-negative bacteria, and then the minimum inhibitory concentration (MIC) of compounds was determined. The results showed that the steroidal thiosemicarbazones derivatives inhibit growth of both types of the bacteria (Gram-positive and Gram-negative). The acetoxy and chloro derivatives of cyclopentyl and cyclohexyl amine thiosemicarbazones were found to have more antibacterial activity than the other derivatives. PMID- 18450331 TI - Synthesis and antibacterial evaluation of novel 4-alkyl substituted phenyl beta aldehyde ketone derivatives. AB - A series of novel 4-alkylphenyl beta-aldehyde ketones and their derivatives were designed and synthesized on the basis of the chemical structures of Houttuynin and beta-lactam antibiotics. Antibacterial activities of these compounds were investigated. The results demonstrated that most of the compounds tested had moderate antibacterial activities against gram-positive pathogen Staphylococcus aureus (ATTC-25923) than Houttuynin, and gram-positive bacteria were more susceptible to the compounds than gram-negative bacteria. Compound 23 was found to be the most potent compound with MIC of 1.0 microg/mL against S. aureus. Particularly, compounds 16, 22 and 23 showed more active antibacterial activities against the clinically important pathogenic bacteria, methicillin-resistant S. aureus (MRSA) than Houttuynin and levofloxacin. The preliminary structure activity relationship (SAR) analysis suggested that (1) the introduction of appropriate alkyl substituents into position 4 of phenyl ring enhanced antibacterial activities of these compounds, and isopropyl substituent might be more favorable; (2) the presence of ketone carbonyl moiety might play a vital role in determining significant antibacterial activities of these compounds. PMID- 18450332 TI - [Chest pain of unusual cause]. PMID- 18450333 TI - Parameters for DNA vaccination using adaptive constant-current electroporation in mouse and pig models. AB - Enhancing the expression of DNA vaccines requires that specific conditions of delivery are optimized. We describe experiments using adaptive constant-current electroporation (EP) in mice and pigs examining parameters such as target muscle, delay between plasmid delivery and onset of EP pulses and DNA vaccine formulation; our studies show that concentrated formulations result in better expression and immunogenicity. Furthermore, various conditions of EP that limit the amount of muscle damage were measured. The results of these studies will help to advance the success of DNA vaccines in animals into success in human clinical trials. PMID- 18450334 TI - Intranasal immunization of young mice with a multigene HIV-1 vaccine in combination with the N3 adjuvant induces mucosal and systemic immune responses. AB - One of the major challenges for the development of an HIV vaccine is to induce potent virus-specific immune responses at the mucosal surfaces where transmission of virus occurs. Intranasal delivery of classical vaccines has been shown to induce good mucosal antibody responses, but so far for genetic vaccines the success has been limited. This study shows that young individuals are sensitive to nasal immunization with a genetic vaccine delivered in a formulation of a lipid adjuvant, the Eurocine N3. Intranasal delivery of a multiclade/multigene HIV-1 genetic vaccine gave rise to vaginal and rectal IgA responses as well as systemic humoral and cellular responses. As electroporation might become the preferred means of delivering genetic vaccines for systemic HIV immunity, nasal delivery by droplet formulation in a lipid adjuvant might become a means of priming or boosting the mucosal immunity. PMID- 18450335 TI - Expression of VP1 protein in the milk of transgenic mice: a potential oral vaccine protects against enterovirus 71 infection. AB - Enterovirus 71 (EV71) is the most common etiological agent detected in cases of hand-foot-and-mouth disease (HFMD) resulting in incidences of neurological complications and fatality in recent years. The clinical data have already shown the significant increase in recent EV71 epidemic activity throughout the Asia Pacific region. Due to the lack of an effective antiviral agent, primary prevention of the disease, including the development of an effective vaccine, has been the top priority in terms of control strategies. In this study, we first generated a transgenic animal system to produce the EV71 VP1 capsid protein under the control of alpha-lactalbumin promoter and alpha-casein leader sequences. A high level of recombinant VP1 protein (2.51 mg/ml) was expressed and secreted into the milk of transgenic mice. Mouse pups that received VP1-transgenic milk orally demonstrated relatively better health conditions after challenge with the respective virus as compared with the non-transgenic milk fed group; moreover, the mice fed with the VP1-milk had body weights similar to those of the PBS placebo control groups. According to the serum-neutralization assay and serum antibody detection, the littermates suckling VP1-milk generated antibodies specific to EV71. Our data suggest that EV71 VP1-containing milk is suitable for development as a potential oral vaccine. PMID- 18450336 TI - Use of continuous results to compare ELISAs for the detection of antibodies to non-structural proteins of foot-and-mouth disease virus. AB - Six tests for detection of antibodies against the non-structural proteins of foot and-mouth disease virus (FMDV) were compared at an international workshop in Brescia, Italy in 2004 on the basis of dichotomous test results. However, as results from all of these assays were also available on a continuous scale, validation was extended by calculating and subsequently analysing the receiver operator characteristic (ROC) curves and likelihood ratios (LR) for each test method. For the purposes of these analyses, test results for a total of 1337 sera were selected from the Brescia workshop dataset, 237 sera that had been obtained from cattle exposed to FMDV and 1100 sera obtained from cattle that were not exposed to the virus; sera from "exposed" cattle were considered to be "true positives" and sera from "non-exposed" cattle were considered to be "true negatives". Analysis of ROC curves showed that at specificities of both 99 and 99.5%, the IZS-Brescia and the Ceditest ELISA had significantly better detection rates in exposed cattle than the other ELISAs. The ROC analysis confirms the previous finding that the IZS-Brescia and the Ceditest ELISAs have both better detection rates in exposed cattle combined with a high specificity. The analysis of likelihood ratios provides information that may be very useful in the interpretation of test results, and a working example is presented to show how these likelihood ratios might be used in an objective approach to deciding the true infection status of surveyed populations. PMID- 18450337 TI - Comparison of atypical furunculosis vaccines in spotted wolffish (Anarhicas minor O.) and Atlantic halibut (Hippoglossus hippoglossus L.). AB - Atypical furunculosis caused by atypical Aeromonas salmonicida is a problem in farming of Atlantic halibut (Hippoglossus hippoglossus) and spotted wolffish (Anarhicas minor) in Norway, and vaccines for marine fish species are not available. Susceptibility to atypical A. salmonicida infection and efficacy of furunculosis vaccines in various fish species indicate that the host responses differ. Here, spotted wolffish was shown to be highly susceptible to intraperitoneal challenge with atypical A. salmonicida compared to halibut, and the two species appeared to respond differently to identical vaccines. Grouping of the atypical A. salmonicida isolates used as vaccines was based on a variable region in the surface A-layer protein, but no clear correlation between vaccine efficacy and A-protein group was found. PMID- 18450338 TI - Comparison of alpha-Type-1 polarizing and standard dendritic cell cytokine cocktail for maturation of therapeutic monocyte-derived dendritic cell preparations from cancer patients. AB - The current "gold standard" for generation of dendritic cell (DC) used in DC based cancer vaccine studies is maturation of monocyte-derived DCs with tumor necrosis factor-alpha (TNF-alpha)/IL-1beta/IL-6 and prostaglandin E(2) (PGE(2)). Recently, a protocol for producing so-called alpha-Type-1 polarized dendritic cells (alphaDC1) in serum-free medium was published based on maturation of monocyte-derived DCs with TNF-alpha/IL-1-beta/polyinosinic:polycytidylic acid (poly-I:C)/interferon (IFN)-alpha and IFN-gamma. This DC maturation cocktail was described to fulfill the criteria for optimal DC generation and to be superior to the standard DC (sDC) cocktail as it induced fully mature DCs with potent IL 12p70 secretion together with CCR7 expression which is necessary for priming of a TH1 response and for migration to the draining lymph node, respectively. In this study, we tested the adaptation of alphaDC1 maturation cocktail to a protocol for clinical grade DC generation from cancer patients performed in X-VIVO 15 medium. We showed that alphaDC1 in this protocol induce lower up-regulation of CD83 and several other maturation markers, co-stimulatory molecules and CCR7 together with higher up-regulation of inhibitory molecules such as PD-L1, ILT2, ILT3 as compared to sDC. Although alphaDC1 matured DCs secreted more IL-12p70 and IL-23 these DCs had lower or similar stimulatory capacity compared to sDCs when used as stimulating cells in mixed lymphocyte reaction (MLR) or for induction of autologous influenza antigen specific T lymphocytes. Thus, our observations underline that alphaDC1 maturation cannot be directly adapted to alternative protocols for DC generation. Also, this study indicates the necessity for further investigation of correlation between in vitro DC parameters and their in vivo efficacy in clinical vaccination trials. PMID- 18450339 TI - Participation in two phase II prophylactic HIV vaccine trials in the UK. AB - There will be a continued imperative to recruit large numbers of healthy volunteers to early phase prophylactic HIV vaccine (PHV) trials. We studied mechanisms associated with participation in two related phase II PHV trials. The most cited reasons for volunteering were altruism and a personal connection to HIV. The most successful recruiting strategies targeted organisations dealing with HIV, health or social issues, or were directed to large audiences through the mass media. However, circulated emails and word of mouth were the most resource-effective approaches. Group discussions and the collection of a pool of potential volunteers were much less effective than one-to-one discussions and immediate screening after recruitment. We utilised our findings to devise key recommendations to assist PHV trial teams who are planning future studies. PMID- 18450340 TI - A meta-analysis of human papillomavirus type-distribution in women from South Asia: implications for vaccination. AB - OBJECTIVE: To determine human papillomavirus (HPV) prevalence and type distribution in women from South Asia, with and without cervical lesions, in order to estimate the impact of an HPV 16/18 prophylactic vaccine in this region and to assess additional types that should be incorporated in new vaccines. METHODS: A meta-analysis was conducted that included studies using polymerase chain reaction to detect HPV-16, -18, -6, -11 and at least one other HPV type, with a minimum of 20 cases in each grade of lesion. Total as well as type specific prevalence of various HPV types were estimated, stratified by cervical lesion grade, using Stata 9.0 software package. RESULTS: Nine studies from India fulfilled the inclusion criteria. A total of 558, 52, 52 and 3061 women, respectively with invasive cervical cancer (ICC), high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL) and normal cytology/histology were included. Overall HPV prevalence was 94.6%, 86.5%, 65.4% and 12.0% in women with ICC, HSIL, LSIL and normal cytology/histology, respectively. In ICC, HPV-16 was the predominant type (64.8%), followed by HPV-18, -45, -33, -35, -58, -59 and -31. The estimated HPV 16/18 positive fraction was 78.9% in women with ICC (87.7% in North and 77.2% in South India), 61.5% with HSIL, 30.8% with LSIL and 3.9% in women with normal cytology/histology. There was no difference in overall HPV prevalence in cervical cancer between North and South India (P=0.063). However, HPV-16 and -45 appeared to be more prevalent in North India (P=0.018 and 0.013, respectively), while HPV 35 appeared to be more prevalent in South India (P=0.033). CONCLUSION: It is estimated that HPV-16/18 vaccines will provide over 75% protection against ICC in South Asia. HPV-45, -33, -35 and -58 account for an additional 20% of cervical cancer in this region. The addition of these additional HPV types in a second generation vaccine could provide optimal cervical cancer prevention in this region. PMID- 18450341 TI - In vivo hierarchy of individual T-cell epitope-specific helper T-cell subset against an intracellular bacterium. AB - Cellular immunity is indispensable for efficient protection against intracellular bacterial infection. CD4+ and CD8+ T cells specific for a variety of antigenic peptides derived from particular bacteria are induced after the infection. T cells recognizing different antigenic peptides have been speculated to have different functions in terms of the protective immunity. We here induced individual CD4+ T cells specific for each antigenic peptide derived from Listeria monocytogenes independently with DNA vaccines using gene gun bombardment and compared the CD4+ T-cell populations for their ability on the specific protective immunity against lethal listerial challenge and analyzed their characteristics. PMID- 18450342 TI - Estimating the exposure of small mammals at three sites within the Chernobyl exclusion zone--a test application of the ERICA Tool. AB - An essential step in the development of any modelling tool is the validation of its predictions. This paper describes a study conducted within the Chernobyl exclusion zone to acquire data to conduct an independent test of the predictions of the ERICA Tool which is designed for use in assessments of radiological risk to the environment. Small mammals were repeatedly trapped at three woodland sites between early July and mid-August 2005. Thermoluminescent dosimeters mounted on collars were fitted to Apodemus flavicollis, Clethrionomys glareolus and Microtus spp. to provide measurements of external dose rate. A total of 85 TLDs were recovered. All animals from which TLDs were recovered were live-monitored to determine (90)Sr and (137)Cs whole-body activity concentrations. A limited number of animals were also analysed to determine (239,240)Pu activity concentrations. Measurements of whole-body activity concentrations and dose rates recorded by the TLDs were compared to predictions of the ERICA-Tool. The predicted (90)Sr and (137)Cs mean activity concentrations were within an order of magnitude of the observed data means. Whilst there was some variation between sites in the agreement between measurements and predictions this was consistent with what would be expected from the differences in soil types at the sites. Given the uncertainties of conducting a study such as this, the agreement observed between the TLD results and the predicted external dose rates gives confidence to the predictions of the ERICA Tool. PMID- 18450343 TI - Application of the ERICA Integrated Approach to the Drigg coastal sand dunes. AB - The EC-funded project 'Environmental Risks from Ionising Contaminants: Assessment and Management' (ERICA) developed an 'Integrated Approach' for assessing the impact of ionising radiation on ecosystems. This paper presents the application of the ERICA Integrated Approach, supported by a software programme (the ERICA Tool) and guidance documentation, to an assessment of the Drigg coastal sand dunes (Cumbria, UK). Targeted sampling provided site-specific data for sand dune biota, including amphibians and reptiles. Radionuclides reported included (90)Sr, (99)Tc, (137)Cs, (238)Pu, (239+240)Pu and (241)Am. Site-specific data were compared to predictions derived using the ERICA Tool. Some under- and over predictions of biota activity concentrations were identified but can be explained by the specific ecological characteristics and contamination mechanism of the dunes. Overall, the results indicated no significant impact of ionising radiation on the sand dune biota and the Integrated Approach was found to be a flexible and effective means of conducting a radiation impact assessment. PMID- 18450344 TI - Radionuclide tracing of water masses and processes in the water column and sediment in the Algerian Basin. AB - Caesium-137 and (239,240)PU were analysed in the water column along the Algerian coast. The (137)Cs activity concentration in surface water increased from the west to the east from 1.6 to 3.3 mBq L(-1), documenting a presence of Modified Atlantic Water (MAW) in the region. Higher concentrations observed in deep waters may be due to an intrusion of Levantine Intermediate Water (LIW), which has been carrying higher levels of (137)Cs from Chernobyl accident. The (239,240)Pu sub surface concentration peaked at about 250 m water depth as a result of biogeochemical processes in the water column. The observed (239,240)Pu/(137)Cs activity ratio at the surface (0.003) was significantly lower than that in global fallout (0.04). This decrease exceeds that expected from radioactive decay of (137)Cs, and confirms that Pu due to its adsorption on sinking particles is more effectively removed from surface layers than is (137)Cs. An increase of the (239,240)Pu/(137)Cs activity ratio with depth suggests that (239,240)Pu, similarly as (137)Cs, should be also transported by advection to maintain the observed ratios in deep waters. An intrusion of LIW may enhance therefore both the (137)Cs and (239,240)Pu concentrations in deep waters. The average (238)Pu/(239+240)Pu activity ratio in seawater was 0.03+/-0.02, confirming a global fallout origin of Pu in the Algerian Basin. Caesium-137 and (239,240)Pu inventories in the water column were estimated to be from 2.7+/-0.5 kBq m(-2) to 3.8+/-0.7 kBq m(-2), and from 13.8+/-2.6 Bq m(-2) to 41+/-7B qm(-2), respectively. The (137)Cs massic activities in surface sediment were almost constant, the average activity was 9.0+/-0.8 Bq kg(-1). Sedimentation rates obtained using the (210)Pb method were from 0.1 to 0.7 cm y(-1), and resulting penetration depths of (137)Cs in the sediment cores were from 15 to over 40 cm. The (137)Cs peaks found in the sediment cores were associated with the Chernobyl accident (1986) and global fallout (1964). The (137)Cs inventories in the sediment were increasing from the west (180 Bq m(-2)) to the east (350 Bq m(-2)). PMID- 18450345 TI - Osteotomy--prefixation. PMID- 18450346 TI - Consequences of a decentralized healthcare governance model: measuring regional authority support for patient choice in Sweden. AB - What are the implications of a decentralized model of healthcare governance? This case study on patient choice in Sweden is an attempt to shed light on this issue. Due to decentralization and constitutional rights of self-determination, the regional authorities in Sweden, called County Councils (CCs), have far-reaching rights to manage the healthcare sector. The fact that patient choice is considered to be a soft law or a soft governance regulation, opens it up to regional variation. To examine the CCs level of support of patient choice, an index is presented. The Patient Choice Index (PCI) shows that there is extensive variation among the CCs. To explain the causes of these variations, a number of hypotheses are tested. The analyses imply that ideology and economy, and more specifically the CCs' governing majorities and running net profits, are major explanations for the level of support. A number of conclusions can be drawn from the results of this study. In short, the CCs appear to act according to a local point of view, which means that there is no functioning national patient choice standard, and thus patients do not have equal access to healthcare and patients' rights are unevenly distributed. Furthermore, the CCs' financial conditions and governing majorities seem to undermine equivalent reform realization in a national context. In summary, the results of this study emphasize the conflict between regional self-governance and national equality, which is particularly visible in the decentralized Swedish healthcare model. PMID- 18450347 TI - The meaning of the survivor identity for women with breast cancer. AB - "Survivor" has become a ubiquitous and largely unquestioned term in culture and cancer discourse. While anecdotal evidence suggests women with breast cancer find fault with survivor images and discourse, the extent to which women identify with or reject the survivor identity has not been empirically studied. This paper examines whether women treated for breast cancer embrace survivorship. Data come from 39 in-depth interviews with women in the United States who completed treatment for breast cancer 3-18 months prior to the interview. Despite the positive meanings attached to survivorship, many women altered the meaning of survivorship or rejected survivorship. In particular, the survivor discourse alienated women who struggle with the threat of recurrence, who feel their cancer experience was not severe enough to merit this title, or who desire a private disease experience. These findings illustrate the failure of our cultural conceptions of cancer to adequately reflect lived experience and highlight how individuals actively "craft" illness meanings. PMID- 18450348 TI - Debating war-trauma and post-traumatic stress disorder (PTSD) in an interdisciplinary arena. AB - Researchers have tried to determine and verify the effects of violent conflicts on the mental health of those affected by focusing on war trauma, posttraumatic stress disorder (PTSD), and other trauma-related disorders. This, in turn, led to the development of different kinds of theories and aid programs that aim at preventing and treating the consequences of violence and mental health. Until now, there is no agreement on the public health value of the concept of PTSD and no agreement on the appropriate type of mental-health care. Instead, psychiatrists have engaged in sometimes fierce discussions over the universality of war trauma, PTSD, and other trauma-related disorders. The two most polar positions are those who try to validate PTSD as a universal and cross-culturally valid psychopathological response to traumatic distress which may be cured or ameliorated with (Western) clinical and psychosocial therapeutic measures, and those who argue that the Western discourse on trauma only makes sense in the context of a particular cultural and moral framework and, therefore, becomes problematic in the context of other cultural and social settings. Although these positions seem mutually exclusive, their debates have led to the development of less radical approaches toward war-trauma and PTSD. The purpose of this literature review is to analyse the discourses on and debates over war-trauma and PTSD in the psychiatric literature in order to establish a better understanding for the diverse conceptualizations, interpretations and proposed healing strategies. Moreover, I discuss the cultural construction and conceptualization of war-trauma and PTSD from an anthropological perspective and show how anthropologists contribute to psychiatric debates so as to ensure more sophisticated diagnoses and healing strategies in culturally diverse contexts. PMID- 18450349 TI - Reasons for disclosing depression matter: the consequences of having egosystem and ecosystem goals. AB - People with depression often conceal their depression and do not seek help, in part because of the stigma associated with mental illness. We propose two motivational systems for the self: egosystem motivations, concerned with protecting and inflating desired self-images, and ecosystem motivations, concerned with contributing or supporting others. Using a sample of 48 individuals at a Midwestern university, USA, this study examined motivations for disclosing or concealing a concealable stigma, to test the hypotheses that: (1) these motivations load on two factors corresponding to egosystem and ecosystem goals, and (2) ecosystem motivations for disclosure have more positive effects on disclosure and psychological well-being. We found that people with egosystem goals disclosed less, and also experienced lower psychological well-being when they did disclose. Conversely, people with ecosystem goals disclosed more and experienced greater psychological well-being while doing so. Implications of these findings for deciding when and to whom to disclose one's depression are discussed. PMID- 18450350 TI - Stigma and coercion in the context of outpatient treatment for people with mental illnesses. AB - The policies and institutional practices developed to care for people with mental illnesses have critical relevance to the production of stigma as they can induce it, minimize it or even block it. This manuscript addresses two prominent and competing perspectives on the consequences for stigma of using coercion to insure compliance with outpatient mental health services. The Coercion to Beneficial Treatment perspective (Torrey, E. F., & Zdanowicz, M. (2001). Outpatient commitment: what, why, and for whom. Psychiatric Services, 52(3), 337-341) holds that the judicious use of coercion facilitates treatment engagement, aides in symptom reduction, and, in the long run, reduces stigma. The Coercion to Detrimental Stigma perspective (Pollack, D. A. (2004). Moving from Coercion to Collaboration in Mental Health Sevices DHHS (SMA) 04-3869. In Rockville, MD: Center for Mental Health Services, Substance Abuse and Mental Health Services Administration) claims that coercion increases stigmatization resulting in low self-esteem, a compromised quality of life, and increased symptoms. We examine these differing perspectives in a longitudinal study of 184 people with serious mental illness, 76 of whom were court ordered to outpatient treatment and 108 who were not. They were recruited from treatment facilities in the New York boroughs of the Bronx and Queens. We measure coercion in two ways: by assignment to mandated outpatient treatment and with a measure of self-reported coercion. The longitudinal analysis allows stringent tests of predictions derived from each perspective and finds evidence to support certain aspects of each. Consistent with the Coercion to Beneficial Treatment perspective, we found that improvements in symptoms lead to improvements in social functioning. Also consistent with this perspective, assignment to mandated outpatient treatment is associated with better functioning and, at a trend level, to improvements in quality of life. At the same time the Coercion to Detrimental Stigma perspective is supported by findings showing that self-reported coercion increases felt stigma (perceived devaluation-discrimination), erodes quality of life and through stigma leads to lower self-esteem. Future policy needs not only to find ways to insure that people who need treatment receive it, but to achieve such an outcome in a manner that minimizes circumstances that induce perceptions of coercion. PMID- 18450352 TI - District-based malaria epidemic early warning systems in East Africa: perceptions of acceptability and usefulness among key staff at health facility, district and central levels. AB - Malaria epidemics represent a significant public health problem in the highlands of Africa. Many of these epidemics occur in low resource settings, where the development of an effective system for malaria surveillance has been a key challenge. Between 2001 and 2006, the Highland Malaria Project (HIMAL) established a programme to develop and test a district-based surveillance system for the early detection and control of malaria epidemics in four pilot districts in Kenya and Uganda. An innovative feature of the programme was the devolution of responsibility for the detection of epidemics from the central Ministry of Health to District Health Management Teams. The implementation of the programme offered the opportunity to test both the technical aspects of the system and to examine the practical issues relating to the operation of the programme in the context of the existing health system. To investigate the attitude of key staff towards the programme, and their perceptions of its impact on their working practices, interviews were carried out among 52 health staff at district level and in the Ministries of Health in Kenya and Uganda. The transfer of responsibility for the early detection of epidemics to the districts had resulted in perceptions of individual empowerment among district-based staff. This, together with improved support supervision, was a key factor in sustaining motivation and improved surveillance. The enhanced support supervision also produced capacity benefits that extended beyond improved malaria surveillance. However, these improvements occurred in the context of increased logistical support (the provision of transport, fuel and travel allowances) which the participants believed was essential to the functioning of an effective system. With this proviso, the district-based malaria early warning system was perceived to be manageable, effective and sustainable in the context of the current health system. PMID- 18450353 TI - The role of white matter hyperintensities and medial temporal lobe atrophy in age related executive dysfunctioning. AB - Various studies support an association between white matter hyperintensities (WMH) and deficits in executive function in nondemented ageing. Studies examining executive functions and WMH have generally adopted executive function as a phrase including various functions such as flexibility, inhibition, and working memory. However, these functions include distinctive cognitive processes and not all may be affected as a result of WMH. Furthermore, atrophy of the medial temporal lobe (MTA) is frequently observed in ageing. Nevertheless, in previous studies of nondemented ageing MTA was not considered when examining a relationship between white matter and executive function. The goal of the present study was to examine how WMH and MTA relate to a variety of executive functions, including flexibility, fluency, inhibition, planning, set shifting, and working memory. Strong correlations were observed between WMH and MTA and most of the executive functions. However, only MTA was related to flexibility and set shifting performance. Regression analysis furthermore showed that MTA was the strongest predictor of working memory, after which no further significant association with WMH was noted. Alternatively, both MTA and periventricular hyperintensities independently predicted inhibition performance. These findings emphasize the importance of MTA when examining age-related decline in executive functioning. PMID- 18450354 TI - Catatonic syndrome in central pontine/extrapontine myelinolysis: a case report. PMID- 18450355 TI - The possible role of ammonia toxicity on the exposure, deposition, retention, and the bioavailability of nicotine during smoking. AB - A complete and rigorous review is presented of the possible effect(s) of ammonia on the exposure, deposition and retention of nicotine during smoking and the bioavailability of nicotine to the smoker. There are no toxicological data in humans regarding ammonia exposure within the context of tobacco smoke. Extrapolation from occupational exposure of ammonia to smoking in humans suggests minimal, non-toxicological effects, if any. No direct study has examined the effect of the ammonia on the total rate or amount of nicotine reaching the arterial bloodstream or brains of smokers. Machine-smoking methods have been reported which accurately quantify >99% of the nicotine in mainstream (MS) smoke for a wide variety of commercial and test cigarettes, including a series of experimental cigarettes having a range in MS smoke ammonia yields using the US Federal Trade Commission (FTC) protocol. However, the actual exposure of nicotine to smokers depends on their own smoking behavior. The nicotine ring system is relatively thermally stable. Protonated nicotine forms nicotine which evaporates before the nicotine ring system decomposes. The experimental data indicate that neither nicotine transfer from tobacco to MS smoke nor nicotine bioavailability to the smoker increases with an increase in any of the following properties: tobacco soluble ammonia, MS smoke ammonia, "tobacco pH" or "smoke pH" at levels found in commercial cigarettes. Gas phase nicotine deposits primarily in the mouth and upper respiratory tract. To the extent that ammonia increases the deposition of nicotine in the buccal cavity and upper respiratory tract during smoking, the total rate and amount of nicotine into the arterial bloodstream and to the central nervous system will decrease. Charged nicotine analogues are actively transported in a number of tissues. This active transport system appears to be insensitive to pH and the form of nicotine in the biological milieu, suggesting that protonated nicotine may be a substrate for active transport. Neither "smoke pH" of commercial cigarettes nor "smoke pHeff" nor the fraction of non-protonated nicotine in tobacco smoke particulate matter are useful, practical smoke parameters for providing understanding or predictability of nicotine bioavailability to smokers. Greater than 95% of both ammonia and nicotine are in the gas phase of environmental tobacco, and both are likely to deposit in the buccal cavity and upper respiratory tract following exposure. PMID- 18450356 TI - An unexpected plasma cholinesterase activity rebound after challenge with a high dose of the nerve agent VX. AB - Organophosphorus chemical warfare agents (nerve agents) are to be feared in military operations as well as in terrorist attacks. Among them, VX (O-ethyl-S-[2 (diisopropylamino)ethyl] methylphosphonothioate) is a low volatility liquid that represents a percutaneous as well as an inhalation hazard if aerosolized. It is a potent irreversible cholinesterase (ChE) inhibitor that causes severe signs and symptoms, including respiratory dysfunction that stems from different mechanisms. VX-induced pulmonary oedema was previously reported in dogs but mechanisms involved are not well understood, and its clinical significance remains to be assessed. An experimental model was thus developed to study VX-induced cardiovascular changes and pulmonary oedema in isoflurane-anaesthetized swine. In the course of this study, we observed a fast and unexpected rebound of plasma ChE activity following inhibition provoked by the intravenous injection of 6 and 12 microg kg(-1) of VX. In whole blood ChE activity, the rebound could stay unnoticed. Further investigations showed that the rebound of plasma esterase activity was neither related to spontaneous reactivation of ChE nor to VX-induced increase in paraoxonase/carboxylesterase activities. A bias in Ellman assay, haemoconcentration or severe liver cytolysis were also ruled out. All in all, these results suggest that the rebound was likely due to the release of butyrylcholinesterase into the blood stream from ChE producing organs. Nature of the organ(s) and mechanisms involved in enzyme release will need further investigations as it may represent a mechanism of defence, i.e. VX scavenging, that could advantageously be exploited. PMID- 18450358 TI - Reduced novelty-P3 associated with increased behavioral distractibility in schizophrenia. AB - Behavioral and electrophysiological brain responses were used to examine the relationship between the vulnerability to distraction and the orienting response in schizophrenia. Nineteen schizophrenics and nineteen matched healthy controls were instructed to ignore task-irrelevant auditory stimuli while they classified capital letters and digits. The auditory sequences contained repetitive standard tones occasionally replaced by complex novel sounds. Relative to controls, patients showed an increased behavioral distraction, as indicated by a larger response time increase caused by novel sounds, and a disturbance in the attention orienting toward distracting stimuli, as indicated by a reduced novelty-P3. This behavioral-electrophysiological dissociation may stem from a limited pool of available resources. Thus, the few attentional resources directed toward novel stimuli would be sufficient to cause an important decrease of the similarly reduced amount of resources assigned to task-relevant stimuli, resulting in a striking impairment of the ongoing task performance. PMID- 18450357 TI - 15-Deoxy-delta 12,14-prostaglandin J2 induces apoptosis via JNK-mediated mitochondrial pathway in osteoblastic cells. AB - The cyclopentenone prostaglandin 15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) induces apoptosis in various cell types. However, the underlying mechanism of 15d PGJ2-induced apoptosis is not fully understood. The present study was undertaken to determine the molecular mechanism by which 15d-PGJ2 induces apoptosis in MC3T3 E1 mouse osteoblastic cells. 15d-PGJ2 caused a concentration- and time-dependent apoptotic cell death. 15d-PGJ2 induced a transient activation of ERK1/2 and sustained activation of JNK. 15d-PGJ2-induced cell death was prevented by the JNK inhibitor SP6001, but not by inhibitors of ERK1/2 and p38. JNK activation by 15d PGJ2 was blocked by antioxidants N-acetylcysteine (NAC) and GSH. 15d-PGJ2 caused ROS generation and 15d-PGJ2-induced cell death was prevented by antioxidants, suggesting involvement of ROS generation in 15d-PGJ2-induced cell death. 15d-PGJ2 triggered the mitochondrial apoptotic pathway indicated by enhanced Bax expression, loss of mitochondrial membrane potential, cytochrome c release, and caspase-3 activation. The JNK inhibitor blocked these events induced by 15d-PGJ2. Taken together, these results suggest that the 15d-PGJ2 induces cell death through the mitochondrial apoptotic pathway dependent of ROS and JNK activation in osteoblastic cells. PMID- 18450359 TI - Alternative treatments of the cost of time in recreational demand models: an application to whitewater kayaking in Ireland. AB - The measurement of travel costs in recreational demand modeling has been a contentious issue for many decades. This article explores the use of a number of alternative methods of incorporating time costs in the travel cost modeling process. Travel cost values where the opportunity cost of time is excluded, where it is included as a percentage of the individual's reported wage rate and where it based on an estimated wage from a secondary data source (the European Community Household Panel) are compared and then used in a conditional logit model to estimate the demand for whitewater kayaking in Ireland. We then evaluate the effect of different treatments of the cost of travel time on the welfare impacts of a number of different management scenarios for kayaking rivers in Ireland, and find that statistically significant differences emerge. PMID- 18450360 TI - Do bubble characteristics affect recanalization in stroke patients treated with microbubble-enhanced sonothrombolysis? AB - Administration of microbubbles (MB) may augment the effect of ultrasound-enhanced systemic thrombolysis in acute stroke. Bubble structural characteristics may influence the effect of MB on sonothrombolysis. We aimed to compare the effects of galactose-based air-filled MB (Levovist) and sulphur hexafluoride-filled MB (Sonovue) on recanalization and clinical outcome. One hundred thirty-eight i.v. recombinant tissue plasminogen activator-(tPA-) treated patients with middle cerebral artery (MCA) occlusion were studied. Presence and location of arterial occlusion and recanalization (RE) were assessed using the thrombolysis in brain ischemia (TIBI) flow grading system. Patients underwent 2 h of continuous transcranial Doppler (TCD) monitoring and received three bolus of MB after 2, 20 and 40 min of tPA bolus. Ninety-one patients received Levovist (LV) and 47 received Sonovue (SV). NIHSS scores were obtained at baseline and after 24 h. Modified Rankin Scale (mRS) score was used to assess outcome at 3 mo. Median admission NIHSS was 17. On TCD, 96 (69.6%) patients had a proximal and 42 (30.4%) a distal MCA occlusion. Age, baseline NIHSS, clot location, stroke subtypes and time to treatment were similar between LV and SV groups. Recanalization rates after 1 h (32.2%/35.6%), 2 h (50.0%/46.7%) and 6 h (63.8%/54.5%) were similar in LV/SV groups (p > 0.3). Clinical improvement (NIHSS decrease >or= 4 points) at 24 h was similar in both groups (54.9%/51.1%, p = 0.400), as well as symptomatic intracranial haemorrhage rate (3.3%/2.1%, p = 0.580) and in-hospital mortality (8.1%/9.3%, p = 0.531). Similarly, the type of MB administered did not affect long-term outcome after sonothrombolysis. Forty-four percent of patients in the LV group and 48.5% in the SV group achieved functional independence (mRS